MedJournals

Medical Research Creating healthy heart environment Neeraj Parakh, G Karthikeyan, Balram Bhargava The Indian Journal of Medical Research 2015 142(3):235-237 The role of vitamin D in polycystic ovary syndrome Ming-Wei Lin, Meng-Hsing Wu The Indian Journal of Medical Research 2015 142(3):238-240 Knowledge of serotype prevalence & burden of invasive pneumococcal disease: A prerequisite to vaccine introduction in the country Reba Kanungo The Indian Journal of Medical Research 2015 142(3):241-244 Role of oxidative stress & transient receptor potential in chronic obstructive pulmonary disease Protiti Bose, Rashmi Bathri, Lalit Kumar, VK Vijayan, KK Maudar The Indian Journal of Medical Research 2015 142(3):245-260 Chronic obstructive pulmonary disease (COPD) affect millions of people worldwide and is known to be one of the leading causes of death. The highly sensitive airways protect themselves from irritants by cough and sneeze which propel endogenous and exogenous substances to minimize airway noxious effects. One noxious effect of these substances is activation of peripheral sensory nerve endings of nociceptor neurons innervating these airways lining thus transmitting dangerous signals from the environment to the central nervous system (CNS). Nociceptor neurons include transient receptor potential (TRP) ion channels, especially the vanilloid and ankyrin subfamilies, TRPV1/A1 which can be activated by noxious chemical challenges in models of airways disease. As oxidative stress may activate airways sensory neurons and contribute to COPD exacerbations we sought to review the role that TRP channel activation by oxidative signals may have on airway responses. i0 t would be prudent to target the TRP channels with antagonists and lower systemic oxidative stress with agents that can modulate TRP expression and boost the endogenous levels of antioxidants for treatment and management of COPD.  High sensitivity C-reactive protein (hsCRP) & cardiovascular disease: An Indian perspective Deepak Y Kamath, Denis Xavier, Alben Sigamani, Prem Pais The Indian Journal of Medical Research 2015 142(3):261-268 The role of low grade systemic inflammation as evidenced by elevated high sensitivity C-reactive protein (hsCRP) levels in the pathogenesis of atherosclerotic vascular disease has been intensely investigated through observational studies and clinical trials in the past two decades. On the basis of evidence that has accrued, hsCRP measurement has been integrated into the Reynolds risk scoring system to predict cardiovascular risk. The JUPITER trial proved the benefit of statins in cardiovascular risk reduction in patients with low grades of systemic inflammation and 'normal' cholesterol levels. However, substantial evidence has been generated from western studies. We, therefore, conducted a scoping review for studies done in India with a view to identify gaps in evidence and make further recommendations. Most Indian studies had small sample sizes and short term follow ups. There were no large population based prospective studies where patients were followed up for long periods of time for major cardiovascular end points. An analysis of the hsCRP level from the control arms of case-control studies derived a mean hsCRP value of 1.88 mg/l, which is higher than the western population where values < 1 mg/l are classified as low cardiovascular risk. Further large prospective cohort studies with longer term follow ups are essential before we can make further recommendations to integrate hsCRP into risk prediction models for cardiovascular disease prevention. Aripiprazole for treating irritability in children & adolescents with autism: A systematic review Ahmad Ghanizadeh, Sylvie Tordjman, Nematollah Jaafari The Indian Journal of Medical Research 2015 142(3):269-275 Background & objectives: No clear therapeutic benefits of antipsychotics have been reported for the treatment of behavioural symptoms in autism. This systematic review provides an assessment of evidence for treating irritability in autism by aripiprazole. Methods: The databases of MEDLINE/PubMed and Google Scholar were searched for relevant articles about the effect of aripiprazole in children with autism. The articles were searched according to the inclusion and exclusion criteria specifed for this review. All the double-blind, controlled, randomized, clinical trials examining the efficacy of aripiprazole for treating children and adolescents with autism were included. Results: From the 93 titles identified, 26 were irrelevant and 58 were evaluated for more details. Only five articles met the inclusive criteria. The evidence from precise randomized double blind clinical trials of aripiprazole for the treatment of autism in children and adolescents was convincing enough to recommend aripiprazole. Adverse effects were not very common and were usually mild. Interpretation & conclusions: Current evidence suggests that aripiprazole is as effective and safe as risperidone for treating irritability in autism. However, further studies with larger sample size and longer duration are required.  Association of vitamin D receptor gene polymorphisms with polycystic ovary syndrome among Indian women Shilpi Dasgupta, Joyita Dutta, Sandhya Annamaneni, Neelaveni Kudugunti, Mohan Reddy Battini The Indian Journal of Medical Research 2015 142(3):276-285 Background & objectives: The Vitamin-D receptor (VDR) regulates vitamin D levels and calcium metabolism in the body and these are known to be associated with endocrine dysfunctions, insulin resistance and type-2 diabetes in polycystic ovarian syndrome (PCOS). Studies on VDR polymorphisms among PCOS women are sparse. We undertook this study to investigate the association pattern of VDR polymorphisms (Cdx2, Fok1, Apa1 and Taq1) with PCOS among Indian women. Methods: For the present study, 250 women with PCOS and 250 normal healthy control women were selected from Hyderabad city, Telangana, India. The four VDR polymorphisms were genotyped and analysed using ASM-PCR (allele specific multiple PCR) and PCR-RFLP (restriction fragment length polymorphism). Results: The genotype and allele frequency distributions of only Cdx2 showed significant difference between the PCOS cases and control women, indicating protective role of this SNP against PCOS phenotype. However, significant association was observed between VDR genotypes and some of the PCOS specific clinical/biochemical traits. For example, Fok1 showed a significant genotypic difference for the presence of infertility and Cdx2 genotpes showed association with testosterone levels. Further, the two haplotypes, ACCA and ACTA, were found to be significantly associated with PCOS indicating haplotype specific risk. Interpretation & conclusions: Although VDR polymorphisms have not shown significant association with PCOS, in view of functional significance of the SNPs considered, one cannot yet rule out the possibility of their association with PCOS. Further, specifically designed studies on large cohorts are required to conclusively establish the role of VDR polymorphisms in PCOS, particularly including data on vitamin D levels. Pneumococcal serotypes associated with invasive disease in under five children in India & implications for vaccine policy V Balaji, Ranjith Jayaraman, Valsan Philip Verghese, PR Baliga, T Kurien The Indian Journal of Medical Research 2015 142(3):286-292 Background & objectives: Streptococcus pneumoniae is a major cause of morbidity and mortality especially in children less than five years, particularly in India. We present data on S.pneumoniae infections in children less than five years age group, with response to its serotype distribution, antibiotic resistance profile and available vaccines expected coverage. Methods: Children aged less than five, who were suspected for invasive pneumococcal disease were included in the study and their sterile body fluids were investigated for the presence of S. pneumoniae. Invasive S. pneumoniae isolates from sterile body fluids were identified by bile solubility and optochin susceptibility test. Pneumococcal serotyping was performed with co-agglutination technique and reconfirmed with multiplex PCR. Results: The most common pneumococcal serotypes causing invasive infections in children less than five years of age were 14, 19F, 5, 6A and 6B. Of the 114 S. pneumoniae isolates studied, 110 (96.4%) were non-susceptible to co-trimoxazole and 30 per cent were non-susceptible to erythromycin, 5.2 per cent of the isolates were non-susceptible to penicillin and only 0.8 per cent was non-susceptible to cefotaxime. Interpretation & conclusions: Our results indicate that PCV-10 can protect against 64 per cent of serotypes causing invasive pneumococcal infections. Use of PCV-13 in this region can provide increase in protection upto 74.6 per cent against serotypes causing invasive pneumococcal infections. Incorporating PCV-13 in the Universal Immunization Programme may provide incremental protection against IPD serotypes in the southern region of the country. Distribution of blood pressure & correlates of hypertension in school children aged 5-14 years from North East India Prasanta Kr Borah, Utpala Devi, Dipankar Biswas, Hem Ch Kalita, Meenakshi Sharma, Jagadish Mahanta The Indian Journal of Medical Research 2015 142(3):293-300 Background & objectives: Elevated blood pressure (BP) in the young predicts serious cardiovascular events in the adults. High prevalence of adult hypertension reported from Assam, North East (NE) India may be linked with elevated blood pressure in the childhood. The present study was an attempt to describe the distribution of BP and correlates of hypertension in children aged 5-14 yr. Methods: A total of 10,003 school children from 99 schools of Dibrugarh district, Assam, NE India, were surveyed by stratified random cluster method. Blood pressure, demographic and anthropometric information were recorded. Blood pressure was categorized in to normal, prehypertension, stage I and stage II hypertension. Results: Girls had significantly higher (104.2 ± 12.0 vs. 103.2 ± 11.6 mm Hg, p0 <0.001) mean systolic blood pressure (SBP) than boys. Both SBP and diastolic blood pressure (DBP) revealed significant correlation with age, height, weight and BMI in overall and in gender specific analysis. Hypertension was found in 7.6 per cent school children (Boys: 7.3%, Girls: 7.8%). In multivariable analysis older age (OR 3.3, 95% CI: 2.82-3.91), children from tea garden community (OR 1.3, 95% CI: 1.08-1.55) and other community (OR 1.4, 95% CI: 1.18-1.73) and overweight (OR 1.5, 95% CI: 1.1-2.1) were independently associated with hypertension. Interpretation & conclusions:Mean blood pressure in the young school children of 5-14 yr was high. A programme comprising screening, early detection and health promotion through school health programmes may help prevent future complications of hypertension. Adherence to anti-retroviral therapy & factors associated with it: A community based cross-sectional study from West Bengal, India Sobha Pahari, Sitesh Roy, Alpana Mandal, Shymal Kuila, Samiran Panda The Indian Journal of Medical Research 2015 142(3):301-310 Background & objectives: Failure to adhere to anti-retroviral therapy (ART) can lead to a range of unfavourable consequences impacting upon people living with HIV (PLH) and society. It is, therefore, paramount that ART adherence is measured in a reliable manner and factors associated with adherence are identified. Lack of such data from West Bengal necessitated undertaking the current study. Methods: Participants were included during August-October, 2011 from three Drop-In-Centres (DICs) from the three districts of West Bengal, India. ART-adherence was calculated by using formula based on pill-count and records collected from ART-card in possession of each of the 128 consenting adult PLH. Information on self-reported adherence, socio-demography, and adherence influencing issues was also collected through interviewer-administered questionnaire. Results: Of the 128 PLH, 99 (77%) and 93 (73%) PLH had ≥90 per cent and ≥95 per cent adherence, respectively to ART. Conversely, subjective reporting captured much higher proportion of PLH as 'well adherent'; a finding having implications for ongoing ART programme. Factors, independently associated with poor adherence (<90%), were '7 th to 12 th month period of ART intake' (adjusted OR=9.5; 90% CI 1.9 - 47.3; p0 =0.02) and 'non-disclosure of HIV status to family members' (adjusted OR=4; 90% CI 1.3 - 13; P=0.05. Results at 95 per cent adherence cut-off were similar. Interpretation & conclusions: Enabling environment, which would encourage people to disclose their HIV status and in turn seek adherence partners from families and beyond and ongoing adherence-counselling appear to be important issues in the programme. Relevance of these study findings in wider context is conceivable.  Read More » Journal of Postgraduate Medicine As I approach the end of my life… Sunil Pandya Journal of Postgraduate Medicine 2015 61(4):217-220 Improving quality of informed consent in clinical research A Bhatt Journal of Postgraduate Medicine 2015 61(4):221-222 Utility of portable monitoring in the diagnosis of obstructive sleep apnea U Krishnaswamy, A Aneja, R Mohan Kumar, T Prasanna Kumar Journal of Postgraduate Medicine 2015 61(4):223-229 Obstructive sleep apnea (OSA) is a common but underdiagnosed sleep disorder, which is associated with systemic consequences such as hypertension, stroke, metabolic syndrome, and ischemic heart disease. Nocturnal laboratory-based polysomnography (PSG) is the gold standard test for diagnosis of OSA. PSG consists of a simultaneous recording of multiple physiologic parameters related to sleep and wakefulness including electroencephalography (EEG), electrooculography (EOG), surface electromyography (EMG), airflow measurement using thermistor and nasal pressure transducer, pulse oximetry and respiratory effort (thoracic and abdominal). Multiple alternative and simpler methods that record respiratory parameters alone for diagnosing OSA have been developed in the past two decades. These devices are called portable monitors (PMs) and enable performing sleep studies at a lower cost with shorter waiting times. It has been observed and reported that comprehensive sleep evaluation coupled with the use of PMs can fulfill the unmet need for diagnostic testing in various out-of-hospital settings in patients with suspected OSA. This article reviews the available medical literature on PMs in order to justify the utility of PMs in the diagnosis of OSA, especially in resource-poor, high-disease burden settings. The published practice parameters for the use of these devices have also been reviewed with respect to their relevance in the Indian setting. Prevalence of angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism in South Indian population with hypertension and chronic kidney disease R Shanmuganathan, R Kumaresan, P Giri Journal of Postgraduate Medicine 2015 61(4):230-234 Context: Chronic Kidney Disease (CKD) is associated with a high risk of developing further severe complications such as, cardiovascular disease and eventually End Stage Renal Disease (ESRD) leading to death. Hypertension plays a key role in the progression of renal failure and is also a chief risk factor for the occurrence of End Stage Renal Disease (ESRD). Aim: This study investigates the possible association of insertion (I) and deletion (D) polymorphism of ACE gene in patients of Chronic Kidney Disease (CKD) with and without hypertension (HT). Settings and Design: Total 120 participants with 30 members in each group (Control, HT, CKD and CKD-HT) were chosen followed by informed consent. Materials and Methods: Blood samples were collected and subjected to biochemical analyses and nested PCR amplification was performed to genotype the DNA, for ACE I/D using specific primers. Statistical Analysis: Statistical analyses were performed using SPSS version 13. Allele and genotypic frequency was calculated by direct gene counting method. Comparison of the different genotypes was done by using Chi square test. Odd's ratios were calculated with a 95% confidence interval limit. Results: The ACE genotype were distributed as II, 27 (90%); DD, 2 (6.67%) and ID, 1 (3.33%) in control, II, 1 (3.33%); DD, 5 (16.67%) and ID, 24 (80%) in HT, II, 4 (13.33%); DD, 24 (80%) and ID, 2 (6.67%) in CKD and II, 0 (0%); DD, 2 (6.67%) and ID, 28 (93.33%) in CKD-HT group. Conclusions: D allele of ACE gene confers a greater role in genetic variations underlying CKD and hypertension. This result suggest that CKD patients should be offered analysis for defects in ACE I/D polymorphisms, especially if they are hypertensive. PIRO concept: Staging of sepsis S Rathour, S Kumar, V Hadda, A Bhalla, N Sharma, S Varma Journal of Postgraduate Medicine 2015 61(4):235-242 Introduction: Sepsis is common presenting illness to the emergency services and one of the leading causes of hospital mortality. Researchers and clinicians have realized that the systemic inflammatory response syndrome concept for defining sepsis is less useful and lacks specificity. The predisposition, infection (or insult), response and organ dysfunction (PIRO) staging of sepsis similar to malignant diseases (TNM staging) might give better information. Materials and Methods: A prospective observational study was conducted in emergency medical services attached to medicine department of a tertiary care hospital in Northern India. Patients with age 18 years or more with proven sepsis were included in the first 24 hours of the diagnosis. Two hundred patients were recruited. Multivariate logistic regression analysis was done to assess the factors that predicted in-hospital mortality. Results: Two hundred patients with proven sepsis, admitted to the emergency medical services were analysed. Male preponderance was noted (M: F ratio = 1.6:1). Mean age of study cohort was 50.50 ± 16.30 years. Out of 200 patients, 116 (58%) had in-hospital mortality. In multivariate logistic regression analysis, the factors independently associated with in-hospital mortality for predisposition component of PIRO staging were age >70 years, chronic obstructive pulmonary disease, chronic liver disease, cancer and presence of foley's catheter; for infection/ insult were pneumonia, urinary tract infection and meningitis/encephalitis; for response variable were tachypnea (respiratory rate >20/minute) and bandemia (band >5%). Organ dysfunction variables associated with hospital mortality were systolic blood pressure <90mm Hg, prolonged activated partial thromboplastin time, raised serum creatinine, partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio <300, decreased urine output in first two hours of emergency presentation and Glasgow coma scale ≤9. Each of the components of PIRO had good predictive capability for in-hospital mortality but the total score was more accurate than the individual score and increasing PIRO score was associated with higher in-hospital mortality. The area under receiver operating characteristic curve for cumulative PIRO staging system as a predictor of in-hospital mortality was 0.94. Conclusion: This study finds PIRO staging as an important tool to stratify and prognosticate hospitalised patients with sepsis at a tertiary care center. The simplicity of score makes it more practical to be used in busy emergencies as it is based on four easily assessable components. Prevalence of autism spectrum disorders among children (1-10 years of age) - Findings of a mid-term report from Northwest India SK Raina, V Kashyap, AK Bhardwaj, D Kumar, V Chander Journal of Postgraduate Medicine 2015 61(4):243-246 Background: India is the second most populous country of the world. A large portion of the population of this country is below 20 years of age but still there is a paucity of information about the prevalence and incidence of many developmental disorders. This study was planned to estimate the prevalence of autism spectrum disorders (ASDs) in the selected areas (tribal, rural, and urban) of a northern state of India, Himachal Pradesh. Methods: A cross-sectional two-phase study was conducted covering all the children in the range of 1-10 years of age. Phase one included screening of all the children in the age group of 1-10 years, with the help of an indigenous assessment tool for autism. The sociodemographic profile of the participants was also recorded during phase one. Phase two involved the clinical evaluation of individuals who were suspected of autism on screening. Results: The results show a prevalence rate of 0.9/1000. The highest prevalence rate was observed in the rural area. Conclusions: Socioeconomic status (SES) may be one of the fundamental indicators for ASDs in India. Intersecting pentagons as surrogate for identifying the use of mini mental state examination in assessment of dementia in a largely illiterate population SK Raina, A Maria, V Chander, S Raina Journal of Postgraduate Medicine 2015 61(4):247-250 Background and Rationale: The mini-mental state evaluation (MMSE) is often used to identify patients with dementia. One component of the MMSE is the intersecting pentagon copying (IPC) test, which may be difficult to be used in an illiterate population. Materials and Methods: A post hoc analysis on an elderly population (60 years and above) from Himachal Pradesh was carried out. The data of only 1,513 elderly individuals out of a total of 2,000 participants with a score of more than 26 (nondemented) out of a possible score of 30 on cognitive battery available were used. The scores on the IPC were evaluated and their association with some demographic variables was also assessed. Results: Illiterate participants, female participants, those with greater age, and the rural/tribal population groups faced the most difficulty in drawing the intersecting pentagons and even greater difficulty in drawing them correctly. Discussion: The IPC presents challenges for people who are illiterate and the scoring method needs to be addressed and changed particularly when the test is used in largely illiterate populations. Incidence and factors associated with medication nonadherence in patients with mental illness: A cross-sectional study JM Lucca, M Ramesh, G Parthasarathi, D Ram Journal of Postgraduate Medicine 2015 61(4):251-256 Background: In spite of the progress made in the treatment of psychiatric disorders during the last few decades, nonadherence continues to be a frequent phenomenon, often associated with potentially severe clinical consequences and increased health-care costs. There are numerous factors associated with medication nonadherence in patients with mental illness. The aim of the study was to determine the incidence and factors associated with medication nonadherence among psychiatric outpatients. Materials and Methods: A cross-sectional study was carried out in the outpatient psychiatric department of an Indian tertiary care private hospital over a period of 1 year. Patients aged 18 years and above who presented with mental illness as diagnosed by the International Classification of Diseases (ICD)-10 and who were receiving at least one psychotropic medication for at least 1 month were included in the study. Medication adherence was assessed using the Medication Adherence Rating Scale (MARS). Results: Of the 400 patients, 172 (43%) were nonadherent to their prescribed medications. There is a statistically significant association between the education (P = 0.001), number of drugs (P = 0.002), family income (P = 0.013), and nonadherence. Among the 172 patients, 33.5 % were nonadherent to their therapy due to patient-related factors followed by drug-related factors (32%) and disease-related factors (31%). Conclusion: The overall incidence of medication nonadherence in patients with mental illness was 43%. Numerous factors contributed to medication nonadherence. Strategies need to be developed and implemented to enhance medication adherence, and thereby achieve a better therapeutic outcome in patients with mental illness. An audit of consent refusals in clinical research at a tertiary care center in India SJ Thaker, BH Figer, NJ Gogtay, UM Thatte Journal of Postgraduate Medicine 2015 61(4):257-263 Background and Rationale: Ensuring research participants' autonomy is one of the core ethical obligations of researchers. This fundamental principle confers on every participant the right to refuse to take part in clinical research, and the measure of the number of consent refusals could be an important metric to evaluate the quality of the informed consent process. This audit examined consent refusals among Indian participants in clinical studies done at our center. Materials and Methods: The number of consent refusals and their reasons in 10 studies done at our center over a 5-year period were assessed. The studies were classified by the authors according to the type of participant (healthy vs patients), type of sponsor (investigator-initiated vs pharmaceutical industry), type of study (observational vs interventional), level of risk [based on the Indian Council of Medical Research (ICMR) "Ethical Guidelines for Biomedical Research on Human Participants"], available knowledge of the intervention being studied, and each patient's disease condition. Results: The overall consent refusal rate was 21%. This rate was higher among patient participants [23.8% vs. healthy people (14.9%); P = 0.002], in interventional studies [33.6% vs observational studies (7.5%); P < 0.0001], in pharmaceutical industry-sponsored studies [34.7% vs investigator-initiated studies (7.2%); P < 0.0001], and in studies with greater risk (P < 0.0001). The most common reasons for consent refusals were multiple blood collections (28%), inability to comply with the study protocol (20%), and the risks involved (20%). Conclusion: Our audit suggests the adequacy and reasonable quality of the informed consent process using consent refusals as a metric. Fish gall bladder consumption presenting as acute renal failure A Gupta, ND Karnik, VA Gupta, NK Hase Journal of Postgraduate Medicine 2015 61(4):264-265 A forty two year old male was admitted with history of anuria and breathlessness following consumption of raw rohu fish gall bladder. He had azotemia and required hemodialysis. His renal failure improved over a period of about four weeks. Incidences have been reported from South East Asian countries associating consumption of raw rohu fish gall bladder with acute renal failure. Read More » MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. Introducing MODICA - a secure, HIPAA-compliant medical camera app and cloud storage service for the iPhone. If you use your mobile device to take photos of patient cases, you should consider a solution designed specifically for medical photography. MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. MODICA can help you: Keep medical and personal images separate Stay compliant with privacy rules using the encrypted cloud backup service Obtain and save patient consent directly in the app Securely share photos with colleagues MODICA is free and available now from iTunes. Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. Introducing MODICA - a secure, HIPAA-compliant medical camera app and cloud storage service for the iPhone. If you use your mobile device to take photos of patient cases, you should consider a solution designed specifically for medical photography. MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. MODICA can help you: Keep medical and personal images separate Stay compliant with privacy rules using the encrypted cloud backup service Obtain and save patient consent directly in the app Securely share photos with colleagues MODICA is free and available now from iTunes. Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. Introducing MODICA - a secure, HIPAA-compliant medical camera app and cloud storage service for the iPhone. If you use your mobile device to take photos of patient cases, you should consider a solution designed specifically for medical photography. MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. MODICA can help you: Keep medical and personal images separate Stay compliant with privacy rules using the encrypted cloud backup service Obtain and save patient consent directly in the app Securely share photos with colleagues MODICA is free and available now from iTunes. Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Maternal and Child Health Journal Erratum to: Gestational Weight Gain and Health Outcomes 18 Years Later in Urban Black Women Three Positive Parenting Practices and Their Correlation with Risk of Childhood Developmental, Social, or Behavioral Delays: An Analysis of the National Survey of Children's Health Abstract Objectives (1) Investigate the relationship between three specific positive parenting practices (PPP)—reading to children, engaging in storytelling or singing, and eating meals together as a family—and parent-reported risk of developmental, behavioral, or social delays among children between the ages of 1–5 years in the US. (2) Determine if a combination of these parenting practices has an effect on the outcome. Methods Chi square and multiple logistic regression analyses were used to analyze cross-sectional data from the National Survey of Children's Health 2011/2012 in regards to the relationship between each of the three individual PPP as well as a total PPP score and the child's risk of being developmentally, socially, or behaviorally delayed (N = 21,527). Risk of delay was calculated using the Parents' Evaluation of Developmental Status Questionnaire, which is a parental self-report measure that has been correlated with diagnosed child delays. These analyses controlled for poverty and parental education. All analyses were completed using SAS Version 9.3. Results A strong correlation was found between each of the three PPP as well as the total PPP score and the child's risk of developmental, social, or behavioral delays (p < 0.05 for each test). These associations were found to have a dose–response relationship (p < 0.05 in all but one analysis). Conclusions Daily engagement in PPP could possibly reduce children's risk of delay, and specifically engaging in all three PPP may have greater benefit. Adverse Childhood Experiences, the Medical Home, and Child Well-Being Abstract Objectives To examine the relationship between adverse childhood experiences (ACE), access to a medical home and a global measure of well-being among children ages 6–17 using the 2011–2012 National Survey of Children's Health. Methods Multivariate linear regressions assessed the associations between each adverse experience and an index of child well-being with and without the impact of other events. The number of ACE was summed for each respondent and the analyses were repeated with the cumulative score as a continuous variable. The cumulative model was repeated with the addition of an interaction term between ACE score and medical home access. All analyses were conducted separately for children ages 6–11 and adolescents 12–17. Results Over half (53 %) of US children ages 6–17 have experienced some adverse experience during childhood. Over a quarter (28 %) has experienced at least two adverse experiences, while 15 % have experienced three or more hardships. Results suggest that the accumulation of ACE reduces well-being in children. The associations remained significant after controlling for gender, race/ethnicity, age, parental education, special health condition, and medical home access. Medical home access was consistently associated with higher levels of child well-being and was a significant moderator of the relationship between the total ACE and child well-being among children ages 6–11. Children with ACE exposure and access to a medical home have higher levels of well-being than comparable children without access to a medical home. Conclusions for Practice Children exposed to adverse experiences have measurably lower levels of well-being, although younger children with access to a medical home are protected at increasing exposure. Gestational Age at First Antenatal Care Visit in Malawi Abstract Objectives This paper examines the gestational age at first antenatal care (ANC) visit and factors associated with timely initiation of ANC in Malawi in a context where maternal and child health services are generally provided for free. Methods Lognormal survival models are applied to Demographic and Health Survey data from a nationally representative sample of women (n = 13,588) of child-bearing age. Results The findings of this study show that less than 30 % of pregnant women initiate ANC within the World Health Organization recommended gestational timeframe of 16 weeks or earlier. The hazard analysis shows a gradient in the initiation of ANC by maternal education level, with least educated mothers most likely to delay their first ANC visit. However, after adjusting for variables capturing intimate partner violence in the multivariate models, the effect of maternal education attenuated and lost statistical significance. Other significant predictors of gestational age at first ANC include media exposure, perceived distance from health facility, age, and birth order. Conclusions for Practice The findings of the study link domestic violence directly with the gestational age at which mothers initiate ANC, suggesting that gender-based violence may operate through delayed initiation of ANC to undermine maternal and child health outcomes. Developmental Surveillance and Referral in a Traditionally Medically Underserved Border Community Abstract Purpose Early identification and referral have been shown to improve long-term outcomes for children with disabilities. However, the number of children enrolled in early intervention services continues to be lower than the number of children confirmed to be developmentally delayed later in life. This study investigated the pattern of developmental surveillance and referral practices of pediatricians in a traditionally medically underserved border community. Description An online survey was created by members of a community/academic partnership. Emails were followed up with a personal contact to doctor's offices to increase the response rate. Assessment Response rate for the survey was 26.7 %. Most respondents reported using a combination of formal screening tools and parent interviews to complete developmental screenings in their practice with the Modified Checklist of Autism in Toddlers being the most commonly used tool. Conclusion Although most respondents reported referring children for the Individuals with Disabilities Education Act Part C services, gaps were identified in available services and in the referral process that need to be addressed. Additionally, future studies need to evaluate the efficacy of a referral and feedback system to improve earlier access to intervention services for children with disabilities. The Association Between Diabetes Mellitus Among American Indian/Alaska Native Populations with Preterm Birth in Eight US States from 2004–2011 Abstract Objectives Assess risk of preterm birth associated with diabetes mellitus (DM) among American Indian and Alaska Natives (AI/AN), a population with increased risk of DM and preterm birth, and examine whether this association differed by state of residence. Methods We used surveillance data from the Pregnancy Risk Assessment Monitoring System from 12,400 AI/AN respondents with singleton births in Alaska, Minnesota, Nebraska, New Mexico, Oklahoma, Oregon, Utah, and Washington from 2004–2011. We conducted multivariable logistic regression models to estimate the odds ratio adjusted for maternal age and prepregnancy BMI with all observations and then stratified by state. Results DM was reported in 5.92 % of the study population and preterm birth occurred in 8.95 % of births. Women with DM had 1.92 times higher odds of having a preterm birth than women without DM [95 % confidence interval (CI) 1.21–2.78]. After stratifying on state, women with DM in Nebraska had the greatest odds of preterm birth [aOR 6.63, (95 % CI 3.80–11.6)] while women in Alaska saw a protective effect from DM [aOR 0.17, (95 % CI 0.07–0.42)] compared to women without DM. Conclusion Overall, AI/AN women with DM had significantly greater odds of preterm birth compared to AI/AN women without DM across states. Substantial differences in this association between states calls for increased public health efforts in high-risk areas as well as further research to assess whether differences are attributable to diagnosis, reporting, tribal, healthcare or lifestyle factors. Afraid of Delivering at the Hospital or Afraid of Delivering at Home: A Qualitative Study of Thai Hmong Families' Decision-Making About Maternity Services Abstract Thailand has high rates of maternity services; both antenatal care (ANC) and hospital delivery are widely used by its citizens. A recent Northern Thailand survey showed that Hmong women used maternity services at lower rates. Our objectives were to identify Hmong families' socio-cultural reasons for using and not using maternity services, and suggest ways to improve Hmong women's use of maternity services. In one Hmong village, we classified all 98 pregnancies in the previous 5 years into four categories: no ANC/home birth, ANC/home, no ANC/hospital, ANC/hospital. We conducted life-history case studies of 4 women from each category plus their 12 husbands, and 17 elders. We used grounded theory to guide qualitative analysis. Families not using maternity services considered pregnancy a normal process that only needed traditional home support. In addition, they disliked institutional processes that interfered with cultural birth practices, distrusted discriminatory personnel, and detested invasive, involuntary hospital procedures. Families using services perceived physical needs or potential delivery risks that could benefit from obstetrical assistance not available at home. While they disliked aspects of hospital births, they tolerated these conditions for access to obstetrical care they might need. Families also considered cost, travel distance, and time as structural issues. The families ultimately balanced their fear of delivering at home with their fear of delivering at the hospital. Providing health education about pregnancy risks, and changing healthcare practices to accommodate Hmong people's desires for culturally-appropriate family-centered care, which are consistent with evidence-based obstetrics, might improve Hmong women's use of maternity services. Diet, Pre-pregnancy BMI, and Gestational Weight Gain in Puerto Rican Women Abstract Objectives To describe the dietary patterns in pregnant woman and determine the association between diet factors, pre-pregnancy Body Mass Index (BMI) and socio-demographic characteristics with gestational weight gain (GWG). Methods This is a secondary analysis of a longitudinal cohort study of pregnant women exploring the risk factors for preterm birth, the Puerto Rico Testsite for Exploring Contamination Threats program. Recruitment was conducted during 2011–2014. Data was collected from multiple sources. GWG was calculated using maternal weight recorded in the medical records at the first and last prenatal visits and classified according to the Institute of Medicine guidelines. Sociodemographic characteristics were obtained at baseline using an interviewed-based questionnaire. Participants completed a self-administered food frequency questionnaire at 20–28 weeks to assess dietary patterns. Analysis of associations between variables was conducted using Chi Square tests. Results A total of 160 women with term pregnancies were included in this analysis. Mean pre-pregnancy BMI was 25.4 ± 5.48 kg/m2, with 44.4 % classified as overweight/obese. Excessive GWG was observed in 24.4 % of the participants. Socio-demographic characteristics were not associated with GWG. Being overweight/obese at the start of pregnancy was significantly associated with excessive GWG (p < 0.05). In addition, women consuming one or more fruit drinks per day were more likely to have an excessive GWG while those consuming less than one fruit drink per day were more likely to have an adequate GWG (p < 0.05). Conclusions for Practice Being obese before pregnancy and frequently consuming fruit drinks were important determinants of excessive GWG in this group. The Relationship Between Maternal Education and Child Health Outcomes in Urban Australian Children in the First 12 Months of Life Abstract Objectives To describe the relationship between maternal education and child health outcomes at 12 months of age in a cohort of children in urban Australia, and to determine whether this relationship could be explained by the intermediate factors of maternal health behaviour and the social environmental context. Methods Data were derived from The Environments for Health Living Griffith Birth Cohort Study. Women attending their third trimester antenatal appointment at one of three public hospitals were recruited between 2006 and 2010 and invited to complete a 48-item, baseline self-administered questionnaire. Twelve months following the birth of their baby, a follow-up questionnaire consisting of 63 items was distributed. Results Women for whom complete follow-up data were not available were different from women who did complete follow-up data. The children of women with follow-up data—whom at the time of their pregnancy had not completed school or whose highest level of education was secondary school or a trade—had respectively a 59 and 57 % increased chance of having had a respiratory/infectious disease or injury in the first year of life (according to parent proxy-reports), compared to children of women with a tertiary education. When maternal behavioural and social environmental factors during pregnancy were included in the model (n=1914), the effect of secondary education was still evident but with a reduced odds ratio of 1.35 (95 % CI 1.07–1.72) and 1.19 (95 % CI 0.87–1.64), respectively. The effect of not having completed school was no longer significant. Conclusions Results indicate that the relationship between maternal education and child outcomes may be mediated by maternal social environmental and behavioural factors. Results are likely an underestimation of the effect size, given the under representation in our cohort of participants with maternal characteristics associated with elevated risk of infant morbidity. Brief Online Self-help Exercises for Postnatal Women to Improve Mood: A Pilot Study Abstract Objectives Giving birth and adjusting to a new baby can be difficult and stressful for new mothers. Negative mood may occur during this time and can affect women, their parenting and the infant's development. This pilot study evaluated a brief online self-help intervention designed to promote positive mood in mothers of babies and toddlers. Methods Women in the UK who had given birth within the previous 18 months were randomly allocated to the online self-help intervention (n = 40) or active comparison group exercise (n = 40) which was matched for time and structure. Mood was measured before and after the intervention. Acceptability was examined at the end of the trial. Results The self-help intervention was acceptable to the majority of women and significantly increased positive mood compared to the comparison condition. This effect persisted after controlling for self-esteem, anxiety and depression. These results suggest that a simple self-help intervention focused on changing beliefs about oneself as a mother can have an immediate impact on women's mood. Conclusions for Practice Further research is need to see whether these improvements continue long-term and what processes underlie these improvements. Read More » Cell Stress and Chaperones Commentary to: 'A comparison of two commercially available ELISA methods for the quantification of human plasma heat shock protein 70 during rest and exercise stress' by Lee et al. 2015 Interactions of Escherichia coli molecular chaperone HtpG with DnaA replication initiator DNA Abstract The bacterial chaperone high-temperature protein G (HtpG), a member of the Hsp90 protein family, is involved in the protection of cells against a variety of environmental stresses. The ability of HtpG to form complexes with other bacterial proteins, especially those involved in fundamental functions, is indicative of its cellular role. An interaction between HtpG and DnaA, the main initiator of DNA replication, was studied both in vivo, using a bacterial two-hybrid system, and in vitro with a modified pull-down assay and by chemical cross-linking. In vivo, this interaction was demonstrated only when htpG was expressed from a high copy number plasmid. Both in vitro assays confirmed HtpG–DnaA interactions. Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint Abstract Acute stress alters anti-bacterial defenses, but the neuroimmunological mechanisms underlying this association are not yet well understood. Metallothionein (MT), a cysteine-rich protein, is a stress response protein that is induced by a variety of chemical, biological, and psychological stressors, and MT has been shown to influence immune activities. We investigated MT's role in the management of anti-bacterial responses that occur during stress, using a C57BL/6 (B6) strain that has targeted disruptions of the Mt1 and Mt2 genes (B6-MTKO), and a B6 strain that has additional copies of Mt (B6-MTTGN). The well-characterized listeriosis model was used to examine immune mechanisms that are altered by a 1-h stress treatment (cold-restraint, CR) administered just prior to bacterial infection. Intriguingly, MT gene doses both greater and lower than that of wild-type (WT) B6 mice were associated with improved host defenses against Listeria monocytogenes (LM). This augmented protection was diminished by CR stress in the MTKO mice, but transgenic mice with additional MT copies had no CR stress-induced increase in their listerial burden. During the transition from innate to adaptive immunity, on day 3 after infection, oxidative burst and apoptosis were assessed by flow cytometric methods, and cytokine transcription was measured by real-time quantitative PCR. MT gene expression and CR-stress affected the expression of IL-6 and TNFα. Additionally, these genetic and environmental modulations altered the generation of ROS responses as well as the number of apoptotic cells in livers and spleens. Although the level of MT altered the listerial response, MT expression was equally elevated by listerial infection with or without CR stress. These results indicate the ability of MT to regulate immune response mechanisms and demonstrate that increased amounts of MT can eliminate the immunosuppression induced by CR. The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review Abstract As an intracellular polypeptide, heat shock protein 70 (HSP70) can be exposed on the plasma membrane and/or released into the circulation. However, the role of HSP70 in various nondisease and disease conditions remains unknown. Quantitative methods for the detection of HSP70 have been used in clinical studies, revealing that an increase in circulating HSP70 is associated with various types of exercise, elderly patients presenting with inflammation, mobile phones, inflammation, sepsis, chronic obstructive pulmonary disease, asthma, carotid intima-media thickness, glutamine-treated ill patients, mortality, diabetes mellitus, active chronic glomerulonephritis, and cancers. Circulating HSP70 decreases with age in humans and in obstructive sleep apnea, arteriosclerosis, atrial fibrillation (AF) following coronary artery bypass surgery, nonalcoholic fatty liver disease, moderate-to-severe alcoholic fatty liver disease, hepatic steatosis, and Helicobacter pylori infection. In conclusion, quantitative methods can be used to detect HSP70, particularly in determining circulating HSP70 levels, using more convenient and rapid screening methods. Studies have shown that changes in HSP70 are associated with various nondisease and disease conditions; thus, HSP70 might be a novel potential biomarker reflecting various nondisease conditions and also the severity of disease conditions. However, the reliability and accuracy, as well as the underlying mechanism, of this relationship remain poorly understood, and large-sample clinical research must be performed to verify the role. Chaperonin containing T-complex polypeptide subunit eta is a potential marker of joint contracture: an experimental study in the rat Abstract Joint contracture is a fibroproliferative disorder that restricts joint mobility, resulting in tissue degeneration and deformity. However, the etiology of joint contracture is still unknown. Chaperonin containing T-complex polypeptide subunit eta (CCT-eta) is reported to increase in fibrotic diseases. The purpose of this study was to investigate whether CCT-eta is implicated in joint contracture and to determine the role of CCT-eta in the progression of joint contracture by analyzing a rat model. We immobilized the left knee joint of rat by internal fixation for 8 weeks. The non-immobilized right leg served as a control. The range of motion (ROM) of the knee was investigated. Fibroblasts were obtained from the posterior joint capsule of the joints. The outcome was followed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, fibroblast migration assay, and collagen assay. The effect of CCT-eta on the functions of fibroblasts was observed by utilizing a short inhibitory RNA (siRNA) targeting CCT-eta. The ROM of the immobilized joints was significantly limited compared to the contralateral joints (p < 0.05). Fibroblasts derived from the contractive joints showed higher mRNA and protein expressions of CCT-eta in parallel with alpha-smooth muscle actin (α-SMA) compared to the cells from the contralateral knees (p < 0.05). siRNA-mediated downregulation of CCT-eta inhibited the expressions of both CCT-eta and α-SMA. Moreover, the reduction of CCT-eta also significantly decreased fibroblast functions such as cell mobility and collagen synthesis (all p < 0.05). Our findings indicate that CCT-eta appears to be a potential marker of joint contracture disease. Moderate- and high-intensity exhaustive exercise in the heat induce a similar increase in monocyte Hsp72 Abstract This study examined the relationship between exhaustive exercise in the heat at moderate and high intensities on the intracellular heat shock protein 72 (iHsp72) response. Twelve male subjects cycled to exhaustion at 60 and 75 % of maximal oxygen uptake in hot conditions (40 °C, 50 % RH). iHsp72 concentration was measured in monocytes before, at exhaustion and 24 h after exercise. Rectal temperature, heart rate and oxygen uptake were recorded during exercise. Volitional exhaustion occurred at 58.9 ± 12.1 and 27.3 ± 9.5 min (P < 0.001) and a rectal temperature of 39.8 ± 0.4 and 39.2 ± 0.6 °C (P = 0.002), respectively, for 60 and 75 %. The area under the curve above a rectal temperature of 38.5 °C was greater at 60 % (17.5 ± 6.6 °C min) than 75 % (3.4 ± 4.8 °C min; P < 0.001), whereas the rate of increase in rectal temperature was greater at 75 % (5.1 ± 1.7 vs. 2.2 ± 1.4 °C h−1; P < 0.001). iHsp72 concentration increased similarly at exhaustion relative to pre-exercise (P = 0.044) and then increased further at 24 h (P < 0.001). Multiple regression analysis revealed no predictor variables associated with iHsp72 expression; however, a correlation was observed between exercise intensities for the increase in iHsp expression at exhaustion and 24 h (P < 0.05). These results suggest that iHsp72 expression increased in relation to the level of hyperthermia attained and sustained at 60 % and the higher metabolic rate and greater rate of increase in core temperature at 75 %, with the further increase in iHsp72 concentration 24 h after exercise reinforcing its role as a chaperone and cytoprotective agent. Identification and expression analysis of a heat-shock protein 70 gene in Polycelis sp. Abstract Heat-shock protein 70 (HSP70) is ubiquitously found in a variety of organisms and plays an important role in cytoprotection, environmental monitoring, and disease resistance. In this study, the full-length complementary DNA (cDNA) of hsp70 from planarian Polycelis sp. was first cloned using rapid amplification of cDNA ends (RACE). The expression levels of Pyhsp70 were analyzed in the presence of various stressors by real-time PCR, and its temporal-spatial expression patterns were also examined in both intact and regenerative animals by whole-mount in situ hybridization. The results show that (1) the deduced amino acid sequence of Pyhsp70 includes three typical HSP70 family signature motifs and is highly conserved during evolution; (2) Pyhsp70 expression is induced by prolonged starvation, tissue damage, and ionic liquid but inhibited by high or low temperatures; and (3)Pyhsp70 mRNA is mainly expressed in the head peripheral region and in the regenerating blastema during regeneration. These results suggest that the highly expressed Pyhsp70 gene may contribute to enhance cytoprotection and tolerance against stress-induced molecular damage, and the migration of neoblasts to the wound, which might also be involved in the proliferation and differentiation of neoblasts. Our work provides basic data for the study of stress responses and regenerative mechanism in freshwater planarians. Imaging stress Abstract Recent innovations in cell biology and imaging approaches are changing the way we study cellular stress, protein misfolding, and aggregation. Studies have begun to show that stress responses are even more variegated and dynamic than previously thought, encompassing nano-scale reorganization of cytosolic machinery that occurs almost instantaneously, much faster than transcriptional responses. Moreover, protein and mRNA quality control is often organized into highly dynamic macromolecular assemblies, or dynamic droplets, which could easily be mistaken for dysfunctional "aggregates," but which are, in fact, regulated functional compartments. The nano-scale architecture of stress-response ranges from diffraction-limited structures like stress granules, P-bodies, and stress foci to slightly larger quality control inclusions like juxta nuclear quality control compartment (JUNQ) and insoluble protein deposit compartment (IPOD), as well as others. Examining the biochemical and physical properties of these dynamic structures necessitates live cell imaging at high spatial and temporal resolution, and techniques to make quantitative measurements with respect to movement, localization, and mobility. Hence, it is important to note some of the most recent observations, while casting an eye towards new imaging approaches that offer the possibility of collecting entirely new kinds of data from living cells. Unfolding the complexities of ER chaperones in health and disease: report on the 11th international calreticulin workshop Abstract The 11th International Calreticulin workshop was held May 15–18, 2015 at New York University School of Medicine-Langone Medical Center, New York. The meeting highlighted many of the new discoveries in the past 2 years involving the important role of molecular chaperones in physiological and pathological processes. Crucial to the understanding of these disease processes was the role of chaperones in maintaining quality control of protein processing in the endoplasmic reticulum, the importance of Ca2 regulation acting through its action in stress-related diseases, and the trafficking of glycoproteins to the cell surface. Central to maintaining healthy cell physiology is the correct ER-associated protein degradation of specific misfolded proteins. Information on different mechanisms involved in the degradation of misfolded proteins was revealed. This was a landmark meeting for the chaperone field in terms of new insights into their roles in physiology. These insights included the unfolded protein response, innate/adaptive immunity, tissue repair, the functions of calreticulin/chaperones from the cell surface, and extracellular environment. Diseases included neurodegenerative disorders, prion disease, autoimmunity, fibrosis-related disease, the host immune response to cancer, and hematologic diseases associated with calreticulin mutations. The 12th calreticulin workshop is planned for the spring of 2017 in Delphi, Greece. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice Abstract Social stressors evolving from individual and population interactions produce stress reactions in many organisms (including humans), influencing homeostasis, altering the activity of the immunological system, and thus leading to various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) in cancer promotion and to assess oxidative stress outcomes in terms of various in vivo biochemical parameters, oxidative stress markers, DNA damage, and the development of skin tumors in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz(a)anthracene (DMBA) alone (topical), and DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical) and exposure to CUS prior to DMBA or DMBA-TPA treatments and sacrificed after 16 weeks of treatment. Prior exposure to CUS significantly increased the pro-oxidant effect of carcinogen, depicted by compromised levels of antioxidants in the circulation and skin, accompanied by enhanced lipid peroxidation, plasma corticosterone, and marker enzymes as compared to DMBA-alone or DMBA-TPA treatments. DNA damage results corroborated the above biochemical outcomes. Also, the development of skin tumors (in terms of their incidence, tumor yield, and tumor burden) in mice in the presence and absence of stress further strongly supported our above biochemical measurements. CUS may work as a promoter of carcinogenesis by enhancing the pro-oxidant potential of carcinogens. Further studies may be aimed at the development of interventions for disease prevention by identifying the relations between psychological factors and DNA damage. Read More » Integrative and Comparative Biology - current issue The Power of Physiology in Changing Landscapes: Considerations for the Continued Integration of Conservation and Physiology The growing field of conservation physiology applies a diversity of physiological traits (e.g., immunological, metabolic, endocrine, and nutritional traits) to understand and predict organismal, population, and ecosystem responses to environmental change and stressors. Although the discipline of conservation physiology is gaining momentum, there is still a pressing need to better translate knowledge from physiology into real-world tools. The goal of this symposium, "Physiology in Changing Landscapes: An Integrative Perspective for Conservation Biology", was to highlight that many current investigations in ecological, evolutionary, and comparative physiology are necessary for understanding the applicability of physiological measures for conservation goals, particularly in the context of monitoring and predicting the health, condition, persistence, and distribution of populations in the face of environmental change. Here, we outline five major investigations common to environmental and ecological physiology that can contribute directly to the progression of the field of conservation physiology: (1) combining multiple measures of physiology and behavior; (2) employing studies of dose–responses and gradients; (3) combining a within-individual and population-level approach; (4) taking into account the context-dependency of physiological traits; and (5) linking physiological variables with fitness metrics. Overall, integrative physiologists have detailed knowledge of the physiological systems that they study; however, communicating theoretical and empirical knowledge to conservation biologists and practitioners in an approachable and applicable way is paramount to the practical development of physiological tools that will have a tangible impact for conservation. Fishing for Effective Conservation: Context and Biotic Variation are Keys to Understanding the Survival of Pacific Salmon after Catch-and-Release Acute stressors are commonly experienced by wild animals but their effects on fitness rarely are studied in the natural environment. Billions of fish are captured and released annually around the globe across all fishing sectors (e.g., recreational, commercial, subsistence). Whatever the motivation, release often occurs under the assumption of post-release survival. Yet, capture by fisheries (hereafter "fisheries-capture") is likely the most severe acute stressor experienced in the animal's lifetime, which makes the problem of physiological recovery and survival of relevance to biology and conservation. Indeed, fisheries managers require accurate estimates of mortality to better account for total mortality from fishing, while fishers desire guidance on strategies for reducing mortality and maintaining the welfare of released fish, to maximize current and future opportunities for fishing. In partnership with stakeholders, our team has extensively studied the effects of catch-and-release on Pacific salmon in both marine and freshwater environments, using biotelemetry and physiological assessments in a combined laboratory-based and field-based approach. The emergent theme is that post-release rates of mortality are consistently context-specific and can be affected by a suite of interacting biotic and abiotic factors. The fishing gear used, location of a fishery, water temperature, and handling techniques employed by fishers each can dramatically affect survival of the salmon they release. Variation among individuals, co-migrating populations, and between sexes all seem to play a role in the response of fish to capture and in their subsequent survival, potentially driven by pre-capture pathogen-load, maturation states, and inter-individual variation in responsiveness to stress. Although some of these findings are fascinating from a biological perspective, they all create unresolved challenges for managers. We summarize our findings by highlighting the patterns that have emerged most consistently, and point to areas of uncertainty that require further research. Conservation Physiology of an Uncatchable Animal: The North Atlantic Right Whale (Eubalaena glacialis) The North Atlantic right whale, Eubalaena glacialis (NARW), a critically endangered species that has been under intensive study for nearly four decades, provides an excellent case study for applying modern methods of conservation physiology to large whales. By combining long-term sighting histories of known individuals with physiological data from newer techniques (e.g., body condition estimated from photographs; endocrine status derived from fecal samples), physiological state and levels of stress can be estimated despite the lack of any method for nonlethal capture of large whales. Since traditional techniques for validating blood assays cannot be used in large whales, assays of fecal hormones have been validated using information on age, sex, and reproductive state derived from an extensive NARW photo-identification catalog. Using this approach, fecal glucocorticoids have been found to vary dramatically with reproductive state. It is therefore essential that glucocorticoid data be interpreted in conjunction with reproductive data. A case study correlating glucocorticoids with chronic noise is presented as an example. Keys to a successful research program for this uncatchable species have included: consistent population monitoring over decades, data-sharing across institutions, an extensive photo-identification catalog that documents individual histories, and consistent efforts at noninvasive collection of samples over years. Future research will require flexibility to adjust to changing distributions of populations. Species Introductions and Their Cascading Impacts on Biotic Interactions in desert riparian ecosystems Desert riparian ecosystems of North America are hotspots of biodiversity that support many sensitive species, and are in a region experiencing some of the highest rates of climatic alteration in North America. Fremont cottonwood, Populus fremontii, is a foundation tree species of this critical habitat, but it is threatened by global warming and regional drying, and by a non-native tree/shrub, Tamarix spp., all of which can disrupt the mutualism between P. fremontii and its beneficial mycorrhizal fungal communities. Specialist herbivorous leaf beetles (Diorhabda spp.) introduced for biocontrol of Tamarix are altering the relationship between this shrub and its environment. Repeated episodic feeding on Tamarix foliage by Diorhabda results in varying rates of dieback and mortality, depending on genetic variation in allocation of resources, growing conditions, and phenological synchrony between herbivore and host plant. In this article, we review the complex interaction between climatic change and species introductions and their combined impacts on P. fremontii and their associated communities. We anticipate that (1) certain genotypes of P. fremontii will respond more favorably to the presence of Tamarix and to climatic change due to varying selection pressures to cope with competition and stress; (2) the ongoing evolution of Diorhabda's life cycle timing will continue to facilitate its expansion in North America, and will over time enhance herbivore impact to Tamarix; (3) defoliation by Diorhabda will reduce the negative impact of Tamarix on P. fremontii associations with mycorrhizal fungi; and (4) spatial variability in climate and climatic change will modify the capacity for Tamarix to survive episodic defoliation by Diorhabda, thereby altering the relationship betweenTamarix and P. fremontii, and its associated mycorrhizal fungal communities. Given the complex biotic/abiotic interactions outlined in this review, conservation biologists and riparian ecosystem managers should strive to identify and conserve the phenotypic traits that underpin tolerance and resistance to stressors such as climate change and species invasion. Such efforts will greatly enhance conservation restoration efficacy for protecting P. fremontiiforests and their associated communities. Geophysiology of Wood Frogs: Landscape Patterns of Prevalence of Disease and Circulating Hormone Concentrations across the Eastern Range One of the major challenges for conservation physiologists is to determine how current or future environmental conditions relate to the health of animals at the population level. In this study, we measured prevalence of disease, mean condition of the body, and mean resting levels of corticosterone and testosterone in a total of 28 populations across the years 2011 and 2012, and correlated these measures of health to climatic suitability of habitat, using estimates from a model of the ecological niche of the wood frog's geographic range. Using the core-periphery hypothesis as a theoretical framework, we predicted a higher prevalence and intensity of infection of Batrachochytrium dendrobatidis (Bd) and ranaviruses, two major amphibian pathogens causing disease, and higher resting levels of circulating corticosterone, an indicator of allostatic load incurred from living in marginal habitats. We found thatBd infections were rare (2% of individuals tested), while infections with ranavirus were much more common: ranavirus-infected individuals were found in 92% of ponds tested over the 2 years. Contrary to our predictions, rates of infection with ranaviruses were positively correlated with quality of the habitat with the highest prevalence at the core of the range, and plasma corticosterone concentrations measured when frogs were at rest were not correlated with quality of the habitat, the prevalence of ranavirus, or the intensity of infection. Prevalence and mean viral titers of ranavirus infection were higher in 2012 than in 2011, which coincided with lower levels of circulating corticosterone and testosterone and an extremely early time of breeding due to relatively higher temperatures during the winter. In addition, the odds of having a ranavirus infection increased with decreased body condition, and if animals had an infection, viral titers were positively correlated to levels of circulating testosterone concentration. By resolving these patterns, experiments can be designed to test hypotheses about the mechanisms that produce them, such as whether transmission of the ranavirus and tolerance of the host are greater or whether virulence is lower in populations within core habitats. While there is debate about which metrics serve as the best bioindicators of population health, the findings of this study demonstrate the importance of long-term monitoring of multiple physiological parameters to better understand the dynamic relationship between the environment and the health of wildlife populations over space and time. Linking Landscape-Scale Disturbances to Stress and Condition of Fish: Implications for Restoration and Conservation Humans have dramatically altered landscapes as a result of urban and agricultural development, which has led to decreases in the quality and quantity of habitats for animals. This is particularly the case for freshwater fish that reside in fluvial systems, given that changes to adjacent lands have direct impacts on the structure and function of watersheds. Because choices of habitat have physiological consequences for organisms, animals that occupy sub-optimal habitats may experience increased expenditure of energy or homeostatic overload that can cause negative outcomes for individuals and populations. With the imperiled and threatened status of many freshwater fish, there is a critical need to define relationships between land use, quality of the habitat, and physiological performance for resident fish as an aid to restoration and management. Here, we synthesize existing literature to relate variation in land use at the scale of watersheds to the physiological status of resident fish. This examination revealed that landscape-level disturbances can influence a host of physiological properties of resident fishes, ranging from cellular and genomic levels to the hormonal and whole-animal levels. More importantly, these physiological responses have been integrated into traditional field-based monitoring protocols to provide a mechanistic understanding of how organisms interact with their environment, and to enhance restoration. We also generated a conceptual model that provides a basis for relating landscape-level changes to physiological responses in fish. We conclude that physiological sampling of resident fish has the potential to assess the effects of landscape-scale disturbances on freshwater fish and to enhance restoration and conservation. Conservation Physiology and Conservation Pathogens: White-Nose Syndrome and Integrative Biology for Host-Pathogen Systems Conservation physiology aims to apply an understanding of physiological mechanisms to management of imperiled species, populations, or ecosystems. One challenge for physiologists hoping to apply their expertise to conservation is connecting the mechanisms we study, often in the laboratory, with the vital rates of populations in the wild. There is growing appreciation that infectious pathogens can threaten populations and species, and represent an important issue for conservation. Conservation physiology has much to offer in terms of addressing the threat posed to some host species by infectious pathogens. At the same time, the well-developed theoretical framework of disease ecology could provide a model to help advance the application of physiology to a range of other conservation issues. Here, I use white-nose syndrome (WNS) in hibernating North American bats as an example of a conservation problem for which integrative physiological research has been a critical part of research and management. The response to WNS highlights the importance of a well-developed theoretical framework for the application of conservation physiology to a particular threat. I review what is known about physiological mechanisms associated with mortality from WNS and emphasize the value of combining a strong theoretical background with integrative physiological studies in order to connect physiological mechanisms with population processes and thereby maximize the potential benefits of conservation physiology. Introduction to the Symposium--Unsteady Aquatic Locomotion with Respect to Eco-Design and Mechanics The importance of unsteadiness in the aquatic environment has come to the forefront in understanding locomotor mechanics in nature. The impact of unsteadiness, starting with control of posture and trajectories during aquatic locomotion, is ultimately expressed in energy costs, morphology, and fitness. Unsteadiness from both internal and external perturbations for aquatic animals is important at scales ranging from micro to macro to global. Stability Design and Response to Waves by Batoids Unsteady flows in the marine environment can affect the stability and locomotor costs of animals. For fish swimming at shallow depths, waves represent a form of unsteady flow. Waves consist of cyclic oscillations, during which the water moves in circular or elliptical orbits. Large gravity waves have the potential to displace fish both cyclically and in the direction of wave celerity for animals floating in the water column or holding station on the bottom. Displacement of a fish can exceed its stability control capability when the size of the wave orbit is equivalent to the size of the fish. Previous research into compensatory behaviors of fishes to waves has focused on pelagic osteichthyan fishes with laterally compressed bodies. However, dorsoventrally compressed batoid rays must also contend with waves. Examination of rays subjected to waves showed differing strategies for stability between pelagic and demersal species. Pelagic cownose rays (Rhinoptera bonasus) would glide through or be transported by waves, maintaining a positive dihedral of the wing-like pectoral fins. Demersal Atlantic stingrays (Dasyatis sabina) and freshwater rays (Potamotrygon motoro) maintained contact with the bottom and performed compensatory fin motions and body postures. The ability to limit displacement due to wave action by the demersal rays was also a function of the bottom texture. The ability of rays to maintain stability due to wave action suggests mechanisms to compensate for the velocity flux of the water impinging on the large projected area of the enlarged pectoral fins of rays. Living in a Turbulent World--A New Conceptual Framework for the Interactions of Fish and Eddies The natural habitats of fishes are characterized by movements of water driven by a multitude of physical processes of either natural or human origin. The resultant unsteadiness is exacerbated when flow interacts with surfaces, such as the bottom and banks, and protruding objects, such as corals, boulders, and woody debris. There is growing interest in the impacts on performance and behavior of fishes swimming in "turbulent flows". The ability of fishes to stabilize their postures and their swimming trajectories is thought to be important in determining species' distributions and densities, and hence the resultant assemblages in various habitats. A theoretical framework is proposed to quantify the interactions of fish and flows. Dimensionless parameters are derived based on a physical description of the flow structures and different regimes are predicted describing fishes' responses to a wide range of physical perturbations. We found the ratio of eddy size to fish size, the "momentum ratio" (ratio between momentum of the eddy and the momentum of the fish), as well as the time of interaction between eddy and fish to be especially important in determining thresholds for the fish's posture and trajectory. Read More » Integrative and Comparative Biology - Advance Access Unbiased View of Synaptic and Neuronal Gene Complement in Ctenophores: Are There Pan-neuronal and Pan-synaptic Genes across Metazoa? Hypotheses of origins and evolution of neurons and synapses are controversial, mostly due to limited comparative data. Here, we investigated the genome-wide distribution of the bilaterian "synaptic" and "neuronal" protein-coding genes in non-bilaterian basal metazoans (Ctenophora, Porifera, Placozoa, and Cnidaria). First, there are no recognized genes uniquely expressed in neurons across all metazoan lineages. None of the so-called pan-neuronal genes such as embryonic lethal abnormal vision (ELAV), Musashi, or Neuroglobin are expressed exclusively in neurons of the ctenophore Pleurobrachia. Second, our comparative analysis of about 200 genes encoding canonical presynaptic and postsynaptic proteins in bilaterians suggests that there are no true "pan-synaptic" genes or genes uniquely and specifically attributed to all classes of synapses. The majority of these genes encode receptive and secretory complexes in a broad spectrum of eukaryotes. Trichoplax (Placozoa) an organism without neurons and synapses has more orthologs of bilaterian synapse-related/neuron-related genes than do ctenophores—the group with well-developed neuronal and synaptic organization. Third, the majority of genes encoding ion channels and ionotropic receptors are broadly expressed in unicellular eukaryotes and non-neuronal tissues in metazoans. Therefore, they cannot be viewed as neuronal markers. Nevertheless, the co-expression of multiple types of ion channels and receptors does correlate with the presence of neural and synaptic organization. As an illustrative example, the ctenophore genomes encode a greater diversity of ion channels and ionotropic receptors compared with the genomes of the placozoan Trichoplax and the demosponge Amphimedon. Surprisingly, both placozoans and sponges have a similar number of orthologs of "synaptic" proteins as we identified in the genomes of two ctenophores. Ctenophores have a distinct synaptic organization compared with other animals. Our analysis of transcriptomes from 10 different ctenophores did not detect recognized orthologs of synthetic enzymes encoding several classical, low-molecular-weight (neuro)transmitters; glutamate signaling machinery is one of the few exceptions. Novel peptidergic signaling molecules were predicted for ctenophores, together with the diversity of putative receptors including SCNN1/amiloride-sensitive sodium channel-like channels, many of which could be examples of a lineage-specific expansion within this group. In summary, our analysis supports the hypothesis of independent evolution of neurons and, as corollary, a parallel evolution of synapses. We suggest that the formation of synaptic machinery might occur more than once over 600 million years of animal evolution. Animal Social Networks Jens Krause, Richard James, Daniel Franks, and Darren Croft, editors. Retraction: Twenty-Five Years on: Introduction to the Symposium on Integrative Biology of Crocodilia Balancing Biomechanical Constraints: Optimal Escape Speeds When There Is a Trade-off between Speed and Maneuverability The ability for prey to escape a pursuing predator is dependent both on the prey's speed away from the threat and on their ability to rapidly change directions, or maneuverability. Given that the biomechanical trade-off between speed and maneuverability limits the simultaneous maximization of both performance traits, animals should not select their fastest possible speeds when running away from a pursuing predator but rather a speed that maximizes the probability of successful escape. We explored how variation in the relationship between speed and maneuverability—or the shape of the trade-off—affects the optimal choice of speed for escaping predators. We used tablet-based games that simulated interactions between predators and prey (human subjects acting as predators attempting to capture "prey" moving across a screen). By defining a specific relationship between speed and maneuverability, we could test the survival of each of the possible behavioral choices available to this phenotype, i.e., the best combination of speed and maneuverability for prey fitness, based on their ability to escape. We found that the shape of the trade-off function affected the prey's optimal speed for success in escaping, the prey's maximum performance in escaping, and the breadth of speeds over which the prey's performance was high. The optimal speed for escape varied only when the trade-off between speed and maneuverability was non-linear. Phenotypes possessing trade-off functions for which maneuverability was only compromised at high speeds exhibited lower optimal speeds. Phenotypes that exhibited greater increases in maneuverability for any decrease in speed were more likely to have broader ranges of performance, meaning that individuals could attain their maximum performance across a broader range of speeds. We also found that there was a differential response of the subject's learning to these different components of locomotion. With increased experience through repeated trials, subjects were able to successfully catch faster and faster dots. However, no improvement was observed in the subject's ability to capture more maneuverable prey. Our work highlights the costs of high-speed movement on other traits, including maneuverability, which make the use of an animal's fastest speeds unlikely, even when attempting to escape predators. By investigating the shape of the trade-off functions between speed and maneuverability and the way the environment and morphology mediates this trade-off, we can begin to understand why animals choose to move at the speeds they do when they are running away from predators or attempting to capture prey. A Mathematical Model and MATLAB Code for Muscle-Fluid-Structure Simulations This article provides models and code for numerically simulating muscle–fluid–structure interactions (FSIs). This work was presented as part of the symposium on Leading Students and Faculty to Quantitative Biology through Active Learning at the society-wide meeting of the Society for Integrative and Comparative Biology in 2015. Muscle mechanics and simple mathematical models to describe the forces generated by muscular contractions are introduced in most biomechanics and physiology courses. Often, however, the models are derived for simplifying cases such as isometric or isotonic contractions. In this article, we present a simple model of the force generated through active contraction of muscles. The muscles' forces are then used to drive the motion of flexible structures immersed in a viscous fluid. An example of an elastic band immersed in a fluid is first presented to illustrate a fully-coupled FSI in the absence of any external driving forces. In the second example, we present a valveless tube with model muscles that drive the contraction of the tube. We provide a brief overview of the numerical method used to generate these results. We also include as Supplementary Material a MATLAB code to generate these results. The code was written for flexibility so as to be easily modified to many other biological applications for educational purposes. The Dynamic Evolutionary History of Pancrustacean Eyes and Opsins Pancrustacea (Hexapoda plus Crustacea) display an enormous diversity of eye designs, including multiple types of compound eyes and single-chambered eyes, often with color vision and/or polarization vision. Although the eyes of some pancrustaceans are well-studied, there is still much to learn about the evolutionary paths to this amazing visual diversity. Here, we examine the evolutionary history of eyes and opsins across the principle groups of Pancrustacea. First, we review the distribution of lateral and median eyes, which are found in all major pancrustacean clades (Oligostraca, Multicrustacea, and Allotriocarida). At the same time, each of those three clades has taxa that lack lateral and/or median eyes. We then compile data on the expression of visual r-opsins (rhabdomeric opsins) in lateral and median eyes across Pancrustacea and find no evidence for ancient opsin clades expressed in only one type of eye. Instead, opsin clades with eye-specific expression are products of recent gene duplications, indicating a dynamic past, during which opsins often changed expression from one type of eye to another. We also investigate the evolutionary history of peropsins and r-opsins, which are both known to be expressed in eyes of arthropods. By searching published transcriptomes, we discover for the first time crustacean peropsins and suggest that previously reported odonate opsins may also be peropsins. Finally, from analyzing a reconciled, phylogenetic tree of arthropod r-opsins, we infer that the ancestral pancrustacean had four visual opsin genes, which we call LW2, MW1, MW2, and SW. These are the progenitors of opsin clades that later were variously duplicated or lost during pancrustacean evolution. Together, our results reveal a particularly dynamic history, with losses of eyes, duplication and loss of opsin genes, and changes in opsin expression between types of eyes. Morphological, Molecular, and Hormonal Basis of Limb Regeneration across Pancrustacea Regeneration is a developmental process that allows an organism to re-grow a lost body part. Historically, the most studied aspect of limb regeneration across Pancrustacea is its morphological basis and its dependence on successful molting. Although there are distinct morphological differences in regeneration processes between insects and crustaceans, in both groups the phenomenon is initiated via formation of a blastema, followed by proliferation, dedifferentiation, and redifferentiation of blastemal cells to generate a functional limb. In recent years, with the availability of sequence data and tools to manipulate gene expression, the emphasis of this field has shifted toward the genetic basis of limb regeneration. Among insects this focus is on genes that are known to be required during the development of legs in embryos. RNA interference-mediated functional studies conducted during regeneration of imaginal discs of Drosophila melanogaster, and nymphal legs of Gryllus bimaculatus reveal that several conserved pathways and transcription factors (Wingless, Decapentaplegic, Hedgehog, Dachshund) are required for successful regeneration. In contrast to studies on the regeneration of insects' limbs, work on crustaceans has focused on the hormonal basis of the re-growth of limbs. Regeneration in decapods, like Uca pugilator and Gecarcinus lateralis, occurs in discrete phases of growth in tandem with the stages of the molt cycle. Recent studies have shown that ecdysteroid hormone signaling is necessary for blastemal proliferation. Although the current research emphases of limb regeneration in insect and crustacean are fairly distinct, the results generated by functional studies of a wide array of regeneration genes will be beneficial for generating testable regeneration models. Introduction to the Symposium "Leading Students and Faculty to Quantitative Biology through Active Learning" The broad aim of this symposium and set of associated papers is to motivate the use of inquiry-based, active-learning teaching techniques in undergraduate quantitative biology courses. Practical information, resources, and ready-to-use classroom exercises relevant to physicists, mathematicians, biologists, and engineers are presented. These resources can be used to address the lack of preparation of college students in STEM fields entering the workforce by providing experience working on interdisciplinary and multidisciplinary problems in mathematical biology in a group setting. Such approaches can also indirectly help attract and retain under-represented students who benefit the most from "non-traditional" learning styles and strategies, including inquiry-based, collaborative, and active learning. Using Active Learning to Teach Concepts and Methods in Quantitative Biology This article provides a summary of the ideas discussed at the 2015 Annual Meeting of the Society for Integrative and Comparative Biology society-wide symposium on Leading Students and Faculty to Quantitative Biology through Active Learning. It also includes a brief review of the recent advancements in incorporating active learning approaches into quantitative biology classrooms. We begin with an overview of recent literature that shows that active learning can improve students' outcomes in Science, Technology, Engineering and Math Education disciplines. We then discuss how this approach can be particularly useful when teaching topics in quantitative biology. Next, we describe some of the recent initiatives to develop hands-on activities in quantitative biology at both the graduate and the undergraduate levels. Throughout the article we provide resources for educators who wish to integrate active learning and technology into their classrooms. How Fast Should an Animal Run When Escaping? An Optimality Model Based on the Trade-Off Between Speed and Accuracy How fast should animals move when trying to survive? Although many studies have examined how fast animals can move, the fastest speed is not always best. For example, an individual escaping from a predator must run fast enough to escape, but not so fast that it slips and falls. To explore this idea, we developed a simple mathematical model that predicts the optimal speed for an individual running from a predator along a straight beam. A beam was used as a proxy for straight-line running with severe consequences for missteps. We assumed that success, defined as reaching the end of the beam, had two broad requirements: (1) running fast enough to escape a predator, and (2) minimizing the probability of making a mistake that would compromise speed. Our model can be tailored to different systems by revising the predator's maximal speed, the prey's stride length and motor coordination, and the dimensions of the beam. Our model predicts that animals should run slower when the beam is narrower or when coordination is worse. Read More » JBIC Journal of Biological Inorganic Chemistry Erratum to: Biological consequences of zinc deficiency in the pathomechanisms of selected diseases What factors influence the reactivity of C–H hydroxylation and C=C epoxidation by [Fe IV (L ax )(1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane)(O)] n+ Abstract Density functional theory is used to investigate geometric structures and mechanisms for hydroxylation and epoxidation from propene for four non-heme iron complexes, [FeIV(Lax)(TMC)(O)]n+, which are the inverted isomers of [FeIV(O)(TMC)(Lax)]n+ (Lax = acetonitrile (AN), monoanionic trifluoroacetate (TF), azide (N3), thiolate (SR)). The Fe(IV)O unit is found to be sterically less hindered in [FeIV(Lax)(TMC)(O)]n+ than that in [FeIV(O)(TMC)(Lax)]n+. Becke, three-parameter, Lee–Yang–Parr (B3LYP) calculations show that hydroxylation and epoxidation proceed via a two-state-reactivity on competing triplet and quintet spin surfaces; and the reactions have been invariably mediated by the S = 2 state. The reaction pathways computed reveal that 2-AN is the most reactive in the four [FeIV(Lax)(TMC)(O)]n+ complexes; along the reaction pathway, the axial ligand moves away from the iron center, and thus, the energy of the LUMO decreases. The anionic axial ligand, which is more electron releasing than neutral AN, shows a strong overlap of iron orbitals. Thus, the anionic ligand does not move away from the iron center. The H-abstraction is affected by the tunneling contribution, the more electron donation power of the axial ligand, the more effect of the tunneling contribution. Adding the tunneling correction, the relative reactivity of the hydroxylation follows the trend: 2-AN > 2-SR ≈ 2-N3 > 2-TF. However, for the epoxidation, the reactivity is in the following order of 2-AN > 2-TF > 2-N3 > 2-SR. Except for 2-AN, 2-X (Lax = TF, N3, SR) complexes chemoselectively hydroxylate even in the presence of a C=C double bond. Inhibition of cyclin-dependent kinase CDK1 by oxindolimine ligands and corresponding copper and zinc complexes Abstract Oxindolimine-copper(II) and zinc(II) complexes that previously have shown to induce apoptosis, with DNA and mitochondria as main targets, exhibit here significant inhibition of kinase CDK1/cyclin B protein. Copper species are more active than the corresponding zinc, and the free ligand shows to be less active, indicating a major influence of coordination in the process, and a further modulation by the coordinated ligand. Molecular docking and classical molecular dynamics provide a better understanding of the effectiveness and kinase inhibition mechanism by these compounds, showing that the metal complex provides a stronger interaction than the free ligand with the ATP-binding site. The metal ion introduces charge in the oxindole species, giving it a more rigid conformation that then becomes more effective in its interactions with the protein active site. Analogous experiments resulted in no significant effect regarding phosphatase inhibition. These results can explain the cytotoxicity of these metal complexes towards different tumor cells, in addition to its capability of binding to DNA, and decreasing membrane potential of mitochondria. Graphical Abstract Evaluation of fluorophore-tethered platinum complexes to monitor the fate of cisplatin analogs Abstract The platinum drugs cisplatin, carboplatin, and oxaliplatin are highly utilized in the clinic and as a consequence have been extensively studied in the laboratory setting, sometimes by generating fluorophore-tagged analogs. Here, we synthesized two Pt(II) complexes containing ethane-1,2-diamine ligands linked to a BODIPY fluorophore, and compared their biological activity with previously reported Pt(II) complexes conjugated to carboxyfluorescein and carboxyfluorescein diacetate. The cytotoxicity and DNA damage capacity of Pt–fluorophore complexes was compared to cisplatin, and the Pt–BODIPY complexes were found to be more cytotoxic with reduced cytotoxicity in cisplatin-resistant cells. Microscopy revealed a predominately cytosolic localization, with nuclear distribution at higher concentrations. Spheroids grown from parent and resistant cells revealed penetration of Pt–BODIPY into spheroids, and retention of the cisplatin-resistant spheroid phenotype. While most activity profiles were retained for the Pt–BODIPY complexes, accumulation in resistant cells was only slightly affected, suggesting that some aspects of Pt–fluorophore cellular pharmacology deviate from cisplatin. Density functional theory calculations on the active site of biotin synthase: mechanism of S transfer from the Fe 2 S 2 cluster and the role of 1st and 2nd sphere residues Abstract Density functional theory (DFT) calculations are performed on the active site of biotin synthase (BS) to investigate the sulfur transfer from the Fe2S2 cluster to dethiobiotin (DTB). The active site is modeled to include both the 1st and 2nd sphere residues. Molecular orbital theory considerations and calculation on smaller models indicate that only an S atom (not S2−) transfer from an oxidized Fe2S2 cluster leads to the formation of biotin from the DTB using two adenosyl radicals generated from S-adenosyl-l-methionine. The calculations on larger protein active site model indicate that a 9-monothiobiotin bound reduced cluster should be an intermediate during the S atom insertion from the Fe2S2 cluster consistent with experimental data. The Arg260 bound to Fe1, being a weaker donor than cysteine bound to Fe2, determines the geometry and the electronic structure of this intermediate. The formation of this intermediate containing the C9–S bond is estimated to have a ΔG≠ of 17.1 kcal/mol while its decay by the formation of the 2nd C6–S bond is calculated to have a ΔG≠ of 29.8 kcal/mol, i.e. the 2nd C–S bond formation is calculated to be the rate determining step in the cycle and it leads to the decay of the Fe2S2 cluster. Significant configuration interaction (CI), present in these transition states, helps lower the barrier of these reactions by ~30–25 kcal/mol relative to a hypothetical outer-sphere reaction. The conserved Phe285 residue near the Fe2S2 active site determines the stereo selectivity at the C6 center of this radical coupling reaction. Graphical Abstract Reaction mechanism of BS investigated using DFT calculations. Strong CI and the Phe285 residue control the kinetic rate and stereochemistry of the product.  Investigating the effect of gallium curcumin and gallium diacetylcurcumin complexes on the structure, function and oxidative stability of the peroxidase enzyme and their anticancer and antibacterial activities Abstract Curcumin has a wide spectrum of biological and pharmacological activities including anti-inflammatory, antioxidant, antiproliferative, antimicrobial and anticancer activities. Complexation of curcumin with metals has gained attention in recent years for improvement of its stability. In this study, the effect of gallium curcumin and gallium diacetylcurcumin on the structure, function and oxidative stability of horseradish peroxidase (HRP) enzyme were evaluated by spectroscopic techniques. In addition to the enzymatic investigation, the cytotoxic effect of the complexes was assessed on bladder, MCF-7 breast cancer and LNCaP prostate carcinoma cell lines by MTT assay. Furthermore, antibacterial activity of the complexes against S. aureus and E. coli was explored by dilution test method. The results showed that the complexes improve activity of HRP and also increase its tolerance against the oxidative condition. After addition of the complexes, affinity of HRP for hydrogen peroxide substrate decreases, while the affinity increases for phenol substrate. Circular dichroism, intrinsic and synchronous fluorescence spectra showed that the enzyme structure around the catalytic heme group becomes less compact and also the distance between the heme group and tryptophan residues increases due to binding of the complexes to HRP. On the whole, it can be concluded that the change in the enzyme structure upon binding to the gallium curcumin and gallium diacetylcurcumin complexes results in an increase in the antioxidant efficiency and activity of the peroxidise enzyme. The result of anticancer and antibacterial activities suggested that the complexes exhibit the potential for cancer treatment, but they have no significant antibacterial activity. Graphical Abstract Bismuth(III) α-hydroxy carboxylates: highly selective toxicity of glycolates towards Leishmania major Abstract Eight bismuth(III) complexes derived from the simple α-hydroxycarboxylic acids; gluconic (H6-glu), tartaric (H4-tar), mandelic (H2-man), malic (H3-mal) and glycolic (H2-gly) have been synthesised and characterised. The complexes are formed through direct treatment of the organic acids with Bi(NO3)3·5H2O ([Bi(H2-tar)(H3-tar)] 2, [Bi(mal)(NO3)(H2O)2] 6, [Bi(gly)(NO3)(H2O)] 8) or Bi(O t Bu)3 ([Bi(H-tar)(H2O)2] 1, [Bi(man)(H-man)(H2O)] 4, [Bi2(H-mal)3] 5, [Bi(gly)(H-gly)] 7), or through metathesis of the sodium salts with Bi(NO3)3·5H2O ([Bi(H3-glu)] 3). Reactions with both glucuronic and mucic acid proved to be unsuccessful. Small crystals of [Bi(gly)4(NO3)4(H2O)4]·5H2O 8were obtained from aqueous solution and analysed by synchrotron X-ray diffraction. The data were relatively poor but composition and connectivity were established, confirming and supporting other analyses. Those complexes which displayed sufficient solubility; 2, 4, 7 and 8, were tested for their anti-Leishmanial activity against parasite promastigotes and amastigotes, and for toxicity against human fibroblast cells. All four complexes and their parent acids showed no toxicity towards either the promastigotes or fibroblast cells. However, the two glycolate complexes showed selective toxicity towards amastigotes with complex 8 providing for a low % viability of 1.8 ± 0.9 at 50.0 µM. Graphical Abstract Novel bismuth(III) complexes derived from α-hydroxycarboxylic acids have been synthesised, characterised and assessed for their anti-leishmanial activity. The glycolate complexes are selectively toxic against parasite amastigotes, with all complexes being non-toxic towards promastigotes and human fibroblast cells.  Interaction between lanthanide ions and Saccharomyces cerevisiae cells Abstract Lanthanides are a group of non-essential elements with important imaging and therapeutic applications. Although trivalent lanthanide ions (Ln3+) are used as potent blockers of Ca2+ channels, the systematic studies correlating Ln3+ accumulation and toxicity to Ca2+ channel blocking activity are scarce. In this study, we made use of the eukaryotic model Saccharomyces cerevisiae to investigate the correlation between Ln3+ accumulation, their toxicity and their capacity to block the exogenous stress-induced Ca2+ influx into the cytosol. It was found that the Ln3+ blocked the Ca2+ entry into the yeast cells only when present at concentration high enough to allow rapid binding to cell surface. At lower concentrations, Ln3+ were taken up by the cell, but Ca2+ blockage was no longer achieved. At 1 mM concentration, all ions from the Ln3+ series could block Ca2+ entry into cytosol with the exception of La3+, and to a lesser extent, Pr3+ and Nd3+. The plasma membrane Ca2+-channel Cch1/Mid1 contributed to La3+ and Gd3+ entry into the cells, with a significant preference for La3+. The results open the possibility to obtain cells loaded with controlled amounts and ratios of Ln3+. Effects of the ruthenium-based drug NAMI-A on the roles played by TGF-β1 in the metastatic process Abstract The ruthenium-based drug NAMI-A, characterised by its selectivity against solid tumour metastases, promotes TGF-β1-dependent fibrosis and the reduction of the release of MMPs in the primary tumour. The aim of the study was to examine the interaction of NAMI-A with TGF-β1 in the process of metastasis formation. NAMI-A (1) affects the secretion of TGF-β1 in metastatic MDA-MB-231 cells rather than in non-tumorigenic HBL-100 cells, (2) prevails over TGF-β1 with regard to the invasive capacity of the treated cells, and (3) contrasts integrin-dependent migration stimulated by TGF-β1. It, thus, appears that the effects of NAMI-A on cell invasion and migration are best summarised as an interference with TGF-β1 and a reduction of its activity in these events. At a molecular level, the similar activity of NAMI-A and TGF-β1 on RhoA GTPase supports its interaction with cell surface integrins while TGF-β1 can activate it by interaction with its TGFβR receptor. The inhibition of TGF-β1-induced migration of MDA-MB-231 cells by NAMI-A cannot simply be attributed to a modulation of the Smad2 and p38MAPK pathways. In conclusion, the effects of NAMI-A on the biological role of TGF-β1 in cancer metastasis are insufficient to attribute the responsibility for the anti-metastatic activity of the ruthenium-based drug to this target alone. Graphical Abstract Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease Abstract The influenza virus PA endonuclease is an attractive target for the development of novel anti-influenza virus therapeutics, which are urgently needed because of the emergence of drug-resistant viral strains. Reported PA inhibitors are assumed to chelate the divalent metal ion(s) (Mg2+ or Mn2+) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In the present work, a series of salicylaldehyde thiosemicarbazone derivatives have been synthesized and evaluated for their ability to inhibit the PA-Nter catalytic activity. Compounds 1–6 have been evaluated against influenza virus, both in enzymatic assays with influenza virus PA-Nter and in virus yield assays in MDCK cells. In order to establish a structure–activity relationship, the hydrazone analogue of the most active thiosemicarbazone has also been evaluated. Since chelation may represent a mode of action of such class of molecules, we studied the interaction of two of them, one with and one without biological activity versus the PA enzyme, towards Mg2+, the ion that is probably involved in the endonuclease activity of the heterotrimeric influenza polymerase complex. The crystal structure of the magnesium complex of the o-vanillin thiosemicarbazone ligand 1 is also described. Moreover, docking studies of PA endonuclease with compounds 1 and 2 were performed, to further analyse the possible mechanism of action of this class of inhibitors. Read More » Österreichische Wasser- und Abfallwirtschaft Produkte Ökologischer Vergleich von Sammelsystemen für Leicht- und Metallverpackungen im Land Salzburg Zusammenfassung Sammelsysteme für Verpackungen sind derzeit aufgrund sich verändernder gesetzlicher Rahmenbedingungen von besonderer Bedeutung für die abfallwirtschaftliche Planung. In der vorliegenden Arbeit werden die Umweltauswirkungen ausgewählter Varianten zur Sammlung und Verwertung von Leicht- und Metallverpackungen am Beispiel eines Bundeslandes (Salzburg) untersucht. Dabei wurden Varianten mit einer umfassenden Sammlung aller Leicht- und Metallverpackungen ab Haus und die Hohlkörpersammlung sowie der Ist-Zustand verglichen. Um die ökologischen Auswirkungen dieser Varianten zu untersuchen, wurden zunächst Materialflüsse, insbesondere die Massenverschiebungen von Leicht- und Metallverpackungen, zwischen getrennter Sammlung und Restmüll modelliert. Im Anschluss wurde eine Ökobilanz nach ISO 14040 erstellt. Dabei wurden alle wesentlichen Prozesse der Sammlung, Transport, Sortierung, Verwertung und Beseitigung einbezogen. Bei der Wirkungsabschätzung wurden für derartige Studien typische Wirkungskategorien wie Klimawandel, Ressourcenverbrauch, Versauerung, Humantoxizität, Sommersmog und das Ozonzerstörungspotenzial gewählt. Die Ergebnisse zeigen, dass die umfassende Sammlung und stoffliche Verwertung der Verpackungsmaterialien im Vergleich zur Hohlkörpersammlung deutlich größere Umweltentlastung mit sich bringt als die Zusatzbelastungen aus der erforderlichen Sammlung. Metallverpackungen, insbesondere Nichteisenmetallverpackungen haben – trotz vergleichsweise geringer Menge – einen erheblichen Einfluss auf das Gesamtergebnis. Ökobilanz in der Abfallwirtschaft öwav-Kalender Panorama Abfallsammlung und -transporte: eine gesamtheitliche Umweltbetrachtung für Österreich Zusammenfassung Im Zuge des Projektes „Benchmarking der österreichischen Abfallwirtschaft" wurde eine Begutachtung der österreichischen Transportwege für Abfälle unternommen. Ziel war es eine Abschätzung der Umweltwirkungen des Abfalltransportes für Österreich durchzuführen und darzustellen, welche durchschnittlichen Strecken für Sammlung und Behandlung zurückgelegt werden. Hierzu wurde einerseits eine ExpertInnenbefragung über Distanzen und Fahrzeugeigenschaften durchgeführt sowie andererseits eine Recherche mittels Online-Routenberechnungstool der Transportdistanzen von Großraumregionen zu nahe gelegenen Behandlungsanlagen unternommen. Für eine Abfallmenge von 17 Mio. t ergibt sich hiermit eine Gesamtkilometeranzahl von 932 Mio. tkm mit einem Treibstoffverbrauch an Diesel von 203 Mio. l. Für die österreichische Abfallwirtschaft konnte mittels einer Lebenszyklusanalyse ein Global Warming Potential von 148.600 t CO2-Äq. Emissionen errechnet werden. Verbandsnachrichten Aktuell Umweltauswirkungen der pyrolytischen Verkohlung Zusammenfassung Die Herstellung von Pflanzenkohle aus Bioabfällen als potentiell neue Abfallbehandlungsmöglichkeit sowie ihre Bedeutung bei der Bodensubstratherstellung (bzw. als Bodenverbesserungsmittel) und damit als Möglichkeit der Kohlenstoffspeicherung in Böden hat in Österreich erst seit kurzer Zeit Beachtung gefunden. Pflanzenkohlen werden industriell z. B. mittels Pyrolyseverfahren hergestellt, wobei erste industrielle Produktionsanlagen erst in den letzten Jahren in Betrieb genommen wurden. Bei diesen vergleichsweise neuen Technologien müssen die Umweltauswirkungen größtenteils erst untersucht und das Herstellungsverfahren entsprechend evaluiert werden. In Österreich befindet sich aktuell eine Pilotanlage zur Pflanzenkohleproduktion in Betrieb. Erhebungen und Analysen während des Pilotbetriebes boten die Möglichkeit einer erstmaligen umfassenden Bewertung der umweltrelevanten Auswirkungen, welche bei der Herstellung von Pflanzenkohle aus diversen biogenen Abfallströmen entstehen können. Als Inputmaterial zum Einsatz kommen in der untersuchten Anlage vorwiegend Getreidespelzen und Papierfaserschlamm. Für die Umweltbewertung wurde eine umfassende Primärdaten-Erhebung durchgeführt. Die Bewertung der umweltrelevanten Auswirkungen erfolgte mittels Methode der Ökobilanzierung nach der europäischen Norm EN ISO 14040 ff (Umweltmanagement Ökobilanz – Grundsätze und Rahmenbedingungen, 2006). Aus den Ergebnissen der Umweltbewertung sollten einerseits Optimierungspotentiale erkannt und andererseits die Vor- und Nachteile einzelner Inputmaterialien abgeleitet werden. Die Ergebnisse zeigen, dass sich durch die Herstellung von Pflanzenkohle eine positive reduzierende Wirkung auf den Treibhauseffekt ergibt. So konnten beim untersuchten Herstellungsverfahren insgesamt 1,1 kg CO2-Äquivalente pro hergestelltem Kilogramm Trockenmasse Pflanzenkohle eingespart werden. Ökologische Bewertung unterschiedlicher Verwertungspfade von Altspeisefetten aus Haushalten in Österreich Zusammenfassung Unsachgemäße Entsorgung von Altspeisefetten in Haushalten über das Kanalsystem führt zu ökonomischen und ökologischen Schäden, beispielsweise an Abwasserreinigungsanlagen, sowie zum Verlust einer energiereichen Ressource. Ausgehend von Tirol wurde mittlerweile in vielen Teilen Österreichs und angrenzenden Ländern ein Getrenntsammelsystem für Altspeisefette aus Haushalten eingerichtet, mit dem bis zu 1 kg Altspeisefett pro Einwohner und Jahr gesammelt wird. In dieser Arbeit wird die Treibhausgasbilanz (THG-Bilanz) von drei verschiedenen Verwertungswegen (1) Veresterung zu Biodiesel, 2) Verstromung in einem Blockheizkraftwerk (BHKW), 3) Vergärung als Co-Substrat) von Altspeisefetten aus Haushalten in Österreich untersucht. Read More » Theoretical Medicine and Bioethics Dominic Wilkinson: Death or disability? The "Carmentis Machine" and decision - making for critically ill children 2015-10-01 02:00:00 AM Διαβάστε περισσότεραΑρχή Gurch Randhawa and Silke Schicktanz (eds.): Public engagement in organ donation and transplantation 2015-10-01 02:00:00 AM Διαβάστε περισσότεραΑρχή Slowed ageing, welfare, and population problems 2015-10-01 02:00:00 AM Abstract Biological studies have demonstrated that it is possible to slow the ageing process and extend lifespan in a wide variety of organisms, perhaps including humans. Making use of the findings of these studies, this article examines two problems concerning the effect of life extension on population size and welfare. The first—the problem of overpopulation—is that as a result of life extension too many people will co-exist at the same time, resulting in decreases in average welfare. The second—the problem of underpopulation—is that life extension will result in too few people existing across time, resulting in decreases in total welfare. I argue that overpopulation is highly unlikely to result from technologies that slow ageing. Moreover, I claim that the problem of underpopulation relies on claims about life extension that are false in the case of life extension by slowed ageing. The upshot of these arguments is that the population problems discussed provide scant reason to oppose life extension by slowed ageing. Διαβάστε περισσότεραΑρχή Phronesis as an ideal in professional medical ethics: some preliminary positionings and problematics 2015-10-01 02:00:00 AM Abstract Phronesis has become a buzzword in contemporary medical ethics. Yet, the use of this single term conceals a number of significant conceptual controversies based on divergent philosophical assumptions. This paper explores three of them: on phronesis as universalist or relativist, generalist or particularist, and natural/painless or painful/ambivalent. It also reveals tensions between Alasdair MacIntyre's take on phronesis, typically drawn upon in professional ethics discourses, and Aristotle's original concept. The paper offers these four binaries as a possible analytical framework for classifying and evaluating accounts of phronesis in the medical ethics literature. It argues that to make sense of phronesis as a putative ideal in professional medical ethics—for example, with the further aim of crafting interventions to cultivate phronesis in medical ethics education—the preliminary question of which conception of phronesis is most serviceable for the aim in question needs to be answered. The paper identifies considerable lack of clarity in the current discursive field on phronesis and suggests how that shortcoming can be ameliorated. Διαβάστε περισσότεραΑρχή Towards a balanced approach to identifying conflicts of interest faced by institutional review boards 2015-10-01 02:00:00 AM Abstract The welfare and protection of human subjects is critical to the integrity of clinical investigation and research. Institutional review boards (IRBs) were thus set up to be impartial reviewers of research protocols in clinical research. Their main role is to stand between the investigator and her human subjects in order to ensure that the welfare of human subjects are protected. While there is much literature on the conflicts of interest (CIs) faced by investigators and researchers in clinical investigations, an area that is less explored is CIs that may affect members of IRBs during the institutional ethics review of clinical investigations. This article examines the notion of CIs in clinical research and attempts to develop a framework for a clearer and more balanced approach to identifying CIs that may influence members of IRBs and impede their independence. It will also apply the proposed framework to demonstrate how IRBs possess, or at least may appear to possess, forms of financial CIs and non-financial CIs. The proper identification and management of these CIs is critical to preserving the integrity of clinical investigations and achieving the primary aim of human subjects protection. Διαβάστε περισσότεραΑρχή Christine Overall: Why have children? The ethical debate 2015-08-01 03:00:00 AM Διαβάστε περισσότεραΑρχή Eric J Cassell: The nature of clinical medicine: the return of the clinician 2015-08-01 03:00:00 AM Διαβάστε περισσότεραΑρχή Impure placebo is a useless concept 2015-08-01 03:00:00 AM Abstract Placebos are allegedly used widely in general practice. Surveys reporting high level usage, however, have combined two categories, 'pure' and 'impure' placebos. The wide use of placebos is explained by the high level usage of impure placebos. In contrast, the prevalence of the use of pure placebos has been low. Traditional pure placebos are clinically ineffective treatments, whereas impure placebos form an ambiguous group of diverse treatments that are not always ineffective. In this paper, we focus on the impure placebo concept and demonstrate problems related to it. We also show that the common examples of impure placebos are not meaningful from the point of view of clinical practice. We conclude that the impure placebo is a scientifically misleading concept and should not be used in scientific or medical literature. The issues behind the concept, however, deserve serious attention in future research. Διαβάστε περισσότεραΑρχή Artificial agents, good care, and modernity 2015-08-01 03:00:00 AM Abstract When is it ethically acceptable to use artificial agents in health care? This article articulates some criteria for good care and then discusses whether machines as artificial agents that take over care tasks meet these criteria. Particular attention is paid to intuitions about the meaning of 'care', 'agency', and 'taking over', but also to the care process as a labour process in a modern organizational and financial-economic context. It is argued that while there is in principle no objection to using machines in medicine and health care, the idea of them functioning and appearing as 'artificial agents' is problematic and attends us to problems in human care which were already present before visions of machine care entered the stage. It is recommended that the discussion about care machines be connected to a broader discussion about the impact of technology on human relations in the context of modernity. Διαβάστε περισσότεραΑρχή Professional ethics in extreme circumstances: responsibilities of attending physicians and healthcare providers in hunger strikes 2015-08-01 03:00:00 AM Abstract Hunger strikes potentially present a serious challenge for attending physicians. Though rare, in certain cases, a conflict can occur between the obligations of beneficence and autonomy. On the one hand, physicians have a duty to preserve life, which entails intervening in a hunger strike before the hunger striker loses his life. On the other hand, physicians' duty to respect autonomy implies that attending physicians have to respect hunger strikers' decisions to refuse nutrition. International medical guidelines state that physicians should follow the strikers' unpressured advance directives. When physicians encounter an unconscious striker, in the absence of reliable advance directives, the guidelines advise physicians to make a decision on the basis of the patient's values, previously expressed wishes, and best interests. I argue that if there are no advance directives and the striker has already lost his competence, the physician has the responsibility to resuscitate the striker. Once the striker regains his decision-making capacity, he should be asked about his decision. If he is determined to continue fasting and refuses treatment, the physician has a moral obligation to respect this decisions and follow his advance directives. Διαβάστε περισσότεραΑρχή Niklas Juth, Christian Munthe: The ethics of screening in healthcare and medicine: serving society or serving the patient? 2015-06-01 03:00:00 AM Διαβάστε περισσότεραΑρχή Keith Wailoo, Julie Livingston, Steven Epstein, Robert Aronowitz (eds): Three shots at prevention: the HPV vaccine and the politics of medicine's simple solutions 2015-06-01 03:00:00 AM Διαβάστε περισσότεραΑρχή Norbert Konrad, Birgit Völlm and, David N. Weisstub (Eds.): Ethical issues in prison psychiatry 2015-06-01 03:00:00 AM Διαβάστε περισσότεραΑρχή Epidemiology and the bio-statistical theory of disease: a challenging perspective 2015-06-01 03:00:00 AM Abstract Christopher Boorse's bio-statistical theory (BST) of health and disease argues that the central discipline on which theoretical medicine relies is physiology. His theory has been much discussed but little has been said about its focus on physiology or, conversely, about the role that other biomedical disciplines may play in establishing a theoretical concept of health. Since at least the 1950s, epidemiology has gained in strength and legitimacy as an independent medical science that contributes to our knowledge of health and disease. Indeed, it not only provides important information about disease distribution and aetiology, but the risk-factor approach it employs seems to challenge BST's binary conception of health and disease. The objective of the article is to show, firstly, how important information deriving from descriptive and analytical epidemiology forms part of our contemporary medical concepts of health and disease, and secondly, that these elements are not taken into account by BST in a satisfactory way. The article's central contention, therefore, is that if the project of defining the theoretical concept of health is to be maintained, more importance should be accorded to the contribution made by epidemiology—alongside physiology—in defining health. Διαβάστε περισσότεραΑρχή Palliative sedation, foregoing life-sustaining treatment, and aid-in-dying: what is the difference? 2015-06-01 03:00:00 AM Abstract After a review of terminology, I identify—in addition to Margaret Battin's list of five primary arguments for and against aid-in-dying—the argument from functional equivalence as another primary argument. I introduce a novel way to approach this argument based on Bernard Lonergan's generalized empirical method (GEM). Then I proceed on the basis of GEM to distinguish palliative sedation, palliative sedation to unconsciousness when prognosis is less than two weeks, and foregoing life-sustaining treatment from aid-in-dying. I conclude (1) that aid-in-dying must be justified on its own merits and not on the basis of these well-established palliative care practices; and (2) that societies must decide, in weighing the merits of aid-in-dying, whether or not to make the judgment that no life is better than life-like-this (however this is specified) part of their operative value structure. Διαβάστε περισσότεραΑρχή A fallacious jar? The peculiar relation between descriptive premises and normative conclusions in neuroethics 2015-06-01 03:00:00 AM Abstract Ethical questions have traditionally been approached through conceptual analysis. Inspired by the rapid advance of modern brain imaging techniques, however, some ethical questions appear in a new light. For example, hotly debated trolley dilemmas have recently been studied by psychologists and neuroscientists alike, arguing that their findings can support or debunk moral intuitions that underlie those dilemmas. Resulting from the wedding of philosophy and neuroscience, neuroethics has emerged as a novel interdisciplinary field that aims at drawing conclusive relationships between neuroscientific observations and normative ethics. A major goal of neuroethics is to derive normative ethical conclusions from the investigation of neural and psychological mechanisms underlying ethical theories, as well as moral judgments and intuitions. The focus of this article is to shed light on the structure and functioning of neuroethical arguments of this sort, and to reveal particular methodological challenges that lie concealed therein. We discuss the methodological problem of how one can—or, as the case may be, cannot—validly infer normative conclusions from neuroscientific observations. Moreover, we raise the issue of how preexisting normative ethical convictions threaten to invalidate the interpretation of neuroscientific data, and thus arrive at question-begging conclusions. Nonetheless, this is not to deny that current neuroethics rightly presumes that moral considerations about actual human lives demand empirically substantiated answers. Therefore, in conclusion, we offer some preliminary reflections on how the discussed methodological challenges can be met. Διαβάστε περισσότεραΑρχή Comments on Mohammed Abouelleil Rashed's "a critical perspective on second-order empathy in understanding psychopathology: phenomenology and ethics" 2015-04-01 02:00:00 AM Abstract Understanding the mental life of persons with psychosis/schizophrenia has been the crucial challenge of psychiatry since its origins, both for scientific models as well as for every therapeutic encounter between persons with and without psychosis/schizophrenia. Nonetheless, a preliminary understanding is always the first step of phenomenological as well as other qualitative research methods addressing persons with psychotic experiences in their life-world. In contrast to Rashed's assertions, in order to achieve such understanding, phenomenological psychopathologists need not necessarily adopt the transcendental-phenomenological attitude, which, however, is often required if performing phenomenological philosophy. Additionally, in the course of these (non-philosophical) scientific endeavors, differences between persons with psychosis/schizophrenia and so-called normal people seem to have a methodological function and value driving the scientist in her enterprise. Yet, these differences do not extend to ethical dimensions, and therefore, do not by any means touch ethical equality. Διαβάστε περισσότεραΑρχή I. Glenn Cohen and Holly F. Lynch (eds.): Human subjects research regulation: perspectives on the future 2015-04-01 02:00:00 AM Διαβάστε περισσότεραΑρχή Martin Gunnarson and Fredrik Svenaeus (eds): The body as gift, resource, and commodity: exchanging organs, tissues, and cells in the 21st century 2015-04-01 02:00:00 AM Διαβάστε περισσότεραΑρχή Double trouble: Should double embryo transfer be banned? 2015-04-01 02:00:00 AM Abstract What role should legislation or policy play in avoiding the complications of in-vitro fertilization? In this article, we focus on single versus double embryo transfer, and assess three arguments in favour of mandatory single embryo transfer: risks to the mother, risks to resultant children, and costs to society. We highlight significant ethical concerns about each of these. Reproductive autonomy and non-paternalism are strong enough to outweigh the health concerns for the woman. Complications due to non-identity cast doubt on the extent to which children are harmed. Twinning may offer an overall benefit rather than burden to society. Finally, including the future health costs for children (not yet born) in reproductive policy is inconsistent with other decisions. We conclude that mandatory single embryo transfer is not justified and that a number of countries should reconsider their current embryo transfer policy. Διαβάστε περισσότεραΑρχή Read More » Rare Diseases OrphaNews : the newsletter of the Rare Disease Community  Editorial  RD-ACTION: the new European Rare Disease Joint Action RD-ACTION, the new Joint Action consisting of the member states of the European Union for rare diseases, was launched on 17 September in Luxembourg, under the auspices of John Ryan, Acting Director of the Health Division and Food Security (DG Health), Jacques Remacle, Head of Health CHAFEA unit (Consumers, Health, Agriculture and Food Executive Agency) and Patrice Dosquet, representing the French Ministry of Health. Following the two previous Joint Actions - Orphanet Joint Action and EUCERD - RD-ACTION represents renewed support of the European Commission (EC) to rare diseases, through its Directorate General for Health (DG SANTE). RD-ACTION has three main objectives: - to contribute to the implementation, by member states, the recommendations of the EC Panel in relation to policies on these diseases, - support the development of Orphanet and make it sustainable, and finally - help Member States to introduce the ORPHA code in their health systems to make rare diseases visible. With a global budget of €8,344,079, this work will last three years (until June 2018), following the logic of coherence and continuity vis-à-vis the previous actions, but aims to go further in terms of concrete implementation and consolidation policies. This action is coordinated by Orphanet (INSERM), bringing together no less than 63 European and non-European participants. The responsibility of implementing the various actions will be carried out by Orphanet (Ana Rath), University of Newcastle (Kate Bushby, coordinator of theEUCERD Joint Action which just ended), the German Institute for Documentation and Medical Information DIMDI (Stefanie Weber), the University of Vienna (Till Voigtländer) and EURORDIS (Yann LeCam). The National Bank of Rare Diseases Data (BNDMR) represented by Rémy Choquet, will work towards the codification, notably the requirement of definition and bringing solutions to the Member States for the implementation of coding rare diseases. DIMDI and the Register of the Venetian region (Paola Facchin) will drive the implementation and testing of these solutions. EURORDIS will work towards dissemination actions along with Orphanet and Higher Health Institute (ISS, Italy). The dissemination actions include the 8th European Conference on Rare Diseases and Orphan Products, 26-28 May 2016, Edinburgh. The Directorate General of Health (DGS France, represented by Patrice Dosquet) will lead the work towards a financially sustainable European Orphanet database. RD-ACTION was designed in the spirit of integration and coherence between the data produced by Orphanet, which provides, among others, the necessary analysis towards policy recommendations, and political action that will then guide the production, operation and dissemination of this data. Participants will ensure effective communication between the reality of each state and the EC Panel, in order to concretely support the implementation of their recommendations. Read the European Commission press release on RD ACTION     Spotlight on...  Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future  On 15 September, over 50 participants from across Europe attended the Final Conference of the EUCERD Joint Action. This event was organised to show case the achievements of the Joint Action, which ran from March 2012 to November 2015, and to analyse the current state of the art of rare disease activity across the European Union, by exploring progress and remaining challenges in key areas such as healthcare, social care and research. The even was a good opportunity to strenghten collaborations with the stakeholders present and relevant initiatives in the field, and to provided the apt moment to hand over the activities led by the Joint Action to the next Joint Action on rare diseases, RD-Action (see Editorial). The outcomes of the EUCERD Joint Action, in particular the resources and recommendations elaborated in collaboration with the European Union Committee of Experts on Rare Diseases and EC Expert Group on Rare Diseases, were presented in the morning session. Participants heard about topics as diverse as quality of care and centres of expertise, RD European Reference Networks, social services for RD, cross-border genetic testing and the codification of rare diseases. The work lead in the context of the Joint Action in support to the EUCERD and Commission Expert Group on Rare Diseases has led to the adoption of 5 recommendations in the past three years, with two other recommendations, on genetic testing and social care under discussion currently. In terms of important resources for the community, the Joint Action also supported the elaboration of the annual report on the State of the Art of Rare Diseases Activities in Europe, a 'go-to' source of information on activities in the field of at national and European level aimed at promoting the exchange of information and monitoring the implementation of rare disease policy: this report will continue to be produced in a more dynamic format in the future RD-Action (see Editorial). The presentations of the activities of the Joint Action were followed by three sessions dedicated to priority areas in the field of rare diseases, informing participants about the latest outcomes of a number of European projects in each area and the efforts made by the EUCERD Joint Action to explore synergies and to link this work into the discussions at the level of the EC Expert Group on Rare Diseases. The first of these sessions was dedicated to Rare Disease Research, Therapeutics and Translation into the Sphere of Health, with presentations from the Rare Best-Practices project, Burqol-RD, a project aimed at exploring the impact of health policies, interventions and treatments in the field of rare diseases, the transnational research support mechanism E-Rare, and the International Rare Disease Research Consortium concerning the impact of IRDiRC policies at national level. The main issued discussed during this session was that of sustainability of the resources produced via these initiatives, and the importance in particular of research into health economics, as regards rare diseases, to inform the implementation of rare disease policies at national level. The following session explored the integration of the results of a number of initiatives concerning rare disease registries, a field where the EU has invested resources through a multitude of projects (such as EPIRARE, the EUCERD Joint Action, and the PARENT Joint Action) with a view to developing an appropriate model for a European Platform for Rare Disease Registration. This platform, recently created at the EC's Joint Research Centre in Ispra, Italy, has to date taken over the responsibilities for the management of the central support of the Eurocat congenital anomalies registry, and the European Surveillance of Cerebal Palsy registry. Stakeholders in the field of rare diseases are still waiting from the JRC confirmation of the governance structure, road map and list of services to be provided by the Platform. In particular, Member States who are in the process of creating national rare disease registration systems, or who are considering this direction, are looking for confirmation of the possible support that will be provided, and the guidelines for interoperability (such as a minimum data set) which could be expected. The final session was dedicated to national plans and strategies for rare diseases, in particular support to the implementation of national activities in this area. The EUCERD Joint Action, continuing the activities of the Europlan project (2008-2011) supported the organisation of over 20 national conferences and debrief sessions across Europe with the close collaboration of national patient alliances and organisations, to ensure the tranmission of European recommendations at national level and appropriate support to Member States in the elaboration and/or implementation of their initiatives. To date, nearly all European Member States have adopted a plan/strategy for rare diseases, with those not yet having adopted a plan in the final stages of elaboration. The next challenge will be the implementation of these plans/strategies, for which very few have a dedicated budget and for some of which need to be translated into concrete actions. The EUCERD Joint Action, through the national conferences and an analysis of these plans, has been able to extract a number of good practices that could help Member States in the implementation of their plans, which will be available shortly. The day finished by establishing the list of possible priorities in the rare disease policy field to be explored by the Expert Group on Rare Diseases with the support of the new RD-Action for rare diseases (see Editorial). The Commission and the Coordinator of the EUCERD Joint Action, Kate Bushby, thanked the partners and the many participants in the conferences and workshops organised over the past 3 years, for their hard work and wished them success in the future work of the next Joint Action. The report of the conference will soon be available online.     EU Policy News  EMA  Submit expressions of interest to represent civil society at the EMA  The Health and Food Safety Directorate-General of the European Commission has extended the deadline for its calls for expressions of interest to represent civil society in two scientific committees of the European Medicines Agency (EMA): the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Advanced Therapies (CAT). For both calls, expressions of interest should be submitted to the European Commission no later than 18 October 2015, either by email or post. Further information on the assessment criteria and the application process can be found on the Commission's website. Call for civil society members to join two EMA committees     National & International Policy Developments  Comprehensive policy for patients with rare diseases in Philippines  The House of Representatives in Philippines recently approved a comprehensive policy on services for patients with rare diseases that will provide them with timely and adequate access to healthcare, information, and products to treat their conditions. This will be done primarily through the establishment of a comprehensive and sustainable health system for identification, referral, and management of patients with rare diseases—integrated within the current public health system; and the inclusion of rare disease benefit package in PhilHealth. The bill stipulates giving regulatory and fiscal incentives to support research and development activities on rare diseases and manufacturing of affordable drugs or products. Likewise, the bill provides for the design and maintenance of a rare disease registry containing data on cases, patients, drugs and products for rare diseases. Data from the registry will be used in policy formulation. The provisions in the bill are set to address the current challenges being faced by patients afflicted with rare diseases, their families and caregivers, and their healthcare providers. This bill defines a rare disease as one that affects 1/20,000 in the Philippines. It provides a preliminary list of rare diseases and the provision of inclusion of others under the advisement of the National Institute of Health in the United States. Read the report on this topic by National Academy of Science and Technology, Philippines  Other European news  The rare disease persons card implementation in Portugal  The Portuguese Ministry of Health Shared Services and Directorate General of Health, recently announced the implementation of the Rare Disease Person's Card (RDPC). Coded using the ORPHA code system, this card is meant to identify the rare disease patient and display the relevant information of the condition as well as information especially required during an emergency situation. An article published in Procedia Computer Science describes the process of preparation, approval and the regulatory model of the card. According to the authors, due to nascent stage of the implementation of these cards, there is still room for the card to evolve and expand. Still, 828 cards have been requested through the family physician of the concerned patients, regarding 738 different rare diseases, half of which have been activated. The card is increasing awareness and empowerment of rare disease's patients, pushing the project forward and improving health care. Download the document from Direcção-Geral da Saúde Read the open access article   Sample of the adult British population want genetic testing of children for adult-onset conditions  Almost all the guidelines published till date on genetic testing on children for adult onset conditions recommend deferring such tests unless there is a clear indication that it will prevent the future outcome of the condition. Whether the general public agrees with this recommendation is addressed in an article published in European Journal of Human Genetics. Testing the attitudes of a representative sample of the adult-British public revealed that, contrary to the guidance documents, 47% believed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. Younger respondents of the survey and men were more likely to support this kind of testing as well as carrier testing. The authors also presented 4 arguments in support of deferring testing to the participants, out of which "a child's future ability to decide for her/himself if and when to be tested" was generally the least supported argument in the sample. However, the authors noted that women were significantly more likely to consider all 4 arguments as valid to defer testing for adult onset conditions. Read the Open Access article   Sample of Danish population want disclosure of incidental findings from NGS studies  Another article has studied an equally contentious issue –disclosure of incidental findings - is published in European Journal of Human Genetics. Here the authors also find that contrary to the recommendations of professional organisations, participants in next generation studies wanted disclosure of all incidental findings. The authors investigated if participants recruited from the Region of Southern Denmark want disclosure of incidental findings and which ones would they want to know more about. According to the authors most participants wanted disclosure of all incidental findings; only 3% did not want any disclosure, while 36% wanted disclosure only on actionable variants. According to the authors due to the disparity of opinion between the official recommendation and the sample studies "options for reporting IFs in research studies (could) be incorporated in the consent form." Consult the Pubmed abstract  Other International News  Discussion paper by the Australian government to support people with chronic and complex health conditions  To better support people with chronic and complex health conditions, the Australian Government has released a discussion paper by the Primary Health Care Advisory Group, to examine options for health reform and provide a report to the Australian Government in late 2015. The paper is designed to set out the case for change and introduce some possible options to improve primary health care for people with chronic and complex conditions. In order to engage all stakeholders, consultation will be held with the Advisory Group. Results of the survey that accompanied the discussion paper will be out shortly. Read more on Therapeutic Goods Administration, Australia   Contradictions of public health policies geared to rare disorders in Brazil  A paper published in Portuguese presents information of the rare disease health policy in Brazil, using the example of Ostegenesis Imperfecta. The paper details the contradictions, especially with respect to therapeutic decisions and the strengthening of the specialized network for addressing this condition which are expressed in the drafting and final text of the new law. Consult the Pubmed abstract   Sickle cell disease among children in Africa  An article published in International Journal of Africa Nursing Sciences provides an integrative review of 63 references related sickle cell disease among children in Africa, focussing on the incidence, prevalence, morbidity, and mortality; current practices and challenges related to screening, diagnosis, and treatment. From this data the authors also provide recommendations for practice, policy, and research to improve health outcomes of children with sickle cell disease in Africa. Read the Open Access article  Guidance Documents and Recommendations  22q11.2 deletion syndrome: guidelines for the management  Consult the Pubmed abstract  To read more about "22q11.2 deletion syndrome"  Genet Med. ; 17(8):599-609 ; August 2015  Cushing syndrome: guidelines on treatment  Consult the Pubmed abstract  To read more about "Cushing syndrome"  J Clin Endocrinol Metab. ; 100(8):2807-31 ; August 2015  Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment  Consult the Pubmed abstract  To read more about "Congenital hypogonadotropic hypogonadism"  Nat Rev Endocrinol. ; 11(9):547-64 ; September 2015  Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment  Consult the Pubmed abstract  To read more about "Pemphigus vulgaris" To read more about "Pemphigus foliaceus" To read more about "Bullous pemphigoid"  J Dtsch Dermatol Ges.   Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management  Consult the Pubmed abstract  To read more about "Facioscapulohumeral dystrophy"  Neurology ; 85(4):357-64 ; July 2015  Bioinformatics, Registries and Data Management  How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population  Guidelines such as Code of Federal Regulations and WMA Declaration of Helsinki recommend expressed consent from the paediatric population before inclusion of their health data in biobanks. This issue has brought forth many ethical concerns especially with regards to the child's role in these procedures which is discussed in an article published in European Journal of Human Genetics. The authors of this article provide the results of an international multiple-case study which included four biobanks addressing diverse health concerns with the collection of a variety of data from the paediatric population. They addressed "four themes linked to the child's role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate." This study recognises the motives to involve consent of the child where respect for the child as an intrinsic motive to involve children while adherence to regulation was recognised by all as important. The authors also detail how personal verbal information is utilised for informing the child even though it is not mentioned in the regulation. While the authors say that assent and consent differs between biobanks, the question of how respecting dissent - is followed by the biobanks is unclear. The authors also show that although children agree to participate in biobanks to different reasons, coercion from parents may be the overarching one. The authors believe that these "insight(s) (are) valuable when designing paediatric biobank governance." Read the Open Access article   Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders  An article published in Genetics Research discusses how next generation sequencing (NGS) based research on rare diseases has come a long way and the effect of long tail economics on rare diseases research. Long tail statistics has been commonly used to understand the rise of internet retailers, crowdfunding, crowdsourcing etc., where a large share of the data rests within its tail unlike a normal distribution. The authors believe that the trend observed in rare disease research, especially in terms of the developments in NGS, can benefit from the two themes derived from long tailed economics - increased access and reduced cost. In this context, increased access would mean that the researcher would be able to look through a sea of data produced thanks to whole genome and whole exome sequencing and find what they are looking for (gene, disease, phenotype) . They also detail the developments in bioinformatics that has led to the development of this enormous amount of data which in turn required better curative and sharing efforts. The authors refer reduced cost to the reduction of overhead costs by centralising resources where the curative and sharing efforts come in play. They also address the issue of reimbursement that comes with the rising cost of sequencing. According to the authors "as a long-tailed problem, continued discovery of rare diseases requires a funding infrastructure that can sustainably support the work needed to identify the great number of rare diseases", for which they believe a good source is crowdfunding. The authors believe that "the principles derived from long-tail economics shape our understanding of the recent development of this field and offer insight towards needed improvements." The authors of this article belong to the Rare Genomics Institute that has recently launched 10 crowdfunding campaigns to sequence exomes of rare disease patients. Read the PubMed abstract  Screening and Testing  Regulating laboratory developed tests in the United States: the current controversy  A perspective published by stakeholders in Genetic Testing and Molecular Biomarkerscomments on the current legislation mandating the United States Food and Drug Administration as the regulatory body overseeing Laboratory Developed Tests (LDTs). The authors explain that historically LDTs are subject to regulation by the Clinical Laboratory Improvement Amendments (CLIA) of Centers for Medicare and Medicaid Services (CMS). However, in 2015, the FDA announced the establishment of the FDA/CMS Task Force on LDT Quality Requirements to oversee changes to the LDT regulatory landscape. The FDA described a premarket review process that would require confirmation of the analytical and clinical validity of new LDTs before the lab is permitted to administer those tests. Following this announcement a debate has ensued in the context of the 21st Century Cures Act with valid arguments from supporters and detractors due to which the Congress has requested for feedback. However, the resulting whitepaper did not contain specific information directly addressing this issue. The authors express concern that stakeholders are still speculating about the trajectory of LDT regulation. Access the review   Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests  A related article published in the Food and Drug Law Journal addresses FDA's current mandate to regulate laboratory developed diagnostic tests. The author believes that this oversight could prove to be intrusive and has the potential to slow the progress of genomic discovery, interfere with scientific inquiry and suppress investigators' and clinicians' rights to freedom of speech and prove to be federalist in action (U.S wants states to mandate practise of medicine). According to the author this article is written with the goal to help genomics researchers understand how FDA's research regulations may apply to research that uses high-throughput DNA sequencing. Read the Open Access article   Newborn screening in Australia: current environment and future perspectives  The current state of newborn bloodspot screening in Australia and the lessons it needs to learn from international programmes to upgrade its operation is explained in Frontiers in Public Health. The authors say that NBS has been operating successfully in Australia for almost 50 years but currently it does not have any coherent national policy or decision-making process that is concurrently agreed by government. The authors describe the policy environment in the United States, United Kingdom and New Zealand which could provide useful information. In Australia the establishment of the Australian Screening Advisory Committee in 2001, now known as the Standing Committee on Screening has played an important role in providing guidance on what constitutes a good screening program through the development of the Population-Based Screening Framework in 2008. However, the authors believe that Australia is operating in an environment, which lacks a considered decision-making process for government, particularly in regards to assessing conditions for screening. The authors believe that changes to newborn screening programs should be planned instead of being reactive often in response to new technologies. The authors provide several options to overcome the funding barrier, which they describe as chief obstacle, to developing and implementing a national decision-making framework for newborn screening in Australia. They believe that a national decision-making approach, supported by state implementation of decisions, would support consistent decision making across local-level programs. Read the Open Access article   Patenting Genetic diagnostic methods  An article published in the Journal of Law and Medicine reviewed and analysed the relevant law in Australia and the United States to assist sponsors claiming patents for "diagnostic methods associated with genome-wide association studies (GWAS), adopting methodologies using next generation sequencing (NGS) and single nucleotide polymorphism (SNP)." The authors provide reasonable solutions to commonly experienced questions while patenting these technologies: experimental reproducibility and the credibility and veracity of the technology. Read the Open Access article     Ethical, Legal & Social Issues  Living with Marfan syndrome: the patients view  A study published in Clinical Genetics explores the psychosocial aspects of Marfan syndrome (MFS) by collecting available literature followed by synthesising and critically appraising them. The authors studied 15 articles that satisfied the eligibility criteria and found that MFS significantly impacts various areas of the patient's life such as education, work, family and transition to adulthood. They also experienced decreased Health Related Quality of life, depression and anxiety. Interestingly, the authors also noted that the studies show there was a considerable disconnect between the discomfort that the patient experiences and how professionals view it. According to the authors the studies demonstrate that "the subjective perception of discomfort did not necessarily match the medical severity of a disease." Consult the Pubmed abstract     New Syndromes  Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4  Using exome analysis, the authors identified recessive mutations in SLC1A4 in ten Ashkenazi-Jewish patients from eight families who shared similar clinical features of developmental delay, microcephaly and hypomyelination. Seizure disorder was variably present. Consult the Pubmed abstract  J Med Genet. ; 52(8):541-7 ; August 2015  Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation  The authors described a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability in two unrelated individuals. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. Consult the Pubmed abstract  Eur J Med Genet. ; 58(8):387-91 ; August 2015  Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X  The authors presented 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with intellectual disability and various other features including hypotonia, movement disorders, behaviour problems, corpus callosum hypoplasia, and epilepsy. They also found missense variants in DDX3X in males from three families with intellectual disability suggestive of X-linked inheritance. Consult the Pubmed abstract  Am J Hum Genet. ; 97(2):343-52 ; August 2015  Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63  The authors reported on a 3-year-old male with intellectual disability, characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion leading to haploinsufficiency of TP63. The father, carrying the same deletion, presented with cleft palate, nail dystrophy and learning difficulties. Consult the Pubmed abstract  Eur J Med Genet. ; 58(8):400-5 ; August 2015  New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations  The authors characterized three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. Consult the Pubmed abstract  Hum Mol Genet. ; 24(17):4984-96 ; September 2015  Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2  The authors studied a consanguineous Palestinian Arab family presenting an autosomal recessive progressive myoclonus epilepsy with early ataxia. A novel homozygous missense mutation was identified in LMNB2 that segregated with the progressive myoclonus epilepsy in the family. Consult the Pubmed abstract  Hum Mol Genet. ; 24(16):4483-90 ; August 2015  Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations  The authors reported inherited dysregulation of protein phosphatase activity as a cause of intellectual disability. De novo missense mutations in PPP2R5D and PPP2R1A were identified in 16 individuals with mild to severe intellectual disability, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. Consult the Pubmed abstract  J Clin Invest. ; 125(8):3051-62 ; August 2015    New Genes    Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins  Consult the Pubmed abstract  To read more about "Atypical Rett syndrome"  Eur J Hum Genet. ; 23(9):1171-5 ; September 2015  22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype  Consult the Pubmed abstract  To read more about "22q11.2 deletion syndrome"  Hum Mutat. ; 36(8):797-807 ; August 2015  X-linked intellectual disability due to THOC2 mutations in four families  Consult the Pubmed abstract  Am J Hum Genet. ; 97(2):302-10 ; August 2015  Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586  Consult the Pubmed abstract  To read more about "Hydrolethalus" To read more about "Short rib-polydactyly syndrome, Majewski type" To read more about "Short rib-polydactyly syndrome, Beemer-Langer type"  Am J Hum Genet. ; 97(2):311-8 ; August 2015  Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient  Consult the Pubmed abstract  To read more about "Coenzyme Q10 deficiency"  Eur J Hum Genet. ; 23(9):1254-8 ; September 2015  Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child  Consult the Pubmed abstract  J Med Genet. ; 52(8):532-40 ; August 2015  Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D  Consult the Pubmed abstract  To read more about "Overgrowth syndrome"  Hum Mol Genet. ; 24(17):4775-9 ; September 2015  Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family  Consult the Pubmed abstract  To read more about "Cone rod dystrophy"  Hum Mutat. ; 36(9):836-41 ; September 2015  Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11  Consult the Pubmed abstract  To read more about "Megacystis-microcolon-intestinal hypoperistalsis syndrome"  Eur J Hum Genet. ; 23(9):1266-8 ; September 2015  Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion  Consult the Pubmed abstract  To read more about "Heterotaxia" To read more about "Situs inversus totalis"  Eur J Hum Genet. ; 23(9):1262-5 ; September 2015  Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations  Consult the Pubmed abstract  To read more about "Familial idiopathic steroid-resistant nephrotic syndrome"  Eur J Hum Genet. ; 23(9):1192-9 ; September 2015  Small cell lung cancer: somatic mutations in TP53, TP73 and RB1  Consult the Pubmed abstract  To read more about "Small cell lung cancer"  Nature ; 524(7563):47-53 ; August 2015  Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR  Consult the Pubmed abstract  Nat Genet. ; 47(8):861-3 ; August 2015  Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene  Consult the Pubmed abstract  To read more about "Fetal akinesia deformation sequence"  Eur J Hum Genet. ; 23(9):1151-7 ; September 2015  Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions  Consult the Pubmed abstract  Hum Mutat. ; 36(9):842-50 ; September 2015  Keratoconus: WNT10A exonic variant increases the risk of disease  Consult the Pubmed abstract  To read more about "Keratoconus"  Hum Mol Genet. ; 24(17):5060-8 ; September 2015    Research in Action  Clinical Research  Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific  Consult the Pubmed abstract  To read more about "Dravet syndrome"  Neurology ; 85(7):596-603 ; August 2015  Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate  Consult the Pubmed abstract  To read more about "Progressive familial intrahepatic cholestasis type 2"  Hepatology ; 62(2):558-66 ; August 2015  Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema  Consult the Pubmed abstract  To read more about "Alpha-1-antitrypsin deficiency"  Lancet ; 386(9991):360-8 ; July 2015  Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy  Consult the Pubmed abstract Consult the study on Orphanet  To read more about "Recessive dystrophic epidermolysis bullosa-generalized other" To read more about "Severe generalized recessive dystrophic epidermolysis bullosa"  J Invest Dermatol. ; 135(9):2319-21 ; September 2015  Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness  Consult the Pubmed abstract  To read more about "Facioscapulohumeral dystrophy"  Neurology ; 85(5):396-403 ; August 2015  Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy  Consult the Pubmed abstract  To read more about "Extranodal nasal NK/T cell lymphoma"  Mol Ther. ; 23(8):1401-9 ; August 2015  Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients  Consult the Pubmed abstract  To read more about "Carcinoma of the ampulla of Vater" To read more about "Cholangiocarcinoma" To read more about "Carcinoma of gallbladder and extrahepatic biliary tract"  Lancet Oncol. ; 16(8):967-78 ; August 2015  Paraganglioma in pregnancy: a case series and review of the literature  Consult the Pubmed abstract  J Clin Endocrinol Metab. ; 100(8):3202-9 ; August 2015  Salla disease: 13-year follow-up of Finnish patients  Consult the Pubmed abstract  To read more about "Salla disease"  J Neurodev Disord. ; 7(1):20 ; 2015  Therapeutic Approaches    Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models  Consult the abstract  To read more about "Jervell and Lange-Nielsen syndrome"  Rare Diseases ; 1(3) :1-4 ; 2015  Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice  Consult the Pubmed abstract  To read more about "Huntington disease"  Hum Mol Genet. ; 24(17):4958-70 ; September 2015  Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus  Consult the Pubmed abstract  To read more about "Ebola hemorrhagic fever"  J Clin Invest. ; 125(8):3241-55 ; August 2015  Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model  Consult the Pubmed abstract  To read more about "Dystrophic epidermolysis bullosa"  Mol Ther. ; 23(8):1368-79 ; August 2015  Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model  Consult the Pubmed abstract  To read more about "Retinitis pigmentosa"  Mol Ther. ; 23(8):1308-19 ; August 2015  Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models  Consult the Pubmed abstract  To read more about "Leber congenital amaurosis" To read more about "Retinitis pigmentosa"  Gene Ther. ; 22(8):619-27 ; August 2015  Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model  Consult the Pubmed abstract  To read more about "Duchenne muscular dystrophy"  Mol Ther. ; 23(8):1285-97 ; August 2015  Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice  Consult the Pubmed abstract  To read more about "Steinert myotonic dystrophy"  Hum Mol Genet. ; 24(17):4971-83 ; September 2015  Fragile X-associated tremor/ataxia syndrome: new inducible mouse model  Consult the Pubmed abstract  To read more about "Fragile X-associated tremor/ataxia syndrome"  Hum Mol Genet. ; 24(17):4948-57 ; September 2015  Diagnostic Approaches    Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified  Consult the Pubmed abstract  To read more about "Walker-Warburg syndrome"  Eur J Med Genet. ; 58(8):372-5 ; August 2015  Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis  Consult the Pubmed abstract  To read more about "Susac syndrome"  Neurology ; 85(7):610-8 ; August 2015  CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging  Consult the Pubmed abstract  To read more about "CARASIL"  Neurology ; 85(5):459-63 ; August 2015    Patient Management and Therapy  Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment  Consult the fisrt abstract Consult the second abstract  To read more about "Cystic fibrosis"  Expert Opinion on Orphan Drugs. ; 3(8):957-966; 3(8):933-943 ; August 2015  Fanconi anemia: review on gene therapy  Consult the abstract  To read more about "Fanconi anemia"  Expert Opinion on Orphan Drugs. ; 3(8):899-910 ; August 2015  Lymphangioleiomyomatosis: review on new treatments  Consult the Pubmed abstract  To read more about "Lymphangioleiomyomatosis"  Lung ; 193(4):467-75 ; August 2015  Blepharospasm: review on alternatives to botulinum toxin for the management Id:  Consult the abstract  Expert Opinion on Orphan Drugs ; 3(8):877-885 ; August 2015  Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management  Consult the first abstract Consult the second abstract  To read more about "Congenital isolated hyperinsulinism"  Expert Opinion on Orphan Drugs ; 3(8):887-898 ; August 2015Research and Reports in Endocrine Disorders ; (5):103-117 ; July 2015  Kawasaki disease: a review  Consult the Pubmed abstract  To read more about "Kawasaki disease"  Nat Rev Rheumatol. ; 11(8):475-82 ; August 2015  Paediatric rheumatology: review on lessons from oncology to optimize treatment  Consult the Pubmed abstract  Nat Rev Rheumatol. ; 11(8):493-9 ; August 2015  Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation  Consult the abstract  To read more about "Metachromatic leukodystrophy"  Expert Opinion on Orphan Drugs ; 3(8):911-919 ; August 2015  B-cell non-Hodgkin lymphoma: review on the treatment  Consult the abstract  To read more about "B-cell non-Hodgkin lymphoma"  Expert Opinion on Orphan Drugs ; 3(8):921-932 ; August 2015  Huntington disease: a review  Consult the abstract  To read more about "Huntington disease"  Rare Diseases ; Volume 3, Issue 1 ; 2015  MECP2 disorders: a review  Consult the Pubmed abstract  To read more about "Trisomy Xq28" To read more about "Rett syndrome"  J Clin Invest. ; 125(8):2914-23 ; August 2015  Glycogen storage disease due to acid maltase deficiency: a review  Consult the abstract  To read more about "Glycogen storage disease due to acid maltase deficiency"  Rare Diseases ; Volume 3, Issue 1 ; 2015  Congenital generalized lipodystrophies: a review  Consult the Pubmed abstract  Nat Rev Endocrinol. ; 11(9):522-34 ; September 2015  Ribosomopathies: a review  Consult the abstract  Rare Diseases ; Volume 3, Issue 1 ; 2015  Duchenne muscular dystrophy: a review  Consult the abstract  To read more about "Duchenne muscular dystrophy"  Rare Diseases ; Volume 3, Issue 1 ; 2015  Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening  Consult the abstract  To read more about "Familial dilated cardiomyopathy"  Expert Opinion on Orphan Drugs ; 3(8):869-876 ; August 2015  Tuberous sclerosis: review on pathophysiology  Consult the abstract  To read more about "Tuberous sclerosis"  Rare Diseases ; Volume 3, Issue 1 ; 2015  West-Nile encephalitis: a review  Consult the Pubmed abstract  To read more about "West-Nile encephalitis"  Lancet Infect Dis. ; 15(8):951-9 ; August 2015  Idiopathic interstitial pneumonias with connective tissue diseases features: a review  Consult the Pubmed abstract  Respirology ; [Epub ahead of print] ; July 2015  Primary biliary cirrhosis and primary sclerosing cholangitis: a review  Consult the Pubmed abstract  To read more about "Primary biliary cirrhosis" To read more about "Primary sclerosing cholangitis"  Hepatology ; 62(2):635-43 ; August 2015  Eosinophilic esophagitis and gastroenteritis: a review  Consult the Pubmed abstract  To read more about "Eosinophilic esophagitis" To read more about "Eosinophilic gastroenteritis" To read more about "Eosinophilic colitis"  Curr Allergy Asthma Rep. ; 15(9):558 ; September 2015  T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment  Consult the abstract  To read more about "T-cell large granular lymphocyte leukemia"  Expert Opinion on Orphan Drugs ; 3(8):859-867 ; August 2015  One new and nine updated GeneReviews published  GeneReviews are expert-authored, peer-reviewed disease descriptions ("chapters") presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions. One new GeneReviews has been published for: Lysosomal acid lipase deficiency Nine updated GeneReviews have been published for: Cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders Andersen-Tawil syndrome EZH2-related overgrowth Hereditary leiomyomatosis and renal cell cancer Myotonia congenita TP63-related disorders Von Hippel-Lindau syndrome Mucolipidosis IV OTOF-related deafness    Orphan Drugs  Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe  Since the introduction of conditional marketing authorisation by the European Medicines Agency in 2004, patients have gained access to drugs which fulfil an urgent and unmet need. A paper published in European Journal of Internal Medicine examines whether the conditionally approved drugs manage to obtain comprehensive evidence confirming that the risk-benefit balance is positive to obtain full marketing authorisation and the time taken to reach it. The authors identified 24 products conditionally authorised for sale, between the years 2006-2015, out of which 9 were orphan drugs and 3 had orphan status. Till date 10 medicinal products have been switched to regular approval while 14 of them are still under conditional approval. The authors demonstrate that the median time for the ten conditional approvals to finish their specific obligations and switch to regular marketing authorisations was five years, noting delays, discrepancies and lack of information on some of these drugs. Overall, the median time allowed to address the specific obligations is four years. The median time to fulfil obligations for drugs still conditional is nearly twice that of those converted. Of the 14 medicinal products still under conditional approval, nine have specific obligations whose timeframes go beyond 2015 but some of these did not have up-to-date information on the trials that need to conducted to address the obligations. Out of the drugs that have to fulfil their obligations this year, almost all of them have delays and discrepancies. From the data gathered the authors caution that the conditionally approved drugs without fully established clinical value are in the market for long periods and question whether the public health advantage outweigh the risks of limited clinical information. Consult the Pubmed abstract   Wanted: new models of pricing and reimbursement for gene therapies  The debate on pricing and reimbursement is currently rife, especially in the area of rare diseases. Gene therapy and its pricing add another layer of complexity as discussed in an article published in Nature Biotechnology (discussed in OrphaNews) on Glybera – a gene therapy with a whopping €1.1 million price tag for a one-time treatment. In the same journal, how the 'payers,' either public or private, are concerned with both the price levels routinely mentioned for gene therapies and the pricing and reimbursement (P&R) approaches is discussed in a Letter to the Editor. The authors contacted payers in the United States and Western Europe to identify their top two choices for payment. They report that in the absence of health system constraints, payers prefer annuities as it reduces initial financial strain, leadS to predictable yearly budget impact and reflect the ongoing value of gene therapy. However, the authors point out that in the real world, approaches based on a lump sum payment represent the large majority. According to the authors payers might accept high price tags for gene therapies if industry develops sound and rational pricing & reimbursement approaches based on payer perceived value. The survey demonstrated that payers preferred that gene-therapy reimbursements should model organ transplants procedures (a one-time procedure) rather than protein-replacement therapy (requires frequent dosage). The article suggests a new era in pharmaceutical economics where 'cost-effectiveness' may not necessarily be equated with 'affordability'. Access the Letter to the Editor  Regulatory News  FDA approves new orphan drug to treat 20 patients worldwide The U.S. Food and Drug Administration (FDA) approved Xuriden (uridine triacetate), the first FDA approved treatment for patients with hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disorder, which has been reported in approximately 20 patients worldwide. Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesise uridine. Signs and symptoms of the disease include blood abnormalities, urinary tract obstruction, failure to thrive, and developmental delays. The approval of this drug was based on the results from a 4‑patient 6‑week clinical trial with a 6‑month extension phase. Wellstat - the sponsor of this drug has not yet disclosed the price of this ultra orphan drug Read the FDA press release   New treatment option for patients with multiple myeloma  The European Medicines Agency (EMA) has recommended granting a marketing authorisation for Kyprolis (carfilzomib) to treat patients with multiple myeloma whose disease has relapsed (i.e. the cancer has come back after receiving at least one prior course of therapy). Kyprolis is for use in combination with the cancer medicines lenalidomide and dexamethasone. Multiple myeloma is a rare and life-threatening cancer of a type of white blood cell, called plasma cells, which originate in the bone marrow. Carfilzomib is the first irreversible, highly-selective, proteasome inhibitor for multiple myeloma. The irreversible binding to the targeted proteasome leads to a more sustained inhibition with minimal inhibition of other non-targeted enzymes. Read the EMA press release     Grants    Medical Research Grant Application Guidelines : Progeria Research Foundation  The foundation is proving several grants such as Innovator Awards, Established Innovator Award, and Specialty Award. Details are provided on their website   AFM Telethon: Call for proposals  Several call for proposals are being made available by AFM Telethon. They have published a call for proposals for Spinal Muscular Atrophy and Collagen VI Call for Projects. For further information   Neuronal Ceroid Lipofuscinosis Research Award  For the sixth time the Foundation announces and donates the NCL Research Award. They invite medical and basic science researchers worldwide to submit innovative project proposals that are either clinically oriented or cover translational aspects of CLN3 biology which can contribute to finding a cure for juvenile NCL. We particularly encourage also submissions from scientists working in related biomedical areas such as other lysosomal storage diseases, endolysosomal cell biology and neurodegenerative disorders. Together with the existing NCL research community our goal is to move promising therapeutic avenues forward to help JNCL patients. The grant (50,000 euros) serves as seed money supporting a one year postdoctoral fellowship to help young scientists progressing CLN3 research in academia or industry. Deadline: October 31, 2015 For further information   BMBF Funding initiative: innovative stem cell technologies for personalized medicine  The German Federal Ministry for Education and Research (BMBF) has announced a new funding initiative for the development and use of innovative stem cell technologies. The initiative aims at funding interdisciplinary research collaborations which are geared towards unlocking the full potential of novel reprogramming technologies and iPS cells for practical use. For this, a pooling of expertise from applied basic and clinical research is needed, for example of research groups from the life sciences, medicine, pharmacology and relevant technical disciplines. The funding can be applied for in two modules: "therapy" and "model & test systems". Deadline for applications is 30 November 2015. More information (in German)   8th Call for SMA research proposals  This Call is open to any research project aimed at finding a therapy for Spinal Muscular Atrophy (SMA) or elucidating the basic pathophysiological processes of the disease. SMA‐Europe aims to help the international scientific and medical community in its search for therapies for SMA. Preferences will be given to projects with the greatest potential to overcome barriers to translate science into effective treatments. Two types of research grants will be awarded for up to two years: 1. Operating Grants 2. Postdoctoral Fellowship Application deadline: 9 December 2015 For further information     Partnersearch, Job Opportunities  ECRIN ERIC job vacancies  ECRIN‐Eric is currently in the process of recruiting for its office based in Paris (France) a Capacity Project Manager, an Operations Project Manager and a Secretary. This is a unique opportunity for a motivated individual who wishes to further develop his/her career in biomedical research and his/her experience of multinational research projects. The ECRIN Capacity Project Manager will be in charge of the project management for the structuring projects with ECRIN involvement. For further information   Civil Society representatives: Call for expression of interest is open for the EMA Management Board  The Commission is launching a selection procedure to appoint the Civil Society representatives in the Management Board of the European Medicines Agency (EMA), in London. Four members from Civil Society will be appointed: two members representing patients' organisations, one member representing doctors' organisations and one member representing veterinarians' organisations. The term of office of the current members expires on 20 March 2016. For further information     Courses & Educational Initiatives    The 2nd Biennial Australian Rare Lung Disease Short Course  Date: 16-17 October, 2015 Venue: Sydney, Australia The joint venture between Lung Foundation Australia and the Thoracic Society of Australia and New Zealand (TSANZ) will provide updates on the latest in research, diagnosis, therapy and care for Interstitial Lung Disease. The program boasts an exceptional selection of Australian specialists as well as keynote presentations from international speaker, Professor Kevin Flaherty (USA). For further information or to register please visit:www.lungfoundation.com.au   Courses offered by Recordati Rare Diseases Foundation  The Recordati Rare Diseases Foundation is offering five courses planned for next year. For further information, please contact Cecilia Kellquist, Coordinator and member of the board, ckellquist@rrd-foundation.org/www.rrd-foundation.org. Neurotransmitter focus course  Date: 9-10 November 2015 Venue: Venice, Italy in partnership with University Hospital for Child and Adolescent Medicine of Heidelberg and University Hospital of Padua. Registration deadline: 26th September   EMA workshop on demonstrating significant benefit of orphan medicines  Date: 7 December, 2015 Venue: London, United Kingdom The European Medicines Agency (EMA) is organising a workshop on 7 December 2015 to discuss the approach that should be followed by medicine developers to demonstrate the significant benefit of an orphan medicine over existing treatments. Demonstrating a significant benefit is one of the criteria medicines that treat rare diseases must fulfil to benefit from 10 years of market exclusivity once they have been authorised. The workshop will bring together medicine developers, regulators, healthcare professionals, academia, patients, health technology assessment bodies and healthcare payers who need toregister by 31 October 2015 if they wish to participate. The workshop will also be broadcast live. For further information   European Cytogenetesists Association  Date: February/March of each year Venue: Nimes, France This course is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification. The students will be trained to identify genetic abnormalities for diagnosis and prognosis, and for fundamental and applied research using both classical and molecular cytogenetic techniques. The course is co-organized by E.C.A. and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training. An application for CME points will also be made for 2016. For further information   EMA workshop on pre-licencing activities  Date: 9 March, 2016 Venue: Barcelona, Spain In collaboration with EMA, E-Rare will organize a workshop dedicated to Interactions between EMA and RD researchers on pre-licensing activities. The workshop will take place from 09:00 to 16:00 on the 9 of March 2015 in Barcelona, before the official start of the RE(ACT) meeting. It will be open to all researchers and interested stakeholders. The places for Face-to-face meetings with EMA officers are limited! If you would like to participate, please send an email to juliane.halftermeyer@agencerecherche.fr for further instructions.     What's on Where?    CLIMB Newborn Screening Conference  Date: 10 October, 2015 Venue: Birmingham, UK The CLIMB Newborn Screening Conference will be exploring four new conditions on the newborn screening programme, as well as current metabolic conditions. Midwives will have the opportunity to find out more about conditions that affect infants, including MCADD, PKU, Maple Syrup Disease and Glutaric Aciduria Type 1. For further information   Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico  Date: 15-16 October (ICORD), 12-16 October (Global Rare Disease Week, Mexico) Venue: Mexico City, Mexico ICORD 2015 will be held in México FD (México) 15-16 October in association with FEMEXER (the Mexican Federation of Rare Diseases) and GEISER Foundation (the Group of Linkage, Research and Support for Rare Diseases in Latin America). The event is part of the "Global Rare Diseases Week, Mexico 2015″ and back to back with the 4th Latin American meeting of Rare Diseases on October 12 and the Discoveries and Innovations in Orphan Drugs Congress, October 13-14. For further information   6th South Eastern European Cystic Fibrosis Conference  Date: 19-20 October, 2015 Venue: Bucharest, Romania This regional conference is a 2‐day symposium in Romania, addressing physicians, allied health professionals and patient representatives from the South Eastern European and Mediterranean region. For further information   NORD Summit  Date: 21-22 October, 2015 Venue: Virginia, United States The 2015 Breakthrough Summit is concentrated with innovative content and convenes the top leaders from the FDA, NIH, Industry, Patient Groups, Payers and Research Institutions to address the progress of rare disease diagnosis, genomics, drug development, patient engagement, patient-centered research models, product approva ls, FDA oversight and market access to orphan products. For further information   13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015  Date: 20-22 October, 2015 Venue: Beijing, China This conference will provide a unique opportunity for researchers from all over the world to meet, network, and forge new scientific interactions. For further information   The BioData World Congress 2015  Date: 21-22 October, 2015 Venue: Cambridge, United Kingdom This conference is held with the support of Intel, The Wellcome Trust Sanger Institute, The European Bioinformatics Institute, The Babraham Institute, BIA, BioNow, The Pharmacogenetics and Stratified Medicine Network and the Pistoia Alliance, BioData World Congress. For further information   6th World Congress on Targeting Mitochondria  Date: 21-22 October, 2015 Venue: Berlin, Germany This 6th World Congress on Targeting Mitochondria will cover a variety of new strategies and innovations as well as clinical applications in Mitochondrial Medicine. For further information   The AANEM Annual Meeting  Date: 28 -31 October, 2015 Venue: Hawaii, United States The AANEM Annual Meeting is the premier educational event for those involved in neuromuscular (NM) and electrodiagnostic (EDX) medicine. Earn over 30 continuing education credits through interactive workshops, lively discussions, and engaging sessions. For further information   4th European Congress on Rett Syndrome  Date: 30 October – 1 November, 2015 Venue: Rome, Italy For further information   First European Congress on Hereditary ATTR amyloidosis ECATTR  Date: 2-3 November, 2015 Venue: Paris, France The European Congress for HATTR will allow the meeting of the specialists of all European countries and the sharing of experience. The effort will be to further improve the early diagnosis of sporadic cases and genetic carriers, to review anti-amyloid treatments and clinical trials, to improve genetic counselling. For further information   2nd International Primary Immunodeficiencies Congress (IPIC)  Date: 5-6 November, 2015 Venue: Budapest, Hungary The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the Second International Primary Immunodeficiencies Congress (IPIC). This event will build on the successful outcomes of the first IPIC, attended by 400 participants. The congress will consist of a two-day programme and is open to all stakeholders with an interest in clinical management of primary immunodeficiencies (PIDs). For further information   Sixth Croatian Congress of Human Genetics  Date: 5-7 November, 2015 Venue: Zagreb, Croatia This conference will be an opportunity for education of the young interested in new achievements in various areas of genetics – clinical genetics, cytogenetics, molecular genetics and anthropology, and also to highlight the importance of prevention, diagnostics and treatment of rare diseases. For further information   16th International Conference on Human Genome Variation and Complex Genome Analysis  Date: 11-13 November, 2015 Venue: California, United States HGV2015 will bring together approximately 180 delegates (selected on the basis of their abstract submission) in a workshop-style atmosphere, with 25 internationally recognized speakers. For further information   Statistical analysis of massive genomic data  Date: 19-20 November, 2015 Venue: Evry, France This two-day cross-disciplinary conference will bring together biologists, geneticists, clinicians, bioinformaticians and statisticians in order to discuss emerging challenges raised by the analysis of high-throughput genomic data, and present dedicated innovative approaches. For further information   The Rett Syndrome Journey: Pathways to Follow  Date: 19-21 November, 2015 Venue: Victoria, Australia 'Pathways to Follow' on the journey with Rett syndrome will be explored in such areas as communication, health, therapies, education, equipment, caring for the carer, Commonwealth government, trusts, siblings, adulthood, family and equipment, to name just a few. For further information   6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals  Date: 21-22 November, 2015 Venue: Amsterdam, The Netherlands The 6th European Symposium on Rare Anaemias is an activity of the ENERCA project which aims to disseminate up-to-date knowledge and increase the public awareness about congenital and rare anaemias. This year, transversal topics centered on common medical problems of patients with sickle cell, thalassaemia and other forms of haemolytic anaemia will be one of the key points of the symposium. For further information   International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases  Date: 26 – 28 November, 2015 Venue: Geneva, Switzerland The aim of this second unique forum is to bring together some 200 participants from around the world, including scientists and clinicians, start-up leaders, and families of patients groups, to inform and strengthen exchange and cooperation. For further information   Clinical trials in small populations : Methodological challenges and solutions  Date: 30th November - 1 December 2015 Venue: London, UK The movement towards genetically tailored treatment regimens will further increase the number of small populations for whom new treatments are sought. This two day meeting will bring together researchers and practitioners to discuss state of the art methods for trials in small populations. For further information   CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference  Date: 9-10 January, 2016 Venue: Brussels, Belgium This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers. For further information   CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference  Date: 9-10 January, 2016 Venue: Brussels, Belgium This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers. For further information   BPSU Rare Disease Conference 2016  Date: 23 February, 2016 Venue: Birmingham, United Kingdom The conference will explore the theme 'Rare disease in paediatrics – from birth to transition'. It will centre on the child's journey from diagnosis through transition and end of life care. For further information   Clinical Innovation & Outsourcing  Date: 9-10 March, 2016 Venue: London, UK Clinical Outsourcing & Partnering World is the largest industry event focusing on the strategic and operational considerations in clinical outsourcing. It is a place where serious business contacts are made. Attended by senior decision makers, it's a platform which facilitates meetings between your sales force and prospects and it's a cost effective sponsorship package with year round advantage. For further information   The RE(ACT) Congress  Date: 9-10 March, 2016 Venue: Barcelona, Spain The congress aims to bring together world leaders and young scientist from a variety of breaking through scientific field to present cutting edge research, to discuss results and to exchange ideas. Moreover, many patients and patient organization, which are committed in research, will be present to share their experience. For further information   MYOLOGY 2016 Fifth International Congress of Myology  Date: 14-18 March, 2016 Venue: Lyon, France Held for the first time in 2000, MYOLOGY has become a unique opportunity for international experts in the field to exchange and confront the emerging therapeutic approaches, but also to share the first clinical results. The science and medicine of muscle have reached a new milestone. In Myology 2016, no doubt there will be new results, new breakthroughs to share all together. For further information   13th International Congress of Human Genetics (ICHG) 2016  Date: 3-7 April, 2016 Venue: Kyoto, Japan Hosted by the East-Asian Union of Human Genetic Societies (EAUHGS) and the Japan Society of Human Genetics, the 13th ICHG will focus on progress in genome analysis technologies and big data in order to explore disease mechanisms and treatment opportunities. Registrations open in 2015. For further information   8th Alstrom Syndrome International Conference  Date: 12-16 May, 2016 Venue: Massachusetts, USA This international conference will have a scientific symposium for clinicians and researchers as well as sessions for parents, caretakers and patient organisations. For further information   17th EMSOS Nurse and allied professional Group Meeting  Date: 12-16 May, 2016 Venue: Massachusetts, USA The meeting will be focussing on Ewing sarcoma, margins, pelvic tumours, targeted therapy; open sessions will offer the opportunity to report and discuss the latest results in all fields. For further information   European Association of Centres of Medical Ethics Conference  Date: 8 -10 September, 2016 Venue: Leuven; Belgium The focus of this year's conference is on a variety of highly relevant ethical issues in health care:  Organizational Ethics in Health Care: Principles, Cases and Practical Solutions  Ethical Issues in Care for Older Persons  Ethical, Legal and Social Developments in Human Genomics  Ethics and Integrity in Research For further information   9th ISNS International meeting/10th ISNS European Regional meeting  Date: 11-14 September, 2016 Venue: The Hague, the Netherlands The conference will aid the sharing of neonatal screening experiences for congenital metabolic disorders, its clinical diagnostics and follow-up, and will facilitate learning from other experiences. The programme will consist of plenary lectures, oral presentations and poster sessions and will be attractive for professionals, patient/advocacy groups, policy makers and industrial partners. The programme will include evaluation of performance of neonatal screening systems and strategies for improvement. For further information   ESID European Society for Immunodeficiencies: Biennial meeting  Date: 21-24 September, 2016 Venue: Barcelona, Spain Sessions at this meeting will be devoted to understanding primary immunodeficiencies and their clinical aspects. For further information     Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Rare Diseases OrphaNews : the newsletter of the Rare Disease Community  Editorial  RD-ACTION: the new European Rare Disease Joint Action RD-ACTION, the new Joint Action consisting of the member states of the European Union for rare diseases, was launched on 17 September in Luxembourg, under the auspices of John Ryan, Acting Director of the Health Division and Food Security (DG Health), Jacques Remacle, Head of Health CHAFEA unit (Consumers, Health, Agriculture and Food Executive Agency) and Patrice Dosquet, representing the French Ministry of Health. Following the two previous Joint Actions - Orphanet Joint Action and EUCERD - RD-ACTION represents renewed support of the European Commission (EC) to rare diseases, through its Directorate General for Health (DG SANTE). RD-ACTION has three main objectives: - to contribute to the implementation, by member states, the recommendations of the EC Panel in relation to policies on these diseases, - support the development of Orphanet and make it sustainable, and finally - help Member States to introduce the ORPHA code in their health systems to make rare diseases visible. With a global budget of €8,344,079, this work will last three years (until June 2018), following the logic of coherence and continuity vis-à-vis the previous actions, but aims to go further in terms of concrete implementation and consolidation policies. This action is coordinated by Orphanet (INSERM), bringing together no less than 63 European and non-European participants. The responsibility of implementing the various actions will be carried out by Orphanet (Ana Rath), University of Newcastle (Kate Bushby, coordinator of theEUCERD Joint Action which just ended), the German Institute for Documentation and Medical Information DIMDI (Stefanie Weber), the University of Vienna (Till Voigtländer) and EURORDIS (Yann LeCam). The National Bank of Rare Diseases Data (BNDMR) represented by Rémy Choquet, will work towards the codification, notably the requirement of definition and bringing solutions to the Member States for the implementation of coding rare diseases. DIMDI and the Register of the Venetian region (Paola Facchin) will drive the implementation and testing of these solutions. EURORDIS will work towards dissemination actions along with Orphanet and Higher Health Institute (ISS, Italy). The dissemination actions include the 8th European Conference on Rare Diseases and Orphan Products, 26-28 May 2016, Edinburgh. The Directorate General of Health (DGS France, represented by Patrice Dosquet) will lead the work towards a financially sustainable European Orphanet database. RD-ACTION was designed in the spirit of integration and coherence between the data produced by Orphanet, which provides, among others, the necessary analysis towards policy recommendations, and political action that will then guide the production, operation and dissemination of this data. Participants will ensure effective communication between the reality of each state and the EC Panel, in order to concretely support the implementation of their recommendations. Read the European Commission press release on RD ACTION     Spotlight on...  Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future  On 15 September, over 50 participants from across Europe attended the Final Conference of the EUCERD Joint Action. This event was organised to show case the achievements of the Joint Action, which ran from March 2012 to November 2015, and to analyse the current state of the art of rare disease activity across the European Union, by exploring progress and remaining challenges in key areas such as healthcare, social care and research. The even was a good opportunity to strenghten collaborations with the stakeholders present and relevant initiatives in the field, and to provided the apt moment to hand over the activities led by the Joint Action to the next Joint Action on rare diseases, RD-Action (see Editorial). The outcomes of the EUCERD Joint Action, in particular the resources and recommendations elaborated in collaboration with the European Union Committee of Experts on Rare Diseases and EC Expert Group on Rare Diseases, were presented in the morning session. Participants heard about topics as diverse as quality of care and centres of expertise, RD European Reference Networks, social services for RD, cross-border genetic testing and the codification of rare diseases. The work lead in the context of the Joint Action in support to the EUCERD and Commission Expert Group on Rare Diseases has led to the adoption of 5 recommendations in the past three years, with two other recommendations, on genetic testing and social care under discussion currently. In terms of important resources for the community, the Joint Action also supported the elaboration of the annual report on the State of the Art of Rare Diseases Activities in Europe, a 'go-to' source of information on activities in the field of at national and European level aimed at promoting the exchange of information and monitoring the implementation of rare disease policy: this report will continue to be produced in a more dynamic format in the future RD-Action (see Editorial). The presentations of the activities of the Joint Action were followed by three sessions dedicated to priority areas in the field of rare diseases, informing participants about the latest outcomes of a number of European projects in each area and the efforts made by the EUCERD Joint Action to explore synergies and to link this work into the discussions at the level of the EC Expert Group on Rare Diseases. The first of these sessions was dedicated to Rare Disease Research, Therapeutics and Translation into the Sphere of Health, with presentations from the Rare Best-Practices project, Burqol-RD, a project aimed at exploring the impact of health policies, interventions and treatments in the field of rare diseases, the transnational research support mechanism E-Rare, and the International Rare Disease Research Consortium concerning the impact of IRDiRC policies at national level. The main issued discussed during this session was that of sustainability of the resources produced via these initiatives, and the importance in particular of research into health economics, as regards rare diseases, to inform the implementation of rare disease policies at national level. The following session explored the integration of the results of a number of initiatives concerning rare disease registries, a field where the EU has invested resources through a multitude of projects (such as EPIRARE, the EUCERD Joint Action, and the PARENT Joint Action) with a view to developing an appropriate model for a European Platform for Rare Disease Registration. This platform, recently created at the EC's Joint Research Centre in Ispra, Italy, has to date taken over the responsibilities for the management of the central support of the Eurocat congenital anomalies registry, and the European Surveillance of Cerebal Palsy registry. Stakeholders in the field of rare diseases are still waiting from the JRC confirmation of the governance structure, road map and list of services to be provided by the Platform. In particular, Member States who are in the process of creating national rare disease registration systems, or who are considering this direction, are looking for confirmation of the possible support that will be provided, and the guidelines for interoperability (such as a minimum data set) which could be expected. The final session was dedicated to national plans and strategies for rare diseases, in particular support to the implementation of national activities in this area. The EUCERD Joint Action, continuing the activities of the Europlan project (2008-2011) supported the organisation of over 20 national conferences and debrief sessions across Europe with the close collaboration of national patient alliances and organisations, to ensure the tranmission of European recommendations at national level and appropriate support to Member States in the elaboration and/or implementation of their initiatives. To date, nearly all European Member States have adopted a plan/strategy for rare diseases, with those not yet having adopted a plan in the final stages of elaboration. The next challenge will be the implementation of these plans/strategies, for which very few have a dedicated budget and for some of which need to be translated into concrete actions. The EUCERD Joint Action, through the national conferences and an analysis of these plans, has been able to extract a number of good practices that could help Member States in the implementation of their plans, which will be available shortly. The day finished by establishing the list of possible priorities in the rare disease policy field to be explored by the Expert Group on Rare Diseases with the support of the new RD-Action for rare diseases (see Editorial). The Commission and the Coordinator of the EUCERD Joint Action, Kate Bushby, thanked the partners and the many participants in the conferences and workshops organised over the past 3 years, for their hard work and wished them success in the future work of the next Joint Action. The report of the conference will soon be available online.     EU Policy News  EMA  Submit expressions of interest to represent civil society at the EMA  The Health and Food Safety Directorate-General of the European Commission has extended the deadline for its calls for expressions of interest to represent civil society in two scientific committees of the European Medicines Agency (EMA): the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Advanced Therapies (CAT). For both calls, expressions of interest should be submitted to the European Commission no later than 18 October 2015, either by email or post. Further information on the assessment criteria and the application process can be found on the Commission's website. Call for civil society members to join two EMA committees     National & International Policy Developments  Comprehensive policy for patients with rare diseases in Philippines  The House of Representatives in Philippines recently approved a comprehensive policy on services for patients with rare diseases that will provide them with timely and adequate access to healthcare, information, and products to treat their conditions. This will be done primarily through the establishment of a comprehensive and sustainable health system for identification, referral, and management of patients with rare diseases—integrated within the current public health system; and the inclusion of rare disease benefit package in PhilHealth. The bill stipulates giving regulatory and fiscal incentives to support research and development activities on rare diseases and manufacturing of affordable drugs or products. Likewise, the bill provides for the design and maintenance of a rare disease registry containing data on cases, patients, drugs and products for rare diseases. Data from the registry will be used in policy formulation. The provisions in the bill are set to address the current challenges being faced by patients afflicted with rare diseases, their families and caregivers, and their healthcare providers. This bill defines a rare disease as one that affects 1/20,000 in the Philippines. It provides a preliminary list of rare diseases and the provision of inclusion of others under the advisement of the National Institute of Health in the United States. Read the report on this topic by National Academy of Science and Technology, Philippines  Other European news  The rare disease persons card implementation in Portugal  The Portuguese Ministry of Health Shared Services and Directorate General of Health, recently announced the implementation of the Rare Disease Person's Card (RDPC). Coded using the ORPHA code system, this card is meant to identify the rare disease patient and display the relevant information of the condition as well as information especially required during an emergency situation. An article published in Procedia Computer Science describes the process of preparation, approval and the regulatory model of the card. According to the authors, due to nascent stage of the implementation of these cards, there is still room for the card to evolve and expand. Still, 828 cards have been requested through the family physician of the concerned patients, regarding 738 different rare diseases, half of which have been activated. The card is increasing awareness and empowerment of rare disease's patients, pushing the project forward and improving health care. Download the document from Direcção-Geral da Saúde Read the open access article   Sample of the adult British population want genetic testing of children for adult-onset conditions  Almost all the guidelines published till date on genetic testing on children for adult onset conditions recommend deferring such tests unless there is a clear indication that it will prevent the future outcome of the condition. Whether the general public agrees with this recommendation is addressed in an article published in European Journal of Human Genetics. Testing the attitudes of a representative sample of the adult-British public revealed that, contrary to the guidance documents, 47% believed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. Younger respondents of the survey and men were more likely to support this kind of testing as well as carrier testing. The authors also presented 4 arguments in support of deferring testing to the participants, out of which "a child's future ability to decide for her/himself if and when to be tested" was generally the least supported argument in the sample. However, the authors noted that women were significantly more likely to consider all 4 arguments as valid to defer testing for adult onset conditions. Read the Open Access article   Sample of Danish population want disclosure of incidental findings from NGS studies  Another article has studied an equally contentious issue –disclosure of incidental findings - is published in European Journal of Human Genetics. Here the authors also find that contrary to the recommendations of professional organisations, participants in next generation studies wanted disclosure of all incidental findings. The authors investigated if participants recruited from the Region of Southern Denmark want disclosure of incidental findings and which ones would they want to know more about. According to the authors most participants wanted disclosure of all incidental findings; only 3% did not want any disclosure, while 36% wanted disclosure only on actionable variants. According to the authors due to the disparity of opinion between the official recommendation and the sample studies "options for reporting IFs in research studies (could) be incorporated in the consent form." Consult the Pubmed abstract  Other International News  Discussion paper by the Australian government to support people with chronic and complex health conditions  To better support people with chronic and complex health conditions, the Australian Government has released a discussion paper by the Primary Health Care Advisory Group, to examine options for health reform and provide a report to the Australian Government in late 2015. The paper is designed to set out the case for change and introduce some possible options to improve primary health care for people with chronic and complex conditions. In order to engage all stakeholders, consultation will be held with the Advisory Group. Results of the survey that accompanied the discussion paper will be out shortly. Read more on Therapeutic Goods Administration, Australia   Contradictions of public health policies geared to rare disorders in Brazil  A paper published in Portuguese presents information of the rare disease health policy in Brazil, using the example of Ostegenesis Imperfecta. The paper details the contradictions, especially with respect to therapeutic decisions and the strengthening of the specialized network for addressing this condition which are expressed in the drafting and final text of the new law. Consult the Pubmed abstract   Sickle cell disease among children in Africa  An article published in International Journal of Africa Nursing Sciences provides an integrative review of 63 references related sickle cell disease among children in Africa, focussing on the incidence, prevalence, morbidity, and mortality; current practices and challenges related to screening, diagnosis, and treatment. From this data the authors also provide recommendations for practice, policy, and research to improve health outcomes of children with sickle cell disease in Africa. Read the Open Access article  Guidance Documents and Recommendations  22q11.2 deletion syndrome: guidelines for the management  Consult the Pubmed abstract  To read more about "22q11.2 deletion syndrome"  Genet Med. ; 17(8):599-609 ; August 2015  Cushing syndrome: guidelines on treatment  Consult the Pubmed abstract  To read more about "Cushing syndrome"  J Clin Endocrinol Metab. ; 100(8):2807-31 ; August 2015  Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment  Consult the Pubmed abstract  To read more about "Congenital hypogonadotropic hypogonadism"  Nat Rev Endocrinol. ; 11(9):547-64 ; September 2015  Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment  Consult the Pubmed abstract  To read more about "Pemphigus vulgaris" To read more about "Pemphigus foliaceus" To read more about "Bullous pemphigoid"  J Dtsch Dermatol Ges.   Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management  Consult the Pubmed abstract  To read more about "Facioscapulohumeral dystrophy"  Neurology ; 85(4):357-64 ; July 2015  Bioinformatics, Registries and Data Management  How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population  Guidelines such as Code of Federal Regulations and WMA Declaration of Helsinki recommend expressed consent from the paediatric population before inclusion of their health data in biobanks. This issue has brought forth many ethical concerns especially with regards to the child's role in these procedures which is discussed in an article published in European Journal of Human Genetics. The authors of this article provide the results of an international multiple-case study which included four biobanks addressing diverse health concerns with the collection of a variety of data from the paediatric population. They addressed "four themes linked to the child's role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate." This study recognises the motives to involve consent of the child where respect for the child as an intrinsic motive to involve children while adherence to regulation was recognised by all as important. The authors also detail how personal verbal information is utilised for informing the child even though it is not mentioned in the regulation. While the authors say that assent and consent differs between biobanks, the question of how respecting dissent - is followed by the biobanks is unclear. The authors also show that although children agree to participate in biobanks to different reasons, coercion from parents may be the overarching one. The authors believe that these "insight(s) (are) valuable when designing paediatric biobank governance." Read the Open Access article   Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders  An article published in Genetics Research discusses how next generation sequencing (NGS) based research on rare diseases has come a long way and the effect of long tail economics on rare diseases research. Long tail statistics has been commonly used to understand the rise of internet retailers, crowdfunding, crowdsourcing etc., where a large share of the data rests within its tail unlike a normal distribution. The authors believe that the trend observed in rare disease research, especially in terms of the developments in NGS, can benefit from the two themes derived from long tailed economics - increased access and reduced cost. In this context, increased access would mean that the researcher would be able to look through a sea of data produced thanks to whole genome and whole exome sequencing and find what they are looking for (gene, disease, phenotype) . They also detail the developments in bioinformatics that has led to the development of this enormous amount of data which in turn required better curative and sharing efforts. The authors refer reduced cost to the reduction of overhead costs by centralising resources where the curative and sharing efforts come in play. They also address the issue of reimbursement that comes with the rising cost of sequencing. According to the authors "as a long-tailed problem, continued discovery of rare diseases requires a funding infrastructure that can sustainably support the work needed to identify the great number of rare diseases", for which they believe a good source is crowdfunding. The authors believe that "the principles derived from long-tail economics shape our understanding of the recent development of this field and offer insight towards needed improvements." The authors of this article belong to the Rare Genomics Institute that has recently launched 10 crowdfunding campaigns to sequence exomes of rare disease patients. Read the PubMed abstract  Screening and Testing  Regulating laboratory developed tests in the United States: the current controversy  A perspective published by stakeholders in Genetic Testing and Molecular Biomarkerscomments on the current legislation mandating the United States Food and Drug Administration as the regulatory body overseeing Laboratory Developed Tests (LDTs). The authors explain that historically LDTs are subject to regulation by the Clinical Laboratory Improvement Amendments (CLIA) of Centers for Medicare and Medicaid Services (CMS). However, in 2015, the FDA announced the establishment of the FDA/CMS Task Force on LDT Quality Requirements to oversee changes to the LDT regulatory landscape. The FDA described a premarket review process that would require confirmation of the analytical and clinical validity of new LDTs before the lab is permitted to administer those tests. Following this announcement a debate has ensued in the context of the 21st Century Cures Act with valid arguments from supporters and detractors due to which the Congress has requested for feedback. However, the resulting whitepaper did not contain specific information directly addressing this issue. The authors express concern that stakeholders are still speculating about the trajectory of LDT regulation. Access the review   Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests  A related article published in the Food and Drug Law Journal addresses FDA's current mandate to regulate laboratory developed diagnostic tests. The author believes that this oversight could prove to be intrusive and has the potential to slow the progress of genomic discovery, interfere with scientific inquiry and suppress investigators' and clinicians' rights to freedom of speech and prove to be federalist in action (U.S wants states to mandate practise of medicine). According to the author this article is written with the goal to help genomics researchers understand how FDA's research regulations may apply to research that uses high-throughput DNA sequencing. Read the Open Access article   Newborn screening in Australia: current environment and future perspectives  The current state of newborn bloodspot screening in Australia and the lessons it needs to learn from international programmes to upgrade its operation is explained in Frontiers in Public Health. The authors say that NBS has been operating successfully in Australia for almost 50 years but currently it does not have any coherent national policy or decision-making process that is concurrently agreed by government. The authors describe the policy environment in the United States, United Kingdom and New Zealand which could provide useful information. In Australia the establishment of the Australian Screening Advisory Committee in 2001, now known as the Standing Committee on Screening has played an important role in providing guidance on what constitutes a good screening program through the development of the Population-Based Screening Framework in 2008. However, the authors believe that Australia is operating in an environment, which lacks a considered decision-making process for government, particularly in regards to assessing conditions for screening. The authors believe that changes to newborn screening programs should be planned instead of being reactive often in response to new technologies. The authors provide several options to overcome the funding barrier, which they describe as chief obstacle, to developing and implementing a national decision-making framework for newborn screening in Australia. They believe that a national decision-making approach, supported by state implementation of decisions, would support consistent decision making across local-level programs. Read the Open Access article   Patenting Genetic diagnostic methods  An article published in the Journal of Law and Medicine reviewed and analysed the relevant law in Australia and the United States to assist sponsors claiming patents for "diagnostic methods associated with genome-wide association studies (GWAS), adopting methodologies using next generation sequencing (NGS) and single nucleotide polymorphism (SNP)." The authors provide reasonable solutions to commonly experienced questions while patenting these technologies: experimental reproducibility and the credibility and veracity of the technology. Read the Open Access article     Ethical, Legal & Social Issues  Living with Marfan syndrome: the patients view  A study published in Clinical Genetics explores the psychosocial aspects of Marfan syndrome (MFS) by collecting available literature followed by synthesising and critically appraising them. The authors studied 15 articles that satisfied the eligibility criteria and found that MFS significantly impacts various areas of the patient's life such as education, work, family and transition to adulthood. They also experienced decreased Health Related Quality of life, depression and anxiety. Interestingly, the authors also noted that the studies show there was a considerable disconnect between the discomfort that the patient experiences and how professionals view it. According to the authors the studies demonstrate that "the subjective perception of discomfort did not necessarily match the medical severity of a disease." Consult the Pubmed abstract     New Syndromes  Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4  Using exome analysis, the authors identified recessive mutations in SLC1A4 in ten Ashkenazi-Jewish patients from eight families who shared similar clinical features of developmental delay, microcephaly and hypomyelination. Seizure disorder was variably present. Consult the Pubmed abstract  J Med Genet. ; 52(8):541-7 ; August 2015  Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation  The authors described a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability in two unrelated individuals. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. Consult the Pubmed abstract  Eur J Med Genet. ; 58(8):387-91 ; August 2015  Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X  The authors presented 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with intellectual disability and various other features including hypotonia, movement disorders, behaviour problems, corpus callosum hypoplasia, and epilepsy. They also found missense variants in DDX3X in males from three families with intellectual disability suggestive of X-linked inheritance. Consult the Pubmed abstract  Am J Hum Genet. ; 97(2):343-52 ; August 2015  Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63  The authors reported on a 3-year-old male with intellectual disability, characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion leading to haploinsufficiency of TP63. The father, carrying the same deletion, presented with cleft palate, nail dystrophy and learning difficulties. Consult the Pubmed abstract  Eur J Med Genet. ; 58(8):400-5 ; August 2015  New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations  The authors characterized three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. Consult the Pubmed abstract  Hum Mol Genet. ; 24(17):4984-96 ; September 2015  Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2  The authors studied a consanguineous Palestinian Arab family presenting an autosomal recessive progressive myoclonus epilepsy with early ataxia. A novel homozygous missense mutation was identified in LMNB2 that segregated with the progressive myoclonus epilepsy in the family. Consult the Pubmed abstract  Hum Mol Genet. ; 24(16):4483-90 ; August 2015  Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations  The authors reported inherited dysregulation of protein phosphatase activity as a cause of intellectual disability. De novo missense mutations in PPP2R5D and PPP2R1A were identified in 16 individuals with mild to severe intellectual disability, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. Consult the Pubmed abstract  J Clin Invest. ; 125(8):3051-62 ; August 2015    New Genes    Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins  Consult the Pubmed abstract  To read more about "Atypical Rett syndrome"  Eur J Hum Genet. ; 23(9):1171-5 ; September 2015  22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype  Consult the Pubmed abstract  To read more about "22q11.2 deletion syndrome"  Hum Mutat. ; 36(8):797-807 ; August 2015  X-linked intellectual disability due to THOC2 mutations in four families  Consult the Pubmed abstract  Am J Hum Genet. ; 97(2):302-10 ; August 2015  Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586  Consult the Pubmed abstract  To read more about "Hydrolethalus" To read more about "Short rib-polydactyly syndrome, Majewski type" To read more about "Short rib-polydactyly syndrome, Beemer-Langer type"  Am J Hum Genet. ; 97(2):311-8 ; August 2015  Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient  Consult the Pubmed abstract  To read more about "Coenzyme Q10 deficiency"  Eur J Hum Genet. ; 23(9):1254-8 ; September 2015  Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child  Consult the Pubmed abstract  J Med Genet. ; 52(8):532-40 ; August 2015  Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D  Consult the Pubmed abstract  To read more about "Overgrowth syndrome"  Hum Mol Genet. ; 24(17):4775-9 ; September 2015  Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family  Consult the Pubmed abstract  To read more about "Cone rod dystrophy"  Hum Mutat. ; 36(9):836-41 ; September 2015  Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11  Consult the Pubmed abstract  To read more about "Megacystis-microcolon-intestinal hypoperistalsis syndrome"  Eur J Hum Genet. ; 23(9):1266-8 ; September 2015  Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion  Consult the Pubmed abstract  To read more about "Heterotaxia" To read more about "Situs inversus totalis"  Eur J Hum Genet. ; 23(9):1262-5 ; September 2015  Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations  Consult the Pubmed abstract  To read more about "Familial idiopathic steroid-resistant nephrotic syndrome"  Eur J Hum Genet. ; 23(9):1192-9 ; September 2015  Small cell lung cancer: somatic mutations in TP53, TP73 and RB1  Consult the Pubmed abstract  To read more about "Small cell lung cancer"  Nature ; 524(7563):47-53 ; August 2015  Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR  Consult the Pubmed abstract  Nat Genet. ; 47(8):861-3 ; August 2015  Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene  Consult the Pubmed abstract  To read more about "Fetal akinesia deformation sequence"  Eur J Hum Genet. ; 23(9):1151-7 ; September 2015  Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions  Consult the Pubmed abstract  Hum Mutat. ; 36(9):842-50 ; September 2015  Keratoconus: WNT10A exonic variant increases the risk of disease  Consult the Pubmed abstract  To read more about "Keratoconus"  Hum Mol Genet. ; 24(17):5060-8 ; September 2015    Research in Action  Clinical Research  Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific  Consult the Pubmed abstract  To read more about "Dravet syndrome"  Neurology ; 85(7):596-603 ; August 2015  Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate  Consult the Pubmed abstract  To read more about "Progressive familial intrahepatic cholestasis type 2"  Hepatology ; 62(2):558-66 ; August 2015  Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema  Consult the Pubmed abstract  To read more about "Alpha-1-antitrypsin deficiency"  Lancet ; 386(9991):360-8 ; July 2015  Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy  Consult the Pubmed abstract Consult the study on Orphanet  To read more about "Recessive dystrophic epidermolysis bullosa-generalized other" To read more about "Severe generalized recessive dystrophic epidermolysis bullosa"  J Invest Dermatol. ; 135(9):2319-21 ; September 2015  Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness  Consult the Pubmed abstract  To read more about "Facioscapulohumeral dystrophy"  Neurology ; 85(5):396-403 ; August 2015  Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy  Consult the Pubmed abstract  To read more about "Extranodal nasal NK/T cell lymphoma"  Mol Ther. ; 23(8):1401-9 ; August 2015  Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients  Consult the Pubmed abstract  To read more about "Carcinoma of the ampulla of Vater" To read more about "Cholangiocarcinoma" To read more about "Carcinoma of gallbladder and extrahepatic biliary tract"  Lancet Oncol. ; 16(8):967-78 ; August 2015  Paraganglioma in pregnancy: a case series and review of the literature  Consult the Pubmed abstract  J Clin Endocrinol Metab. ; 100(8):3202-9 ; August 2015  Salla disease: 13-year follow-up of Finnish patients  Consult the Pubmed abstract  To read more about "Salla disease"  J Neurodev Disord. ; 7(1):20 ; 2015  Therapeutic Approaches    Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models  Consult the abstract  To read more about "Jervell and Lange-Nielsen syndrome"  Rare Diseases ; 1(3) :1-4 ; 2015  Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice  Consult the Pubmed abstract  To read more about "Huntington disease"  Hum Mol Genet. ; 24(17):4958-70 ; September 2015  Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus  Consult the Pubmed abstract  To read more about "Ebola hemorrhagic fever"  J Clin Invest. ; 125(8):3241-55 ; August 2015  Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model  Consult the Pubmed abstract  To read more about "Dystrophic epidermolysis bullosa"  Mol Ther. ; 23(8):1368-79 ; August 2015  Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model  Consult the Pubmed abstract  To read more about "Retinitis pigmentosa"  Mol Ther. ; 23(8):1308-19 ; August 2015  Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models  Consult the Pubmed abstract  To read more about "Leber congenital amaurosis" To read more about "Retinitis pigmentosa"  Gene Ther. ; 22(8):619-27 ; August 2015  Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model  Consult the Pubmed abstract  To read more about "Duchenne muscular dystrophy"  Mol Ther. ; 23(8):1285-97 ; August 2015  Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice  Consult the Pubmed abstract  To read more about "Steinert myotonic dystrophy"  Hum Mol Genet. ; 24(17):4971-83 ; September 2015  Fragile X-associated tremor/ataxia syndrome: new inducible mouse model  Consult the Pubmed abstract  To read more about "Fragile X-associated tremor/ataxia syndrome"  Hum Mol Genet. ; 24(17):4948-57 ; September 2015  Diagnostic Approaches    Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified  Consult the Pubmed abstract  To read more about "Walker-Warburg syndrome"  Eur J Med Genet. ; 58(8):372-5 ; August 2015  Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis  Consult the Pubmed abstract  To read more about "Susac syndrome"  Neurology ; 85(7):610-8 ; August 2015  CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging  Consult the Pubmed abstract  To read more about "CARASIL"  Neurology ; 85(5):459-63 ; August 2015    Patient Management and Therapy  Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment  Consult the fisrt abstract Consult the second abstract  To read more about "Cystic fibrosis"  Expert Opinion on Orphan Drugs. ; 3(8):957-966; 3(8):933-943 ; August 2015  Fanconi anemia: review on gene therapy  Consult the abstract  To read more about "Fanconi anemia"  Expert Opinion on Orphan Drugs. ; 3(8):899-910 ; August 2015  Lymphangioleiomyomatosis: review on new treatments  Consult the Pubmed abstract  To read more about "Lymphangioleiomyomatosis"  Lung ; 193(4):467-75 ; August 2015  Blepharospasm: review on alternatives to botulinum toxin for the management Id:  Consult the abstract  Expert Opinion on Orphan Drugs ; 3(8):877-885 ; August 2015  Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management  Consult the first abstract Consult the second abstract  To read more about "Congenital isolated hyperinsulinism"  Expert Opinion on Orphan Drugs ; 3(8):887-898 ; August 2015Research and Reports in Endocrine Disorders ; (5):103-117 ; July 2015  Kawasaki disease: a review  Consult the Pubmed abstract  To read more about "Kawasaki disease"  Nat Rev Rheumatol. ; 11(8):475-82 ; August 2015  Paediatric rheumatology: review on lessons from oncology to optimize treatment  Consult the Pubmed abstract  Nat Rev Rheumatol. ; 11(8):493-9 ; August 2015  Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation  Consult the abstract  To read more about "Metachromatic leukodystrophy"  Expert Opinion on Orphan Drugs ; 3(8):911-919 ; August 2015  B-cell non-Hodgkin lymphoma: review on the treatment  Consult the abstract  To read more about "B-cell non-Hodgkin lymphoma"  Expert Opinion on Orphan Drugs ; 3(8):921-932 ; August 2015  Huntington disease: a review  Consult the abstract  To read more about "Huntington disease"  Rare Diseases ; Volume 3, Issue 1 ; 2015  MECP2 disorders: a review  Consult the Pubmed abstract  To read more about "Trisomy Xq28" To read more about "Rett syndrome"  J Clin Invest. ; 125(8):2914-23 ; August 2015  Glycogen storage disease due to acid maltase deficiency: a review  Consult the abstract  To read more about "Glycogen storage disease due to acid maltase deficiency"  Rare Diseases ; Volume 3, Issue 1 ; 2015  Congenital generalized lipodystrophies: a review  Consult the Pubmed abstract  Nat Rev Endocrinol. ; 11(9):522-34 ; September 2015  Ribosomopathies: a review  Consult the abstract  Rare Diseases ; Volume 3, Issue 1 ; 2015  Duchenne muscular dystrophy: a review  Consult the abstract  To read more about "Duchenne muscular dystrophy"  Rare Diseases ; Volume 3, Issue 1 ; 2015  Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening  Consult the abstract  To read more about "Familial dilated cardiomyopathy"  Expert Opinion on Orphan Drugs ; 3(8):869-876 ; August 2015  Tuberous sclerosis: review on pathophysiology  Consult the abstract  To read more about "Tuberous sclerosis"  Rare Diseases ; Volume 3, Issue 1 ; 2015  West-Nile encephalitis: a review  Consult the Pubmed abstract  To read more about "West-Nile encephalitis"  Lancet Infect Dis. ; 15(8):951-9 ; August 2015  Idiopathic interstitial pneumonias with connective tissue diseases features: a review  Consult the Pubmed abstract  Respirology ; [Epub ahead of print] ; July 2015  Primary biliary cirrhosis and primary sclerosing cholangitis: a review  Consult the Pubmed abstract  To read more about "Primary biliary cirrhosis" To read more about "Primary sclerosing cholangitis"  Hepatology ; 62(2):635-43 ; August 2015  Eosinophilic esophagitis and gastroenteritis: a review  Consult the Pubmed abstract  To read more about "Eosinophilic esophagitis" To read more about "Eosinophilic gastroenteritis" To read more about "Eosinophilic colitis"  Curr Allergy Asthma Rep. ; 15(9):558 ; September 2015  T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment  Consult the abstract  To read more about "T-cell large granular lymphocyte leukemia"  Expert Opinion on Orphan Drugs ; 3(8):859-867 ; August 2015  One new and nine updated GeneReviews published  GeneReviews are expert-authored, peer-reviewed disease descriptions ("chapters") presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions. One new GeneReviews has been published for: Lysosomal acid lipase deficiency Nine updated GeneReviews have been published for: Cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders Andersen-Tawil syndrome EZH2-related overgrowth Hereditary leiomyomatosis and renal cell cancer Myotonia congenita TP63-related disorders Von Hippel-Lindau syndrome Mucolipidosis IV OTOF-related deafness    Orphan Drugs  Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe  Since the introduction of conditional marketing authorisation by the European Medicines Agency in 2004, patients have gained access to drugs which fulfil an urgent and unmet need. A paper published in European Journal of Internal Medicine examines whether the conditionally approved drugs manage to obtain comprehensive evidence confirming that the risk-benefit balance is positive to obtain full marketing authorisation and the time taken to reach it. The authors identified 24 products conditionally authorised for sale, between the years 2006-2015, out of which 9 were orphan drugs and 3 had orphan status. Till date 10 medicinal products have been switched to regular approval while 14 of them are still under conditional approval. The authors demonstrate that the median time for the ten conditional approvals to finish their specific obligations and switch to regular marketing authorisations was five years, noting delays, discrepancies and lack of information on some of these drugs. Overall, the median time allowed to address the specific obligations is four years. The median time to fulfil obligations for drugs still conditional is nearly twice that of those converted. Of the 14 medicinal products still under conditional approval, nine have specific obligations whose timeframes go beyond 2015 but some of these did not have up-to-date information on the trials that need to conducted to address the obligations. Out of the drugs that have to fulfil their obligations this year, almost all of them have delays and discrepancies. From the data gathered the authors caution that the conditionally approved drugs without fully established clinical value are in the market for long periods and question whether the public health advantage outweigh the risks of limited clinical information. Consult the Pubmed abstract   Wanted: new models of pricing and reimbursement for gene therapies  The debate on pricing and reimbursement is currently rife, especially in the area of rare diseases. Gene therapy and its pricing add another layer of complexity as discussed in an article published in Nature Biotechnology (discussed in OrphaNews) on Glybera – a gene therapy with a whopping €1.1 million price tag for a one-time treatment. In the same journal, how the 'payers,' either public or private, are concerned with both the price levels routinely mentioned for gene therapies and the pricing and reimbursement (P&R) approaches is discussed in a Letter to the Editor. The authors contacted payers in the United States and Western Europe to identify their top two choices for payment. They report that in the absence of health system constraints, payers prefer annuities as it reduces initial financial strain, leadS to predictable yearly budget impact and reflect the ongoing value of gene therapy. However, the authors point out that in the real world, approaches based on a lump sum payment represent the large majority. According to the authors payers might accept high price tags for gene therapies if industry develops sound and rational pricing & reimbursement approaches based on payer perceived value. The survey demonstrated that payers preferred that gene-therapy reimbursements should model organ transplants procedures (a one-time procedure) rather than protein-replacement therapy (requires frequent dosage). The article suggests a new era in pharmaceutical economics where 'cost-effectiveness' may not necessarily be equated with 'affordability'. Access the Letter to the Editor  Regulatory News  FDA approves new orphan drug to treat 20 patients worldwide The U.S. Food and Drug Administration (FDA) approved Xuriden (uridine triacetate), the first FDA approved treatment for patients with hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disorder, which has been reported in approximately 20 patients worldwide. Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesise uridine. Signs and symptoms of the disease include blood abnormalities, urinary tract obstruction, failure to thrive, and developmental delays. The approval of this drug was based on the results from a 4‑patient 6‑week clinical trial with a 6‑month extension phase. Wellstat - the sponsor of this drug has not yet disclosed the price of this ultra orphan drug Read the FDA press release   New treatment option for patients with multiple myeloma  The European Medicines Agency (EMA) has recommended granting a marketing authorisation for Kyprolis (carfilzomib) to treat patients with multiple myeloma whose disease has relapsed (i.e. the cancer has come back after receiving at least one prior course of therapy). Kyprolis is for use in combination with the cancer medicines lenalidomide and dexamethasone. Multiple myeloma is a rare and life-threatening cancer of a type of white blood cell, called plasma cells, which originate in the bone marrow. Carfilzomib is the first irreversible, highly-selective, proteasome inhibitor for multiple myeloma. The irreversible binding to the targeted proteasome leads to a more sustained inhibition with minimal inhibition of other non-targeted enzymes. Read the EMA press release     Grants    Medical Research Grant Application Guidelines : Progeria Research Foundation  The foundation is proving several grants such as Innovator Awards, Established Innovator Award, and Specialty Award. Details are provided on their website   AFM Telethon: Call for proposals  Several call for proposals are being made available by AFM Telethon. They have published a call for proposals for Spinal Muscular Atrophy and Collagen VI Call for Projects. For further information   Neuronal Ceroid Lipofuscinosis Research Award  For the sixth time the Foundation announces and donates the NCL Research Award. They invite medical and basic science researchers worldwide to submit innovative project proposals that are either clinically oriented or cover translational aspects of CLN3 biology which can contribute to finding a cure for juvenile NCL. We particularly encourage also submissions from scientists working in related biomedical areas such as other lysosomal storage diseases, endolysosomal cell biology and neurodegenerative disorders. Together with the existing NCL research community our goal is to move promising therapeutic avenues forward to help JNCL patients. The grant (50,000 euros) serves as seed money supporting a one year postdoctoral fellowship to help young scientists progressing CLN3 research in academia or industry. Deadline: October 31, 2015 For further information   BMBF Funding initiative: innovative stem cell technologies for personalized medicine  The German Federal Ministry for Education and Research (BMBF) has announced a new funding initiative for the development and use of innovative stem cell technologies. The initiative aims at funding interdisciplinary research collaborations which are geared towards unlocking the full potential of novel reprogramming technologies and iPS cells for practical use. For this, a pooling of expertise from applied basic and clinical research is needed, for example of research groups from the life sciences, medicine, pharmacology and relevant technical disciplines. The funding can be applied for in two modules: "therapy" and "model & test systems". Deadline for applications is 30 November 2015. More information (in German)   8th Call for SMA research proposals  This Call is open to any research project aimed at finding a therapy for Spinal Muscular Atrophy (SMA) or elucidating the basic pathophysiological processes of the disease. SMA‐Europe aims to help the international scientific and medical community in its search for therapies for SMA. Preferences will be given to projects with the greatest potential to overcome barriers to translate science into effective treatments. Two types of research grants will be awarded for up to two years: 1. Operating Grants 2. Postdoctoral Fellowship Application deadline: 9 December 2015 For further information     Partnersearch, Job Opportunities  ECRIN ERIC job vacancies  ECRIN‐Eric is currently in the process of recruiting for its office based in Paris (France) a Capacity Project Manager, an Operations Project Manager and a Secretary. This is a unique opportunity for a motivated individual who wishes to further develop his/her career in biomedical research and his/her experience of multinational research projects. The ECRIN Capacity Project Manager will be in charge of the project management for the structuring projects with ECRIN involvement. For further information   Civil Society representatives: Call for expression of interest is open for the EMA Management Board  The Commission is launching a selection procedure to appoint the Civil Society representatives in the Management Board of the European Medicines Agency (EMA), in London. Four members from Civil Society will be appointed: two members representing patients' organisations, one member representing doctors' organisations and one member representing veterinarians' organisations. The term of office of the current members expires on 20 March 2016. For further information     Courses & Educational Initiatives    The 2nd Biennial Australian Rare Lung Disease Short Course  Date: 16-17 October, 2015 Venue: Sydney, Australia The joint venture between Lung Foundation Australia and the Thoracic Society of Australia and New Zealand (TSANZ) will provide updates on the latest in research, diagnosis, therapy and care for Interstitial Lung Disease. The program boasts an exceptional selection of Australian specialists as well as keynote presentations from international speaker, Professor Kevin Flaherty (USA). For further information or to register please visit:www.lungfoundation.com.au   Courses offered by Recordati Rare Diseases Foundation  The Recordati Rare Diseases Foundation is offering five courses planned for next year. For further information, please contact Cecilia Kellquist, Coordinator and member of the board, ckellquist@rrd-foundation.org/www.rrd-foundation.org. Neurotransmitter focus course  Date: 9-10 November 2015 Venue: Venice, Italy in partnership with University Hospital for Child and Adolescent Medicine of Heidelberg and University Hospital of Padua. Registration deadline: 26th September   EMA workshop on demonstrating significant benefit of orphan medicines  Date: 7 December, 2015 Venue: London, United Kingdom The European Medicines Agency (EMA) is organising a workshop on 7 December 2015 to discuss the approach that should be followed by medicine developers to demonstrate the significant benefit of an orphan medicine over existing treatments. Demonstrating a significant benefit is one of the criteria medicines that treat rare diseases must fulfil to benefit from 10 years of market exclusivity once they have been authorised. The workshop will bring together medicine developers, regulators, healthcare professionals, academia, patients, health technology assessment bodies and healthcare payers who need toregister by 31 October 2015 if they wish to participate. The workshop will also be broadcast live. For further information   European Cytogenetesists Association  Date: February/March of each year Venue: Nimes, France This course is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification. The students will be trained to identify genetic abnormalities for diagnosis and prognosis, and for fundamental and applied research using both classical and molecular cytogenetic techniques. The course is co-organized by E.C.A. and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training. An application for CME points will also be made for 2016. For further information   EMA workshop on pre-licencing activities  Date: 9 March, 2016 Venue: Barcelona, Spain In collaboration with EMA, E-Rare will organize a workshop dedicated to Interactions between EMA and RD researchers on pre-licensing activities. The workshop will take place from 09:00 to 16:00 on the 9 of March 2015 in Barcelona, before the official start of the RE(ACT) meeting. It will be open to all researchers and interested stakeholders. The places for Face-to-face meetings with EMA officers are limited! If you would like to participate, please send an email to juliane.halftermeyer@agencerecherche.fr for further instructions.     What's on Where?    CLIMB Newborn Screening Conference  Date: 10 October, 2015 Venue: Birmingham, UK The CLIMB Newborn Screening Conference will be exploring four new conditions on the newborn screening programme, as well as current metabolic conditions. Midwives will have the opportunity to find out more about conditions that affect infants, including MCADD, PKU, Maple Syrup Disease and Glutaric Aciduria Type 1. For further information   Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico  Date: 15-16 October (ICORD), 12-16 October (Global Rare Disease Week, Mexico) Venue: Mexico City, Mexico ICORD 2015 will be held in México FD (México) 15-16 October in association with FEMEXER (the Mexican Federation of Rare Diseases) and GEISER Foundation (the Group of Linkage, Research and Support for Rare Diseases in Latin America). The event is part of the "Global Rare Diseases Week, Mexico 2015″ and back to back with the 4th Latin American meeting of Rare Diseases on October 12 and the Discoveries and Innovations in Orphan Drugs Congress, October 13-14. For further information   6th South Eastern European Cystic Fibrosis Conference  Date: 19-20 October, 2015 Venue: Bucharest, Romania This regional conference is a 2‐day symposium in Romania, addressing physicians, allied health professionals and patient representatives from the South Eastern European and Mediterranean region. For further information   NORD Summit  Date: 21-22 October, 2015 Venue: Virginia, United States The 2015 Breakthrough Summit is concentrated with innovative content and convenes the top leaders from the FDA, NIH, Industry, Patient Groups, Payers and Research Institutions to address the progress of rare disease diagnosis, genomics, drug development, patient engagement, patient-centered research models, product approva ls, FDA oversight and market access to orphan products. For further information   13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015  Date: 20-22 October, 2015 Venue: Beijing, China This conference will provide a unique opportunity for researchers from all over the world to meet, network, and forge new scientific interactions. For further information   The BioData World Congress 2015  Date: 21-22 October, 2015 Venue: Cambridge, United Kingdom This conference is held with the support of Intel, The Wellcome Trust Sanger Institute, The European Bioinformatics Institute, The Babraham Institute, BIA, BioNow, The Pharmacogenetics and Stratified Medicine Network and the Pistoia Alliance, BioData World Congress. For further information   6th World Congress on Targeting Mitochondria  Date: 21-22 October, 2015 Venue: Berlin, Germany This 6th World Congress on Targeting Mitochondria will cover a variety of new strategies and innovations as well as clinical applications in Mitochondrial Medicine. For further information   The AANEM Annual Meeting  Date: 28 -31 October, 2015 Venue: Hawaii, United States The AANEM Annual Meeting is the premier educational event for those involved in neuromuscular (NM) and electrodiagnostic (EDX) medicine. Earn over 30 continuing education credits through interactive workshops, lively discussions, and engaging sessions. For further information   4th European Congress on Rett Syndrome  Date: 30 October – 1 November, 2015 Venue: Rome, Italy For further information   First European Congress on Hereditary ATTR amyloidosis ECATTR  Date: 2-3 November, 2015 Venue: Paris, France The European Congress for HATTR will allow the meeting of the specialists of all European countries and the sharing of experience. The effort will be to further improve the early diagnosis of sporadic cases and genetic carriers, to review anti-amyloid treatments and clinical trials, to improve genetic counselling. For further information   2nd International Primary Immunodeficiencies Congress (IPIC)  Date: 5-6 November, 2015 Venue: Budapest, Hungary The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the Second International Primary Immunodeficiencies Congress (IPIC). This event will build on the successful outcomes of the first IPIC, attended by 400 participants. The congress will consist of a two-day programme and is open to all stakeholders with an interest in clinical management of primary immunodeficiencies (PIDs). For further information   Sixth Croatian Congress of Human Genetics  Date: 5-7 November, 2015 Venue: Zagreb, Croatia This conference will be an opportunity for education of the young interested in new achievements in various areas of genetics – clinical genetics, cytogenetics, molecular genetics and anthropology, and also to highlight the importance of prevention, diagnostics and treatment of rare diseases. For further information   16th International Conference on Human Genome Variation and Complex Genome Analysis  Date: 11-13 November, 2015 Venue: California, United States HGV2015 will bring together approximately 180 delegates (selected on the basis of their abstract submission) in a workshop-style atmosphere, with 25 internationally recognized speakers. For further information   Statistical analysis of massive genomic data  Date: 19-20 November, 2015 Venue: Evry, France This two-day cross-disciplinary conference will bring together biologists, geneticists, clinicians, bioinformaticians and statisticians in order to discuss emerging challenges raised by the analysis of high-throughput genomic data, and present dedicated innovative approaches. For further information   The Rett Syndrome Journey: Pathways to Follow  Date: 19-21 November, 2015 Venue: Victoria, Australia 'Pathways to Follow' on the journey with Rett syndrome will be explored in such areas as communication, health, therapies, education, equipment, caring for the carer, Commonwealth government, trusts, siblings, adulthood, family and equipment, to name just a few. For further information   6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals  Date: 21-22 November, 2015 Venue: Amsterdam, The Netherlands The 6th European Symposium on Rare Anaemias is an activity of the ENERCA project which aims to disseminate up-to-date knowledge and increase the public awareness about congenital and rare anaemias. This year, transversal topics centered on common medical problems of patients with sickle cell, thalassaemia and other forms of haemolytic anaemia will be one of the key points of the symposium. For further information   International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases  Date: 26 – 28 November, 2015 Venue: Geneva, Switzerland The aim of this second unique forum is to bring together some 200 participants from around the world, including scientists and clinicians, start-up leaders, and families of patients groups, to inform and strengthen exchange and cooperation. For further information   Clinical trials in small populations : Methodological challenges and solutions  Date: 30th November - 1 December 2015 Venue: London, UK The movement towards genetically tailored treatment regimens will further increase the number of small populations for whom new treatments are sought. This two day meeting will bring together researchers and practitioners to discuss state of the art methods for trials in small populations. For further information   CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference  Date: 9-10 January, 2016 Venue: Brussels, Belgium This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers. For further information   CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference  Date: 9-10 January, 2016 Venue: Brussels, Belgium This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers. For further information   BPSU Rare Disease Conference 2016  Date: 23 February, 2016 Venue: Birmingham, United Kingdom The conference will explore the theme 'Rare disease in paediatrics – from birth to transition'. It will centre on the child's journey from diagnosis through transition and end of life care. For further information   Clinical Innovation & Outsourcing  Date: 9-10 March, 2016 Venue: London, UK Clinical Outsourcing & Partnering World is the largest industry event focusing on the strategic and operational considerations in clinical outsourcing. It is a place where serious business contacts are made. Attended by senior decision makers, it's a platform which facilitates meetings between your sales force and prospects and it's a cost effective sponsorship package with year round advantage. For further information   The RE(ACT) Congress  Date: 9-10 March, 2016 Venue: Barcelona, Spain The congress aims to bring together world leaders and young scientist from a variety of breaking through scientific field to present cutting edge research, to discuss results and to exchange ideas. Moreover, many patients and patient organization, which are committed in research, will be present to share their experience. For further information   MYOLOGY 2016 Fifth International Congress of Myology  Date: 14-18 March, 2016 Venue: Lyon, France Held for the first time in 2000, MYOLOGY has become a unique opportunity for international experts in the field to exchange and confront the emerging therapeutic approaches, but also to share the first clinical results. The science and medicine of muscle have reached a new milestone. In Myology 2016, no doubt there will be new results, new breakthroughs to share all together. For further information   13th International Congress of Human Genetics (ICHG) 2016  Date: 3-7 April, 2016 Venue: Kyoto, Japan Hosted by the East-Asian Union of Human Genetic Societies (EAUHGS) and the Japan Society of Human Genetics, the 13th ICHG will focus on progress in genome analysis technologies and big data in order to explore disease mechanisms and treatment opportunities. Registrations open in 2015. For further information   8th Alstrom Syndrome International Conference  Date: 12-16 May, 2016 Venue: Massachusetts, USA This international conference will have a scientific symposium for clinicians and researchers as well as sessions for parents, caretakers and patient organisations. For further information   17th EMSOS Nurse and allied professional Group Meeting  Date: 12-16 May, 2016 Venue: Massachusetts, USA The meeting will be focussing on Ewing sarcoma, margins, pelvic tumours, targeted therapy; open sessions will offer the opportunity to report and discuss the latest results in all fields. For further information   European Association of Centres of Medical Ethics Conference  Date: 8 -10 September, 2016 Venue: Leuven; Belgium The focus of this year's conference is on a variety of highly relevant ethical issues in health care:  Organizational Ethics in Health Care: Principles, Cases and Practical Solutions  Ethical Issues in Care for Older Persons  Ethical, Legal and Social Developments in Human Genomics  Ethics and Integrity in Research For further information   9th ISNS International meeting/10th ISNS European Regional meeting  Date: 11-14 September, 2016 Venue: The Hague, the Netherlands The conference will aid the sharing of neonatal screening experiences for congenital metabolic disorders, its clinical diagnostics and follow-up, and will facilitate learning from other experiences. The programme will consist of plenary lectures, oral presentations and poster sessions and will be attractive for professionals, patient/advocacy groups, policy makers and industrial partners. The programme will include evaluation of performance of neonatal screening systems and strategies for improvement. For further information   ESID European Society for Immunodeficiencies: Biennial meeting  Date: 21-24 September, 2016 Venue: Barcelona, Spain Sessions at this meeting will be devoted to understanding primary immunodeficiencies and their clinical aspects. For further information     Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Rare Diseases OrphaNews : the newsletter of the Rare Disease Community  Editorial  RD-ACTION: the new European Rare Disease Joint Action RD-ACTION, the new Joint Action consisting of the member states of the European Union for rare diseases, was launched on 17 September in Luxembourg, under the auspices of John Ryan, Acting Director of the Health Division and Food Security (DG Health), Jacques Remacle, Head of Health CHAFEA unit (Consumers, Health, Agriculture and Food Executive Agency) and Patrice Dosquet, representing the French Ministry of Health. Following the two previous Joint Actions - Orphanet Joint Action and EUCERD - RD-ACTION represents renewed support of the European Commission (EC) to rare diseases, through its Directorate General for Health (DG SANTE). RD-ACTION has three main objectives: - to contribute to the implementation, by member states, the recommendations of the EC Panel in relation to policies on these diseases, - support the development of Orphanet and make it sustainable, and finally - help Member States to introduce the ORPHA code in their health systems to make rare diseases visible. With a global budget of €8,344,079, this work will last three years (until June 2018), following the logic of coherence and continuity vis-à-vis the previous actions, but aims to go further in terms of concrete implementation and consolidation policies. This action is coordinated by Orphanet (INSERM), bringing together no less than 63 European and non-European participants. The responsibility of implementing the various actions will be carried out by Orphanet (Ana Rath), University of Newcastle (Kate Bushby, coordinator of theEUCERD Joint Action which just ended), the German Institute for Documentation and Medical Information DIMDI (Stefanie Weber), the University of Vienna (Till Voigtländer) and EURORDIS (Yann LeCam). The National Bank of Rare Diseases Data (BNDMR) represented by Rémy Choquet, will work towards the codification, notably the requirement of definition and bringing solutions to the Member States for the implementation of coding rare diseases. DIMDI and the Register of the Venetian region (Paola Facchin) will drive the implementation and testing of these solutions. EURORDIS will work towards dissemination actions along with Orphanet and Higher Health Institute (ISS, Italy). The dissemination actions include the 8th European Conference on Rare Diseases and Orphan Products, 26-28 May 2016, Edinburgh. The Directorate General of Health (DGS France, represented by Patrice Dosquet) will lead the work towards a financially sustainable European Orphanet database. RD-ACTION was designed in the spirit of integration and coherence between the data produced by Orphanet, which provides, among others, the necessary analysis towards policy recommendations, and political action that will then guide the production, operation and dissemination of this data. Participants will ensure effective communication between the reality of each state and the EC Panel, in order to concretely support the implementation of their recommendations. Read the European Commission press release on RD ACTION     Spotlight on...  Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future  On 15 September, over 50 participants from across Europe attended the Final Conference of the EUCERD Joint Action. This event was organised to show case the achievements of the Joint Action, which ran from March 2012 to November 2015, and to analyse the current state of the art of rare disease activity across the European Union, by exploring progress and remaining challenges in key areas such as healthcare, social care and research. The even was a good opportunity to strenghten collaborations with the stakeholders present and relevant initiatives in the field, and to provided the apt moment to hand over the activities led by the Joint Action to the next Joint Action on rare diseases, RD-Action (see Editorial). The outcomes of the EUCERD Joint Action, in particular the resources and recommendations elaborated in collaboration with the European Union Committee of Experts on Rare Diseases and EC Expert Group on Rare Diseases, were presented in the morning session. Participants heard about topics as diverse as quality of care and centres of expertise, RD European Reference Networks, social services for RD, cross-border genetic testing and the codification of rare diseases. The work lead in the context of the Joint Action in support to the EUCERD and Commission Expert Group on Rare Diseases has led to the adoption of 5 recommendations in the past three years, with two other recommendations, on genetic testing and social care under discussion currently. In terms of important resources for the community, the Joint Action also supported the elaboration of the annual report on the State of the Art of Rare Diseases Activities in Europe, a 'go-to' source of information on activities in the field of at national and European level aimed at promoting the exchange of information and monitoring the implementation of rare disease policy: this report will continue to be produced in a more dynamic format in the future RD-Action (see Editorial). The presentations of the activities of the Joint Action were followed by three sessions dedicated to priority areas in the field of rare diseases, informing participants about the latest outcomes of a number of European projects in each area and the efforts made by the EUCERD Joint Action to explore synergies and to link this work into the discussions at the level of the EC Expert Group on Rare Diseases. The first of these sessions was dedicated to Rare Disease Research, Therapeutics and Translation into the Sphere of Health, with presentations from the Rare Best-Practices project, Burqol-RD, a project aimed at exploring the impact of health policies, interventions and treatments in the field of rare diseases, the transnational research support mechanism E-Rare, and the International Rare Disease Research Consortium concerning the impact of IRDiRC policies at national level. The main issued discussed during this session was that of sustainability of the resources produced via these initiatives, and the importance in particular of research into health economics, as regards rare diseases, to inform the implementation of rare disease policies at national level. The following session explored the integration of the results of a number of initiatives concerning rare disease registries, a field where the EU has invested resources through a multitude of projects (such as EPIRARE, the EUCERD Joint Action, and the PARENT Joint Action) with a view to developing an appropriate model for a European Platform for Rare Disease Registration. This platform, recently created at the EC's Joint Research Centre in Ispra, Italy, has to date taken over the responsibilities for the management of the central support of the Eurocat congenital anomalies registry, and the European Surveillance of Cerebal Palsy registry. Stakeholders in the field of rare diseases are still waiting from the JRC confirmation of the governance structure, road map and list of services to be provided by the Platform. In particular, Member States who are in the process of creating national rare disease registration systems, or who are considering this direction, are looking for confirmation of the possible support that will be provided, and the guidelines for interoperability (such as a minimum data set) which could be expected. The final session was dedicated to national plans and strategies for rare diseases, in particular support to the implementation of national activities in this area. The EUCERD Joint Action, continuing the activities of the Europlan project (2008-2011) supported the organisation of over 20 national conferences and debrief sessions across Europe with the close collaboration of national patient alliances and organisations, to ensure the tranmission of European recommendations at national level and appropriate support to Member States in the elaboration and/or implementation of their initiatives. To date, nearly all European Member States have adopted a plan/strategy for rare diseases, with those not yet having adopted a plan in the final stages of elaboration. The next challenge will be the implementation of these plans/strategies, for which very few have a dedicated budget and for some of which need to be translated into concrete actions. The EUCERD Joint Action, through the national conferences and an analysis of these plans, has been able to extract a number of good practices that could help Member States in the implementation of their plans, which will be available shortly. The day finished by establishing the list of possible priorities in the rare disease policy field to be explored by the Expert Group on Rare Diseases with the support of the new RD-Action for rare diseases (see Editorial). The Commission and the Coordinator of the EUCERD Joint Action, Kate Bushby, thanked the partners and the many participants in the conferences and workshops organised over the past 3 years, for their hard work and wished them success in the future work of the next Joint Action. The report of the conference will soon be available online.     EU Policy News  EMA  Submit expressions of interest to represent civil society at the EMA  The Health and Food Safety Directorate-General of the European Commission has extended the deadline for its calls for expressions of interest to represent civil society in two scientific committees of the European Medicines Agency (EMA): the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Advanced Therapies (CAT). For both calls, expressions of interest should be submitted to the European Commission no later than 18 October 2015, either by email or post. Further information on the assessment criteria and the application process can be found on the Commission's website. Call for civil society members to join two EMA committees     National & International Policy Developments  Comprehensive policy for patients with rare diseases in Philippines  The House of Representatives in Philippines recently approved a comprehensive policy on services for patients with rare diseases that will provide them with timely and adequate access to healthcare, information, and products to treat their conditions. This will be done primarily through the establishment of a comprehensive and sustainable health system for identification, referral, and management of patients with rare diseases—integrated within the current public health system; and the inclusion of rare disease benefit package in PhilHealth. The bill stipulates giving regulatory and fiscal incentives to support research and development activities on rare diseases and manufacturing of affordable drugs or products. Likewise, the bill provides for the design and maintenance of a rare disease registry containing data on cases, patients, drugs and products for rare diseases. Data from the registry will be used in policy formulation. The provisions in the bill are set to address the current challenges being faced by patients afflicted with rare diseases, their families and caregivers, and their healthcare providers. This bill defines a rare disease as one that affects 1/20,000 in the Philippines. It provides a preliminary list of rare diseases and the provision of inclusion of others under the advisement of the National Institute of Health in the United States. Read the report on this topic by National Academy of Science and Technology, Philippines  Other European news  The rare disease persons card implementation in Portugal  The Portuguese Ministry of Health Shared Services and Directorate General of Health, recently announced the implementation of the Rare Disease Person's Card (RDPC). Coded using the ORPHA code system, this card is meant to identify the rare disease patient and display the relevant information of the condition as well as information especially required during an emergency situation. An article published in Procedia Computer Science describes the process of preparation, approval and the regulatory model of the card. According to the authors, due to nascent stage of the implementation of these cards, there is still room for the card to evolve and expand. Still, 828 cards have been requested through the family physician of the concerned patients, regarding 738 different rare diseases, half of which have been activated. The card is increasing awareness and empowerment of rare disease's patients, pushing the project forward and improving health care. Download the document from Direcção-Geral da Saúde Read the open access article   Sample of the adult British population want genetic testing of children for adult-onset conditions  Almost all the guidelines published till date on genetic testing on children for adult onset conditions recommend deferring such tests unless there is a clear indication that it will prevent the future outcome of the condition. Whether the general public agrees with this recommendation is addressed in an article published in European Journal of Human Genetics. Testing the attitudes of a representative sample of the adult-British public revealed that, contrary to the guidance documents, 47% believed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. Younger respondents of the survey and men were more likely to support this kind of testing as well as carrier testing. The authors also presented 4 arguments in support of deferring testing to the participants, out of which "a child's future ability to decide for her/himself if and when to be tested" was generally the least supported argument in the sample. However, the authors noted that women were significantly more likely to consider all 4 arguments as valid to defer testing for adult onset conditions. Read the Open Access article   Sample of Danish population want disclosure of incidental findings from NGS studies  Another article has studied an equally contentious issue –disclosure of incidental findings - is published in European Journal of Human Genetics. Here the authors also find that contrary to the recommendations of professional organisations, participants in next generation studies wanted disclosure of all incidental findings. The authors investigated if participants recruited from the Region of Southern Denmark want disclosure of incidental findings and which ones would they want to know more about. According to the authors most participants wanted disclosure of all incidental findings; only 3% did not want any disclosure, while 36% wanted disclosure only on actionable variants. According to the authors due to the disparity of opinion between the official recommendation and the sample studies "options for reporting IFs in research studies (could) be incorporated in the consent form." Consult the Pubmed abstract  Other International News  Discussion paper by the Australian government to support people with chronic and complex health conditions  To better support people with chronic and complex health conditions, the Australian Government has released a discussion paper by the Primary Health Care Advisory Group, to examine options for health reform and provide a report to the Australian Government in late 2015. The paper is designed to set out the case for change and introduce some possible options to improve primary health care for people with chronic and complex conditions. In order to engage all stakeholders, consultation will be held with the Advisory Group. Results of the survey that accompanied the discussion paper will be out shortly. Read more on Therapeutic Goods Administration, Australia   Contradictions of public health policies geared to rare disorders in Brazil  A paper published in Portuguese presents information of the rare disease health policy in Brazil, using the example of Ostegenesis Imperfecta. The paper details the contradictions, especially with respect to therapeutic decisions and the strengthening of the specialized network for addressing this condition which are expressed in the drafting and final text of the new law. Consult the Pubmed abstract   Sickle cell disease among children in Africa  An article published in International Journal of Africa Nursing Sciences provides an integrative review of 63 references related sickle cell disease among children in Africa, focussing on the incidence, prevalence, morbidity, and mortality; current practices and challenges related to screening, diagnosis, and treatment. From this data the authors also provide recommendations for practice, policy, and research to improve health outcomes of children with sickle cell disease in Africa. Read the Open Access article  Guidance Documents and Recommendations  22q11.2 deletion syndrome: guidelines for the management  Consult the Pubmed abstract  To read more about "22q11.2 deletion syndrome"  Genet Med. ; 17(8):599-609 ; August 2015  Cushing syndrome: guidelines on treatment  Consult the Pubmed abstract  To read more about "Cushing syndrome"  J Clin Endocrinol Metab. ; 100(8):2807-31 ; August 2015  Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment  Consult the Pubmed abstract  To read more about "Congenital hypogonadotropic hypogonadism"  Nat Rev Endocrinol. ; 11(9):547-64 ; September 2015  Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment  Consult the Pubmed abstract  To read more about "Pemphigus vulgaris" To read more about "Pemphigus foliaceus" To read more about "Bullous pemphigoid"  J Dtsch Dermatol Ges.   Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management  Consult the Pubmed abstract  To read more about "Facioscapulohumeral dystrophy"  Neurology ; 85(4):357-64 ; July 2015  Bioinformatics, Registries and Data Management  How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population  Guidelines such as Code of Federal Regulations and WMA Declaration of Helsinki recommend expressed consent from the paediatric population before inclusion of their health data in biobanks. This issue has brought forth many ethical concerns especially with regards to the child's role in these procedures which is discussed in an article published in European Journal of Human Genetics. The authors of this article provide the results of an international multiple-case study which included four biobanks addressing diverse health concerns with the collection of a variety of data from the paediatric population. They addressed "four themes linked to the child's role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate." This study recognises the motives to involve consent of the child where respect for the child as an intrinsic motive to involve children while adherence to regulation was recognised by all as important. The authors also detail how personal verbal information is utilised for informing the child even though it is not mentioned in the regulation. While the authors say that assent and consent differs between biobanks, the question of how respecting dissent - is followed by the biobanks is unclear. The authors also show that although children agree to participate in biobanks to different reasons, coercion from parents may be the overarching one. The authors believe that these "insight(s) (are) valuable when designing paediatric biobank governance." Read the Open Access article   Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders  An article published in Genetics Research discusses how next generation sequencing (NGS) based research on rare diseases has come a long way and the effect of long tail economics on rare diseases research. Long tail statistics has been commonly used to understand the rise of internet retailers, crowdfunding, crowdsourcing etc., where a large share of the data rests within its tail unlike a normal distribution. The authors believe that the trend observed in rare disease research, especially in terms of the developments in NGS, can benefit from the two themes derived from long tailed economics - increased access and reduced cost. In this context, increased access would mean that the researcher would be able to look through a sea of data produced thanks to whole genome and whole exome sequencing and find what they are looking for (gene, disease, phenotype) . They also detail the developments in bioinformatics that has led to the development of this enormous amount of data which in turn required better curative and sharing efforts. The authors refer reduced cost to the reduction of overhead costs by centralising resources where the curative and sharing efforts come in play. They also address the issue of reimbursement that comes with the rising cost of sequencing. According to the authors "as a long-tailed problem, continued discovery of rare diseases requires a funding infrastructure that can sustainably support the work needed to identify the great number of rare diseases", for which they believe a good source is crowdfunding. The authors believe that "the principles derived from long-tail economics shape our understanding of the recent development of this field and offer insight towards needed improvements." The authors of this article belong to the Rare Genomics Institute that has recently launched 10 crowdfunding campaigns to sequence exomes of rare disease patients. Read the PubMed abstract  Screening and Testing  Regulating laboratory developed tests in the United States: the current controversy  A perspective published by stakeholders in Genetic Testing and Molecular Biomarkerscomments on the current legislation mandating the United States Food and Drug Administration as the regulatory body overseeing Laboratory Developed Tests (LDTs). The authors explain that historically LDTs are subject to regulation by the Clinical Laboratory Improvement Amendments (CLIA) of Centers for Medicare and Medicaid Services (CMS). However, in 2015, the FDA announced the establishment of the FDA/CMS Task Force on LDT Quality Requirements to oversee changes to the LDT regulatory landscape. The FDA described a premarket review process that would require confirmation of the analytical and clinical validity of new LDTs before the lab is permitted to administer those tests. Following this announcement a debate has ensued in the context of the 21st Century Cures Act with valid arguments from supporters and detractors due to which the Congress has requested for feedback. However, the resulting whitepaper did not contain specific information directly addressing this issue. The authors express concern that stakeholders are still speculating about the trajectory of LDT regulation. Access the review   Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests  A related article published in the Food and Drug Law Journal addresses FDA's current mandate to regulate laboratory developed diagnostic tests. The author believes that this oversight could prove to be intrusive and has the potential to slow the progress of genomic discovery, interfere with scientific inquiry and suppress investigators' and clinicians' rights to freedom of speech and prove to be federalist in action (U.S wants states to mandate practise of medicine). According to the author this article is written with the goal to help genomics researchers understand how FDA's research regulations may apply to research that uses high-throughput DNA sequencing. Read the Open Access article   Newborn screening in Australia: current environment and future perspectives  The current state of newborn bloodspot screening in Australia and the lessons it needs to learn from international programmes to upgrade its operation is explained in Frontiers in Public Health. The authors say that NBS has been operating successfully in Australia for almost 50 years but currently it does not have any coherent national policy or decision-making process that is concurrently agreed by government. The authors describe the policy environment in the United States, United Kingdom and New Zealand which could provide useful information. In Australia the establishment of the Australian Screening Advisory Committee in 2001, now known as the Standing Committee on Screening has played an important role in providing guidance on what constitutes a good screening program through the development of the Population-Based Screening Framework in 2008. However, the authors believe that Australia is operating in an environment, which lacks a considered decision-making process for government, particularly in regards to assessing conditions for screening. The authors believe that changes to newborn screening programs should be planned instead of being reactive often in response to new technologies. The authors provide several options to overcome the funding barrier, which they describe as chief obstacle, to developing and implementing a national decision-making framework for newborn screening in Australia. They believe that a national decision-making approach, supported by state implementation of decisions, would support consistent decision making across local-level programs. Read the Open Access article   Patenting Genetic diagnostic methods  An article published in the Journal of Law and Medicine reviewed and analysed the relevant law in Australia and the United States to assist sponsors claiming patents for "diagnostic methods associated with genome-wide association studies (GWAS), adopting methodologies using next generation sequencing (NGS) and single nucleotide polymorphism (SNP)." The authors provide reasonable solutions to commonly experienced questions while patenting these technologies: experimental reproducibility and the credibility and veracity of the technology. Read the Open Access article     Ethical, Legal & Social Issues  Living with Marfan syndrome: the patients view  A study published in Clinical Genetics explores the psychosocial aspects of Marfan syndrome (MFS) by collecting available literature followed by synthesising and critically appraising them. The authors studied 15 articles that satisfied the eligibility criteria and found that MFS significantly impacts various areas of the patient's life such as education, work, family and transition to adulthood. They also experienced decreased Health Related Quality of life, depression and anxiety. Interestingly, the authors also noted that the studies show there was a considerable disconnect between the discomfort that the patient experiences and how professionals view it. According to the authors the studies demonstrate that "the subjective perception of discomfort did not necessarily match the medical severity of a disease." Consult the Pubmed abstract     New Syndromes  Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4  Using exome analysis, the authors identified recessive mutations in SLC1A4 in ten Ashkenazi-Jewish patients from eight families who shared similar clinical features of developmental delay, microcephaly and hypomyelination. Seizure disorder was variably present. Consult the Pubmed abstract  J Med Genet. ; 52(8):541-7 ; August 2015  Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation  The authors described a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability in two unrelated individuals. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. Consult the Pubmed abstract  Eur J Med Genet. ; 58(8):387-91 ; August 2015  Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X  The authors presented 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with intellectual disability and various other features including hypotonia, movement disorders, behaviour problems, corpus callosum hypoplasia, and epilepsy. They also found missense variants in DDX3X in males from three families with intellectual disability suggestive of X-linked inheritance. Consult the Pubmed abstract  Am J Hum Genet. ; 97(2):343-52 ; August 2015  Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63  The authors reported on a 3-year-old male with intellectual disability, characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion leading to haploinsufficiency of TP63. The father, carrying the same deletion, presented with cleft palate, nail dystrophy and learning difficulties. Consult the Pubmed abstract  Eur J Med Genet. ; 58(8):400-5 ; August 2015  New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations  The authors characterized three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. Consult the Pubmed abstract  Hum Mol Genet. ; 24(17):4984-96 ; September 2015  Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2  The authors studied a consanguineous Palestinian Arab family presenting an autosomal recessive progressive myoclonus epilepsy with early ataxia. A novel homozygous missense mutation was identified in LMNB2 that segregated with the progressive myoclonus epilepsy in the family. Consult the Pubmed abstract  Hum Mol Genet. ; 24(16):4483-90 ; August 2015  Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations  The authors reported inherited dysregulation of protein phosphatase activity as a cause of intellectual disability. De novo missense mutations in PPP2R5D and PPP2R1A were identified in 16 individuals with mild to severe intellectual disability, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. Consult the Pubmed abstract  J Clin Invest. ; 125(8):3051-62 ; August 2015    New Genes    Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins  Consult the Pubmed abstract  To read more about "Atypical Rett syndrome"  Eur J Hum Genet. ; 23(9):1171-5 ; September 2015  22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype  Consult the Pubmed abstract  To read more about "22q11.2 deletion syndrome"  Hum Mutat. ; 36(8):797-807 ; August 2015  X-linked intellectual disability due to THOC2 mutations in four families  Consult the Pubmed abstract  Am J Hum Genet. ; 97(2):302-10 ; August 2015  Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586  Consult the Pubmed abstract  To read more about "Hydrolethalus" To read more about "Short rib-polydactyly syndrome, Majewski type" To read more about "Short rib-polydactyly syndrome, Beemer-Langer type"  Am J Hum Genet. ; 97(2):311-8 ; August 2015  Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient  Consult the Pubmed abstract  To read more about "Coenzyme Q10 deficiency"  Eur J Hum Genet. ; 23(9):1254-8 ; September 2015  Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child  Consult the Pubmed abstract  J Med Genet. ; 52(8):532-40 ; August 2015  Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D  Consult the Pubmed abstract  To read more about "Overgrowth syndrome"  Hum Mol Genet. ; 24(17):4775-9 ; September 2015  Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family  Consult the Pubmed abstract  To read more about "Cone rod dystrophy"  Hum Mutat. ; 36(9):836-41 ; September 2015  Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11  Consult the Pubmed abstract  To read more about "Megacystis-microcolon-intestinal hypoperistalsis syndrome"  Eur J Hum Genet. ; 23(9):1266-8 ; September 2015  Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion  Consult the Pubmed abstract  To read more about "Heterotaxia" To read more about "Situs inversus totalis"  Eur J Hum Genet. ; 23(9):1262-5 ; September 2015  Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations  Consult the Pubmed abstract  To read more about "Familial idiopathic steroid-resistant nephrotic syndrome"  Eur J Hum Genet. ; 23(9):1192-9 ; September 2015  Small cell lung cancer: somatic mutations in TP53, TP73 and RB1  Consult the Pubmed abstract  To read more about "Small cell lung cancer"  Nature ; 524(7563):47-53 ; August 2015  Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR  Consult the Pubmed abstract  Nat Genet. ; 47(8):861-3 ; August 2015  Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene  Consult the Pubmed abstract  To read more about "Fetal akinesia deformation sequence"  Eur J Hum Genet. ; 23(9):1151-7 ; September 2015  Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions  Consult the Pubmed abstract  Hum Mutat. ; 36(9):842-50 ; September 2015  Keratoconus: WNT10A exonic variant increases the risk of disease  Consult the Pubmed abstract  To read more about "Keratoconus"  Hum Mol Genet. ; 24(17):5060-8 ; September 2015    Research in Action  Clinical Research  Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific  Consult the Pubmed abstract  To read more about "Dravet syndrome"  Neurology ; 85(7):596-603 ; August 2015  Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate  Consult the Pubmed abstract  To read more about "Progressive familial intrahepatic cholestasis type 2"  Hepatology ; 62(2):558-66 ; August 2015  Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema  Consult the Pubmed abstract  To read more about "Alpha-1-antitrypsin deficiency"  Lancet ; 386(9991):360-8 ; July 2015  Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy  Consult the Pubmed abstract Consult the study on Orphanet  To read more about "Recessive dystrophic epidermolysis bullosa-generalized other" To read more about "Severe generalized recessive dystrophic epidermolysis bullosa"  J Invest Dermatol. ; 135(9):2319-21 ; September 2015  Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness  Consult the Pubmed abstract  To read more about "Facioscapulohumeral dystrophy"  Neurology ; 85(5):396-403 ; August 2015  Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy  Consult the Pubmed abstract  To read more about "Extranodal nasal NK/T cell lymphoma"  Mol Ther. ; 23(8):1401-9 ; August 2015  Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients  Consult the Pubmed abstract  To read more about "Carcinoma of the ampulla of Vater" To read more about "Cholangiocarcinoma" To read more about "Carcinoma of gallbladder and extrahepatic biliary tract"  Lancet Oncol. ; 16(8):967-78 ; August 2015  Paraganglioma in pregnancy: a case series and review of the literature  Consult the Pubmed abstract  J Clin Endocrinol Metab. ; 100(8):3202-9 ; August 2015  Salla disease: 13-year follow-up of Finnish patients  Consult the Pubmed abstract  To read more about "Salla disease"  J Neurodev Disord. ; 7(1):20 ; 2015  Therapeutic Approaches    Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models  Consult the abstract  To read more about "Jervell and Lange-Nielsen syndrome"  Rare Diseases ; 1(3) :1-4 ; 2015  Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice  Consult the Pubmed abstract  To read more about "Huntington disease"  Hum Mol Genet. ; 24(17):4958-70 ; September 2015  Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus  Consult the Pubmed abstract  To read more about "Ebola hemorrhagic fever"  J Clin Invest. ; 125(8):3241-55 ; August 2015  Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model  Consult the Pubmed abstract  To read more about "Dystrophic epidermolysis bullosa"  Mol Ther. ; 23(8):1368-79 ; August 2015  Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model  Consult the Pubmed abstract  To read more about "Retinitis pigmentosa"  Mol Ther. ; 23(8):1308-19 ; August 2015  Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models  Consult the Pubmed abstract  To read more about "Leber congenital amaurosis" To read more about "Retinitis pigmentosa"  Gene Ther. ; 22(8):619-27 ; August 2015  Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model  Consult the Pubmed abstract  To read more about "Duchenne muscular dystrophy"  Mol Ther. ; 23(8):1285-97 ; August 2015  Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice  Consult the Pubmed abstract  To read more about "Steinert myotonic dystrophy"  Hum Mol Genet. ; 24(17):4971-83 ; September 2015  Fragile X-associated tremor/ataxia syndrome: new inducible mouse model  Consult the Pubmed abstract  To read more about "Fragile X-associated tremor/ataxia syndrome"  Hum Mol Genet. ; 24(17):4948-57 ; September 2015  Diagnostic Approaches    Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified  Consult the Pubmed abstract  To read more about "Walker-Warburg syndrome"  Eur J Med Genet. ; 58(8):372-5 ; August 2015  Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis  Consult the Pubmed abstract  To read more about "Susac syndrome"  Neurology ; 85(7):610-8 ; August 2015  CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging  Consult the Pubmed abstract  To read more about "CARASIL"  Neurology ; 85(5):459-63 ; August 2015    Patient Management and Therapy  Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment  Consult the fisrt abstract Consult the second abstract  To read more about "Cystic fibrosis"  Expert Opinion on Orphan Drugs. ; 3(8):957-966; 3(8):933-943 ; August 2015  Fanconi anemia: review on gene therapy  Consult the abstract  To read more about "Fanconi anemia"  Expert Opinion on Orphan Drugs. ; 3(8):899-910 ; August 2015  Lymphangioleiomyomatosis: review on new treatments  Consult the Pubmed abstract  To read more about "Lymphangioleiomyomatosis"  Lung ; 193(4):467-75 ; August 2015  Blepharospasm: review on alternatives to botulinum toxin for the management Id:  Consult the abstract  Expert Opinion on Orphan Drugs ; 3(8):877-885 ; August 2015  Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management  Consult the first abstract Consult the second abstract  To read more about "Congenital isolated hyperinsulinism"  Expert Opinion on Orphan Drugs ; 3(8):887-898 ; August 2015Research and Reports in Endocrine Disorders ; (5):103-117 ; July 2015  Kawasaki disease: a review  Consult the Pubmed abstract  To read more about "Kawasaki disease"  Nat Rev Rheumatol. ; 11(8):475-82 ; August 2015  Paediatric rheumatology: review on lessons from oncology to optimize treatment  Consult the Pubmed abstract  Nat Rev Rheumatol. ; 11(8):493-9 ; August 2015  Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation  Consult the abstract  To read more about "Metachromatic leukodystrophy"  Expert Opinion on Orphan Drugs ; 3(8):911-919 ; August 2015  B-cell non-Hodgkin lymphoma: review on the treatment  Consult the abstract  To read more about "B-cell non-Hodgkin lymphoma"  Expert Opinion on Orphan Drugs ; 3(8):921-932 ; August 2015  Huntington disease: a review  Consult the abstract  To read more about "Huntington disease"  Rare Diseases ; Volume 3, Issue 1 ; 2015  MECP2 disorders: a review  Consult the Pubmed abstract  To read more about "Trisomy Xq28" To read more about "Rett syndrome"  J Clin Invest. ; 125(8):2914-23 ; August 2015  Glycogen storage disease due to acid maltase deficiency: a review  Consult the abstract  To read more about "Glycogen storage disease due to acid maltase deficiency"  Rare Diseases ; Volume 3, Issue 1 ; 2015  Congenital generalized lipodystrophies: a review  Consult the Pubmed abstract  Nat Rev Endocrinol. ; 11(9):522-34 ; September 2015  Ribosomopathies: a review  Consult the abstract  Rare Diseases ; Volume 3, Issue 1 ; 2015  Duchenne muscular dystrophy: a review  Consult the abstract  To read more about "Duchenne muscular dystrophy"  Rare Diseases ; Volume 3, Issue 1 ; 2015  Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening  Consult the abstract  To read more about "Familial dilated cardiomyopathy"  Expert Opinion on Orphan Drugs ; 3(8):869-876 ; August 2015  Tuberous sclerosis: review on pathophysiology  Consult the abstract  To read more about "Tuberous sclerosis"  Rare Diseases ; Volume 3, Issue 1 ; 2015  West-Nile encephalitis: a review  Consult the Pubmed abstract  To read more about "West-Nile encephalitis"  Lancet Infect Dis. ; 15(8):951-9 ; August 2015  Idiopathic interstitial pneumonias with connective tissue diseases features: a review  Consult the Pubmed abstract  Respirology ; [Epub ahead of print] ; July 2015  Primary biliary cirrhosis and primary sclerosing cholangitis: a review  Consult the Pubmed abstract  To read more about "Primary biliary cirrhosis" To read more about "Primary sclerosing cholangitis"  Hepatology ; 62(2):635-43 ; August 2015  Eosinophilic esophagitis and gastroenteritis: a review  Consult the Pubmed abstract  To read more about "Eosinophilic esophagitis" To read more about "Eosinophilic gastroenteritis" To read more about "Eosinophilic colitis"  Curr Allergy Asthma Rep. ; 15(9):558 ; September 2015  T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment  Consult the abstract  To read more about "T-cell large granular lymphocyte leukemia"  Expert Opinion on Orphan Drugs ; 3(8):859-867 ; August 2015  One new and nine updated GeneReviews published  GeneReviews are expert-authored, peer-reviewed disease descriptions ("chapters") presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions. One new GeneReviews has been published for: Lysosomal acid lipase deficiency Nine updated GeneReviews have been published for: Cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders Andersen-Tawil syndrome EZH2-related overgrowth Hereditary leiomyomatosis and renal cell cancer Myotonia congenita TP63-related disorders Von Hippel-Lindau syndrome Mucolipidosis IV OTOF-related deafness    Orphan Drugs  Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe  Since the introduction of conditional marketing authorisation by the European Medicines Agency in 2004, patients have gained access to drugs which fulfil an urgent and unmet need. A paper published in European Journal of Internal Medicine examines whether the conditionally approved drugs manage to obtain comprehensive evidence confirming that the risk-benefit balance is positive to obtain full marketing authorisation and the time taken to reach it. The authors identified 24 products conditionally authorised for sale, between the years 2006-2015, out of which 9 were orphan drugs and 3 had orphan status. Till date 10 medicinal products have been switched to regular approval while 14 of them are still under conditional approval. The authors demonstrate that the median time for the ten conditional approvals to finish their specific obligations and switch to regular marketing authorisations was five years, noting delays, discrepancies and lack of information on some of these drugs. Overall, the median time allowed to address the specific obligations is four years. The median time to fulfil obligations for drugs still conditional is nearly twice that of those converted. Of the 14 medicinal products still under conditional approval, nine have specific obligations whose timeframes go beyond 2015 but some of these did not have up-to-date information on the trials that need to conducted to address the obligations. Out of the drugs that have to fulfil their obligations this year, almost all of them have delays and discrepancies. From the data gathered the authors caution that the conditionally approved drugs without fully established clinical value are in the market for long periods and question whether the public health advantage outweigh the risks of limited clinical information. Consult the Pubmed abstract   Wanted: new models of pricing and reimbursement for gene therapies  The debate on pricing and reimbursement is currently rife, especially in the area of rare diseases. Gene therapy and its pricing add another layer of complexity as discussed in an article published in Nature Biotechnology (discussed in OrphaNews) on Glybera – a gene therapy with a whopping €1.1 million price tag for a one-time treatment. In the same journal, how the 'payers,' either public or private, are concerned with both the price levels routinely mentioned for gene therapies and the pricing and reimbursement (P&R) approaches is discussed in a Letter to the Editor. The authors contacted payers in the United States and Western Europe to identify their top two choices for payment. They report that in the absence of health system constraints, payers prefer annuities as it reduces initial financial strain, leadS to predictable yearly budget impact and reflect the ongoing value of gene therapy. However, the authors point out that in the real world, approaches based on a lump sum payment represent the large majority. According to the authors payers might accept high price tags for gene therapies if industry develops sound and rational pricing & reimbursement approaches based on payer perceived value. The survey demonstrated that payers preferred that gene-therapy reimbursements should model organ transplants procedures (a one-time procedure) rather than protein-replacement therapy (requires frequent dosage). The article suggests a new era in pharmaceutical economics where 'cost-effectiveness' may not necessarily be equated with 'affordability'. Access the Letter to the Editor  Regulatory News  FDA approves new orphan drug to treat 20 patients worldwide The U.S. Food and Drug Administration (FDA) approved Xuriden (uridine triacetate), the first FDA approved treatment for patients with hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disorder, which has been reported in approximately 20 patients worldwide. Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesise uridine. Signs and symptoms of the disease include blood abnormalities, urinary tract obstruction, failure to thrive, and developmental delays. The approval of this drug was based on the results from a 4‑patient 6‑week clinical trial with a 6‑month extension phase. Wellstat - the sponsor of this drug has not yet disclosed the price of this ultra orphan drug Read the FDA press release   New treatment option for patients with multiple myeloma  The European Medicines Agency (EMA) has recommended granting a marketing authorisation for Kyprolis (carfilzomib) to treat patients with multiple myeloma whose disease has relapsed (i.e. the cancer has come back after receiving at least one prior course of therapy). Kyprolis is for use in combination with the cancer medicines lenalidomide and dexamethasone. Multiple myeloma is a rare and life-threatening cancer of a type of white blood cell, called plasma cells, which originate in the bone marrow. Carfilzomib is the first irreversible, highly-selective, proteasome inhibitor for multiple myeloma. The irreversible binding to the targeted proteasome leads to a more sustained inhibition with minimal inhibition of other non-targeted enzymes. Read the EMA press release     Grants    Medical Research Grant Application Guidelines : Progeria Research Foundation  The foundation is proving several grants such as Innovator Awards, Established Innovator Award, and Specialty Award. Details are provided on their website   AFM Telethon: Call for proposals  Several call for proposals are being made available by AFM Telethon. They have published a call for proposals for Spinal Muscular Atrophy and Collagen VI Call for Projects. For further information   Neuronal Ceroid Lipofuscinosis Research Award  For the sixth time the Foundation announces and donates the NCL Research Award. They invite medical and basic science researchers worldwide to submit innovative project proposals that are either clinically oriented or cover translational aspects of CLN3 biology which can contribute to finding a cure for juvenile NCL. We particularly encourage also submissions from scientists working in related biomedical areas such as other lysosomal storage diseases, endolysosomal cell biology and neurodegenerative disorders. Together with the existing NCL research community our goal is to move promising therapeutic avenues forward to help JNCL patients. The grant (50,000 euros) serves as seed money supporting a one year postdoctoral fellowship to help young scientists progressing CLN3 research in academia or industry. Deadline: October 31, 2015 For further information   BMBF Funding initiative: innovative stem cell technologies for personalized medicine  The German Federal Ministry for Education and Research (BMBF) has announced a new funding initiative for the development and use of innovative stem cell technologies. The initiative aims at funding interdisciplinary research collaborations which are geared towards unlocking the full potential of novel reprogramming technologies and iPS cells for practical use. For this, a pooling of expertise from applied basic and clinical research is needed, for example of research groups from the life sciences, medicine, pharmacology and relevant technical disciplines. The funding can be applied for in two modules: "therapy" and "model & test systems". Deadline for applications is 30 November 2015. More information (in German)   8th Call for SMA research proposals  This Call is open to any research project aimed at finding a therapy for Spinal Muscular Atrophy (SMA) or elucidating the basic pathophysiological processes of the disease. SMA‐Europe aims to help the international scientific and medical community in its search for therapies for SMA. Preferences will be given to projects with the greatest potential to overcome barriers to translate science into effective treatments. Two types of research grants will be awarded for up to two years: 1. Operating Grants 2. Postdoctoral Fellowship Application deadline: 9 December 2015 For further information     Partnersearch, Job Opportunities  ECRIN ERIC job vacancies  ECRIN‐Eric is currently in the process of recruiting for its office based in Paris (France) a Capacity Project Manager, an Operations Project Manager and a Secretary. This is a unique opportunity for a motivated individual who wishes to further develop his/her career in biomedical research and his/her experience of multinational research projects. The ECRIN Capacity Project Manager will be in charge of the project management for the structuring projects with ECRIN involvement. For further information   Civil Society representatives: Call for expression of interest is open for the EMA Management Board  The Commission is launching a selection procedure to appoint the Civil Society representatives in the Management Board of the European Medicines Agency (EMA), in London. Four members from Civil Society will be appointed: two members representing patients' organisations, one member representing doctors' organisations and one member representing veterinarians' organisations. The term of office of the current members expires on 20 March 2016. For further information     Courses & Educational Initiatives    The 2nd Biennial Australian Rare Lung Disease Short Course  Date: 16-17 October, 2015 Venue: Sydney, Australia The joint venture between Lung Foundation Australia and the Thoracic Society of Australia and New Zealand (TSANZ) will provide updates on the latest in research, diagnosis, therapy and care for Interstitial Lung Disease. The program boasts an exceptional selection of Australian specialists as well as keynote presentations from international speaker, Professor Kevin Flaherty (USA). For further information or to register please visit:www.lungfoundation.com.au   Courses offered by Recordati Rare Diseases Foundation  The Recordati Rare Diseases Foundation is offering five courses planned for next year. For further information, please contact Cecilia Kellquist, Coordinator and member of the board, ckellquist@rrd-foundation.org/www.rrd-foundation.org. Neurotransmitter focus course  Date: 9-10 November 2015 Venue: Venice, Italy in partnership with University Hospital for Child and Adolescent Medicine of Heidelberg and University Hospital of Padua. Registration deadline: 26th September   EMA workshop on demonstrating significant benefit of orphan medicines  Date: 7 December, 2015 Venue: London, United Kingdom The European Medicines Agency (EMA) is organising a workshop on 7 December 2015 to discuss the approach that should be followed by medicine developers to demonstrate the significant benefit of an orphan medicine over existing treatments. Demonstrating a significant benefit is one of the criteria medicines that treat rare diseases must fulfil to benefit from 10 years of market exclusivity once they have been authorised. The workshop will bring together medicine developers, regulators, healthcare professionals, academia, patients, health technology assessment bodies and healthcare payers who need toregister by 31 October 2015 if they wish to participate. The workshop will also be broadcast live. For further information   European Cytogenetesists Association  Date: February/March of each year Venue: Nimes, France This course is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification. The students will be trained to identify genetic abnormalities for diagnosis and prognosis, and for fundamental and applied research using both classical and molecular cytogenetic techniques. The course is co-organized by E.C.A. and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training. An application for CME points will also be made for 2016. For further information   EMA workshop on pre-licencing activities  Date: 9 March, 2016 Venue: Barcelona, Spain In collaboration with EMA, E-Rare will organize a workshop dedicated to Interactions between EMA and RD researchers on pre-licensing activities. The workshop will take place from 09:00 to 16:00 on the 9 of March 2015 in Barcelona, before the official start of the RE(ACT) meeting. It will be open to all researchers and interested stakeholders. The places for Face-to-face meetings with EMA officers are limited! If you would like to participate, please send an email to juliane.halftermeyer@agencerecherche.fr for further instructions.     What's on Where?    CLIMB Newborn Screening Conference  Date: 10 October, 2015 Venue: Birmingham, UK The CLIMB Newborn Screening Conference will be exploring four new conditions on the newborn screening programme, as well as current metabolic conditions. Midwives will have the opportunity to find out more about conditions that affect infants, including MCADD, PKU, Maple Syrup Disease and Glutaric Aciduria Type 1. For further information   Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico  Date: 15-16 October (ICORD), 12-16 October (Global Rare Disease Week, Mexico) Venue: Mexico City, Mexico ICORD 2015 will be held in México FD (México) 15-16 October in association with FEMEXER (the Mexican Federation of Rare Diseases) and GEISER Foundation (the Group of Linkage, Research and Support for Rare Diseases in Latin America). The event is part of the "Global Rare Diseases Week, Mexico 2015″ and back to back with the 4th Latin American meeting of Rare Diseases on October 12 and the Discoveries and Innovations in Orphan Drugs Congress, October 13-14. For further information   6th South Eastern European Cystic Fibrosis Conference  Date: 19-20 October, 2015 Venue: Bucharest, Romania This regional conference is a 2‐day symposium in Romania, addressing physicians, allied health professionals and patient representatives from the South Eastern European and Mediterranean region. For further information   NORD Summit  Date: 21-22 October, 2015 Venue: Virginia, United States The 2015 Breakthrough Summit is concentrated with innovative content and convenes the top leaders from the FDA, NIH, Industry, Patient Groups, Payers and Research Institutions to address the progress of rare disease diagnosis, genomics, drug development, patient engagement, patient-centered research models, product approva ls, FDA oversight and market access to orphan products. For further information   13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015  Date: 20-22 October, 2015 Venue: Beijing, China This conference will provide a unique opportunity for researchers from all over the world to meet, network, and forge new scientific interactions. For further information   The BioData World Congress 2015  Date: 21-22 October, 2015 Venue: Cambridge, United Kingdom This conference is held with the support of Intel, The Wellcome Trust Sanger Institute, The European Bioinformatics Institute, The Babraham Institute, BIA, BioNow, The Pharmacogenetics and Stratified Medicine Network and the Pistoia Alliance, BioData World Congress. For further information   6th World Congress on Targeting Mitochondria  Date: 21-22 October, 2015 Venue: Berlin, Germany This 6th World Congress on Targeting Mitochondria will cover a variety of new strategies and innovations as well as clinical applications in Mitochondrial Medicine. For further information   The AANEM Annual Meeting  Date: 28 -31 October, 2015 Venue: Hawaii, United States The AANEM Annual Meeting is the premier educational event for those involved in neuromuscular (NM) and electrodiagnostic (EDX) medicine. Earn over 30 continuing education credits through interactive workshops, lively discussions, and engaging sessions. For further information   4th European Congress on Rett Syndrome  Date: 30 October – 1 November, 2015 Venue: Rome, Italy For further information   First European Congress on Hereditary ATTR amyloidosis ECATTR  Date: 2-3 November, 2015 Venue: Paris, France The European Congress for HATTR will allow the meeting of the specialists of all European countries and the sharing of experience. The effort will be to further improve the early diagnosis of sporadic cases and genetic carriers, to review anti-amyloid treatments and clinical trials, to improve genetic counselling. For further information   2nd International Primary Immunodeficiencies Congress (IPIC)  Date: 5-6 November, 2015 Venue: Budapest, Hungary The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the Second International Primary Immunodeficiencies Congress (IPIC). This event will build on the successful outcomes of the first IPIC, attended by 400 participants. The congress will consist of a two-day programme and is open to all stakeholders with an interest in clinical management of primary immunodeficiencies (PIDs). For further information   Sixth Croatian Congress of Human Genetics  Date: 5-7 November, 2015 Venue: Zagreb, Croatia This conference will be an opportunity for education of the young interested in new achievements in various areas of genetics – clinical genetics, cytogenetics, molecular genetics and anthropology, and also to highlight the importance of prevention, diagnostics and treatment of rare diseases. For further information   16th International Conference on Human Genome Variation and Complex Genome Analysis  Date: 11-13 November, 2015 Venue: California, United States HGV2015 will bring together approximately 180 delegates (selected on the basis of their abstract submission) in a workshop-style atmosphere, with 25 internationally recognized speakers. For further information   Statistical analysis of massive genomic data  Date: 19-20 November, 2015 Venue: Evry, France This two-day cross-disciplinary conference will bring together biologists, geneticists, clinicians, bioinformaticians and statisticians in order to discuss emerging challenges raised by the analysis of high-throughput genomic data, and present dedicated innovative approaches. For further information   The Rett Syndrome Journey: Pathways to Follow  Date: 19-21 November, 2015 Venue: Victoria, Australia 'Pathways to Follow' on the journey with Rett syndrome will be explored in such areas as communication, health, therapies, education, equipment, caring for the carer, Commonwealth government, trusts, siblings, adulthood, family and equipment, to name just a few. For further information   6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals  Date: 21-22 November, 2015 Venue: Amsterdam, The Netherlands The 6th European Symposium on Rare Anaemias is an activity of the ENERCA project which aims to disseminate up-to-date knowledge and increase the public awareness about congenital and rare anaemias. This year, transversal topics centered on common medical problems of patients with sickle cell, thalassaemia and other forms of haemolytic anaemia will be one of the key points of the symposium. For further information   International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases  Date: 26 – 28 November, 2015 Venue: Geneva, Switzerland The aim of this second unique forum is to bring together some 200 participants from around the world, including scientists and clinicians, start-up leaders, and families of patients groups, to inform and strengthen exchange and cooperation. For further information   Clinical trials in small populations : Methodological challenges and solutions  Date: 30th November - 1 December 2015 Venue: London, UK The movement towards genetically tailored treatment regimens will further increase the number of small populations for whom new treatments are sought. This two day meeting will bring together researchers and practitioners to discuss state of the art methods for trials in small populations. For further information   CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference  Date: 9-10 January, 2016 Venue: Brussels, Belgium This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers. For further information   CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference  Date: 9-10 January, 2016 Venue: Brussels, Belgium This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers. For further information   BPSU Rare Disease Conference 2016  Date: 23 February, 2016 Venue: Birmingham, United Kingdom The conference will explore the theme 'Rare disease in paediatrics – from birth to transition'. It will centre on the child's journey from diagnosis through transition and end of life care. For further information   Clinical Innovation & Outsourcing  Date: 9-10 March, 2016 Venue: London, UK Clinical Outsourcing & Partnering World is the largest industry event focusing on the strategic and operational considerations in clinical outsourcing. It is a place where serious business contacts are made. Attended by senior decision makers, it's a platform which facilitates meetings between your sales force and prospects and it's a cost effective sponsorship package with year round advantage. For further information   The RE(ACT) Congress  Date: 9-10 March, 2016 Venue: Barcelona, Spain The congress aims to bring together world leaders and young scientist from a variety of breaking through scientific field to present cutting edge research, to discuss results and to exchange ideas. Moreover, many patients and patient organization, which are committed in research, will be present to share their experience. For further information   MYOLOGY 2016 Fifth International Congress of Myology  Date: 14-18 March, 2016 Venue: Lyon, France Held for the first time in 2000, MYOLOGY has become a unique opportunity for international experts in the field to exchange and confront the emerging therapeutic approaches, but also to share the first clinical results. The science and medicine of muscle have reached a new milestone. In Myology 2016, no doubt there will be new results, new breakthroughs to share all together. For further information   13th International Congress of Human Genetics (ICHG) 2016  Date: 3-7 April, 2016 Venue: Kyoto, Japan Hosted by the East-Asian Union of Human Genetic Societies (EAUHGS) and the Japan Society of Human Genetics, the 13th ICHG will focus on progress in genome analysis technologies and big data in order to explore disease mechanisms and treatment opportunities. Registrations open in 2015. For further information   8th Alstrom Syndrome International Conference  Date: 12-16 May, 2016 Venue: Massachusetts, USA This international conference will have a scientific symposium for clinicians and researchers as well as sessions for parents, caretakers and patient organisations. For further information   17th EMSOS Nurse and allied professional Group Meeting  Date: 12-16 May, 2016 Venue: Massachusetts, USA The meeting will be focussing on Ewing sarcoma, margins, pelvic tumours, targeted therapy; open sessions will offer the opportunity to report and discuss the latest results in all fields. For further information   European Association of Centres of Medical Ethics Conference  Date: 8 -10 September, 2016 Venue: Leuven; Belgium The focus of this year's conference is on a variety of highly relevant ethical issues in health care:  Organizational Ethics in Health Care: Principles, Cases and Practical Solutions  Ethical Issues in Care for Older Persons  Ethical, Legal and Social Developments in Human Genomics  Ethics and Integrity in Research For further information   9th ISNS International meeting/10th ISNS European Regional meeting  Date: 11-14 September, 2016 Venue: The Hague, the Netherlands The conference will aid the sharing of neonatal screening experiences for congenital metabolic disorders, its clinical diagnostics and follow-up, and will facilitate learning from other experiences. The programme will consist of plenary lectures, oral presentations and poster sessions and will be attractive for professionals, patient/advocacy groups, policy makers and industrial partners. The programme will include evaluation of performance of neonatal screening systems and strategies for improvement. For further information   ESID European Society for Immunodeficiencies: Biennial meeting  Date: 21-24 September, 2016 Venue: Barcelona, Spain Sessions at this meeting will be devoted to understanding primary immunodeficiencies and their clinical aspects. For further information     Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Rare DiseaseS OrphaNews Europe : 10 October 2015 Editorial RD-ACTION: the new European  Joint Action Spotlight on... Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future EU Policy News EMA Submit expressions of interest to represent civil society at the EMA National & International Policy Developments Comprehensive policy for patients with rare diseases in Philippines Other European news The rare disease persons card implementation in Portugal Sample of the adult British population want genetic testing of children for adult-onset conditions Sample of Danish population want disclosure of incidental findings from NGS studies Other International News Discussion paper by the Australian government to support people with chronic and complex health conditions Contradictions of public health policies geared to rare disorders in Brazil Sickle cell disease among children in Africa Guidance Documents and Recommendations 22q11.2 deletion syndrome: guidelines for the management Cushing syndrome: guidelines on treatment Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management Bioinformatics, Registries and Data Management How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders Screening and Testing Regulating laboratory developed tests in the United States: the current controversy Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests Newborn screening in Australia: current environment and future perspectives Patenting Genetic diagnostic methods Ethical, Legal & Social Issues Living with Marfan syndrome: the patients view New Syndromes Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4 Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63 New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2 Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations New Genes Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins 22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype X-linked intellectual disability due to THOC2 mutations in four families Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586 Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11 Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations Small cell lung cancer: somatic mutations in TP53, TP73 and RB1 Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions Keratoconus: WNT10A exonic variant increases the risk of disease Research in Action Clinical Research Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients Paraganglioma in pregnancy: a case series and review of the literature Salla disease: 13-year follow-up of Finnish patients Therapeutic Approaches Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice Fragile X-associated tremor/ataxia syndrome: new inducible mouse model Diagnostic Approaches Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging Patient Management and Therapy Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment Fanconi anemia: review on gene therapy Lymphangioleiomyomatosis: review on new treatments Blepharospasm: review on alternatives to botulinum toxin for the management Id: Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management Kawasaki disease: a review Paediatric rheumatology: review on lessons from oncology to optimize treatment Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation B-cell non-Hodgkin lymphoma: review on the treatment Huntington disease: a review MECP2 disorders: a review Glycogen storage disease due to acid maltase deficiency: a review Congenital generalized lipodystrophies: a review Ribosomopathies: a review Duchenne muscular dystrophy: a review Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening Tuberous sclerosis: review on pathophysiology West-Nile encephalitis: a review Idiopathic interstitial pneumonias with connective tissue diseases features: a review Primary biliary cirrhosis and primary sclerosing cholangitis: a review Eosinophilic esophagitis and gastroenteritis: a review T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment One new and nine updated GeneReviews published Orphan Drugs Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe Wanted: new models of pricing and reimbursement for gene therapies Regulatory News FDA approves new orphan drug to treat 20 patients worldwide New treatment option for patients with multiple myeloma Grants Medical Research Grant Application Guidelines : Progeria Research Foundation AFM Telethon: Call for proposals Neuronal Ceroid Lipofuscinosis Research Award BMBF Funding initiative: innovative stem cell technologies for personalized medicine 8th Call for SMA research proposals Partnersearch, Job Opportunities ECRIN ERIC job vacancies Civil Society representatives: Call for expression of interest is open for the EMA Management Board Courses & Educational Initiatives The 2nd Biennial Australian Rare Lung Disease Short Course Courses offered by Recordati Rare Diseases Foundation EMA workshop on demonstrating significant benefit of orphan medicines European Cytogenetesists Association EMA workshop on pre-licencing activities What's on Where? CLIMB Newborn Screening Conference Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico 6th South Eastern European Cystic Fibrosis Conference NORD Summit 13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015 The BioData World Congress 2015 6th World Congress on Targeting Mitochondria The AANEM Annual Meeting 4th European Congress on Rett Syndrome First European Congress on Hereditary ATTR amyloidosis ECATTR 2nd International Primary Immunodeficiencies Congress (IPIC) Sixth Croatian Congress of Human Genetics 16th International Conference on Human Genome Variation and Complex Genome Analysis Statistical analysis of massive genomic data The Rett Syndrome Journey: Pathways to Follow 6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases Clinical trials in small populations : Methodological challenges and solutions CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference BPSU Rare Disease Conference 2016 Clinical Innovation & Outsourcing The RE(ACT) Congress MYOLOGY 2016 Fifth International Congress of Myology 13th International Congress of Human Genetics (ICHG) 2016 8th Alstrom Syndrome International Conference 17th EMSOS Nurse and allied professional Group Meeting European Association of Centres of Medical Ethics Conference 9th ISNS International meeting/10th ISNS European Regional meeting ESID European Society for Immunodeficiencies: Biennial meeting Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Rare DiseaseS OrphaNews Europe : 10 October 2015 Editorial RD-ACTION: the new European  Joint Action Spotlight on... Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future EU Policy News EMA Submit expressions of interest to represent civil society at the EMA National & International Policy Developments Comprehensive policy for patients with rare diseases in Philippines Other European news The rare disease persons card implementation in Portugal Sample of the adult British population want genetic testing of children for adult-onset conditions Sample of Danish population want disclosure of incidental findings from NGS studies Other International News Discussion paper by the Australian government to support people with chronic and complex health conditions Contradictions of public health policies geared to rare disorders in Brazil Sickle cell disease among children in Africa Guidance Documents and Recommendations 22q11.2 deletion syndrome: guidelines for the management Cushing syndrome: guidelines on treatment Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management Bioinformatics, Registries and Data Management How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders Screening and Testing Regulating laboratory developed tests in the United States: the current controversy Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests Newborn screening in Australia: current environment and future perspectives Patenting Genetic diagnostic methods Ethical, Legal & Social Issues Living with Marfan syndrome: the patients view New Syndromes Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4 Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63 New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2 Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations New Genes Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins 22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype X-linked intellectual disability due to THOC2 mutations in four families Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586 Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11 Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations Small cell lung cancer: somatic mutations in TP53, TP73 and RB1 Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions Keratoconus: WNT10A exonic variant increases the risk of disease Research in Action Clinical Research Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients Paraganglioma in pregnancy: a case series and review of the literature Salla disease: 13-year follow-up of Finnish patients Therapeutic Approaches Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice Fragile X-associated tremor/ataxia syndrome: new inducible mouse model Diagnostic Approaches Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging Patient Management and Therapy Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment Fanconi anemia: review on gene therapy Lymphangioleiomyomatosis: review on new treatments Blepharospasm: review on alternatives to botulinum toxin for the management Id: Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management Kawasaki disease: a review Paediatric rheumatology: review on lessons from oncology to optimize treatment Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation B-cell non-Hodgkin lymphoma: review on the treatment Huntington disease: a review MECP2 disorders: a review Glycogen storage disease due to acid maltase deficiency: a review Congenital generalized lipodystrophies: a review Ribosomopathies: a review Duchenne muscular dystrophy: a review Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening Tuberous sclerosis: review on pathophysiology West-Nile encephalitis: a review Idiopathic interstitial pneumonias with connective tissue diseases features: a review Primary biliary cirrhosis and primary sclerosing cholangitis: a review Eosinophilic esophagitis and gastroenteritis: a review T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment One new and nine updated GeneReviews published Orphan Drugs Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe Wanted: new models of pricing and reimbursement for gene therapies Regulatory News FDA approves new orphan drug to treat 20 patients worldwide New treatment option for patients with multiple myeloma Grants Medical Research Grant Application Guidelines : Progeria Research Foundation AFM Telethon: Call for proposals Neuronal Ceroid Lipofuscinosis Research Award BMBF Funding initiative: innovative stem cell technologies for personalized medicine 8th Call for SMA research proposals Partnersearch, Job Opportunities ECRIN ERIC job vacancies Civil Society representatives: Call for expression of interest is open for the EMA Management Board Courses & Educational Initiatives The 2nd Biennial Australian Rare Lung Disease Short Course Courses offered by Recordati Rare Diseases Foundation EMA workshop on demonstrating significant benefit of orphan medicines European Cytogenetesists Association EMA workshop on pre-licencing activities What's on Where? CLIMB Newborn Screening Conference Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico 6th South Eastern European Cystic Fibrosis Conference NORD Summit 13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015 The BioData World Congress 2015 6th World Congress on Targeting Mitochondria The AANEM Annual Meeting 4th European Congress on Rett Syndrome First European Congress on Hereditary ATTR amyloidosis ECATTR 2nd International Primary Immunodeficiencies Congress (IPIC) Sixth Croatian Congress of Human Genetics 16th International Conference on Human Genome Variation and Complex Genome Analysis Statistical analysis of massive genomic data The Rett Syndrome Journey: Pathways to Follow 6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases Clinical trials in small populations : Methodological challenges and solutions CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference BPSU Rare Disease Conference 2016 Clinical Innovation & Outsourcing The RE(ACT) Congress MYOLOGY 2016 Fifth International Congress of Myology 13th International Congress of Human Genetics (ICHG) 2016 8th Alstrom Syndrome International Conference 17th EMSOS Nurse and allied professional Group Meeting European Association of Centres of Medical Ethics Conference 9th ISNS International meeting/10th ISNS European Regional meeting ESID European Society for Immunodeficiencies: Biennial meeting Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Atlas of Thyroid CytoPathology,http://t.co/Wu5WKrTTuD Atlas of Thyroid CytoPathology Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » Atlas of Thyroid CytoPathology,http://t.co/Wu5WKrTTuD Atlas of Thyroid CytoPathology Alexandros Sfakianakis Anapafseos 5 . Agios Nikolaos Crete.Greece.72100 2841026182,6932607174 Read More » AJP: Regulatory, Integrative and Comparative Physiology Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses. The present study investigated the type 1 cannabinoid receptor (CB1R) as a potential candidate to mediate the homeostatic responses triggered by 24 hours of water deprivation (WD), which constitutes primarily a hydroelectrolytic challenge and also significantly impacts energy homeostasis. The present results demonstrated for the first time that CB1R mRNA expression is increased in the hypothalamus of WD rats. Furthermore, the administration of ACEA, a CB1R selective agonist, potentiated WD-induced dipsogenic effect, whereas AM251, a CB1R antagonist, attenuated not only water but also salt intake in response to WD. In parallel with the modulation of thirst and salt appetite, we confirmed that CB1Rs are essential for the development of appropriated neuroendocrine responses. Although the administration of ACEA or AM251 did not produce any effects on WD-induced vasopressin (AVP) secretion, oxytocin (OXT) plasma concentrations were significantly decreased in WD rats treated with ACEA. At the genomic level, ACEA significantly decreased AVP and OXT mRNA expression in the hypothalamus of WD rats, whereas AM251 potentiated both basal and WD-induced stimulatory effects on the transcription of AVP and OXT genes. In addition, we showed that WD alone upregulates proopiomelanocortin, Agouti-related protein, melanin-concentrating hormone and Orexin A mRNA levels in the hypothalamus, and that CB1Rs regulate main central peptidergic pathways controlling food intake, being most of these effects also significantly influenced by the hydration status. In conclusion, the present study demonstrated that CB1Rs participate in the homeostatic responses regulating fluid balance and energy homeostasis during WD. Hypothalamic fatty acid sensing in Senegalese sole (Solea senegalensis):response to long-chain saturated, monounsaturated, and polyunsaturated (n-3) fatty acids We assessed the presence of fatty acid (FA) sensing mechanisms in hypothalamus of Senegalese sole (Solea senegalensis) and investigated their sensitivity to FA chain length and/or level of unsaturation. Stearate (SA, saturated FA), oleate (OA, monounsaturated FA of the same chain length), α-linolenate (ALA, a n-3 PUFA of the same chain length), and eicosapentanoate (EPA, a n-3 PUFA of a larger chain length) were injected intraperitoneally. Parameters related to FA sensing and neuropeptide expression in the hypothalamus were assessed after 3h and changes in accumulated food intake after 4, 24, and 48 h. Three FA sensing systems characterized in rainbow trout were also found in Senegalese sole, and were activated by OA in a way similar to that previously characterized in rainbow trout and mammals. These hypothalamic FA sensing systems were also activated by ALA, differing from mammals, where n-3 PUFA do not seem to activate FA sensors. This might suggest additional roles and highlights the importance of n-3 PUFA in fish diets, especially in marine species. The activation of FA sensing seems to be partially dependent on acyl chain length and degree of saturation, as no major changes were observed after treating fish with SA or EPA. The activation of FA sensing systems by OA and ALA, but not SA or EPA, is further reflected in the expression of hypothalamic neuropeptides involved in the control of food intake. Both OA and ALA enhanced anorexigenic capacity compatible with the activation of FA sensing systems. Microvascular oxygen partial pressure during hyperbaric oxygen in diabetic rat skeletal muscle Hyperbaric oxygen (HBO) is a major therapeutic treatment for ischemic ulcerations that perforate skin and underlying muscle in diabetic patients. These lesions do not heal effectively, in part, because of the hypoxic microvascular O2 partial pressures (PmvO2) resulting from diabetes-induced cardiovascular dysfunction which alters the dynamic balance between O2 delivery and utilization rates. We tested the hypothesis that HBO in diabetic muscle would exacerbate the hyperoxic PmvO2 dynamics due, in part, to a reduction or slowing of the cardiovascular, sympathetic nervous and respiratory system responses to acute HBO exposure. Adult male Wistar rats were divided randomly into diabetic (DIA: Streptozotocin i.p.) and healthy (CONT) groups. A small animal hyperbaric chamber was pressurized with oxygen (100% O2) to 3.0 ATA at 0.2 ATA/min. Phosphorescence quenching techniques were used to measure PmvO2 in tibialis anterior muscle of anesthetized rats during HBO. Lumbar sympathetic nerve activity (LSNA), heart rate (HR) and respiratory rate (RR) were measured electrophysiologically. During the normobaric hyperoxia and HBO, DIA tibialis anterior PmvO2 increased faster than CONT. Subsequently, PmvO2 remained elevated at similar levels in CONT. Sympathetic nervous system, cardiac and respiratory responses to HBO were slower in DIA versus CONT. HBO treatment increases tibialis anterior muscle PmvO2 more rapidly and for a longer duration in DIA than CONT, but not to a greater level. Whereas, respiratory, cardiovascular and LSNA responses to HBO are profoundly slowed in DIA only the cardiovascular arm (via HR) may contribute to the muscle vascular incompetence and these faster PmvO2 kinetics. Impact of Blood Pressure Perturbations on Arterial Stiffness Although the associations between chronic levels of arterial stiffness and blood pressure (BP) have been fairly well studied, it is not clear if and how much arterial stiffness is influenced by acute perturbations in BP. The primary aim of this study was to determine magnitudes of BP-dependence of various measures of arterial stiffness during acute BP perturbation maneuvers. Fifty apparently healthy subjects, including 25 young (20-40 years) and 25 older adults (60-80 years), were studied. A variety of BP perturbations, including head-up tilt, head-down tilt, mental stress, isometric handgrip exercise, and cold pressor test, were used in order to encompass BP changes induced by physical, mental, and/or physiological stimuli. When each index of arterial stiffness was plotted with mean BP, all arterial stiffness indices, including cardio-ankle vascular index or CAVI (r=0.50), carotid-femoral pulse wave velocity or cfPWV (r=0.51), brachial-ankle pulse wave velocity or baPWV (r=0.61), arterial compliance (r=-0.42), elastic modulus (r=0.52), arterial distensibility (r=-0.32), β-stiffness index (r=0.19), and Young's modulus (r=0.35) were related to mean BP (all P<0.01). Changes in CAVI, cfPWV, baPWV, and elastic modulus were significantly associated with changes in mean BP in the pooled conditions while changes in arterial compliance, arterial distensibility, β-stiffness index, and Young's modulus were not. In conclusion, this study demonstrated that BP changes in response to various forms of pressor stimuli were associated with the corresponding changes in arterial stiffness indices and that the strengths of associations with BP varied widely depending on what arterial stiffness indices were examined. In vivo evidence for unidentified leptin-induced circulating factors that control white fat mass Fat transplants increase body fat mass without changing the energy status of an animal and provide a tool for investigating control of total body fat. Early transplant studies found that small pieces of transplanted fat took on the morphology of the transplant recipient. Experiments described here tested whether this response was dependent upon expression of leptin receptors in either transplanted fat or the recipient mouse. Fat from leptin receptor deficient db/db mice or wild type mice was placed subcutaneously in db/db mice. After 12 weeks cell size distribution in the transplant was the same as in endogenous fat of the recipient. Thus wild type fat cells, which express leptin receptors, were enlarged in a hyperleptinemic environment indicating that leptin does not directly control adipocyte size. By contrast, db/db or wild type fat transplanted into wild type mice decreased in size, suggesting that a functional leptin system in the recipient is required for body fat mass to be controlled. In the final experiment wild type fat was transplanted into a db/db mouse parabiosed to either another db/db mouse to an ob/ob mouse or in control pairs in which both parabionts were ob/ob mice. Transplants increased in size in db/db-db/db pairs, decreased in db/db-ob/ob pairs and did not change in ob/ob-ob/ob pairs. We propose that leptin from db/db parabionts activated leptin receptors in their ob/ob partners. This in turn stimulated release of unidentified circulating factors which travelled back to the db/db partner and acted on the transplant to reduce fat cell size. Postural influence on intracranial and cerebral perfusion pressure in ambulatory neurosurgical patients We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP: mean arterial pressure (MAP) - ICP) in neurosurgical patients undergoing 24-hour ICP monitoring as part of their diagnostic workup. We identified 9 patients (5 women, age 44±20 yrs.; mean±SD) who were "as normal as possible" i.e. without indication for neurosurgical intervention (e.g. focal lesions, global edema, abnormalities in ICP-profile or cerebrospinal fluid dynamics). ICP (tip-transducer probe, Raumedic) in the brain parenchyma (N=7) or in the lateral ventricles (N=2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared to the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4±3.8 to 14.3±4.7 and 19±4.7 mmHg, P<0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8±3.6 and 1.3±3.6 mmHg and ICP reached -2.4±4.2 mmHg when standing up (P<0.05). Concordant changes in MAP maintained CPP at 77±7 mmHg regardless of body position (P=0.95). During head-down tilt, the increase in ICP corresponded to a hydrostatic pressure gradient with reference just below the heart, likely reflecting the venous hydrostatic indifference point. When upright, the decrease in ICP was attenuated, corresponding to formation of a separate hydrostatic gradient with reference to the base of the skull, likely reflecting the site of venous collapse. ICP therefore seems to be governed by pressure in the draining veins and collapse of neck veins may protect the brain from being exposed to a large negative pressure when upright. Despite positional changes in ICP, MAP keeps CPP tightly regulated. Aging augments renal vasoconstrictor response to orthostatic stress in humans The ability of the human body to maintain arterial blood pressure (BP) during orthostatic stress is determined by several reflex neural mechanisms. Renal vasoconstriction progressively increases during graded elevations in lower body negative pressure (LBNP). This sympathetically mediated response redistributes blood flow to the systemic circulation to maintain BP. However, how healthy aging affects the renal vasoconstrictor response to LBNP is unknown. Therefore, ten young (25 ± 1 years; mean ± SE) and ten older (66 ± 2 years) subjects underwent graded LBNP (-15 and -30 mmHg) while beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), arterial blood pressures (BP; Finometer), and heart rate (HR; electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular variables were similar between groups, except diastolic BP was higher in older subjects (P < 0.05). Increases in RVR during LBNP were greater in the older group compared to the young group (older: -15 mmHg 10 ± 3%, -30 mmHg 20 ± 5%; young: -15 mmHg 2 ± 2%, -30 mmHg 6 ± 2%; P < 0.05). RBFV tended to decrease more (P = 0.10) and mean BP tended to decrease less (P = 0.09) during LBNP in the older group compared to the young group. Systolic and diastolic BP, pulse pressure, and HR responses to LBNP were similar between groups. These findings suggest that aging augments the renal vasoconstrictor response to orthostatic stress in humans. Effects of passive heat stress on human somatosensory processing We herein investigated the effects of passive heat stress on human somatosensory processing recorded by somatosensory-evoked potentials (SEPs). Fifteen healthy subjects received a median nerve stimulation at the left wrist under two thermal conditions: Heat stress and normothermic Time Control. The latencies and amplitudes of P14, N20, P25, N35, P45, and N60 at C4' and P14, N18, P22, and N30 at Fz were evaluated. Under the Heat stress condition, SEPs were recorded at normothermic baseline (1st), early in heat stress (2nd), when esophageal temperature had increased by ~1.0 °C (3rd) and ~2.0 °C (4th), and after heat stress (5th). In the Time control condition, SEPs were measured at the same time intervals as those in the Heat stress condition. The peak latencies and amplitudes of SEPs did not change early in heat stress. However, the latencies of P14, N20, and N60 at C4' and P14, N18, and P22 at Fz were significantly shorter in the 4th session than in the 1st session. Furthermore, the peak amplitudes of P25 and N60 at C4', and P22 and N30 at Fz decreased with increases in body temperature. On the other hand, under the Time control condition, no significant differences were observed in the amplitudes or latencies of any component of SEPs. These results suggested that the conduction velocity of the ascending somatosensory input was accelerated by increases in body temperature, and hyperthermia impaired the neural activity of cortical somatosensory processing. The role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure Heart Failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan ((a non-selective ETA and ETB receptor antagonist) (8 mg/kg/h) on resting levels of CSNA, arterial pressure and heart rate were determined in conscious normal sheep (n= 6) and sheep with pacing induced HF (n= 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts / 100 heart beats, P < 0.01). Infusion of tezosentan for 60 minutes significantly decreased resting MAP in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg respectively; p<0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals, but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF. Editorial Focus: Cardiac responses to hypoxia and reoxygenation in Drosophila. New insights into evolutionary conserved gene responses N/A PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short- and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways The endocannabinoids are lipid-derived signaling molecules that control feeding and energy balance by activating CB1-type cannabinoid receptors in the brain and peripheral tissues. Previous studies have shown that oral exposure to dietary fat stimulates endocannabinoid signaling in the rat small intestine, which provides positive feedback that drives further food intake and preference for fat-rich foods. We now describe an unexpectedly broader role for cholinergic signaling of the vagus nerve in the production of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the small intestine. We show that food deprivation increases levels of 2-AG and its lipid precursor, 1,2-diacylglycerol, in rat jejunum mucosa in a time-dependent manner. This response is abrogated by surgical resection of the vagus nerve or pharmacological blockade of small intestinal subtype-3 muscarinic acetylcholine (m3mAch) receptors, but not inhibition of subtype-1 muscarinic acetylcholine (m1 mAch). We further show that blockade of peripheral CB1 receptors or intestinal m3 mAch receptors inhibits refeeding in fasted rats. The results suggest that food deprivation stimulates 2-AG-dependent CB1 receptor activation through a mechanism that requires efferent vagal activation of m3 mAch receptors in the jejunum, which, in turn, may promote feeding after a fast. Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression Major depression is known to be associated with cardiovascular abnormalities, and oxidative stress has been suggested to play a role. We tested the hypothesis that antidepressant treatment reduces oxidative stress and endothelial dysfunctions in the chronic mild stress (CMS) model of depression in rats. Rats with >30% reduction in sucrose intake after 4 wk of CMS were defined in the study as CMS-susceptible and compared with unstressed controls. Sixteen CMS-susceptible and eight unstressed rats were treated during weeks 5 to 8 of the CMS protocol with escitalopram. Escitalopram-treated rats with >20% recovery in the sucrose consumption during the last 2 wk of treatment were defined as escitalopram responders. Rats that did not reach these criteria were defined as escitalopram nonresponders. In the open field test, escitalopram responders demonstrated anxiolytic effect of treatment. In mesenteric small arteries, escitalopram affected neither NO nor cyclooxygenase-1 (COX-1)-mediated vasodilation. Escitalopram potentiated endothelium-dependent hyperpolarization-like response, which was suppressed in the vehicle-treated CMS-susceptible rats and reduced COX-2-dependent relaxation, which was elevated in the vehicle-treated CMS-susceptible rats. Escitalopram did not affect blood pressure and heart rate, which were elevated in the vehicle-treated CMS-susceptible rats. Oxidative stress markers were changed in association with CMS in liver, heart, and brain. Escitalopram normalized oxidative stress markers in the majority of tissues. This study demonstrates that the antidepressant effect of escitalopram is associated with partial improvement of endothelial function in small arteries affecting COX-2 and endothelium-dependent hyperpolarization-like pathways. Gene expression of peripheral blood mononuclear cells is affected by cold exposure Because of the discovery of brown adipose tissue (BAT) in humans, there is increased interest in the study of induction of this thermogenic tissue as a basis to combat obesity and related complications. Cold exposure is one of the strongest stimuli able to activate BAT and to induce the appearance of brown-like (brite) adipocytes in white fat depots (browning process). We analyzed the potential of peripheral blood mononuclear cells (PBMCs) to reflect BAT and retroperitoneal white adipose tissue (rWAT) response to 1-wk cold acclimation (4°C) at different ages of rat development (1, 2, 4, and 6 mo). As expected, cold exposure increased fatty acid β-oxidation capacity in BAT and rWAT (increased Cpt1a expression), explaining increased circulating nonesterified free fatty acids and decreased adiposity. Cold exposure increased expression of the key thermogenic gene, Ucp1, in BAT and rWAT, but only in 1-mo-old animals. Additionally, other brown/brite markers were affected by cold during the whole developmental period studied in BAT. However, in rWAT, cold exposure increased studied markers mainly at early age. PBMCs did not express Ucp1, but expressed other brown/brite markers, which were cold regulated. Of particular interest, PBMCs reflected adipose tissue-increased Cpt1a mRNA expression in response to cold (in older animals) and browning induction occurring in rWAT of young animals (1 mo) characterized by increased Cidea expression and by the appearance of a high number of multilocular CIDE-A positive adipocytes. These results provide evidence pointing to PBMCs as an easily obtainable biological material to be considered to perform browning studies with minimum invasiveness. IL-15R{alpha} is a determinant of muscle fuel utilization, and its loss protects against obesity IL-15Rα is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15Rα take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15Rα promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15Rα on metabolism and obesity are currently unknown. We report that mice lacking IL-15Rα (IL-15Rα–/–) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15Rα–/– mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15Rα–/– are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15Rα in metabolism and obesity. Lesser suppression of energy intake by orally ingested whey protein in healthy older men compared with young controls Protein-rich supplements are used widely for the management of malnutrition in young and older people. Protein is the most satiating of the macronutrients in young. It is not known how the effects of oral protein ingestion on energy intake, appetite, and gastric emptying are modified by age. The aim of the study was to determine the suppression of energy intake by protein compared with control and underlying gastric-emptying and appetite responses of oral whey protein drinks in eight healthy older men (69–80 yr) compared with eight young male controls (18–34 yr). Subjects were studied on three occasions to determine the effects of protein loads of 30 g/120 kcal and 70 g/280 kcal compared with a flavored water control-drink (0 g whey protein) on energy intake (ad libitum buffet-style meal), and gastric emptying (three-dimensional-ultrasonography) and appetite (0–180 min) in a randomized, double-blind, cross-over design. Energy intake was suppressed by the protein compared with control (P = 0.034). Suppression of energy intake by protein was less in older men (1 ± 5%) than in young controls (15 ± 2%; P = 0.008). Cumulative energy intake (meal+drink) on the protein drink days compared with the control day increased more in older (18 ± 6%) men than young (1 ± 3%) controls (P = 0.008). Gastric emptying of all three drinks was slower in older men (50% gastric-emptying time: 68 ± 5 min) than young controls (36 ± 5 min; P = 0.007). Appetite decreased in young, while it increased in older (P < 0.05). In summary, despite having slower gastric emptying, elderly men exhibited blunted protein-induced suppression of energy intake by whey protein compared with young controls, so that in the elderly men, protein ingestion increased overall energy intake more than in the young men. Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m–2·min–1)-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P < 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P < 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/min) were lower (P < 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P < 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P < 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals. Reduced sweet and fatty fluid intake after Roux-en-Y gastric bypass in rats is dependent on experience without change in stimulus motivational potency Here we assessed how intake reductions induced by Roux-en-Y gastric bypass surgery (RYGB) occur within and across access periods by examining drinking microstructure. After training, RYGB (n = 8–10) or sham-operated (SHAM, n = 12) rats were given 60-min access first to 0.3 M sucrose, then to 5% Intralipid, and finally to milk-chocolate Ensure Plus across 5 days each. Initially, total licks taken during the first meal of sucrose and Intralipid by RYGB and SHAM rats did not differ, but, across subsequent test periods, RYGB rats licked less than SHAM rats. First Ensure meal size also did not differ between RYGB and SHAM rats, but SHAM rats increased licking across test periods while the behavior of RYGB rats remained stable. The intake differences between the surgical groups, when they occurred, were most often due to smaller burst sizes in RYGB rats. Importantly, the surgical-group difference in sucrose and Intralipid intakes could not be explained by altered palatability of these solutions because, throughout testing, both groups had similar early meal licking behavior thought to represent the motivational potency of stimulus orosensory features. Although, overall, RYGB rats displayed lower early meal licking of Ensure relative to the SHAM rats, this appeared to be driven primarily by increases in the latter group across test periods; the RYGB group stayed relatively stable. Collectively, these results suggest that some level of postoral experience with these stimuli and/or their components is necessary before intake differences emerge between surgical groups, and, even when differences occur, often immediate taste-motivated ingestive behavior remains unaltered. Influence of menopause and Type 2 diabetes on pulmonary oxygen uptake kinetics and peak exercise performance during cycling o An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (TRegs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4+/CD25+ T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 ± 2 mmHg in NP (n= 12) to 127 ± 2 mmHg in RUPP (n = 21) but decreased to 118 ± 2 mmHg in RUPP+NP TRegs (n = 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-α and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 ± 58.7 and 603 ± 88.1 RLU·min–1·mg–1 in RUPP and significantly decreased to 178 ± 27.8 and 171 ± 55.6 RLU·min–1·mg–1, respectively, in RUPP+NP TRegs; AT1-AA was 17.81 ± 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 ± 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-α, and AT1-AA, which have been shown to increase blood pressure during pregnancy. Read More »