Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5
Άγιος Νικόλαος Κρήτη 72100
2841026182
6032607174

Δευτέρα 19 Δεκεμβρίου 2016

Continuous Peripheral Nerve Blocks: An Update of the Published Evidence and Comparison With Novel, Alternative Analgesic Modalities

imageA continuous peripheral nerve block (CPNB) consists of a percutaneously inserted catheter with its tip adjacent to a target nerve/plexus through which local anesthetic may be administered, providing a prolonged block that may be titrated to the desired effect. In the decades after its first report in 1946, a plethora of data relating to CPNB was published, much of which was examined in a 2011 Anesthesia & Analgesia article. The current update is an evidence-based review of the CPNB literature published in the interim. Novel insertion sites include the adductor canal, interpectoral, quadratus lumborum, lesser palatine, ulnar, superficial, and deep peroneal nerves. Noteworthy new indications include providing analgesia after traumatic rib/femur fracture, manipulation for adhesive capsulitis, and treating abdominal wall pain during pregnancy. The preponderance of recently published evidence suggests benefits nearly exclusively in favor of catheter insertion using ultrasound guidance compared with electrical stimulation, although little new data are available to help guide practitioners regarding the specifics of ultrasound-guided catheter insertion (eg, optimal needle–nerve orientation). After some previous suggestions that automated, repeated bolus doses could provide benefits over a basal infusion, there is a dearth of supporting data published in the past few years. An increasing number of disposable infusion pumps does now allow a similar ability to adjust basal rates, bolus volume, and lockout times compared with their electronic, programmable counterparts, and a promising area of research is communicating with and controlling pumps remotely via the Internet. Large, prospective studies now document the relatively few major complications during ambulatory CPNB, although randomized, controlled studies demonstrating an actual shortening of hospitalization duration are few. Recent evidence suggests that, compared with femoral infusion, adductor canal catheters both induce less quadriceps femoris weakness and improve mobilization/ambulation, although the relative analgesia afforded by each remains in dispute. Newly published data demonstrate that the incidence and/or severity of chronic, persistent postsurgical pain may, at times, be decreased with a short-term postoperative CPNB. Few new CPNB-related complications have been identified, although large, prospective trials provide additional data regarding the incidence of adverse events. Lastly, a number of novel, alternative analgesic modalities are under development/investigation. Four such techniques are described and contrasted with CPNB, including single-injection peripheral nerve blocks with newer adjuvants, liposome bupivacaine used in wound infiltration and peripheral nerve blocks, cryoanalgesia with cryoneurolysis, and percutaneous peripheral nerve stimulation.

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From Contact to Contactless Pulse Oximetry: Can You Measure Me Now?

imageNo abstract available

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Capturing Essential Information to Achieve Safe Interoperability

imageIn this article, we describe the role of "clinical scenario" information to assure the safety of interoperable systems, as well as the system's ability to deliver the requisite clinical functionality to improve clinical care. Described are methods and rationale for capturing the clinical needs, workflow, hazards, and device interactions in the clinical environment. Key user (clinician and clinical engineer) needs and system requirements can be derived from this information, therefore, improving the communication from clinicians to medical device and information technology system developers. This methodology is intended to assist the health care community, including researchers, standards developers, regulators, and manufacturers, by providing clinical definition to support requirements in the systems engineering process, particularly those focusing on development of Integrated Clinical Environments described in standard ASTM F2761. Our focus is on identifying and documenting relevant interactions and medical device capabilities within the system using a documentation tool called medical device interface data sheetsa and mitigating hazardous situations related to workflow, product usability, data integration, and the lack of effective medical device-health information technology system integration to achieve safe interoperability. Portions of the analysis of a clinical scenario for a "patient-controlled analgesia safety interlock" are provided to illustrate the method. Collecting better clinical adverse event information and proposed solutions can help identify opportunities to improve current device capabilities and interoperability and support a learning health system to improve health care delivery. Developing and analyzing clinical scenarios are the first steps in creating solutions to address vexing patient safety problems and enable clinical innovation. A Web-based research tool for implementing a means of acquiring and managing this information, the Clinical Scenario Repository™ (MD PnP Program), is described.

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Active and Passive Optical Imaging Modality for Unobtrusive Cardiorespiratory Monitoring and Facial Expression Assessment

imageBecause of their obvious advantages, active and passive optoelectronic sensor concepts are being investigated by biomedical research groups worldwide, particularly their camera-based variants. Such methods work noninvasively and contactless, and they provide spatially resolved parameter detection. We present 2 techniques: the active photoplethysmography imaging (PPGI) method for detecting dermal blood perfusion dynamics and the passive infrared thermography imaging (IRTI) method for detecting skin temperature distribution. PPGI is an enhancement of classical pulse oximetry. Approved algorithms from pulse oximetry for the detection of heart rate, heart rate variability, blood pressure-dependent pulse wave velocity, pulse waveform-related stress/pain indicators, respiration rate, respiratory variability, and vasomotional activity can easily be adapted to PPGI. Although the IRTI method primarily records temperature distribution of the observed object, information on respiration rate and respiratory variability can also be derived by analyzing temperature change over time, for example, in the nasal region, or through respiratory movement. Combined with current research areas and novel biomedical engineering applications (eg, telemedicine, tele-emergency, and telemedical diagnostics), PPGI and IRTI may offer new data for diagnostic purposes, including assessment of peripheral arterial and venous oxygen saturation (as well as their differences). Moreover, facial expressions and stress and/or pain-related variables can be derived, for example, during anesthesia, in the recovery room/intensive care unit and during daily activities. The main advantages of both monitoring methods are unobtrusive data acquisition and the possibility to assess vital variables for different body regions. These methods supplement each other to enable long-term monitoring of physiological effects and of effects with special local characteristics. They also offer diagnostic advantages for intensive care patients and for high-risk patients in a homecare/outdoor setting. Selected applications have been validated at our laboratory using optical PPGI and IRTI techniques in a stand-alone or hybrid configuration. Additional research and validation is required before these preliminary results can be introduced for clinical applications.

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Applying Computer Models to Realize Closed-Loop Neonatal Oxygen Therapy

imageBACKGROUND: Within the context of automating neonatal oxygen therapy, this article describes the transformation of an idea verified by a computer model into a device actuated by a computer model. Computer modeling of an entire neonatal oxygen therapy system can facilitate the development of closed-loop control algorithms by providing a verification platform and speeding up algorithm development. METHODS: In this article, we present a method of mathematically modeling the system's components: the oxygen transport within the patient, the oxygen blender, the controller, and the pulse oximeter. Furthermore, within the constraints of engineering a product, an idealized model of the neonatal oxygen transport component may be integrated effectively into the control algorithm of a device, referred to as the adaptive model. Manual and closed-loop oxygen therapy performance were defined in this article by 3 criteria in the following order of importance: percent duration of SpO2 spent in normoxemia (target SpO2 ± 2.5%), hypoxemia (less than normoxemia), and hyperoxemia (more than normoxemia); number of 60-second periods 95% SpO2; and number of manual adjustments. RESULTS: Results from a clinical evaluation that compared the performance of 3 closed-loop control algorithms (state machine, proportional-integral-differential, and adaptive model) with manual oxygen therapy on 7 low-birth-weight ventilated preterm babies, are presented. Compared with manual therapy, all closed-loop control algorithms significantly increased the patients' duration in normoxemia and reduced hyperoxemia (P

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The Need to Apply Medical Device Informatics in Developing Standards for Safe Interoperable Medical Systems

imageMedical device and health information technology systems are increasingly interdependent with users demanding increased interoperability. Related safety standards must be developed taking into account these systems' perspective. In this article, we describe the current development of medical device standards and the need for these standards to address medical device informatics. Medical device information should be gathered from a broad range of clinical scenarios to lay the foundation for safe medical device interoperability. Five clinical examples show how medical device informatics principles, if applied in the development of medical device standards, could help facilitate the development of safe interoperable medical device systems. These examples illustrate the clinical implications of the failure to capture important signals and device attributes. We provide recommendations relating to the coordination between historically separate standards development groups, some of which focus on safety and effectiveness and others focus on health informatics. We identify the need for a shared understanding among stakeholders and describe organizational structures to promote cooperation such that device-to-device interactions and related safety information are considered during standards development.

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Advanced Uses of Pulse Oximetry for Monitoring Mechanically Ventilated Patients

imagePulse oximetry is an undisputable standard of care in clinical monitoring. It combines a spectrometer to detect hypoxemia with a plethysmograph for the diagnosis, monitoring, and follow-up of cardiovascular diseases. These pulse oximetry capabilities are extremely useful for assessing the respiratory and circulatory status and for monitoring of mechanically ventilated patients. On the one hand, the key spectrography-derived function of pulse oximetry is to evaluate a patient's gas exchange that results from a particular ventilatory treatment by continuously and noninvasively measuring arterial hemoglobin saturation (SpO2). This information helps to maintain patients above the hypoxemic levels, leading to appropriate ventilator settings and inspired oxygen fractions. However, whenever higher than normal oxygen fractions are used, SpO2 can mask existing oxygenation defects in ventilated patients. This limitation, resulting from the S shape of the oxyhemoglobin saturation curve, can be overcome by reducing the oxygen fraction delivered to the patient in a controlled and stepwise manner. This results in a SpO2/FIO2 diagram, which allows a rough characterization of a patient's gas exchange, shunt, and the amount of lung area with a low ventilation/perfusion ratio without the need of blood sampling. On the other hand, the photoplethysmography-derived oximeter function has barely been exploited for the purpose of monitoring hemodynamics in mechanically ventilated patients. The analysis of the photoplethysmography contour provides useful real-time and noninvasive information about the interaction of heart and lungs during positive pressure ventilation. These hemodynamic monitoring capabilities are related to both the assessment of preload dependency—mainly by analyzing the breath-by-breath variation of the photoplethysmographic signals—and the analysis of arterial impedance, which examines the changes in the plethysmographic amplitude, contour, and derived indexes. In this article, we present and describe these extended monitoring capabilities and propose a more holistic monitoring concept that takes advantage of these advanced uses of pulse oximetry in the monitoring of ventilated patients. Today's monitors need to be improved if such novel functionalities were to be offered for clinical use. Future developments and clinical evaluations are needed to establish the true potential of these advanced monitoring uses of pulse oximetry.

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Effect of Tapentadol on Splenic Cytokine Production in Mice.

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BACKGROUND: Opioid drugs affect immunity, but not all opioid drugs share the same immunomodulatory properties. Tapentadol is an analgesic drug with a dual synergistic mechanism of action: [micro]-opioid receptor agonism and noradrenaline reuptake inhibition. Weaker [micro]-opioid receptor agonism combined with noradrenaline reuptake inhibition results in potent analgesia with reduced opioid side effects. We evaluated the impact of tapentadol on splenic cytokine in normal and in hyperalgesia/allodynia mice, comparing it with morphine and reboxetine, a noradrenaline reuptake inhibitor. METHODS: Tapentadol, reboxetine, and morphine were injected subcutaneously into naive and mice that underwent sciatic nerve chronic constriction injury, and their effect on splenic cytokines (interferon-[gamma] [IFN-[gamma]], interleukin [IL]-2, IL-10, and IL-4) was measured by enzyme-linked immunosorbent assay after acute or chronic treatment. Nociceptive thresholds, thermal hyperalgesia, and allodynia also were assessed. Data were analyzed with 2-way analysis of variance (behavior) or 1-way analysis of variance (cytokines) followed by Bonferroni post hoc test. RESULTS: Primary outcomes of our study were the effects of drugs on splenic cytokines. Our data indicate that acute tapentadol did not modify cytokine production in comparison with animals that received saline, whereas morphine suppressed all the cytokines: saline versus morphine 10 mg/kg (mean difference [MD], 95% confidence interval [CI]: IFN-[gamma] = 12,400 [7760, 17,040], P

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Influence of possible predictor variables on the outcome of primary oral squamous cell carcinoma: a retrospective study of 392 consecutive cases at a single centre

Publication date: Available online 19 December 2016
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): D. Loeffelbein, L.M. Ritschl, F.D. Güll, M. Roth, K.-D. Wolff, T. Mücke
The successful treatment of oral squamous cell carcinoma (OSCC) depends on the treatment strategy. The prognosis is most often linked to the stage at initial presentation, but the effect of patient-related parameters on overall survival remains uncertain. In this study, 392 consecutive cases of OSCC seen between 2007 and 2013 at a single centre were analyzed retrospectively. Overall survival was assessed and univariate and multivariate Cox proportional hazards regression was used to identify associations between possible tumour-specific and patient-related variables and survival. The 5-year overall survival rate of the 392 patients (T stage 1–4) was 62.5%. Univariate analysis showed that sex, age, T stage, N stage, Union for International Cancer Control (UICC) stage, American Society of Anesthesiologists (ASA) status, operating time >400min, and length of in-patient stay >15 days were significantly associated with overall survival (all P<0.05). Tumour location, alcohol abuse, and smoking were found not to have a significant influence (all P>0.05). Age, T, N, and M stages, UICC stage, residual tumour status, recurrence, ASA status, and operating time >400min were found to have a significant influence on overall survival in the multivariate analysis (each P<0.05). These findings confirm that postoperative survival does not depend only on tumour-related characteristics. ASA status needs to be considered in treatment planning, as it significantly predicts patient survival.



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Influence of possible predictor variables on the outcome of primary oral squamous cell carcinoma: a retrospective study of 392 consecutive cases at a single centre

The successful treatment of oral squamous cell carcinoma (OSCC) depends on the treatment strategy. The prognosis is most often linked to the stage at initial presentation, but the effect of patient-related parameters on overall survival remains uncertain. In this study, 392 consecutive cases of OSCC seen between 2007 and 2013 at a single centre were analyzed retrospectively. Overall survival was assessed and univariate and multivariate Cox proportional hazards regression was used to identify associations between possible tumour-specific and patient-related variables and survival.

http://ift.tt/2hllFjK

Effects of Hypericum perforatum on the healing of xenografts: a histomorphometric study in rabbits

The aim of this study was to investigate effects of the Hypericum perforatum (St John's Wort) on bone healing in rabbit calvarium. Ten male New Zealand rabbits each had three bicortical defects made in the calvarial bones, which were filled with xenograft, xenograft+H perforatum oil extract, and autogenous graft. Four weeks postoperatively all rabbits were killed and the bony defects examined histomorphometrically. Tissue compartments including new bone (p<0.001), marrow space (p<0.001), and residual bone grafts (p=0.014) differed significantly among groups (p=0.00?).

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Infant Oral Mutilation – a Child Protection Issue?

Background: Infant oral mutilation (IOM) is a traditional practice involving "gouing out" of infant healthy tooth buds using crude methods in non-sterile conditions. It is usually performed by village healers in low income countries as an accepted remedy for common childhood illness, potentially leading to dento-alveolar and systemic complications including death.

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Open surgery of the TMJ – What are the real Indications?

Open joint TMJ surgery is undertaken for a variety of reasons, and not all of these are associated with positive outcomes.

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The effect of deprivation on the Incidence of Mandibular fractures in a British city

Aim: To examine the relationship between social and material deprivation and mandibular fractures.

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To biopsy or not to biopsy? That is the question...

Introduction: Non melanoma skin cancers (NMSC) are common cancers affecting nearly 100,000 people in the UK every year.

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Sentinel lymph node biopsy for head and neck melanoma - a multi-centre study examining efficacy and safety

Introduction: Sentinel lymph node biopsy (SLNB) is a highly accurate staging procedure for malignant melanoma (MM). The use of SLNB in head and neck melanoma has recently gained popularity as it is thought to offer useful prognostic information as upstaging of disease can allow patients to enter novel trial based targeted therapies.

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Urgent or Not? Analysis of referrals to Oral and Maxillofacial Surgery in NHS Lanarkshire in a 1 month period

Background: New patient referrals are largely from GPs and GDPs and at times are inappropriate in content or nature (marked urgent unnecessarily). Whilst vital some patients are seen urgently, others must be seen routinely for time management and fairness.

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Sentinel node biopsy for primary salivary gland tumours; feasibility study of a new technique

Introduction/Aims: There is no consensus on management of the N0 neck in patients with primary salivary neoplasms. Lymphatic drainage of the salivary glands is not well understood and elective neck dissection may miss the at risk lymph nodes. Sentinel node biopsy (SNB) is an accurate staging tool in other solid tumours but has not been widely described in salivary gland disease. We show that lymphatic drainage from primary salivary malignancy can be accurately mapped using a combination of SPECT/CT and navigational surgery.

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Do new NICE oral cancer referral guidelines (NG12) risk delay in cancer diagnosis? An audit comparing outcomes of the new guidelines against old guidelines

Introduction: The National Institute for Health and Care Excellence (NICE) publish referral guidance for two week wait (2WW) suspected cancer referrals (CG27 2005, NG12 2015). NG12 updated CG27 and now recommends certain presentations, if identified by a GP, should be referred to a dentist for assessment (criterion 1.8.4). We compared NG12 to CG27 in a cohort of patients referred to an Oral and Maxillofacial Surgery department to assess likely impact on outcomes.

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The use of a skin regeneration system for multiple intra-oral purposes

Objective: To trial the use of Integra© skin regeneration system intra-orally to avoid the necessity for mucosal flaps, free flaps or skin grafts

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Quality of Informed Consent Given to Surgical Skin Cancer Patients at Gloucester Royal Hospital

Background: The Oral and Maxillofacial Department at Gloucester Royal Hospital provides on average 500 surgical removals of skin cancer lesions per year.

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Injuries to the head and neck in Homer's Odyssey

The odyssey is one of the most famous and influential poems ever conceived and together with the Iliad are considered to be the most prominent and representative works of the ancient Greek epic poetry. Our purpose was to retrieve and systematically record the head and neck injuries mentioned in the Odyssey.

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A Clinical Audit on the Management of Oral Lichen Planus within the Oral and Maxillo-facial Department at the University Hospital of Manchester

Introduction: Lichen planus is an inflammatory, autoimmune mucocutaneous disease. Oral lichen planus (OLP) has a documented malignant transformation risk of 1-3%, therefore it is important that patients are followed up appropriately.

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Impact of malignant cerebral artery infarction guidelines on the profile of the cranioplasty service

Background: Early decompressive craniectomy (DC) for malignant middle cerebral artery (MCA) infarction leads to improved survival, as demonstrated by three multicenter randomized controlled trials (DECIMAL, DESTINY, HAMLET). The survivors of a malignant MCA stroke manifest complex medical and neurological problems along with extensive calvarial defects that require cranioplasty.

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The Inclusion of Mandibular Condyles in Orthopantomogram radiographs for Trauma cases: a retrospective audit at a Regional Maxillofacial Unit

Aims: In this retrospective study, we aim to analyse Orthopantomogram (OPG) x-rays taken for mandibular fractures at a major trauma facility. This is to determine their overall diagnostic viability and particularly the inclusion of the mandibular condyles.

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Unilateral and bilateral temporomandibular joint reconstruction in children using autogenous costochondral grafting: An outcome study of 60 patients over a 28-year period

Costochondral grafting (CCG) for temporomandibular joint (TMJ) reconstruction can be diversely used for both congenital and acquired TMJ absence or malfunction. Using a CCG gained increasing popularity in children due to its growth potential and autogenous origin. The disadvantages are its unpredictable growth pattern and ankylosis risks.

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An audit to assess handover techniques at Sheffield Teaching Hospitals

Introduction: Effective clinical handover is paramount in a successful patient journey, ensuring excellence in health-care quality and safety. Studies have shown that poor handover can result in patient harm and this is no different for dental core trainees on the maxillofacial ward.

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Implant Rehabilitation of Hypodontia Patients: Surgical Considerations

Aims: To evaluate the surgical and clinical outcomes of hypodontia patients undergoing surgical management and implant rehabilitation between the Queen Elizabeth Hospital Birmingham (QEHB) and the Birmingham Dental Hospital (BDH)

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Throat packs; are we compliant with NPSA guidelines?

The use of throat packs can be contentious with the decision undertaken by surgeon, anaesthetist or both. Blackburn and Knepil undertook a national BAOMS questionnaire on throat pack usage in 2008. Afterwards National Patient Safety Advice (NPSA) guidelines followed with no subsequent update. We report an audit of compliance with these in Hull Royal Infirmary.

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Minimally traumatic submental intubation- a novel dilational technique

Aims: Submental intubation is widely accepted as a safe and effective alternative to nasal intubation or tracheostomy in head and neck surgery patients. However, forceful or careless dilation can cause significant bleeding and swelling to the soft tissues, increasing the likelihood of troublesome sublingual haematoma and other airway related issues.

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Letter to the editor regarding cardiac arrest with vagal stimulation during intraoperative nerve monitoring



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Reply to letter to the editor regarding cardiac arrest after vagal stimulation in intraoperative neuromonitoring



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A Decade of Experience of Management of Thyroglossal Duct Cyst in a Tertiary Care Hospital: Differentiation Between Children and Adults

Abstract

Variations in thyroglossal duct cysts (TGDCs) between children and adult are mentioned very little in literature. The lesion mostly found in children but adult population also possesses this anomaly. The aim of this study was to determine the differences in clinical presentations and surgical outcomes of TGDC between children and adults. A retrospective chart review of all patients with TGDCs managed in our hospital from July 2004 to June 2014. All records were reviewed for age, sex, location of cyst in neck and with relation to hyoid bone, size, postoperative complication and recurrence rates. Differences between children and adults were assessed. A total of 39 patients (21 children and 18 adults) were treated for TGDC. Of the pediatric group, 71.4% were male and 28.5% were female, whereas 72.2% of the adults were male and 27.7% were female. Adults were more likely to develop other complaints like neck pain, dysphagia and dyspnea. Position was almost similar in both age groups with midline and infrahyoid location while laterality was seen in adult only. Size of Cyst was found to be larger in adults. The recurrence and post operative complication rates between children and adults were not significantly different. TGDC has male predominance. Clinical presentations were almost similar in both age groups. Although lateral deviation, increase size of cyst and recurrences were seen in adults only, Sistrunk procedure is recommended as a safe and standard surgical treatment in both age groups.



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Thyroid High-Impact Articles

FREE ACCESS through January 2, 2017.
Read Now:

Thyronamines and Derivatives: Physiological Relevance, Pharmacological Actions, and Future Research Directions
Carolin Stephanie Hoefig, Riccardo Zucchi, Josef Köhrle

Circulating 3-T1AM and 3, 5-T2 in Critically Ill Patients: A Cross-Sectional Observational Study
Lies Langouche, Ina Lehmphul, Sarah Vander Perre, Josef Köhrle, Greet Van den Berghe

Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis
Johanna Wichman, Kristian Hillert Winther, Steen Joop Bonnema, Laszlo Hegedüs

Cervical Lymph Node Metastases After Thyroidectomy for Papillary Thyroid Carcinoma Usually Remain Stable for Years
Chisato Tomoda, Kiminori Sugino, Kenichi Matsuzu, Takashi Uruno, Keiko Ohkuwa, Wataru Kitagawa, Mitsuji Nagahama, Koichi Ito

Reference Intervals of Thyroid Function During Pregnancy: Self-Sequential Longitudinal Study Versus Cross-Sectional Study
Xiaomei Zhang, Baoting Yao, Chenyan Li, Jinyuan Mao, Weiwei Wang, Xiaochen Xie, Xiaochun Teng, Cheng Han, Weiwei Zhou, Chenyang Li, Bin Xu, Lihua Bi, Tao Meng, Jianling Du, Shaowei Zhang, Zhengnan Gao, Liu Yang, Chenling Fan, Weiping Teng, Zhongyan Shan

The post Thyroid High-Impact Articles appeared first on American Thyroid Association.



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“Gauze Technique” in the Treatment of the Fungus Ball of the Maxillary Sinus: A Technique as Simple as It Is Effective

Fungus ball of maxillary sinus generally affects immunocompetent and nonatopic subjects. Although endoscopic removal is the current gold standard treatment, removal is at times difficult due to an accumulation of fungal elements in the anterior ad inferior recesses. Aim. To present our experience of maxillary fungus ball treated by the "gauze technique" that avoids these removal difficulties. Materials and Methods. A retrospective, cross-sectional, and descriptive study of 25 patients affected by maxillary fungus ball was carried out: 19 were treated by the "gauze technique" and 6 were treated without "gauze technique." Results. A comparison was made between the two groups for surgery procedure time, length of hospitalization, time from surgery to nasal unpacking, complications, and postsurgical patient satisfaction. The only statistically significant difference observed was a shorter surgical procedure time () for the "gauze technique." Conclusions. The data obtained in this study demonstrated that the "gauze technique" is a safe, simple, and quick technique, able to reduce surgery procedure time whilst providing excellent functional outcomes and patient satisfaction.

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Role of Google Glass in improving patient satisfaction for otolaryngology residents: A pilot study

Abstract

Objectives

To demonstrate the feasibility and efficacy of the Google Glass as a tool to improve patient satisfaction and patient-physician communication for otolaryngology residents in the outpatient clinic setting. The primary outcome of the study was to improve patient satisfaction scores based on physician communication related questions from Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys.

Study Design

Prospective randomized trial.

Setting

Tertiary care hospital.

Subject and Methods

To evaluate the effect on patient satisfaction, five residents were recorded using the Google Glass in an outpatient clinic setting by 50 randomized patients. Modified surveys based on the CG-CAHPS survey were completed by patients at the conclusion of each clinic encounter. The recorded videos were evaluated by 2 independent faculty. Summarized data and video were distributed to each resident for review as the intervention. The residents were recorded again by 45 additional patients with evaluation by patients and faculty.

Results

After intervention, the scores from faculty-surveys regarding patient satisfaction including the subject of better explanations (p>0.001), listening carefully (p>0.001), addressing patient questions (p>0.001), displaying respect (p>0.001), and spending adequate time (p=0.0005) all significantly improved, as well as overall performance (p=0.014). The scores from patient-surveys did significantly improve.

Conclusion

This study demonstrates the improvements in patient satisfaction and patient-physician communication can be achieved with the use of Google Glass as a first person recording device in the outpatient otolaryngology clinic setting.

This article is protected by copyright. All rights reserved.



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Balloon tuboplasty in patients with Eustachian tube dysfunction: A prospective study in 39 patients (55 ears)

Abstract

Eustachian tube dysfunction (ETD) is estimated to affect approximately 1% of the UK population.1 ETD and subsequent inadequate middle ear ventilation has been implicated in the pathogenesis of otological diseases including otitis media with effusion (OME), retraction pockets, tympanic membrane (TM) perforation and cholesteatoma.2

This article is protected by copyright. All rights reserved.



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Pinnaplasty: Improved access to the anti-helical fold

Abstract

Prominent ears affect a significant proportion of the population with some studies quoting rates of 5%. (1) Many techniques have been described over the years including, cartilage sparing, cartilage cutting, cartilage scoring and suturing.(2) Some of the more recent techniques describe the efficacy of incisionless pinnaplasty in selected cases. (2) Each technique has advantages and disadvantages with no overall consensus on the optimal technique. Pinnaplasty has several recognised complications including haematoma, infection, skin or cartilage necrosis, re-protrusion, asymmetry, suture expulsion and keloid scarring. (3)

This article is protected by copyright. All rights reserved.



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New surgical scoring system to predict postoperative mortality

Abstract

Purpose

There is still no easy and highly useful method to comprehensively assess both preoperative and intraoperative patient statuses to predict postoperative outcomes. We attempted to develop a new scoring system that would enable a comprehensive assessment of preoperative and intraoperative patient statuses instantly at the end of anesthesia, predicting postoperative mortality.

Methods

The study included 32,555 patients who underwent surgery under general or regional anesthesia from 2008 to 2012. From the anesthesia records, extracted factors, including patient characteristics and American Society of Anesthesiologists physical status classification (ASA-PS), and three intraoperative indexes (the lowest heart rate, lowest mean arterial pressure, and estimated volume of blood loss) are used to calculate the surgical Apgar score (sAs). The sAs and ASA-PS, and surgical Apgar score combined with American Society of Anesthesiologists physical status classification (SASA), which combines the sAs and ASA-PS into a single adjusted scale, were compared and analyzed with postoperative 30-day mortality.

Results

Increased severity of the sAs, ASA-PS and SASA was correlated with significantly higher mortality. The risk of death was elevated by 3.65 for every 2-point decrease in the sAs, by 6.4 for every 1-point increase in the ASA-PS, and by 9.56 for every 4-point decrease in the SASA. The ROC curves of the sAs and ASA-PS alone also individually demonstrated high validity (AUC = 0.81 for sAs and 0.79 for ASA-PS, P < 0.001). The SASA was even more valid (AUC = 0.87, P < 0.001).

Conclusions

The sAs and ASA-PS were shown to be extremely useful for predicting 30-day mortality after surgery. An even higher predictive ability was demonstrated by the SASA, which combines these simple and effective scoring systems.



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Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model

Abstract

Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment.



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A novel environmental exposure index and its interaction with familial susceptibility on oral cancer in non-smokers and non-drinkers: a case–control study

Abstract

The objective of this study was to explore the collective effect of environmental factors and its interaction with familial susceptibility on oral cancer among non-smokers and non-drinkers (NSND). A hospital-based case–control study, including 319 oral cancer patients and 994 frequency-matched controls, was conducted in Fujian, China. We raised a weighed environmental exposure index according to nine significant environmental factors obtained from multivariable logistic regression model. And then, the index was classified into three categories according to the tertiles of controls (<1.34, 1.34–2.43, and >2.43). Multiplicative and additive interactions were evaluated between environmental exposure index and family cancer history. Our results showed that environmental exposure index was associated with an increased risk of oral cancer especially for those with family cancer history. Compared to subjects with low environmental exposure index and without family cancer history, those with high index and family cancer history showed the highest magnitude of OR in oral cancer risk (OR 10.40, 95% CI 5.46–19.80). Moreover, there was a multiplicative interaction between environmental exposure index and family cancer history for the risk of oral cancer (P < 0.001). This study puts forward a novel environmental exposure index, which enables a comprehensive evaluation on the overall effect of environmental risk factors on oral cancer among NSND and may interact with family cancer history. Further studies are warranted to explore the underlying mechanisms.



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A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus

Abstract

The majority of tinnitus patients are affected by chronic idiopathic tinnitus, and almost 60 different treatment modalities have been reported. The present study is a multidisciplinary systematic analysis of the evidence for the different forms of treatment for chronic tinnitus. The results are used to form the basis of an S3 guideline. A systematic search was carried out in PubMed and the Cochrane Library. The basis for presenting the level of evidence was the evidence classification of the Oxford Centre of Evidence-based Medicine. Whenever available, randomised controlled trials were given preference for discussing therapeutic issues. All systematic reviews and meta-analyses were assessed for their methodological quality, and effect size was taken into account. As the need for patient counselling is self-evident, specific tinnitus counselling should be performed. Due to the high level of evidence, validated tinnitus-specific, cognitive behavioural therapy is strongly recommended. In addition, auditory therapeutic measures can be recommended for the treatment of concomitant hearing loss and comorbidities; those should also be treated with drugs whenever appropriate. In particular, depression should be treated, with pharmacological support if necessary. If needed, psychiatric treatment should also be given on a case-by-case basis. With simultaneous deafness or hearing loss bordering on deafness, a CI can also be indicated. For auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation.



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10 Tech Advances That Can Change Medicine

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Medscape editor-in-chief Eric Topol outlines the best technological advances in medicine of the last year.
Medscape

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Can Lavender and Tea Tree Oils Hurt Kids?

Although there is no definitive proof that lavender and tea tree oils act as endocrine disruptors, studies suggest a possible link.
Medscape Pediatrics

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Allergic Sensitization at School Age is a Systemic Low-grade Inflammatory Disorder

Abstract

Background

Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization.

Methods

High sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6mo (N=214) and 7yrs (N=277) in children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at age ½, 1½, 4 and 6yrs by specific-IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principle component analyses (PCA).

Results

Adjusted for gender, recent infections and a CRP genetic risk-score, hs-CRP at 7yrs was associated with concurrent elevated specific-IgE against any allergen (adjusted OR (aOR) =1.40; 95% CI, 1.14-1.72; p=0.001), aeroallergens (aOR, 1.43; 1.15-1.77; p=0.001), food allergens (aOR, 1.31; 95% CI, 1.02-1.67; p=0.04), sensitization without any clinical allergy symptoms (aOR=1.40; 1.06-1.85; p=0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariantly associated with sensitization, but multi-parametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6mo were not associated with subsequent development of sensitization phenotypes.

Conclusions

Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early onset NCD.

This article is protected by copyright. All rights reserved.



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Seasonal differences of tympanogram and middle ear findings in children

Abstract

Background

It is a known fact that bacterial or viral acute otitis media occurs more frequently in the winter months. Only a few older studies on seasonal differences in middle ear findings are available. These studies are based solely on tympanography, without correlation to intraoperative middle ear findings. This study addresses the question of whether seasonal differences can be found in the preoperative tympanogram and in the corresponding intraoperative findings in children with chronic middle ear problems.

Patients and methods

This retrospective study included patients who had undergone myringotomy with or without tympanostomy tube insertion at the Charité–Universitätsmedizin Berlin between January and December 2011. Corresponding to the catarrhal phases, winter months were defined as those from November to April; summer months from May to October. The preoperative tympanogram and the documented intraoperative middle ear finding were statistically analyzed for seasonal differences.

Results

A total of 654 ears from 206 male and 127 female patients with mean age 3.7 ± 2.5 years were analyzed. In the majority of cases, a type B tympanogram was found (n = 376; 57.5%), whereas the middle ear was filled with air in 19.1% of cases. No significant seasonal differences were found for either the intraoperative middle ear findings or the preoperative tympanograms (p > 0.05).

Conclusion

For children with a typical history of chronic otitis media without effusion and chronic tube ventilation dysfunction, myringotomy with or without tympanostomy tube insertion is indicated independently of the season. The results indicate that a wait-and-see approach with hope of improvement during the summer months is not rational.



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Cochleaimplantatversorgung bei einseitiger Taubheit oder asymmetrischem Hörverlust

Zusammenfassung

Hintergrund

Die Rehabilitation von Patienten mit einseitiger Taubheit („single-sided deafness", SSD) oder asymmetrischem Hörverlust kann mit konventionellen (Bi)CROS-Hörgeräten („(bilateral) contralateral routing of signals", knochenverankerten Hörsystemen („bone-anchored hearing systems", BAHS) oder mit Cochleaimplantaten (CI) erfolgen. Bisher gibt es nur kleine Fallserien über den Versorgungserfolg bei SSD-Patienten nach CI-Operation und nur wenige vergleichende Arbeiten zur Evaluation des Rehabilitationserfolgs.

Ziel der Arbeit

Ziel war es, die erfolgreiche Behandlung der einseitigen Taubheit und des asymmetrischen Hörverlusts mit einem CI im Vergleich zum unversorgten monauralen Hören und mit den Therapieoptionen BAHS und (Bi)CROS anhand einer großen Patientenzahl nachzuweisen.

Material und Methoden

In einer monozentrischen Studie wurden 45 Patienten mit einseitiger Taubheit und 40 Patienten mit asymmetrischem Hörverlust nach sorgfältiger Indikationsstellung mit einem CI versorgt. Sowohl präoperativ als auch 12 Monate nach CI-Versorgung wurden das monaurale Sprachverstehen im Störgeräusch und die Lokalisationsfähigkeit mit (Bi)CROS-HG und BAHS-Testgeräten (am Testbügel) sowie die subjektive Beurteilung mit dem Fragebogen Speech, Spatial and Qualities of Hearing Scale (SSQ) erfasst.

Ergebnisse

Erstmals lässt sich hier der Erfolg der binauralen Rehabilitation mittels CI anhand einer großen Patientenzahl und deren Vorteil gegenüber (Bi)CROS und BAHS anhand einer kleineren Subgruppe nachweisen und somit die Indikation für diese Behandlung bestätigen. Patienten mit erworbener Taubheit und einer Taubheitsdauer von mehr als 10 Jahren weisen einen vergleichbaren Nutzen mit dem CI gegenüber kurzzeitertaubten Patienten auf.



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Metal Hypersensitivity Reactions to Orthopedic Implants

Abstract

Total hip and knee replacement surgery using metal alloy devices is common. Type IV allergic reactions to these implants occur, though infrequently. While uncommon, peri-implant metal allergic reactions may cause significant morbidity for the affected individual—including aseptic loosening, pseudotumor formation and frank device failure. It is challenging to predict who will have these reactions, even in those with established pre-implant metal allergy. At this time, the scientific literature clearly supports few conclusions. Despite this, we believe several conclusions can be made: routine pre-implant testing in asymptomatic individuals is not indicated; listen to patient's concerns about metal allergy if the concern arises; patch testing is probably the best pre- and post-implant screening test; post-implantation testing is controversial and even positive LTT or patch test does not definitively diagnose morbidity from a metal allergy; and complete recovery following revision placement of an immunologically inert device is diagnostic. More research is needed to scientifically approach this issue.



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Efficacy and Safety of 5-Fluorouracil 0.5%/Salicylic Acid 10% in the Field-Directed Treatment of Actinic Keratosis: A Phase III, Randomized, Double-Blind, Vehicle-Controlled Trial

Abstract

Introduction

Due to the high prevalence of actinic keratosis (AK) and potential for lesions to become cancerous, clinical guidelines recommend that all are treated. The objective of this study was to evaluate the efficacy and safety of 5-fluorouracil (5-FU) 0.5%/salicylic acid 10% as field-directed treatment of AK lesions.

Methods

This multicenter, double-blind, vehicle-controlled study (NCT02289768) randomized adults, with a 25 cm2 area of skin on their face, bald scalp, or forehead covering 4–10 clinically confirmed AK lesions (grade I/II), 2:1 to treatment or vehicle applied topically once daily for 12 weeks. The primary endpoint was the proportion of patients with complete clinical clearance (CCC) of lesions in the treatment field 8 weeks after the end of treatment. Secondary endpoints included partial clearance (PC; ≥75% reduction) of lesions. Safety outcomes were assessed.

Results

Of 166 patients randomized, 111 received 5-FU 0.5%/salicylic acid 10% and 55 received vehicle. At 8 weeks after the end of treatment, CCC was significantly higher with 5-FU 0.5%/salicylic acid 10% than with vehicle [49.5% vs. 18.2%, respectively; odds ratio (OR) 3.9 (95% CI) 1.7, 8.7; P = 0.0006]. Significantly more patients achieved PC of lesions with treatment than with vehicle [69.5% vs. 34.6%, respectively; OR 4.9 (95% CI 2.3, 10.5); P < 0.0001]. Treatment-emergent adverse events, predominantly related to application- and administration-site reactions, were more common with 5-FU 0.5%/salicylic acid 10% than with vehicle (99.1% vs. 83.6%).

Conclusions

Compared with vehicle, field-directed treatment of AK lesions with 5-FU 0.5%/salicylic acid 10% was effective in terms of CCC. Safety outcomes were consistent with the known and predictable safety profile.

Trial registration

NCT02289768.

Funding

Almirall S.A.



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T cell receptor gene recombinations in human tumor specimen exome files: detection of T cell receptor-β VDJ recombinations associates with a favorable oncologic outcome for bladder cancer

Abstract

Understanding tumor-resident T cells is important for cancer prognosis and treatment options. Conventional, solid tumor specimen exome files can be searched directly for recombined T cell receptor (TcR)-α segments; RNASeq files can include TcR-β VDJ recombinations. To learn whether there are medically relevant uses of exome-based detection of TcR V(D)J recombinations in the tumor microenvironment, we searched cancer genome atlas and Moffitt Cancer Center, tumor specimen exome files for TcR-β, TcR-γ, and TcR-δ recombinations, for bladder and stomach cancer. We found that bladder cancer exomes with productive TcR-β recombinations had a significant association with No Subsequent Tumors and a positive response to drug treatments, with p < 0.004, p < 0.05, and p < 0.004, depending on the sample sets examined. We also discovered the opportunity to detect productive TcR-γ and TcR-δ recombinations in the tumor microenvironment, via the tumor specimen exome files.



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Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model

Abstract

Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment.



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Mastozytose

Zusammenfassung

Die Mastozytose ist eine seltene Krankheit mit Vermehrung von klonalen Mastzellen im Gewebe. Sie tritt fast ausschließlich sporadisch auf. Das Krankheitsspektrum ist heterogen und reicht von isoliertem Hautbefall mit normaler Lebenserwartung bis zu seltenen aggressiven Formen mit sehr schlechter Prognose. Häufig sind Kinder betroffen. Während bei ihnen fast ausschließlich eine rein kutane Mastozytose besteht und der Hautbefall polymorph ist, ist der Hautbefall bei Erwachsenen kleinfleckig makulopapulös und zu über 80 % mit einem Knochenmarkbefall und der aktivierenden D816V-Mutation im c‑KIT-Rezeptor-Gen verbunden. Die Erkrankung kann eine Vielzahl von Symptomen aufweisen wie Pruritus, Diarrhö, Bauchkrämpfen, Palpitationen und Flush. Gehäuft besteht eine Osteoporose, bei aggressiven Formen kommt es auch zu Osteolysen mit pathologischen Frakturen. Besonders gefährdet sind die Patienten durch Hymenopterenstiche, die zu schweren Anaphylaxien führen können. Die Therapie ist symptomatisch, zytoreduktive Therapien sind therapierefraktären und aggressiven Formen vorbehalten.



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Partielles Ansprechen einer Lichturtikaria auf Omalizumab

Zusammenfassung

Die Therapie der Lichturtikaria gilt als schwierig. In einigen Fällen wurde über das gute Ansprechen auf den Anti-IgE-Antikörper Omalizumab (Xolair®), der bereits zur Therapie der chronischen spontanen Urtikaria zugelassen ist, berichtet. Wir stellen hier eine 50-jährige Patientin vor, die seit 5 Jahren über das lokale Auftreten von juckenden und brennenden Hautrötungen und Schwellungen unter Besonnung klagte, wobei gelegentlich auch Schockfragmente auftraten. Orale Antihistaminika in 3‑ bis 4‑facher Dosierung und die topische Anwendung eines Sunblockers hatten sich unter Langzeitfeldbedingungen nur als teilweise wirksam erwiesen. In der Lichttestung fanden sich urtikarielle Sofortreaktionen auf niedrige Dosen UVB und UVA. Drei Wochen nach s. c.-Gabe von 300 mg Omalizumab fand sich die minimale Urtikaria-auslösende Dosis (MUD) von UVB um das mindestens 20-Fache (von <0,001 auf 0,02 J/cm2) und von UVA um das 4‑Fache (von 0,1 auf 0,4 J/cm2) erhöht, und die Patientin gab jetzt fehlenden Juckreiz im Testareal an. Dagegen blieb die MUD von UVA1 unverändert bei 5,0 J/cm2. Der Urtikaria-Aktivitätssore über 7 Tage (UAS7) von 30 Punkten unmittelbar vor der Therapie verringerte sich in der zweiten und dritten Woche auf jeweils 14 Punkte. Insgesamt fand sich im vorliegenden Fall ein partielles Ansprechen der Lichturtikaria auf die Omalizumab-Therapie.



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Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer [IMMUNE REGULATION]

Thymic dendritic cells (DC) delete self-antigen–specific thymocytes, and drive development of Foxp3-expressing immunoregulatory T cells. Unlike medullary thymic epithelial cells, which express and present peripheral self-antigen, DC must acquire self-antigen to mediate thymic negative selection. One such mechanism entails the transfer of surface MHC–self peptide complexes from medullary thymic epithelial cells to thymic DC. Despite the importance of thymic DC cross-dressing in negative selection, the factors that regulate the process and the capacity of different thymic DC subsets to acquire MHC and stimulate thymocytes are poorly understood. In this study intercellular MHC transfer by thymic DC subsets was investigated using an MHC-mismatch–based in vitro system. Thymic conventional DC (cDC) subsets signal regulatory protein α (SIRPα+) and CD8α+ readily acquired MHC class I and II from thymic epithelial cells but plasmacytoid DC were less efficient. Intercellular MHC transfer was donor-cell specific; thymic DC readily acquired MHC from TEC plus thymic or splenic DC, whereas thymic or splenic B cells were poor donors. Furthermore DC origin influenced cross-dressing; thymic versus splenic DC exhibited an increased capacity to capture TEC-derived MHC, which correlated with direct expression of EpCAM by DC. Despite similar capacities to acquire MHC–peptide complexes, thymic CD8α+ cDC elicited increased T cell stimulation relative to SIRPα+ cDC. DC cross-dressing was cell-contact dependent and unaffected by lipid raft disruption of donor TEC. Furthermore, blocking PI3K signaling reduced MHC acquisition by thymic CD8α+ cDC and plasmacytoid DC but not SIRPα+ cDC. These findings demonstrate that multiple parameters influence the efficiency of and distinct mechanisms drive intercellular MHC transfer by thymic DC subsets.



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Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3 [IMMUNE REGULATION]

Application of dendritic cells (DCs) to prime responses to tumor Ags provides a promising approach to immunotherapy. However, only a limited number of DCs can be manufactured from adult precursors. In contrast, pluripotent embryonic stem (ES) cells represent an inexhaustible source for DC production, although it remains a major challenge to steer directional differentiation because ES cell–derived cells are typically immature with impaired functional capacity. Consistent with this notion, we found that mouse ES cell–derived DCs (ES-DCs) represented less mature cells compared with bone marrow–derived DCs. This finding prompted us to compare the gene expression profile of the ES cell– and adult progenitor-derived, GM-CSF–instructed, nonconventional DC subsets. We quantified the mRNA level of 17 DC-specific transcription factors and observed that 3 transcriptional regulators (Irf4, Spi-B, and Runx3) showed lower expression in ES-DCs than in bone marrow–derived DCs. In light of this altered gene expression, we probed the effects of these transcription factors in developing mouse ES-DCs with an isogenic expression screen. Our analysis revealed that forced expression of Irf4 repressed ES-DC development, whereas, in contrast, Runx3 improved the ES-DC maturation capacity. Moreover, LPS-treated and Runx3-activated ES-DCs exhibited enhanced T cell activation and migratory potential. In summary, we found that ex vivo–generated ES-DCs had a compromised maturation ability and immunogenicity. However, ectopic expression of Runx3 enhances cytokine-driven ES-DC development and acts as an instructive tool for the generation of mature DCs with enhanced immunogenicity from pluripotent stem cells.



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A CD80-Biased CTLA4-Ig Fusion Protein with Superior In Vivo Efficacy by Simultaneous Engineering of Affinity, Selectivity, Stability, and FcRn Binding [NOVEL IMMUNOLOGICAL METHODS]

Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation. The majority of CTLA4 molecules showing the largest potency gains in primary in vitro and ex vivo human cell assays, using PBMCs from type 1 diabetes patients, had significant improvements in CD80, but only modest gains in CD86 binding. We furthermore observed different potency rankings between our lead molecule MEDI5265, abatacept, and belatacept, depending on which type of APC was used, with MEDI5265 consistently being the most potent. We then created fusions of both stability- and potency-optimized CTLA4 moieties with human Fc variants conferring extended plasma t1/2. In a cynomolgus model of T cell–dependent Ab response, the CTLA4-Ig variant MEDI5265 could be formulated at >100 mg/ml for s.c. administration and showed superior efficacy and significantly prolonged serum t1/2. The combination of higher stability and potency with prolonged pharmacokinetics could be compatible with very infrequent, s.c. dosing while maintaining a similar level of immune suppression to more frequently and i.v. administered licensed therapies.



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Generation of a Novel HLA Class I Transgenic Mouse Model Carrying a Knock-in Mutation at the {beta}2-Microglobulin Locus [NOVEL IMMUNOLOGICAL METHODS]

We generated a series of monochain HLA class I knock-in (KI) mouse strains, in which a chimeric HLA class I molecule (α1/α2 domain of HLA-A*0201, HLA-A*0301, HLA-A*2402, or HLA-A*3101 and α3 domain of H-2Db) was covalently linked with 15 aa to human β2-microglobulin (β2m) and introduced into the endogenous mouse β2m locus. In homozygous KI mice, mouse β2m gene disruption resulted in loss of the endogenous H-2 class I molecules and reduction in the peripheral CD8+ T cell population that was partially restored by monochain HLA class I expression. A gene dosage-dependent expression of HLA, similar to that in human PBMCs, was detected in heterozygous and homozygous HLA KI mice. Upon vaccination with various virus epitopes, HLA-restricted, epitope-specific CTLs were induced in HLA KI mice, similar to the response in the commonly used HLA transgenic mice. Importantly, the CTL responses induced in heterozygous KI mice were similar to those in homozygous KI mice. These results suggest that coexpression of H-2 class I does not affect HLA-restricted CTL responses in HLA KI mice, which differs from the situation reported for monochain HLA Tg x β2m–/– mice. Furthermore, we generated double KI mice harboring two different HLA (HLA-A*2402 and HLA-A*0301) KI alleles, which showed a CTL response against both HLA-A24 and HLA-A3 epitopes when immunized with a mixture of both peptides. These results indicated that this HLA class I KI mouse model provides powerful research tools not only for the study of HLA class I–restricted CTL responses, but also for preclinical vaccine evaluation.



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Accurate Structure Prediction of CDR H3 Loops Enabled by a Novel Structure-Based C-Terminal Constraint [NOVEL IMMUNOLOGICAL METHODS]

Ab structure prediction has made great strides, but accurately modeling CDR H3 loops remains elusive. Unlike the other five CDR loops, CDR H3 does not adopt canonical conformations and must be modeled de novo. During Antibody Modeling Assessment II, we found that biasing simulations toward kinked conformations enables generating low–root mean square deviation models (Weitzner et al. 2014. Proteins 82: 1611–1623), and since then, we have presented new geometric parameters defining the kink conformation (Weitzner et al. 2015. Structure 23: 302–311). In this study, we use these parameters to develop a new biasing constraint. When applied to a benchmark set of high-quality CDR H3 loops, the average minimum root mean square deviation sampled is 0.93 Å, compared with 1.34 Å without the constraint. We then test the performance of the constrained de novo method for homology modeling and rigid-body docking and present the results for 1) the Antibody Modeling Assessment II targets, 2) the 2009 RosettaAntibody benchmark set, and 3) the high-quality set.



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Essential Role of mTORC1 in Self-Renewal of Murine Alveolar Macrophages [MUCOSAL IMMUNOLOGY]

Alveolar macrophages (AM) have the capacity of local self-renewal through adult life; however, mechanisms that regulate AM self-renewal remain poorly understood. We found that myeloid-specific deletion of Raptor, an essential component of the mammalian/mechanistic target of rapamycin complex (mTORC)1, resulted in a marked decrease of this population of cells accompanying altered phenotypic features and impaired phagocytosis activity. We demonstrated further that Raptor/mTORC1 deficiency did not affect AM development, but compromised its proliferative activity at cell cycle entry in the steady-state as well as in the context of repopulation in irradiation chimeras. Mechanically, mTORC1 confers AM optimal responsiveness to GM-CSF–induced proliferation. Thus, our results demonstrate an essential role of mTORC1 for AM homeostasis by regulating proliferative renewal.



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Distribution and Activation of CD8+ T Cells in the Duodenal Mucosa before and after HIV Seroconversion [MUCOSAL IMMUNOLOGY]

CD8+ T cells in the intestinal mucosa influence the HIV-associated pathogenesis, but little is known about the dynamics of mucosal CD8+ T cell counts and activation of these cells during the course of infection. In this study, mucosal CD8+ T cells in the duodenum were studied at different stages of HIV infection, starting from the seronegative phase. In seronegative acute HIV infection, CD8+ T cell counts increased in the epithelium, but not in the lamina propria. Infiltration of the lamina propria by peripherally expanded CD8+ T cells was observed after seroconversion. Highest increase in the expression of perforin, the rate-limiting molecule for cytotoxic CD8+ T cell activity, was evident in the lamina propria of seronegative acutely HIV-infected patients. The number of perforin-expressing cells in the lamina propria of acutely HIV-infected patients was positively associated with biomarkers of enterocyte damage and microbial translocation. After seroconversion, perforin expression was downregulated in the lamina propria, but not in the epithelium. In conclusion, our findings demonstrate that intraepithelial and lamina propria CD8+ T cells exhibit different dynamics of numerical alteration and cytotoxic activity in HIV-infected patients. Moreover, our results suggest that perforin-dependent cytotoxic mechanisms by CD8+ T cells could impair the intestinal mucosal barrier already in the seronegative phase of acute HIV infection, thereby inducing microbial translocation as one of the earliest pathological events in HIV infection.



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Complement Protein C1q Enhances Macrophage Foam Cell Survival and Efferocytosis [INNATE IMMUNITY AND INFLAMMATION]

In the atherosclerotic lesion, macrophages ingest high levels of damaged modified low-density lipoproteins (LDLs), generating macrophage foam cells. Foam cells undergo apoptosis and, if not efficiently cleared by efferocytosis, can undergo secondary necrosis, leading to plaque instability and rupture. As a component of the innate immune complement cascade, C1q recognizes and opsonizes modified forms of LDL, such as oxidized or acetylated LDL, and promotes ingestion by macrophages in vitro. C1q was shown to be protective in an atherosclerosis model in vivo. Therefore, this study aimed to investigate whether ingestion of modified LDL in the presence of C1q alters macrophage foam cell survival or function. In an unbiased transcriptome analysis, C1q was shown to modulate expression of clusters of genes involved in cell death and apoptosis pathways in human monocyte–derived macrophages ingesting modified LDL; this was validated by quantitative PCR in human and murine macrophages. C1q downregulated levels and activity of active caspase-3 and PARP-1 in human and mouse macrophages during ingestion of modified LDL. This led to a measurable increase in survival and decrease in cell death, as measured by alamarBlue and propidium iodide assays, respectively. C1q opsonization also increased phagocytosis and efferocytosis in macrophage foam cells. These data suggest that C1q promotes macrophage survival during ingestion of excess cholesterol, as well as improves foam cell efferocytic function. This may be important in slowing disease progression and provides insight into the protective role of C1q in early atherosclerosis.



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PGI2 Controls Pulmonary NK Cells That Prevent Airway Sensitization to House Dust Mite Allergen [INNATE IMMUNITY AND INFLAMMATION]

In allergic asthma, inhalation of airborne allergens such as the house dust mite (HDM) effectively activates both innate and adaptive immunity in the lung mucosa. To determine the role of the eicosanoid PGI2 and its receptor IP during allergic airway sensitization, HDM responses in mice lacking a functional IP receptor (i.e., PGI2 IP receptor–deficient [IP–/–]) were compared with wild type (WT) mice. Surprisingly, IP–/– mice had increased numbers of pulmonary CD3NK1.1+Ly49b+ NK cells producing IFN- that was inversely associated with the number of type 2 innate lymphoid cells (ILC2s) expressing IL-33Rα and IL-13 compared with WT animals. This phenomenon was associated with elevated CX3CL1 levels in the airways of IP–/– mice and treatment with a neutralizing Ab to CX3CL1 reduced IFN- production by the lung NK cells. Remarkably, IP–/– mice were less responsive to HDM challenge than WT counterparts because intranasal instillation of the allergen induced markedly reduced levels of airway eosinophils, CD4+ lymphocyte infiltration, and mucus production, as well as depressed levels of CCL2 chemokine and Th2 cytokines. NK cells were responsible for such attenuated responses because depletion of NK1.1+ cells in IP–/– mice restored both the HDM-induced lung inflammation and ILC2 numbers, whereas transfer of CD3NK1.1+ NK cells into the airways of WT hosts suppressed the inflammatory response. Collectively, these data demonstrate a hitherto unknown role for PGI2 in regulating the number and properties of NK cells resident in lung tissue and reveal a role for NK cells in limiting lung tissue ILC2s and preventing allergic inflammatory responses to inhaled HDM allergen.



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Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis via NF-{kappa}B [INNATE IMMUNITY AND INFLAMMATION]

IL-23 activates the synthesis and production of leukotriene B4 (LTB4) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB4 and its receptor LTB4R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB4 and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB4 pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-B ligand bone marrow cells derived from BLT1+/+ and/or BLT1–/– mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP+ cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-B and phosphorylated IB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF--B ligand–induced activation of intracellular calcium flux in vitro. Our data show that LTB4 and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB4 and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.



http://ift.tt/2h3xCNo

Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1-Dependent Pathway: Implications for Fetal Growth Restriction [INNATE IMMUNITY AND INFLAMMATION]

Excessive placental inflammation is associated with several pathological conditions, including stillbirth and fetal growth restriction. Although infection is a known cause of inflammation, a significant proportion of pregnancies have evidence of inflammation without any detectable infection. Inflammation can also be triggered by endogenous mediators, called damage associated molecular patterns or alarmins. One of these damage-associated molecular patterns, uric acid, is increased in the maternal circulation in pathological pregnancies and is a known agonist of the Nlrp3 inflammasome and inducer of inflammation. However, its effects within the placenta and on pregnancy outcomes remain largely unknown. We found that uric acid (monosodium urate [MSU]) crystals induce a proinflammatory profile in isolated human term cytotrophoblast cells, with a predominant secretion of IL-1β and IL-6, a result confirmed in human term placental explants. The proinflammatory effects of MSU crystals were shown to be IL-1–dependent using a caspase-1 inhibitor (inhibits IL-1 maturation) and IL-1Ra (inhibits IL-1 signaling). The proinflammatory effect of MSU crystals was accompanied by trophoblast apoptosis and decreased syncytialization. Correspondingly, administration of MSU crystals to rats during late gestation induced placental inflammation and was associated with fetal growth restriction. These results make a strong case for an active proinflammatory role of MSU crystals at the maternal–fetal interface in pathological pregnancies, and highlight a key mediating role of IL-1. Furthermore, our study describes a novel in vivo animal model of noninfectious inflammation during pregnancy, which is triggered by MSU crystals and leads to reduced fetal growth.



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P2Y6 Receptor Antagonist MRS2578 Inhibits Neutrophil Activation and Aggregated Neutrophil Extracellular Trap Formation Induced by Gout-Associated Monosodium Urate Crystals [INNATE IMMUNITY AND INFLAMMATION]

Human neutrophils (polymorphonuclear leukocytes [PMNs]) generate inflammatory responses within the joints of gout patients upon encountering monosodium urate (MSU) crystals. Neutrophil extracellular traps (NETs) are found abundantly in the synovial fluid of gout patients. The detailed mechanism of MSU crystal–induced NET formation remains unknown. Our goal was to shed light on possible roles of purinergic signaling and neutrophil migration in mediating NET formation induced by MSU crystals. Interaction of human neutrophils with MSU crystals was evaluated by high-throughput live imaging using confocal microscopy. We quantitated NET levels in gout synovial fluid supernatants and detected enzymatically active neutrophil primary granule enzymes, myeloperoxidase, and human neutrophil elastase. Suramin and PPADS, general P2Y receptor blockers, and MRS2578, an inhibitor of the purinergic P2Y6 receptor, blocked NET formation triggered by MSU crystals. AR-C25118925XX (P2Y2 antagonist) did not inhibit MSU crystal–stimulated NET release. Live imaging of PMNs showed that MRS2578 represses neutrophil migration and blocked characteristic formation of MSU crystal–NET aggregates called aggregated NETs. Interestingly, the store-operated calcium entry channel inhibitor (SK&F96365) also reduced MSU crystal–induced NET release. Our results indicate that the P2Y6/store-operated calcium entry/IL-8 axis is involved in MSU crystal–induced aggregated NET formation, but MRS2578 could have additional effects affecting PMN migration. The work presented in the present study could lead to a better understanding of gouty joint inflammation and help improve the treatment and care of gout patients.



http://ift.tt/2h3xDAW

Soluble TNF Regulates TACE via AP-2{alpha} Transcription Factor in Mouse Dendritic Cells [INNATE IMMUNITY AND INFLAMMATION]

Dendritic cells (DCs), the essential immunoregulatory and APCs, are major producers of the central mediator of inflammation, soluble TNF-α (sTNF). sTNF is generated by TNF-α converting enzyme (TACE) proteolytic release of the transmembrane TNF (tmTNF) ectodomain. The mechanisms of TACE and sTNF regulation in DCs remain elusive. This study newly defines that sTNF regulates TACE in mouse DCs by engaging the AP-2α transcription factor. We found that the expression of AP-2α was higher, whereas the expression and activity of TACE were lower, in wild-type DCs (wtDCs) than in TNF knockout (TNFko) DCs. Exogenous sTNF rapidly and simultaneously induced increases of AP-2α expression and decreases of TACE expression and activity in wtDCs and TNFko DCs, indicating that AP-2α and TACE are inversely dependent on sTNF and are functionally associated. To define this functional association, we identified an AP-2α binding site in TACE promoter and demonstrated, using EMSAs and chromatin immunoprecipitation assays, that AP-2α could bind to TACE promoter in a TNF-dependent manner. Additionally, sTNF simultaneously enhanced AP-2α expression and decreased TACE promoter luciferase activity in DCs. Similarly, transfection of AP-2α cDNA decreased TACE promoter luciferase activity, TACE expression, and TACE enzymatic activity in wtDCs or TNFko DCs. In contrast, transfection of AP-2α small interfering RNA increased TACE promoter luciferase activity, TACE expression, and TACE enzymatic activity in wtDCs. These results show that TACE is a target of, and is downregulated by, sTNF-induced AP-2α transcription factor in DCs.



http://ift.tt/2i8lBUy

Myeloid-Specific Gene Deletion of Protein Phosphatase 2A Magnifies MyD88- and TRIF-Dependent Inflammation following Endotoxin Challenge [INNATE IMMUNITY AND INFLAMMATION]

Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns is mediated by various protein kinases, and PP2A plays a counter-regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the α isoform of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells. The myeloid-specific knockout mice (lyM-PP2Afl/fl) showed higher mortality in response to endotoxin challenge and bacterial infection. Upon LPS challenge, serum levels of TNF-α, KC, IL-6, and IL-10 were significantly increased in lyM-PP2Afl/fl mice, and increased phosphorylation was observed in MAPK pathways (p38, ERK, JNK) and the NF-B pathway (IKKα/β, NF-B p65) in bone marrow–derived macrophages (BMDMs) from knockout mice. Heightened NF-B activation was not associated with degradation of IBα; instead, enhanced phosphorylation of the NF-B p65 subunit and p38 phosphorylation-mediated TNF-α mRNA stabilization appear to contribute to the increased TNF-α expression. In addition, increased IL-10 expression appears to be due to PP2ACα-knockout–induced IKKα/β hyperactivation. Microarray experiments indicated that the Toll/IL-1R domain–containing adaptor inducing IFN-β/ TNFR-associated factor 3 pathway was highly upregulated in LPS-treated PP2ACα-knockout BMDMs, and knockout BMDMs had elevated IFN-α/β production compared with control BMDMs. Serum IFN-β levels from PP2ACα-knockout mice treated with LPS were also greater than those in controls. Thus, we demonstrate that PP2A plays an important role in regulating inflammation and survival in the setting of septic insult by targeting MyD88- and Toll/IL-1R domain–containing adaptor inducing IFN-β–dependent pathways.



http://ift.tt/2h3KAun

Pulmonary Dendritic Cell Subsets Shape the Respiratory Syncytial Virus-Specific CD8+ T Cell Immunodominance Hierarchy in Neonates [INFECTIOUS DISEASE AND HOST RESPONSE]

Young infants are generally more susceptible to viral infections and experience more severe disease than do adults. CD8+ T cells are important for viral clearance, and although often ineffective in neonates they can be protective when adequately stimulated. Using a murine CB6F1/J hybrid model of respiratory syncytial virus (RSV) infection, we previously demonstrated that the CD8+ T cell immunodominance hierarchy to two RSV-derived epitopes, KdM282–90 and DbM187–195, was determined by the age at infection. To determine whether age-dependent RSV-specific CD8+ T cell responses could be modified through enhanced innate signaling, we used TLR4 or TLR9 agonist treatment at the time of infection, which remarkably changed the neonatal codominant response to an adult-like KdM282–90 CD8+ T cell immunodominant response. This shift was associated with an increase in the number of conventional dendritic cells, CD11b+ and CD103+ dendritic cells, in the lung-draining lymph node, as well as increased expression of the costimulatory molecule CD86. The magnitude of the KdM282–90 CD8+ T cell response in TLR agonist–treated neonates could be blocked with Abs against CD80 and CD86. These studies demonstrate the age-dependent function of conventional dendritic cells, their role in determining immunodominance hierarchy, and epitope-specific CD8+ T cell requirements for costimulation, all of which influence the immune response magnitude. The unique impact of TLR agonists on neonatal T cell responses is important to consider for RSV vaccines designed for young infants.



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Blocking Virus Replication during Acute Murine Cytomegalovirus Infection Paradoxically Prolongs Antigen Presentation and Increases the CD8+ T Cell Response by Preventing Type I IFN-Dependent Depletion of Dendritic Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

Increasing amounts of pathogen replication usually lead to a proportionate increase in size and effector differentiation of the CD8+ T cell response, which is attributed to increased Ag and inflammation. Using a murine CMV that is highly sensitive to the antiviral drug famciclovir to modulate virus replication, we found that increased virus replication drove increased effector CD8+ T cell differentiation, as expected. Paradoxically, however, increased virus replication dramatically decreased the size of the CD8+ T cell response to two immunodominant epitopes. The decreased response was due to type I IFN–dependent depletion of conventional dendritic cells and could be reproduced by specific depletion of dendritic cells from day 2 postinfection or by sterile induction of type I IFN. Increased virus replication and type I IFN specifically inhibited the response to two immunodominant epitopes that are known to be dependent on Ag cross-presented by DCs, but they did not inhibit the response to "inflationary" epitopes whose responses can be sustained by infected nonhematopoietic cells. Our results show that type I IFN can suppress CD8+ T cell responses to cross-presented Ag by depleting cross-presenting conventional dendritic cells.



http://ift.tt/2h3ySzO

Autocrine Type I IFN Signaling in Dendritic Cells Stimulated with Fungal {beta}-Glucans or Lipopolysaccharide Promotes CD8 T Cell Activation [INFECTIOUS DISEASE AND HOST RESPONSE]

Type I IFNs are key mediators of immune defense against viruses and bacteria. Type I IFNs were also previously implicated in protection against fungal infection, but their roles in antifungal immunity have not been thoroughly investigated. A recent study demonstrated that bacterial and fungal β-glucans stimulate IFN-β production by dendritic cells (DCs) following detection by the Dectin-1 receptor, but the effects of β-glucan–induced type I IFNs have not been defined. We investigated whether type I IFNs regulate CD8 T cell activation by fungal β-glucan particle–stimulated DCs. We demonstrate that β-glucan–stimulated DCs induce CD8 T cell proliferation, activation marker (CD44 and CD69) expression, and production of IFN-, IL-2, and granzyme B. Moreover, we show that type I IFNs support robust CD8 T cell activation (proliferation and IFN- and granzyme B production) by β-glucan–stimulated DCs in vitro and in vivo due to autocrine effects on the DCs. Specifically, type I IFNs promote Ag presentation on MHC I molecules, CD86 and CD40 expression, and the production of IL-12 p70, IL-2, IL-6, and TNF-α by β-glucan–stimulated DCs. We also demonstrate a role for autocrine type I IFN signaling in bacterial LPS-induced DC maturation, although, in the context of LPS stimulation, this mechanism is not so critical for CD8 T cell activation (promotes IFN- production but not proliferation or granzyme B production). This study provides insight into the mechanisms underlying CD8 T cell activation during infection, which may be useful in the rational design of vaccines directed against pathogens and tumors.



http://ift.tt/2i8ibky

IL-17-Producing Innate and Pathogen-Specific Tissue Resident Memory {gamma}{delta} T Cells Expand in the Lungs of Bordetella pertussis-Infected Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

T cells play a role in protective immunity to infection at mucosal surface, but also mediate pathology in certain autoimmune diseases through innate IL-17 production. Recent reports have suggested that T cells can have memory analogous to conventional αβ T cells. In this study we have examined the role of T cells in immunity to the respiratory pathogen Bordetella pertussis. T cells, predominantly V41 cells, produced IL-17 in the lungs as early as 2 h after infection. The bacterial burden during primary infection was significantly enhanced and the induction of antimicrobial peptides was reduced in the absence of early IL-17. A second peak of T cells is detected in the lungs 7–14 d after challenge and these T cells were pathogen specific. T cells, exclusively V4, from the lungs of infected but not naive mice produced IL-17 in response to heat-killed B. pertussis in the presence of APC. Furthermore, T cells from the lungs of mice reinfected with B. pertussis produced significantly more IL-17 than T cells from infected unprimed mice. T cells with a tissue resident memory T cell phenotype (CD69+CD103+) were expanded in the lungs during infection with B. pertussis and proliferated rapidly after rechallenge of convalescent mice. Our findings demonstrate that lung T cells provide an early source of innate IL-17, which promotes antimicrobial peptide production, whereas pathogen-specific V4 cells function in adaptive immunological memory against B. pertussis.



http://ift.tt/2h3Gy57

Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

The coordination of macrophage polarization is essential for the robust regenerative potential of skeletal muscle. Repair begins with a phase mediated by inflammatory monocytes (IM) and proinflammatory macrophages (M1), followed by polarization to a proregenerative macrophage (M2) phenotype. Recently, regulatory T cells (Tregs) were described as necessary for this M1 to M2 transition. We report that chronic infection with the protozoan parasite Toxoplasma gondii causes a nonresolving Th1 myositis with prolonged tissue damage associated with persistent M1 accumulation. Surprisingly, Treg ablation during chronic infection rescues macrophage homeostasis and skeletal muscle fiber regeneration, showing that Tregs can directly contribute to muscle damage. This study provides evidence that the tissue environment established by the parasite could lead to a paradoxical pathogenic role for Tregs. As such, these findings should be considered when tailoring therapies directed at Tregs in inflammatory settings.



http://ift.tt/2i8gALq

Platelets Mediate Host Defense against Staphylococcus aureus through Direct Bactericidal Activity and by Enhancing Macrophage Activities [INFECTIOUS DISEASE AND HOST RESPONSE]

Platelets are the chief effector cells in hemostasis. However, recent evidence suggests they have multiple roles in host defense against infection. Reports by us and others showed that platelets functionally contribute to protection against Staphylococcus aureus infection. In the current study, the capacity of mouse platelets to participate in host defense against S. aureus infection was determined by assessing two possibilities. First, we determined the ability of platelets to kill S. aureus directly; and, second, we tested the possibility that platelets enhance macrophage phagocytosis and intracellular killing of S. aureus. In this study we report evidence in support of both mechanisms. Platelets effectively killed two different strains of S. aureus. A clinical isolate of methicillin-resistant S. aureus was killed by platelets (>40% killing in 2 h) in a thrombin-dependent manner whereas a methicillin-sensitive strain was killed to equal extent but did not require thrombin. Interestingly, thrombin-stimulated platelets also significantly enhanced peritoneal macrophage phagocytosis of both methicillin-resistant S. aureus and methicillin-sensitive S. aureus by >70%, and restricted intracellular growth by >40%. Enhancement of macrophage anti-S. aureus activities is independent of contact with platelets but is mediated through releasable products, namely IL-1β. These data confirm our hypothesis that platelets participate in host defense against S. aureus both through direct killing of S. aureus and enhancing the antimicrobial function of macrophages in protection against S. aureus infection.



http://ift.tt/2h3Ezy0

Transoral Robotic Technique Aids Occult Cancer Detection

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Transoral robotic surgery (TORS) helps detect and treat occult mucosal squamous cell carcinomas in patients with cervical lymph node metastasis and no known primary tumor, according to a retrospective case series.
Reuters Health Information

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Pulp stones prevalence in a historical sample from Radom, Poland (AD 1791–1811).

Abstract

This paper provides an investigation of pulp stones in a sample drawn from the historical population of Radom, Poland, dating to between AD 1791 and 1811. This study seeks to determine the frequency of pulp stones, and assess the association between pulp stones and sex, age, dental caries, and dental wear. A total of 780 teeth from 121 adult individuals of both sexes (45 females, 76 males) were examined. Analysis was limited to molars. The average age-at-death of each individual was estimated. Total wear scores across the molars were calculated for each individual. Pulp stones were identified by a portable dental X-ray machine. Pulp stones were found in 94 of 121 individuals and in 273 of 780 molars. No statistically significant correlation was found between pulp stones and age-at-death (p = 0.7625) and sex (p = 0.0915), but a significant relationship was found between pulp stones and dental wear (p < 0.0001) and dental caries (p = 0.0016). Our study found that molars affected by highly advanced dental wear were significantly more often accompanied by pulp stones than molars that had experienced limited wear. Similarly, significant correlations were observed for dental caries. It means that pulp stone formation appears to have been contingent upon the irritation of the tooth crown by factors such as forces acting on the tooth crown leading to dental wear or dental caries.



http://ift.tt/2h4W9mN

Lifestyle Guidance for Pediatric Patients with Atopic Dermatitis Based on Age-Specific Physiological Function of Skin

Pediatric Allergy, Immunology, and Pulmonology Dec 2016, Vol. 29, No. 4: 196-201.


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Epicutaneous Sensitization in Patients with Atopic Dermatitis

Pediatric Allergy, Immunology, and Pulmonology Dec 2016, Vol. 29, No. 4: 170-173.


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New Perspectives in the Treatment of Atopic Dermatitis in the Pediatric Population

Pediatric Allergy, Immunology, and Pulmonology Dec 2016, Vol. 29, No. 4: 189-195.


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Probiotics and Prebiotics in the Prevention and Treatment of Atopic Dermatitis

Pediatric Allergy, Immunology, and Pulmonology Dec 2016, Vol. 29, No. 4: 174-180.


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Massive Transfusion Protocols: A Survey of Academic Medical Centers in the United States

imageBACKGROUND: Massive transfusion protocols (MTPs) have been adopted in many hospitals, and they may improve outcomes, as well as decrease the number of blood products transfused. However, there are no specific guidelines regarding the number and types of products that should be included in these protocols. MTPs may vary from hospital to hospital. METHODS: A short, web-based survey was sent to blood bank medical directors at academic institutions to learn details about MTPs. RESULTS: A total of 107 survey requests were sent, and 56 were completed (52% response rate). All who responded had an MTP in place. Nearly all (n = 55, 98.2% [95% CI, 90.6%–99.7%]) base their protocol on delivery of fixed amounts and ratios of blood products, with only a minority incorporating any elements of laboratory-directed therapy. The most common target, red blood cell (RBC):plasma ratio, is 1:1 (n = 39, 69.9% [95% CI, 56.7%–80.1%] of respondents). The majority (n = 36, 64.3% [95% CI, 51.2%–75.6%]) provide 6 or more units of red blood cells in the first MTP packet. CONCLUSIONS: One-hundred percent of survey respondents had an MTP in place. Despite a lack of published guidelines regarding MTPs, the survey results demonstrated substantial uniformity in numbers of products and target transfusion ratios.

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Trends and Challenges in Clinical Monitoring: Papers From the 2015 IAMPOV Symposium

No abstract available

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In Response

No abstract available

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Peripheral Nerve Catheters: Ready for a Central Role?

No abstract available

http://ift.tt/2gUq4ZW

Successful Personalities in Anesthesiology and Acute Care Medicine: Are We Selecting, Training, and Supporting the Best?

No abstract available

http://ift.tt/2i1UDlq

Maybe the Wand Does Matter?

No abstract available

http://ift.tt/2gUAkBf

Intramuscular Fentanyl and Ketorolac Associated with Superior Pain Control After Pediatric Bilateral Myringotomy and Tube Placement Surgery: A Retrospective Cohort Study

imageBACKGROUND: Bilateral myringotomy and pressure equalization tube insertion (BMT) is the most common surgery in children. Multiple anesthetic techniques for BMT have been proposed, but that which reliably promotes ideal recovery remains unclear. We sought to assess associations between anesthetic regimens that included single-agent (fentanyl or ketorolac) or dual-agent (fentanyl and ketorolac) analgesic therapy and the primary outcome of maximal postanesthesia care unit (PACU) pain score. Secondary outcomes included in-hospital rescue analgesic administration, recovery time, and emesis incidence. METHODS: Principal analysis was conducted on a retrospective cohort of 3669 children aged 6 months to

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Implementation of Massive Transfusion Protocols in the United States: The Relationship Between Evidence and Practice

No abstract available

http://ift.tt/2i1XICb

Continuous Peripheral Nerve Blocks: An Update of the Published Evidence and Comparison With Novel, Alternative Analgesic Modalities

imageA continuous peripheral nerve block (CPNB) consists of a percutaneously inserted catheter with its tip adjacent to a target nerve/plexus through which local anesthetic may be administered, providing a prolonged block that may be titrated to the desired effect. In the decades after its first report in 1946, a plethora of data relating to CPNB was published, much of which was examined in a 2011 Anesthesia & Analgesia article. The current update is an evidence-based review of the CPNB literature published in the interim. Novel insertion sites include the adductor canal, interpectoral, quadratus lumborum, lesser palatine, ulnar, superficial, and deep peroneal nerves. Noteworthy new indications include providing analgesia after traumatic rib/femur fracture, manipulation for adhesive capsulitis, and treating abdominal wall pain during pregnancy. The preponderance of recently published evidence suggests benefits nearly exclusively in favor of catheter insertion using ultrasound guidance compared with electrical stimulation, although little new data are available to help guide practitioners regarding the specifics of ultrasound-guided catheter insertion (eg, optimal needle–nerve orientation). After some previous suggestions that automated, repeated bolus doses could provide benefits over a basal infusion, there is a dearth of supporting data published in the past few years. An increasing number of disposable infusion pumps does now allow a similar ability to adjust basal rates, bolus volume, and lockout times compared with their electronic, programmable counterparts, and a promising area of research is communicating with and controlling pumps remotely via the Internet. Large, prospective studies now document the relatively few major complications during ambulatory CPNB, although randomized, controlled studies demonstrating an actual shortening of hospitalization duration are few. Recent evidence suggests that, compared with femoral infusion, adductor canal catheters both induce less quadriceps femoris weakness and improve mobilization/ambulation, although the relative analgesia afforded by each remains in dispute. Newly published data demonstrate that the incidence and/or severity of chronic, persistent postsurgical pain may, at times, be decreased with a short-term postoperative CPNB. Few new CPNB-related complications have been identified, although large, prospective trials provide additional data regarding the incidence of adverse events. Lastly, a number of novel, alternative analgesic modalities are under development/investigation. Four such techniques are described and contrasted with CPNB, including single-injection peripheral nerve blocks with newer adjuvants, liposome bupivacaine used in wound infiltration and peripheral nerve blocks, cryoanalgesia with cryoneurolysis, and percutaneous peripheral nerve stimulation.

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The Association Between Preoperative Hemoglobin A1C and Postoperative Glycemic Variability on 30-Day Major Adverse Outcomes Following Isolated Cardiac Valvular Surgery

imageBACKGROUND: Preoperative hemoglobin A1c (HbA1c) and postoperative glycemic variability predict major adverse events (MAEs) after coronary artery bypass grafting in a protocolized glycemic control setting. However, the influence of preoperative HbA1c and postoperative glycemic variability in isolated cardiac valvular surgery is unknown. In this study, we sought to establish (a) whether preoperative HbA1c could identify patients at increased risk of MAEs and (b) whether postoperative glycemic variability was associated with MAEs after isolated cardiac valvular surgery. METHODS: Patients >18 years of age undergoing isolated valve surgery from January 2008 to December 2013 were enrolled in this prospective, single-center, observational cohort study with IRB approval. Patient demographics, intraoperative data, and postoperative MAEs were extracted from the institutional Society of Thoracic Surgery (STS) database. The primary outcome, MAEs, was a composite of in-hospital death, myocardial infarction, reoperations, sternal infection, cardiac tamponade, pneumonia, stroke, or renal failure. Glycemic variability in the postoperative period was assessed by the coefficient of variation. Patents were stratified by HbA1c levels (

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A Practical Approach to Obstetric Anesthesia, 2nd Edition

No abstract available

http://ift.tt/2gUiVc5

The Association Between Cyanosis and Thromboelastometry (ROTEM) in Children With Congenital Heart Defects: A Retrospective Cohort Study

imageBACKGROUND: Children with congenital heart defects (CHD) have quantitative and qualitative differences in coagulation compared with healthy children. Secondary to polycythemia and increased deformability of red blood cells, cyanosis may be an important confounding factor for altered whole-blood coagulation in this population with potential implications for interpreting intraoperative thromboelastometry (TEM) for children with CHD undergoing major surgery. The primary aim of the study was to evaluate the association between cyanosis in children with CHD and measures of whole-blood coagulation determined using TEM (ROTEM [Tem International, GmbH, Munich, Germany]). METHODS: In this retrospective cohort study, children who underwent congenital cardiac surgery in a 12-month period between April 2014 and 2015 were investigated. Children who were receiving antiplatelet or anticoagulant medications in the preoperative period were excluded. Eligible children were categorized by the presence of cyanosis, defined as an oxyhemoglobin concentration ≤85%. Multivariable linear regression analyses were used to determine the relationship between cyanosis and TEM outcomes (primary outcome, fibrinogen/fibrin polymerization [FibTEM] maximal clot firmness [MCF]) adjusting for potential confounding factors. RESULTS: Three hundred forty-five TEM profiles from 320 children were included in the cohort for analysis. Twenty-two percent (76/345) of children had cyanotic CHD. Clot firmness measured using the FibTEM assay was decreased in cyanotic children compared with noncyanotic children, median difference (95% confidence interval) interim [2 (0–3) mm; P = .01], and maximal [2 (1–3) mm; P = .01] clot firmness. The association between cyanosis and fibrinogen/fibrin polymerization clot firmness was not significant (A10, P = .7; MCF, P = .7) after adjusting for confounding factors (hematocrit, platelet count, and sex). There was a significant association between cyanosis and intrinsically activated clot firmness (A10, P = .03; MCF, P = .02), but not other TEM outcomes, after adjusting for confounding factors. CONCLUSIONS: Cyanotic children had decreased clot firmness in the fibrinogen/fibrin polymerization component of the clot compared with noncyanotic children, but the association between cyanosis and clot firmness was accounted for by differences in hematocrit, platelet count, and sex between groups. These findings will help guide the identification and treatment of coagulopathy in this vulnerable population.

http://ift.tt/2gUrZNY

Identification of Severe Mitral Stenosis Using Real-Time Three-Dimensional Transesophageal Echocardiography During a Left Ventricular Assist Device Insertion: Erratum

No abstract available

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Coronary Artery Fistula to Left Atrium Uncovered After Mitral Valve Replacement

imageNo abstract available

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Implications of Perioperative Team Setups for Operating Room Management Decisions

imageBACKGROUND: Team performance has been studied extensively in the perioperative setting, but the managerial impact of interprofessional team performance remains unclear. We hypothesized that the interplay between anesthesiologists and surgeons would affect operating room turnaround times, and teams that worked together over time would become more efficient. METHODS: We analyzed 13,632 surgical cases at our hospital that involved 64 surgeons and 48 anesthesiologists. We detrended and adjusted the data for potential confounders including age, American Society of Anesthesiologists physical status, and surgical list (scheduled cases of specific surgical specialties). The surgical lists were categorized as ear, nose, and throat surgery; trauma surgery; general surgery; and gynecology. We assessed the relationship between turnaround times and assignment of different anesthesiologists to specific surgeons using a Monte Carlo simulation. RESULTS: We found significant differences in team performances among the different surgical lists but no team learning. We constructed managerial decision tables for the assignment of anesthesiologists to specific surgeons at our hospital. We defined a decision algorithm based on these tables. Our analysis indicated that had this algorithm been used in staffing the operating room for the surgical cases represented in our data, median turnaround times would have a reduction potential of 6.8% (95% confidence interval 6.3% to 7.1%). CONCLUSIONS: A surgeon is usually predefined for scheduled surgeries (surgical list). Allocation of the right anesthesiologist to a list and to a surgeon can affect the team performance; thus, this assignment has managerial implications regarding the operating room efficiency affecting turnaround times and thus potentially overutilized time of a list at our hospital.

http://ift.tt/2i1Ts5j