Δευτέρα 21 Μαΐου 2018
Vocal Cord Lateralization in Bilateral Abductor Paralysis by Extra-Endo Laryngeal Suture Technique: A Case Series
Abstract
Bilateral Abductor vocal cord paralysis is certainly amongst the most emergent situation an otorhinolaryngologist come across during his/her practice. The treatment of this condition has undergone prominent shift from a blind life-saving "Tracheostomy" to more exquisite and promising laryngeal function preserving surgeries. The objective of the study is to throw light on our experience of a novel method of lateralization of vocal cord in six patients. The procedure was found to be reliable as well as associated with numerous advantages including shorter operating time and lesser intra operative manipulation on larynx. The method is less irritant (knot on outer aspect of larynx), adjustable (knot can be tightened and loosened accordingly) and reversible (knot can be removed if patient recovers). Additional benefits of the practice are smooth learning curve and economic in nature. The procedure has also been modified from quadruple prick to triple prick technique by us. This development further led to decreased operative time as well as lowered risk of trauma to larynx.
https://ift.tt/2GDzjuk
Vocal Cord Lateralization in Bilateral Abductor Paralysis by Extra-Endo Laryngeal Suture Technique: A Case Series
Abstract
Bilateral Abductor vocal cord paralysis is certainly amongst the most emergent situation an otorhinolaryngologist come across during his/her practice. The treatment of this condition has undergone prominent shift from a blind life-saving "Tracheostomy" to more exquisite and promising laryngeal function preserving surgeries. The objective of the study is to throw light on our experience of a novel method of lateralization of vocal cord in six patients. The procedure was found to be reliable as well as associated with numerous advantages including shorter operating time and lesser intra operative manipulation on larynx. The method is less irritant (knot on outer aspect of larynx), adjustable (knot can be tightened and loosened accordingly) and reversible (knot can be removed if patient recovers). Additional benefits of the practice are smooth learning curve and economic in nature. The procedure has also been modified from quadruple prick to triple prick technique by us. This development further led to decreased operative time as well as lowered risk of trauma to larynx.
https://ift.tt/2GDzjuk
Microparticle Release from Cell Lines and Its Anti-influenza Activity
Viral Immunology, Ahead of Print.
https://ift.tt/2IH3hzh
Rethinking the prescription of biotin for dermatologic conditions
Dermatologic Therapy, EarlyView.
https://ift.tt/2IAzpZA
Frequency of mitochondrial m.1555A > G mutation in Syrian patients with non-syndromic hearing impairment
Mitochondrial maternally inherited hearing impairment (HI) appears to be increasing in frequency. The incidence of mitochondrial defects causing HI is estimated to be between 6 and 33% of all hearing deficienc...
https://ift.tt/2x3nPAQ
The Contribution of Telemedicine to Humanitarian Surgery
Telemedicine enables us to push back the geographical and interactive boundaries of medicine. With a role in humanitarian missions, it is particularly pertinent at two key stages: the preparation phase, and at postoperative follow-up after the mission. It is our intention to describe our experience of telemedicine within a humanitarian context.Four teleconsultations were organized between departments of maxillofacial surgery in Caen (France) and in Bamako (Mali). 21 patients were assessed regarding their care.
https://ift.tt/2kd1Yh1
Validation of a simulator for cranial graft lift training: Face, content, and construct validity
Surgical skills can be improved through practical exercise. The use of specimens, human as well as animal, or live animals for surgical training is limited due to ethical concerns. Drawbacks of simulators are costs, fidelity and creditibility. Thus, simulators must be evaluated objectively to determine their validity before they can be used as teaching modalities. The aim of this study was to verify the face content and construct validity of a novel model-based simulator for lifting tabula externa transplants from the parietal skull.
https://ift.tt/2s1N4xx
Mechanical analysis of cranial distractor attachment with three different resorbable fixation systems
Distraction osteogenesis (DO) has become increasingly popular to correct craniosynostosis. Disadvantages of DO include the secondary operation needed for device removal and titanium screw related dura injury. To reduce invasiveness of the secondary device removal operation and to overcome titanium-related problems, fixation of the cranial distractor with resorbable materials is a potential alternative. New resorbable fixation methods, such as ultrasound-activated pins (UAPs) or heat-activated pins (HAPs), allow faster attachment on thinner bone than conventional resorbable screws (CRSs) since tapping is not required.
https://ift.tt/2kd1Huv
Dental implants in patients with ectodermal dysplasia: a systematic review
This study sought to assess the clinical outcome and survival rate of oral implants placed in individuals with ectodermal dysplasia (ED), based on previously published studies.
https://ift.tt/2x75qTw
A retrospective cohort study: do patients with graves’ disease need to be euthyroid prior to surgery?
The 2016 American Thyroid Association guidelines indicate that patients with Graves' disease who undergo a thyroidectomy should be rendered euthyroid through the use of antithyroid drugs (ATD) prior to surgery...
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Characteristics of laryngopharyngeal reflux in patients with chronic otitis media
To summarize the characteristics of laryngopharyngeal reflux (LPR) in patients with chronic otitis media.
https://ift.tt/2KLyFO2
Association of ibuprofen use with post-tonsillectomy bleeding in older children
Evaluate post-tonsillectomy outcomes in children discharged with ibuprofen versus those without.
https://ift.tt/2IXo312
Dermatofibrosarcoma Protuberans: A Retrospective Study of Clinicopathological Features and Related Akt/mTOR, STAT3, ERK, Cyclin D1, and PD-L1 Expression
In dermatofibrosarcoma protuberans, fibrosarcomatous subtype and inadequate surgical margin portend aggressive behavior. Complex factors of frequent local recurrence, larger tumor size, deeper invasion, fibrosarcomatous or myxoid subtype, and cyclin D1 high expression appear to predict worse outcome. Patients with dermatofibrosarcoma protuberans exhibiting any risk factor should be followed up comprehensively.
https://ift.tt/2IBGzNd
Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB [INNATE IMMUNITY AND INFLAMMATION]
Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid–activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid–sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.
https://ift.tt/2IxjPhc
The Respiratory Environment Diverts the Development of Antiviral Memory CD8 T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]
Our understanding of memory CD8+ T cells has been largely derived from acute, systemic infection models. However, memory CD8+ T cells generated from mucosal infection exhibit unique properties and, following respiratory infection, are not maintained in the lung long term. To better understand how infection route modifies memory differentiation, we compared murine CD8+ T cell responses to a vesicular stomatitis virus (VSV) challenge generated intranasally (i.n.) or i.v. The i.n. infection resulted in greater peak expansion of VSV-specific CD8+ T cells. However, this numerical advantage was rapidly lost during the contraction phase of the immune response, resulting in memory CD8+ T cell numerical deficiencies when compared with i.v. infection. Interestingly, the antiviral CD8+ T cells generated in response to i.n. VSV exhibited a biased and sustained proportion of early effector cells (CD127loKLRG1lo) akin to the developmental program favored after i.n. influenza infection, suggesting that respiratory infection broadly favors an incomplete memory differentiation program. Correspondingly, i.n. VSV infection resulted in lower CD122 expression and eomesodermin levels by VSV-specific CD8+ T cells, further indicative of an inferior transition to bona fide memory. These results may be due to distinct (CD103+CD11b+) dendritic cell subsets in the i.n. versus i.v. T cell priming environments, which express molecules that regulate T cell signaling and the balance between tolerance and immunity. Therefore, we propose that distinct immunization routes modulate both the quality and quantity of antiviral effector and memory CD8+ T cells in response to an identical pathogen and should be considered in CD8+ T cell–based vaccine design.
https://ift.tt/2kgh31o
Farnesyltransferase Inhibition Exacerbates Eosinophilic Inflammation and Airway Hyperreactivity in Mice with Experimental Asthma: The Complex Roles of Ras GTPase and Farnesylpyrophosphate in Type 2 Allergic Inflammation [MUCOSAL IMMUNOLOGY]
Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)–277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1% OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane–anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 μM FTI-277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13–induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13–induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras-independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma.
https://ift.tt/2IDW4o1
Deletion of Inflammasome Components Is Not Sufficient To Prevent Fatal Inflammation in Models of Familial Hemophagocytic Lymphohistiocytosis [INNATE IMMUNITY AND INFLAMMATION]
Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition that occurs in patients with genetic defects of cytotoxicity (familial HLH [FHL]) or secondary to other immunological disorders such as juvenile idiopathic arthritis. HLH is characterized by elevated levels of serum IL-18 and other cytokines. Moreover, a novel clinical entity has been recently identified in which constitutive NLRC4 inflammasome activation leads to severe HLH. Altogether, these clinical observations suggest that inflammasome activation is a central event in the development of all HLH forms and that inflammasome blockade could alleviate inflammation in FHL patients. To formally address this question, we invalidated genes encoding for Caspase-1 or the inflammasome adapter ASC in perforin-deficient mice that were subsequently infected with lymphocytic or mouse choriomeningitis virus as models of FHL. These deletions nearly abrogated IL-18 production occurring during HLH in all models. However, they did not reduce serum IFN- levels at the peak of the inflammatory reaction nor did they modulate inflammatory parameters at mid and late stages or fatal outcome. These data show that inflammasome blockade is not sufficient to prevent cytokine storm and lethality in mouse models of FHL and suggest that different pathophysiological mechanisms underlie HLH in genetic defects of cytotoxicity and genetic forms of inflammasome activation.
https://ift.tt/2IxjQ4K
Links between Immunologic Memory and Metabolic Cycling [BRIEF REVIEWS]
Treatments for metabolic diseases, such as diet and therapeutics, often provide short-term therapy for metabolic stressors, but relapse is common. Repeated bouts of exposure to, and relief from, metabolic stimuli results in a phenomenon we call "metabolic cycling." Recent human and rodent data suggest metabolic cycling promotes an exaggerated response and ultimately worsened metabolic health. This is particularly evident with cycling of body weight and hypertension. The innate and adaptive immune systems have a profound impact on development of metabolic disease, and current data suggest that immunologic memory may partially explain this association, especially in the context of metabolic cycling. In this Brief Review, we highlight recent work in this field and discuss potential immunologic mechanisms for worsened disease prognosis in individuals who experience metabolic cycling.
https://ift.tt/2GChc8f
Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2 [INNATE IMMUNITY AND INFLAMMATION]
Retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) play a critical role in inducing antiviral innate immune responses by activating IFN regulatory factor 3 (IRF3) and NF-B, which regulates the transcription of type I IFN and inflammatory cytokines. Antiviral innate immune responses are also regulated by posttranscriptional and translational mechanisms. In this study, we identified an RNA-binding protein HuR as a regulator for RLR signaling. Overexpression of HuR, but not of other Hu members, increased IFN-β promoter activity. HuR-deficient macrophage cells exhibited decreased Ifnb1 expression after RLR stimulation, whereas they showed normal induction after stimulation with bacterial LPS or immunostimulatory DNA. Moreover, HuR-deficient cells displayed impaired nuclear translocation of IRF3 after RLR stimulation. In HuR-deficient cells, the mRNA expression of Polo-like kinase (PLK) 2 was markedly reduced. We found that HuR bound to the 3' untranslated region of Plk2 mRNA and increased its stabilization. PLK2-deficient cells also showed reduced IRF3 nuclear translocation and Ifnb mRNA expression during RLR signaling. Together, these findings suggest that HuR bolsters RLR-mediated IRF3 nuclear translocation by controlling the stability of Plk2 mRNA.
https://ift.tt/2kggWTw
Cutting Edge: Identification of Marginal Reticular Cells as Phagocytes of Apoptotic B Cells in Germinal Centers [CUTTING EDGE]
Germinal centers (GCs) in secondary lymphoid organs generate large numbers of apoptotic B cells that must be eliminated by phagocytes to prevent the development of autoimmune diseases. Although tingible body macrophages engulf apoptotic GC B cells, whether stromal cells are also involved in this process is unclear. In this study, we identified marginal reticular cells (MRCs) as novel nonprofessional phagocytes for the clearance of apoptotic GC B cells in the spleen. We used CD19eGFP (CD19creZ/EG) mice, which express enhanced GFP (eGFP) under the control of CD19cre expression, to track B cells in the GCs after immunization with NP-chicken globulin plus aluminum salt. We demonstrated that the MRC population, as determined by expression of podoplanin or Rankl, specifically showed an eGFP signal in the cytoplasm after immunization. These results suggest that MRCs contribute to the clearance of apoptotic B cells in GCs.
https://ift.tt/2IzUHXo
Vasoactive Intestinal Peptide Ameliorates Acute Myocarditis and Atherosclerosis by Regulating Inflammatory and Autoimmune Responses [AUTOIMMUNITY]
Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events. In this study, we investigate the therapeutic effects of VIP in various well-established preclinical models of experimental autoimmune myocarditis and atherosclerosis. Intraperitoneal injection of VIP during the effector phase of experimental autoimmune myocarditis in susceptible BALB/c mice significantly reduced its prevalence, ameliorated signs of heart hypertrophy and injury, attenuated myocardial inflammatory infiltration, and avoided subsequent profibrotic cardiac remodeling. This effect was accompanied by a reduction of Th17-driven cardiomyogenic responses in peripheral lymphoid organs and in the levels of myocardial autoantibodies. In contrast, acute and chronic atherosclerosis was induced in apolipoprotein E–deficient mice fed a hyperlipidemic diet and subjected to partial carotid ligation. Systemic VIP treatment reduced the number and size of atherosclerotic plaques in carotid, aorta, and sinus in hypercholesterolemic mice. VIP reduced Th1-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and their draining lymph nodes. VIP also regulated cholesterol efflux in macrophages and reduced the formation of foam cells and their presence in atherosclerotic plaques. Finally, VIP inhibited proliferation and migration of smooth muscle cells and neointima formation in a mouse model of complete carotid ligation. These findings encourage further studies aimed to assess whether VIP can be used as a pharmaceutical agent to treat heart inflammation and atherosclerosis.
https://ift.tt/2s1I3Fg
NKp46 Calibrates Tumoricidal Potential of Type 1 Innate Lymphocytes by Regulating TRAIL Expression [INNATE IMMUNITY AND INFLAMMATION]
NK cells are a subset of group 1 innate lymphocytes that recognize and eliminate virus-infected and transformed cells. During the course of their development, NK cells acquire a repertoire of activating and inhibitory receptors, which ultimately define their reactivity against target cells. The array of receptors and their specificity during early developmental stages will control and imprint functional properties of NK cells, a process known as "NK cell education." Innate lymphoid cells (ILCs) are a diverse group of lymphocytes, which, like NK cells, do not rely on somatically rearranged Ag receptors for recognition. Among ILC subsets, ILC1s are most like NK cells functionally. Prototypic ILC1s reside in the liver, and a large part of their function is attributed to the expression of TRAIL, a TNF superfamily member with a well-documented antitumor activity. In this article, we show that TRAIL expression on mouse ILC1s is controlled by an activating receptor NKp46, which has been previously shown to control NK cell education. In the absence of NKp46, ILC1s fail to express normal levels of TRAIL on the surface, which results in diminished cytotoxicity toward TRAIL receptor-positive targets. To our knowledge, these findings provide the first evidence of a role of NKp46 in ILC1s that calibrates their antitumor response.
https://ift.tt/2s2HXgL
PD-L1/B7-H1 Inhibits Viral Clearance by Macrophages in HSV-1-Infected Corneas [IMMUNE REGULATION]
Immune privilege helps protect the cornea from damaging inflammation but can also impair pathogen clearance from this mucosal surface. Programmed death-ligand 1 (PD-L1 or B7-H1) contributes to corneal immune privilege by inhibiting the function of a variety of immune cells. We asked whether programmed death-1 (PD-1)/PD-L1 interaction regulates HSV-1 clearance from infected corneas. We show that PD-L1 is constitutively expressed in the corneal epithelium and is upregulated upon HSV-1 corneal infection, with peak expression on CD45+ cells NK cells, dendritic cells, neutrophils, and macrophages and CD45– corneal epithelial cells at 4 d postinfection (dpi). As early as 1 dpi, HSV-1–infected corneas of B7-H1–/– mice as compared with wild-type mice showed increased chemokine expression and this correlated with increased migration of inflammatory cells into the viral lesions and decreased HSV-1 corneal titers. Local PD-L1 blockade caused a similar increase in viral clearance, suggesting a local effect of PD-1/PD-L1 in the cornea. The enhanced HSV-1 clearance at 2 dpi resulting from PD-1/PD-L1 blockade is mediated primarily by a monocyte/macrophage population. Studies in bone marrow chimeras demonstrated enhanced viral clearance when PD-L1 was absent only from nonhematopoietic cells. We conclude that PD-L1 expression on corneal cells negatively impacts the ability of the innate immune system to clear HSV-1 from infected corneas.
https://ift.tt/2IzATDe
The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism [INNATE IMMUNITY AND INFLAMMATION]
Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with Staphylococcus aureus and Candida albicans that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection.
https://ift.tt/2rYeXqc
Identification of a Transcriptionally Forward {alpha} Gene and Two {upsilon} Genes within the Pigeon (Columba livia) IgH Gene Locus [IMMUNOGENETICS]
Compared with mammals, the bird Ig genetic system relies on gene conversion to create an Ab repertoire, with inversion of the IgA-encoding gene and very few cases of Ig subclass diversification. Although gene conversion has been studied intensively, class-switch recombination, a mechanism by which the IgH C region is exchanged, has rarely been investigated in birds. In this study, based on the published genome of pigeon (Columba livia) and high-throughput transcriptome sequencing of immune-related tissues, we identified a transcriptionally forward α gene and found that the pigeon IgH gene locus is arranged as μ-α-1-2. In this article, we show that both DNA deletion and inversion may result from IgA and IgY class switching, and similar junction patterns were observed for both types of class-switch recombination. We also identified two subclasses of genes in pigeon, which share low sequence identity. Phylogenetic analysis suggests that divergence of the two pigeon genes occurred during the early stage of bird evolution. The data obtained in this study provide new insight into class-switch recombination and Ig gene evolution in birds.
https://ift.tt/2GChax9
Synthesis of Human Neutrophil Extracellular Traps Contributes to Angiopoietin-Mediated In Vitro Proinflammatory and Proangiogenic Activities [INNATE IMMUNITY AND INFLAMMATION]
Neutrophil extracellular traps (NETs) are composed of nuclear DNA in a web-like structure extruded from neutrophils in response to either bacterial infection or inflammation. We previously reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of both angiopoietins (Ang1 and Ang2) to induce proinflammatory activities, such as synthesis and release of platelet-activating factor, upregulation of β2 integrin complex (CD11/CD18), and neutrophil chemotaxis. In contrast, only Ang1 but not Ang2 is capable of promoting translational and transcriptional activities in neutrophils. In this article, we addressed whether Ang1 and/or Ang2 could modulate the release of NETs and if they contribute to angiopoietin-mediated proinflammatory activities. We observed that Ang1 and Ang2, alone or combined (10 nM, 3 h), increase NET synthesis and release by 2.5-fold as compared with PBS-treated neutrophils. The release of NETs is Tie2 dependent and requires downstream intracellular participation of PI3K, p38, and p42/44 MAPK pathways; reactive oxygen species production; intracellular calcium store depletion; and protein arginine deiminase 4 activation. These isolated NETs induced neutrophil and endothelial cell activation, leading to neutrophil adhesion onto human extracellular matrix and HUVEC and in vitro formation of capillary-like tubes by endothelial cells. Our study reports the capacity of Ang1 and Ang2 to promote the release of NETs and that these NETs contribute to angiopoietin-mediated in vitro proinflammatory and proangiogenic activities.
https://ift.tt/2s3oQmN
Cyclooxygenase-1 and -2 Play Contrasting Roles in Listeria-Stimulated Immunity [IMMUNOTHERAPY AND VACCINES]
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are commonly used for pain relief and fever reduction. NSAIDs are used following childhood vaccinations and cancer immunotherapies; however, how NSAIDs influence the development of immunity following these therapies is unknown. We hypothesized that NSAIDs would modulate the development of an immune response to Listeria monocytogenes–based immunotherapy. Treatment of mice with the nonspecific COX inhibitor indomethacin impaired the generation of cell-mediated immunity. This phenotype was due to inhibition of the inducible COX-2 enzyme, as treatment with the COX-2–selective inhibitor celecoxib similarly inhibited the development of immunity. In contrast, loss of COX-1 activity improved immunity to L. monocytogenes. Impairments in immunity were independent of bacterial burden, dendritic cell costimulation, or innate immune cell infiltrate. Instead, we observed that PGE2 production following L. monocytogenes is critical for the formation of an Ag-specific CD8+ T cell response. Use of the alternative analgesic acetaminophen did not impair immunity. Taken together, our results suggest that COX-2 is necessary for optimal CD8+ T cell responses to L. monocytogenes, whereas COX-1 is detrimental. Use of pharmacotherapies that spare COX-2 activity and the production of PGE2 like acetaminophen will be critical for the generation of optimal antitumor responses using L. monocytogenes.
https://ift.tt/2kf70ty
Mapping Interaction Sites on Human Chemokine Receptors by Deep Mutational Scanning [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
Chemokine receptors CXCR4 and CCR5 regulate WBC trafficking and are engaged by the HIV-1 envelope glycoprotein gp120 during infection. We combine a selection of human CXCR4 and CCR5 libraries comprising nearly all of ~7000 single amino acid substitutions with deep sequencing to define sequence-activity landscapes for surface expression and ligand interactions. After consideration of sequence constraints for surface expression, known interaction sites with HIV-1–blocking Abs were appropriately identified as conserved residues following library sorting for Ab binding, validating the use of deep mutational scanning to map functional interaction sites in G protein–coupled receptors. Chemokine CXCL12 was found to interact with residues extending asymmetrically into the CXCR4 ligand-binding cavity, similar to the binding surface of CXCR4 recognized by an antagonistic viral chemokine previously observed crystallographically. CXCR4 mutations distal from the chemokine binding site were identified that enhance chemokine recognition. This included disruptive mutations in the G protein–coupling site that diminished calcium mobilization, as well as conservative mutations to a membrane-exposed site (CXCR4 residues H792.45 and W1614.50) that increased ligand binding without loss of signaling. Compared with CXCR4–CXCL12 interactions, CCR5 residues conserved for gp120 (HIV-1 BaL strain) interactions map to a more expansive surface, mimicking how the cognate chemokine CCL5 makes contacts across the entire CCR5 binding cavity. Acidic substitutions in the CCR5 N terminus and extracellular loops enhanced gp120 binding. This study demonstrates how comprehensive mutational scanning can define functional interaction sites on receptors, and novel mutations that enhance receptor activities can be found simultaneously.
https://ift.tt/2s7IBK3
Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138+ Cells [INFECTIOUS DISEASE AND HOST RESPONSE]
Streptococcus pneumoniae commonly resides asymptomatically in the nasopharyngeal (NP) cavity of healthy individuals but can cause life-threatening pulmonary and systemic infections, particularly in the elderly. NP colonization results in a robust immune response that protects against invasive infections. However, the duration, mechanism, and cellular component of such responses are poorly understood. In this study, we found that repeated NP exposure of mice to S. pneumoniae TIGR4 strain results in pneumococcal-specific Ab responses that protect against lethal lung challenge. Abs were necessary and sufficient for protection because Ab-deficient μMT mice did not develop postexposure protection, only becoming resistant to lung infection after transfer of immune sera from NP-exposed mice. T cells contributed to immunity at the time of NP exposure, but neither CD4+ nor CD8+ T cells were required. The protective activity was detectable 20 wk after exposure and was maintained in irradiated mice, suggesting involvement of long-lived Ab-secreting cells (ASC), which are radioresistant and secrete Abs for extended periods of time in the absence of T cells or persistent Ag. CD138+ bone marrow cells, likely corresponding to long-lived ASC, were sufficient to confer protection. NP exposure of aged mice failed to protect against subsequent lung infection despite eliciting a robust Ab response. Furthermore, transfer of CD138+ bone marrow cells or sera from NP-exposed old mice failed to protect naive young mice. These findings suggest that NP exposure elicits extended protection against pneumococcal lung infection by generating long-lived CD138+ ASC and that the protective efficacy of these responses declines with age.
https://ift.tt/2GCgO9N
Development of Dengue Virus Serotype-Specific NS1 Capture Assays for the Rapid and Highly Sensitive Identification of the Infecting Serotype in Human Sera [NOVEL IMMUNOLOGICAL METHODS]
Dengue fever can be caused by one of four distinct dengue virus (DENV) serotypes that cocirculate in many parts of the world. Point of care serotype-specific nonstructural protein-1 (NS1) capture assays for the rapid serotyping of DENV in human sera would greatly support epidemiological surveillance and potentially also prognosis in individual patients. To ensure both serotype specificity and broad coverage of variants within serotypes, we have applied an innovative approach for the generation and selection of serotype-specific anti-NS1 mAbs. To elicit mAbs against conformational epitopes, NMRI mice were immunized with living HEK 293 transfectants expressing the native target Ags in multiple display on the cell surface. For each serotype, three different NS1 sequence variants were sequentially used for immunization of mice, hybridoma selection, and capture assay development, respectively. Selection of optimal combinations of capturing and detecting mAbs yielded highly sensitive and specific NS1 serotyping ELISAs (st-ELISAs) for the four serotypes. st-ELISA testing of 41 dengue patient sera showed a 100% concordance with the serotype determined by serotype-specific reverse transcriptase real-time quantitative PCR. The respective NS1 variants could be detected for ~10 d after the onset of illness. Ab-dependent enhancement of DENV infections may be associated with a specific range of pre-existing anti-DENV serological Ab titers. Testing of patient sera with the developed st-ELISAs will not only be useful for epidemiological studies and surveillance, but it may also help to develop and validate assays that can distinguish protective versus enhancing Ab responses for risk assessment for the development of severe dengue disease in individual patients.
https://ift.tt/2s1HOtQ
What are the defining characteristics of the most cited publications in orthognathic surgery?
The purpose of this study was to identify the characteristics associated with highly cited papers in orthognathic surgery. This was a cohort study of articles published in the English-language literature from 1900 to 2017. Citation databases were searched for papers related to orthognathic surgery and the most frequently cited papers were identified. For each paper, the following variables were collected: region of origin, time-period of publication, corresponding author specialty, journal of publication, topic area, study design, and number of citations.
https://ift.tt/2s2l115
The epidemiology of oral human papillomavirus infection in healthy populations: A systematic review and meta-analysis
Publication date: July 2018
Source:Oral Oncology, Volume 82
Author(s): Samantha Tam, Shuangshuang Fu, Li Xu, Kate J. Krause, David R. Lairson, Hongyu Miao, Erich M. Sturgis, Kristina R. Dahlstrom
Human papillomavirus (HPV) is a potentially oncogenic sexually transmitted infection. As the incidence of oropharyngeal cancer (OPC) caused by oral HPV infections is rising, further investigation into the natural history of such infections is needed. This systematic review and meta-analysis aimed to synthesize data on the prevalence, incidence, clearance, and persistence of oral HPV infections in healthy individuals.A systematic review of literature published between January 1995 and August 2017 was conducted using Ovid MEDLINE, PubMed, Embase, and the Cochrane Library. Meta-analysis of prevalence and incidence data was conducted. Clearance and persistence data were extracted. Sixty-six studies met the inclusion criteria. Meta-analysis demonstrated an overall prevalence of 7.7% for all types of HPV and 1.4% for high-risk HPV16. The overall incidence was 4.38 cases per 1000 person-months for all HPV types and 0.92 cases per 1000 person-months for HPV16.This systematic review and meta-analysis demonstrated that oral HPV infection has a lower prevalence and incidence than cervicogenital HPV infection in healthy individuals. Nonetheless, oral HPV is still an important concern, given its oncogenicity and the rising incidence of oropharyngeal cancer. Consistency of methodology will allow for better future comparisons, particularly of infection clearance and persistence.
https://ift.tt/2LfN6dY
New observations in tumor cell plasticity: mutational profiling in a case of metastatic melanoma with biphasic sarcomatoid transdifferentiation
Abstract
We describe a highly unusual case of metastatic melanoma in a 61-year-old female that manifested as a single groin lymph node metastasis accompanied by two distinct, subcutaneous sarcomatoid tumors on the same leg, without evidence of a primary tumor. Characterization encompassed extensive immunohistochemical staining as well as next-generation sequencing (NGS). The lymph node metastasis showed obvious features of melanoma. The two subcutaneous lesions, however, were morphologically and immunohistochemically consistent with high-grade myxofibrosarcoma and soft tissue mixed tumor, respectively. All three lesions were BRAF wild-type and found to harbor an identical NRAS p.Q61R mutation. Metachronic intestinal metastases, showing intermingled conventional and sarcomatoid morphology, as well as an identical genetic phenotype, corroborated these findings. The concordant genetic profile provided evidence of biphasic sarcomatoid transdifferentiation of melanoma. Interestingly, the lack of genetic heterogeneity between the three morphologically distinct tumors suggests factors other than genetic mutations to be involved in melanoma transdifferentiation.
https://ift.tt/2IzhQJe
A back-to-back tumor composed of papillary renal cell carcinoma and oncocytoma treated by laparoscopic partial nephrectomy: a case report
Renal oncocytoma is the most common benign renal tumor, and papillary renal cell carcinoma is the second most common histologic subtype of renal cell carcinoma. Renal tumors containing different components suc...
https://ift.tt/2kf2U4H
Molar pregnancy with normal viable fetus presenting with severe pre-eclampsia: a case report
While gestational trophoblastic disease is not rare, hydatidiform mole with a coexistent live fetus is a very rare condition occurring in 0.005 to 0.01% of all pregnancies. As a result of the rarity of this co...
https://ift.tt/2s37juZ
Contribution of Cochlear Compression to Discrimination of Rippled Spectra in On- and Low-frequency Noise
Abstract
The goal of the study was to assess cochlear compression when rippled-spectrum signals are perceived in noise assuming that the noise might produce both masking and confounding effects. In normal listeners, discrimination between rippled signals with and without ripple phase reversals was assessed in background noise. The signals were band-limited (0.5 oct at a − 6-dB level) rippled noise centered at 2 kHz, with a ripple density of 3.5 oct−1. The noise (masker) was band-limited nonrippled noise centered at either 2 kHz (on-frequency masker) or 1 kHz (low-frequency masker). The masker was simultaneously presented with the signals. Masker levels at the discrimination threshold were measured as a function of the signal level using the adaptive (staircase) two-alternative forced-choice procedure. For the on-frequency masker, the searched-for function had a slope of 0.98 dB/dB. For the low-frequency masker, the function had a slope of 1.19 dB/dB within a signal level range of 30 to 40 dB sound pressure level (SPL) and as low as 0.15 dB/dB within a signal level range of 70 to 80 dB SPL. These results were interpreted as indicating compression of responses to both the signal and on-frequency masker and no compression of the effect of the low-frequency masker. In conditions when above-threshold signals are presented in simultaneous noise (the masker), cochlear compression manifests to a substantial degree despite possible confounding effects.
https://ift.tt/2Lk3KZV
Contribution of Cochlear Compression to Discrimination of Rippled Spectra in On- and Low-frequency Noise
Abstract
The goal of the study was to assess cochlear compression when rippled-spectrum signals are perceived in noise assuming that the noise might produce both masking and confounding effects. In normal listeners, discrimination between rippled signals with and without ripple phase reversals was assessed in background noise. The signals were band-limited (0.5 oct at a − 6-dB level) rippled noise centered at 2 kHz, with a ripple density of 3.5 oct−1. The noise (masker) was band-limited nonrippled noise centered at either 2 kHz (on-frequency masker) or 1 kHz (low-frequency masker). The masker was simultaneously presented with the signals. Masker levels at the discrimination threshold were measured as a function of the signal level using the adaptive (staircase) two-alternative forced-choice procedure. For the on-frequency masker, the searched-for function had a slope of 0.98 dB/dB. For the low-frequency masker, the function had a slope of 1.19 dB/dB within a signal level range of 30 to 40 dB sound pressure level (SPL) and as low as 0.15 dB/dB within a signal level range of 70 to 80 dB SPL. These results were interpreted as indicating compression of responses to both the signal and on-frequency masker and no compression of the effect of the low-frequency masker. In conditions when above-threshold signals are presented in simultaneous noise (the masker), cochlear compression manifests to a substantial degree despite possible confounding effects.
https://ift.tt/2Lk3KZV
Novel non-invasive early detection of lung cancer using liquid immunobiopsy metabolic activity profiles
Abstract
Lung cancer is the leading cause of cancer death worldwide. Survival is largely dependent on the stage of diagnosis: the localized disease has a 5-year survival greater than 55%, whereas, for spread tumors, this rate is only 4%. Therefore, the early detection of lung cancer is key for improving prognosis. In this study, we present an innovative, non-invasive, cancer detection approach based on measurements of the metabolic activity profiles of immune system cells. For each Liquid ImmunoBiopsy test, a 384 multi-well plate is loaded with freshly separated PBMCs, and each well contains 1 of the 16 selected stimulants in several increasing concentrations. The extracellular acidity is measured in both air-open and hermetically-sealed states, using a commercial fluorescence plate reader, for approximately 1.5 h. Both states enable the measurement of real-time accumulation of 'soluble' versus 'volatile' metabolic products, thereby differentiating between oxidative phosphorylation and aerobic glycolysis. The metabolic activity profiles are analyzed for cancer diagnosis by machine-learning tools. We present a diagnostic accuracy study, using a multivariable prediction model to differentiate between lung cancer and control blood samples. The model was developed and tested using a cohort of 200 subjects (100 lung cancer and 100 control subjects), yielding 91% sensitivity and 80% specificity in a 20-fold cross-validation. Our results clearly indicate that the proposed clinical model is suitable for non-invasive early lung cancer diagnosis, and is indifferent to lung cancer stage and histological type.
https://ift.tt/2rX1qA1
Association of Protein Expression p53 Mutants with Regional Lymph Gland Status on type III Carcinoma Nasofaring Patients
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant disease originating from the nasopharyngeal epithelial cells. The molecular mechanism of cancer occurrence is a change in the oncogene and tumor suppressor genes. One of the tumor suppressor genes that mutate in cancer cells is the mutant p53 gene. One of nasopharyngeal carcinoma progression is determined by the status of regional lymph gland. The enormous regional lymph node has a poor prognosis. To analyze the expression of the mutant p53 protein in Nasopharyngeal carcinoma (NPC) that correlated with regional lymph gland status (N) as a clinical manifestation. Expression of mutant p53 protein from NPC tissue paraffin block with immunohistochemical cracking technique was using monoclonal rabbit Anti Human p53 clone 318-6-11 (Dako, North America, Inc., 6392 Via Real Carpinteria, CA 93013 USA), microscope light binoculars was assessed visually by an Anatomical Pathology Consultant. Positive expression of p53 mutants was obtained 57.58% from all the sample in N0 by 0 subjects, N1 was 6 subjects, N2 was 7 subjects, and N3 was 7 subjects. The results of Mann–Whitney U test was p = 0.706, then there was no significant (p > 0.05) correlation between positive expression of p53 protein in type III WHO NPC with the regional lymph gland were N0, N1, N2, and N3. There was no significant between expression protein p53 mutants' regional and lymph gland in type III WHO NPC.
https://ift.tt/2IBrI13
Association of Protein Expression p53 Mutants with Regional Lymph Gland Status on type III Carcinoma Nasofaring Patients
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant disease originating from the nasopharyngeal epithelial cells. The molecular mechanism of cancer occurrence is a change in the oncogene and tumor suppressor genes. One of the tumor suppressor genes that mutate in cancer cells is the mutant p53 gene. One of nasopharyngeal carcinoma progression is determined by the status of regional lymph gland. The enormous regional lymph node has a poor prognosis. To analyze the expression of the mutant p53 protein in Nasopharyngeal carcinoma (NPC) that correlated with regional lymph gland status (N) as a clinical manifestation. Expression of mutant p53 protein from NPC tissue paraffin block with immunohistochemical cracking technique was using monoclonal rabbit Anti Human p53 clone 318-6-11 (Dako, North America, Inc., 6392 Via Real Carpinteria, CA 93013 USA), microscope light binoculars was assessed visually by an Anatomical Pathology Consultant. Positive expression of p53 mutants was obtained 57.58% from all the sample in N0 by 0 subjects, N1 was 6 subjects, N2 was 7 subjects, and N3 was 7 subjects. The results of Mann–Whitney U test was p = 0.706, then there was no significant (p > 0.05) correlation between positive expression of p53 protein in type III WHO NPC with the regional lymph gland were N0, N1, N2, and N3. There was no significant between expression protein p53 mutants' regional and lymph gland in type III WHO NPC.
https://ift.tt/2IBrI13
A retrospective cohort study: do patients with graves’ disease need to be euthyroid prior to surgery?
Abstract
Background
The 2016 American Thyroid Association guidelines indicate that patients with Graves' disease who undergo a thyroidectomy should be rendered euthyroid through the use of antithyroid drugs (ATD) prior to surgery to avoid complications such as a thyroid storm. At times, the use of ATDs can have limited efficacy and therefore some patients will inevitably remain biochemically hyperthyroid at the time of surgery.
The aim of this study is to assess if hyperthyroid patients undergoing a thyroidectomy are at an increased risk of developing a thyroid storm in comparison to euthyroid patients. Furthermore, this study seeks to establish a correlation between thyroid storm identified by the levels of thyroid hormones (T3 and T4) and the level of thyroid stimulating hormone (TSH).
Methods
A retrospective cohort study was conducted at two Canadian centers, one in Montreal and the other in Nova Scotia. Sixty-seven patients undergoing thyroidectomy for Graves' disease from January 2006 to December 2016 were evaluated.
Results
The study comprised 67 participants with a mean age of 46 years (range16–78 years). A total of 78% of patients were on methimazole, 34% on beta-blockers, 27% on potassium iodine solution, 10% on propylthiouracil and 7% on steroids. At the time of surgery 21% were in an overt hyperthyroid state and 33% were in a subclinical hyperthyroid state. The average TSH level of 0.03 mIUL/L (range 0.01–0.23 mIUL/L). Sixteen percent of patients had a TSH level less than 0.01 mIUL/L. The average free T4 level was 29.58 pmol/L (range 11.5–95.2 pmol/L). The average total T3 level was 11.52 nmol/L (range 4.5–29.1 nmol/L) and free T3 level was 6.35 pmol/L (range 6.1–6.6 pmol/L). No patient developed thyroid storm.
Conclusions
In our study, biochemically hyperthyroid patients undergoing thyroidectomy did not develop thyroid storm. Additional studies with larger sample sizes are needed to better understand the risk of thyroid storm in hyperthyroid patients.
https://ift.tt/2LeDkJ7
Frequency of mitochondrial m.1555A > G mutation in Syrian patients with non-syndromic hearing impairment
Abstract
Background
Mitochondrial maternally inherited hearing impairment (HI) appears to be increasing in frequency. The incidence of mitochondrial defects causing HI is estimated to be between 6 and 33% of all hearing deficiencies. Mitochondrial m.1555A > G mutation is the first mtDNA mutation associated with non-syndromic sensorineural deafness and also with aminoglycoside induced HI. Its prevalence varied geographically between different populations.
Methods
We carried out PCR, restriction enzyme based screening, and sequencing of 337 subjects (including 132 patients diagnosed clinically with hereditary deafness) from 54 families from Syria for m.1555A > G mitochondrial mutation.
Results
Mitochondrial m.1555A > G mutation was detected in one of fifty-four families (1.85%), six out of the 132 (4.5%) of all patients with NSHI and one propositus of the 205 individuals with normal hearing (0.48%).
Conclusion
This is the first study to report prelingual deafness causative gene mutations identified by sequencing technology in Syrian families. It is obvious from the results that the testing for the m.1555A > G mutation is useful for diagnosis of hearing loss in Syrian patients and should also be considered prior to treatment with aminoglycosides in predisposed individuals.
https://ift.tt/2KKimRB
Cost comparison and safety of emergency department conscious sedation for the removal of ear foreign bodies
Publication date: July 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 110
Author(s): Michael D. Olson, Jessica Saw, Sue L. Visscher, Karthik Balakrishnan
ObjectivesThe purpose of this study is to investigate the relative cost and safety of ear foreign body (FB) removal via conscious sedation in the emergency department.MethodsA retrospective review of patients presenting from 2000 to 2015 to the emergency department at Mayo Clinic, Rochester, Minnesota was performed. 63 patients requiring sedation for ear foreign body removal were identified. Descriptive data, safety data, and costs were obtained for the study.ResultsThere were no appreciable differences in patient safety outcomes and otologic outcomes in patients who received sedation in the emergency department or anesthesia in the operating room for FB removal. Cost analysis demonstrated increased cost associated with operating room utilization verses conscious sedation in the emergency department, with the greatest cost increase being in patients evaluated first in the emergency department and then sent to the operating room.ConclusionsEar foreign body removal in the emergency department is shows a similar safety profile to removal in the operating room, but at a markedly lower cost. Emergency department conscious sedation should be considered a viable option in appropriately selected patients with this common problem given these results.
https://ift.tt/2rWnU4g
Assessment of posterior choanal obstruction caused by adenoidal hypertrophy: Intra-operative mirror versus rigid nasendoscopic examination
Publication date: July 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 110
Author(s): Ahmed Eweiss, Chadwan Al Yaghchi, Sunil Sharma, Phui Yee Wong
ObjectivesThe aim of the study is to compare the degree of posterior choanal obstruction caused by adenoidal hypertrophy intra-operatively, when assessed by mirror versus rigid nasendoscopic examination, in children undergoing adenoidectomy.MethodsThis is a prospective blinded study including all consecutive paediatric cases undergoing adenoidectomy under care of the senior author during the period from June 2015 to December 2016. All cases were performed under general anaesthesia. The degree of posterior choanal obstruction caused by adenoidal hypertrophy was assessed in each patient using both a rigid nasendoscope and a nasopharyngeal mirror. Photographs of the choanae and the adenoids were obtained for both methods. Two independent ENT specialists (a registrar and a consultant), who were blinded to the clinical history and identity of the patients, assessed these photographs. Assessors scored the degree of choanal obstruction on the right and left sides separately out of 100%. The scores were analysed using the Two-Sample equal variance T-test function.ResultsA total of 26 patients were included; all of them were children aged between 2 and 13 years. A total of 52 choanae were assessed and photographed, resulting in 52 photographs for the nasendoscopic views and 26 photographs for the mirror views.The trans-nasal nasendoscopic views consistently showed a significantly higher degree of posterior choanal obstruction compared to trans-oral mirror examination views (P-value < 0.001). There was no significant difference between the scores of both assessors (P-value > 0.05). In 8 of the 26 patients (30.7%), the registrar's decision would have changed from not proceeding with surgery had he only used the mirror view, to proceeding with surgery had he also used the nasoendoscopic view. This was the case for 6 of the 26 patients (23%) reviewed by the consultant. There were three patients in common in which both the registrar and the consultant would have similarly changed decisions.ConclusionIntra-operative nasendoscopy is more sensitive than mirror examination in assessing the degree of posterior choanal obstruction due to adenoidal hypertrophy. It is important to consider nasendoscopy in patients with symptoms of adenoidal hypertrophy where mirror examination of the posterior choanae is negative.
https://ift.tt/2IBweNj
Lidocaine Reduces Muscle Tremor is Beneficial for Intraoperative Recurrent Laryngeal Nerve Monitoring
Conditions: Thyroid Cancer; Neck Cancer; Recurrent Laryngeal Nerve Injuries; Accessory Nerve Injuries; EMG: Repetitive Nerve Stimulation Abnormality
Intervention: Drug: Lidocaine
Sponsor: Bo Wang,MD
Recruiting
https://ift.tt/2IAv7l0
Intervention: Drug: Lidocaine
Sponsor: Bo Wang,MD
Recruiting
https://ift.tt/2IAv7l0
Finger-prick Autologous Blood (FAB) for Use in Dry Mouth
Conditions: Xerostomia; Xerostomia Due to Radiotherapy; Xerostomia Due to Hyposecretion of Salivary Gland
Intervention: Other: Finger-prick Autologous Blood (FAB)
Sponsor: Bedford Hospital NHS Trust
Not yet recruiting
https://ift.tt/2x2zboM
Intervention: Other: Finger-prick Autologous Blood (FAB)
Sponsor: Bedford Hospital NHS Trust
Not yet recruiting
https://ift.tt/2x2zboM
Pre- and Postoperative Nutrition in Head and Neck Cancer Patients
Condition: Head and Neck Cancer
Interventions: Dietary Supplement: Nutritional supplement (Protein + MIX); Dietary Supplement: Nutritional supplement (Protein)
Sponsors: University of Copenhagen; Rigshospitalet, Denmark
Not yet recruiting
https://ift.tt/2IXMaN4
Interventions: Dietary Supplement: Nutritional supplement (Protein + MIX); Dietary Supplement: Nutritional supplement (Protein)
Sponsors: University of Copenhagen; Rigshospitalet, Denmark
Not yet recruiting
https://ift.tt/2IXMaN4
Hypoalgesic Effect of Electrical Current and Cervical Manipulation
Condition: Pain
Interventions: Device: Application of TENS; Device: CJM; Device: Placebo TENS; Device: Placebo CJM
Sponsor: Universidade Federal de Sao Carlos
Recruiting
https://ift.tt/2KK3wdQ
Interventions: Device: Application of TENS; Device: CJM; Device: Placebo TENS; Device: Placebo CJM
Sponsor: Universidade Federal de Sao Carlos
Recruiting
https://ift.tt/2KK3wdQ
Multiple ulcers on the face due to infection after thread‐lifting
The Journal of Dermatology, EarlyView.
https://ift.tt/2Li1NgN
How to measure the immunosuppressive activity of MDSC: assays, problems and potential solutions
Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of mononuclear and polymorphonuclear myeloid cells, which are present at very low numbers in healthy subjects, but can expand substantially under disease conditions. Depending on disease type and stage, MDSC comprise varying amounts of immature and mature differentiation stages of myeloid cells. Validated unique phenotypic markers for MDSC are still lacking. Therefore, the functional analysis of these cells is of central importance for their identification and characterization. Various disease-promoting and immunosuppressive functions of MDSC are reported in the literature. Among those, the capacity to modulate the activity of T cells is by far the most often used and best-established read-out system. In this review, we critically evaluate the assays available for the functional analysis of human and murine MDSC under in vitro and in vivo conditions. We also discuss critical issues and controls associated with those assays. We aim at providing suggestions and recommendations useful for the contemporary biological characterization of MDSC.
https://ift.tt/2GDUuMK
Hematopoietic Stem Cell Transplantation for Progressive Combined Immunodeficiency and Lymphoproliferation in Activated PI3K
Publication date: Available online 18 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Tsubasa Okano, Kohsuke Imai, Yuki Tsujita, Noriko Mitsuiki, Kenichi Yoshida, Chikako Kamae, Kenichi Honma, Kanako Mitsui-Sekinaka, Yujin Sekinaka, Tamaki Kato, Katsuyuki Hanabusa, Eri Endo, Takehiro Takashima, Haruka Hiroki, Tzu-Wen Yeh, Keisuke Tanaka, Masakazu Nagahori, Ikuya Tsuge, Yuki Bando, Fuminori Iwasaki, Yoshiaki Shikama, Masami Inoue, Tomiko Kimoto, Naohiko Moriguchi, Yuki Yuza, Takashi Kaneko, Kyoko Suzuki, Tomoyo Matsubara, Yoshihiro Maruo, Tomoaki Kunitsu, Tomoko Waragai, Hideki Sano, Yuko Hashimoto, Kazuhiro Tasaki, Osamu Suzuki, Toshihiko Shirakawa, Motohiro Kato, Toru Uchiyama, Masataka Ishimura, Tetsuzo Tauchi, Hiroshi Yagasaki, Shiann-Tarng Jou, Hsin-Hui Yu, Hirokazu Kanegane, Sven Kracker, Anne Durandy, Daiei Kojima, Hideki Muramatsu, Taizo Wada, Yuzaburo Inoue, Hidetoshi Takada, Seiji Kojima, Seishi Ogawa, Osamu Ohara, Shigeaki Nonoyama, Tomohiro Morio
BackgroundActivated phosphatidylinositol-3-OH kinase-delta (PI3Kδ) syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory infections, lymphoid hyperplasia, and herpesviridae infections due to germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) may be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, method, and outcomes of HSCT for APDS1 remain undefined.ObjectiveOur objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT.MethodsWe retrospectively reviewed the medical records of cohorts undergoing HSCT at collaborating facilities.ResultsThirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence, and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced intensity conditioning (RIC). Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT.ConclusionPatients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based RIC-HSCT ameliorated clinical symptoms, but transplant-related complications were frequent, including graft failure.
Graphical abstract
Teaser
Clinical analysis of 23 patients with APDS1 revealed poor long-term event-free survival (39.6%) with a broad spectrum of clinical manifestations. Fludarabine-based RIC-HSCT could be an effective treatment, but complications and engraftment failure were frequent.https://ift.tt/2rZ1zD6
Context matters: Th2 polarization resulting from pollen composition and not from protein-intrinsic allergenicity
Publication date: Available online 18 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Lorenz Aglas, Stefanie Gilles, Renate Bauer, Sara Huber, Galber R. Araujo, Geoffrey Mueller, Sandra Scheiblhofer, Marie Amisi, Hieu-Hoa Dang, Peter Briza, Barbara Bohle, Jutta Horejs-Hoeck, Claudia Traidl-Hoffmann, Fatima Ferreira
Teaser
In contrast to the pollen context, the major allergen Bet v 1 alone is not responsible for Th2 polarization in allergic sensitization. These findings are highly relevant for birch pollen allergy prophylaxis.https://ift.tt/2x1H91e
Detection of IL-36y via non-invasive tape stripping reliably discriminates psoriasis from atopic eczema
Publication date: Available online 18 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Anna Berekméri, Anne Latzko, Adewonuola Alase, Tom Macleod, Joseph S. Ainscough, Philip Laws, Mark Goodfield, Andrew Wright, Philip Helliwell, Sara Edward, Gordon D. Brown, Delyth M. Reid, Joerg Wenzel, Martin Stacey, Miriam Wittmann
Teaser
This report demonstrates that sampling and detection of IL-36γ protein by non-invasive tape stripping of skin lesion provides a highly sensitive and selective diagnostic for psoriatic inflammation.https://ift.tt/2rX2JPs
Novel Peptide Nanoparticle Biased Antagonist of CCR3 Blocks Eosinophil Recruitment and Airway Hyperresponsiveness
Publication date: Available online 17 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Milica Grozdanovic, Kimberly G. Laffey, Hazem Abdelkarim, Ben Hitchinson, Anantha Harijith, Hyung-Geon Moon, Gye Young Park, Lee K. Rousslang, Joanne C. Masterson, Glenn T. Furuta, Nadya I. Tarasova, Vadim Gaponenko, Steven J. Ackerman
BackgroundChemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason may be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance.ObjectiveWe sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G-protein signaling, but enable or promote receptor internalization.MethodsSelf-assembly of R321 peptide into nanoparticles and peptide binding to CCR3 were analyzed by dynamic light scattering and NMR. Inhibitory activity on CCR3 signaling was assessed in vitro using flow cytometry, confocal microscopy, and western blot analysis in a CCR3+ eosinophil cell line and blood eosinophils. In vivo effects of R321 were assessed using a triple allergen mouse asthma model.ResultsR321 self-assembles into nanoparticles and binds directly to CCR3, altering receptor function. IC50 values for eotaxin-induced chemotaxis of blood eosinophils are in the low nanomolar range. R321 inhibits only the early phase of ERK1/2 activation and not the late phase generally associated with β-arrestin recruitment and receptor endocytosis, promoting CCR3 internalization and degradation. In vivo, R321 effectively blocks eosinophil recruitment into the lungs and airways and prevents airway hyperresponsiveness in a mouse eosinophilic asthma model.ConclusionsR321 is a potent and selective antagonist of the CCR3 signaling cascade. Inhibition through a biased mode of antagonism may hold significant therapeutic promise by eluding the formation of drug tolerance.
Graphical abstract
Teaser
Chemokine receptor CCR3 is a promising target for blocking eosinophil recruitment in allergic diseases. We developed a novel CCR3 antagonist that blocks eosinophil migration, prevents development of airway hyperresponsiveness, and avoids the development of tolerance.https://ift.tt/2GDsBEu
Autoinflammatory mutation in NLRC4 reveals an LRR-LRR oligomerization interface
Publication date: Available online 17 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Fiona Moghaddas, Ping Zeng, Yuxia Zhang, Heike Schützle, Sebastian Brenner, Sigrun R. Hofmann, Reinhard Berner, Yuanbo Zhao, Bingtai Lu, Xiaoyun Chen, Li Zhang, Suyun Cheng, Stefan Winkler, Kai Lehmberg, Scott W. Canna, Peter E. Czabotar, Ian P. Wicks, Dominic De Nardo, Christian M. Hedrich, Huasong Zeng, Seth L. Masters
BackgroundMonogenic autoinflammatory disorders are characterised by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome forming proteins such as NLRC4.ObjectiveHere we investigate the mechanism by which a novel mutation in the leucine rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease.MethodsWe studied two unrelated patients with early onset macrophage activation syndrome (MAS) harboring the same de novo mutation in NLRC4. In vitro, inflammasome complex formation was quantified using flow cytometric analysis of ASC specks. CRISPR/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1β/IL-18 were quantified by flow cytometry and ELISA respectively.ResultsThe c.G1965C/p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1-dependent cell death, and IL-1β/IL-18 production. ASC contributed to p.W655C NLRC4 mediated cytokine release, but not cell death. Mutation of p.W655 activated the NLRC4 inflammasome complex by engaging with two interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012 and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or T3SS effector (PrgI) stimulation of the NLRC4 inflammasome complex.ConclusionThis is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important, previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.
Graphical abstract
Teaser
Two patients with macrophage activation syndrome and elevated serum IL-18 levels were found to have a novel gain-of-function mutation in the leucine rich repeat domain of NLRC4.https://ift.tt/2Iyo8ZL
Association of ST2 polymorphisms with atopy, asthma and leukemia
Publication date: Available online 19 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Melissa H. Bloodworth, Mark Rusznak, Lisa Bastarache, Janey Wang, Joshua C. Denny, R. Stokes Peebles
https://ift.tt/2rWC7xa
Solitary Chemosensory Cells are a Primary Epithelial Source of Interleukin-25 in Chronic Rhinosinusitis with Nasal Polyps
Publication date: Available online 17 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Michael A. Kohanski, Alan D. Workman, Neil N. Patel, Li-Yin Hung, Julie P. Shtraks, Bei Chen, Mariel Blasetti, Laurel Doghramji, David W. Kennedy, Nithin D. Adappa, James N. Palmer, De'Broski R. Herbert, Noam A. Cohen
BackgroundIL-25 can function as an early signal for the respiratory Type 2 response characteristic of allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). In the mouse gut, tuft cells are the epithelial source of IL-25. However, the source of human airway epithelial IL-25 has remained elusive.ObjectiveIn this study, we sought to determine if the solitary chemosensory cell (SCC) is the predominant source of IL-25 in the sinonasal epithelium.MethodFlow cytometry and immunofluorescence for SCCs and IL-25 were used to interrogate polyp and turbinate tissue from patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucus was collected during acute inflammatory exacerbations from patients with CRSwNP or CRS without nasal polyps and IL-25 levels determined by Enzyme Linked Immuno-Sorbent Assay (ELISA). Lastly, sinonasal epithelial cultures derived from polyp and turbinate tissue were stimulated with IL-13 and analyzed for SCC proliferation and IL-25 production.ResultsThis study demonstrates that a discrete cell type, likely a solitary chemosensory cell (SCC), characterized by expression of the taste-associated G-protein, gustducin, and the intestinal tuft cell marker, doublecortin-like kinase 1, DCAMKL1, is the predominant source of IL-25 in the human upper airway. Additionally, we show that patients with CRSwNP have increased numbers of SCCs in nasal polyp tissue and in-vitro IL-13 exposure both increased proliferation and induced apical secretion of IL-25 into the mucus layer.ConclusionsInflammatory sinus polyps but not adjacent turbinate tissue have an expansion of a solitary chemosensory cell population that is the source of epithelial IL-25.
Teaser
Solitary chemosensory cells are the epithelial source of IL-25 in nasal polyps and may be a marker of upper airway inflammations.https://ift.tt/2kbEUiE
Food allergy guidance in the United States Military: A work group report from the AAAAI Military Allergy and Immunology Assembly (MAIA)
Publication date: Available online 17 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Kirk Waibel, Rachel Lee, Christopher Coop, Yun Mendoza, Kevin White
A diagnosis of food allergy adversely impacts one's ability to join or remain in the military. Inadequate knowledge or misconceptions of current military-specific standards regarding food allergy and how these apply to enlistment, induction, and retention in the United States military can potentially lead to inaccurate counseling as each military service has specific regulations which impact the evaluation and decision-making process. Recognizing this knowledge gap, the American Allergy, Asthma, and Immunology (AAAAI) Military Allergy and Immunology Assembly (MAIA) established a Work Group who reviewed and summarized all aspects of military instructions, policies, and regulations regarding IgE mediated food allergy. A flowchart was developed outlining each step of the military entry process for an individual with a history of food allergy. Further, summary tables were made to provide improved "fluency" regarding each service's medical regulations while key considerations were outlined for the allergist who is evaluating an individual who is seeking military entry or retention. Both civilian and military allergists play an essential role in the evaluation, counseling, and management of patients with a food allergy history. Understanding the service-specific language and regulations regarding food allergy will improve the allergist's awareness, counseling, and management of these individuals.
https://ift.tt/2rY8KuA
Prévalence des effets indésirables de l’hydroxychloroquine (Plaquenil®) dans une population dermatologique : étude rétrospective sur 102 patients
Publication date: Available online 20 May 2018
Source:Annales de Dermatologie et de Vénéréologie
Author(s): P. Tétu, A. Hamelin, B. Lebrun-Vignes, A. Soria, A. Barbaud, C. Francès, F. Chasset
ButL'objectif de cette étude était d'étudier la prévalence des effets indésirables (EI) et celle de l'arrêt de l'hydroxychloroquine (HCQ) pour EI dans une population issue d'un recrutement dermatologique.Patients et méthodesIl s'agissait d'une étude rétrospective incluant consécutivement entre janvier 2013 et juin 2014 tous les patients traités ou ayant reçu de l'HCQ. Les EI étaient déclarés à partir d'un questionnaire standardisé puis évalués par un interrogatoire et un examen clinique systématique permettant de guider les éventuelles explorations paracliniques nécessaires. L'imputabilité médicamenteuse était évaluée par la méthode française de pharmacovigilance. Le critère de jugement principal était la prévalence des EI pour lesquels l'HCQ avait un score d'imputabilité intrinsèque « I » supérieur à 2.RésultatsAu total, 102 patients ont été inclus dont 93 femmes, d'âge médian 44,5 ans (22–90). L'indication de l'HCQ était principalement le lupus cutané (n=70). Cinquante-cinq patients ont déclaré au moins un EI. Parmi les 91 EI déclarés, 59 (65 %) étaient imputables (score I>2), avec une prédominance des EI digestifs (n=30) et cutanés (n=21). Les EI étaient responsables d'un arrêt définitif de l'HCQ dans 19 cas. Parmi eux, 8 (42 %) n'étaient pas imputables à l'HCQ. Parmi les 8 diagnostics de maculopathie, 5 ont été infirmés par une équipe ophtalmologique spécialisée.ConclusionPlus de la moitié des patients ont rapporté des EI sous HCQ et ces EI ont été responsables d'un arrêt définitif de l'HCQ dans un tiers des cas. Une évaluation précise de l'imputabilité est nécessaire, en particulier pour les EI oculaires car dans deux tiers des cas ils n'étaient pas imputables à l'HCQ.AimOur aim was to assess the prevalence of adverse effects (AEs) pertaining to the use and withdrawal of hydroxychloroquine (HCQ) in dermatological outpatients.Patients and methodsWe conducted a retrospective study between January 2013 and June 2014 that included consecutive patients currently or previously receiving HCQ seen in our department. AEs were collated using a standardized questionnaire and validated by clinical and laboratory examination. Drug causality was evaluated using the updated French drug reaction causality assessment method. The main evaluation criterion was the prevalence of AEs in which HCQ had an intrinsic imputability score of I>2.ResultsWe included 102 patients (93 of whom were women, with a median age of 44.5; range: 22–90years). HCQ was given for cutaneous lupus in most cases (n=70). At least one AE was reported for 55 patients. Among the 91 reported AEs, 59 (65%) had an HCQ intrinsic imputability score I>2. AEs were responsible for permanent HCQ discontinuation in 19 cases. Of these, 8 were unrelated to HCQ based on imputability score. The most common AEs associated with HCQ were gastrointestinal and cutaneous signs. Of the 8 patients diagnosed with retinopathy, only 3 were confirmed after reevaluation.ConclusionAEs associated with HCQ were reported for over 50% of patients and were responsible for permanent HCQ discontinuation in one-third of cases. A more in-depth evaluation of imputability seems necessary, particularly regarding ophthalmological symptoms, since in two thirds of cases the reasons for discontinuation were not related to HCQ.
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The basophil proteome in chronic spontaneous urticaria distinguishes responders to omalizumab from non‐responders
Clinical &Experimental Allergy, EarlyView.
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Effects of cardiac output on the onset of rocuronium-induced neuromuscular block in elderly patients
Abstract
Purpose
The aim of this study was to elucidate the relationship between the onset of rocuronium-induced neuromuscular block and arterial pressure-based cardiac output (CO) in elderly patients.
Methods
Forty elderly patients aged 65–83 years were enrolled in this study. After induction of anesthesia, contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation were acceleromyographically evaluated and 1 mg/kg rocuronium was administered following CO measurement. The correlation between onset of rocuronium action and CO was analyzed.
Results
The mean [SD] CO reduced after induction of anesthesia from 5.1 [1.8] L/min to 3.8 [1.1] L/min. The onset time of rocuronium-induced neuromuscular block was 110.3 [23.9] s (range 60–165). There was a statistically significant inverse correlation between the onset time of rocuronium and CO [onset time (s) = − 13.2·CO + 159.7, R2 = 0.376].
Conclusions
In the elderly, CO influences the onset of action of rocuronium.
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Endothelium-dependent vasodilation in the cerebral arterioles of rats deteriorates during acute hyperglycemia and then is restored by reducing the glucose level
Abstract
Purpose
Acute hyperglycemia in patients with traumatic brain injury correlates with a poor neurological outcome. We investigated the endothelium function of rat cerebral arterioles during acute hyperglycemia and after reducing the glucose levels using insulin. We also examined whether or not oxidative stress was involved in the cerebral arteriole response to acute hyperglycemia.
Methods
In isoflurane-anesthetized, mechanically ventilated rats, we used closed cranial window preparation to measure the changes in the pial arteriolar diameter following the topical application of acetylcholine (ACh) or adenosine. We examined the pial arteriolar vasodilator response before hyperglycemia, during hyperglycemia, and after reducing the glucose level using insulin. After intravenous pretreatment with an NADPH oxidase inhibitor (apocynin or diphenylene iodonium), we reexamined the pial arteriolar vasodilator response following the topical application of ACh.
Results
Under control conditions, the topical application of ACh dose-dependently dilated the cerebral arterioles. The vasodilatory responses to topical ACh were impaired during hyperglycemia and improved after the administration of insulin. The vasodilatory responses to topical adenosine were not affected by the glucose levels. In the apocynin or diphenylene iodonium pretreatment group, the topical application of ACh dilated the cerebral arterioles during hyperglycemia.
Conclusion
Acute hyperglycemia induces a dysfunction of the endothelium-dependent vasodilation of rat cerebral arterioles. The dysfunction can be reversed by improving the acute hyperglycemia and it can be prevented entirely by the administration of NADPH oxidase inhibitors. These results could suggest that controlling the glucose levels works protectivity to endothelium function of cerebral arterioles.
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