In this issue

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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.

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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.

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Microparticle Release from Cell Lines and Its Anti-influenza Activity

Viral Immunology, Ahead of Print.


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Rethinking the prescription of biotin for dermatologic conditions

Dermatologic Therapy, EarlyView.


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Carbapenem-non-Susceptible Haemophilus influenzae with Penicillin-Binding Protein 3 containing Amino Acid Insertion [PublishAheadOfPrint]

Prevalence of β-lactamase-negative ampicillin-resistant Haemophilus influenzae (BLNAR) has become a clinical concern. In BLNAR, amino acid substitutions in penicillin-binding protein 3 (PBP3) are relevant to the β-lactam resistance. Carbapenem-non-susceptible H. influenzae isolates have been rarely reported. Through antimicrobial susceptibility testing and nucleotide sequence analysis of ftsI, encoding PBP3, and utilizing a collection of H. influenzae clinical isolates in our laboratory, we obtained a carbapenem-non-susceptible clinical isolate (NUBL1772) that possessed an altered PBP3 containing V525_N526insM. The aim of this study was to reveal the effect of altered PBP3 containing V525_N526insM on reduced carbapenem susceptibility. After generating recombinant strains with altered ftsI, we performed antimicrobial susceptibility testing and competitive binding assays with fluorescent penicillin (Bocillin FL) and carbapenems. Elevated carbapenem MICs were found for the recombinant strain harboring the entire ftsI gene of NUBL1772. The recombinant PBP3 of NUBL1772 also exhibited reduced binding to carbapenem. These results demonstrate that altered PBP3 containing V525_N526insM influences reduced carbapenem susceptibility. The revertant mutant lacking the V525_N526insM exhibited lower MICs of carbapenem than NUBL1772, suggesting that this insertion affects reduced carbapenem susceptibility. MICs of β-lactam for NUBL1772 was higher than those for the recombinant possessing ftsI of NUBL1772. NUBL1772 harbored AcrR with early termination, resulting in low-level transcription of acrB and high efflux pump activity. These findings suggest that the disruption of AcrR also contributes to the reduced carbapenem susceptibility found in NUBL1772. Our results provide the first evidence that the altered PBP3 containing V525_N526insM is responsible for reduced susceptibility to carbapenem in H. influenzae.

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Molecular Analysis of a blaIMP-1-Harboring Class 3 Integron in Multidrug-Resistant Pseudomonas fulva [PublishAheadOfPrint]

A multidrug-resistant (MDR) Pseudomonas fulva was isolated in 2006 from a urine sample. The isolate harbored the bla_IMP-1 gene, which was located in a chromosomal Tn402-like class 3 integron as a gene cassette array of aacA31-fosE-bla_IMP-1. Two mutations in gyrA and one mutation in parC were detected in quinolone resistance-determining regions (QRDRs). We report a full-length, novel bla_IMP-1-carrying class 3 integron. This integron and together with mutations in QRDRs could have influenced the MDR phenotypes.

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Replacement by site-saturation mutagenesis of residue 119 in NDM-1 metallo-{beta}-lactamase: a kinetic study [PublishAheadOfPrint]

NDM-1 is a subclass B1 metallo-β-lactamase which exhibits a broad activity spectrum against β-lactam antibiotics. In this study we report the kinetic study of six Q119X variants obtained by site-directed mutagenesis on NDM-1. All Q119X variants were able to hydrolyze very efficiently carbapenems, penicillins and 1^st, 2^nd, 3^rd and 4^th generation cephalosporins. In particular, Q119E, Q119Y, Q119V and Q119K mutants showed an improvement of k_cat/K_m towards penicillins respect to NDM-1. The catalytic efficiency of Q119K variant is about 65- and 70-fold higher than that of NDM-1 for benzylpenicillin and carbenicillin, respectively. The Q119K and Q119Y enzymes have k_cat/K_m values for ceftazidime of about 25- and 89-fold higher than NDM-1.

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Clonal spread in Candida glabrata bloodstream isolates and fluconazole resistance affected by prolonged exposure: a 12-year single-center study in Belgium [PublishAheadOfPrint]

Candida glabrata is a major cause of candidemia in immunocompromised patients and is characterized by a high-level of fluconazole resistance. In the present study, acquisition of antifungal resistance and potential clonal spread of C. glabrata were explored at a single center over a 12-year period by analyzing 187 independent clinical C. glabrata bloodstream isolates. One strain was found to be micafungin resistant due to a mutation in the FKS2 gene. Fluconazole resistance remained stable throughout the period and was observed in 20 (10.7%) of the isolates. Analysis of the antifungal consumption data revealed that recent prior exposure to fluconazole increased the risk to be infected by a resistant strain. In particular, the duration of the treatment was significantly longer for patients infected by a resistant isolate while total and mean daily doses received did not impact the acquisition of resistance in C. glabrata. No link between genotype and resistance was found. However, multilocus variable-number tandem-repeat analyses indicated a potential intra-hospital spread of some isolates between patients. These isolates shared the same genetic profile and infected patients were hospitalized in the same unit during an overlapping period. Finally, quantitative real-time PCR analyses showed that, unlike other ABC efflux pumps, CgCDR1 was significantly more expressed in resistant strains, suggesting that it would be more involved in FLC resistance. Our study provides additional evidence that a proper administration of fluconazole is required to limit resistance and that strict hand hygiene is necessary to avoid possible spreading of C. glabrata isolates between patients.

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Translation elongation factor 4 (LepA) contributes to tetracycline susceptibility by stalling elongating ribosomes [PublishAheadOfPrint]

Even though elongation factor 4 (EF4) is the third most conserved protein in bacteria, its physiological functions remain largely unknown and its proposed molecular mechanisms are conflicting among previous studies. In the present study we show that growth of an Escherichia coli strain is more susceptible to tetracycline than its EF4 knockout strain. In consistence with previous studies, our results suggested that EF4 affects ribosome biogenesis when tetracycline is present. Through ribosome profiling analysis, we discovered that EF4 causes 1-nucleotide shifting of ribosomal footprints on mRNA when cells have been exposed to tetracycline. In addition, when tetracycline is present, EF4 inhibits the elongation of protein synthesis, which leads to the accumulation of ribosomes in the early segment of mRNA. Together, when cells are exposed to tetracycline, EF4 alters both ribosome biogenesis and the elongation phase of protein synthesis.

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Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects [PublishAheadOfPrint]

WCK 5222 is a combination of cefepime and the novel beta-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 grams cefepime/1 gram zidebactam administered as a 1-hour intravenous infusion every 8 hours for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8 or 10 hours after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over an 8-hour and 10-hour interval following the first and seventh doses, respectively. Penetration ratios were calculated from the AUC_0–8 for plasma, ELF and AM using mean and median concentrations at each BAL sampling time. Plasma C_max and AUC of cefepime and zidebactam increased by 8% to 9% after the seventh versus first dose of WCK 5222. The respective AUC_0-8 values based on mean concentrations for cefepime and zidebactam in ELF were 127.9 and 52.0 mg·h/liter, and 87.9 and 13.2 mg·h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC_0-8 values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.

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Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells [PublishAheadOfPrint]

Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects in the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, a hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors (VFs) has not been assessed, to date. We report here on testing paired combinations of four Pseudomonas aeruginosa VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistimethate (CMS)/colistin and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, toxins, and their combinations were evaluated by simultaneous measurement of mitochondrial metabolic, total transcriptional/translational, and the Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO and 1-HP, were cytotoxic at clinically relevant concentrations (100-150 μM) and prompted a significant increase in the oxidative stress-induced transcriptional activity in surviving cells. The polymyxin antibiotics arrested the cell proliferation at clinically achievable (< 1 mM) concentrations, as well, with CMS displaying a surprisingly high cytotoxicity (ED₅₀ = 180 μM) in BEAS-2B. The dose-response curves were probed by the median-effect analysis which established a synergistically enhanced cytotoxicity of the PYO/CMS combination in all three airway cell lines; a particularly strong effect was observed in the BEAS-2B cells, with the combination index (CI) = 0.27 at ED₅₀. PCA, PCN, and 1-HP potentiated CMS cytotoxicity to a smaller extent. The cytotoxicity of CMS could be reduced with 10 mM N-acetyl-cysteine. Iron chelators, while ineffective against the polymyxins, could rescue all three bronchial epithelial cell lines treated with lethal PYO or CMS/PYO doses. These findings suggest further evaluations of CMS safety are needed, along with a search for means to moderate the potentially cytotoxic interactions.

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Pharmacokinetics of piperaquine and safety profile of dihydroartemisinin-piperaquine co-administered with antiretroviral therapy in malaria-uninfected HIV-positive Malawian adults. [PublishAheadOfPrint]

There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus infected (HIV+) individuals taking antiretroviral therapy (ART). In a two step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared area under the concentration-time curve (AUC_{0-28 days}) and safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for three days as an intitial safety check in four groups (n=6/group) of HIV+ adults (age≥18 years): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART, and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral naïve, (ii) on efavirenz-based ART and (iii) on nevirapine-based ART (n=10-15/group). Ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to limited number of participants who were on this second line ART and were eligible for recruitment. Piperaquine's AUC_{0-28 days} in both steps was 43% lower among participants on efavirenz-based ART compared to ART naïve participants. There were no significant differences in AUC_{0-28 days} between the other ART groups and the ART naïve group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although well tolerated at half and full standard adult treatment courses, efavirenz based antiretroviral regimen was associated with reduced piperaquine exposure which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings.

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Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-Resistant Staphylococcus aureus (MRSA) in an in vitro Biofilm Model [PublishAheadOfPrint]

Biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) infections are challenging due to increasing antibiotic resistance. Synergistic activity of lipopeptides and lipoglycopeptides with β-lactams has been demonstrated for MRSA, but little is known about biofilm-embedded organisms. Our objective was to evaluate two telavancin (TLV) dosage regimens (7.5 mg/kg and 10 mg/kg q 24h)alone and in combination with ceftaroline (CPT) (600 mg q 8 h) or rifampin (RIF) (450 mg q 12h) against two biofilm-producing MRSA (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacy of the antibiotic combinations over 72h. Overall, there were no significant differences observed between the two TLV dosing regimens either alone or in combination with RIF or CPT against these strains. Both TLV dosing regimens or CPT alone demonstrated killing but did not reach bactericidal reduction at 72h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains with a rapid decrease in CFU/ml at 4h that was bactericidal and maintained over the 72h experiment (- 3.75 log10CFU/ml from baseline; P <0.0001). Of interest, no enhanced activity was observed for TLV combined with CPT. No development of resistance was observed in any of the combination models. However, resistance to RIF developed as early as 24h with MIC values exceeding 32 mg/L. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that the TLV 7.5 and 10mg/kg q24h are equally effective in eradicating biofilm-associated MRSA in vitro.

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In vitro and in vivo activity of contezolid (MRX-I) against Mycobacterium tuberculosis [PublishAheadOfPrint]

The in vitro activity of contezolid (MRX-I) against clinical isolates of M. tuberculosis was evaluated using a microtiter broth dilution assay. MRX-I was as effective in vitro as linezolid (LZD). MRX-I and LZD were subsequently studied in BALB/c mice infected intranasally with M. tuberculosis Erdman. MRX-I and LZD at 100mg/kg significantly reduced the bacterial load in lungs compared to the untreated early and late controls.

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In vivo and in vitro effects of a ClpP activating antibiotic against vancomycin resistant enterococci [PublishAheadOfPrint]

Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been sufficiently characterized for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both Enterococcus faecalis and Enterococcus faecium with an MIC₉₀ of 0.016 μg/ml and 0.031 μg/ml, respectively. ClpP purified from E. faecium was found to bind ADEP4 using surface plasmon resonance analysis and ClpP activation by ADEP4 was demonstrated biochemically with a β -casein digestion assay. In addition, E. faecium ClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In kill curves, ADEP4 was found to be bactericidal against stationary phase vancomycin resistant E. faecalis (VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 also eradicated mature VRE biofilms in combination with partnering antibiotics within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to the clinically used combinations of ampicillin and gentamicin or ampicillin and daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 co-administered with ampicillin was significantly more effective than either drug alone. These data suggest ClpP activating antibiotics may be useful for treating enterococcal infections.

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The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on Minimal Inhibitory Concentration Determination [PublishAheadOfPrint]

The observed MIC may depend on the number of bacteria initially inoculated into the assay. This phenomenon is termed the inoculum effect (IE) and is often most pronounced for β-lactams in strains expressing β-lactamase enzymes. The Clinical and Laboratory Standards Institute (CLSI) recommended inoculum is 5 x 10⁵ CFU mL^-1 with an acceptable range of 2-8 x 10⁵ CFU mL^-1. IE testing is typically performed using an inoculum 100-fold greater than the CLSI recommended inoculum. Therefore, it remains unknown whether the IE influences MICs during testing performed according to CLSI guidelines. Here, we utilized inkjet printing technology to test the IE on cefepime, meropenem, and ceftazidime-avibactam. First, we determined that inkjet dispense volume correlated well with the number of bacteria delivered to microwells in two-fold (R² = 0.99) or 1.1-fold (R² = 0.98) serial dilutions. We then quantified the IE by dispensing orthogonal titrations of bacterial cells and antibiotics. For cefepime resistant and susceptible dose-dependent strains, a 2-fold increase in inoculum resulted in a 1.6 Log₂-fold increase in MIC. For carbapenemase-producing strains, each 2-fold reduction in inoculum resulted in a 1.26 Log₂-fold reduction in meropenem MIC. At the lower end of the CLSI allowable inoculum range, minor error rates of 34.8% were observed for meropenem when testing a resistant strain set. Ceftazidime-avibactam was not subject to an appreciable IE. Our results suggest that IE is sufficiently pronounced for meropenem and cefepime in multidrug-resistant Gram-negative pathogens to affect categorical interpretations during standard laboratory testing.

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Incidences of Pseudomonas associated Ventilator-associated pneumonia within studies of respiratory tract applications of polymyxin: testing the Stoutenbeek concurrency postulates. [PublishAheadOfPrint]

Regimens containing topical polymyxin appear highly effective at preventing Ventilator-associated pneumonia (VAP) overall and more-so, gram negative VAP. However, Soutenbeek's postulates, that VAP incidences within studies of topical antibiotics would depend on the context of whether the component (control and intervention) groups of each study were concurrent versus non-concurrent, remain untested.

The literature was searched for concurrent control (CC) versus non-concurrent control (NCC) designed studies of respiratory tract applications of topical polymyxin to mechanically ventilated (MV) patients that reported Pseudomonas associated Ventilator-associated pneumonia (PsVAP) incidences. Studies of various interventions other than topical polymyxin (non-polymyxin studies) served to provide additional points of reference. The PsVAP incidences within the component groups of all studies were benchmarked against groups from observational studies. This was undertaken by meta-regression using generalized estimating equation methods. Dot plots, caterpillar plots and funnel plots enable visual benchmarking.

The PsVAP benchmark (and 95 % confidence interval) derived from 102 observational groups is 4.6 % (4.0-5.3 %). By contrast, the mean PsVAP within NCC polymyxin intervention groups (1.6 %; 1.0 – 4.5 %) is lower than all other component group categories. The mean PsVAP within CC polymyxin control groups (9.9 %; 7.6 – 12.8 %) is higher than all other component group categories.

The PsVAP incidences of control and intervention groups of studies of respiratory tract applications of polymyxin is dependent on whether the groups were within a concurrent versus non-concurrent study. Soutenbeek's concurrency postulates are validated.

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The metabolism of piperaquine to its antiplasmodial metabolites and their pharmacokinetic profiles in healthy volunteers [PublishAheadOfPrint]

As a partner antimalarial for artemisinin drug-based combination therapy (ACT), piperaquine (PQ) can be metabolized into two major metabolites, including piperaquine N-oxide (M1) and N,N-dioxide (M2). To better understand the antimalarial potency of PQ, the antimalarial activity of PQ metabolites (M1 and M2) was studied in vitro (Plasmodium strains Pf3D7 and PfDd2) and in vivo (murine Plasmodium yoelii) in this study. The recrudescence and survival time of infected mice were also recorded after drug treatment. The pharmacokinetic profiles of PQ and its two metabolites (M1 and M2) were investigated in healthy subjects after oral doses of two widely used ACT regimens, i.e., Duo-Cotecxin (dihydroartemisinin plus piperaquine phosphate) and Artequick (artemisinin plus piperaquine). Remarkable antiplasmodial activity was found for PQ (IC₅₀ 4.5 nM against Pf3D7 and IC₅₀ 6.9 nM against PfDd2 strain; ED₉₀ of 1.3 mg/kg), M1 (IC₅₀ 25.5 nM against Pf3D7 and IC₅₀ 38.7 nM against PfDd2 strain; ED₉₀ of 1.3 mg/kg) and M2 (IC₅₀ 31.2 nM against Pf3D7 and IC₅₀ 33.8 nM against PfDd2 strain; ED₉₀ of 2.9 mg/kg). Compared with PQ, M1 showed comparable efficacy, in terms of recrudescence and survival time, and M2 had relatively weaker antimalarial potency. PQ and its two metabolites displayed a long elimination half-life (~11 days for PQ, ~9 days for M1 and ~4 days for M2), and they accumulated after repeated administrations. The contribution of two PQ metabolites to the efficacy of piperaquine as a partner drug of ACT for the treatment of malaria should be considered for PQ dose optimization.

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Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity [PublishAheadOfPrint]

Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even rarely mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Confining to first-line antituberculosis drugs, this review addresses whether and how oxidative stress, and more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction, may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection and pre-existing liver disease. Importantly, these comorbid conditions are associated with oxidative stress and beyond, per se. Thus, the shared pathogenetic mechanism(s) for liver injury might be in operation, due to disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. More translational research to unravel the pathogenesis, inclusive of the underlying molecular bases, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is clinical research pertaining to the advances in therapy, with antioxidants and beyond. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.

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High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice [PublishAheadOfPrint]

Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrP^C) into the infectious form (PrP^Sc). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein folding neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis, and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS). We previously reported that the bile acid, ursodeoxycholic acid (UDCA), given early in disease, prolonged incubation periods in male RML-infected mice. Here we expand on this result to include tauro-ursodeoxycholic acid (TUDCA) treatment trials and delayed UDCA treatment. We demonstrate that, despite a high dose of TUDCA given early in disease, there was no significant difference in incubation periods between treated and untreated cohorts, regardless of sex. In addition, delayed treatment with a high dose of UDCA resulted in a significant shortening of the average survival time for both male and female mice when compared to their sex-matched controls, with evidence of increased BiP, a marker of apoptosis, in treated female mice. Our findings suggest that treatment with high dose TUDCA provides no therapeutic benefit and that delayed treatment with high dose UDCA is ineffective and could potentially worsen outcomes.

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EUCAST Determination of olorofim (F901318) susceptibility of mould species, method validation and MICs [PublishAheadOfPrint]

Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and some other moulds. Here we addressed technical aspects for EUCAST olorofim testing and generated contemporary MIC data.

EUCAST E.Def 9.3.1 testing was performed comparing two plate preparation methods (serial-dilution in medium (serial-plates) versus pre-dilution in DMSO (ISO-plates)), two lots of olorofim, visual (visual-MIC) versus spectrophotometer (spec-MIC) reading and four polystyrene plates using 34-53 Aspergillus isolates from five genera. Subsequently, olorofim MICs were compared to itraconazole, voriconazole, posaconazole and amphotericin B MICs for 298 clinical mould isolates (2016-2017). Wild-type upper limits (WT-UL) were determined following EUCAST principles for ECOFF setting.

Olorofim median MICs comparing serial-plates and ISO-plates were identical (25/36, 69%) or one dilution apart (11/36, 31%). Inter-person agreement for visual-MICs was 92-94%/100% for ≤1/≤2 dilutions, respectively. Visual-MICs across tested microtitre plates and olorofim lots revealed only discrete differences (≤1 dilution lower for treated plates). No single spec-MIC criteria was applicable to all species.

Olorofim MICs were low against 275 Aspergillus spp. isolates (modal-MIC=0.06 mg/L, MIC range <0.004-0.25 mg/L) and three dermatophytes (MICs 0.03-0.06 mg/L). MICs against Fusarium were diverse with full inhibition of F. proliferatum (MIC=0.016), 50% growth inhibition of Fusarium solani at 1-2 mg/L and no inhibition of F. dimerum.

Olorofim displayed potent in vitro activity against most mould isolates and was associated with limited variation in EUCAST susceptibility testing.

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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...

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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.

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Association of ibuprofen use with post-tonsillectomy bleeding in older children

Evaluate post-tonsillectomy outcomes in children discharged with ibuprofen versus those without.

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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.

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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.

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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 (CD127^loKLRG1^lo) 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.

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Discovering the Cause of Wiskott-Aldrich Syndrome and Laying the Foundation for Understanding Immune Cell Structuring [PILLARS OF IMMUNOLOGY]

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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

Pillars Article: Isolation of a Novel Gene Mutated in Wiskott-Aldrich Syndrome. Cell. 1994. 78: 635-644 [PILLARS OF IMMUNOLOGY]

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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.

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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 CD19^eGFP (CD19^creZ/EG) mice, which express enhanced GFP (eGFP) under the control of CD19^cre 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.

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In This Issue [IN THIS ISSUE]

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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 H79^2.45 and W161^4.50) 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.

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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...

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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...

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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

Studies on the mechanism of allosteric regulation of M. tuberculosis ATP-phosphoribosyltransferase

Sintra Pisco, João; (2018) Studies on the mechanism of allosteric regulation of M. tuberculosis ATP-phosphoribosyltransferase. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2IQrhnd

Factorial structure of the locomotor disability scale in a sample of adults with mobility impairments in Bangladesh

Mahmud, I; Clarke, L; Nahar, N; Ploubidis, GB; (2018) Factorial structure of the locomotor disability scale in a sample of adults with mobility impairments in Bangladesh. Health and Quality of Life Outcomes , 16 , Article 81. 10.1186/s12955-018-0903-1 . Green open access

https://ift.tt/2KIxgHY

Insights into Pharmacotherapy Management for Parkinson's Disease Patients Using Wearables Activity Data.

Nguyen, V; Kunz, H; Taylor, P; Acosta, D; (2018) Insights into Pharmacotherapy Management for Parkinson's Disease Patients Using Wearables Activity Data. Stud Health Technol Inform , 247 pp. 156-160. 10.3233/978-1-61499-852-5-156 . Green open access

https://ift.tt/2IC3PdS

Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles

Sutherland, HS; Tong, AST; Choi, PJ; Conole, D; Blaser, A; Franzblau, SG; Cooper, CB; ... Palmer, BD; + view all Sutherland, HS; Tong, AST; Choi, PJ; Conole, D; Blaser, A; Franzblau, SG; Cooper, CB; Upton, AM; Lotlikar, MU; Denny, WA; Palmer, BD; - view fewer (2018) Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles. Bioorganic & Medicinal Chemistry , 26 (8) pp. 1797-1809. 10.1016/j.bmc.2018.02.026 . Green open access

https://ift.tt/2wYRVW7

Profiling and Grouping Space-time Activity Patterns of Urban Individuals

Shen, Jianan; (2018) Profiling and Grouping Space-time Activity Patterns of Urban Individuals. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2IC3LLa

Approximate Oracles and Synergy in Software Energy Search Spaces

Bruce, BR; Petke, J; Harman, M; Barr, ET; (2018) Approximate Oracles and Synergy in Software Energy Search Spaces. IEEE Transactions on Software Engineering 10.1109/TSE.2018.2827066 . (In press). Green open access

https://ift.tt/2KG0mrg

Electronic conductivity of solid and liquid (Mg, Fe)O computed from first principles

Holmstrom, E; Stixrude, L; Scipioni, R; Foster, AS; (2018) Electronic conductivity of solid and liquid (Mg, Fe)O computed from first principles. Earth and Planetary Science Letters , 490 pp. 11-19. 10.1016/j.epsl.2018.03.009 .

https://ift.tt/2IUt9eB

Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients (POPPI): protocol for a cluster-randomised clinical trial of a complex intervention

Richards-Belle, A; Mouncey, PR; Wade, D; Brewin, CR; Emerson, LM; Grieve, R; Harrison, DA; ... POPPI Trial Investigators, POPPITI; + view all Richards-Belle, A; Mouncey, PR; Wade, D; Brewin, CR; Emerson, LM; Grieve, R; Harrison, DA; Harvey, S; Howell, D; Mythen, M; Sadique, Z; Smyth, D; Weinman, J; Welch, J; Rowan, KM; POPPI Trial Investigators, POPPITI; - view fewer (2018) Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients (POPPI): protocol for a cluster-randomised clinical trial of a complex intervention. BMJ Open , 8 (2) , Article e020908. 10.1136/bmjopen-2017-020908 . Green open access

https://ift.tt/2KGaqk4

Russia and the European Far Right

Shekhovtsov, Anton; (2018) Russia and the European Far Right. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2KGVguR

Evolving better RNAfold structure prediction

Langdon, WB; Petke, J; Lorenz, R; (2018) Evolving better RNAfold structure prediction. In: Genetic Programming. EuroGP 2018. (pp. pp. 220-236). Springer International Publishing: Cham, Switzerland. Green open access

https://ift.tt/2ID9Bfa

Resolution of cystoid macular edema following arginine-restricted diet and vitamin B6 supplementation in a case of gyrate atrophy.

Casalino, G; Pierro, L; Manitto, MP; Michaelides, M; Bandello, F; (2018) Resolution of cystoid macular edema following arginine-restricted diet and vitamin B6 supplementation in a case of gyrate atrophy. Journal of AAPOS 10.1016/j.jaapos.2017.12.016 . (In press).

https://ift.tt/2IzElhh

Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study

Ryom, L; Lundgren, JD; El-Sadr, W; Reiss, P; Kirk, O; Law, M; Phillips, A; ... D:A:D study group, .; + view all Ryom, L; Lundgren, JD; El-Sadr, W; Reiss, P; Kirk, O; Law, M; Phillips, A; Weber, R; Fontas, E; d' Arminio Monforte, A; De Wit, S; Dabis, F; Hatleberg, CI; Sabin, C; Mocroft, A; D:A:D study group, .; - view fewer (2018) Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study. The Lancet HIV 10.1016/S2352-3018(18)30043-2 . (In press).

https://ift.tt/2KIO5SO

Yorkshire and Humber's internal migration exchanges

Dennett, AR; (2008) Yorkshire and Humber's internal migration exchanges. Yorkshire and Humber Regional Review , 18 (3) pp. 17-19.

https://ift.tt/2IWdCec

Somatosensory-evoked delta brush activity in very pre-term infants

Whitehead, K; Laudiano-Dray, P; Pressler, R; Meek, J; Fabrizi, L; (2018) Somatosensory-evoked delta brush activity in very pre-term infants. Presented at: 31st International Congress of Clinical Neurophysiology (ICCN) of the IFCN, Washington, DC, USA.

https://ift.tt/2KE8Vmv

Differences in response to antiretroviral therapy in HIV-positive patients being treated for tuberculosis in Eastern Europe, Western Europe and Latin America

Caro-Vega, Y; Schultze, A; Efsen, AMW; Post, FA; Panteleev, A; Skrahin, A; Miro, JM; ... Crabtree-Ramirez, B; + view all Caro-Vega, Y; Schultze, A; Efsen, AMW; Post, FA; Panteleev, A; Skrahin, A; Miro, JM; Girardi, E; Podlekareva, DN; Lundgren, JD; Sierra-Madero, J; Toibaro, J; Andrade-Villanueva, J; Tetradov, S; Fehr, J; Cayla, J; Losso, MH; Miller, RF; Mocroft, A; Kirk, O; Crabtree-Ramirez, B; - view fewer (2018) Differences in response to antiretroviral therapy in HIV-positive patients being treated for tuberculosis in Eastern Europe, Western Europe and Latin America. BMC Infectious Diseases , 18 , Article 191. 10.1186/s12879-018-3077-x . Green open access

https://ift.tt/2IZdD0X

6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

Tong, AST; Choi, PJ; Blaser, A; Sutherland, HS; Tsang, SKY; Guillemont, J; Motte, M; ... Conole, D; + view all Tong, AST; Choi, PJ; Blaser, A; Sutherland, HS; Tsang, SKY; Guillemont, J; Motte, M; Cooper, CB; Andries, K; Van den Broeck, W; Franzblau, SG; Upton, AM; Denny, WA; Palmer, BD; Conole, D; - view fewer (2017) 6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis. ACS Medicinal Chemistry Letters , 8 (10) pp. 1019-1024. 10.1021/acsmedchemlett.7b00196 . Green open access

https://ift.tt/2KE8zwb

hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency

Segertiz, C; Rashid, T; Miguel, M; Serra Paola, M; Ordonez, A; Morell, C; Kaserman, J; ... Vallier, L; + view all Segertiz, C; Rashid, T; Miguel, M; Serra Paola, M; Ordonez, A; Morell, C; Kaserman, J; Madrigal, P; Hannan, N; Gatto, L; Tan, L; Wilson, A; Lilley, K; Marciniak, S; Gooptu, B; Lomas, DA; Vallier, L; - view fewer (2018) hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency. Journal of Hepatology (In press).

https://ift.tt/2IDYrqU

The microbial ecology of human-associated bacterial communities

Shaw, LP; (2018) The microbial ecology of human-associated bacterial communities. Doctoral thesis (Ph.D), UCL (University College London). Green open access

https://ift.tt/2KI5BXz

Discovery of a meteoritic ejecta layer containing unmelted impactor fragments at the base of Paleocene lavas, Isle of Skye, Scotland

Drake, SM; Beard, AD; Jones, AP; Brown, DJ; Fortes, AD; Millar, IL; Carter, A; ... Downes, H; + view all Drake, SM; Beard, AD; Jones, AP; Brown, DJ; Fortes, AD; Millar, IL; Carter, A; Baca, J; Downes, H; - view fewer (2018) Discovery of a meteoritic ejecta layer containing unmelted impactor fragments at the base of Paleocene lavas, Isle of Skye, Scotland. Geology , 46 (2) pp. 171-174. 10.1130/G39452.1 . Green open access

https://ift.tt/2IzieaJ

Genetic analysis of multiple system atrophy and related movement disorders

Schottlaender, Lucia Valentina; (2018) Genetic analysis of multiple system atrophy and related movement disorders. Doctoral thesis (Ph.D), UCL (University College London).

https://ift.tt/2KIEGLi

Biological Therapies for Cancer

A fact sheet that provides an overview of how the immune system functions and describes the actions of biological therapies, such as monoclonal antibodies, cytokines, therapeutic vaccines, the bacterium bacillus Calmet-Guérin, cancer-killing viruses, gene therapy, and adoptive T-cell transfer.

https://ift.tt/2lmaQ68

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

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

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

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

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




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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.


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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.



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