Arsenic enhances cell death and DNA damage induced by ultraviolet B exposure in mouse epidermal cells through the production of reactive oxygen species

Summary

Background

Ultraviolet (UV)B radiation has long been considered a carcinogen in both epidemiological surveys and experimental studies. However, recent work has suggested that different dosages of UVB exert different influences on cells. There are also co‐carcinogenesis factors such as arsenic that affect the role of UVB.

Aim

To explore the co‐carcinogenesis effect of UVB and arsenic on the mouse epidermal cell line JB6 and the mechanism underlying it.

Methods

Growth of JB6 cells was measured by MTT assay. We carried out a comet assay to determine the DNA damage caused by UVB and arsenic, and tested the expression of DNA repair protein by western blotting. Reactive oxygen species (ROS) were measured using DCF and DHE staining, and changes in antioxidant enzymes were assessed using western blotting.

Results

Viability assays showed that arsenic increased the UVB‐induced death rate. Arsenic enhanced DNA damage caused by UVB both directly by injury to double‐stranded DNA and indirectly by reducing the capability of DNA repair in JB6 cells. All of these effects are the results of increased ROS generation and reduced expression of the antioxidant enzyme superoxide dismutase (SOD)1.

Conclusion

Arsenic was found to enhance UVB‐induced production of ROS and to downregulate SOD1 expression, leading to DNA damage and apoptosis in mouse skin cells. The combination of arsenic and UVB exposure was found to differentially regulate the expression of SOD1 and SOD2.

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The role of therapeutic drug monitoring in treatment optimization in tuberculosis and diabetes mellitus co-morbidity [Letters]

With great interest we read the paper by Alfarisi et al reporting the effects of diabetes mellitus (DM) on the pharmacokinetics and pharmacodynamics of tuberculosis treatment (1)....

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Evaluation of carbapenems for multi/extensive-drug resistant Mycobacterium tuberculosis treatment [Pharmacology]

M/XDR-TB has become an increasing threat in high burden countries but also in affluent regions due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of M. tuberculosis. To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo and clinical data on carbapenems in the treatment of M. tuberculosis and detection of knowledge gaps, in order to target future research.

In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and lab strains of M. tuberculosis, are consistent. In vitro the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore is it practically impossible to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, one prospective, two observational and seven retrospective clinical studies to assess effectiveness, safety and tolerability of three different carbapenems (imipenem, meropenem and ertapenem). Presently we found no clear evidence to select one particular carbapenem among the different candidate compounds, to design an effective M/XDR-TB regimen. Therefore more clinical evidence and dose optimization substantiated by hollow fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

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Inhibitors of Signaling Pathways that Block Reversal of HIV-1 Latency [Antiviral Agents]

Signaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal. The screen was carried-out in the absence or presence of three mechanistically distinct latency reversing agents (LRAs), namely prostratin, panobinostat and JQ-1. We identified inhibitors that only blocked the activity of a specific LRA, as well as inhibitors that blocked the activity of all LRAs. For example, we identified 12 inhibitors targeted toward protein kinase C or downstream kinases that blocked the activity of prostratin. We also identified 12 kinase inhibitors that blocked reversal of HIV-1 latency irrespective of the LRA used in the screen. Of these danusertib, an Aurora kinase inhibitor, and PF-3758309, a PAK4 inhibitor, were the most potent. The 50% inhibitory concentrations in the 24ST1NLESG cells ranged from 40-147 nM for danusertib (selectivity indices >150) and from 0.1-1nM for PF-3758309 (selectivity indices >3,300). Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity, or the maintenance of HIV-1 latency; and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia.

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Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon [Pharmacology]

Introduction Mefloquine is evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and its metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated and potential covariates influencing the pharmacokinetic properties were assessed.

Materials and Methods A population pharmacokinetic analysis was performed with 264 pregnant women of a randomized controlled trial evaluating a single and split-dose regimen of two 15 mg/kg mefloquine dosings at least one month separated versus SP-IPTp. Both mefloquine enantiomers and its carboxy-metabolite (CMQ), measured in plasma and cord, were applied for pharmacokinetic modelling using NONMEM 7.3.

Results Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group the mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r²=0.84) at delivery. With the investigated dosing regimens prophylactic levels are not constantly achieved. A modelling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented.

Discussion This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens, however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as valuable tool for researchers and clinicians to develop and optimise alternative dosing regimens for IPTp in pregnant women.

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The Role of Rifampin against Staphylococcal Biofilm Infections in Vitro, in Animal Models, and in Orthopedic Device-Related Infections. [Minireviews]

Rifampin has been used as an agent in combination therapy in orthopedic device-related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro, in animal models, and in clinical ODRI. Available data are gathered in order to present the rational use of rifampin combinations in patients with periprosthetic joint infection (PJI). In-vitro data, animal data and available clinical data in the field of staphylococcal PJI will be reviewed. The role of rifampin is well-defined in patients with PJI and is indicated in those who fulfill the Infectious Diseases Society of America criteria for debridement and implant retention or one-stage exchange. It should be used with care because of the danger of rapid emergence of resistance. Potential drug interactions should be considered.

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In-vivo gentamicin susceptibility test for prevention of bacterial biofilms in bone tissue and on implants [Susceptibility]

Objectives: To set up an in-vivo gentamicin susceptibility test for biofilm prevention in bone tissue and on implants.

Methods: Twenty-five pigs were allocated to six groups. Group A (n=6) was inoculated with saline. Groups B (n=6), C (n=3), D (n=3), E (n=3) and F (n=4) were inoculated with 10 μL saline containing 10⁴ CFU of Staphylococcus aureus. Different concentrations based on the minimal inhibitory concentrations (MIC) of gentamicin to the specific strain were added to the 10 μL inoculum of Groups C (160xMIC), D (1,600xMIC), E (16,000xMIC) and F (160,000xMIC). The inoculums were injected into a pre-drilled tibial implant cavity followed by insertion of a steel implant (2 x 15 mm). The pigs were euthanized after five days. In-vitro, all the used doses were found bacteriostatic after up to 6 hours.

Results: All implant cavities of pigs inoculated with bacteria and bacteria + 160xMIC or 1,600xMIC were positive for S. aureus. In each of the Groups E (16,000xMIC) and F (160,000xMIC) 2/3 and 1/4 of the implant cavities were S. aureus positive, respectively. By grouping Groups C + D (<10,000xMIC) and Groups E + F (>10,000xMIC) a significant decrease of implant attached bacteria was only seen between the high MIC value group and Group B. Histologically, it was demonstrated that 1,600, 16,000 and 160,000 x MIC resulted in a peri-implant tissue reaction comparable to saline inoculated animals.

Conclusion: In-vivo, the antimicrobial tolerance of the inoculated planktonic bacteria was increased by in-vivo specific factors of acute inflammation. This resulted in bacterial aggregation and biofilm formation which further increased the gentamicin tolerance. Thus, susceptibility patterns in-vitro might not reflect the actual in-vivo susceptibility locally within a developing infectious area.

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A diagnostic algorithm to investigate pyrazinamide and ethambutol resistance in rifampicin resistant Mycobacterium tuberculosis isolates in a low incidence setting [Susceptibility]

Phenotypic drug susceptibility testing (DST) for the two first-line tuberculosis drugs ethambutol and pyrazinamide is known to yield unreliable and inaccurate results. In this prospective study, we propose a diagnostic algorithm combining phenotypic DST with Sanger sequencing to inform clinical decision-making for drug resistant Mycobacterium tuberculosis complex isolates. Sequencing results were validated using whole genome sequences (WGS) of the isolates. Resistance-conferring mutations obtained by pncA sequencing correlated well with phenotypic DST results for pyrazinamide. Phenotypic resistance to ethambutol was only partly explained by mutations in the embB 306 codon. Additional resistance conferring mutations were found in the embB gene at codons 354, 406 and 497. In several isolates that tested ethambutol susceptible by phenotypic DTS, well-known resistance conferring embB mutations were determined. Thus, targeted Sanger sequencing beyond embB 306 codon or WGS together with phenotypic DST should be employed to ensure reliable ethambutol drug susceptibility as basis for rational design of MDR-TB regimens with or without ethambutol.

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Identification of a novel gene associated with high-level {beta}-lactam resistance in heterogeneous vancomycin-intermediate Staphylococcus aureus strain Mu3 and methicillin-resistant S. aureus strain N315 [Mechanisms of Resistance]

β-lactam resistance levels vary among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, mediated by chromosomal mutations and exogenous resistance gene mecA. However, MRSA resistance mechanisms are incompletely understood. A P440L mutation in the RNA polymerase β' subunit (RpoC) in slow-vancomyicn-intermediate S. aureus (sVISA) strain V6-5 is associated with conversion of heterogeneous VISA (hVISA) to sVISA. Herein, we found a V6-5-derivative strain (L4) with significantly decreased MICs to oxacillin (OX) and vancomycin. Whole-genome sequencing revealed that L4 has nonsense mutations in two genes, relQ encoding (p)ppGpp synthetase, an alarmone of the stringent response, and a gene of unknown function. relQ deletion in the hVISA strain Mu3 did not affect OX MIC. However, introducing nonsense mutation of the unknown gene into Mu3 decreased OX MIC, whereas wild-type gene recovered high-level resistance. Thus, mutation of this unknown gene (ehoM) decreased β-lactam resistance in Mu3 and L4. Presence of relQ in a multi-copy plasmid restored high-level resistance in strain L4 but not in the ehoM mutant Mu3 strain, indicating a genetic interaction between ehoM and relQ depending on the L4 genetic background. While mupirocin (stringent response inducer) can increase the β-lactam resistance of MRSA, mupirocin supplementation in an ehoM deletion mutant of N315 did not elevate resistance. ehoM expression in N315 was induced by mupirocin, and the relative amount of ehoM transcript in Mu3 was higher than in N315 induced by the stringent response. Our findings indicate that ehoM plays an essential role in high-level β-lactam resistance in MRSA via the stringent response.

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APX001 is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis [Experimental Therapeutics]

Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. We evaluated the in vitro activity of APX001A against A. fumigatus and the in vivo activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of A. fumigatus with a minimum effective concentration (MEC) of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 (CYP) enzymes, enhanced APX001A exposures (AUC) 16- to 18-fold and enhanced serum half-life from ~1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA as compared to posaconazole treatment. Treatment of mice with 78 mg/kg QD, 78 mg/kg BID, or 104 mg/kg QD APX001 significantly enhanced median survival time and prolonged Day 21 post-infection overall survival when compared to placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log₁₀ conidial equivalents/gram tissue) vs the untreated control and resolved the infection as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad spectrum, first in class treatment for invasive fungal infections.

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Pre-Exposure to Isavuconazole Increases the Virulence of Mucorales but not Aspergillus fumigatus in a Drosophila melanogaster Infection Model [Clinical Therapeutics]

Breakthrough mucormycosis in patients receiving isavuconazole prophylaxis or therapy has been reported. We compared the impact of isavuconazole and voriconazole exposure on the virulence of clinical isolates of Aspergillus fumigatus and different Mucorales species in a Drosophila melanogaster infection model. In contrast to A. fumigatus, a hyper-virulent phenotype was found in all tested Mucorales upon pre-exposure to either voriconazole or isavuconazole. These findings may contribute to the explanation of breakthrough mucormycosis in isavuconazole-treated patients.

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ERG6 and ERG2 are major targets conferring reduced susceptibility to amphotericin B in clinical Candida glabrata isolates in Kuwait [Mechanisms of Resistance]

Candida glabrata is intrinsically less susceptible to azoles and resistance to echinocandins and reduced susceptibility to amphotericin B has also been detected. Molecular mechanisms of reduced susceptibility (RS) to amphotericin B (AMB) were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1646 C. glabrata isolates were tested by Etest and results for 12 selected isolates were confirmed by reference broth microdilution. PCR-sequencing of three (ERG2, ERG6 and ERG11) genes was performed for all RS-AMB and 5 selected wild-type C. glabrata isolates by using gene-specific primers. Total cell sterol content was analyzed by gas chromatography-mass spectrometry. Phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6 or ERG11 and total sterol content was similar to reference strains. A nonsynonymous (AGA48AAA, R48K) ERG6 mutation was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286/Tyr192/Leu341 and 2 isolates contained nonsynonymous (V126F or C198F) mutation in ERG6 and their sterol content were consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous (G119S or G122S) ERG2 mutation and their sterol content were consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H+L381M mutations while 7 isolates contained only synonymous mutations in ERG11. All isolates with ERG6/ERG2/ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates.

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Host cell metabolism contributes to delayed-death kinetics of apicoplast inhibitors in Toxoplasma gondii [Mechanisms of Action]

Toxoplasma gondii and related human parasites contain an essential plastid organelle called the apicoplast. Clinically-used antibiotics and other inhibitors that disrupt apicoplast biogenesis cause a mysterious "delayed-death" phenotype in which parasite growth is unaffected during the first lytic cycle of inhibitor treatment but is severely inhibited in the second lytic cycle even after drug removal. Critical to understanding the complex downstream cellular effects of these drug classes is the timing of apicoplast loss during inhibitor treatment and how it relates to this peculiar growth phenotype. Here we show that, upon treatment with diverse classes of apicoplast inhibitors, newly-replicated T. gondii parasites in the first lytic cycle initially form apicoplasts with defects in protein import or genome replication and eventually fail to inherit the apicoplast altogether. Despite the accumulation of parasites with defective or missing apicoplasts, growth is unaffected during the first lytic cycle, as previously observed. Strikingly, concomitant inhibition of host cell isoprenoid biosynthesis results in growth inhibition in the first lytic cycle and unmasks the apicoplast defects. These results suggest that defects in and even complete loss of the apicoplast in T. gondii are partially rescued by scavenging of host cell metabolites leading to death that is delayed. Our findings uncover host cell interactions that can alleviate apicoplast inhibition and highlight key differences in "delayed-death" inhibitors between T. gondii and Plasmodium falciparum.

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Genetic mechanisms behind the spread of reduced susceptibility to azithromycin in Shigella isolated from men who have sex with men, in Quebec, Canada [Mechanisms of Resistance]

We analysed 254 Shigella spp., isolates collected in Québec, Canada, during 2013-2014. Overall, 23.6% of isolates showed reduced susceptibility to azithromycin (RSA) encoded by mphA (11.6%), ermB (1.7%) or by both genes (86.7%). Shigella strains with RSA were mostly isolated from men who have sex with men (68.8% or higher) from the Montreal region. Complete sequence analysis of six selected plasmids from Shigella sonnei and different serotypes of Shigella flexneri emphasized the role of IS26 in RSA dissemination.

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Impact of Antifungal Compounds on Viability and Anti-Aspergillus Activity of Human Natural Killer Cells [Experimental Therapeutics]

Despite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients. In vitro studies and animal models suggest that the adoptive transfer of Natural Killer (NK) cells could be a promising immunotherapeutic option in this setting. As it is unclear whether viability and function of human NK cells are affected by common antifungal agents, we analyzed the interaction of various concentrations of amphotericin B-deoxycholate (AmB-D), liposomal amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole with human NK cells. When adding NK cells to therapeutic concentrations of antifungal agents, a significant increase of the antifungal effect was seen for caspofungin and voriconazole, whereas NK cells significantly decreased the hyphal damage of escalated doses of AmB-D. In contrast, therapeutic concentrations of all antifungal compounds tested did not have a negative effect on proliferation, viability, and the release of soluble immunomodulatory molecules of NK cells. These data indicate that therapeutic concentrations of the antifungal agents tested do not negatively affect the functional properties of human NK cells, which is a prerequisite for further studies evaluating NK cells as antifungal immunotherapy in immunocompromised patients suffering from invasive aspergillosis.

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Omadacycline gut microbiome exposure does not induce Clostridium difficile proliferation or toxin production in a model that simulates the proximal, medial and distal human colon [Clinical Therapeutics]

A clinically reflective model of the human colon was used to investigate the effects of the broad-spectrum antibiotic omadacycline on the gut microbiome, and subsequent potential to induce simulated Clostridium difficile infection (CDI). Triple stage chemostat gut models were inoculated with pooled human faecal slurry from healthy volunteers (age ≥60 years). Models were challenged twice with 107 cfu C. difficile spores (PCR ribotype 027). Omadacycline effects were assessed in a single gut model. Observations were confirmed in a parallel study with omadacycline and moxifloxacin. Antibiotic instillation was performed once daily for 7 days. The models were observed for 3 weeks post-antibiotic challenge. Gut microbiota populations and C. difficile total viable and spore counts were enumerated daily by culture. Cytotoxin titres and antibiotic concentrations were also measured. Gut microbiota populations were stable before antibiotic challenge. Moxifloxacin instillation caused a ~4 log₁₀ cfu/mL decline in enterococci and Bacteroides fragilis group populations, and a ~3 log₁₀ cfu/mL decline in bifidobacteria and lactobacilli, followed by simulated CDI (vegetative cell proliferation and detectable toxin). In both models, omadacycline instillation decreased populations of bifidobacteria (~8 log₁₀ cfu/mL), B. fragilis group populations (7-8 log₁₀ cfu/mL), lactobacilli (2-6 log₁₀ cfu/mL), and enterococci (4-6 log₁₀ cfu/mL). Despite these microbial shifts, there was no evidence of C. difficile germination or toxin production. In contrast to moxifloxacin, omadacycline exposure did not facilitate simulated CDI, suggesting this antibiotic may have a low propensity to induce CDI in the clinical setting.

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Fluconazole-Induced Alopecia: Examination in an animal model and human cohort [Mechanisms of Action]

Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair-cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken.

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Population pharmacokinetics and pharmacodynamics of bezlotoxumab in adults with primary and recurrent Clostridium difficile infection [Clinical Therapeutics]

The fully human monoclonal antibody bezlotoxumab is indicated for preventing recurrence of Clostridioides (formerly Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI and at high risk for CDI recurrence. The efficacy and safety of 10 mg/kg bezlotoxumab was demonstrated in two Phase 3 trials: MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Here, a population pharmacokinetic (popPK) analysis is reported using data from MODIFY I and II (n=1515), and from three Phase 1 trials (n=72) to characterize bezlotoxumab PK in Phase 3 clinical trial participants and in healthy subjects. A stepwise covariate search was conducted to identify factors influencing PK. Post-hoc estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence.

Bezlotoxumab PK was described by a two-compartment model with linear elimination and allometric scaling for clearance and volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black vs non-black), and albumin level as significant covariates, the impact of these factors was not clinically meaningful based on the totality of PK and clinical experience.

Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the Phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10 mg/kg dose across the Phase 3 population with no dose adjustments necessary over a broad demographic background.

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Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication [Antiviral Agents]

Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell–derived astrocytes was less susceptible to sofosbuvir compared to the hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection–dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg/day, and prevented mortality in a neonate mouse model at 40 and 80 mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

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APX001 and Other Gwt1 inhibitor Prodrugs are Effective in Experimental Coccidioides immitis Pneumonia [Experimental Therapeutics]

Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis, and C. posadasii that are endemic in the southwestern US and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extra-pulmonary sites of infection are very difficult to treat and often require life-long azole therapy. APX001A is the first in a new class of broad spectrum antifungal agents which inhibit Gwt1, an enzyme which is required for localization of glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates of Coccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once-daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, two hours after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001 and APX2097-treated mice survived significantly longer than control and fluconazole treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis.

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Genome location dictates the transcriptional response to PolC-inhibition in Clostridium difficile [Mechanisms of Action]

Clostridium difficile is a potentially lethal gut pathogen that causes nosocomial and community acquired infections. Limited treatment options and reports of reduced susceptibility to current treatment emphasize the necessity for novel antimicrobials. The DNA-polymerase of gram-positive organisms is an attractive target for the development of antimicrobials. ACX-362E (N2-(3,4-Dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine; MorE-DCBG) is a DNA polymerase inhibitor in pre-clinical development as a novel therapeutic against C. difficile infection. This synthetic purine shows preferential activity against C. difficile PolC over those of other organisms in vitro and is effective in an animal model of C. difficile infection. In this study we have determined its efficacy against a large collection of clinical isolates. At concentrations below the minimal inhibitory concentration, the presumed slowing (or stalling) of replication forks due to ACX-362E leads to a growth defect. We have determined the transcriptional response of C. difficile to replication inhibition and observed an overrepresentation of up-regulated genes near the origin of replication in the presence of PolC-inhibitors, but not when cells were subjected to sub-inhibitory concentrations of other antibiotics. This phenomenon can be explained by a gene dosage shift, as we observed a concomitant increase in the ratio between origin-proximal versus terminus-proximal gene copy number upon exposure to PolC-inhibitors. Moreover, we show that certain genes differentially regulated under PolC-inhibition are controlled by the origin-proximal general stress response regulator sigma factor B. Together, these data suggest that genome location both directly and indirectly determines the transcriptional response to replication inhibition in C. difficile.

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The clinical burden of allergic rhinitis in five Middle Eastern countries: results of the SNAPSHOT program

The SNAPSHOT program provides current data on the allergic rhinitis burden in the adult general population of five Middle Eastern countries (Egypt, Turkey, Kuwait, Saudi Arabia and the United Arab Emirates, th...

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Characterization of tenascin-C as a novel biomarker for asthma: utility of tenascin-C in combination with periostin or immunoglobulin E

Extracellular matrix proteins tenascin-C (TNC) and periostin, which were identified as T-helper cell type 2 cytokine-induced genes in human bronchial epithelial cells, accumulate in the airway basement membran...

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Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis

Chorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of...

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Racial differences in Atopic Dermatitis

Atopic dermatitis (AD), the most common chronic inflammatory skin disease,1 usually starts in early infancy, and can develop into a life-long therapeutic challenge, especially in its moderate-to-severe form.2 The etiology of this complex disease remains only partly understood, but it is most likely based on a complex interplay of genetic predisposition, skin barrier dysfunction, and environmental factors.3 AD is now understood to be an immune mediated disease with contributions of multiple inflammatory pathways, and particularly Type 2-associated inflammation.

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"Drug Allergy in children and adults: is it the double X chromosome?"

It is well established that autoimmune diseases, atopic conditions and asthma affect adult females more frequently than adult males. This discrepancy typically develops after childhood and affects females differently depending on their life cycle. As children, males have higher total and allergen specific IgE levels than females and are more likely to suffer from atopic disease and asthma than girls. However, as adults, this prevalence reverses and females are more likely to develop atopic conditions such as food allergies, atopic dermatitis, urticaria, angioedema and asthma.

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Implementation of the NIAID Peanut Allergy Guidelines: Outcomes and Experience

The publication of the Learning Early About Peanut Allergy (LEAP) study in 2015 represented a paradigm shift in the field of food allergy with the finding of an 81% reduction in the incidence of peanut allergy when early introduction of peanut was compared to strict avoidance in high risk infants.1 In 2017, the National Institute of Allergy and Infectious Disease (NIAID) provided official recommendations for early peanut introduction with the publication of the Addendum Guidelines to the 2010 Guidelines for Diagnosis and Management of Food Allergy in the United States.

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AllergyWatch - Feb-19

From Allergy Watch Vol 20, July-Aug 2018

https://ift.tt/2FwgZrS

The Glycerin Associated Pain (GAP) Study

Fifty percent glycerin is often used in allergen immunotherapy (AIT) extracts to preserve extract potency.1 However, glycerin is also an irritant and it is recommended to dilute glycerin to reduce pain and inflammation associated with immunotherapy.2, 3 The 2011 allergen immunotherapy practice parameter warns that "higher glycerin concentrations are associated with injection pain, which correlates with the total amount of glycerin injected."4 To date, two studies evaluating the role of glycerin during allergen immunotherapy differed regarding their methods and conclusions.

https://ift.tt/2qT9X6e

Immediate-hypersensitivity reactions to proton pump inhibitors – experience in a medical department

Proton pump inhibitors (PPIs) are prescribed worldwide for the treatment of acid-peptic diseases1,2,3. They antagonize the enzyme H+/K+ ATPase in gastric cells, inhibiting acid secretion and raising gastric pH3,4. Side effects related to PPIs are reported in only 1-3% of treated patients1,5. Omeprazole, esomeprazole and pantoprazole have a similar chemical structure, differing from rabeprazole and lansoprazole1,5.

https://ift.tt/2FvtiEB

Asthma in the Melting Pot

America is becoming more diverse, with minority groups increasing at higher rates than whites. The health implications are vast, impacting all medical conditions. However, as asthma remains a persistent public health problem where the disease burden is higher in minorities and low income populations – the need to find solutions is crucial 1. These disparities or differences have been documented and defined to a significant degree in the literature, but what is lacking are solutions to tackle these differences.

https://ift.tt/2qTTrmv

Inpatient Beta-lactam test-dose Protocol promotes Antimicrobial Stewardship in Patients with History of Penicillin Allergy

Penicillin allergy is the most commonly reported drug allergy in hospitalized patients, resulting in increased second-line antibiotic use, nosocomial infections, and healthcare utilization. Given that the vast majority of patients are not truly allergic, a safe strategy that empowers the admitting physician is needed.

https://ift.tt/2FwdmCe

A CASE OF NON-IMMUNOLOGIC ANAPHYLAXIS TO N-ACETYLCYSTEINE IN A PATIENT WHO OVERDOSED ON ACETAMINOPHEN

Management of acetaminophen toxicity typically involves administering N-acetylcysteine (NAC) in order to prevent hepatic injury. While NAC is considered the gold standard of therapy, it is also associated with risk of non-immunologic anaphylaxis. This case illustrates a less commonly recognized reaction to NAC and provides an opportunity to review management of acetaminophen toxicity in patients who demonstrate such a reaction.

https://ift.tt/2qT9Mb4

Disposable otoscope specula cryotherapy for lesions in convoluted or sensitive locations

https://ift.tt/2KhArr9

TAOK3 Regulates Canonical TCR Signaling by Preventing Early SHP-1-Mediated Inactivation of LCK [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Activation of LCK is required for canonical TCR signaling leading to T cell responses. LCK activation also initiates a negative feedback loop mediated by the phosphatase SHP-1 that turns off TCR signaling. In this article, we report that the thousand-and-one amino acid kinase 3 (TAOK3) is a key regulator of this feedback. TAOK3 is a serine/threonine kinase expressed in many different cell types including T cells. TAOK3-deficient human T cells had impaired LCK-dependent TCR signaling resulting in a defect in IL-2 response to canonical TCR signaling but not to bacterial superantigens, which use an LCK-independent pathway. This impairment was associated with enhanced interaction of LCK with SHP-1 after TCR engagement and rapid termination of TCR signals, a defect corrected by TAOK3 reconstitution. Thus, TAOK3 is a positive regulator of TCR signaling by preventing premature SHP-1–mediated inactivation of LCK. This mechanism may also regulate signaling by other Src family kinase-dependent receptors.

https://ift.tt/2qWP7my

Aeroallergens Exacerbate Histoplasma capsulatum Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Allergens such as house dust mites (HDM) and papain induce strong Th2 responses, including elevated IL-4, IL-5, and IL-13 and marked eosinophilia in the airways. Histoplasma capsulatum is a dimorphic fungal pathogen that induces a strong Th1 response marked by IFN- and TNF-α production, leading to rapid clearance in nonimmunocompromised hosts. Th1 responses are generally dominant and overwhelm the Th2 response when stimuli for both are present, although there are instances when Th2 stimuli downregulate a Th1 response. We determined if the Th2 response to allergens prevents the host from mounting a Th1 response to H. capsulatum in vivo. C57BL/6 mice exposed to HDM or papain and infected with H. capsulatum exhibited a dominant Th2 response early, characterized by enhanced eosinophilia and elevated Th2 cytokines in lungs. These mice manifested exacerbated fungal burdens, suggesting that animals skewed toward a Th2 response by an allergen are less able to clear the H. capsulatum infection despite an intact Th1 response. In contrast, secondary infection is not exacerbated by allergen exposure, indicating that the memory response may suppress the Th2 response to HDM and quickly clear the infection. In conclusion, an in vivo skewing toward Th2 by allergens exacerbates fungal infection, even though there is a concurrent and unimpaired Th1 response to H. capsulatum.

https://ift.tt/2Fu0rRa

Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms [INNATE IMMUNITY AND INFLAMMATION]

We have previously reported that a group of host cellular microRNAs (miRNAs; miR-34a-5p, miR-122-5p, miR-145-5p, miR-146a-5p, miR-210-3p) are released into the blood during sepsis, some of which are capable of inducing complement activation, cytokine production, and leukocyte migration. Extracellular vesicles (EVs) have been proposed as vehicles for extracellular miRNA-mediated intercellular communication. However, the biological function of plasma EVs and the associated miRNAs in sepsis are largely unknown. In this study, we tested the hypothesis that plasma EVs in sepsis are proinflammatory and EV-associated miRNAs are responsible for EV-induced cytokine production. Compared with those of sham mice, the plasma EVs from septic mice were slightly smaller (157 ± 2 versus 191 ± 6 nm, p < 0.0001), but more abundant [(1.6 ± 0.14) x 10¹⁰ versus (0.93 ± 0.14) x 10¹⁰/ml plasma, p < 0.003]. miRNA array revealed that among 65 miRNAs, 8 miRNAs exhibited >1.5-fold increase in septic EVs compared with sham EVs, including miR-126-3p, miR-122-5p, miR-146a-5p, miR-145-5p, miR-26a-5p, miR-150-5p, miR-222-3p, and miR-181a-5p. Septic but not sham EVs were proinflammatory, promoting IL-6, TNF-α, IL-1β, and MIP-2 production. The effects of EVs were resistant to polymyxin B (an endotoxin inhibitor) but significantly inhibited by anti-miR inhibitors against miR-34a, miR-122, and miR-146a. Moreover, the septic EV-induced cytokine production was attenuated in TLR7^–/– or MyD88^–/– cells but remained the same in TLR3^–/– or Trif^–/– cells. In vivo, mice i.p. injected with septic EVs had marked peritoneal neutrophil migration, which was significantly attenuated in MyD88^–/– mice. Taken together, these data demonstrate that plasma EVs of septic animals play an important role in inflammation, and EV-associated miRNAs likely mediate the cytokine production via TLR7-MyD88 signaling.

https://ift.tt/2qTGitN

Correction: Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138+ Cells [CORRECTIONS]

https://ift.tt/2qTGeKz

Unique Composition of Intronless and Intron-Containing Type I IFNs in the Tibetan Frog Nanorana parkeri Provides New Evidence To Support Independent Retroposition Hypothesis for Type I IFN Genes in Amphibians [IMMUNOGENETICS]

In vertebrates, intron-containing and intronless type I IFN genes have recently been reported in amphibian model species Xenopus tropicalis and X. laevis. However, whether intronless type I IFNs in amphibians are the ancestral genes of type I IFNs in amniotes or just represent the independent divergence in amphibians is unknown or even uninvestigated. In this study, both intron-containing and intronless type I IFN genes, as well as their receptor genes, were identified in the Tibetan frog Nanorana parkeri. The evidence obtained from homology, synteny, phylogeny, and divergence time showed that intronless type I IFN genes in N. parkeri and in Xenopus might have arisen from two independent retroposition events occurred in these two lineages, and the retrotransposition causing the generation of intronless type I IFN genes in amniotes is another independent event beyond the two in amphibians. It can then be proposed that intronless type I IFNs in N. parkeri and Xenopus may not be the ancestral genes of intronless type I IFNs in amniotes but may just represent two independent bifurcations in the amphibian lineage. Furthermore, both intronless and intron-containing type I IFNs in N. parkeri showed strong ability in inducing the expression of IFN-stimulated genes and the strong antiviral activity against frog virus 3. The present study thus provides the evolutionary evidence to support the independent retroposition hypothesis for the occurrence of intronless type I IFN genes in amphibians and contributes to a functional understanding of type I IFNs in this group of vertebrates.

https://ift.tt/2qTGkSr

ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism [INNATE IMMUNITY AND INFLAMMATION]

The A20-binding inhibitor of NF-B 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding–defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2. The ABIN2[D310N] mice displayed intestinal inflammation and hypersensitivity to dextran sodium sulfate–induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1β–dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE₂ was reduced in mouse embryonic fibroblasts and intestinal myofibroblasts (IMFs) from ABIN2[D310N] mice. These observations are similar to those reported for the Tpl2 knockout (KO) mice (Roulis et al. 2014. Proc. Natl. Acad. Sci. USA 111: E4658–E4667), but the IL-1β–dependent production of COX2 and PGE₂ in mouse embryonic fibroblasts or IMFs was unaffected by pharmacological inhibition of Tpl2 in wild-type mice. The expression of ABIN2 is decreased drastically in Tpl2 KO mice. These and other lines of evidence suggest that the hypersensitivity of Tpl2 KO mice to dextran sodium sulfate–induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE₂ production in IMFs by a Tpl2 kinase–independent pathway.

https://ift.tt/2Fzc7lF

Consequences of Hypoxia for the Pulmonary Alveolar Epithelial Cell Innate Immune Response [INNATE IMMUNITY AND INFLAMMATION]

Pulmonary innate immune responses involve a highly regulated multicellular network to defend the enormous surface area of the lung. Disruption of these responses renders the host susceptible to pneumonia. Alveolar epithelial cells (AEC) are a critical source of innate immune molecules such as GM-CSF, which determine the functional maturation of alveolar macrophages. In many pulmonary diseases, heterogeneous ventilation leads to regional hypoxia in the lung. The effect of hypoxia on AEC innate immune function is unknown. We now report that exposure of primary murine AEC to hypoxia (1% oxygen) for 24 h results in significant suppression of key innate immune molecules, including GM-CSF, CCL2, and IL-6. This exposure did not cause toxicity but did induce stabilization of hypoxia-inducible factor 1α protein (HIF-1α) and shift to glycolytic metabolism. Focusing on GM-CSF, we found that hypoxia greatly decreased the rate of GM-CSF transcription. Hypoxia both decreased NF-B signaling in AEC and induced chromosomal changes, resulting in decreased accessibility in the GM-CSF proximal promoter of target sequences for NF-B binding. In mice exposed to hypoxia in vivo (12% oxygen for 2 d), lung GM-CSF protein expression was reduced. In vivo phagocytosis of fluorescent beads by alveolar macrophages was also suppressed, but this effect was reversed by treatment with GM-CSF. These studies suggest that in critically ill patients, local hypoxia may contribute to the susceptibility of poorly ventilated lung units to infection through complementary effects on several pathways, reducing AEC expression of GM-CSF and other key innate immune molecules.

https://ift.tt/2FvogrH

Type 2 Innate Lymphoid Cells Impede IL-33-Mediated Tumor Suppression [TUMOR IMMUNOLOGY]

Although a number of studies have recently explored the contribution of the adaptive immunity in IL-33–mediated antitumor effects, innate immune involvement has been poorly characterized. Utilizing Rag1^–/– mice (lacking T and B lymphocytes), we show in this study that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to inhibit tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33–mediated antitumor effects depend on expansion and activation of NK cells. Interestingly, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s) via its receptor, ST2, which in turn inhibited NK activation and cytotoxicity. This IL-33–induced ILC2 activity coincided with greater expression of the immunosuppressive ectoenzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, offering a potential mechanism by which ILC2s might suppress NK cell–mediated tumor killing. Thus, our data reveal an important contribution of IL-33–induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, regardless of adaptive immunity.

https://ift.tt/2qTGg59

Kimishige Ishizaka, M.D., Ph.D. (AAI 58), December 3, 1925 to July 6, 2018 [IN MEMORIAM]

https://ift.tt/2qWmwOg

Speech Perception with Spectrally Non-overlapping Maskers as Measure of Spectral Resolution in Cochlear Implant Users

Abstract

Poor spectral resolution contributes to the difficulties experienced by cochlear implant (CI) users when listening to speech in noise. However, correlations between measures of spectral resolution and speech perception in noise have not always been found to be robust. It may be that the relationship between spectral resolution and speech perception in noise becomes clearer in conditions where the speech and noise are not spectrally matched, so that improved spectral resolution can assist in separating the speech from the masker. To test this prediction, speech intelligibility was measured with noise or tone maskers that were presented either in the same spectral channels as the speech or in interleaved spectral channels. Spectral resolution was estimated via a spectral ripple discrimination task. Results from vocoder simulations in normal-hearing listeners showed increasing differences in speech intelligibility between spectrally overlapped and interleaved maskers as well as improved spectral ripple discrimination with increasing spectral resolution. However, no clear differences were observed in CI users between performance with spectrally interleaved and overlapped maskers, or between tone and noise maskers. The results suggest that spectral resolution in current CIs is too poor to take advantage of the spectral separation produced by spectrally interleaved speech and maskers. Overall, the spectrally interleaved and tonal maskers produce a much larger difference in performance between normal-hearing listeners and CI users than do traditional speech-in-noise measures, and thus provide a more sensitive test of speech perception abilities for current and future implantable devices.

https://ift.tt/2Tpb2zH

Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing, Perceptuomotor Speed, and Executive Functioning in Younger and Older Listeners

Abstract

Older adults typically have difficulty identifying speech that is temporally distorted, such as reverberant, accented, time-compressed, or interrupted speech. These difficulties occur even when hearing thresholds fall within a normal range. Auditory neural processing speed, which we have previously found to predict auditory temporal processing (auditory gap detection), may interfere with the ability to recognize phonetic features as they rapidly unfold over time in spoken speech. Further, declines in perceptuomotor processing speed and executive functioning may interfere with the ability to track, access, and process information. The current investigation examined the extent to which age-related differences in time-compressed speech identification were predicted by auditory neural processing speed, perceptuomotor processing speed, and executive functioning. Groups of normal-hearing (up to 3000 Hz) younger and older adults identified 40, 50, and 60 % time-compressed sentences. Auditory neural processing speed was defined as the P1 and N1 latencies of click-induced auditory-evoked potentials. Perceptuomotor processing speed and executive functioning were measured behaviorally using the Connections Test. Compared to younger adults, older adults exhibited poorer time-compressed speech identification and slower perceptuomotor processing. Executive functioning, P1 latency, and N1 latency did not differ between age groups. Time-compressed speech identification was independently predicted by P1 latency, perceptuomotor processing speed, and executive functioning in younger and older listeners. Results of model testing suggested that declines in perceptuomotor processing speed mediated age-group differences in time-compressed speech identification. The current investigation joins a growing body of literature suggesting that the processing of temporally distorted speech is impacted by lower-level auditory neural processing and higher-level perceptuomotor and executive processes.

https://ift.tt/2A6uLeH

Clinical features of poorly differentiated thyroid papillary carcinoma

To investigate the clinical feature of the poorly differentiated thyroid papillary carcinoma.

https://ift.tt/2qUxiEH

T Regulatory Cell Subpopulations Associated with Recent Ultraviolet Radiation Exposure in a Skin Cancer Screening Cohort [CLINICAL AND HUMAN IMMUNOLOGY]

UV radiation (UVR) causing DNA damage is a well-documented risk factor for nonmelanoma skin cancer. Although poorly understood, UVR may also indirectly contribute to carcinogenesis by promoting immune evasion. To our knowledge, we report the first epidemiological study designed to investigate the association between quantitative measures of UVR, obtained using a spectrophotometer, and circulating T regulatory (Treg) cells. In addition to total Treg cells, the proportion of functionally distinct Treg cell subsets defined by CD45RA and CD27 phenotypic markers, graded expression of FOXP3 and CD25, and those expressing cutaneous lymphocyte–associated Ag and the chemokine receptor CCR4 were enumerated in 350 individuals undergoing routine skin cancer screening exams and determined not to have prevalent skin cancer. No associations were identified for UVR exposure or the overall proportion of circulating Treg cells; however, Treg cell subpopulations with an activation-associated phenotype, CD45RA^–/CD27^–, and those expressing cutaneous homing receptors were significantly positively associated with UVR. These subpopulations of Treg cells also differed by age, sex, and race. After stratification by natural skin tone, and adjusting for age and sex, we found that spectrophotometer-based measures of UVR exposure, but not self-reported measures of past sun exposure, were positively correlated with the highest levels of these Treg cell subpopulations, particularly among lighter-skinned individuals. Findings from this large epidemiologic study highlight the diversity of human Treg cell subpopulations associated with UVR, thus raising questions about the specific coordinated expression of CD45RA, CD27, CCR4, and cutaneous lymphocyte–associated Ag on Treg cells and the possibility that UVR contributes to nonmelanoma skin cancer carcinogenesis through Treg cell–mediated immune evasion.

https://ift.tt/2FtMAKw

In This Issue [IN THIS ISSUE]

https://ift.tt/2Kh0WNo

Distinct Roles for CD4+ Foxp3+ Regulatory T Cells and IL-10-Mediated Immunoregulatory Mechanisms during Experimental Visceral Leishmaniasis Caused by Leishmania donovani [INFECTIOUS DISEASE AND HOST RESPONSE]

The outcome of intracellular parasitic infection can be determined by the immunoregulatory activities of natural regulatory CD4⁺ Foxp3⁺ T (Treg) cells and the anti-inflammatory cytokine IL-10. These mechanisms protect tissue but can also suppress antiparasitic CD4⁺ T cell responses. The specific contribution of these regulatory pathways during human parasitic diseases remains unclear. In this study, we investigated the roles of Treg cells and IL-10 during experimental visceral leishmaniasis caused by Leishmania donovani infection of C57BL/6 mice. We report only a limited contribution of Treg cells in suppressing antiparasitic immunity, but important roles in delaying the development of splenic pathology and restricting leukocyte expansion. We next employed a range of cell-specific, IL-10– and IL-10R–deficient mice and found these Treg cell functions were independent of IL-10. Instead, conventional CD4⁺ T cells and dendritic cells were the most important cellular sources of IL-10, and the absence of IL-10 in either cell population resulted in greater control of parasite growth but also caused accelerated breakdown in splenic microarchitecture. We also found that T cells, dendritic cells, and other myeloid cells were the main IL-10–responding cells because in the absence of IL-10R expression by these cell populations, there was greater expansion of parasite-specific CD4⁺ T cell responses associated with improved control of parasite growth. Again, however, there was also an accelerated breakdown in splenic microarchitecture in these animals. Together, these findings identify distinct, cell-specific, immunoregulatory networks established during experimental visceral leishmaniasis that could be manipulated for clinical advantage.

https://ift.tt/2qX2UcR

Opening the Black Box of Immunosuppression [PILLARS OF IMMUNOLOGY]

https://ift.tt/2BhLGNj

Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho [IMMUNE SYSTEM DEVELOPMENT]

Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10–100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klotho-sufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D–deprived diet. We observed that a vitamin D–deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels.

https://ift.tt/2KhywTg

Pillars Article: Cyclosporin A Specifically Inhibits Function of Nuclear Proteins Involved in T Cell Activation. Science. 1989. 246: 1617-1620 [PILLARS OF IMMUNOLOGY]

https://ift.tt/2Bi2h3j

Innate Lymphoid Cells Have Decreased HLA-DR Expression but Retain Their Responsiveness to TLR Ligands during Sepsis [INNATE IMMUNITY AND INFLAMMATION]

Sepsis, one of the leading causes of death in intensive care units, is caused by a dysregulated host response to infection that leads to life-threatening organ dysfunction. The proinflammatory and anti-inflammatory responses activated by the infecting microorganism become systemic, and the sustained anti-inflammatory response induces a state of immunosuppression that is characterized by decreased expression of HLA-DR on monocytes, T cell apoptosis, and reduced production of TNF-α by monocytes and macrophages in response to TLR ligands. Innate lymphoid cells (ILCs) are lymphocytes that lack Ag-specific receptors and lineage-specific markers; they express HLA-DR and are activated by cytokines and by direct recognition of microbial molecules. In this study, we evaluated if ILCs are affected by the anti-inflammatory response during sepsis. We found that the number of peripheral blood ILCs was decreased in septic patients compared with healthy volunteers; this decrease was caused by a reduction in ILC1 and ILC3 and is associated with apoptosis, because ILCs from septic patients expressed active caspase 3. ILCs from septic patients had decreased HLA-DR expression but increased expression of the activating receptors NKp46 and NKp44; they also showed a sustained expression of CD127 (IL-7R α-chain) and retained their capacity to produce TNF-α in response to TLR ligands. These results indicate that during sepsis, ILCs have decreased HLA-DR expression and die via apoptosis, similar to monocytes and T cells, respectively. However, other effector functions of ILCs (activation through NKp46 and NKp44, TNF-α production) may remain unaffected by the immunosuppressive environment prevailing in septic patients.

https://ift.tt/2Kilrcq

IL-17 in Renal Immunity and Autoimmunity [BRIEF REVIEWS]

The kidney is an organ particularly susceptible to damage caused by infections and autoimmune conditions. Renal inflammation confers protection against microbial infections. However, if unchecked, unresolved inflammation may lead to kidney damage. Although proinflammatory cytokine IL-17 is required for immunity against extracellular pathogens, dysregulated IL-17 response is also linked to autoimmunity. In this review, we will discuss the current knowledge of IL-17 activity in the kidney in context to renal immunity and autoimmunity and raise the intriguing question to what extent neutralization of IL-17 is beneficial or harmful to renal inflammation.

https://ift.tt/2BhLsWt

Increased Mitochondrial Biogenesis and Reactive Oxygen Species Production Accompany Prolonged CD4+ T Cell Activation [IMMUNE REGULATION]

Activation of CD4⁺ T cells to proliferate drives cells toward aerobic glycolysis for energy production while using mitochondria primarily for macromolecular synthesis. In addition, the mitochondria of activated T cells increase production of reactive oxygen species, providing an important second messenger for intracellular signaling pathways. To better understand the critical changes in mitochondria that accompany prolonged T cell activation, we carried out an extensive analysis of mitochondrial remodeling using a combination of conventional strategies and a novel high-resolution imaging method. We show that for 4 d following activation, mouse CD4⁺ T cells sustained their commitment to glycolysis facilitated by increased glucose uptake through increased expression of GLUT transporters. Despite their limited contribution to energy production, mitochondria were active and showed increased reactive oxygen species production. Moreover, prolonged activation of CD4⁺ T cells led to increases in mitochondrial content and volume, in the number of mitochondria per cell and in mitochondrial biogenesis. Thus, during prolonged activation, CD4⁺ T cells continue to obtain energy predominantly from glycolysis but also undergo extensive mitochondrial remodeling, resulting in increased mitochondrial activity.

https://ift.tt/2KikYqG

Cutting Edge: Human Vagus Produces Specialized Proresolving Mediators of Inflammation with Electrical Stimulation Reducing Proinflammatory Eicosanoids [CUTTING EDGE]

Inflammatory resolution is a process that, when uncontrolled, impacts many organs and diseases. As an active, self-limited inflammatory process, resolution involves biosynthesis of specialized proresolving mediators (SPM) (e.g., lipoxins, resolvins [Rv], protectins, and maresins). Because vagal stimulation impacts inflammation, we examined human and mouse vagus ex vivo to determine if they produce lipid mediators. Using targeted lipid mediator metabololipidomics, we identified lipoxins, Rv, and protectins produced by both human and mouse vagus as well as PGs and leukotrienes. Human vagus produced SPM (e.g., RvE1, NPD1/PD1, MaR1, RvD5, and LXA₄) on stimulation that differed from mouse (RvD3, RvD6, and RvE3), demonstrating species-selective SPM. Electrical vagus stimulation increased SPM in both human and mouse vagus as did incubations with Escherichia coli. Electrical vagus stimulation increased SPM and decreased PGs and leukotrienes. These results provide direct evidence for vagus SPM and eicosanoids. Moreover, they suggest that this vagus SPM circuit contributes to a new proresolving vagal reflex.

https://ift.tt/2BhLopH

Lipoxin B4 Enhances Human Memory B Cell Antibody Production via Upregulating Cyclooxygenase-2 Expression [IMMUNOTHERAPY AND VACCINES]

Vaccination has been the most effective way to prevent or reduce infectious diseases; examples include the eradication of smallpox and attenuation of tetanus and measles. However, there is a large segment of the population that responds poorly to vaccines, in part because they are immunocompromised because of disease, age, or pharmacologic therapy and are unable to generate long-term protection. Specialized proresolving mediators are endogenously produced lipids that have potent proresolving and anti-inflammatory activities. Lipoxin B₄ (LXB₄) is a member of the lipoxin family, with its proresolving effects shown in allergic airway inflammation. However, its effects on the adaptive immune system, especially on human B cells, are not known. In this study, we investigated the effects of LXB₄ on human B cells using cells from healthy donors and donors vaccinated against influenza virus in vitro. LXB₄ promoted IgG Ab production in memory B cells and also increased the number of IgG-secreting B cells. LXB₄ enhanced expression of two key transcription factors involved in plasma cell differentiation, BLIMP1 and XBP1. Interestingly, LXB₄ increased expression of cyclooxygenase-2 (COX2), an enzyme that is required for efficient B cell Ab production. The effects of LXB₄ are at least partially COX2-dependent as COX2 inhibitors attenuated LXB₄-stimulated BLIMP1 and Xpb-1 expression as well as IgG production. Thus, our study reveals for the first time, to our knowledge, that LXB₄ boosts memory B cell activation through COX2 and suggests that LXB₄ can serve as a new vaccine adjuvant.

https://ift.tt/2KikTTU

Divergent TCR-Initiated Calcium Signals Govern Recruitment versus Activation of Human Alloreactive Effector Memory T Cells by Endothelial Cells [ANTIGEN RECOGNITION AND RESPONSES]

Early human allograft rejection can be initiated when circulating human host versus graft Ag-specific CD8 and CD4 effector memory T cells directly recognize MHC class I and II, respectively, expressed on the luminal surface by endothelium lining graft blood vessels. TCR engagement triggers both graft entry (TCR-driven transendothelial migration or TEM) and production of proinflammatory cytokines. Both TCR-driven TEM and cytokine expression are known to depend on T cell enzymes, myosin L chain kinase, and calcineurin, respectively, that are activated by cytoplasmic calcium and calmodulin, but whether the sources of calcium that control these enzymes are the same or different is unknown. Using superantigen or anti-CD3 Ab presented by cultured human dermal microvascular cells to freshly isolated peripheral blood human effector memory T cells under conditions of flow (models of alloantigen recognition in a vascularized graft), we tested the effects of pharmacological inhibitors of TCR-activated calcium signaling pathways on TCR-driven TEM and cytokine expression. We report that extracellular calcium entry via CRAC channels is the dominant contributor to cytokine expression, but paradoxically these same inhibitors potentiate TEM. Instead, calcium entry via TRPV1, L-Type Ca_v, and pannexin-1/P2X receptors appear to control TCR-driven TEM. These data reveal new therapeutic targets for immunosuppression.

https://ift.tt/2Bi5XSQ

Computationally Designed Bispecific MD2/CD14 Binding Peptides Show TLR4 Agonist Activity [INNATE IMMUNITY AND INFLAMMATION]

Toll-like receptor 4 plays an important role in the regulation of the innate and adaptive immune response. The majority of TLR4 activators currently in clinical use are derivatives of its prototypic ligand LPS. The discovery of innovative TLR4 activators has the potential of providing new therapeutic immunomodulators and adjuvants. We used computational design methods to predict and optimize a total of 53 cyclic and linear peptides targeting myeloid differentiation 2 (MD2) and cluster of differentiation 14 (CD14), both coreceptors of human TLR4. Activity of the designed peptides was first assessed using NF-B reporter cell lines expressing either TLR4/MD2 or TLR4/CD14 receptors, then binding to CD14 and MD2 confirmed and quantified using MicroScale Thermophoresis. Finally, we incubated select peptides in human whole blood and observed their ability to induce cytokine production, either alone or in synergy with LPS. Our data demonstrate the advantage of computational design for the discovery of new TLR4 peptide activators with little structural resemblance to known ligands and indicate an efficient strategy with which to identify TLR4 targeting peptides that could be used as easy-to-produce alternatives to LPS-derived molecules in a variety of settings.

https://ift.tt/2Khywme

Calcium-Sensing Receptor Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1: Epitopes, Specificity, Functional Affinity, IgG Subclass, and Effects on Receptor Activity [AUTOIMMUNITY]

A major manifestation of autoimmune polyendocrine syndrome type 1 (APS1) is hypoparathyroidism, which is suggested to result from aberrant immune responses against the parathyroid glands. The calcium-sensing receptor (CaSR), which plays a pivotal role in maintaining calcium homeostasis by sensing blood calcium levels and regulating release of parathyroid hormone (PTH), is an autoantibody target in APS1. In this study, the aim was to characterize the binding sites, specificity, functional affinity, IgG subclass, and functional effects of CaSR autoantibodies using phage-display technology, ELISA, and bioassays. The results indicated that CaSR autoantibody binding sites were at aa 41–69, 114–126, 171–195, and 260–340 in the extracellular domain of the receptor. Autoantibodies against CaSR epitopes 41–69, 171–195, and 260–340 were exclusively of the IgG1 subclass. Autoantibody responses against CaSR epitope 114–126 were predominantly of the IgG1 with a minority of the IgG3 subclass. Only autoantibodies recognizing CaSR epitopes 114–126 and 171–195 affected receptor activity; inositol-phosphate accumulation was increased significantly in HEK293-CaSR cells, and PTH secretion from PTH-C1 cells was reduced significantly when either were incubated with purified Ab and Ca²⁺ compared with Ca²⁺ alone. In conclusion, although the majority of APS1 patients do not have CaSR-stimulating autoantibodies, the hypoparathyroid state in a small minority of patients is the result of functional suppression of the parathyroid glands.

https://ift.tt/2BhLe1z

TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-{kappa}B1 Activation [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced cytidine deaminase (AID). In response to T cell–dependent (TD) Ags, CSR can be induced by CD40 signaling in B cells. TNFR-associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell–intrinsic TRAF2 or TRAF3 (B-TRAF2 or B-TRAF3) knockout mice were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development, and enlarged peripheral lymphoid organs. However, it remains unknown whether deficiency of B-TRAF2 or B-TRAF3 differentially affects TD humoral immune responses and CD40-induced CSR. In this article, we show that B-TRAF2 is essential for optimal isotype switching induced by in vivo TD Ag immunization or by engaging CD40 in vitro. Our data clarify the controversial role of B-TRAF3 and confirm its dispensability in CD40-induced CSR. Mechanistically, CD40-induced AID expression was markedly impaired by B-TRAF2, but not B-TRAF3, deficiency. Moreover, B-TRAF2 deficiency causes defective activation of the NF-B1 complex in a CD40-autonomous manner, and restoring CD40-induced NF-B1 activation in TRAF2-deficient B cells rescues AID expression and CSR. We conclude that TRAF2 is essential but TRAF3 is dispensable for TD humoral immunity and CD40-induced CSR. Our studies provide significant biological bases for optimizing treatment of B cell–associated immune disorders by targeting CD40 signaling.

https://ift.tt/2KikJfg

Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis [AUTOIMMUNITY]

Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9–induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9–induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9–mediated IL-23 and IL-36a production of Thy-1N rats.

https://ift.tt/2BiPAFD

Limited Phenotypic and Functional Plasticity of Influenza Virus-Specific Memory CD8+ T Cells during Activation in an Alternative Cytokine Environment [IMMUNE REGULATION]

Naive CD8⁺ T cells show phenotypic, functional, and epigenetic plasticity, enabling differentiation into distinct cellular states. However, whether memory CD8⁺ T cells demonstrate similar flexibility upon recall is poorly understood. We investigated the potential of influenza A virus (IAV)-specific memory CD8⁺ T cells from mice to alter their phenotype and function in response to reactivation in the presence of IL-4 and anti–IFN- Ab (type 2 conditions). Compared with naive CD8⁺ T cells, only a small proportion of IAV-specific memory T cells exhibited phenotypic and functional plasticity after clonal activation under type 2 conditions. The potential for modulation of cell-surface phenotype (CD8α expression) was associated with specific epigenetic changes at the Cd8a locus, was greater in central memory T cells than effector memory T cells, and was observed in endogenous memory cells of two TCR specificities. Using a novel technique for intracellular cytokine staining of small clonal populations, we showed that IAV-specific memory CD8⁺ T cells reactivated under type 2 conditions displayed robust IFN- expression and, unlike naive CD8⁺ T cells activated under type 2 conditions, produced little IL-4 protein. Secondary activation of memory cells under type 2 conditions increased GATA-3 levels with minimal change in T-bet levels. These data suggest that a small population of memory cells, especially central memory T cells, exhibits plasticity; however, most IAV-specific memory CD8⁺ T cells resist reprogramming upon reactivation and retain the functional state established during priming.

https://ift.tt/2Kfofqz

Fc{gamma}RIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa Mice [AUTOIMMUNITY]

C57BL/6 (B6).FcRIIb^–/–.Yaa mice spontaneously develop lethal lupus nephritis. To define the cell type–specific role of FcRIIb in Yaa-associated lupus, we established B cell– (CD19^Cre.Yaa), myeloid cell– (C/EBPα^Cre.Yaa), and dendritic cell– (DC) (CD11c^Cre.Yaa) specific FcRIIb-deficient B6.Yaa mouse strains. CD19^Cre.Yaa mice developed milder lupus than B6.FcRIIb^–/–.Yaa mice, indicating that FcRIIb deficiency on B cells is not sufficient for the development of severe disease. Surprisingly, C/EBPα^Cre.Yaa mice also showed autoantibody production and mild lupus similar to that in CD19^Cre.Yaa mice, whereas CD11c^Cre.Yaa mice stayed disease free. These observations indicate that FcRIIb deficiency in B cells and myeloid cells, but not DCs, contributes to the severe disease in B6.FcRIIb^–/–.Yaa mice. Flow cytometric analysis showed that the frequency of peripheral Gr-1^– but not Gr-1⁺ monocyte was increased in B6.FcRIIb^–/–.Yaa and C/EBPα^Cre.Yaa but not CD19^Cre.Yaa mice, suggesting a link between FcRIIb deficiency on myeloid cells and the high frequency of Gr-1^– monocytes. RNA sequencing revealed that compared with Gr-1⁺ monocytes, Gr-1^– monocytes expressed higher levels of the B cell–stimulating cytokines BSF-3, IL-10, and IL-1β, the DC markers CD11c, CD83, and Adamdec1, and the antiapoptotic factors Bcl2 and Bcl6. In conclusion, in Yaa-associated lupus nephritis, FcRIIb on B cells and myeloid cells modulates B cell activation via different but synergistic pathways. Gr-1^– monocytes are the most likely candidate myeloid cells involved.

https://ift.tt/2Biokak

Loss of Canonical Notch Signaling Affects Multiple Steps in NK Cell Development in Mice [IMMUNE REGULATION]

Within the hematopoietic system, the Notch pathway is critical for promoting thymic T cell development and suppressing the B and myeloid lineage fates; however, its impact on NK lymphopoiesis is less understood. To study the role of Notch during NK cell development in vivo, we investigated different NK cell compartments and function in Rbp-Jk^fl/flVav-Cre^tg/+ mice, in which Rbp-Jk, the major transcriptional effector of canonical Notch signaling, was specifically deleted in all hematopoietic cells. Peripheral conventional cytotoxic NK cells in Rbp-Jk–deleted mice were significantly reduced and had an activated phenotype. Furthermore, the pool of early NK cell progenitors in the bone marrow was decreased, whereas immature NK cells were increased, leading to a block in NK cell maturation. These changes were cell intrinsic as the hematopoietic chimeras generated after transplantation of Rbp-Jk–deficient bone marrow cells had the same NK cell phenotype as the Rbp-Jk–deleted donor mice, whereas the wild-type competitors did not. The expression of several crucial NK cell regulatory pathways was significantly altered after Rbp-Jk deletion. Together, these results demonstrate the involvement of canonical Notch signaling in regulation of multiple stages of NK cell development.

https://ift.tt/2KgA0NI

Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti-Citrullinated Protein/Peptide Antibody [AUTOIMMUNITY]

Quantification of Abs toward a single epitope is critical to understanding immunobiological processes. In autoimmunity, the prognostic value of the serological profiles of patients draws much attention, but the detection of Abs toward a single epitope is not well controlled. Particularly, the rheumatoid arthritis (RA)–specific anti–citrullinated protein/peptide Abs (ACPA) are specific to a two-atom change on arginyl residues and are considered a heterogeneous family of Abs. As a model, we studied ACPA to decipher how peptide features used as immunosorbent impact Ab detection. We synthesized 30 peptides encompassing immunodominant epitopes of citrullinated fibrin differing by their length and biotin location and tested them using ELISA with 120 sera from RA and non-RA rheumatic disease controls, generating over 3000 experimental measurements. We showed that minor molecular changes in peptide chemical structure had dramatic consequences. Even when peptides exhibited the same epitope, measured Ab titers were extremely variable, and patients' seropositivity was discordant in up to 50% of cases. The distance between epitope and biotin was the most critical parameter for efficient Ab detection irrespective of biotin position or peptide length. Finally, we identified a 15-mer peptide bearing a single citrullinated epitope detecting almost all ACPA-positive sera, thus revealing a high degree of homogeneity in RA autoimmune response. This integrative analysis deciphers the dramatic impact of the molecular design of peptide-based technologies for epitope-specific Ab quantification. It provides a model for assay development and highlights that the studies using such technologies can give a wrong perception of biological processes and therefore that medical use of data must be cautious.

https://ift.tt/2Bi2d3z

Speech Perception with Spectrally Non-overlapping Maskers as Measure of Spectral Resolution in Cochlear Implant Users

Abstract

Poor spectral resolution contributes to the difficulties experienced by cochlear implant (CI) users when listening to speech in noise. However, correlations between measures of spectral resolution and speech perception in noise have not always been found to be robust. It may be that the relationship between spectral resolution and speech perception in noise becomes clearer in conditions where the speech and noise are not spectrally matched, so that improved spectral resolution can assist in separating the speech from the masker. To test this prediction, speech intelligibility was measured with noise or tone maskers that were presented either in the same spectral channels as the speech or in interleaved spectral channels. Spectral resolution was estimated via a spectral ripple discrimination task. Results from vocoder simulations in normal-hearing listeners showed increasing differences in speech intelligibility between spectrally overlapped and interleaved maskers as well as improved spectral ripple discrimination with increasing spectral resolution. However, no clear differences were observed in CI users between performance with spectrally interleaved and overlapped maskers, or between tone and noise maskers. The results suggest that spectral resolution in current CIs is too poor to take advantage of the spectral separation produced by spectrally interleaved speech and maskers. Overall, the spectrally interleaved and tonal maskers produce a much larger difference in performance between normal-hearing listeners and CI users than do traditional speech-in-noise measures, and thus provide a more sensitive test of speech perception abilities for current and future implantable devices.

https://ift.tt/2Tpb2zH

Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing, Perceptuomotor Speed, and Executive Functioning in Younger and Older Listeners

Abstract

Older adults typically have difficulty identifying speech that is temporally distorted, such as reverberant, accented, time-compressed, or interrupted speech. These difficulties occur even when hearing thresholds fall within a normal range. Auditory neural processing speed, which we have previously found to predict auditory temporal processing (auditory gap detection), may interfere with the ability to recognize phonetic features as they rapidly unfold over time in spoken speech. Further, declines in perceptuomotor processing speed and executive functioning may interfere with the ability to track, access, and process information. The current investigation examined the extent to which age-related differences in time-compressed speech identification were predicted by auditory neural processing speed, perceptuomotor processing speed, and executive functioning. Groups of normal-hearing (up to 3000 Hz) younger and older adults identified 40, 50, and 60 % time-compressed sentences. Auditory neural processing speed was defined as the P1 and N1 latencies of click-induced auditory-evoked potentials. Perceptuomotor processing speed and executive functioning were measured behaviorally using the Connections Test. Compared to younger adults, older adults exhibited poorer time-compressed speech identification and slower perceptuomotor processing. Executive functioning, P1 latency, and N1 latency did not differ between age groups. Time-compressed speech identification was independently predicted by P1 latency, perceptuomotor processing speed, and executive functioning in younger and older listeners. Results of model testing suggested that declines in perceptuomotor processing speed mediated age-group differences in time-compressed speech identification. The current investigation joins a growing body of literature suggesting that the processing of temporally distorted speech is impacted by lower-level auditory neural processing and higher-level perceptuomotor and executive processes.

https://ift.tt/2A6uLeH

Ist sicher: Active Surveillance beim Prostatakarzinom mit niedrigem Risiko

https://ift.tt/2DL15rL

The long-term outcomes of breast implants studied

A recent analysis on existing data unearths information about the rare but serious long-term risks associated with silicone breast implants.

https://ift.tt/2DvWzfN

Personalisierte Medizin im Bereich entzündlicher Hauterkrankungen

Zusammenfassung

Hintergrund

Für eine ausreichende Versorgung von Patienten mit chronisch entzündlichen Hauterkrankungen müssen neue Konzepte entwickelt und Biomarker identifiziert werden.

Fragestellung

Dargestellt werden neue Marker sowie deren Qualität und Implikation für den klinischen Alltag.

Material und Methode

Es erfolgen die Diskussion von Grundlagenarbeiten und die Zusammenfassung neuer Entwicklungen der personalisierten Medizin im Bereich chronisch entzündlicher Hauterkrankungen.

Ergebnisse

Vielversprechende Biomarker für unterschiedliche Entitäten des chronisch entzündlichen Formenkreises wurden bereits vorgeschlagen, bedürfen jedoch einer prospektiven Validierung und Umsetzung in kostengünstige, praktikable Tests.

Schlussfolgerungen

Der Weg zur personalisierten Medizin im Gebiet der chronisch entzündlicher Hauterkrankungen ist noch weit und bedarf nicht zuletzt einer multizentrischen Kollaboration zur Validierung und Implementierung von Biomarkern.

https://ift.tt/2zhRWTF

Versatility of cervicofacial flaps: Cervical‐medial cheek flap for reconstruction in cutaneous substance loss of the inner cheek

Abstract

Background

Preservation of facial harmony is a major challenge in reconstruction after resection of head and neck skin tumors. For large medial cheek‐skin defects, we used a derived posterior‐based cervicofacial flap, or cervical‐medial cheek flap (CMCF).

Methods

We present a retrospective review of cases treated at a university‐based cancer center. Patient characteristics, surgical technique, and complication rates are described.

Results

Eighteen patients were treated between 2014 and 2017 with reconstruction for integumentary cheek defect after skin tumor surgery using CMCF. Mean defect size was 5.7 cm in length and 3.9 cm in width. The main histological subtype was lentigo maligna (33.3%). We report no flap necrosis but 4 minor complications occurred over a mean follow‐up of 14.4 months. At last follow‐up, satisfaction rate was very high (88.9%) with no evidence of recurrence.

Conclusion

The CMCF is a promising yet infrequently used option in medial cheek reconstruction, with excellent cosmetic and functional outcomes.

https://ift.tt/2QVUVIv

Impact of treatment expertise on the outcome of patients with head and neck cancer treated within 6 randomized trials

Abstract

Background

We evaluated the impact of center expertise, in terms of number of patients treated, on the overall survival (OS) and progression‐free survival (PFS) of patients with head and neck squamous cell carcinoma (SCC).

Methods

We performed a pooled analysis including data from 6 randomized trials in head and neck SCC conducted in Italy. We evaluated the association between OS or PFS and the number of patients recruited by the center.

Results

The outcome of 903 patients who had received radiotherapy (RT) was analyzed (median follow‐up 76 months). The hazard ratio (HR) comparing the third and the first quartiles of the distribution of number of patients per center showed an advantage in PFS (HR 0.59, range 0.53‐0.65, P < .0001) and in OS (HR 0.70, 0.60‐0.81, P < .0001) for centers with a higher number of patients recruited. A similar benefit was observed in PFS (HR 0.63, 0.60‐0.66) and OS (HR 0.74, 0.69‐0.79) considering the mean number of patients per year.

Conclusions

The PFS and OS were longer for patients treated in high‐case‐volume centers.

https://ift.tt/2PDEWC7

A COMMON THERAPY FOR ALLERGIC REACTION YET A RARELY SUSPECTED CAUSE OF HYPERSENSITIVITY

While corticosteroid allergy is uncommon, reactions have been described. Increasing reports suggest the frequency of steroid reactions may be increasing, though the exact incidence is unknown.

https://ift.tt/2KffH3b

TOXIC EPIDERMAL NECROLYSIS COMPLICATED BY CHRONIC INFLAMMATORY KERATITIS/CONJUNCTIVITIS AND INFLAMMATORY PERIPHERAL NEURITIS

We present a patient who developed chronic keratitis and conjunctivitis, inflammatory neuropathy of the hands, and onychomadesis as complications of her toxic epidermal necrolysis (TEN). Neuropathy was treated with glucocorticoids, methotrexate, and high dose IVIG; however the keratitis and conjunctivitis were resistant and required adalimumab. To the best of our knowledge, there are no other reports of inflammatory neuropathy as a sequelae of Stevens Johnson Syndrome (SJS)/TEN, nor management of chronic ocular inflammation with adalimumab.

https://ift.tt/2Bg9SzE

SEMINAL FLUID SENSITIVITY: ABSTINENCE IS NOT THE ANSWER

Seminal fluid sensitivity with localized late phase symptoms and successful intravaginal desensitization is described.

https://ift.tt/2Kicks0

NOT ALL LIP SWELLING IS ANGIOEDEMA

Cheilitis granulomatosa (CG) is a rare form of recurrent or persistent swelling of one or both lips and one form of orofacial granulomatosis. It is important for allergists to consider the need for mucosal biopsy in patients initially referred for angioedema, especially if the lip swelling has been persistent.

https://ift.tt/2Biy6sX

THREE CASES OF DELAYED-ONSET REPETITIVE EMESIS AFTER AVOCADO INGESTION

Food Protein-Induced Enterocolitis (FPIES) is a non-IgE mediated gastrointestinal food hypersensitivity typically presenting in infancy with vomiting and diarrhea, but can progress to shock. Rarely reported as an FPIES trigger, avocado is listed as among low-risk complementary foods to introduce for infants in the first international consensus guidelines for FPIES. Here we report 3 cases of FPIES to avocado.

https://ift.tt/2KfuF9e

EDUCATIONAL OUTCOMES OF AN ANAPHYLAXIS SIMULATION ACTIVITY AMONG MEDICAL STUDENTS AND RESIDENTS¶

Failure to recognize anaphylaxis or delayed epinephrine auto-injector (EAI) administration may result in poor patient outcomes.  Clinical simulation is an educational method used for environment-controlled, team-based learning.

https://ift.tt/2Bg9Asy

GENETIC TESTING IDENTIFIES CAUSE OF ENTEROPATHY AND GROWTH FAILURE IN A 10 YEAR OLD MALE

Enteropathies with features of celiac disease or inflammatory bowel disease (IBD) should spark consideration of an immunodeficiency when presenting at an early age.

https://ift.tt/2KeVkTG

HIGHER STARTING DOSE PROTOCOLS IN CORONARY ARTERY DISEASE PATIENTS WITH ASPIRIN HYPERSENSITIVITY

Aspirin is a cornerstone of atherosclerosis therapy, but 1.5% of coronary artery disease (CAD) patients report aspirin allergy. Past protocols of challenge and/or desensitization for aspirin allergy excluded acute coronary syndrome (ACS) patients and/or started at low doses. Recent studies propose higher starting doses with fewer steps. The safety and efficacy of these newer protocols are not established, especially in the acute setting where the ability to tolerate aspirin is time-sensitive.

https://ift.tt/2BgaghA

NEWBORN T-CELL RECOMBINATION EXCISION CIRCLE SCREENING REVEALS NON-ARCHETYPAL DIGEORGE PATIENT

DiGeorge Syndrome (DGS) is a spectrum of disorders with variable manifestations including congenital heart malformations, immunodeficiency, facial dysmorphism, hypocalcemia, and developmental delay, leading to diagnosis at a wide age range.1 Patients without classic cardiac malformations frequently remain undiagnosed longer, diagnosed only after developing recurrent infections, learning difficulties, or mental health problems. 2

https://ift.tt/2KeTGl5

SOCIO-DEMOGRAPHIC DIFFERENCES IN PATIENTS HOSPITALIZED FOR ANAPHYLAXIS IN THE UNITED STATES

Anaphylactic shock is a life-threatening emergency that can lead to significant morbidity and mortality. Data from European studies have shown significant disparities in healthcare utilization for anaphylaxis, however there are limited studies describing the association between socioeconomic status and patient characteristics for hospitalizations related to anaphylaxis in the United States.

https://ift.tt/2BgPkH0

URTICARIA, NAUSEA, AND VOMITING, IS THIS THE GALT ENZYME DEFICIENCY?

Galactosemia is a rare genetic disorder not frequently encountered in clinical practice. GALT enzyme deficiency is in the spectrum of non IgE mediated food intolerance. However, when encountered with symptoms consistent anaphylaxis, the possibility of an IgE mediated reaction should not be excluded.

https://ift.tt/2KgNQj0

DIRECT ORAL AMOXICILLIN CHALLENGE WITHOUT PRELIMINARY SKIN TESTING IN PATIENTS WITH REPORTED PENICILLIN ALLERGY

10% of hospitalized patients report penicillin allergy; studies indicate that ∼98% are not truly allergic. Unconfirmed penicillin allergy labels pose public health risks, and evaluation is recommended to improve antibiotic stewardship. While the most widely accepted protocol is penicillin skin testing (PST) followed by oral amoxicillin challenge, time constraints and resources may preclude this. Recent literature supports the safety and efficacy of direct oral amoxicillin challenge in low-risk individuals.

https://ift.tt/2BgPk9Y

A CASE OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE, CHRONIC LUNG DISEASE, AND RECURRENT INFECTIONS

Very early onset inflammatory bowel disease (VEOIBD) may correlate with multiple immunodeficiencies, including severe combined immunodeficiency (SCID), common variable immunodeficiency (CVID), chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome (WAS), and IL-10 signaling defects. It may be difficult to differentiate between intestinal inflammation and immune dysfunction leading to systemic symptoms and elevated inflammatory markers. This patient, a 5-year-old male with very early onset Crohn's disease, chronic lung disease, 1p36 duplication, failure to thrive, eczema, and systemic infections including Candidemia, Klebsiella bacteremia, histoplasmosis, recurring pneumonia, multiple upper respiratory and sinus infections, and recurring IBD flares, presented due to concern for underlying primary immunodeficiency.

https://ift.tt/2KeV9I0

IMPROVING EMERGENCY CARE FOR ANAPHYLAXIS: IMPACT OF A CLINICAL PATHWAY IN A PEDIATRIC EMERGENCY DEPARTMENT

Emergency Department (ED) management of anaphylaxis has not kept pace with advances in knowledge. Epinephrine use and utilization of guideline-based practice recommendations remains sub-optimal, particularly in children. We implemented a clinical pathway in our pediatric ED in August 2017 to improve care.

https://ift.tt/2Bh2vIj

SECONDARY IMMUNODEFICIENCY DUE TO GAMING DISORDER

Gaming disorder is a new ICD-11 diagnosis wherein obsessive video-gaming results in an interference of daily activities, which can lead to downstream health effects such as cachexia and malnutrition. We report a patient whose gaming disorder led to severe malnutrition and secondary immunodeficiency.

https://ift.tt/2Kmdh2V

PREDICTIVE DECLINE IN PEANUT SKIN TEST AND RAST AMONG PEANUT-ALLERGIC CHILDREN UNDERGOING HIGH-DOSE ORAL IMMUNOTHERAPY

Peanut immunotherapy remains a limited form of treatment for peanut allergic children. Limitations primarily stem from small study sizes, significant adverse events, unclear long-term immunological outcomes and the inability to reach tolerance. In our cohort of peanut anaphylaxis patients undergoing tolerance induction oral immunotherapy, we sought to determine the rate of decline in peanut skin prick testing (SPT) and RAST results following one year of high-dose, weekly peanut immunotherapy.

https://ift.tt/2BgK8D4

DIFFERENTIAL DIAGNOSIS IN PEDIATRIC SEVERE ASTHMA

Despite drug treatment, a small percentage of patients with asthma cannot reach control. Therefore, it is important to have differential diagnosis in mind.

https://ift.tt/2KeTEtt

PERCEPTION AND PRACTICE OF SUBLINGUAL IMMUNOTHERAPY AMONG PRACTICING ALLERGISTS IN THE US: 2018 FOLLOW-UP SURVEY.

Limited information regarding current trends of sublingual immunotherapy (SLIT) use in the United States and perception of SLIT relative to 2007 and 2013 is available, especially in light of recent FDA-approved SLIT options.

https://ift.tt/2BfR9nB

RESOLUTION OF MILK-PROTEIN ALLERGY AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN A PATIENT WITH IPEX SYNDROME

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is due to a FOXP3 gene mutation leading to regulatory T cell dysfunction and multi-organ autoimmunity. Patients present in infancy with protracted diarrhea, dermatitis, insulin-dependent diabetes mellitus, and thyroiditis. Some patients may have severe food allergies. We present a patient with IPEX syndrome whose milk protein allergy resolved after receiving a stem cell transplant for his primary immunodeficiency.

https://ift.tt/2KfUS7K

COMPARATIVE STUDY OF βS-LACTAM DE-LABELING ON THE FREQUENCY OF PERI-OPERATIVE VANCOMYCIN USE

Vancomycin is the antibiotic of choice in β-lactam allergic adults undergoing surgical antibiotic prophylaxis. Because it is a suboptimal option, in 2015 a pre-operative drug allergy screening program began at the Montreal General Hospital (MGH). It de-labeled 94 % of patients evaluated, reducing vancomycin use to 3 %. To validate the program effectiveness a prospective study comparing the Royal Victoria Hospital (RVH), which lacked de-labeling was undertaken.The aim of the study was to determine the effect of a de-labeling program on vancomycin use.

https://ift.tt/2Bit4gh

Pneumatic long-wave generation of tsunami-length waveforms and their runup

McGovern, DJ; Robinson, T; Chandler, ID; Allsop, W; Rossetto, T; (2018) Pneumatic long-wave generation of tsunami-length waveforms and their runup. Coastal Engineering , 138 pp. 80-97. 10.1016/j.coastaleng.2018.04.006 .

https://ift.tt/2ziZHJc

BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis

Pediaditakis, I; Kourgiantaki, A; Prousis, KC; Potamitis, C; Xanthopoulos, KP; Zervou, M; Calogeropoulou, T; ... Gravanis, A; + view all Pediaditakis, I; Kourgiantaki, A; Prousis, KC; Potamitis, C; Xanthopoulos, KP; Zervou, M; Calogeropoulou, T; Charalampopoulos, I; Gravanis, A; - view fewer (2016) BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis. Frontiers in Pharmacology , 7 , Article 512. 10.3389/fphar.2016.00512 . Green open access

https://ift.tt/2OOvSVO

The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population

Rydberg Sterner, T; Ahlner, F; Blennow, K; Dahlin-Ivanoff, S; Falk, H; Havstam Johansson, L; Hoff, M; ... Skoog, I; + view all Rydberg Sterner, T; Ahlner, F; Blennow, K; Dahlin-Ivanoff, S; Falk, H; Havstam Johansson, L; Hoff, M; Holm, M; Hörder, H; Jacobsson, T; Johansson, B; Johansson, L; Kern, J; Kern, S; Machado, A; Mellqvist Fässberg, M; Nilsson, J; Ribbe, M; Rothenberg, E; Rydén, L; Sadeghi, A; Sacuiu, S; Samuelsson, J; Sigström, R; Skoog, J; Thorvaldsson, V; Waern, M; Westman, E; Wetterberg, H; Zetterberg, H; Zetterberg, M; Zettergren, A; Östling, S; Skoog, I; - view fewer (2018) The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population. European Journal of Epidemiology 10.1007/s10654-018-0459-8 . (In press). Green open access

https://ift.tt/2zcP8Y0

InP-based Optical Comb-locked Tunable Transmitter

Liu, Z; Farwell, S; Wale, M; Richardson, DJ; Slavík, R; (2016) InP-based Optical Comb-locked Tunable Transmitter. In: Proceedings of the Optical Fiber Communication Conference 2016. The Optical Society Green open access

https://ift.tt/2OWqJv2

Mediating migration crises: Sicily and the languages of despair

Filmer, D; Federici, FM; (2018) Mediating migration crises: Sicily and the languages of despair. European Journal of Language Policy , 10 (2) pp. 229-253. 10.3828/ejlp.2018.13 . Green open access

https://ift.tt/2zhCebb

Machine learning models in electronic health records can outperform conventional survival models for predicting patient mortality in coronary artery disease

Steele, AJ; Denaxas, SC; Shah, AD; Hemingway, H; Luscombe, NM; (2018) Machine learning models in electronic health records can outperform conventional survival models for predicting patient mortality in coronary artery disease. PLoS ONE , 13 (8) , Article e0202344. 10.1371/journal.pone.0202344 . Green open access

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MINLO t-channel single-top plus jet

Carrazza, S; Frederix, R; Hamilton, K; Zanderighi, G; (2018) MINLO t-channel single-top plus jet. Journal of High Energy Physics (9) , Article 108. 10.1007/JHEP09(2018)108 . Green open access

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Necroptosis mediates myofibre death in dystrophin-deficient mice

Morgan, JE; Prola, A; Mariot, V; Pini, V; Meng, J; Hourde, C; Dumonceaux, J; ... Bencze, M; + view all Morgan, JE; Prola, A; Mariot, V; Pini, V; Meng, J; Hourde, C; Dumonceaux, J; Conti, F; Relaix, F; Authier, F-J; Tiret, L; Muntoni, F; Bencze, M; - view fewer (2018) Necroptosis mediates myofibre death in dystrophin-deficient mice. Nature Communications , 9 , Article 3655. 10.1038/s41467-018-06057-9 . Green open access

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Developing a theoretical model of professional identity transformation for early career teacher educators

Amott, PM; (2018) Developing a theoretical model of professional identity transformation for early career teacher educators. Presented at: 9th TEAN Conference - The Ambition of Teacher Education, Conference Aston in Birmingham.

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Pore confinement effects and stabilization of carbon nitride oligomers in macroporous silica for photocatalytic hydrogen production

Qiao, S; Mitchell, RW; Coulson, B; Jowett, DV; Johnson, BRG; Brydson, R; Isaacs, M; ... Douthwaite, RE; + view all Qiao, S; Mitchell, RW; Coulson, B; Jowett, DV; Johnson, BRG; Brydson, R; Isaacs, M; Lee, AF; Douthwaite, RE; - view fewer (2016) Pore confinement effects and stabilization of carbon nitride oligomers in macroporous silica for photocatalytic hydrogen production. Carbon , 106 pp. 320-329. 10.1016/j.carbon.2016.05.039 . Green open access

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Reducing myocardial infarct size: Myth or reality

Hausenloy, DJ; (2016) Reducing myocardial infarct size: Myth or reality. Heart and Metabolism (70) pp. 2-3.

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Geometrically-shaped 64-point Constellations via Achievable Information Rates

Chen, B; Okonkwo, C; Lavery, D; Alvarado, A; (2018) Geometrically-shaped 64-point Constellations via Achievable Information Rates. In: Proceedings of the 2018 20th International Conference on Transparent Optical Networks (ICTON). IEEE: Bucharest, Romania. Green open access

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In silico validation of the Autoinflammatory Disease Damage Index

Ter Haar, NM; van Delft, ALJ; Annink, KV; van Stel, H; Al-Mayouf, SM; Amaryan, G; Anton, J; ... Frenkel, J; + view all Ter Haar, NM; van Delft, ALJ; Annink, KV; van Stel, H; Al-Mayouf, SM; Amaryan, G; Anton, J; Barron, KS; Benseler, S; Brogan, PA; Cantarini, L; Cattalini, M; Cochino, A-V; de Benedetti, F; Dedeoglu, F; de Jesus, AA; Demirkaya, E; Dolezalova, P; Durrant, KL; Fabio, G; Gallizzi, R; Goldbach-Mansky, R; Hachulla, E; Hentgen, V; Herlin, T; Hofer, M; Hoffman, HM; Insalaco, A; Jansson, AF; Kallinich, T; Kone-Paut, I; Kozlova, A; Kuemmerle-Deschner, JB; Lachmann, HJ; Laxer, RM; Martini, A; Nielsen, S; Nikishina, I; Ombrello, AK; Özen, S; Papadopoulou-Alataki, E; Quartier, P; Rigante, D; Russo, R; Simon, A; Trachana, M; Uziel, Y; Ravelli, A; Schulert, G; Gattorno, M; Frenkel, J; - view fewer (2018) In silico validation of the Autoinflammatory Disease Damage Index. Annals of the Rheumatic Diseases , 77 (11) pp. 1599-1605. 10.1136/annrheumdis-2018-213725 . Green open access

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