Effects of Microplate Type and Broth Additives on Microdilution MIC Susceptibility Assays [Analytical Procedures]

The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity. For example, daptomycin requires media supplemented with Ca²⁺ and the lipoglycopeptides dalbavancin and oritavancin require Tween-80 to be added to the growth media to prevent depletion of free drug via adsorption to the plastic microplate. In this report we examine systematically the effects of several different plate types on microdilution broth MIC values for a set of antibiotics against Gram-positive and Gram-negative bacteria, both in media alone and in media supplemented with commonly used additives Tween-80, lysed horse blood, and 50% human serum. We observe very significant differences in measured MICs (up to 100-fold) for some lipophilic antibiotics, such as the Gram-positive lipoglycopeptide dalbavancin and the Gram-negative lipopeptide polymyxins, and find that non-specific binding plates can replace the need for surfactant additives. Microtitre plate types and any additives should be specified when reporting broth dilution MIC values as results can vary dramatically for some classes of antibiotics.

https://ift.tt/2quW91L

Whole genome sequencing for predicting clarithromycin resistance in Mycobacterium abscessus [Susceptibility]

Mycobacterium abscessus is emerging as an important pathogen in chronic lung diseases with concern regarding patient to patient transmission. The recent introduction of routine whole genome sequencing (WGS) as a replacement for existing reference techniques in England provides an opportunity to characterise the genetic determinants of resistance. We conducted a systematic review to catalogue all known resistance determining mutations. This knowledge was used to construct a predictive algorithm based on mutations in the erm(41) and rrl genes which was tested on a collection of 203 sequentially acquired clinical isolates for which there was paired genotype/phenotype data. A search for novel resistance determining mutations was conducted using an heuristic algorithm.

The sensitivity of existing knowledge for predicting resistance in clarithromycin was 95% (95% CI 89 - 98%) and the specificity was 66% (95% CI 54 - 76%). Subspecies alone was a poor predictor of resistance to clarithromycin. Eight potential new resistance conferring SNPs were identified. WGS demonstrates probable resistance determining SNPs in regions the NTM-DR line probe cannot detect. These mutations are potentially clinically important as they all occurred in samples predicted to be inducibly resistant, and for which a macrolide would therefore currently be indicated. We were unable to explain all resistance, raising the possibility of the involvement of other as yet unidentified genes.

https://ift.tt/2Qs0KNC

MSH2 gene point mutations are not antifungal resistance markers in Candida glabrata [Mechanisms of Resistance]

The high rates of antifungal resistance in Candida glabrata may be facilitated by the presence of alterations in the MSH2 gene. We aimed to study the sequence of the MSH2 gene in 124 invasive C. glabrata isolates causing incident episodes of candidemia (n=81), subsequent candidemia episodes (n=9), endocarditis (n=2), and in vitro-generated echinocandin-resistant isolates (n=32) and assessed its relationship with genotypes, acquisition of antifungal resistance in vivo and in vitro, and patient prognosis. MSH2 gene was sequenced and isolates were genotyped using six microsatellite markers and MLST based on six housekeeping genes. According to EUCAST, isolates causing candidemia (n = 90) were echinocandin susceptible, and four of them were fluconazole resistant (MIC ≥ 64 mg/L). One isolate from the heart valve was resistant to micafungin and anidulafungin (MIC= 2 mg/L and 1 mg/L, respectively). MSH2 gene mutations were present in 44.4% of incident isolates, the most common being V239L. Presence of MSH2 mutations was not correlated with in vitro or in vivo antifungal resistance. Microsatellite and MLST respectively revealed 27 genotypes and 17 sequence types. Fluconazole-resistant isolates were unrelated. Most MSH2 mutations were found in cluster isolates; conversely, some mutations were found in more than one genotype. No clinical differences – including previous antifungal use – were found between patients infected by wild-type MSH2 gene isolates and isolates with any point mutation. The presence of MSH2 gene mutations in C. glabrata isolates causing candidemia is not correlated with specific genotypes, the promotion of antifungal resistance, or the clinical outcome.

https://ift.tt/2qvROv1

Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment [Pharmacology]

WCK 5222 is a novel β-lactam-β-lactam enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel β-lactam enhancer with a dual action of binding to Gram-negative PBP2 and β-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogens. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in forty-eight subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR). We enrolled mild (n = 6; CLCR 60 to < 90 mL/min), moderate (n = 6; CLCR 30 to < 60 mL/min), severe (n = 6; CLCR < 30 mL/min; not on dialysis), end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR ≥ 90 mL/min). Healthy control subjects, mild and moderate renal impairment subjects received a single 60-min IV infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min IV infusion of WCK 5222, 1.5 g (1 g FEP/0.5 g ZID). Body and renal clearance decreased and plasma half-life (T_1/2) and AUC_0- (hr*µg/mL) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function.

https://ift.tt/2QiIVQR

Effect of rifampin/isoniazid-containing antituberculosis therapy on efavirenz pharmacokinetics in HIV-infected children aged 3 to 14 years old [Clinical Therapeutics]

We compared efavirenz pharmacokinetic (PK) parameters in children with TB/HIV coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children aged 3 to 14 years old with HIV infection with and without TB were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization recommended antituberculosis drugs dosages were used in the co-infected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated LC/MS/MS assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon Rank-sum test and within group by Signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age-Z-score and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz C_max, C_12h, C_min and AUC_0-24h were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C_12h, C_min and AUC_0-24h were lower in TB/HIV co-infected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC_0-24h was higher on than off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children.

https://ift.tt/2qwJ1sS

Inducible cell fusion permits use of competitive fitness profiling in the human pathogenic fungus Aspergillus fumigatus. [Mechanisms of Action]

Antifungal agents directed against novel therapeutic targets are required for treating invasive, chronic and allergic Aspergillus infections. Competitive fitness profiling technologies have been used in a number of bacterial and yeast systems to identify druggable targets however, development of similar systems in filamentous fungi are complicated by the fact that they undergo cell fusion and heterokaryosis. Here we demonstrate that cell fusion in A. fumigatus under standard culture conditions is not predominately constitutive, as with most ascomycetes, but can be induced by a range of extracellular stressors. Using this knowledge, we have developed a barcode-free genetic profiling system that permits high throughput parallel determination of strain fitness in a collection of diploid A. fumigatus mutants. We show heterozygous null mutants in cyp51A and arf2 have reduced fitness in the presence of Itraconazole and Brefeldin A respectively and a heterozygous null of atp17 is resistant to Brefeldin A.

https://ift.tt/2QmRrOX

Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via Both Non-Obligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus [Antiviral Agents]

Human adenovirus (AdV) can cause fatal disease in immune suppressed individuals, but treatment options are limited - in part because the antiviral cytidine analog, cidofovir (CDV), is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, non-nephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. We have therefore examined the effect of CDVpp on DNA synthesis by a purified AdV5 DNA polymerase (pol). CDVpp was incorporated into nascent DNA strands, and promoted a non-obligate form of chain termination (i.e., AdV5 pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 pol. At elevated concentrations, CDVpp inhibited AdV5 pol in a manner consistent with both chain termination and direct inhibition of pol activity. Finally, a recombinant AdV5 virus was constructed, containing pol mutations (V303I, T87I) that were selected following extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated EC50 for BCV, and 1.9 fold increased EC50 for CDV - thus confirming that viral resistance to BCV and CDV can be attributed to mutations in the viral pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA pol, and that their antiviral activity may occur via both (non-obligate) chain termination and (at high concentration) direct inhibition of AdV5 pol activity.

https://ift.tt/2qv8jaI

Azole resistance reduces susceptibility to the tetrazole antifungal VT-1161 [Experimental Therapeutics]

Tetrazole antifungals designed to target fungal lanosterol 14α-demethylase (LDM) appear effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of Candida albicans LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artefacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full-length Saccharomyces cerevisiae LDM with a C-terminal hexahistidine tag (ScLDM6xHis) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely-used triazole drug posaconazole (PCZ). We determined the effect of characterized mutations in LDM on VT-1161 activity and identified drug efflux pumps from fungi, including key fungal pathogens, that efflux VT-1161. The relevance of these yeast-based observations on drug efflux was verified using clinical isolates of C. albicans and C. glabrata. VT-1161 binding elicits a significant conformational difference between the full-length and truncated enzymes not found when posaconazole is bound. Susceptibility to VT-1161 is reduced by ATP-binding cassette (ABC) and major facilitator superfamily (MFS) drug efflux pumps, the overexpression of LDM and mutations within the drug binding pocket of LDM that affect interaction with the tertiary alcohol of the drug.

https://ift.tt/2Qr7b3v

In Vitro Activity of Sulopenem, an Oral Penem, Against Urinary Isolates of Escherichia coli [Susceptibility]

The in vitro activity of sulopenem was assessed against a 2014-2016 collection of 539 urinary isolates of Escherichia coli from Canadian patients using CLSI-defined broth microdilution methodology. A concentration of sulopenem of 0.03 µg/ml inhibited both 50% (MIC₅₀) and 90% (MIC₉₀) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 µg/ml. The in vitro activity of sulopenem was unaffected by non-susceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant (MDR) phenotypes, extended-spectrum β-lactamases (ESBLs), or AmpC β-lactamases.

https://ift.tt/2qwSznO

Characterization of the first OXA-10 natural variant with increased carbapenemase activity [Mechanisms of Resistance]

While carbapenem resistance in Gram-negatives is mainly due to production of efficient carbapenemases, β-lactamases with narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10 type class D β-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study two novel OXA-10 variants were identified as the sole carbapenem hydrolyzing enzymes in meropenem resistant Enterobacteria isolated from hospital waste water and found by NGS to express additional β-lactam resistance mechanisms. The new variants, OXA-655 and OXA-656, were carried by two related IncQ1 broad-host plasmids. Compared to OXA-10 they both harbor a Thr26Met substitution with OXA-655 also baring leucine instead of valine in position 117 of the SAV catalytic motif. Susceptibility profiling of laboratory strains replicating the natural bla_OXA plasmids and of recombinant clones expressing OXA-10 and the novel variants in isogenic background indicated that OXA-655 is a more efficient carbapenemase. The carbapenemase activity of OXA-655 is due to the Val117Leu substitution as shown by steady state kinetic experiments where the k_cat of meropenem hydrolysis was increased 4-fold. In contrast, OXA-655 has no activity towards oxyimino β-lactams while its catalytic efficiency against oxacillin is significantly reduced. Moreover, the Val117Leu variant is more efficient against temocillin and cefoxitin. Molecular dynamics indicated that Val117Leu affects the 117-Leu155 interaction leading to structural shifts in the active site that may alter carbapenem alignment. The evolutionary potential of OXA-10 enzymes towards carbapenem hydrolysis combined with their spread by promiscuous plasmids indicates that they may pose a future clinical threat.

https://ift.tt/2QnsaUK

Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-lactamase Inhibitor, in Combination with Meropenem [Experimental Therapeutics]

Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere™ for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant, Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24 hour AUCs in the thigh infection model. However, for the hollow fiber model, the AUCs were limited to values of 192, 320 or 550 mg*h/L. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by three hour infusion in humans, was the 24 hour free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/L) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 -12 and the magnitude to observe a 1-log kill was 18 – 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow fiber model.

https://ift.tt/2qv3D4A

Emergence of Voriconazole-resistant Aspergillus flavus Isolates in Korean Hospitals: Microsatellite Typing and Resistance Mechanism Analysis [Mechanisms of Resistance]

A recent surveillance study in Korea revealed that 14% (7/50) of Aspergilus flavus clinical isolates had a voriconazole minimum inhibitory concentration ≥ 4 µg/mL. Of seven non-wild-type (non-WT) isolates, six ear isolates from four hospitals shared the same microsatellite genotype. None of non-WT isolates showed cyp51 mutations associated with azole resistance. However, the mean expression levels of efflux pumps (MDR2, atrF, and mfs1) and target (cyp51A) genes exhibited significant differences between non-WT and other isolates.

https://ift.tt/2QheWsu

Rapid Detection of ERG11-Associated Azole Resistance and FKS-Associated Echinocandin Resistance in Candida auris [Mechanisms of Resistance]

Candida auris is an emerging multidrug-resistant yeast that can cause serious invasive infections. Accurate and rapid assessment of antifungal resistance is important for effective patient management. A novel and highly accurate diagnostic platform was established for rapid identification of ERG11 mutations conferring azole resistance and FKS1 mutations associated with echinocandin resistance in C. auris. Using allele-specific molecular beacons and DNA melting curve analysis following asymmetric PCR, a duplex ERG11 assay and a simplex FKS1 HS1 assay were developed to identify the most prominent resistance-associated mutations (Y132F and K143R in ERG11; S639F in FKS1 HS1) within 2 h. Assays were validated by testing a blinded panel of 94 C. auris clinical isolates. The molecular diagnostic results from the assays were 100% concordant with DNA sequencing results. This platform has the potential to overcome the deficiencies of existing in vitro susceptibility-based assays to identify azole and/or echinocandin resistant C. auris, and thus, it holds promise as a surrogate diagnostic method to direct antifungal therapy more effectively.

https://ift.tt/2qv8iDG

Daptomycin resistance and tolerance due to loss-of-function in Staphylococcus aureus dsp1 and asp23 [Mechanisms of Resistance]

Lipopeptide daptomycin is a last line cell membrane-targeting antibiotic to treat multidrug-resistant Staphylococcus aureus. Alarmingly, daptomycin-resistant S. aureus isolates have emerged. The mechanisms underlying daptomycin resistance are diverse, share similarities with resistance to cationic antimicrobial peptides and other lipopeptides, but remain to be fully elucidated. We selected mutants with increased resistance to daptomycin from a library of transposon insertions in ST8 S. aureus HG003. Insertions in conferring increased daptomycin resistance were localized to two genes, one coding for a hypothetical lipoprotein (SAOUHSC_00362, Dsp1), and the other for an alkaline shock protein (SAOUHSC_02441, Asp23). Markerless loss of function mutants were then generated for comparison. All transposon mutants and knockout strains exhibited increased daptomycin resistance compared to wild type and complemented strains. Null and transposon insertion mutants also exhibited increased resistance to cationic antimicrobial peptides. Interestingly, dsp1 also showed increased resistance to vancomycin, a cell wall targeting drug with a different mode of action. Null mutations in both dsp1 and asp23 displayed increased tolerance as reflected by reduced killing to both daptomycin and vancomycin, as well as an increased tolerance to surfactant (Triton X-100). Neither mutant exhibited increased resistance to lysostaphin, a cell wall targeting endopeptidase. These findings identified two genes core to the S. aureus species, that make previously uncharacterized contributions to antimicrobial resistance and tolerance in S. aureus.

https://ift.tt/2QlGwVv

Rutin attenuates vancomycin-induced nephrotoxicity by ameliorating oxidative stress, apoptosis and inflammation in rats [Pharmacology]

Nephrotoxicity is the major limiting factor for the clinical use of vancomycin (VCM) for treatment of serious infections caused by multi-resistant Gram-positive bacteria. This study investigated the renal protective activity of rutin in a rat model of VCM-induced kidney injury in male Wistar rats. VCM intraperitoneally at 200 mg/kg twice daily for 7 successive days resulted in significant elevation of blood urea nitrogen and creatinine as well as urinary N-acetyl-β-D-glucosaminidase. Co-administration of VCM with oral rutin at 150 mg/kg significantly reduced these markers of kidney damage. Rutin also significantly attenuated VCM-induced oxidative stress, inflammatory cell infiltration, apoptosis and decreased IL-1β and TNF-α levels (all P<0.05 or 0.01) in kidneys. Renal recovery from VCM injury was achieved by rutin through increases in Nrf2 and HO-1 and a decrease in NF-B expression. Our results demonstrated a protective effect of rutin on VCM-induced kidney injury through suppression of oxidative stress, apoptosis and down regulation of the inflammatory response. This study highlights a role for oral rutin as an effective intervention to ameliorate nephrotoxicity in patients undergoing VCM therapy.

https://ift.tt/2qxNc7P

Effect of Moxifloxacin plus Pretomanid against Mycobacterium tuberculosis in Log-phase, Acid-phase and Non-Replicating-Persister (NRP)-phase in an in vitro Assay [Experimental Therapeutics]

Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis (M. tuberculosis). However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF towards killing of M. tuberculosis in Logarithmic growth phase (Log-phase), Acid-phase and Non-Replicating Persister phase (NRP-phase). Respective in vitro data generated for H37Rv and 18b strains, was evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco was used to characterize the nature of interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis in Acid-phase (α = 5.56e^–8 with 95% CI = -0.278 to 0.278 and α = 0.408; 95% CI = 0.105 to 0.711), NRP-phase (α = 0.625 with 95% CI =-0.556 to 1.81 and α = 2.92 with 95% CI = 0.215 to 5.63), and Log-phase organisms (α = 1.57e^–6 with 95% CI = -0.930 to 0.930 and α = 1.83e^–6 with 95% CI= -0.929 and 0.929), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.

https://ift.tt/2QiE56g

Genetic correlation of antibiotic susceptibility and resistance genotyping for Mycobacterium abscessus group [Mechanisms of Resistance]

Treatment efficacy of Mycobacterium abscessus infections depends on bacterial genotype. Here the relationship between genotype, as determined using sequence analysis, and antibiotic resistance phenotype was analyzed. The results demonstrate that Mycobacterium abscessus genotype characteristics, including erm(41) sequevar, and mutations of rrl and rrs, are predictive of clarithromycin and amikacin resistance.

https://ift.tt/2qwVEUW

Pharmacodynamics of Minocycline Against Acinetobacter baumannii in a Rat Pneumonia Model [Pharmacology]

Minocycline is currently approved in the US for the treatment of infections caused by susceptible isolates of Acinetobacter spp. The objective of these studies was to determine the minocycline exposures associated with antibacterial effect against A. baumannii in a rat pneumonia model. Rats received minocycline doses as 30 minute intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii, with MICs ranging between 0.03 - 4 mg/L, were studied. In this model, minocycline produced a bacteriostatic effect with a free 24h AUC/MIC of 10 – 16 and produced 1-log of bacterial killing with a free 24h AUC/MIC of 13 – 24. These exposures can be achieved with the current FDA approved dosage regimens of IV minocycline.

https://ift.tt/2QtNIPi

Microbiological Profile of Sarecycline: A Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris [Clinical Therapeutics]

Sarecycline is the first narrow spectrum tetracycline-class antibiotic being developed for acne treatment. In addition to exhibiting activity against important skin/soft tissue pathogens, sarecycline exhibits targeted antibacterial activity against clinical isolates of Cutibacterium acnes. In the current study, sarecycline was 16 to 32-fold less active than broad spectrum tetracyclines—such as minocycline and doxycycline—against aerobic Gram-negative bacilli associated with normal human intestinal microbiome. Also, reduced activity against Escherichia coli was observed in vivo in a murine septicemia model with PD₅₀ values at >40 mg/kg and 5.72 mg/kg for sarecycline and doxycycline, respectively. Sarecycline was also 4 to 8-fold less active against representative anaerobic bacteria that also comprise normal human intestinal microbiome. Additionally, sarecycline displayed a low propensity for resistance development in C. acnes strains, with spontaneous mutation frequencies of 10^–10 at 4 to 8-times the MIC, similar to minocycline and vancomycin. When tested against Gram-positive pathogens with defined tetracycline resistance mechanisms, sarecycline was more active than tetracycline against the tet(K) and tet(M) strains, with MIC ranging from 0.125 to 1.0 ug/mL and 8 ug/mL, respectively, compared with 16 to 64 ug/mL and 64 ug/mL for tetracycline, respectively. However, sarecycline activity in the tet(K) and tet(M) strains were decreased compared to wildtype, which demonstrated MIC ranging from 0.06 to 0.25 ug/mL, though not as pronounced as tetracycline. These findings support sarecycline as a narrow spectrum tetracycline-class antibiotic that is an effective agent for the treatment of acne and further warrants investigation into the potential reduced effects on the gut microbiome.

https://ift.tt/2qv3ez6

Evolution of rifampicin resistance due to substandard drugs in E. coli and M. smegmatis [Mechanisms of Resistance]

Poor-quality medicines undermine the treatment of infectious diseases such as tuberculosis, which requires months of treatment with rifampicin and other drugs. Rifampicin resistance is a critical concern for tuberculosis treatment. While sub-therapeutic doses of medicine are known to select for antibiotic resistance, the effect of drug degradation products on the evolution of resistance is unknown. Here, we demonstrate that substandard drugs that contain degraded active pharmaceutical ingredients select for gene alterations that confer resistance to standard drugs. We generated drug resistant E. coli and M. smegmatis strains by serially culturing bacteria in the presence of the degradation product of rifampicin, rifampicin quinone. We conducted Sanger sequencing to identify mutations in rifampicin resistant populations. Strains resistant to rifampicin quinone developed cross-resistance to the standard drug rifampicin, with some populations showing no growth inhibition at maximum concentrations of rifampicin. Sequencing of the rifampicin quinone treated strains indicated that they acquired mutations in the DNA-dependent RNA polymerase B subunit. These mutations were localized in the rifampicin resistance determining region (RRDR), consistent with other reports of rifampicin resistant E. coli and Mycobacteria. Rifampicin quinone treated mycobacteria also had cross-resistance to other rifamycin class drugs: rifabutin and rifapentine. Our results strongly suggest that substandard drugs not only hinder individual patient outcomes, but also restrict future treatment options by actively contributing to the development of resistance to standard medicines.

https://ift.tt/2QlGtZP

An Unusual Position of Retromandibular Vein in Relation to Facial Nerve: A Rare Case Report

Knowledge of different anatomical structures is very important in parotid surgery to preserve facial nerve. Retromandibular vein is one of the landmarks used to identify facial nerve. So, the relation of the vein with facial nerve is very important in parotid surgery. The typical position of RMV is deep to facial nerve in almost 88% of cases reported in various literatures. Here, we present an unusual position of RMV found during parotid surgery for pleomorphic adenoma.

https://ift.tt/2D4kAdI

American Thyroid Association: Dr. Elizabeth Pearce to Lead 2018-2019 Board of Directors

October 17, 2018—The American Thyroid Association (ATA) announces with pleasure that Elizabeth Pearce, MD, MSc, began a one-year term as president of the Board of Directors at the close of the Annual Meeting, October 7 in Washington, DC. Dr. Pearce has served for the past year as President-Elect.

Newly elected board members are:

Martha Zeiger, MD, President-Elect
Jacqueline Jonklaas, MD, Secretary-Elect
Joshua Klopper, MD, Director
Angela Leung, MD, MSc, Director

Elizabeth Pearce, MD, MSc, Board President

Dr. Pearce is professor of medicine in the Endocrinology, Diabetes, and Nutrition Section at Boston University School of Medicine. She received her undergraduate and medical degrees from Harvard and a masters' degree in epidemiology from the Boston University School of Public Health. She completed her residency in internal medicine at Beth Israel Deaconess Medical Center, and her fellowship in endocrinology at Boston University under the mentorship of Dr. Lewis Braverman. Her research interests include: the sufficiency of dietary iodine in the U.S. and globally; thyroid function in pregnancy; thyroidal effects of exposure to environmental endocrine disruptors; and the cardiovascular effects of subclinical thyroid dysfunction. She has been part of the leadership of the Iodine Global Network (IGN; formerly ICCIDD) since 2009. She is a member of the AACE Thyroid Disease State Network and serves as faculty for the Endocrine Society's annual board review course. She has served on multiple editorial boards, including those for Endocrine Practice, Journal of Clinical Endocrinology and Metabolism, Clinical Endocrinology, European Journal of Clinical Nutrition, and Lancet Diabetes & Endocrinology.

Dr. Pearce has been a member of the American Thyroid Association since 2000. She has chaired both the ATA's Publications and Public Health Committees. She cochaired the 2012 Annual Meeting Program Committee and the 2009 and 2016 Spring Symposia and was a member of the Program Committee for the 2015 International Thyroid Congress. Dr. Pearce has also served as a member of the ATA Finance Committee and the Guidelines Policy Task Force. She was one of the leaders in establishing the ATA's Braverman Lectureship and cochaired the task force for the 2017 Pregnancy Guidelines. She is associate editor for both Thyroid and Clinical Thyroidology journals. She served as a member of the Board of Directors from 2009­ to 2013 and again as president-elect for the past year. Dr. Pearce was the 2011 recipient of the Van Meter Award for outstanding contributions to research on the thyroid gland.

Martha Zeiger, MD, President-Elect

Dr. Martha Zeiger is the S. Hurt Watts professor and chair of surgery at the University of Virginia School of Medicine. Regarded as a world leader in endocrine surgery, she is also an expert in the molecular aspects of thyroid cancer and an experienced academic leader. Her surgical training includes a surgical oncology fellowship, focused on endocrine surgery, at the National Cancer Institute, NIH, prior to joining the faculty at Johns Hopkins University School of Medicine in 1993. There, she built her endocrine surgery practice, established an endocrine surgery fellowship program, and directed an NIH-funded molecular biology laboratory for over 20 years. Today, her research team continues at Johns Hopkins, focusing on the molecular aspects of thyroid cancer.

While at John Hopkins, Dr. Zeiger took the lead as: associate dean for postdoctoral affairs; professor of surgery, oncology, cellular and molecular medicine; associate vice chair of surgery faculty development; and medical director of business development, strategic alliance, and venture technology. While associate dean for postdoctoral affairs, she oversaw 1,200 research fellows in the School of Medicine. She also established a formal program for international postdoctoral fellows.

Dr. Zeiger has held numerous leadership positions in national medical societies: the American Association of Endocrine Surgeons, the American Association of Clinical Endocrinologists, and the ATA. Through AAES, she founded Endocrine Surgery University, an annual course for all endocrine surgery fellows in North America.

She has served on the ATA Board of Directors and many ATA committees, including publications, membership, conflict of interest task force.  She co-chaired the annual meeting program committee in 2011.

Jacqueline Jonklaas, MD, Secretary-Elect

Dr. Jonklaas is currently a professor in the endocrinology division at Georgetown University in Washington, DC, where she completed her medical degree, residency, and fellowship training. As a clinical researcher in the thyroid field, her time is divided between research, clinical activities, and teaching. Dr. Jonklaas's research has focused on the management of hypothyroidism and thyroid cancer. Current research involves examining patient-reported outcomes after radioiodine therapy. Her recent publications address topics such as how to optimize the treatment of hypothyroidism and the outcomes of thyroid cancer patients based on their treatment, age, and gender.

She is the program director of the Georgetown University Clinical Research Unit. She is involved in translational research and the activities of the Georgetown University's Clinical and Translational Science Award. She recently directed the endocrinology courses for Georgetown University Medical School's first- and second-year medical students. She currently teaches in these courses.

She serves on the editorial board of the Journal of Clinical Endocrinology and Metabolism. She is involved in teaching at the national level as a member of the Endocrine Society Self-Assessment Committee.

Dr. Jonklaas has been a member of the ATA since 1999. She has served on several past ATA committees, including the Patient Education and Advocacy Committee, the Surgical Task Force Committee, and the Awards Committee. She was cochair of the ATA Task Force on Thyroid Hormone Replacement, whose guidelines were published in 2014. She previously served on the Board of Directors from 2013–2017, and recently completed a term as the cochair of the Guidelines and Statement Committee. Currently she serves on the Program Committee. She also serves on the editorial board of the ATA journal Thyroid.

Joshua Klopper, MD, Director (Endocrinologist in Community Practice)

Dr. Klopper joined the Colorado Permanente Medical Group (CPMG) of Kaiser Permanente in July 2015 and was appointed chief of the department in April 2016. He was appointed associate clinical professor of medicine in the Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado School of Medicine in October 2015.

He earned a B.S. in psychology in 1995 from Indiana University in Bloomington, Indiana. In 1999 he received his medical degree from the Emory University School of Medicine in Atlanta, Georgia. He completed his internship and residency in internal medicine at the University of Colorado Health Sciences Center in 2002. Dr. Klopper then completed a postdoctoral research fellowship in the Endocrinology Division, prior to starting his endocrinology fellowship at the University of Colorado at Denver Health Sciences Center, completed in 2006.

Dr. Klopper was a full-time faculty member in the Division of Endocrinology at the University of Colorado School of Medicine from 2006–2015, where he specialized in the evaluation and management of thyroid nodules and thyroid cancer, including advanced thyroid cancer. During his academic career, he received grant funding at the local, state, and national level including from the American Cancer Society. He has published original research on the evaluation and management of thyroid nodules and advanced thyroid cancer and has written several book chapters and reviews. Additionally, he participated as an original member of the Thyroid Cancer Care Collaborative development committee. He has served on the Clinical Affairs and Development committees of the ATA as well as on the Endocrine Society Annual Meeting Steering committee. Currently, Dr. Klopper is on the Medical Specialty Peer Review Committee for CPMG and has been codirector of the Endocrine Society's Introductory Hands-On Thyroid Ultrasound Workshop since 2014.

Angela Leung, MD, MSc, Director (Endocrinologist in Academic Practice)

Angela M. Leung, MD, MSc, is an assistant professor of medicine in the Division of Endocrinology, Diabetes, and Metabolism at the UCLA David Geffen School of Medicine and in the VA Greater Los Angeles Healthcare System, and an associate program director of the UCLA/VA endocrinology fellowship program.

She received her undergraduate degree at Occidental College in Los Angeles, her medical degree from the Boston University School of Medicine, and a masters' degree in epidemiology from the Boston University School of Public Health. She completed her internal medicine residency and a clinical and research endocrine fellowship at Boston University Medical Center. Her research areas of interest include iodine deficiency and excess, thyroid toxicant exposures, and maternal-child thyroid health. She is a member of the AACE Thyroid Disease State Network and the editorial board of Endocrine Practice, has participated in the AACE Endocrine Training Support Committee, and was a recipient of the Endocrine Society Early Investigator Award. She has reviewed for several NIH standing and early-career award endocrine study sections; for the U.S. EPA's Biologically-Based Dose Response model to guide perchlorate regulation in U.S. drinking water; and for the EPA's draft toxicity assessments of the thyroid disruptors GenX and perfluorobutane sulfonate. Through the Endocrine Society, she participates in reviewing the effects of thyroid toxicants for the Organization for Economic Cooperation and Development, a global initiative focused on the regulatory policies of endocrine disruptors.

Dr. Leung has been involved in multiple ATA programs and initiatives. She serves on the editorial boards of three ATA journals: Thyroid, Clinical Thyroidology, and Clinical Thyroidology for the Public. She is past Chair of the ATA Public Health Committee (2012–16), during which she led the publication of the ATA's statements on iodine excess and the use of potassium iodide in nuclear accidents; was a member of the Program Committee for the 2016 ATA Annual Meeting; and served as clinical cochair for the 2017 ATA Annual Meeting in Victoria, British Columbia.

The ATA thanks this year's Nominating Committee, chaired by David Steward, and the Secretary-Elect Selection Task Force, chaired by John Morris. We are extremely grateful to all who serve on the Board of Directors. Special thanks go to those who will retire from the Board this year: Regina Castro, MD, Christine Spitzweg, MD, and outgoing Past-President John C. Morris, MD.

###

The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 95th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

• The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
• Annual scientific meetings
• Biennial clinical and research symposia
• Research grant programs for young investigators
• Support of online professional, public, and patient educational programs
• Development of guidelines for clinical management of thyroid disease and thyroid cancer

 The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

The post American Thyroid Association: Dr. Elizabeth Pearce to Lead 2018-2019 Board of Directors appeared first on American Thyroid Association.

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The Mitochondrial Isoform of FASTK Modulates Nonopsonic Phagocytosis of Bacteria by Macrophages via Regulation of Respiratory Complex I [INFECTIOUS DISEASE AND HOST RESPONSE]

Phagocytosis is a pivotal process by which innate immune cells eliminate bacteria. In this study, we explore novel regulatory mechanisms of phagocytosis driven by the mitochondria. Fas-activated serine/threonine kinase (FASTK) is an RNA-binding protein with two isoforms, one localized to the mitochondria (mitoFASTK) and the other isoform to cytosol and nucleus. The mitoFASTK isoform has been reported to be necessary for the biogenesis of the mitochondrial ND6 mRNA, which encodes an essential subunit of mitochondrial respiratory complex I (CI, NADH:ubiquinone oxidoreductase). This study investigates the role and the mechanisms of action of FASTK in phagocytosis. Macrophages from FASTK^/ mice exhibited a marked increase in nonopsonic phagocytosis of bacteria. As expected, CI activity was specifically reduced by almost 50% in those cells. To explore if decreased CI activity could underlie the phagocytic phenotype, we tested the effect of CI inhibition on phagocytosis. Indeed, treatment with CI inhibitor rotenone or short hairpin RNAs against two CI subunits (NDUFS3 and NDUFS4) resulted in a marked increase in nonopsonic phagocytosis of bacteria. Importantly, re-expression of mitoFASTK in FASTK-depleted macrophages was sufficient to rescue the phagocytic phenotype. In addition, we also report that the decrease in CI activity in FASTK^/ macrophages is associated with an increase in phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) and that its inhibition using Compound C reverted the phagocytosis phenotype. Taken together, our results clearly demonstrate for the first time, to our knowledge, that mitoFASTK plays a negative regulatory role on nonopsonic phagocytosis of bacteria in macrophages through its action on CI activity.

https://ift.tt/2QtgaAQ

Leukocyte CD300a Contributes to the Resolution of Murine Allergic Inflammation [INNATE IMMUNITY AND INFLAMMATION]

CD300a is an inhibitory receptor for mast cells and eosinophils in allergic inflammation (AI); however, the spatiotemporal expression of CD300a and its potential roles in the resolution of AI are still to be determined. In this study, employing a mouse model of allergic peritonitis, we demonstrate that CD300a expression on peritoneal cells is regulated from inflammation to resolution. Allergic peritonitis–induced CD300a^–/– mice had a rapid increase in their inflammatory cell infiltrates and tryptase content in the peritoneal cavity compared with wild type, and their resolution process was significantly delayed. CD300a^–/– mice expressed lower levels of ALX/FPR2 receptor on peritoneal cells and had higher levels of LXA₄ in the peritoneal lavage. CD300a activation on mouse bone marrow–derived mast cells regulated ALX/FPR2 expression levels following IgE-mediated activation. Together, these findings indicate a role for CD300a in AI and its resolution, in part via the specialized proresolving mediator LXA₄ and ALX/FPR2 receptor pathway activation.

https://ift.tt/2QmeaKP

Does T Cell Activation Require a Quorum of Lymphocytes? [BRIEF REVIEWS]

Recent reports suggest a quorum of T cells is required to activate T lymphocytes and that this requirement may help explain why scarce lymphocytes, specific for peripheral self-antigen, are rarely activated by Ag. This proposal runs counter to the commonly held framework that the Ag-dependent, but CD4 T lymphocyte–independent, activation of CD8 T lymphocytes, and the activation of CD4 T lymphocytes themselves, can occur when a single CD8 or CD4 T lymphocyte encounters Ag under appropriately dangerous circumstances. We argue that a review of older literature often ignored, as well as of contemporary studies, supports the quorum concept and is difficult to reconcile with the Danger Model.

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MAbTope: A Method for Improved Epitope Mapping [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Abs are very efficient drugs, ~70 of them are already approved for medical use, over 500 are in clinical development, and many more are in preclinical development. One important step in the characterization and protection of a therapeutic Ab is the determination of its cognate epitope. The gold standard is the three-dimensional structure of the Ab/Ag complex by crystallography or nuclear magnetic resonance spectroscopy. However, it remains a tedious task, and its outcome is uncertain. We have developed MAbTope, a docking-based prediction method of the epitope associated with straightforward experimental validation procedures. We show that MAbTope predicts the correct epitope for each of 129 tested examples of Ab/Ag complexes of known structure. We further validated this method through the successful determination, and experimental validation (using human embryonic kidney cells 293), of the epitopes recognized by two therapeutic Abs targeting TNF-α: certolizumab and golimumab.

https://ift.tt/2Qtg4Ju

The Diverse Family of MR1-Restricted T Cells [BRIEF REVIEWS]

Mucosal-associated invariant T (MAIT) cells are characterized by a semi-invariant TCR that recognizes vitamin B metabolite Ags presented by the MHC-related molecule MR1. Their Ag restriction determines a unique developmental lineage, imbuing a tissue-homing, preprimed phenotype with antimicrobial function. A growing body of literature indicates that MR1-restricted T cells are more diverse than the MAIT term implies. Namely, it is increasingly clear that TCR α- and TCR β-chain diversity within the MR1-restricted repertoire provides a potential mechanism of Ag discrimination, and context-dependent functional variation suggests a role for MR1-restricted T cells in diverse physiological settings. In this paper, we summarize MR1-restricted T cell biology, with an emphasis on TCR diversity, Ag discrimination, and functional heterogeneity.

https://ift.tt/2qweyuS

Myoferlin-Mediated Lysosomal Exocytosis Regulates Cytotoxicity by Phagocytes [INNATE IMMUNITY AND INFLAMMATION]

During inflammation, phagocytes release digestive enzymes from lysosomes to degrade harmful cells such as pathogens and tumor cells. However, the molecular mechanisms regulating this process are poorly understood. In this study, we identified myoferlin as a critical regulator of lysosomal exocytosis by mouse phagocytes. Myoferlin is a type II transmembrane protein with seven C2 domains in the cytoplasmic region. It localizes to lysosomes and mediates their fusion with the plasma membrane upon calcium stimulation. Myoferlin promotes the release of lysosomal contents, including hydrolytic enzymes, which increase cytotoxicity. These data demonstrate myoferlin's critical role in lysosomal exocytosis by phagocytes, providing novel insights into the mechanisms of inflammation-related cellular injuries.

https://ift.tt/2Qtg6RC

Cutting Edge: IL-1{alpha} and Not IL-1{beta} Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality [CUTTING EDGE]

Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.

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In This Issue [IN THIS ISSUE]

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Cutting Edge: Quantitative Determination of CD40L Threshold for IL-12 and IL-23 Production from Dendritic Cells [CUTTING EDGE]

Early secretion of IL-12 by mouse dendritic cells (DCs) instructs T cells to make IFN-. However, only activated, but not naive T cells are able to license DCs for IL-12 production. We hypothesized that it might be due to different levels of CD40L expression on the surface of these cells, as CD40 signals are required for IL-12 production. Using quantitative cell-free systems incorporating CD40L in lipid bilayers combined with total internal reflection fluorescence microscopy and flow cytometry, we show that as low as ~200 CD40L molecules/μm² in combination with IL-4 is sufficient to induce IL-12 production by DCs. Remarkably, CD40L alone is adequate to induce IL-23 secretion by DCs. Thus, although activated T cells have somewhat higher levels of CD40L, it is the combination of CD40L and the cytokines they secrete that licenses DCs and influences the effector class of the immune response.

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Differential Activation of Hepatic Invariant NKT Cell Subsets Plays a Key Role in Progression of Nonalcoholic Steatohepatitis [INNATE IMMUNITY AND INFLAMMATION]

Innate immune mechanisms play an important role in inflammatory chronic liver diseases. In this study, we investigated the role of type I or invariant NKT (iNKT) cell subsets in the progression of nonalcoholic steatohepatitis (NASH). We used α-galactosylceramide/CD1d tetramers and clonotypic mAb together with intracytoplasmic cytokine staining to analyze iNKT cells in choline-deficient l-amino acid–defined (CDAA)-induced murine NASH model and in human PBMCs, respectively. Cytokine secretion of hepatic iNKT cells in CDAA-fed C57BL/6 mice altered from predominantly IL-17⁺ to IFN-⁺ and IL-4⁺ during NASH progression along with the downmodulation of TCR and NK1.1 expression. Importantly, steatosis, steatohepatitis, and fibrosis were dependent upon the presence of iNKT cells. Hepatic stellate cell activation and infiltration of neutrophils, Kupffer cells, and CD8⁺ T cells as well as expression of key proinflammatory and fibrogenic genes were significantly blunted in Jα18^–/– mice and in C57BL/6 mice treated with an iNKT-inhibitory RAR- agonist. Gut microbial diversity was significantly impacted in Jα18^–/– and in CDAA diet–fed mice. An increased frequency of CXCR3⁺IFN-⁺T-bet⁺ and IL-17A⁺ iNKT cells was found in PBMC from NASH patients in comparison with nonalcoholic fatty liver patients or healthy controls. Consistent with their in vivo activation, iNKT cells from NASH patients remained hyporesponsive to ex-vivo stimulation with α-galactosylceramide. Accumulation of plasmacytoid dendritic cells in both mice and NASH patients suggest their role in activation of iNKT cells. In summary, our findings indicate that the differential activation of iNKT cells play a key role in mediating diet-induced hepatic steatosis and fibrosis in mice and its potential involvement in NASH progression in humans.

https://ift.tt/2Qme8mb

B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation [IMMUNE REGULATION]

BCR engagement leads to activation and clonal expansion of B cells. The I-A^12% mutant mouse possesses a branch site point mutation in the H2-Aa gene that causes highly reduced I-Aa protein expression. As I-A is a heterodimer made up of I-Aa and I-Ab, reduced I-Aa results not only in reduced surface I-A expression but also in an excess of unpaired I-Ab. B cells that develop in I-A^12% mice proliferated in response to LPS stimulation but failed to do so upon BCR stimulation. Developing I-A^12% B cells were engaged in unfolded protein response due to an excess of unpaired I-Ab. BCR responsiveness was restored by transduced I-Aa expression and by BiP, the unfolded protein response sensor. Reducing the load of unpaired I-Ab also restored BCR responsiveness of I-A^12% B cells. Mef2c protein, a transcription factor required for BCR-stimulated proliferation, was missing in I-A^12% B cells, and that transduced Mef2c expression restored BCR responsiveness. Mef2c protein appeared in I-A^12% B cells after addition of proteasome inhibitors. Mef2c degradation was mediated by Skp2 E3 ligase, and that knockdown of Skp2 mRNA in I-A^12% B cells restored BCR responsiveness. Our results point to a generalized incompatibility between BCR responsiveness and increased Skp2 stability. They also imply the existence of regulatory mechanisms other than Ig gene rearrangement that govern Mef2c turnover in a specific, exquisite, and dynamic fashion.

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RNA Splicing in the Transition from B Cells to Antibody-Secreting Cells: The Influences of ELL2, Small Nuclear RNA, and Endoplasmic Reticulum Stress [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

In the transition from B cells to Ab-secreting cells (ASCs) many genes are induced, such as ELL2, Irf4, Prdm1, Xbp1, whereas other mRNAs do not change in abundance. Nonetheless, using splicing array technology and mouse splenic B cells plus or minus LPS, we found that induced and "uninduced" genes can show large differences in splicing patterns between the cell stages, which could influence ASC development. We found that ~55% of these splicing changes depend on ELL2, a transcription elongation factor that influences expression levels and splicing patterns of ASC signature genes, genes in the cell-cycle and N-glycan biosynthesis and processing pathways, and the secretory versus membrane forms of the IgH mRNA. Some of these changes occur when ELL2 binds directly to the genes encoding those mRNAs, whereas some of the changes are indirect. To attempt to account for the changes that occur in RNA splicing before or without ELL2 induction, we examined the amount of the small nuclear RNA molecules and found that they were significantly decreased within 18 h of LPS stimulation and stayed low until 72 h. Correlating with this, at 18 h after LPS, endoplasmic reticulum stress and Ire1 phosphorylation are induced. Inhibiting the regulated Ire1-dependent mRNA decay with 4u8C correlates with the reduction in small nuclear RNA and changes in the normal splicing patterns at 18 h. Thus, we conclude that the RNA splicing patterns in ASCs are shaped early by endoplasmic reticulum stress and Ire1 phosphorylation and later by ELL2 induction.

https://ift.tt/2Qme5qv

VASP Regulates NK Cell Lytic Granule Convergence [IMMUNE REGULATION]

NK cells eliminate viral-infected and malignant cells through a highly orchestrated series of cytoskeletal rearrangements, resulting in the release of cytolytic granule contents toward the target cell. Central to this process is the convergence of cytolytic granules to a common point, the microtubule-organizing center (MTOC), before delivery to the synapse. In this study, we show that vasodialator-stimulated phosphoprotein (VASP), an actin regulatory protein, localizes to the cytolytic synapse, but surprisingly, shows no impact on conjugate formation or synaptic actin accumulation despite being required for human NK cell–mediated killing. Interestingly, we also find that a pool of VASP copurifies with lytic granules and localizes with lytic granules at the MTOC. Significantly, depletion of VASP decreased lytic granule convergence without impacting MTOC polarization. Using the KHYG-1 cell line in which lytic granules are in a constitutively converged state, we find that either VASP depletion or F-actin destabilization promoted spreading of formerly converged granules. Our results demonstrate a novel requirement for VASP and actin polymerization in maintaining lytic granule convergence during NK cell–mediated killing.

https://ift.tt/2qvFF9G

Potential Use of Genetically Engineered Variable Lymphocyte Receptor B Specific to Avian Influenza Virus H9N2 [NOVEL IMMUNOLOGICAL METHODS]

The variable lymphocyte receptor (VLR) B of jawless vertebrates functions as a secreted Ab of jawed vertebrates and has emerged as an alternative Ab with a single polypeptide chain. After observing an upregulated VLRB response in hagfish immunized with avian influenza virus (AIV) subtype H9N2, we screened AIV H9N2–specific VLRB using a mammalian expression system. To improve the binding avidity of the Ag-specific VLRB to the Ag, we enabled multimerization of the VLRB by conjugating it with C-terminal domain of human C4b-binding protein. To dramatically enhance the expression and secretion of the Ag-specific VLRB, we introduced a glycine–serine linker and the murine Ig leader sequence. The practical use of the Ag-specific VLRB was also demonstrated through various immunoassays, detected by anti-VLRB Ab (11G5). Finally, we found that the Ag-specific VLRB decreased the infectivity of AIV H9N2. Together, our findings suggest that the generated Ag-specific VLRB could be used for various immunoapplications.

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Helminth-Induced Production of TGF-{beta} and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells [IMMUNE REGULATION]

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-β and is associated with TGF-β–dependent in vivo expansion of Foxp3⁺ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-β–dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-β secretion, TGF-β–dependent expansion of Foxp3⁺ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-β. In contrast, TGF-β is not necessary for GATA3 expression by Foxp3⁺ Tregs or by Foxp3^– CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4–mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-β generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

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mTOR- and SGK-Mediated Connexin 43 Expression Participates in Lipopolysaccharide-Stimulated Macrophage Migration through the iNOS/Src/FAK Axis [INFECTIOUS DISEASE AND HOST RESPONSE]

Connexin 43 (Cx43) deficiency was found to increase mortality in a mouse model of bacterial peritonitis, and Cx43 is upregulated in macrophages by LPS treatment. In this study, we characterized a novel signaling pathway for LPS-induced Cx43 expression in RAW264.7 cells and thioglycolate-elicited peritoneal macrophages (TGEMs). LPS alone or LPS-containing conditioned medium (CM) upregulated Cx43. Overexpression or silencing of Cx43 led to the enhancement or inhibition, respectively, of CM-induced TGEM migration. This response involved the inducible NO synthase (iNOS)/focal adhesion kinase (FAK)/Src pathways. Moreover, CM-induced migration was compromised in TGEMs from Cx43^+/– mice compared with TGEMs from Cx43^+/+ littermates. Cx43 was upregulated by a serum/glucocorticoid-regulated kinase 1 (SGK) activator and downregulated, along with inhibition of CM-induced TGEM migration, by knockdown of the SGK gene or blockade of the SGK pathway. LPS-induced SGK activation was abrogated by Torin2, whereas LPS-induced Cx43 was downregulated by both Torin2 and rapamycin. Analysis of the effects of FK506 and methylprednisolone, common immunosuppressive agents following organ transplantation, suggested a link between these immunosuppressive drugs and impaired macrophage migration via the Cx43/iNOS/Src/FAK pathway. In a model of Escherichia coli infectious peritonitis, GSK650349-, an SGK inhibitor, or Torin2-treated mice showed less accumulation of F4/80⁺CD11b⁺ macrophages in the peritoneal cavity, with a delay in the elimination of bacteria. Furthermore, following pretreatment with Gap19, a selective Cx43 hemichannel blocker, the survival of model mice was significantly reduced. Taken together, our study suggested that Cx43 in macrophages was associated with macrophage migration, an important immune process in host defense to infection.

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Androgen and Androgen Receptor as Enhancers of M2 Macrophage Polarization in Allergic Lung Inflammation [IMMUNE REGULATION]

Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Asthmatic women have more M2 macrophages than asthmatic men and androgens have been used as an experimental asthma treatment. In this study, we demonstrate that although androgen (dihydrotestosterone) reconstitution of castrated mice reduced lung inflammation in a mouse model of allergic lung inflammation, it enhanced M2 polarization of AM. This indicates a cell-specific role for androgens. Dihydrotestosterone also enhanced IL-4–stimulated M2 macrophage polarization in vitro. Using mice lacking androgen receptor (AR) in monocytes/macrophages (AR^floxLysMCre), we found that male but not female mice exhibited less eosinophil recruitment and lung inflammation due to impaired M2 polarization. There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment.

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Differentiation of Langerhans Cells from Monocytes and Their Specific Function in Inducing IL-22-Specific Th Cells [INNATE IMMUNITY AND INFLAMMATION]

Human mucosal tissues and skin contain two distinct types of dendritic cell (DC) subsets, epidermal Langerhans cells (LCs) and dermal DCs, which can be distinguished by the expression of C-type lectin receptors, Langerin and DC-SIGN, respectively. Although peripheral blood monocytes differentiate into these distinct subsets, monocyte-derived LCs (moLCs) induced by coculture with GM-CSF, IL-4, and TGF-β1 coexpress both Langerin and DC-SIGN, suggesting that the environmental cues remain unclear. In this study, we show that LC differentiation is TGF-β1 dependent and that cofactors such as IL-4 and TNF-α promote TGF-β1–dependent LC differentiation into Langerin⁺DC-SIGN^– moLCs but continuous exposure to IL-4 blocks differentiation. Steroids such as dexamethasone greatly enhanced TNF-α–induced moLC differentiation and blocked DC-SIGN expression. Consistent with primary LCs, dexamethasone-treated moLCs express CD1a, whereas monocyte-derived DCs (moDCs) express CD1b, CD1c, and CD1d. moDCs but not moLCs produced inflammatory cytokines after stimulation with CD1b and CD1d ligands mycolic acid and α-galactosylceramide, respectively. Strikingly, CD1a triggering with squalene on moLCs but not moDCs induced strong IL-22-producing CD4⁺ helper T cell responses. As IL-22 is an important cytokine in the maintenance of skin homeostasis, these data suggest that CD1a on LCs is involved in maintaining the immune barrier in the skin.

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IL-6 Promotes T Cell Proliferation and Expansion under Inflammatory Conditions in Association with Low-Level ROR{gamma}t Expression [IMMUNE REGULATION]

IL-6 is a critical driver of acute and chronic inflammation and has been reported to act as a T cell survival factor. The influence of IL-6 on T cell homeostasis is not well resolved. We demonstrate that IL-6 signaling drives T cell expansion under inflammatory conditions but not during normal homeostasis. During inflammation, IL-6Rα–deficient T cells are unable to effectively compete with wild type T cells. IL-6 promotes T cell proliferation, and this is associated with low-level expression of the RORt transcription factor. T cells upregulate Rorc mRNA at levels substantially diminished from that seen in Th17 cells. Blockade of RORt through genetic knockout or a small molecule inhibitor leads to T cell expansion defects comparable to those in IL-6Rα–deficient T cells. Our results indicate that IL-6 plays a key role in T cell expansion during inflammation and implicates a role for the transient induction of low-level RORt.

https://ift.tt/2QmecSX

Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells [INNATE IMMUNITY AND INFLAMMATION]

We examined the signaling pathways and cell type–specific responses of IFN regulatory factor (IRF) 5, an immune-regulatory transcription factor. We show that the protein kinases IKKα, IKKβ, IKK, and TANK-binding kinase 1 each confer IRF5 phosphorylation/dimerization, thus extending the family of IRF5 activator kinases. Among primary human immune cell subsets, we found that IRF5 is most abundant in plasmacytoid dendritic cells (pDCs). Flow cytometric cell imaging revealed that IRF5 is specifically activated by endosomal TLR signaling. Comparative analyses revealed that IRF3 is activated in pDCs uniquely through RIG-I–like receptor (RLR) signaling. Transcriptomic analyses of pDCs show that the partitioning of TLR7/IRF5 and RLR/IRF3 pathways confers differential gene expression and immune cytokine production in pDCs, linking IRF5 with immune regulatory and proinflammatory gene expression. Thus, TLR7/IRF5 and RLR–IRF3 partitioning serves to polarize pDC response outcome. Strategies to differentially engage IRF signaling pathways should be considered in the design of immunotherapeutic approaches to modulate or polarize the immune response for specific outcome.

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IL-4 and IL-13 Guide Early Thymic Progenitors To Mature toward Dendritic Cells [IMMUNE SYSTEM DEVELOPMENT]

Recently we reported that IL-4 and IL-13 signaling in murine early thymic progenitors (ETPs) expressing the heteroreceptor (HR) comprising IL-4 receptor α (IL-4Rα) and IL-13 receptor α 1 (IL-13Rα1) activate STAT6 and inhibit ETP maturation potential toward T cells. In this study, we asked whether IL-4 and IL-13 signaling through the HR mobilizes other STAT molecules to shape ETP fate decision. The findings indicate that HR⁺ ETPs undergoing cytokine signaling display increased STAT1, but not STAT3, phosphorylation in addition to STAT6 activation. In parallel, the ETPs had a STAT1-dependent heightened expression of IRF-8, a transcription factor essential for development of CD8α⁺ dendritic cells (DCs). Interestingly, STAT1 phosphorylation and IRF-8 upregulation, which are independent of STAT6 activation, guided ETP maturation toward myeloid cells with a CD8α⁺ DC phenotype. Furthermore, these CD8α⁺ DCs display a thymic resident phenotype, as they did not express SIRPα, a molecule presumed to be involved in cell migration. These findings suggest that IL-4 and IL-13 cytokine-induced HR signaling provides a double-edged sword that simultaneously blocks T cell lineage potential but advances myeloid maturation that could impact T cell selection and central tolerance.

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Pharmacologic inhibition of hypoxia inducible factor (HIF)‐hydroxylases ameliorates allergic contact dermatitis

Allergy, Volume 0, Issue ja, -Not available-.


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Preventive sublingual immunotherapy with House Dust Mite extract modulates epitope diversity in pre‐school children

Allergy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PceH5G

Pulsed‐dye laser as a novel therapeutic approach for post‐filler bruises

Dermatologic Therapy, EarlyView.


https://ift.tt/2D2KOxo

Vestibular assessment in the pediatric population

The Laryngoscope, EarlyView.


https://ift.tt/2PcKtPJ

A farewell from your Editor

Clinical and Experimental Dermatology, Volume 43, Issue 8, Page 867-867, December 2018.


https://ift.tt/2zvPQ25

Issue Information

Clinical and Experimental Dermatology, Volume 43, Issue 8, Page i‐ii, 865-866, December 2018.


https://ift.tt/2SNse1B

Subacute cutaneous lupus erythematosus triggered by an antiviral treatment combination for hepatitis C virus infection

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D5wfsY

The frequency of arthritis in Adamantiades‐Behçet's disease in Greek patients

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PddxXi

HrQoL in hair loss affected patients with Alopecia Areata, Androgenetic Alopecia and Telogen Effluvium: The role of personality traits and psychosocial anxiety

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D5wa8E

Morphological classification of melanoma metastasis with reflectance confocal microscopy

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2P9lAoe

Characteristics of IgG subclasses and complement deposition in BP230‐type bullous pemphigoid

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D5w5lm

Detailed ANA dynamics under adalimumab therapy show no significant correlation to PASI response and MTX co‐treatment: a retrospective study of 98 psoriasis patients

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Pd2qOj

Intravaginal CO2 laser as an emergent treatment of genitourinary syndrome

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2D5vXCo

Rates of Antibiotic Resistance / Sensitivity in Bacterial Cultures of Hidradenitis Suppurativa Patients

Journal of the European Academy of Dermatology and Venereology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PbYeyp

Prediction of Insulin Resistance with Anthropometric and Clinical Laboratory Measures in Nondiabetic Teenagers

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2D5vPmo

Inverse Association Between Antiviral Immunity and Lupus Disease Activity

Viral Immunology, Ahead of Print.


https://ift.tt/2RD94du

Robot-Assisted Reconstruction in Head and Neck Surgical Oncology: The Evolving Role of the Reconstructive Microsurgeon

Transoral robotic surgery (TORS) is gaining more widespread use among head and neck surgical procedures. As experience grows with this technique, so do the indications of when and in which patients it can be used. Already established in the treatment of small oral cavity tumours, it is expanding into larger multi-site resections and resections, such as through-and-through-into-the-neck defects, that will require reconstruction. With robot-assisted surgery advancing, so robot-assisted reconstruction (RAR) is evolving. In this paper, we discuss the evolving role of reconstruction in post-TORS defects as well as the role of RAR in today's practice.
ORL 2018;80:178–185

https://ift.tt/2Dne7eN

Transoral Robotic Surgery Total Laryngectomy

Objective: The aim of our study is to demonstrate our technique for performing transoral robotic surgical total laryngectomy (TORS-TL) with the use of the da Vinci robotic system. Materials and Methods: We provide a comprehensive description of the TORS-TL operative techniques. Two fresh-frozen human cadavers were selected after ethics approval to describe the appropriate step-by-step surgical resection. We adopted a 5-step procedure that was later applied to 2 of our patients. The first patient presented initially with a squamous cell carcinoma (SCC) in the laryngeal glottis area. A lack of clinical response to initial treatment by chemoradiotherapy led to the decision of performing salvage TL surgery. The second patient had a previous history of head and neck SCC (HNSCC); he had no recurrence of his primary tumor but suffered significantly from postoperative breathing and swallowing difficulties due to severe laryngeal incompetence. Results: TORS-TL was successfully performed in all cases. The operative time for the cadavers was approximately 65 and 55 min, respectively. It was significantly longer for the patients, 210 and 235 min, respectively, despite the fact that exactly the same steps were followed throughout all procedures. There were no intra- or postoperative complications or surgical morbidity related to the use of the da Vinci system. Conclusion: TORS-SL for SCC was performed in a safe, reliable, and smooth manner and was shown to be successful in treating our patients. We thus believe that our step-by-step surgical technique for TORS-SL is efficient and reproducible.
ORL 2018;80:171–177

https://ift.tt/2JEUZJP

Hauterkrankungen und Fertilitäts‑/Hormonstörungen

Zusammenfassung

Die männliche Fertilität kann durch eine Vielzahl von Faktoren gestört werden. Neben Umwelt- und Lifestylefaktoren wie Stress, Lärm, Rauchen und Übergewicht können sich auch diverse Erkrankungen negativ auf die Zeugungsfähigkeit und den Hormonhaushalt, insbesondere den Testosteronspiegel, auswirken. Bei vielen Erkrankungen gehen die aktuellen Daten leider noch nicht über Beobachtungen eingeschränkter Fertilität hinaus. In diesem Beitrag sollen v. a. die Erkrankungen aus dem Behandlungsfeld der Dermatologie im Vordergrund stehen. Besonderes Augenmerk wird auf die chronisch entzündlichen und autoimmunen Hauterkrankungen gelegt. Hier zeigen Daten aus den letzten Jahren, dass die überschießende Entzündungsreaktion, die diesen Erkrankungen gemein ist, aller Wahrscheinlichkeit nach auch Einflüsse auf die Fertilität hat und in Interaktion mit der Testosteronkonzentration im Serum steht. Daneben wird auf die Auswirkung von hereditären Hauterkrankungen auf die männliche Fertilität eingegangen, die über Schädigung der Hypothalamus-Hypophysen-Gonaden-Achse direkten Einfluss auf die Zeugungsfähigkeit des Mannes haben können.

https://ift.tt/2JEagKJ

Tagungsbericht vom 13. Kongress der Deutsch-Japanischen Dermatologischen Gesellschaft

https://ift.tt/2Do8uNE

Going Round in Circles with N -> S Acyl Transfer

Macmillan, D; (2017) Going Round in Circles with N -> S Acyl Transfer. Synlett , 28 (13) pp. 1517-1529. 10.1055/s-0036-1588789 . Green open access

https://ift.tt/2RAIYYt

Metabolic rate of major organs and tissues in young adult South Asian women

Shirley, M; Arthurs, O; Seunarine, K; Cole, T; Eaton, SJ; Williams, J; Clark, C; Shirley, M; Arthurs, O; Seunarine, K; Cole, T; Eaton, SJ; Williams, J; Clark, C; Wells, J; - view fewer (2019) Metabolic rate of major organs and tissues in young adult South Asian women. European Journal of Clinical Nutrition (In press).

https://ift.tt/2PESoVt

The future of leadership

Earley, PD; Greany, T; (2017) The future of leadership. In: Earley, PD and Greany, T, (eds.) School Leadership and Education System Reform. Bloomsbury: London, UK.

https://ift.tt/2RzeTbH

How Many Clocks, How Many Times? On the Sensory Basis and Computational Challenges of Circadian Systems

Somers, J; Harper, REF; Albert, JT; (2018) How Many Clocks, How Many Times? On the Sensory Basis and Computational Challenges of Circadian Systems. Frontiers in Behavioral Neuroscience , 12 , Article 211. 10.3389/fnbeh.2018.00211 . Green open access

https://ift.tt/2PIS9ca

Argon plasma improves the tissue integration and angiogenesis of subcutaneous implants by modifying surface chemistry and topography

Griffin, M; Palgrave, R; Butler, P; Kalaskar, DM; Baldovino-Medrano, V; (2018) Argon plasma improves the tissue integration and angiogenesis of subcutaneous implants by modifying surface chemistry and topography. International Journal of Nanomedicine , 13 pp. 6123-6141. 10.2147/IJN.S167637 . Green open access

https://ift.tt/2Rvl1la

'Thresholding ancient religion': a trifold approach

Davies, JP; (2016) 'Thresholding ancient religion': a trifold approach. Presented at: 6th Biennial Threshold Concepts Conference: Thresholds on the Edge, Dalhousie University, Halifax, Nova Scotia, Canada. Green open access

https://ift.tt/2PNHJbn

Limited Open Access in socio-ecological systems: how do communities deal with environmental unpredictability?

Chiaravalloti, R; Dyble, M; (2018) Limited Open Access in socio-ecological systems: how do communities deal with environmental unpredictability? Conservation Letters (In press).

https://ift.tt/2RvljIM

Criteria Weighting for Green Technology Selection as Part of Retrofit Decision Making Process for Existing Non-domestic Buildings

Si, J; Marjanovic-Halburd, L; (2018) Criteria Weighting for Green Technology Selection as Part of Retrofit Decision Making Process for Existing Non-domestic Buildings. Sustainable Cities and Society , 41 pp. 625-638. 10.1016/j.scs.2018.05.051 .

https://ift.tt/2PK0HPO

Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes

Verheyen, A; Diels, A; Reumers, J; Van Hoorde, K; Van den Wyngaert, I; d'Ydewalle, CVO; De Bondt, A; ... Peeters, PJ; + view all Verheyen, A; Diels, A; Reumers, J; Van Hoorde, K; Van den Wyngaert, I; d'Ydewalle, CVO; De Bondt, A; Kuijlaars, J; De Muynck, L; De Hoogt, R; Bretteville, A; Jaensch, S; Buist, A; Cabrera-Socorro, A; Wray, S; Ebneth, A; Roevens, P; Royaux, I; Peeters, PJ; - view fewer (2018) Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes. Stem Cell Reports , 11 (2) pp. 363-379. 10.1016/j.stemcr.2018.06.022 . Green open access

https://ift.tt/2RxUCmQ

Neurogenin3 phosphorylation controls reprogramming efficiency of pancreatic ductal organoids into endocrine cells

Azzarelli, R; Rulands, S; Nestorowa, S; Davies, J; Campinoti, S; Gillotin, S; Bonfanti, P; ... Philpott, A; + view all Azzarelli, R; Rulands, S; Nestorowa, S; Davies, J; Campinoti, S; Gillotin, S; Bonfanti, P; Göttgens, B; Huch, M; Simons, B; Philpott, A; - view fewer (2018) Neurogenin3 phosphorylation controls reprogramming efficiency of pancreatic ductal organoids into endocrine cells. Scientific Reports , 8 , Article 15374. 10.1038/s41598-018-33838-5 . Green open access

https://ift.tt/2PIpyDH

Hidden charge order of interacting Dirac fermions on the honeycomb lattice

Christou, E; Uchoa, B; Kruger, F; (2018) Hidden charge order of interacting Dirac fermions on the honeycomb lattice. Physical Review B , 98 , Article 161120(R). 10.1103/PhysRevB.98.161120 . Green open access

https://ift.tt/2RwnLyO

Heart regeneration in the Mexican cavefish

Yamamoto, Y; Stockdale, W; Lemieux, M; Killen, A; Zhao, J; Hu, Z; Riepsaame, J; ... Mommersteeg, M; + view all Yamamoto, Y; Stockdale, W; Lemieux, M; Killen, A; Zhao, J; Hu, Z; Riepsaame, J; Hamilton, N; Kudoh, T; Riley, P; van Aerle, R; Mommersteeg, M; - view fewer (2018) Heart regeneration in the Mexican cavefish. Cell Reports (In press).

https://ift.tt/2PDf9t2

Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization

Bianchi, M; Turner, HL; Nogal, B; Cottrell, CA; Oyen, D; Pauthner, M; Bastidas, R; ... Hangartner, L; + view all Bianchi, M; Turner, HL; Nogal, B; Cottrell, CA; Oyen, D; Pauthner, M; Bastidas, R; Nedellec, R; McCoy, LE; Wilson, IA; Burton, DR; Ward, AB; Hangartner, L; - view fewer (2018) Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization. Immunity , 49 (2) , Article e8. 10.1016/j.immuni.2018.07.009 . Green open access

https://ift.tt/2RA0qwb

Sustained Effectiveness of Evidence-based Parenting Programmes After the Research Trial Ends

Gray, GR; Totsika, V; Lindsay, G; (2018) Sustained Effectiveness of Evidence-based Parenting Programmes After the Research Trial Ends. Frontiers in Psychology , 9 , Article 2035. 10.3389/fpsyg.2018.02035 . Green open access

https://ift.tt/2PIS6x0

MicroRNAs That Contribute to Coordinating the Immune Response in Drosophila melanogaster

Atilano, ML; Glittenberg, M; Monteiro, A; Copley, RR; Ligoxygakis, P; (2017) MicroRNAs That Contribute to Coordinating the Immune Response in Drosophila melanogaster. Genetics , 207 (1) pp. 163-178. 10.1534/genetics.116.196584 . Green open access

https://ift.tt/2RyQ3Zy

Stable Defects in Semiconductor Nanowires

Sanchez, AM; Gott, JA; Fonseka, HA; Zhang, Y; Liu, H; Beanland, R; (2018) Stable Defects in Semiconductor Nanowires. Nano Letters , 18 (5) pp. 3081-3087. 10.1021/acs.nanolett.8b00620 .

https://ift.tt/2PJDzRy

Young people and transitions in upper secondary education in England: the influence of policy on the ‘local opportunity landscape’

Spours, K; Hodgson, EA; (2017) Young people and transitions in upper secondary education in England: the influence of policy on the 'local opportunity landscape'. In: Youth on the Move. Bloomsbury: London, UK. (In press).

https://ift.tt/2RC44Wt

Ghosts in the Curriculum – Reframing Concepts as Multiplicities

Hardman, MA; (2019) Ghosts in the Curriculum – Reframing Concepts as Multiplicities. Journal of Philosophy of Education

https://ift.tt/2PG9y58

Enhanced Electrochemical Performance of Electrospun V2O5 Fibres Doped With Redox-inactive Metals

Armer, CF; Lübke, M; Johnson, I; McColl, K; Cora, F; Yeoh, JS; Reddy, MV; ... Lowe, A; + view all Armer, CF; Lübke, M; Johnson, I; McColl, K; Cora, F; Yeoh, JS; Reddy, MV; Darr, JA; Li, X; Lowe, A; - view fewer (2018) Enhanced Electrochemical Performance of Electrospun V2O5 Fibres Doped With Redox-inactive Metals. Journal of Solid State Electrochemistry 10.1007/s10008-018-4055-3 . (In press).

https://ift.tt/2RC745g

The production of a physiological puzzle: how Cytisus adami confused and inspired a century’s botanists, gardeners, and evolutionists

Lidwell-Durnin, J; (2018) The production of a physiological puzzle: how Cytisus adami confused and inspired a century's botanists, gardeners, and evolutionists. History and Philosophy of the Life Sciences , 40 , Article 48. 10.1007/s40656-018-0207-0 . Green open access

https://ift.tt/2PEXhxL

Diagnostic performance of temporal artery ultrasound for the diagnosis of giant cell arteritis: a systematic review and meta-analysis of the literature

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Marina Rinagel, Emmanuel Chatelus, Sandrine Jousse-Joulin, Jean Sibilia, Jacques-Eric Gottenberg, François Chasset, Laurent Arnaud

Abstract

Despite major recent advances in the therapeutic management of Giant cell arteritis (GCA), the diagnosis accuracy of temporal artery ultrasound remains controversial in this disease. We performed a systematic review to determine the sensitivity, specificity, and summary positive (LR+) and negative (LR-) likelihood ratios of temporal artery ultrasound for the diagnosis of GCA. For this, we searched EMBASE, MEDLINE and the Cochrane Database of Systematic Reviews without language restriction. Original articles reporting on diagnostic accuracy of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA, were selected. Sensitivity and specificity from each study were used to fit a bivariate diagnosis accuracy model. Of 1280 articles identified, 48 underwent full-text review, and 25 were included. Based on a total of 20 studies, the sensitivity and specificity of hypoechoic halo compared to positive temporal artery biopsy were respectively of 68% (95% CI: 57–78) and 81% (95%CI: 75–86). The summary mean positive and negative likelihood ratios were respectively of 3.64 (95%CI: 2.76–4.73) and 0.40 (0.28–0.52). Taking into account 11 studies reporting on the presence of any abnormal sign on temporal artery ultrasound yielded similar results with largely overlapping 95% confidence interval regions. This study provides the summary estimates of the diagnostic properties of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA. Those parameters allow the calculation of the post-test probability of GCA in a given patient, based on the results of temporal artery ultrasound and will help improving the diagnosis strategy for this common disease.

https://ift.tt/2qutN7B

Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Julie Seguier, Véronique Gelsi-Boyer, Mikael Ebbo, Zeinab Hamidou, Aude Charbonnier, Emmanuelle Bernit, Jean-Marc Durand, Jean-Robert Harlé, Norbert Vey, Nicolas Schleinitz

Abstract

Background

We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis.

Results

From all MDS patients 11% presented with AIMs. These were heterogeneous and the most frequent where polyarthritis (25%) and autoimmune cytopenias (17%). No difference for frequency and type of AIMs was observed for the WHO 2016 MDS subgroups (p = .3). In the case control study WHO classification, karyotype abnormalities, IPSS-R and IPSS were similar in both groups. The overall survival from MDS diagnosis was better in the group with AIMs [10.3 ± 0.6 (IC95% 6.2–12.9) versus 4.8 ± 1.1 years (IC95% 4.2–8.7), p = .04]. The better survival was restricted to MDS with low or intermediate-1 IPSS [11.1 ± 1.5 (IC95% 9.9-NR) versus 8.7 ± 1.3 years (IC95% 4.8–10.3), p = .006]. The better survival was only observed when AIMs diagnosis was timely associated or appeared after MDS diagnosis (p = .04). Factors associated with a better overall survival and survival without AML were steroid dependence [respectively HR = 0.042, p = .003, (IC95% 0.005–0.33) and HR = 0.07, p = .002, (IC95% 0.013–0.39)], a diagnosis of AIMs and MDS timely associated [respectively HR = 0.05, p = .009, (IC95% 0.006–0.478) and HR = 0.1, p = .008, (IC95% 0.018–0.54)] or a diagnosis of AIMs after MDS [respectively HR = 0.024, p = .009, (IC95% 0.001–0.39) and HR = 0.04, p = .008, (IC95% 0.003–0.43)].

Conclusion

Autoimmune and inflammatory diseases associated to MDS are heterogeneous. AIMs diagnosed after or concomitantly to MDS seems associated with a better survival. Prospective studies are necessary to demonstrate that autoimmunity is associated to a better control of the MDS clone.

https://ift.tt/2QiTGCB

Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Roberto Giacomelli, Antonella Afeltra, Alessia Alunno, Elena Bartoloni-Bocci, Onorina Berardicurti, Michele Bombardieri, Alessandra Bortoluzzi, Roberto Caporali, Francesco Caso, Ricard Cervera, Maria Sole Chimenti, Paola Cipriani, Emmanuel Coloma, Fabrizio Conti, Salvatore D'Angelo, Salvatore De Vita, Salvatore Di Bartolomeo, Oliver Distler, Andrea Doria, Eugen Feist

Abstract

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care.

The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

https://ift.tt/2qsHSTd

Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Nicola Luigi Bragazzi, Dennis McGonagle, Samaa Watad, Mohammad Adawi, Naim Mahroum, Giovanni Damiani, Rosalynn Conic, Charlie Bridgewood, Hussein Mahagna, Luca Giacomelli, Roberto Eggenhöffner, Mahmud Mahamid, Paolo Daniele Maria Pigatto, Howard Amital, Abdulla Watad

Abstract

The immunological perturbations associated with systemic lupus erythematosus (SLE) puts many patients at higher risk of infections including pneumococcal pneumonia. However, the uptake and utility of anti-pneumococcal vaccines in SLE patient is both controversial and not completely agreed on. Indeed, several epidemiological studies of anti-pneumococcal vaccine safety and efficacy in SLE have reported short term immunogenicity with elevated anti-pneumococcal antibody titres but inconsistent long term findings with some studies finding poor responses, mainly for long-term immune protection. Moreover, the safety and efficacy of the pneumococcal vaccine in SLE patients remains controversial due to the different types of anti-pneumococcal vaccines, and the heterogeneity of SLE patients. Several reviews addressing anti-pneumococcal vaccination in SLE patients exist, however, to the best of our knowledge, the present is the first systematic review and meta-analysis. To better understand the efficacy and safety of pneumococcal vaccination in SLE, a comprehensive literature search was performed identifying 18 studies in the present systematic reviews and meta-analysis. All studies were designed as longitudinal investigations, two, in particular, were of high quality, being randomized, double-blind trials (RCTs). Four studies had control groups. Sample size ranged from 12 to 204 participants. Vaccine immunogenicity in terms of subjects with protective antibody titers ranged from 36.0% to 97.6%. According to our metanalysis high erythrocyte sedimentation rate (ESR), older earlier SLE, high disease activity, and immunosuppressive therapy were predictors of poor immunogenicity, although belimumab was found to have no significant impact. With regard to safety, no serious adverse events were found, with up to third of cases reporting mild/low-grade and complaints.

In conclusion, due to the high risk of pneumococcal infection in SLE patients and given the safety and, at least partial, effectiveness according our study in such patients, preventive strategies mainly by immunization are required in all age groups and in those needing immunosuppressive therapy, immunization should be given prior the initiation of the treatment.

PROSPERO registration code 103605.

https://ift.tt/2Qp8ZtP

Systemic sclerosis and exposure to heavy metals

Publication date: Available online 4 November 2018

Source: Autoimmunity Reviews

Author(s): Isabelle Marie

Abstract

As a mirror image of the Roman god Janus Bifrons, the environment has a hidden face. To highlight this hidden face of the environment in the field of systemic sclerosis (SSc) will allow to identify responsible agents emerging in the future. To date, there is, in fact, a growing scientific evidence that environmental factors have a crucial impact on both alterations and modulation of epigenetic determinants, resulting in SSc onset and progression. It has been well established that there is a marked correlation between SSc onset and occupational exposure to crystalline silica and organic solvents. More recently, an association between SSc and exposure to heavy metals has further been found, including: antimony, cadmium, lead, mercury. These latter findings interestingly underscore that occupational exposure to heavy metals should be systematically checked in all SSc patients at diagnosis, as the identification of the occupational toxic agent will allow its interruption, which may result in potential improvement of SSc outcome.

https://ift.tt/2Qs0iP2

Autonomic Dysfunction in Early Parkinson's Disease: Results from the United Kingdom Tracking Parkinson's Study

Malek, N; Lawton, MA; Grosset, KA; Bajaj, N; Barker, RA; Burn, DJ; Foltynie, T; ... Grosset, DG; + view all Malek, N; Lawton, MA; Grosset, KA; Bajaj, N; Barker, RA; Burn, DJ; Foltynie, T; Hardy, J; Morris, HR; Williams, NM; Ben-Shlomo, Y; Wood, NW; Grosset, DG; - view fewer (2017) Autonomic Dysfunction in Early Parkinson's Disease: Results from the United Kingdom Tracking Parkinson's Study. Movement Disorders Clinical Practice , 4 (4) pp. 509-516. 10.1002/mdc3.12454 .

https://ift.tt/2zsOtku

Workforce Mobility and Innovation Outcomes

Cornelius, P; Gokpinar, B; Sting, FJ; (2017) Workforce Mobility and Innovation Outcomes. In: (Proceedings) Academy of Management Proceedings. Academy of Management Green open access

https://ift.tt/2SNyGFK

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study

Awdishu, L; Nievergelt, CM; Davenport, A; Murray, PT; Macedo, E; Cerda, J; Chakaravarthi, R; ... Mehta, RL; + view all Awdishu, L; Nievergelt, CM; Davenport, A; Murray, PT; Macedo, E; Cerda, J; Chakaravarthi, R; Ramachandra Rao, SP; Holden, A; Goldstein, SL; Mehta, RL; - view fewer (2016) Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study. Kidney International Reports , 1 (4) pp. 288-298. 10.1016/j.ekir.2016.08.010 . Green open access

https://ift.tt/2zsObtU

An assessment of the role of the falx cerebri and tentorium cerebelli in the cranium of the cat (Felis silvestris catus)

Selles de Lucas, V; Dutel, H; Evans, SE; Groening, F; Sharp, A; Watson, P; Fagan, M; (2018) An assessment of the role of the falx cerebri and tentorium cerebelli in the cranium of the cat (Felis silvestris catus). Journal of the Royal Society Interface , 15 (147) , Article 20180278. 10.1098/rsif.2018.0278 . Green open access

https://ift.tt/2SNgGeT

Co-operation, Leadership and Learning: Fred Hall and the Co-operative College before 1939

Woodin, T; (2017) Co-operation, Leadership and Learning: Fred Hall and the Co-operative College before 1939. In: Hall, R and Winn, J, (eds.) Mass intellectuality and democratic leadership in higher education. (pp. 27-40). Bloomsbury: London, UK.

https://ift.tt/2zsNVeq

Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery—a randomized trial

Danielson, M; Reinsfelt, B; Westerlind, A; Zetterberg, H; Blennow, K; Ricksten, S-E; (2018) Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery—a randomized trial. Journal of Neuroinflammation , 15 (1) , Article 283. 10.1186/s12974-018-1318-y . Green open access

https://ift.tt/2SKWRVg

Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

Sakornsakolpat, P; Prokopenko, D; Lamontagne, M; Reeve, NF; Guyatt, AL; Jackson, VE; Shrine, N; ... International COPD Genetics Consortium, ; + view all Sakornsakolpat, P; Prokopenko, D; Lamontagne, M; Reeve, NF; Guyatt, AL; Jackson, VE; Shrine, N; Qiao, D; Bartz, TM; Kim, DK; Lee, MK; Latourelle, JC; Li, X; Morrow, JD; Obeidat, M; Wyss, AB; Bakke, P; Barr, RG; Beaty, TH; Belinsky, SA; Brusselle, GG; Crapo, JD; de Jong, K; DeMeo, DL; Fingerlin, TE; Gharib, SA; Gulsvik, A; Hall, IP; Hokanson, JE; Kim, WJ; Lomas, DA; London, SJ; Meyers, DA; O'Connor, GT; Rennard, SI; Schwartz, DA; Sliwinski, P; Sparrow, D; Strachan, DP; Tal-Singer, R; Tesfaigzi, Y; Vestbo, J; Vonk, JM; Yim, JJ; Zhou, X; Bossé, Y; Manichaikul, A; Lahousse, L; Silverman, EK; Boezen, HM; Wain, LV; Tobin, MD; Hobbs, BD; Cho, MH; International COPD Genetics Consortium, ; - view fewer (2018) Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations. Nature Genetics (In press).

https://ift.tt/2zv7umn

MOMP from Campylobacter jejuni Is a Trimer of 18-Stranded β-Barrel Monomers with a Ca²⁺ Ion Bound at the Constriction Zone

Ferrara, LGM; Wallat, GD; Moynié, L; Dhanasekar, NN; Aliouane, S; Acosta-Gutiérrez, S; Pagès,, J-M; ... Naismith, JH; + view all Ferrara, LGM; Wallat, GD; Moynié, L; Dhanasekar, NN; Aliouane, S; Acosta-Gutiérrez, S; Pagès,, J-M; Bolla, J-M; Winterhalter, M; Ceccarelli, M; Naismith, JH; - view fewer (2016) MOMP from Campylobacter jejuni Is a Trimer of 18-Stranded β-Barrel Monomers with a Ca²⁺ Ion Bound at the Constriction Zone. Journal of Molecular Biology , 428 (22) pp. 4528-4543. 10.1016/j.jmb.2016.09.021 . Green open access

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Supporting Teachers in Developing Their RiTPACK Through Using Video Cases in an Online Course

Crisan, C; (2018) Supporting Teachers in Developing Their RiTPACK Through Using Video Cases in an Online Course. In: Silverman, J and Hoyos, V, (eds.) Distance Learning, E-Learning and Blended Learning in Mathematics Education. (pp. pp. 165-181). Springer: Cham, Switzerland.

https://ift.tt/2zw6tua

SDN-Actors: Modeling and Verification of SDN Programs

Albert, E; Gómez-Zamalloa, M; Rubio, A; Sammartino, M; Silva, A; (2018) SDN-Actors: Modeling and Verification of SDN Programs. In: Havelund, K and Peleska, J and Roscoe, B and de Vink, E, (eds.) Proceedings of International Symposium on Formal Methods 2018. (pp. pp. 550-567). Springer Nature: Cham, Switzerland.

https://ift.tt/2SNG2Ji

Three-dimensional cell culture: from evolution to revolution

Alhaque, S; Themis, M; Rashidi, H; (2018) Three-dimensional cell culture: from evolution to revolution. Philosophical Transactions B: Biological Sciences , 373 (1750) , Article 20170216. 10.1098/rstb.2017.0216 . Green open access

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UK policy statements on testosterone deficiency

Hackett, G; Kirby, M; Edwards, D; Jones, TH; Rees, J; Muneer, A; (2017) UK policy statements on testosterone deficiency. International Journal of Clinical Practice , 71 (3-4) , Article e12901. 10.1111/ijcp.12901 . Green open access

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Chorea Hyperglycemia Basal Ganglia Syndrome in a 63-Year-Old Male

Chorea hyperglycemia basal ganglia syndrome (CHBG) is a rare condition that manifests within the setting of uncontrolled nonketotic diabetes mellitus. The objective of this case report is to present a patient found to have CHBG and provide a timeline in terms of his workup and subsequent treatment. We also present a commentary on the current understanding of the pathophysiology and treatment and how this was applied to our patient. The case involves a 63-year-old poorly controlled diabetic male who presented with a one-week history of uncontrolled choreiform movements of his left upper extremity. His initial glucose level was 339 mg/dl. HbA1C was 9.9%. CT scan of the head demonstrated an abnormal increased intensity within the right lenticular nucleus and right caudate head most likely due to microcalcifications/mineralization. MRI of the brain demonstrated nonspecific T1 and T2 hyperintense abnormalities in the same area about the right basal ganglia. These findings were consistent with the movement pattern he was displaying and with a diagnosis of CHBG. Gradual control of his blood sugar levels over 48 hours led to resolution of his choreiform symptoms. After better medication adherence as an outpatient, endocrinology follow-up 6 months after discharge found his HbA1C drop to a level of 7.1%. There was no recurrence of his symptoms. CHBG is a rare manifestation of poorly controlled diabetes but is the one that clinicians should be aware of. Early recognition and gradual treatment of elevated blood glucose levels appear to lead to total resolution of choreiform symptoms.

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