Sarcoid uveitis in a patient with multiple neurological lesions: a case report and review of the literature

Neurosarcoidosis is a rare complication, and cranial neuropathy is the most frequent manifestation of this disease. However, few cohesive reports have discussed multiple cranial neuropathies in Japanese patien...

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EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma

Abstract

Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.

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Phylogenomic analysis of extraintestinal pathogenic Escherichia coli ST1193, an emerging multidrug-resistant clonal group [Epidemiology and Surveillance]

The fluoroquinolone-resistant ST1193 clonal group of Escherichia coli, from the ST14 clonal complex (STc14) within phylogenetic group B2, has appeared recently as an important cause of extraintestinal disease in humans. Although this emerging lineage has been characterized to some extent using conventional methods, it has not been studied extensively at the genomic level. Here, we used whole genome sequence analysis to compare 355 ST1193 isolates with 72 isolates from other STs within STc14. Using core genome phylogeny, the ST1193 isolates formed a tightly clustered clade with many genotypic similarities, as compared to ST14 isolates. All ST1193 isolates possessed the same set of three chromosomal mutations conferring fluoroquinolone resistance, carried the fimH64 allele, and were lactose non-fermenting. Analysis revealed an evolutionary progression from K1 to K5 capsular types and acquisition of an F-type virulence plasmid followed by changes in plasmid structure congruent with genome phylogeny. In contrast, the numerous identified antimicrobial resistance genes were distributed incongruently with the underlying phylogeny, suggesting frequent gain or loss of the corresponding resistance gene cassettes despite retention of the presumed carrier plasmids. Pangenome analysis revealed gains and losses of genetic loci occurring during the transition from ST14 to ST1193, and from the K1 to K5 capsular types. Using time-scaled phylogenetic analysis, we estimated that current ST1193 clades first emerged approximately 25 years ago. Overall, ST1193 appears to be a recently emerged clone in which both stepwise and mosaic evolution likely have contributed to epidemiologic success.

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Emergence of Salmonella genomic island 1 variant SGI1-W in a clinical isolate of Providencia stuartii from Egypt [Letters]

Most of the variants of Salmonella genomic island 1 (SGI1) are multidrug resistance (MDR) DNA elements that can be transferred by horizontal gene transfer (HGT) (1)....

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Identification of functional MKK3/6 and MEK1/2homologs from Echinococcus granulosus and investigation of protoscolecidal activity of MAPK signaling pathway inhibitors in vitro and in vivo [Experimental Therapeutics]

Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosus sensu lato. There is an urgent need to develop new drugs for the treatment of this disease. In this study, we identified two new members of MAPK cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from E. granulosus sensu stricto. Both EgMKK1 and EgMKK2 were expressed at the larval stages. As shown by yeast two-hybrid and co-immunoprecipitation analyses, EgMKK1 interacted with the previously identified Egp38 but not with EgERK. EgMKK2, on the other hand, interacted with EgERK. In addition, EgMKK1 and EgMKK2 displayed kinase activity toward the substrate, myelin basic protein. When sorafenib tosylate, PD184352 or U0126-EtOH were added to the medium for in vitro culture of E. granulosus protoscoleces (PSCs) or cysts, an inhibitory and cytolytic effect was observed via suppressed phosphorylation of EgMKKs and EgERK. Non-viability of PSCs treated with sorafenib tosylate or U0126-EtOH, and not with PD184352, was confirmed through bioassay, i.e. inoculation of treated and untreated protoscoleces into mice. In vivo treatment with sorafenib tosylate or U0126-EtOH for 4 weeks of E. granulosus s.s.-infected mice demonstrated a reduction in parasite weight, but the results did not show significant difference. In conclusion, the MAPK cascades were identified as new targets for drug development and E. granulosus was efficiently inhibited by their inhibitors in vitro. The translation of these findings into in vivo efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.

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THE REACTION MECHANISM OF METALLO-{beta}-LACTAMASES IS TUNED BY THE CONFORMATION OF AN ACTIVE SITE MOBILE LOOP [Mechanisms of Resistance]

Carbapenems are "last resort" β-lactam antibiotics, used to treat serious and life-threatening healthcare-associated infections caused by multidrug resistant Gram-negative bacteria. Unfortunately, the worldwide spread of genes coding for carbapenemases among these bacteria is threatening these life-saving drugs. Metallo-β-Lactamases (MβLs) are the largest family of carbapenemases. These are Zn(II)-dependent hydrolases that are active against almost all β-lactam antibiotics. Their catalytic mechanism and the features driving substrate specificity have been matter of intense debate. The active sites of MβLs are flanked by two loops, one of which, loop L3, was shown to adopt different conformations upon substrate or inhibitor binding, and thus being expected to play a role in substrate recognition. However, the sequence heterogeneity observed in this loop in different MβLs has limited the generalizations about its role. Herein we report the engineering of different loops within the scaffold of the clinically relevant carbapenemase NDM-1. We find that the loop sequence dictates its conformation in the unbound form of the enzyme, eliciting different degrees of active site exposure. However, these structural changes have a minor impact on the substrate profile. Instead, we report that the loop conformation determines the protonation rate of key reaction intermediates accumulated during the hydrolysis of different β-lactams in all MβLs. This study demonstrates the existence of a direct link between the conformation of this loop and the mechanistic features of the enzyme, bringing to light an unexplored function of active site loops on MβLs.

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Ceftriaxone absorption enhancement for noninvasive administration as an alternative to injectable solutions [Clinical Therapeutics]

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop non-injectable formulations that can reduce treatment delays in resource limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via non-parenteral administration. This article presents all available ceftriaxone human and animal non-parenteral absorption data, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new rabbit pre-clinical data and discusses the importance of these data for the development of non-injectable formulations for non-invasive treatment. The combined results indicate that rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, Chenodeoxycholate sodium salt (Na-CDC) used as an absorption enhancer at a 125 mg dose together with a 500 mg dose of ceftriaxone, provided 24% rectal absorption of ceftriaxone and Cmax of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for bioavailability of other formulations before human assessment.

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OXA-23, a prevalent mechanism contributing to sulbactam resistance in diverse Acinetobacter baumannii clinical strains [Letters]

Acinetobacter baumannii is one of the most important and threatening pathogens for healthcare-associated infections (HAI), and the treatment for multidrug-resistant A. baumannii (MDRAB) are limited(1, 2)....

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Promising new antifungal treatment targeting chorismate synthase from Paracoccidioides brasiliensis [Chemistry; Biosynthesis]

Paracoccidioidomycosis (PCM), caused by the Paracoccidioides species, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacologic criteria (adsorption-destribution-metabolism-excretion-toxicity) and was, therefore, used in in vitro experiments. Here, we demonstrate that CP1 binds with a dissociation constant of 64±1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity with an IC₅₀ value of 47±5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, the histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with less inflammatory response and is, therefore, a promising candidate and lead structure for the development of drugs useful in PCM treatment.

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Impact of Combination Therapy vs Monotherapy on Mortality from Carbapenem-Resistant Enterobacteriaceae Bacteremia: A Retrospective Observational Study from a Chinese Network [Clinical Therapeutics]

A total of 164 bloodstream infection cases due to carbapenem-resistant Enterobacteriaceae (CRE) in 2013-2017 were retrospectively collected from 36 tertiary hospitals in 19 provinces in China to evaluate outcomes and risk factors for mortality by univariable and multivariable analysis. The most frequent infected species was Klebsiella pneumoniae (69.5%, 114/164). The overall in-hospital and 14-day mortality were 32.9% (54/164) and 31.1% (42/135), respectively. Multivariable analysis revealed that septic shock (adjusted odds ratio [aOR] 6.339, 95% confidence interval [CI] 1.586-25.332, P = 0.009), Pitt bacteremia score (aOR 1.300, 95% CI 1.009-1.676, P = 0.042), and Charlson comorbidity index (aOR 1.392, 95% CI 1.104-1.755, P = 0.005) were independently associated with hazard effect on mortality. Combination therapy, especially tigecycline-based combination therapy had the lowest in-hospital mortality and rates of bacterial clearance. Survival analysis revealed that appropriate therapy was associated with lower 14-day mortality than inappropriate therapy (including non-active therapy, P = 0.022); combination therapy was superior to monotherapy (P = 0.036); metallo-β-lactamase producers resulted in lower 14-day mortality than strains without carbapenemases or KPC-2 producers (P = 0.009); strains with minimum inhibitory concentrations (MICs) > 8 mg/L for meropenem were associated with higher 14-day mortality than that with MICs ≤ 8 mg/L (P = 0.037). Collectively, severity of illness, meropenem MICs > 8 mg/L, carbapenemase-producing types are associated with clinical outcome. Early detection of carbapenemase type and initiating appropriate combination therapy within 96 h might be helpful for improving survival.

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Unveiling the mechanisms of in vitro evolution towards fluconazole resistance of a Candida glabrata clinical isolate: a transcriptomics approach [Mechanisms of Resistance]

Candida glabrata is an emerging fungal pathogen. Its increased prevalence is associated to its ability to rapidly develop antifungal drug resistance, particularly to azoles.

In order to unravel new molecular mechanisms behind azole resistance, a transcriptomics analysis of the evolution of a C. glabrata clinical isolate (044) from azole susceptibility to posaconazole resistance (21^st day), clotrimazole resistance (31^st day) and fluconazole and voriconazole resistance (45^th day), induced by longstanding incubation with fluconazole, was carried out. All the evolved strains were found to accumulate lower concentrations of azole drugs, when compared to the parental strain, while the ergosterol concentration remained mostly constant. However, only the population displaying resistance to all azoles was found to have a GOF mutation in the CgPDR1 gene, leading to the up-regulation of genes encoding multidrug resistance transporters. Intermediate strains, exhibiting posacozole/clotrimazole-resistance and increased fluconazole/voriconazole MIC levels, were found to display alternative ways to resist azole drugs. Particularly, posacozole/clotrimazole-resistance after 31 days was correlated with increased expression of adhesin genes. This finding led us to identify the Epa3 adhesin as a new determinant of azole resistance. Besides being required for biofilm formation, Epa3 expression was found to decrease the intracellular accumulation of azole antifungal drugs.

Altogether, this work provides a glimps of the transcriptomics evolution of a C. glabrata population towards multi-azole resistance, highlighting the multifactorial nature of acquisition of azole resistance, and pointing out a new player in azole resistance.

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FK506 resistance of Saccharomyces cerevisiae Pdr5 and Candida albicans Cdr1 involves mutations in the transmembrane domains and extracellular loops [Mechanisms of Resistance]

The 23-membered-ring macrolide tacrolimus, a commonly used immunosuppressant, also known as FK506, is a broad-spectrum inhibitor and an efflux pump substrate of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters. Little, however, is known about the molecular mechanism by which FK506 inhibits PDR transporter drug efflux. Thus, to obtain further insights we searched for FK506-resistant mutants of Saccharomyces cerevisiae cells overexpressing either the endogenous multidrug efflux pump, Pdr5, or its Candida albicans orthologue, Cdr1. A simple, but powerful, screen gave 69 FK506-resistant mutants with, between them, 72 mutations in either Pdr5 (37) or Cdr1 (35). Twenty mutations were in just three Pdr5/Cdr1 equivalent amino acid positions T550/T540 and T552/S542 of extracellular loop 1 (EL1) and A723/A713 of EL3. Sixty of the 72 mutations were either in the ELs or the extracellular halves of individual transmembrane spans (TMSs), while 11 mutations were found near the centre of individual TMSs, mostly in predicted TMS-TMS contact points, and only two mutations were in the cytosolic nucleotide-binding domains of Pdr5. We propose that FK506 inhibits Pdr5 and Cdr1 drug efflux by slowing transporter opening and/or substrate release, and that FK506-resistance of Pdr5/Cdr1 drug efflux is achieved by modifying critical intramolecular contact points that, when mutated, enable the co-transport of FK506 with other pump substrates. This may also explain why the 35 Cdr1 mutations that caused FK506-insensitivity of fluconazole efflux differed from the 13 Cdr1 mutations that caused FK506-insensitivity of cycloheximide efflux.

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In Response to “Descriptive Survival Study of Nail Melanoma Patients Treated With Functional Surgery vs Distal Amputation”

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The Prognostic Value of Inositol Polyphosphate 5-Phosphatase in Cutaneous Squamous Cell Carcinoma

Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in cancer development and progression. We found that low INPP5A expression is associated with aggressive tumors and poor outcomes. INPP5A is a novel tumor marker that may help in the management of cutaneous squamous cell carcinoma.

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Peroxisome Proliferator-Activated Receptor-{delta} Supports the Metabolic Requirements of Cell Growth in TCR{beta}-Selected Thymocytes and Peripheral CD4+ T Cells [IMMUNE SYSTEM DEVELOPMENT]

During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell cycling and nutrient uptake after TCRβ selection are understood, less is known about the transcriptional programs that regulate the metabolic machinery to promote biomass accumulation during this process. In this article, we report that mice with whole body deficiency in the nuclear receptor peroxisome proliferator-activated receptor– (PPAR^mut) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPAR^mut thymocytes, studies in the OP9–delta-like 4 in vitro system of differentiation revealed that PPAR^mut double-negative 3 cells underwent fewer cell divisions. Naive CD4⁺ T cells from PPAR^mut mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-–deficient thymocytes and peripheral CD4⁺ T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell–restricted deficiency of Ppard starting at the double-positive stage of thymocyte development, although exhibiting defective CD4⁺ T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPAR^mut mice. These findings implicate PPAR- as a regulator of the metabolic program during thymocyte and T cell growth.

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EU Panel Backs Drug for Rare Hereditary Angioedema

Lanadelumab would be the first monoclonal antibody for preventing recurrent attacks of HAE in patients ages 12 years and older.
International Approvals

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Finding a Safe Headphone Volume for Kids

Music—it's wonderful.  These days, we can listen to it anywhere, and it's increasingly mobile.  Many listen using portable players (think iPhones, iPods, Android devices, etc.) and use headphones to do so.

A little background:  Sound is vibration, traveling through the air as sound waves.  These sound waves get funneled by the outer ear to the middle ear, causing the eardrum and ossicles (little ear bones) to vibrate.  The amplified sound wave now travels to the inner ear, where sound is translated (via tiny hair cells, called stereocilia), into a signal and travels via the auditory nerve to the brain.

Measuring Sounds

Sound is measured in decibels (dB).  As a reference, a whisper is 30 dB; normal conversation is around 60 dB.   The louder the sound, the more damage it can cause, and the quicker the damage.  Any sound at or above 85 decibels can cause permanent hearing changes—so we try to protect ears if they may be exposed to constant loud noise. Unfortunately, we're not able to reverse that hearing damage—and repeated long, loud noise exposure can worsen hearing.

Volume Levels

Kids often wear headphones. Many mobile devices can go up to even 100 dB if played at their maximum level.   A number of devices do have some controls to limit volume—which a parent may potentially access.  Lately, some families have also been using volume-limiting headphones, which are supposed to hit a max at 85 dB only.  Unfortunately, not all headphones passed the test: some volume-reduction controls could be bypassed, and other headphones allowed much louder sounds. So….Although volume-reducing headphones may help with protecting kids, parents should definitely still supervise use and monitor volume levels.

A good rule of thumb: Standing at arm's length away, if your child is wearing headphones, he or she should be able to hear you ask a question.

Or, you could use the 80-90 rule:

You can listen at 80%  of volume for 90 minutes/ day.

The higher volume: less time.  Lower volume: more time.

The post Finding a Safe Headphone Volume for Kids appeared first on ChildrensMD.

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Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage-Th17 Cell Axis [TUMOR IMMUNOLOGY]

Intratracheal administration of a novel IL-10 formulation suppressed IL-17–driven, CD4⁺ T cell–dependent tumorigenesis in the LSL-K-ras^G12D murine lung cancer model. Analysis of lung lymphocyte populations demonstrated that antitumor activity of IL-10 was associated with a 5-fold decline in Th17 cell prevalence and a concurrent suppression of inflammatory M1-like macrophage activity. Further phenotypic characterization revealed that macrophages and dendritic cells, but not Th17 cells, expressed IL-10RA on the cell surface with the CD11b⁺F4/80⁺CX3CR1⁺ interstitial macrophages representing the dominant IL-10RA⁺ subset. Consistent with these observations, in vitro stimulation of sorted CD4⁺ T cells with IL-10 did not affect their ability to produce IL-17, whereas similar treatment of purified interstitial macrophages resulted in a dramatic M1 to M2 phenotypic switch. Importantly, preconditioning of macrophages (but not of CD4⁺ T cells) with IL-10 led to potent suppression of CD4⁺ T cell IL-17 production in an in vitro coculture assay, suggesting that IL-10 suppressed Th17 cell activity primarily via its upstream effects on macrophages. In support of this notion, in vivo macrophage depletion resulted in a 5-fold decline in Th17 cell numbers and a concurrent 6-fold reduction in tumor burden. Collectively, these data demonstrate that in the LSL-K-ras^G12D murine lung cancer model, inflammatory macrophage–Th17 cell axis is critical to tumorigenesis and that IL-10 blocks this process primarily via a direct effect on the former. Inhaled IL-10 formulations may be of use in prophylaxis against lung cancer in high-risk patients.

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Proinflammatory Effects of Respiratory Syncytial Virus-Induced Epithelial HMGB1 on Human Innate Immune Cell Activation [INFECTIOUS DISEASE AND HOST RESPONSE]

High mobility group box 1 (HMGB1) is a multifunctional nuclear protein that translocates to the cytoplasm and is subsequently released to the extracellular space during infection and injury. Once released, it acts as a damage-associated molecular pattern and regulates immune and inflammatory responses. Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants and elderly, for which no effective treatment or vaccine is currently available. This study investigated the effects of HMGB1 on cytokine secretion, as well as the involvement of NF-B and TLR4 pathways in RSV-induced HMGB1 release in human airway epithelial cells (AECs) and its proinflammatory effects on several human primary immune cells. Purified HMGB1 was incubated with AECs (A549 and small alveolar epithelial cells) and various immune cells and measured the release of proinflammatory mediators and the activation of NF-B and P38 MAPK. HMGB1 treatment significantly increased the phosphorylation of NF-B and P38 MAPK but did not induce the release of cytokines/chemokines from AECs. However, addition of HMGB1 to immune cells did significantly induce the release of cytokines/chemokines and activated the NF-B and P38 MAPK pathways. We found that activation of NF-B accounted for RSV-induced HMGB1 secretion in AECs in a TLR4-dependent manner. These results indicated that HMGB1 secreted from AECs can facilitate the secretion of proinflammatory mediators from immune cells in a paracrine mechanism, thus promoting the inflammatory response that contributes to RSV pathogenesis. Therefore, blocking the proinflammatory function of HMGB1 may be an effective approach for developing novel therapeutics.

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The Common Key to Class-Switch Recombination and Somatic Hypermutation: Discovery of AID and Its Role in Antibody Gene Diversification [PILLARS OF IMMUNOLOGY]

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Perforin-2 Breaches the Envelope of Phagocytosed Bacteria Allowing Antimicrobial Effectors Access to Intracellular Targets [INFECTIOUS DISEASE AND HOST RESPONSE]

Perforin-2, the product of the MPEG1 gene, limits the spread and dissemination of bacterial pathogens in vivo. It is highly expressed in murine and human phagocytes, and macrophages lacking Perforin-2 are compromised in their ability to kill phagocytosed bacteria. In this study, we used Salmonella enterica serovar Typhimurium as a model intracellular pathogen to elucidate the mechanism of Perforin-2's bactericidal activity. In vitro Perforin-2 was found to facilitate the degradation of Ags contained within the envelope of phagocytosed bacteria. In contrast, degradation of a representative surface Ag was found to be independent of Perforin-2. Consistent with our in vitro results, a protease-sensitive, periplasmic superoxide dismutase (SodCII) contributed to the virulence of S. Typhimurium in Perforin-2 knockout but not wild-type mice. In aggregate, our studies indicate that Perforin-2 breaches the envelope of phagocytosed bacteria, facilitating the delivery of proteases and other antimicrobial effectors to sites within the bacterial cell.

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Pillars Article: Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme. Cell. 2000. 102: 553-563 [PILLARS OF IMMUNOLOGY]

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The Histone Demethylase LSD1 Regulates B Cell Proliferation and Plasmablast Differentiation [SYSTEMS IMMUNOLOGY]

B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and cooperate with the ASC master regulatory transcription factor Blimp-1. The contribution of LSD1 to ASC formation is poorly understood. In this study, we show that LSD1 is necessary for proliferation and differentiation of mouse naive B cells (nB) into plasmablasts (PB). Following LPS inoculation, LSD1-deficient hosts exhibited a 2-fold reduction of splenic PB and serum IgM. LSD1-deficient PB exhibited derepression and superinduction of genes involved in immune system processes; a subset of these being direct Blimp-1 target–repressed genes. Cell cycle genes were globally downregulated without LSD1, which corresponded to a decrease in the proliferative capacity of LSD1-deficient activated B cells. PB lacking LSD1 displayed increased histone H3 lysine 4 monomethylation and chromatin accessibility at nB active enhancers and the binding sites of transcription factors Blimp-1, PU.1, and IRF4 that mapped to LSD1-repressed genes. Together, these data show that LSD1 is required for normal in vivo PB formation, distinguish LSD1 as a transcriptional rheostat and epigenetic modifier of B cell differentiation, and identify LSD1 as a factor responsible for decommissioning nB active enhancers.

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The End of the Binary Era: Revisiting the Spectrum of Tuberculosis [BRIEF REVIEWS]

Human Mycobacterium tuberculosis infection was thought to result in either active symptomatic tuberculosis (TB) or latent asymptomatic infection. It is now clear that this binary classification is insufficient to describe the myriad of infection outcomes. In active TB, symptomatic disease can be mild to severe, with a range of lung and thoracic lymph node involvement or extrapulmonary manifestations. Most humans control the infection and develop latent TB infection, with differential risks of reactivation to active TB. However, some frequently exposed persons appear to be resistant to infection, whereas others may initially become infected yet subsequently eliminate all bacilli. The immunologic factors influencing these varied outcomes are still not clear, but likely involve a range of different responses. In this article, we review the data supporting the spectrum of M. tuberculosis infection in humans as well as data in nonhuman primates that allow dissection of the immune responses leading to the varied outcomes of infection.

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Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus [IMMUNE SYSTEM DEVELOPMENT]

We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r^–/– rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.

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Cutting Edge: Local Proliferation of Uterine Tissue-Resident NK Cells during Decidualization in Mice [CUTTING EDGE]

NK cells accumulate in adult murine and human uteri during decidualization induced physiologically, pathologically, or experimentally. Adoptive transfer studies indicate that uterine NK (uNK) cells arise from circulating progenitors. However, virgin uteri contain few circulating NK1.1⁺CD49a^– conventional NK cells, whereas NK1.1⁺CD49a⁺ tissue-resident NK (trNK) cells are abundant. In this study, we employed a novel, immune-competent NK cell–specific reporter mouse to track accumulation of uNK cells during unmanipulated pregnancies. We identified conventional NK and trNK cells accumulating in both decidua basalis and myometrium. Only trNK cells showed evidence of proliferation. In parabiosis studies using experimentally induced deciduomata, the accumulated uNK cells were proliferating trNK cells; migrating NK cells made no contribution. Together, these data suggest proliferating trNK cells are the source of uNK cells during endometrial decidualization.

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HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface [INFECTIOUS DISEASE AND HOST RESPONSE]

HIV-1 Nef is a multifunctional protein that optimizes virus spread and promotes immune evasion of infected cells to accelerate disease progression in AIDS patients. As one of its activities, Nef reduces the motility of infected CD4⁺ T lymphocytes in confined space. In vivo, Nef restricts T lymphocyte homing to lymph nodes as it reduces the ability for extravasation at the diapedesis step. Effects of Nef on T lymphocyte motility are typically mediated by its ability to reduce actin remodeling. However, interference with diapedesis does not depend on residues in Nef required for inhibition of host cell actin dynamics. In search for an alternative mechanism by which Nef could alter T lymphocyte extravasation, we noted that the viral protein interferes with the polarization of primary human CD4⁺ T lymphocytes upon infection with HIV-1. Expression of Nef alone is sufficient to disrupt T cell polarization, and this effect is conserved among lentiviral Nef proteins. Nef acts by arresting the oscillation of CD4⁺ T cells between polarized and nonpolarized morphologies. Mapping studies identified the binding site for the Nef-associated kinase complex (NAKC) as critical determinant of this Nef activity and a NAKC-binding–deficient Nef variant fails to impair CD4⁺ T lymphocyte extravasation and homing to lymph nodes. These results thus imply the disruption of T lymphocyte polarity via its NAKC binding site as a novel mechanism by which lentiviral Nef proteins alter T lymphocyte migration in vivo.

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A Novel Neutralizing Antibody Specific to the DE Loop of VP1 Can Inhibit EV-D68 Infection in Mice [ANTIGEN RECOGNITION AND RESPONSES]

Enterovirus D68 (EV-D68) belongs to the picornavirus family and was first isolated in CA, USA, in 1962. EV-D68 can cause severe cranial nerve system damage such as flaccid paralysis and acute respiratory diseases such as pneumonia. There are currently no efficient therapeutic methods or effective prophylactics. In this study, we isolated the mAb A6-1 from an EV-D68–infected rhesus macaque (Macaca mulatta) and found that the Ab provided effective protection in EV-D68 intranasally infected suckling mice. We observed that A6-1 bound to the DE loop of EV-D68 VP1 and interfered with the interaction between the EV-D68 virus and α2,6-linked sialic acids of the host cell. The production of A6-1 and its Ab properties present a bridging study for EV-D68 vaccine design and provide a tool for analyzing the process by which Abs can inhibit EV-D68 infection.

https://ift.tt/2NYmiPQ

Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-like Receptors of the Rhesus Macaque [INNATE IMMUNITY AND INFLAMMATION]

The rhesus macaque is an important animal model for AIDS and other infectious diseases; however, studies to address NK cell function in this species have been limited by the lack of defined ligands for killer cell Ig-like receptors (KIRs). To identify ligands for rhesus macaque KIRs, we adopted a novel approach based on a pair of stable cell lines. NFAT-responsive luciferase reporter cell lines expressing the extracellular domains of macaque KIRs fused to the transmembrane and cytoplasmic domains of CD28 and CD3 were incubated with target cells expressing individual MHC class I molecules, and ligand recognition was detected by the MHC class I–dependent upregulation of luciferase. Using this approach, we found that Mamu-KIR3DL01, -KIR3DL06, -KIR3DL08, and -KIR3DSw08 all recognize Mamu-Bw4 molecules but with differing allotype specificity. In contrast, Mamu-KIR3DL05 recognizes Mamu-A and Mamu-A–related molecules, including Mamu-A1*002 and -A3*13, Mamu-B*036, the product of a recombinant Mamu-B allele with α1 and α2 domain sequences derived from a MHC-A gene, and Mamu-AG*01, a nonclassical molecule expressed on placental trophoblasts that originated from an ancestral duplication of a MHC-A gene. These results reveal an expansion of the lineage II KIRs in macaques that recognize Bw4 ligands and identify a nonclassical molecule implicated in placental development and pregnancy as a ligand for Mamu-KIR3DL05. In addition to offering new insights into KIR–MHC class I coevolution, these findings provide an important foundation for investigating the role of NK cells in the rhesus macaque as an animal model for infectious diseases and reproductive biology.

https://ift.tt/2NWVH5B

WDFY4 Is Involved in Symptoms of Systemic Lupus Erythematosus by Modulating B Cell Fate via Noncanonical Autophagy [AUTOIMMUNITY]

Genome-wide association studies have recently illuminated that WDFY4 is genetically associated with systemic lupus erythematosus (SLE) susceptibility in various ethnic groups. Despite strong genetic evidence suggesting a role of WDFY4 in SLE pathogenesis, its functional relevance is largely unknown. In this study, we generated Wdfy4 B lymphocyte conditional knockout (Wdfy4-CKO) mice and found that loss of Wdfy4 led to a decrease in number of total B cells and several subpopulations of B cells in the periphery and a defect in the transition from the pro– to pre–B cell stage in bone marrow. Also, Wdfy4-CKO mice showed impaired Ab responses as compared with controls when challenged with Ag. SLE phenotypes were effectively alleviated in Wdfy4-CKO mice, with significantly diminished pristane-elicited production of autoantibodies and glomerulonephritis. Genetic silencing of WDFY4 in B cells increased lipidation of LC3 independent of p62 and Beclin1, which are essential proteins of canonical autophagy. Our in vivo and in vitro data suggest that WDFY4 facilitates noncanonical autophagic activity. Our findings provide a novel functional link underlying the mechanism of SLE in which WDFY4 influences B cell fate via noncanonical autophagy.

https://ift.tt/2OFnfll

EF Hand Domain Family Member D2 Is Required for T Cell Cytotoxicity [TUMOR IMMUNOLOGY]

Programmed cell death 1 (PD-1) is a major coinhibitory receptor and a member of the immunological synapse (IS). To uncover proteins that regulate PD-1 recruitment to the IS, we searched for cytoskeleton-related proteins that also interact with PD-1 using affinity purification mass spectrometry. Among these proteins, EF hand domain family member D2 (EFHD2), a calcium binding adaptor protein, was functionally and mechanistically analyzed for its contribution to PD-1 signaling. EFHD2 was required for PD-1 to inhibit cytokine secretion, proliferation, and adhesion of human T cells. Interestingly, EFHD2 was also required for human T cell–mediated cytotoxicity and for mounting an antitumor immune response in a syngeneic murine tumor model. Mechanistically, EFHD2 contributed to IS stability, lytic vesicles trafficking, and granzyme B secretion. Altogether, EFHD2 is an important regulator of T cell cytotoxicity and further studies should evaluate its role in T cell–mediated inflammation.

https://ift.tt/2NYmcrs

IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells [AUTOIMMUNITY]

Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.

https://ift.tt/2NUtbBC

High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia [CLINICAL AND HUMAN IMMUNOLOGY]

Killer-cell Ig-like receptor (KIR) genes are inherited as haplotypes. They are expressed by NK cells and linked to outcomes of infectious diseases and pregnancy in humans. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. In this article, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected in both peripheral blood and uterine NK cells. Using this new method, we demonstrate that both blood and uterine NK cells codominantly express KIR2DL1A and KIR2DL1B allotypes but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that KIR2DL1A, not KIR2DL1B, associates with increased disease risk. This method will facilitate our understanding of how individual KIR2DL1 allelic variants affect NK cell function and contribute to disease risk.

https://ift.tt/2OKWZpt

Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae [IMMUNOTHERAPY AND VACCINES]

Novel therapeutics against multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococcal lipooligosaccharide often expresses lacto-N-neotetraose (LNnT), which becomes sialylated in vivo, enhancing factor H (FH) binding and contributing to the organism's ability to resist killing by complement. We previously showed that FH domains 18–20 (with a D-to-G mutation at position 1119 in domain 19) fused to Fc (FHD1119G/Fc) displayed complement-dependent bactericidal activity in vitro and attenuated gonococcal vaginal colonization of mice. Gonococcal lipooligosaccharide phase variation can result in loss of LNnT expression. Loss of sialylated LNnT, although associated with a considerable fitness cost, could decrease efficacy of FHD1119G/Fc. Similar to N. meningitidis, gonococci also bind FH domains 6 and 7 through Neisserial surface protein A (NspA). In this study, we show that a fusion protein comprising FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/Fc) bound to 15 wild-type antimicrobial resistant isolates of N. gonorrhoeae and to each of six lgtA gonococcal deletion mutants. FH6,7/Fc mediated complement-dependent killing of 8 of the 15 wild-type gonococcal isolates and effectively reduced the duration and burden of vaginal colonization of three gonococcal strains tested in wild-type mice, including two strains that resisted complement-dependent killing but on which FH6,7/Fc enhanced C3 deposition. FH/Fc lost efficacy when Fc was mutated to abrogate C1q binding and in C1q^–/– mice, highlighting the requirement of the classical pathway for its activity. Targeting gonococci with FH6,7/Fc provides an additional immunotherapeutic approach against multidrug-resistant gonorrhea.

https://ift.tt/2ODVBFf

Augmentation of Human Monocyte Responses to Lipopolysaccharide by the Protein S and Mer/Tyro3 Receptor Tyrosine Kinase Axis [IMMUNE REGULATION]

Resolution of the inflammatory response requires coordinated regulation of pro- and anti-inflammatory mediator production, together with clearance of recruited inflammatory cells. Many different receptors have been implicated in phagocytosis of apoptotic cells (efferocytosis), including Mer, a receptor tyrosine kinase that can mediate recognition and subsequent internalization of apoptotic cells. In this manuscript, we examine the expression and function of the Tyro3/Axl/Mer (TAM) family of receptors by human monocytes. We demonstrate that the Mer ligand, protein S, binds to the surface of viable monocytes via phosphatidylserine-dependent and -independent mechanisms. Importantly, we have identified a novel role for receptor tyrosine kinase signaling in the augmentation of monocyte cytokine release in response to LPS. We propose that low-level phosphatidylserine exposure on the plasma membrane of viable monocytes allows protein S binding that leads to TAM-dependent augmentation of proinflammatory cytokine production. Our findings identify a potentially important role for TAM-mediated signaling during the initiation phase of inflammation.

https://ift.tt/2NYlHO6

Short Leucine-Rich Proteoglycans Modulate Complement Activity and Increase Killing of the Respiratory Pathogen Moraxella catarrhalis [INFECTIOUS DISEASE AND HOST RESPONSE]

The respiratory pathogen Moraxella catarrhalis is a human-specific commensal that frequently causes acute otitis media in children and stimulates acute exacerbations in chronic obstructive pulmonary disease patients. The exact molecular mechanisms defining host–pathogen interactions promoting pathogenesis are not clearly understood. Limited knowledge hampers vaccine and immunotherapeutic development required to treat this emerging pathogen. In this study, we reveal in detail a novel antibacterial role displayed by short leucine-rich proteoglycans (SLRPs) in concert with complement. We show that fibromodulin (FMOD), osteoadherin (OSAD), and biglycan (BGN) but not decorin (DCN) enhance serum killing of M. catarrhalis. Our results suggest that M. catarrhalis binding to SLRPs is a conserved feature, as the overwhelming majority of clinical and laboratory strains bound all four SLRPs. Furthermore, we resolve the binding mechanism responsible for this interaction and highlight the role of the ubiquitous surface protein (Usp) A2/A2H in mediating binding to host SLRPs. A conserved immune evasive strategy used by M. catarrhalis and other pathogens is the surface acquisition of host complement inhibitors such as C4b-binding protein (C4BP). We observed that FMOD, OSAD, and BGN competitively inhibit binding of C4BP to the surface of M. catarrhalis, resulting in increased C3b/iC3b deposition, membrane attack complex (MAC) formation, and subsequently decreased bacterial survival. Furthermore, both OSAD and BGN promote enhanced neutrophil killing in vitro, both in a complement-dependent and independent fashion. In summary, our results illustrate that SLRPs, FMOD, OSAD, and BGN portray complement-modulating activity enhancing M. catarrhalis killing, defining a new antibacterial role supplied by SLRPs.

https://ift.tt/2OFvbmp

STAT6 and Furin Are Successive Triggers for the Production of TGF-{beta} by T Cells [IMMUNE REGULATION]

Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell–inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β–dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.

https://ift.tt/2OGvqxr

Growth Hormone Deficiency and Nonalcoholic Fatty Liver Disease with Insights from Humans and Animals: Pediatric Implications

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2ODMeW1

Plasma Growth Arrest-Specific 6 Protein and Genetic Variations in the GAS6 Gene in Patients with Metabolic Syndrome

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2ED6GBN

What is Acute Flaccid Myelitis?

Acute Flaccid Myelitis or AFM is a very rare disorder that affects the spinal cord. Though the disorder is uncommon, taking preventative measures and understanding the common symptoms can help you keep your children healthy. Dr. Christina Gurnett discusses everything parents need to know about AFM.

The post What is Acute Flaccid Myelitis? appeared first on ChildrensMD.

https://ift.tt/2q43ZPp

Surfactant protein D alleviates eosinophil‐mediated airway inflammation and remodeling in patients with aspirin‐exacerbated respiratory disease

Allergy, EarlyView.


https://ift.tt/2Sa5gkM

Issue Information

Experimental Dermatology, Volume 27, Issue 11, Page 1192-1192, November 2018.


https://ift.tt/2EDvjOT

Clinical Snippets

Experimental Dermatology, Volume 27, Issue 11, Page i-i, November 2018.


https://ift.tt/2PhW1R0

Update zu HPV-assoziierten Kopf-Hals-Karzinomen – Highlights der ASCO-Jahrestagung 2018

Zusammenfassung

Steigende Inzidenzraten mit dem humanen Papillomvirus (HPV‑)assoziierter Oropharynxkarzinome (OPC) und die deutlich bessere Prognose solcher Tumoren bringen diese Tumorentität in den wissenschaftlichen Fokus. Auf dem diesjährigen Kongress der American Society of Clinical Oncology (ASCO) wurden 291 Arbeiten mit dem Schlüsselwort „HPV" präsentiert, von denen die Mehrheit den Kopf-Hals-Tumoren gewidmet war. Deintensivierte Behandlungen werden aufgrund der erheblichen Spättoxizität konventioneller Therapieregime zunehmend diskutiert, allerdings wurden Ergebnisse von großen prospektiven Phase-III-Studien nicht präsentiert. Jedoch wurden retrospektive Daten zum neuen TNM-Staging (Downstaging der meisten HPV-assoziierten Patienten) und zu weiteren Risikostratifizierungen gezeigt. Auch der alleinige immunhistologische Nachweis von p16 wurde diskutiert. Viele Arbeitsgruppen haben sich auch mit dem Thema der HPV-Assoziation und der prognostischen Relevanz nicht nur bei OPC, sondern auch bei Mundhöhlen‑, Larynx- und Hypopharynxkarzinomen beschäftigt. Neue prognostische Marker wie die Methylierungssignatur scheinen darüber hinaus vielversprechend. Weitere interessante therapeutische Aspekte sind die gleichwertigen Überlebensraten der alleinigen Chirurgie beim HPV-assoziierten OPC im Stadium I. Ein möglicher negativer Effekt auf das Überleben mit HPV-assoziierten OPC im Stadium III mit einer Cisplatindosis von ≤200 mg/m² wurde diskutiert. Insgesamt werden die Ergebnisse der Deeskalationsstudien dringend erwartet, um Patienten mit HPV-assoziierten Kopf-Hals-Tumoren möglichst präzise und schonende Therapien zukommen zu lassen und so langfristig eine gute Lebensqualität zu sichern.

https://ift.tt/2EEFItw

Bismuth‐containing quadruple therapy versus concomitant quadruple therapy as first‐line treatment for Helicobacter Pylori infection in an area of high resistance to clarithromycin: A prospective, cross‐sectional, comparative, open trial

Helicobacter, EarlyView.


https://ift.tt/2Ao4UAn

Condom catheter induced penile skin erosion

Abstract

Condom catheters are known to be discrete, reliable, comfortable and very easy to use which makes them preferable to bladder catheter (Saint et al. (Urinary catheters: What type do men and their nursesprefer? J Am Geriatr SOC 1999;47:1453–1457); Hirsh et al. (Do condom catheter collecting systems cause urinary tract infection? J Am Med Assoc 1979;2:0–1)). Condom catheters are widely used in the management of male urinary incontinence, bedridden patient and geriatric population. They are considered to be safe, however, they are associated with complications in care of an incorrect use. In our hospital setup a 73-year-old male bedridden patient attended the surgical opd with complain of penile skin erosion following condom catheter application for 4 days for which dressing was done to remove the slough for 2 days then circumcision was done. Henceforth, although a less known complications are associated with the condom catheter but if not attended promptly can lead to a grave condition like penile gangrene, necrosis, death (Özkan et al. (Penile strangulation and necrosis due to condom catheter. Int Wound J 2015;12:248–9. doi: 10.1111/iwj.12102. Epub 2013 Jun 11); Johnson (The condom catheter: urinary tract infection and other complications. South Med J 1983;76:579–82)).

https://ift.tt/2PKf0kh

Follicular carcinoma arising in a large ectopic lingual thyroid: a case report and review of literature

Abstract

Ectopic lingual thyroid has been described, however, follicular carcinoma arising within it is an extremely rare entity with only 40 cases reported in the literature. Lingual thyroid carcinoma is undistinguishable from benign enlargement of lingual thyroid, the later should also be differentiated from many oropharyngeal pathologies including but not limited to thyroglossal duct cyst, lipoma, dermoid cyst and salivary gland tumors. Ectopic lingual nature of thyroid tissue can be diagnosed with scintigraphy scan; however, malignant transformation confirms just after pathological examination. Surgical excision remains the best therapy with transoral approach being the most appropriate and favorable among others due to its cosmetic results and lower incidence of infection. Herein, we report a case of an adult female who was diagnosed to have follicular carcinoma of an ectopic lingual thyroid tissue mass. Concerning the size of the mass it was the largest of all reported cases of ectopic thyroid gland.

https://ift.tt/2CZF8oz

A rare case of paratesticular leiomyosarcoma

Abstract

Paratesticular leiomyosarcoma is a rare tumour. It is seldom diagnosed pre-operatively and subsequent secondary resection is often required. Current treatment consensus comprises inguinal radical orchidectomy with high ligation of the spermatic cord. We present a case of a 74-year-old male with a 3-year history of a painless right-sided scrotal mass which following excision was found to be an epididymal leiomyosarcoma. A review of literature and treatment is presented in this article.

https://ift.tt/2PMpeAx

Assessing the effect of multibracket appliance treatment on tooth color by using electronic measurement

Abstract

Background

The purpose of this study was to investigate how tooth color is affected by multibracket appliance (MBA) treatment.

Methods

The color of teeth #14 to #24 of 15 patients with MBA was measured on body and gingival tooth segments using the spectrophotometer Shade Inspector™. Colors of both segments were recorded before start of MBA treatment (baseline T₀), end of MBA treatment (T₁; 2 years ±0.3), and 3 months after T₁ (T₂). A 2D color system and a 3D system served as reference systems.

Multilevel models were used to analyze color change within segments and to compare the difference in color change between segments (treatment effect).

Results

2D system. Changes within tooth segments from T₀ to T₂ were at worst 2.0 units (ΔE in the gingival segment), which is less than the threshold of 2.7 units for a clinically meaningful difference. Confidence intervals for the treatment effect indicated no clinically important differences in color change between body and gingival segments.

3D system. Changes within tooth segments from T₀ to T₂ were at worst 2.3 units (ΔE in the body segment), which is less than the threshold of 2.7 units for a clinically meaningful difference. Confidence intervals for the treatment effect indicated no clinically important differences in color change between body and gingival segments.

Thus, MBA treatment did not lead to clinically relevant changes in tooth color.

Conclusion

Within the limitation of this study the MBA treatment can be seen as a safe method with respect to tooth color.

https://ift.tt/2ytJwIt

Pre-Operative Pregabalin for Post-Operative Pain in Head and Neck Cancer Surgery

Conditions:   Head and Neck Cancer;   Pain, Postoperative
Interventions:   Drug: Pregabalin 150mg;   Other: Placebo
Sponsor:   Augusta University
Not yet recruiting

https://ift.tt/2NVWDak

Study on Association Between Treatment of Allergic Rhinitis and Cognitive Ability in Children

Condition:   Allergic Rhinitis
Intervention:   Other: No intervention
Sponsor:   Chinese University of Hong Kong
Recruiting

https://ift.tt/2q7Lslf

Robotic-assisted Esophagectomy vs. Video-Assisted Thoracoscopic Esophagectomy(REVATE) Trial

Condition:   Esophageal Squamous Cell Carcinoma
Interventions:   Procedure: Robot esophagectomy (RE);   Procedure: Video-assisted thoracoscopic esophagectomy (VATE)
Sponsor:   Chang Gung Memorial Hospital
Not yet recruiting

https://ift.tt/2NVJ8HD

Stellate Ganglion Block in Head and Neck Cancer Surgery

Conditions:   Head and Neck Cancer;   Pain, Postoperative
Intervention:   Procedure: Stellate ganglion block
Sponsor:   Augusta University
Not yet recruiting

https://ift.tt/2q3LUB1

Optimization of virtual water flow via grain trade within China

Wang, Z; Zhang, L; Zhang, Q; Wei, YM; Wang, JW; Ding, X; Mi, Z; (2019) Optimization of virtual water flow via grain trade within China. Ecological Indicators , 97 pp. 25-34. 10.1016/j.ecolind.2018.09.053 .

https://ift.tt/2R6Hh4G

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors

Young, MD; Mitchell, TJ; Braga, FAV; Tran, MGB; Stewart, BJ; Ferdinand, JR; Collord, G; ... Behjati, S; + view all Young, MD; Mitchell, TJ; Braga, FAV; Tran, MGB; Stewart, BJ; Ferdinand, JR; Collord, G; Botting, RA; Popescu, D-M; Loudon, KW; Vento-Tormo, R; Stephenson, E; Cagan, A; Farndon, SJ; Velasco-Herrera, MDC; Guzzo, C; Richoz, N; Mamanova, L; Aho, T; Armitage, JN; Riddick, ACP; Mushtaq, I; Farrell, S; Rampling, D; Nicholson, J; Filby, A; Burge, J; Lisgo, S; Maxwell, PH; Lindsay, S; Warren, AY; Stewart, GD; Sebire, N; Coleman, N; Haniffa, M; Teichmann, SA; Clatworthy, M; Behjati, S; - view fewer (2018) Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science , 361 (6402) pp. 594-599. 10.1126/science.aat1699 . Green open access

https://ift.tt/2AmtZM8

On the Impact of Fixed Point Hardware for Optical Fiber Nonlinearity Compensation Algorithms

Sherborne, T; Banks, B; Semrau, D; Killey, RI; Bayvel, P; Lavery, D; (2018) On the Impact of Fixed Point Hardware for Optical Fiber Nonlinearity Compensation Algorithms. Journal of Lightwave Technology , 36 (20) pp. 5016-5022. 10.1109/JLT.2018.2868115 . Green open access

https://ift.tt/2R6H55s

Spatio-temporal simulation of energy consumption in China's provinces based on satellite night-time light data

Xiao, H; Ma, Z; Mi, Z; Kelsey, J; Zheng, J; Yin, W; Yan, M; (2018) Spatio-temporal simulation of energy consumption in China's provinces based on satellite night-time light data. Applied Energy , 231 pp. 1070-1078. 10.1016/j.apenergy.2018.09.200 .

https://ift.tt/2AnjurY

Anhydrous proton conducting poly(vinyl alcohol) (PVA)/ poly(2-acrylamido-2-methylpropane sulfonic acid) (PAMPS)/1,2,4-triazole composite membrane

Erkartal, M; Aslan, A; Erkilic, U; Dadi, S; Yazaydin, O; Usta, H; Sen, U; (2016) Anhydrous proton conducting poly(vinyl alcohol) (PVA)/ poly(2-acrylamido-2-methylpropane sulfonic acid) (PAMPS)/1,2,4-triazole composite membrane. International Journal of Hydrogen Energy , 41 (26) pp. 11321-11330. 10.1016/j.ijhydene.2016.04.152 . Green open access

https://ift.tt/2R29g5A

Complications of biliary-enteric anastomoses

Kadaba, RS; Bowers, KA; Khorsandi, S; Hutchins, RR; Abraham, AT; Sarker, S-J; Bhattacharya, S; Kadaba, RS; Bowers, KA; Khorsandi, S; Hutchins, RR; Abraham, AT; Sarker, S-J; Bhattacharya, S; Kocher, HM; - view fewer (2017) Complications of biliary-enteric anastomoses. Annals of the Royal College of Surgeons of England , 99 (3) pp. 210-215. 10.1308/rcsann.2016.0293 . Green open access

https://ift.tt/2AoAwpD

Phase Shifters vs Switches: An Energy Efficiency Perspective on Hybrid Beamforming

Payami, S; Balasubramanya, NM; Masouros, C; Sellathurai, M; (2018) Phase Shifters vs Switches: An Energy Efficiency Perspective on Hybrid Beamforming. IEEE Wireless Communications Letters 10.1109/LWC.2018.2846221 . (In press). Green open access

https://ift.tt/2R6GOzs

A psychology of the in between?

Baggs, E; (2018) A psychology of the in between? Constructivist Foundations , 13 (3) pp. 395-397.

https://ift.tt/2AlXT2R

Introduction to the Issue on Hybrid Analog-Digital Signal Processing for Hardware-Efficient Large-Scale Antenna Arrays (Part I)

Masouros, C; Sellathurai, M; Papadias, CB; Dai, L; Yu, W; Sizer, T; (2018) Introduction to the Issue on Hybrid Analog-Digital Signal Processing for Hardware-Efficient Large-Scale Antenna Arrays (Part I). IEEE Journal of Selected Topics in Signal Processing , 12 (2) pp. 253-255. 10.1109/JSTSP.2018.2831009 . Green open access

https://ift.tt/2R6GHE2

Large-scale mammography CAD with deformable conv-nets

Morrell, S; Wojna, Z; Khoo, CS; Ourselin, S; Iglesias, JE; (2018) Large-scale mammography CAD with deformable conv-nets. In: Stoyanov, D and Taylor, Z and Kainz, B and Maicas, G and Beichel, RR and Martel, A and Maier-Hein, L and Bhatia, K and Vercauteren, T and Oktay, O and Carneiro, G and Bradley, AP and Nascimento, J and Min, H and Brown, MS and Jacobs, C and Lassen-Schmidt, B and Mori, K and Petersen, J and San José Estépar, R and Schmidt-Richberg, A and Veiga, C, (eds.) Image Analysis for Moving Organ, Breast, and Thoracic Images: Third International Workshop, RAMBO 2018, Fourth International Workshop, BIA 2018, and First International Workshop, TIA 2018, Held in Conjunction with MICCAI 2018, Granada, Spain, Proceedings. (pp. pp. 64-72). Springer: Cham, Switzerland.

https://ift.tt/2AmKdVB

Multiple roles of integrin-α3 at the neuromuscular junction

Ross, JA; Webster, RG; Lechertier, T; Reynolds, LE; Turmaine, M; Bencze, M; Jamshidi, Y; ... Conti, FJ; + view all Ross, JA; Webster, RG; Lechertier, T; Reynolds, LE; Turmaine, M; Bencze, M; Jamshidi, Y; Cetin, H; Muntoni, F; Beeson, D; Hodilvala-Dilke, K; Conti, FJ; - view fewer (2017) Multiple roles of integrin-α3 at the neuromuscular junction. Journal of Cell Science , 130 (10) pp. 1772-1784. 10.1242/jcs.201103 . Green open access

https://ift.tt/2R28Ufg

The Independent Audio Describer is Dead: Long Live Audio Description!

Fryer, LE; (2018) The Independent Audio Describer is Dead: Long Live Audio Description! Journal of Audiovisual Translation (In press).

https://ift.tt/2AmK58z

Sub-linear lattice-based zero-knowledge arguments for arithmetic circuits

Baum, C; Bootle, J; Cerulli, A; del Pino, R; Groth, J; Lyubashevsky, V; (2018) Sub-linear lattice-based zero-knowledge arguments for arithmetic circuits. In: Shacham, H and Boldyreva, A, (eds.) Advances in Cryptology – CRYPTO 2018: 38th Annual International Cryptology Conference, Santa Barbara, CA, USA, August 19–23, 2018, Proceedings, Part II. (pp. pp. 669-699). Springer: Cham, Switzerland.

https://ift.tt/2R28N3k

‘Lumping or splitting’ in paediatric acute respiratory distress syndrome (PARDS)

De Luca, D; Harrison, DA; Peters, MJ; (2018) 'Lumping or splitting' in paediatric acute respiratory distress syndrome (PARDS). [Editorial comment]. Intensive Care Medicine , 44 (9) pp. 1548-1550. 10.1007/s00134-018-5323-5 .

https://ift.tt/2AmK0lh

Systematic review of the screening, diagnosis, and management of ADHD in children with epilepsy. Consensus paper of the Task Force on Comorbidities of the ILAE Pediatric Commission

Auvin, S; Wirrell, E; Donald, KA; Berl, M; Hartmann, H; Valente, KD; Van Bogaert, P; ... Wilmshurst, JM; + view all Auvin, S; Wirrell, E; Donald, KA; Berl, M; Hartmann, H; Valente, KD; Van Bogaert, P; Cross, JH; Osawa, M; Kanemura, H; Aihara, M; Guerreiro, MM; Samia, P; Vinayan, KP; Smith, ML; Carmant, L; Kerr, M; Hermann, B; Dunn, D; Wilmshurst, JM; - view fewer (2018) Systematic review of the screening, diagnosis, and management of ADHD in children with epilepsy. Consensus paper of the Task Force on Comorbidities of the ILAE Pediatric Commission. Epilepsia , 59 (10) 10.1111/epi.14549 .

https://ift.tt/2R6GcKa

Eros Mutations: Decreased Nadph Oxidase Function and Chronic Granulomatous Disease

Thomas, DC; Charbonnier, L-M; Schejtman, A; Aldhekri, H; Coomber, EL; Dufficy, ER; Beenken, AE; ... Smith, KGC; + view all Thomas, DC; Charbonnier, L-M; Schejtman, A; Aldhekri, H; Coomber, EL; Dufficy, ER; Beenken, AE; Lee, JC; Clare, S; Speak, AO; Thrasher, AJ; Santilli, G; Al-Mousa, H; Alkuraya, FS; Chatila, TA; Smith, KGC; - view fewer (2018) Eros Mutations: Decreased Nadph Oxidase Function and Chronic Granulomatous Disease. Journal of Allergy and Clinical Immunology 10.1016/j.jaci.2018.09.019 . (In press).

https://ift.tt/2AmJVxZ

Midwave Infrared Quantum Dot Quantum Cascade Photodetector Monolithically Grown on Silicon Substrate

Huang, J; Guo, D; Deng, Z; Chen, W; Liu, H; Wu, J; Chen, B; (2018) Midwave Infrared Quantum Dot Quantum Cascade Photodetector Monolithically Grown on Silicon Substrate. Journal of Lightwave Technology , 36 (18) pp. 4033-4038. 10.1109/JLT.2018.2859250 . Green open access

https://ift.tt/2R28wgO

First Demonstration of Velocity Selective Recording From the Pig Vagus Using a Nerve Cuff Shows Respiration Afferents

Metcalfe, BW; Nielsen, TN; Donaldson, NDN; Hunter, AJ; Taylor, JT; (2017) First Demonstration of Velocity Selective Recording From the Pig Vagus Using a Nerve Cuff Shows Respiration Afferents. Biomedical Engineering Letters , 8 (1) pp. 127-136. 10.1007/s13534-017-0054-z .

https://ift.tt/2AmJOCz

Output Tracking of Nonminimum-Phase Systems via Reduced-Order Sliding-Mode Design

Patil, M; Bandyopadhyay, B; Chalanga, A; Arya, H; (2018) Output Tracking of Nonminimum-Phase Systems via Reduced-Order Sliding-Mode Design. IEEE/ASME Transactions on Mechatronics , 23 (4) pp. 1981-1992. 10.1109/TMECH.2018.2836320 . Green open access

https://ift.tt/2R4UyuE

Demonstration of InAs/InGaAs/GaAs Quantum Dots-in-a-Well Mid-Wave Infrared Photodetectors Grown on Silicon Substrate

Chen, W; Deng, Z; Guo, D; Chen, Y; Mazur, Y; Maidaniuk, Y; Benamara, M; ... Chen, B; + view all Chen, W; Deng, Z; Guo, D; Chen, Y; Mazur, Y; Maidaniuk, Y; Benamara, M; Salamo, GJ; Liu, H; Wu, J; Chen, B; - view fewer (2018) Demonstration of InAs/InGaAs/GaAs Quantum Dots-in-a-Well Mid-Wave Infrared Photodetectors Grown on Silicon Substrate. Journal of Lightwave Technology , 36 (13) pp. 2572-2581. 10.1109/JLT.2018.2811388 . Green open access

https://ift.tt/2Am4bzs

Enhancer RNA and NFκB-dependent P300 regulation of ADAMDEC1

Publication date: November 2018

Source: Molecular Immunology, Volume 103

Author(s): Lihua Shi, Song Li, Kelly Maurer, Zhe Zhang, Michelle Petri, Kathleen E. Sullivan

Abstract

We observed increased expression of ADAMDEC1 RNA in monocytes from patients with systemic lupus erythematosus. The precise role of ADAMDEC1 is uncertain and uniquely among metalloproteinases it utilizes a zinc-coordinating aspartic acid residue which allows it to escape inhibition by tissue inhibitor of metalloprotease-3 (TIMP-3). A closely related gene encodes the protein ADAM28, which is not up-regulated in lupus. We leveraged the ability to look at both gene's promoters and enhancers simultaneously. ADAMDEC1 was up-regulated by LPS while ADAM28 was not upregulated in the short term. We identified MAP kinases and NFκB as critical cell pathways regulating the expression of ADAMDEC1. These same pathways were implicated in driving the expression of the ADAMDEC1 upstream enhancer RNAs. We demonstrated that binding of the enhancer RNAs produced from the upstream enhancer were critically important and that p300 bound to both the RNA from the enhancer and the DNA at the enhancer. P300 binding to the enhancer was dependent on NFκB. These data define the critical pathways regulating the expression of ADAMDEC1 and extend our knowledge of the roles of enhancer RNAs and mechanistically links p300 and enhancer RNAs.

Graphical abstract

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Comparison of natural ostiodilatation and endoscopic sinus surgery in the same patient with chronic sinusitis

Publication date: Available online 22 October 2018

Source: Brazilian Journal of Otorhinolaryngology

Author(s): Ahmet Kutluhan, Hüseyin Çetin, Hayati Kale, Özmen Kara, Halil İbrahim Mişe, Tolga Oğuzhan, Kadir Şinasi Bulut

Abstract

Introduction

Chronic rhinosinusitis is a broad clinical syndrome characterized by mucosal inflammation of the nose and paranasal sinuses. In order for the paranasal sinuses to maintain their physiological functions; the ostiomeatal complex drainage pathways must be open. Surgical procedures are an important treatment option in patients who do not respond adequately to medical treatment. Although the methods and instruments used in functional endoscopic sinus surgery have continued to improve in recent years, the scar tissue formed during operation disrupts the drainage of the sinuses and reduces postoperative success. The natural ostiodilatation method, which is performed by balloon sinoplasty method, has become more and more popular in recent years.

Objectives

To compare the technique of balloon sinoplasty with the classical functional endoscopic sinus surgery method by considering the severity of chronic sinusitis on the same patient.

Methods

Total of 61 chronic sinusitis patients was included in the study. Paranasal sinus tomography of the patients was taken and according to the Lund–Mackay scoring, chronic sinusitis levels were determined. Cases were divided into two groups: Group 1 (severe chronic sinusitis group) and Group 2 (mild chronic sinusitis).

Results

There was no statistically significant difference in the results of comparison of sinuses which underwent balloon sinoplasty and classical functional endoscopic sinus surgery in Group 2 after Lund–Mackay scores. However in Group 1, the results of the comparison of postoperative Lund–Mackay scores of the balloon sinoplasty and the classical endoscopic operation were statistically significantly lower than those of the face half operated with the classical functional endoscopic sinus surgery.

Conclusion

The success of balloon sinoplasty in patients with mild sinusitis is the same as in classic functional endoscopic sinus surgery. However, as the severity of sinusitis increases, the efficacy of balloon sinoplasty decreases.

Resumo

Introdução

A rinossinusite crônica é uma síndrome clínica ampla, caracterizada por inflamação da mucosa nasal e seios paranasais. Para que os seios paranasais mantenham suas funções fisiológicas, as vias de drenagem do complexo ostiomeatal devem estar abertas. Os procedimentos cirúrgicos são uma importante opção de tratamento em pacientes que não respondem adequadamente ao tratamento clínico. Embora os métodos e instrumentos utilizados na cirurgia endoscópica funcional dos seios paranasais venham melhorando continuamente, o tecido cicatricial formado durante a cirurgia interrompe a drenagem dos seios nasais e reduz o sucesso pós-operatório. O método natural de dilatação ostial, que é realizado através da técnica de sinuplastia com balão, tem se tornado cada vez mais popular nos últimos anos.

Objetivos

Comparar a técnica de sinuplastia com balão com o método convencional de cirurgia endoscópica, no mesmo paciente, considerando a gravidade da rinossinusite crônica,.

Método

Um total de 61 pacientes com rinossinusite crônica foram incluídos no estudo. Por meio de tomografia dos seios paranasais e, de acordo a escala de Lund-Mackay, foram determinados os graus da rinossinusite crônica. Os casos foram divididos em dois grupos: Grupo 1 (grupo com rinossinusite crônica grave) e Grupo 2 (rinossinusite crônica leve).

Resultados

No Grupo 2 não houve diferença estatisticamente significante, segundo a escala de Lund-Mackay, no resultado da comparação dos seios paranasais nos quais foram realizadas a sinuplastia com balão e por cirurgia endoscópica convencional. No entanto, no Grupo 1, os resultados da comparação dos escores pós-operatórios de Lund-Mackay mostraram-se estatisticamente e significativamente melhores naqueles submetidos à cirurgia endoscópica funcional dos seios paranasais.

Conclusão

O sucesso da sinuplastia com balão em pacientes com rinossinusite leve é o mesmo da cirurgia endoscópica funcional dos seios da face tradicional. No entanto, à medida que a gravidade da rinossinusite aumenta, a eficácia da sinuplastia com balão diminui.

https://ift.tt/2CXV6iP

A Review of the Use and Effectiveness of Digital Health Technologies in Asthma Patients

Publication date: Available online 22 October 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): Elizabeth Unni, Susan Gabriel, Rinat Ariely

https://ift.tt/2S8Mhr6

Salivary gland cell aggregates are derived from self-organization of acinar lineage cells

Publication date: Available online 22 October 2018

Source: Archives of Oral Biology

Author(s): Jomy J. Varghese, M. Eva Hansen, Azmeer Sharipol, Matthew H. Ingalls, Martha A. Ormanoski, Shawn D. Newlands, Catherine E. Ovitt, Danielle S.W. Benoit

Abstract

Objective

The objective of this study was to characterize the mechanism by which salivary gland cells (SGC) aggregate in vitro.

Design

Timelapse microscopy was utilized to analyze the process of salivary gland aggregate formation using both primary murine and human salivary gland cells. The role of cell density, proliferation, extracellular calcium, and secretory acinar cells in aggregate formation was investigated. Finally, the ability of cells isolated from irradiated glands to form aggregates was also evaluated.

Results

Salivary gland cell self-organization rather than proliferation was the predominant mechanism of aggregate formation in both primary mouse and human salivary gland cultures (SGC). Aggregation was found to require extracellular calcium while acinar lineage cells account for ~80% of the total aggregate cell population. Finally, aggregation was not impaired by irradiation.

Conclusions

The data reveal that aggregation occurs as a result of heterogeneous salivary gland cell self-organization rather than from stem cell proliferation and differentiation, contradicting previous dogma. These results suggest a re-evaluation of aggregate formation as a criterion defining salivary gland stem cells.

https://ift.tt/2Rc8aVd

Delineating metabolic dysfunction in cellular metabolism of oral submucous fibrosis using 1H nuclear magnetic resonance spectroscopy

Publication date: Available online 21 October 2018

Source: Archives of Oral Biology

Author(s): Vertika Rai, Surajit Bose, Satadal Saha, Virendra Kumar, Chandan Chakraborty

Abstract

Objective

To delineate the metabolism involved in oral submucous fibrosis progression towards carcinogenesis by ¹H nuclear magnetic resonance spectroscopy.

Methods

The proposed study was designed using ¹H-NMR by comparing the metabolites in the serum sample of oral submucous fibrosis (n = 20) compared to the normal group (n = 20) using ¹H nuclear magnetic resonance spectroscopy. Various statistical analysis like multivariate statistical analysis, Principle component analysis, Partial least squares Discriminant Analysis, Hierarchical cluster analysis was applied to analyze potential serum metabolites.

Results

The results generated from the principle component analysis, partial least squares discriminant analysis and hierarchical cluster analysis are sufficient to distinguish between oral submucous fibrosis group and normal group. A total of 15 significant metabolites associated with main pathways were identified, which correlated with the progression of cancer. Up-regulation of glucose metabolism-related metabolites indicated the high energy demand due to enhanced cell division rate in the oral submucous fibrosis group. A significant increase in lipid metabolism-related metabolites revealed the reprogramming of the fatty acids metabolic pathway to fulfilling the need for cell membrane formation in cancer cells. On the other hand, metabolites related to choline phosphocholine, the metabolic pathway was also altered.

Conclusion

Our findings could identify the differentiating metabolites in the oral submucous fibrosis group. Significant alteration in metabolites in the oral submucous fibrosis group exhibited deregulation in metabolic events. The findings reported in the study can be beneficial to further explain the molecular aspects that lead to the progression of oral submucous fibrosis towards carcinogenesis

Graphical abstract

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Publication Trends Over 55 Years of Behavioral Genetic Research

Ayorech, Z; Selzam, S; Smith-Woolley, E; Knopik, VS; Neiderhiser, JM; DeFries, JC; Plomin, R; (2016) Publication Trends Over 55 Years of Behavioral Genetic Research. Behavior Genetics , 46 (5) pp. 603-607. 10.1007/s10519-016-9786-2 . Green open access

https://ift.tt/2OGfqfb

Socioeconomic Differences in Healthy and Disease-free Life Expectancy Between Ages 50 and 75: a Multi-cohort Study

Head, J; Chungkham, HS; Hyde, M; Zaninotto, P; Alexanderson, K; Stenholm, S; Salo, P; ... Westerlund, H; + view all Head, J; Chungkham, HS; Hyde, M; Zaninotto, P; Alexanderson, K; Stenholm, S; Salo, P; Kivimäki, M; Goldberg, M; Zins, M; Vahtera, J; Westerlund, H; - view fewer (2018) Socioeconomic Differences in Healthy and Disease-free Life Expectancy Between Ages 50 and 75: a Multi-cohort Study. European Journal of Public Health , cky215 10.1093/eurpub/cky215 . Green open access

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The epileptic encephalopathy jungle – from Dr West to the concepts of aetiology-related and developmental encephalopathies

Kalser, J; Cross, JH; (2018) The epileptic encephalopathy jungle – from Dr West to the concepts of aetiology-related and developmental encephalopathies. Current Opinion in Neurology , 31 (2) pp. 216-222. 10.1097/WCO.0000000000000535 .

https://ift.tt/2OCI00R

The Effects of Antipsychotic Treatment on Presynaptic Dopamine Synthesis Capacity in First-Episode Psychosis: A Positron Emission Tomography Study

Jauhar, S; Veronese, M; Nour, MM; Rogdaki, M; Hathway, P; Natesan, S; Turkheimer, F; ... Howes, OD; + view all Jauhar, S; Veronese, M; Nour, MM; Rogdaki, M; Hathway, P; Natesan, S; Turkheimer, F; Stone, J; Egerton, A; McGuire, P; Kapur, S; Howes, OD; - view fewer (2018) The Effects of Antipsychotic Treatment on Presynaptic Dopamine Synthesis Capacity in First-Episode Psychosis: A Positron Emission Tomography Study. Biological Psychiatry 10.1016/j.biopsych.2018.07.003 . (In press). Green open access

https://ift.tt/2NWgNBd

Smaller Hippocampal Ca1 Subfield Volume in Posttraumatic Stress Disorder

Chen, LW; Sun, D; Davis, SL; Haswell, CC; Dennis, EL; Swanson, CA; Whelan, CD; ... Morey, RA; + view all Chen, LW; Sun, D; Davis, SL; Haswell, CC; Dennis, EL; Swanson, CA; Whelan, CD; Gutman, B; Jahanshad, N; Iglesias, JE; Thompson, P; Mid-Atlantic MIRECC Workgroup, ; Wagner, HR; Saemann, P; LaBar, KS; Morey, RA; - view fewer (2018) Smaller Hippocampal Ca1 Subfield Volume in Posttraumatic Stress Disorder. Depression and Anxiety 10.1002/da.22833 . (In press).

https://ift.tt/2OH3wBI

Ultralightweight X-ray Telescope Missions: ORBIS and GEO-X

Ezoe, Y; Miyoshi, Y; Kasahara, S; Kimura, T; Ishikawa, K; Fujimoto, M; Mitsuda, K; ... Branduardi-Raymont, G; + view all Ezoe, Y; Miyoshi, Y; Kasahara, S; Kimura, T; Ishikawa, K; Fujimoto, M; Mitsuda, K; Sahara, H; Isobe, N; Nakajima, H; Ohashi, T; Nagata, H; Funase, R; Ueno, M; Branduardi-Raymont, G; - view fewer (2018) Ultralightweight X-ray Telescope Missions: ORBIS and GEO-X. Journal of Astronomical Telescopes, Instruments, and Systems , 4 (4) , Article 046001. 10.1117/1.JATIS.4.4.046001 . Green open access

https://ift.tt/2NZvmns

Nothing About Us, Without Us: a Case Study of a Consumer-run Organization by and for People on the Autism Spectrum in the Netherlands

van den Bosch, K; Krzeminska, A; Song, EY; van Hal, LBE; Waltz, MM; Ebben, H; (2018) Nothing About Us, Without Us: a Case Study of a Consumer-run Organization by and for People on the Autism Spectrum in the Netherlands. Journal of Management and Organization 10.1017/jmo.2018.54 . Green open access

https://ift.tt/2OEcvnh

Degree-correlations in a Bursting Dynamic Network Model

Vanni, F; Barucca, P; (2018) Degree-correlations in a Bursting Dynamic Network Model. Journal of Economic Interaction and Coordination pp. 1-33. 10.1007/s11403-018-0232-9 .

https://ift.tt/2NWgzKn

Delay-Power-Rate-Distortion Optimization of Video Representations for Dynamic Adaptive Streaming

Li, C; Toni, L; Zou, J; Xiong, H; Frossard, P; (2018) Delay-Power-Rate-Distortion Optimization of Video Representations for Dynamic Adaptive Streaming. IEEE Transactions on Circuits and Systems for Video Technology , 28 (7) pp. 1648-1664. 10.1109/TCSVT.2017.2681024 . Green open access

https://ift.tt/2OElxjT

Epidemiological Tracing of Batrachochytrium Salamandrivorans Identifies Widespread Infection and Associated Mortalities in Private Amphibian Collections

Fitzpatrick, LD; Pasmans, F; Martel, A; Cunningham, AA; (2018) Epidemiological Tracing of Batrachochytrium Salamandrivorans Identifies Widespread Infection and Associated Mortalities in Private Amphibian Collections. Scientific Reports , 8 , Article 13845. 10.1038/s41598-018-31800-z . Green open access

https://ift.tt/2NR1nhv

Animal infection studies of two recently discovered African bat paramyxoviruses, Achimota 1 and Achimota 2

Barr, J; Todd, S; Crameri, G; Foord, A; Marsh, G; Frazer, L; Payne, J; ... Wang, L-F; + view all Barr, J; Todd, S; Crameri, G; Foord, A; Marsh, G; Frazer, L; Payne, J; Harper, J; Baker, KS; Cunningham, AA; Wood, JLN; Middleton, D; Wang, L-F; - view fewer (2018) Animal infection studies of two recently discovered African bat paramyxoviruses, Achimota 1 and Achimota 2. Scientific Reports , 8 (1) , Article 12744. 10.1038/s41598-018-31193-z . Green open access

https://ift.tt/2OEse5z

Translating audio description scripts… into English

Jankowska, A; Milc, M; Fryer, LE; (2017) Translating audio description scripts… into English. SKASE Journal of Translation and Interpretation , 10 (2) pp. 2-16.

https://ift.tt/2NXxlJ1

Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage

Kindinger, LM; MacIntyre, DA; Lee, YS; Marchesi, JR; Smith, A; McDonald, JAK; Terzidou, V; ... Bennett, PR; + view all Kindinger, LM; MacIntyre, DA; Lee, YS; Marchesi, JR; Smith, A; McDonald, JAK; Terzidou, V; Cook, JR; Lees, C; Israfil-Bayli, F; Faiza, Y; Toozs-Hobson, P; Slack, M; Cacciatore, S; Holmes, E; Nicholson, JK; Teoh, TG; Bennett, PR; - view fewer (2016) Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage. Science Translational Medicine , 8 (350) , Article 350ra102. 10.1126/scitranslmed.aag1026 . Green open access

https://ift.tt/2OGpc0Q

Assessing Habitat Quality When Forest Attributes Have Opposing Effects on Abundance and Detectability: a Case Study on Darwin’s Frogs

Valenzuela-Sanchez, A; Schmidt, BR; Perez, C; Altamirano, T; Toledo, V; Perez, I; Teillier, S; ... Soto-Azat, C; + view all Valenzuela-Sanchez, A; Schmidt, BR; Perez, C; Altamirano, T; Toledo, V; Perez, I; Teillier, S; Cunningham, AA; Soto-Azat, C; - view fewer (2019) Assessing Habitat Quality When Forest Attributes Have Opposing Effects on Abundance and Detectability: a Case Study on Darwin's Frogs. Forest Ecology and Management (In press).

https://ift.tt/2NVDJjV

Is There a Doctor in the House? Expert Product Users, Organizational Roles, and Innovation

Katila, R; Thatchenkery, S; Christensen, MQ; Zenios, S; (2017) Is There a Doctor in the House? Expert Product Users, Organizational Roles, and Innovation. Academy of Management Journal , 60 (6) pp. 2415-2437. 10.5465/amj.2014.1112 . Green open access

https://ift.tt/2ODoWiU

The Gambian Epauletted Fruit Bat Shows Increased Genetic Divergence in the Ethiopian Highlands and in an Area of Rapid Urbanisation

Riesle-Sbarbaro, S; Amponsah-Mensah, K; de Vries, S; Nicolas, V; Lalis, A; Suu-Ire, R; Cunningham, AA; ... Sargan, DR; + view all Riesle-Sbarbaro, S; Amponsah-Mensah, K; de Vries, S; Nicolas, V; Lalis, A; Suu-Ire, R; Cunningham, AA; Wood, JLN; Sargan, DR; - view fewer (2019) The Gambian Epauletted Fruit Bat Shows Increased Genetic Divergence in the Ethiopian Highlands and in an Area of Rapid Urbanisation. Ecology and Evolution (In press).

https://ift.tt/2NXrdAm

Sex differences in learning — shared principles across taxa

Molina-García, L; Barrios, A; (2018) Sex differences in learning — shared principles across taxa. Current Opinion in Physiology , 6 pp. 65-74. 10.1016/j.cophys.2018.05.004 .

https://ift.tt/2OEltRb

基于时域有限差分的微放电仿真算法 = Multipactor simulation algorithm based on finite difference in time domain

Zhang, J; You, J; Wang, H; Li, Y; Cui, W; Cui, T; (2017) 基于时域有限差分的微放电仿真算法 = Multipactor simulation algorithm based on finite difference in time domain. Zhongguo Kongjian Kexue Jishu = Chinese Space Science and Technology , 37 (2) pp. 89-95. 10.16708/j.cnki.1000-758X.2017.0036 .

https://ift.tt/2NXwEiT

Random Networks, Graphical Models and Exchangeability

Lauritzen, S; Rinaldo, A; Sadeghi, K; (2018) Random Networks, Graphical Models and Exchangeability. Journal of the Royal Statistical Society: Series B (Statistical Methodology) , 80 (3) pp. 481-508. 10.1111/rssb.12266 .

https://ift.tt/2OFtVj3

Beyond the Basics: Access and Equity in the Expansion of Post-compulsory Schooling in Vietnam

Rolleston, C; Iyer, P; (2018) Beyond the Basics: Access and Equity in the Expansion of Post-compulsory Schooling in Vietnam. International Journal of Educational Development 10.1016/j.ijedudev.2018.09.002 . (In press).

https://ift.tt/2NX9s4i

Prenatal 25-hydroxyvitamin D deficiency affects development of atopic dermatitis via DNA methylation

Publication date: Available online 22 October 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Hyun-Ju Cho, Youn Ho Sheen, Mi-Jin Kang, Seung-Hwa Lee, So-Yeon Lee, Jisun Yoon, Sungsu Jung, Si Hyeon Lee, Young-Ho Kim, Song-I. Yang, Eun Lee, Ju-Hee Seo, Kangmo Ahn, Kyung Won Kim, Dong In Suh, Hye-Sung Won, Mi-Young Lee, Soo Hyun Kim, Suk-Joo Choi, Ja-Young Kwon

https://ift.tt/2CZrBgR

Identification of biomarkers for predicting the response to cyclosporine A therapy in patients with chronic spontaneous urticaria

Publication date: Available online 22 October 2018

Source: Allergology International

Author(s): Takahiro Endo, Shota Toyoshima, Kazuko Kanegae, Satoshi Izaki, Nobuyuki Nishimori, Mana Ito, Kazuko Sugai, Koremasa Hayama, Tadashi Terui, Yoshimichi Okayama

https://ift.tt/2R50XGg

Cumulative incidence of neck recurrence with increasing depth of invasion

Publication date: December 2018

Source: Oral Oncology, Volume 87

Author(s): Justin R. Shinn, C. Burton Wood, Juan M. Colazo, Frank E. Harrell, Sarah L. Rohde, Kyle Mannion

Abstract

Objective

To determine if there is a critical depth of invasion that predicts micrometastasis in early oral tongue cancer.

Methods

Retrospective series identifying patients undergoing primary surgical resection of T1 or T2 oral tongue cancer who elected against neck treatment between 2000 and 2015. Cox proportional-hazard model compared the relative hazard and cumulative incidence of recurrence to depth of invasion. The model used a 2 parameter quadratic effect for depth that was chosen based on Akaike's information criterion.

Results

Ninety-three patients were identified with T1 or T2 oral tongue squamous cell carcinoma and clinically N0 neck undergoing glossectomy without elective neck treatment. 61% were male and median age was 60 years. Median follow up was 45 months, and 76 patients had at least two years of follow up. Thirty-six of 76 patients recurred (47.4%), with 15 recurring in the oral cavity (19.7%) and 21 developing nodal metastasis (27.6%). Cox proportional-hazards quadratic polynomial showed increasing hazard of recurrence with depth of invasion and the cumulative incidence increased sharply within the range of data from 2 to 6 mm depth of invasion.

Conclusions

Depth of invasion is significantly associated with nodal metastasis and has been added to the 8th AJCC staging guidelines. Variable depths of invasion have been associated with regional metastasis; however, there is likely not a critical depth that predicts neck recurrence due to progressive hazards and cumulative risk of occult metastasis. The risk of regional metastasis is likely much greater than previously believed and increases progressively with increasing depth.

https://ift.tt/2S8mejO

Cerebral venous sinus thrombosis in a young female misdiagnosed as migraine ending in a permanent vegetative state: a case report and review of the literature

Cerebral venous thrombosis refers to acute thrombosis or blood clots that can lead to strokes. This illness can be misdiagnosed as a migraine, resulting in a delay in management and catastrophic outcomes. We p...

https://ift.tt/2PcdE4H

An unusual presentation of anomalous left coronary artery from the pulmonary artery (ALCAPA) syndrome in a 70-year-old man: a case report

We present a rare case of anomalous origin of the left coronary artery from the pulmonary artery syndrome in an elderly man, and we describe coronary computed tomographic angiographic imaging findings to impro...

https://ift.tt/2Ezdpgc

Breastfeeding and weaning in ancient populations: Challenges and future directions

International Journal of Osteoarchaeology, Volume 28, Issue 5, Page 477-478, September/October 2018.


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Issue Information ‐ TOC

International Journal of Osteoarchaeology, Volume 28, Issue 5, Page 475-476, September/October 2018.


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Therapeutic approaches to pyogenic granuloma: an updated review

International Journal of Dermatology, EarlyView.


https://ift.tt/2OH56Dm

Pyoderma gangrenosum associated with dulaglutide therapy

International Journal of Dermatology, EarlyView.


https://ift.tt/2NW1cBC

Diffuse palmoplantar keratotic papules and melanosis

International Journal of Dermatology, EarlyView.


https://ift.tt/2OBWazc

Mid borderline leprosy in type Bα Blaschko linear pattern: a rare phenomenon

International Journal of Dermatology, EarlyView.


https://ift.tt/2NVXcRF

The law of food allergy and accommodation in Canadian schools

There is ongoing controversy surrounding the appropriate standards and limits of accommodation of children with food allergies in schools. We identify and explain how relevant Canadian common law, legislation,...

https://ift.tt/2OH4XQk

Pitfalls of immunotherapy: lessons from a patient with CTLA-4 haploinsufficiency

Daclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell prolife...

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In this issue

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