A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

The cadherin superfamily of proteins is defined by the presence of extracellular cadherin (EC) repeats that engage in protein-protein interactions to mediate cell-cell adhesion, cell signaling, and mechanotransduction. The extracellular domains of non-classical cadherins often have a large number of EC repeats along with other subdomains of various folds. Protocadherin-15 (PCDH15), a protein component of the inner-ear tip link filament essential for mechanotransduction, has eleven EC repeats and a membrane adjacent domain (MAD12) of atypical fold.

https://ift.tt/2K8OfUC

Enzymatic Phosphorylation of Ser in a Type I Collagen Peptide

Phosphoproteomics studies have reported phosphorylation at multiple sites within collagen, raising the possibility that these post-translational modifications regulate collagen physical or biological properties. In this study, molecular dynamics simulations and experimental studies were carried out on model peptides to establish foundational principles of phosphorylation of Ser residues in collagen. A (Gly-Xaa-Yaa)11 peptide was designed to include a Ser-containing sequence from type I collagen which was reported to be phosphorylated.

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Mouse ICM organoids reveal three-dimensional cell fate clustering

During mammalian preimplantation, cells of the inner cell mass (ICM) adopt either an embryonic or an extraembryonic fate. This process is tightly regulated in space and time and has been studied previously in mouse embryos and embryonic stem cell models. Current research suggests that cell fates are arranged in a salt-and-pepper pattern of random cell positioning or a spatially alternating pattern. However, the details of the three-dimensional patterns of cell fate specification have been neither investigated in the embryo nor in in vitro systems.

https://ift.tt/2BagFKV

Colonization of Cutibacterium avidum during infant gut microbiota establishment

Abstract

Establishment of the infant gut microbiota affects gut maturation and influences long-term health. Cutibacterium (formerly Propionibacterium) have been identified as early colonizers, but little is known about their function. Using a cultivation-dependent and -independent approach, we determined Cutibacterium prevalence, diversity and functional potential. In feces from a Swiss infant cohort (n = 38), prevalence of Propionibacterium/Cutibacterium decreased from 84% at 2 weeks, to 65% at 4 weeks, 47% at 8 weeks and 41% at 12 weeks of age. Abundance varied among individuals, and persistence depended on the colonization levels at 2 weeks. Cutibacterium isolates (n = 87) were obtained from 10 infants from a smaller cohort (n = 12); restriction fragment length polymorphism clustered isolates in four groups, and all identified as Cutibacterium avidum. Colonization potential and metabolic effects of C. avidum addition were tested in an in vitro continuous intestinal fermentation model mimicking infant proximal colon conditions. Cutibacterium avidum spiked daily at 10⁸ or 10⁹ cells mL⁻¹ colonized, decreased formate and persisted during the washout period. Significant correlations were observed between Propionibacterium/Cutibacterium and lactate-producers and protein-degraders in both reactors and infant feces. Our findings highlight the natural presence of C. avidum and its role as a lactate-consumer and propionate-producer in infants younger than 3 months.

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Evidence for diversifying selection of genetic regions of encoding putative collagen-like host-adhesive fibers in Pasteuria penetrans

Abstract

Pasteuria spp. belong to a group of genetically diverse endospore-forming bacteria (phylum: Firmicutes) that are known to parasitize plant-parasitic nematodes and water fleas (Daphnia spp.). Collagen-like fibres form the nap on the surface of endospores and the genes encoding these sequences have been hypothesised to be involved in the adhesion of the endospores of Pasteuria spp. to their hosts. We report a group of 17 unique collagen-like genes putatively encoded by Pasteuria penetrans (strain: Res148) that formed five different phylogenetic clusters and suggest that collagen-like proteins are an important source of genetic diversity in animal pathogenic Firmicutes including Pasteuria. Additionally, and unexpectedly, we identified a putative collagen-like sequence which had a very different sequence structure to the other collagen-like proteins but was similar to the protein sequences in Megaviruses that are involved in host-parasite interactions. We, therefore, suggest that these diverse endospore surface proteins in Pasteuria are involved in biological functions, such as cellular adhesion; however, they are not of monophyletic origin and were possibly obtained de novo by mutation or possibly through selection acting upon several historic horizontal gene transfer events.

https://ift.tt/2DGykMV

Intra- and inter-field diversity of 2,4-dichlorophenoxyacetic acid-degradative plasmids and their tfd catabolic genes in rice fields of the Mekong delta in Vietnam

Abstract

The tfd genes mediating degradation of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) differ in composition and organization in bacterial isolates from different geographical origin and are carried by different types of mobile genetic elements (MGE). It is not known whether such global diversity of 2,4-D-catabolic MGE and their tfd gene cargo is reflected in the diversity at field scale. The genomic context of the 2,4-D catabolic genes of 2,4-D-degrading isolates from two rice fields with a 2,4-D application history, located in two distant provinces of the Vietnam Mekong delta, was compared. All isolates were β-proteobacteria, were unique for each rice field and carried the catabolic genes on MGE and especially plasmids. Most plasmids were IncP-1β plasmids and carried tfd clusters highly similar to those of the IncP-1β plasmid pJP4, typified by two chlorophenol catabolic gene modules (tfd-I and tfd-II). IncP-1β plasmids from the same field showed small deletions and/or insertions in accessory metabolic genes. One plasmid belonged to an unclassified plasmid group and carries a copy of both tfdA and tfd-II identical to those in the IncP-1β plasmids. Our results indicate intra-field evolution and inter-field exchange of 2,4-D-catabolic IncP-1β plasmids as well as the exchange of tfd genes between different plasmids within a confined local environment.

https://ift.tt/2RXsTwi

Host blood-meal source has a strong impact on gut microbiota of Aedes aegypti

Abstract

Gut microbial communities of mosquitoes can influence vector susceptibility to pathogens, yet the factors that govern their composition remain poorly understood. We investigated the impact of host blood-meal source on gut microbiota of Aedes aegypti L. Adult mosquitoes were fed on human, rabbit or chicken blood and their gut microbiota compared to those of sugar-fed and newly emerged adults. Microbial diversity was significantly reduced in blood-fed and sugar-fed mosquitoes but was restored to the levels of newly emerged adults at 7-days post-blood meal. Microbial composition was strongly influenced by host blood-meal source. Leucobacter spp., Chryseobacterium spp., Elizabethkingia spp. and Serratia spp. were characteristic of newly emerged adults and adults fed on chicken, rabbit and human blood, respectively. Sugar-fed mosquitoes had higher abundance of Pseudomonas spp. and unclassified Acetobacteraceae. Shifts in gut microbial communities in response to host blood-meal source may fundamentally impact pathogen transmission given the well-documented link between specific bacterial taxa and vector susceptibility to a variety of mosquito-borne pathogens and may be a key determinant of individual and population variation in vector competence.

https://ift.tt/2DGGMM6

Mychonastes dominates the photosynthetic picoeukaryotes in Lake Poyang, a river-connected lake

Abstract

Lake Poyang, which is connected to the Yangtze River, is the largest freshwater lake in China and experiences large and frequent changes in water levels. The seasonal diversity and composition of photosynthetic picoeukaryotes (PPEs) in Lake Poyang were investigated from flow-cytometry-sorted samples using MiSeq high-throughput sequencing. Flow cytometric counting indicated that PPEs accounted for 97% of the total picophytoplankton abundance in spring, reaching a maximum value of 6.30 × 10⁴ cells mL⁻¹. PPEs in Lake Poyang showed lower diversity than those in other investigated lakes in the lower reaches of the Yangtze River and were dominated by one OTU (66.29%) affiliated with Mychonastes (Chlorophyceae). Other minor classes of PPEs were found to be sporadically abundant in specific seasons, i.e. Chrysophyceae prevailed in spring and summer, while Eustigmatophyceae was mainly present in winter. This study reports coccal green algae of Mychonastes in Lake Poyang; additionally, these algae are reportedly representative of the prominent plankton in this river-connected lake ecosystem but are often overlooked due to their lack of morphological features. Finally, the sequencing results from the sorted samples of Lake Poyang revealed that the proportion of PPEs was quite low, with an average of 36% of total reads. Many OTUs belonging to heterotrophic picoeukaryotes were also identified in the sorted samples, most of which were affiliated with terrestrial fungi, including Basidiomycota and Ascomycota. The spores of these fungi can disperse in the aquatic environment during the flood seasons, yet their effect on PPEs is still unclear.

https://ift.tt/2RX8jvM

Multilocus sequence typing of Shewanella algae isolates identifies disease-causing Shewanella chilikensis strain 6I4

Abstract

The genus Shewanella is rapidly expanding, with new species being discovered frequently. Four species have been identified as pathogenic to humans, with Shewanella algae being most relevant. Evaluation of the clinical significance of Shewanella spp. still suffers from the imprecision of species identification. In addition, the origin of S. algae strains causing disease is unclear. To shed light upon these questions we re-identified reported S. algae isolates on the species level based on the analysis of the partial sequences of the 16S rRNA and gyrB genes in combination with multilocus sequence typing that included six housekeeping loci. The analysis of a collection of 23 S. algae isolates of clinical and environmental origin, the publicly available genome sequences of six additional S. algae strains and type strains of closely-related species showed the existence of a remarkable haplotypic diversity within the S. algae clade. Three of the analyzed strains are suggested to be assigned to a species different from S. algae. A clinical isolate was thus reclassified as S. chilikensis, thereby constituting the first known case of human infection by this species. Our study emphasizes the application of high resolution molecular markers for species identification. The taxonomic resolution of the S. algae clade is still unclear.

https://ift.tt/2DFNfXL

Can interfaces at bracket‐wire and between teeth in multi‐teeth finite element model be simplified?

Abstract

Objective

Finite element (FE) method's correctness depends heavily on modeling method. This study aimed at determining whether the interfaces at bracket‐wire and between teeth can be simplified for multi‐teeth FE analysis.

Method

A three‐dimensional FE model of a mandible was created from cone‐beam computed tomography scan. Due to symmetry, only a half of the mandible was modeled, which consisted of five teeth (1^st premolar extraction and only 1^st molar), brackets and archwire, periodontal ligament (PDL), cortical bone and cancellous bone. All the bone, teeth, PDL were considered to be isotropic and linear. The En‐masse retraction case was simulated. A detailed model, which has contact elements between the bracket and archwire and between teeth, was developed to allow relative motion at the interfaces. A model with simplified interfacial conditions, which does not allow the relative motion, was also created. The stresses and displacements as results of the treatment on these two models were calculated and compared.

Results

The stress and displacement distributions from the detailed model were more close to reality based on the expected displacement pattern of the clinical case than from the simplified model. The maximum stresses from the two methods were also different. The highest stress from the detailed model is twice as high as from the simplified model.

Conclusions

The detailed model provides much more reasonable results than the simplified model. Thus, the simplified model should not be used to replace the detailed model if the stress magnitude and highest stress location are the expected outcomes.

https://ift.tt/2DEn0B7

Backward sensitivity analysis and reduced‐order covariance estimation in non‐invasive parameter identification for cerebral arteries

Abstract

Using a previously developed inversion platform for functional cerebral medical imaging with ensemble Kalman filters, this work analyses the sensitivity of the results with respect to different parameters entering the physical model and inversion procedure, such as the inlet flow rate from the heart, the choice of the boundary conditions and the non‐symmetry in the network terminations. It also proposes an alternative low complexity construction for the covariance matrix of the hemodynamic parameters of a network of arteries including the circle of Willis. The platform takes as input patient specific blood flow rates extracted from Magnetic Resonance Angiography and Magnetic Resonance Imaging (dicom files) and is applied to several available patients data. The paper presents full analysis of the results for one of these patients, including a sensitivity study with respect to the proximal and distal boundary conditions. The results notably show that the uncertainties on the inlet flow rate led to uncertainties of the same order of magnitude in the estimated parameters (blood pressure and elastic parameters) and that 3‐lumped parameters boundary conditions are necessary for a correct retrieval of the target signals.

https://ift.tt/2RYYe1C

A Monolithic Fluid Structure Interaction Framework Applied to Red Blood Cells

Abstract

A parallel fully‐coupled (monolithic) fluid‐structure interaction (FSI) algorithm has been applied to the deformation of red blood cells (RBCs) in capillaries, where cell deformability has significant effects on blood rheology. In the present FSI algorithm, fluid domain is discretized using the side‐centered unstructured finite volume method based on Arbitrary Lagrangian‐Eulerian (ALE) formulation, meanwhile solid domain is discretized with the classical Galerkin finite element formulation for the Saint Venant‐Kirchhoff material in a Lagrangian frame. In addition, the compatible kinematic boundary condition is enforced at the fluid‐solid interface in order to conserve the mass of cytoplasmic fluid within the red cell at machine precision. In order to solve the resulting large‐scale algebraic linear systems in a fully coupled manner, a new matrix factorization is introduced similar to that of the projection method and the parallel algebraic multigrid solver Boomer AMG is used for the scaled discrete Laplacian provided by the HYPRE library which we access through the PETSc library. Three important physical parameters for the blood ow are simulated and analyzed: (i) the effect of capillary diameter, (ii) the effect of red cell membrane thickness and (iii) the effect of red cell spacing (hematocrit). The numerical calculations initially indicate a shape deformation in which biconcave discoid shape changes to a parachute‐like shape. Furthermore, the parachute‐like cell shape in small capillaries undergoes a cupcake shaped buckling instability, which has not been observed in the literature. The instability forms thin rib‐like features and the red cell deformation is not axisymmetric but three‐dimensional.

https://ift.tt/2DHnN4i

Cancers, Vol. 10, Pages 448: Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition

Cancers, Vol. 10, Pages 448: Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition

Cancers doi: 10.3390/cancers10110448

Authors: Candace J. Poole Wenli Zheng Haesung Lee Danielle Young Atul Lodh Ahmed Chadli Jan van Riggelen

Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.

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A doxycycline‐treated hydroxyapatite implant surface attenuates the progression of peri‐implantitis: A radiographic and histological study in mice

Abstract

Background

Oral rehabilitation with dental implants has become increasingly common; however, the increase of peri‐implantitis is a great concern. Doxycycline (DOX) is a widely used antibiotic that inhibits bacteria growth, inflammation, and bone resorption.

Objectives

To evaluate the progression of peri‐implantitis of hydroxyapatite (HA)‐coated implants with (5 mg/mL, DOX group) or without (HA group) DOX treatment on the surface.

Materials and Methods

The maxillary first molars of 20 male mice were extracted. Eight weeks later, small titanium screw implants coated with thin HA and treated with or without DOX were placed at the extracted sites. Four weeks after implant placement, half of the animals in both groups were sacrificed, and ligatures were placed around the implant necks in the other half. These mice were sacrificed 4 weeks later. The bone around the implants was examined radiologically and histologically.

Results

Four weeks after the ligature placement, the radiographic measurements revealed that peri‐implant bone levels of palatal and mesial sites, and histological measurements showed that bone levels of mesial and distal sites in the DOX group were significantly higher than those in the HA group.

Conclusions

The present results indicating that the DOX‐treated HA implant surface attenuates the progression of peri‐implantitis.

https://ift.tt/2QMeHpE

Neutrophil-to-lymphocyte ratio is superior to platelet-to-lymphocyte ratio as a prognostic predictor in advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy

Future Oncology, Ahead of Print.


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The Gene Mutation Spectrum of Breast Cancer Analyzed by Semiconductor Sequencing Platform

Abstract

To use the semiconductor sequencing platform (SSP) to analyze the gene mutate spectrum of breast cancer patients. We recruited 46 breast cancer patients, and detected the ER/PR/HER2 expression level of the tumor tissue by immunohistochemistry. In addition, combined with SSP technology, we detected 207 hot mutation regions of 50 breast cancer related genes with multiple polymerase chain reaction (PCR) technology. There were 8 cases of grade I, 18 cases of grade II, 20 cases of grade III in 46 breast cancer patients according to histological grade and 12 cases of ER/PR ⁺ HER2 ⁺, 18 cases of ER/PR ⁺ HER2⁻, 13 cases of ER/PR ^- HER2 ⁺, 20 cases of ER/PR ⁻ HER2⁻ according to ER/PR/HER2 status classification. Moreover, we found that there were 33 gene locus mutations of 8 genes including AKT1, APC, BRAF, CDKN2A, KRAS, PTEN, PIK3CA and TP53, but difference was not statistically significant (P > 0.05) when compared these gene mutations (except for PIK3CA) in each groups according to the histological classification of breast cancer and the ER/PR/HER2 classification. PIK3CA mutation rate of grade I was obviously higher than that of grade II ~ III histological grading in breast cancer patients (P < 0.05). Based on our results, we drew a conclusion that the occurrence and development of breast cancer was a process involved multiple genes. Here, we found that PIK3CA played a role in the development of the early stage of breast cancer, which could provide clinical basis for treatment of breast cancer. Moreover, SSP technology could be an effective and sensitive method for detection of gene mutation spectrum in breast cancer.

https://ift.tt/2qOrcWn

Firing properties of ventral medullary respiratory neurons in sino‐aortic denervated rats

New Findings

What is the central question of this study?

After sino‐aortic denervation (SAD) rats present normal levels of mean arterial pressure (MAP), high MAP variability and changes in breathing. However, mechanisms involved in SAD‐induced respiratory changes and their impact on the modulation of sympathetic activity remain unclear. Herein, we characterized the firing frequency of medullary respiratory neurons after SAD.

What is the main finding and its importance?

SAD‐induced prolonged inspiration was associated with a reduced interburst frequency of Pre‐I/I and an increased long‐term variability of Late‐I neurons, but no changes were observed in the Ramp‐I and Post‐I neurons. This imbalance in the respiratory network may contribute to the modulation of sympathetic activity after SAD.

Abstract

In previous studies we documented that after sino‐aortic denervation (SAD) in rats there are significant changes in the breathing pattern, but no significant changes in sympathetic activity and mean arterial pressure (MAP) compared with Sham‐operated rats. However, the neural mechanisms involved in the respiratory changes after SAD and the extent to which they may contribute to the observed normal sympathetic activity and MAP remain unclear. Here, we hypothesized that after SAD, rats present with changes in the firing frequency of the ventral medullary inspiratory and post‐inspiratory neurons. To test this hypothesis, male Wistar rats underwent SAD or Sham surgery and 3 days later were surgically prepared for an in situ preparation. The duration of inspiration significantly increased in SAD rats. During inspiration, the total firing frequency of Ramp‐I, Pre‐I / I, and Late‐I neurons was not different between groups. During post‐inspiration, the total firing frequency of Post‐I neurons was also not different between groups. Furthermore, the data demonstrate a reduced interburst frequency of Pre‐I/I and an increased long‐term variability of Late‐I neurons in SAD compared with Sham rats. These findings indicate that the SAD‐induced prolonged inspiration was not accompanied by alterations in the total firing frequency of the ventral medullary respiratory neurons, but it was associated with changes in the long‐term variability of Late‐I neurons. We suggest that the timing imbalance in the respiratory network in SAD rats may contribute to the modulation of presympathetic neurons after removal of baroreceptor afferents.

This article is protected by copyright. All rights reserved

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Metabolomics for the mountains; bring on the biomarkers!

https://ift.tt/2qMHtem

Histologic transformation of non-small-cell lung cancer in brain metastases

Abstract

Background

Treatment strategies differ substantially for small-cell lung cancer (SCLC), adenocarcinoma and squamous-cell cancer (SCC). Therefore, it is of important significance to identify histologic transformation. There are no reports on histologic transformation in brain metastases (BM) to date. The aim of this study was to analyze the histologic transformation in BM for the first time.

Methods

Medical records were reviewed and patients with both resected BM and primary tumors were examined retrospectively. The histologic diagnosis was confirmed by H&E staining, and additional diagnostic immunohistochemical stains were performed at the discretion of the pathologists. Characteristics of histologic transformation in BM were analyzed.

Results

3 of 24 patients (12.5%) with both resected BM and primary non-small-cell lung cancers (NSCLCs) had evidence of histologic transformation in BM. One case with SCC transformed to adenocarcinoma in brain, one case with adenocarcinoma transformed to SCLC, and another case with adenocarcinoma transformed to SCC. The three cases of histologic transformation were all spontaneous and had not tested gene status.

Conclusions

We disclosed the histologic transformation of NSCLC in BM at a frequency not as low as expected, and speculated it as an evolution promoted by intratumor heterogeneity, though it warrants further prospective multi-institution investigations with comprehensive molecular analysis. Our findings provided further impetus for surgery when the metastatic or recurrent lesion is resectable, and repeated pathologic evaluation to help tailor individualized treatment.

https://ift.tt/2ze2Rhr

Anterior thalamic deep brain stimulation in refractory epilepsy: a randomized, double‐blinded study

Abstract

Objectives

The safety and effect on seizure frequency of anterior thalamic nucleus deep brain stimulation (ANT‐DBS) were studied in this prospective, randomized, double‐blinded study. Patients were followed for 12 months. The first 6 months were blinded with regard to active stimulation or not. After 6 months, all patients received active stimulation.

Material and methods

Bilateral ANT electrodes were implanted into 18 patients suffering from focal, pharmacoresistant epilepsy. Antiepileptic treatment was kept unchanged from three months prior to operation. The Liverpool seizure severity scale (LSSS) was used to measure the burden of epilepsy.

Results

There was no significant difference between the 2 groups at the end of the blinded period at 6 months. However, when considering all patients and comparing 6 months of stimulation with baseline, there was a significant, 22% reduction in the frequency of all seizures (p=0.009). Four patients had ≥ 50% reduction in total seizure frequency and 5 patients ≥ 50% reduction in focal seizures after 6 months of stimulation. No increased effect over time was shown. LSSS at 6 months compared to baseline showed no significant difference between the 2 groups, but a small, significant reduction in LSSS was found when all patients had received stimulation for 6 months.

Conclusions

Our study supports results from earlier studies concerning DBS as a safe treatment option, with effects even in patients with severe, refractory epilepsy. However, our results are not as encouraging as those reported from many other, mainly unblinded, and open studies.

This article is protected by copyright. All rights reserved.

https://ift.tt/2RRqGSS

Efficacy of Co Q10 as Supplementation for Migraine: A Meta‐Analysis

Abstract

Objectives

Migraine ranks among the most frequent neurological disorders globally. Co‐enzyme Q10 (CoQ10) is a nutritional agent that might play a preventative role in migraine. This meta‐analysis aimed to investigate the effects of CoQ10 as a supplemental agent in migraine.

Subjects and methods

Web of Science, PubMed and Cochrane Library were searched for potential articles that assessed the effects of CoQ10 on migraine. Data were extracted by two independent reviewers and analyzed with Revman 5.2 software.

Results

We included 5 studies with 346 patients (120 pediatric and 226 adult subjects) in the meta‐analysis. CoQ10 was comparable with placebo with respect to migraine attacks/month (P = 0.08) and migraine severity/day (P = 0.08). However, CoQ10 was more effective than placebo in reducing migraine days/month (P <0.00001) and migraine duration (P = 0.009).

Conclusion

This is the first study to demonstrate the effects of CoQ10 supplementation on migraine. The results support the use of CoQ10 as a potent therapeutic agent with respect to migraine duration and migraine days per month. Nonetheless, more studies are needed to support the conclusions.

This article is protected by copyright. All rights reserved.

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Rehabilitation in chronic spatial neglect strengthens resting state connectivity

Abstract

Objectives

Rehabilitation of patients with chronic visuospatial neglect is underexplored, and little is known about neural mechanisms that can be exploited to promote recovery. In this study, we present data on resting state functional connectivity within the dorsal attention network (DAN) in chronic neglect patients as they underwent training in a virtual reality (VR) environment that improved left‐side awareness.

Methods

The study included 13 patients with visuospatial neglect persisting more than six months after a right‐sided stroke. The patients underwent resting state functional magnetic resonance imaging (fMRI). Scans were collected at baseline and after five weeks of intense training. We specifically examined resting state functional connectivity within the DAN. In addition, using spatial concordance correlation, we compared changes in the spatial topology of the DAN with that of other networks.

Results

We found a longitudinal increase in interhemispheric functional connectivity between the right frontal eye field and the left intraparietal sulcus following training (pre: 0.33±0.17 [mean±SD]; post 0.45±0.13; P=0.004). The spatial concordance analyses indicated that training influenced the DAN connectivity more than any of the other networks.

Conclusion

Intense VR training that improved left sided awareness in chronic stroke patients also increased sporadic interhemispheric functional connectivity within the DAN. Specifically, a region responsible for saccadic eye movement to the left became more integrated with the left posterior parietal cortex. These results highlight a mechanism that should be exploited in the training of patients with chronic visuospatial neglect.

This article is protected by copyright. All rights reserved.

https://ift.tt/2DHj1n9

GATOR1 variants in Chinese people with sporadic drug‐resistant focal epilepsy

Abstract

Objectives

GATOR1 (Gap Activity TOward Rags 1) is composed of three different subunits, DEPDC5 (DEP domain‐containing protein 5), NPRL2 (nitrogen permease regulator‐like 2), and NPRL3 (nitrogen permease regulator‐like 3), and variants in these three genes have mostly been reported in familial focal epilepsy. However, very few studies have been carried out on sporadic drug‐resistant focal epilepsy patients. In this study, we aimed to identify the frequency of variants in DEPDC5, NPRL2 and NPRL3 in patients with sporadic drug‐resistant focal epilepsy.

Materials & Methods

One hundred and ninety‐three Chinese people with sporadic drug‐resistant focal epilepsy were enrolled in the study. Targeted sequencing of DEPDC5, NPRL2 and NPRL3 was applied at an average coverage depth of 2500x.

Results

In the 193 patients with sporadic focal epilepsy included in this study, the median age was 24.6 years with a median age at onset of 13.99 years, and 130 of these patients had identifiable structural lesions. One possibly pathogenic missense variant of DEPDC5, c.2984G>A, p.Arg995His, was found in one patient (0.52%) with hippocampal sclerosis, and one variant of unknown significance, DEPDC5 c.20A>G, p.Tyr7Cys, was found in two patients with hippocampal sclerosis (1.04%).

Conclusions

Our findings suggested that DEPDC5 might be of more importance than NPRL2 or NPRL3 in Chinese epilepsy patients with sporadic drug‐resistant focal epilepsy. Future research should focus on the mechanism by which the mechanistic target of rapamycin (mTOR) is involved in epileptogenesis in sporadic epilepsy.

This article is protected by copyright. All rights reserved.

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Structural correlates of cognitive impairment in normal pressure hydrocephalus

Abstract

Objectives

The pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present study used automated segmentation methods to investigate whether SDGM structure volumes are associated with cognitive and neuropsychiatric measures.

Methods

Fourteen NPH patients and eight healthy controls were included in the study. Patients completed neuropsychological tests of general cognition, verbal learning and memory, verbal fluency, and measures of apathy and depression pre‐ and post‐shunt surgery. Additionally, patients underwent 3 Tesla T1‐weighted magnetic resonance imaging at baseline and 6 months post‐operatively. Controls were scanned once. SDGM structure volumes were estimated using automated segmentation (FSL FIRST). Since displacement of the caudate nuclei occurred for some patients due to ventriculomegaly, patient caudate volumes were also estimated using manual tracing. Group differences in SDGM structure volumes were investigated, as well as associations between volumes and cognitive and neuropsychiatric measures in patients.

Results

Volumes of the caudate, thalamus, putamen, pallidum, hippocampus, and nucleus accumbens were significantly reduced in the NPH patients compared to controls. In the NPH group, smaller caudate and NAcc volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms, while reduced volume of the pallidum was associated with better performance on the MMSE and reduced apathy.

Conclusions

Striatal volume loss appears to be associated with cognitive and neuropsychiatric changes in NPH.

This article is protected by copyright. All rights reserved.

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Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor

Abstract

This phase 1 study (CO‐338‐044; NCT02740712), conducted in patients with an advanced solid tumor, evaluated the effect of the poly(ADP‐ribose) polymerase inhibitor rucaparib on the pharmacokinetics of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 [CYP] 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P‐glycoprotein substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg twice daily (BID). Geometric mean (GM) ratios (90% CI) of AUC from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93–2.65); S‐warfarin, 1.49 (1.40–1.58); omeprazole, 1.55 (1.32–1.83); midazolam, 1.39 (1.14–1.68); and digoxin, 1.20 (1.12–1.29). There was limited effect on peak concentration of the substrates (GM ratios, 0.99–1.13). At steady state, rucaparib 600 mg BID moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure.

This article is protected by copyright. All rights reserved.

https://ift.tt/2TheufN

Man Talk: Exploring Sexual Communication Between Fathers and Sons in a Minority South African Community

Abstract

Much of what is known about father-child sexual communication is based on studies conducted in North America and more research into under-represented groups is needed. Our exploratory study therefore investigated sexual communication within father-son dyads belonging to a minority group in South Africa. We used a qualitative research design, and a total of 30 in-depth individual interviews were conducted with the members of 15 father-young adult son dyads. Thematic analysis of the data indicated that although both fathers and sons believed that fathers have an important role to play in the sex education of sons, the sexual communication in these dyads were mostly indirect, singular, and father-centered warnings, jokes or speeches. The men in our study would therefore benefit from interventions that equip them with knowledge and skills to function as more effective sexual communicators and educators. Furthermore, we found that limiting hegemonic masculinity ideas underpinned father-son sexual communication, which implies that interventions to empower fathers as effective sex communicators should also challenge and expand ideas and practices involving masculinity and fatherhood. We also identified context-specific issues (e.g., being mindful of how the idea of explicit sexual communication fits with local constructions of respectful father-son relationships) that need to be attended to in such interventions.

https://ift.tt/2zW1nb4

Increased expression of PD1 and CD39 on CD3+CD4+ skin T‐cells in the elderly

Abstract

Normal aging is associated with an impaired systemic immune response contributing to an increased susceptibility to infectious diseases. The aim of this study was to compare the lymphocyte phenotype in human skin from old and young healthy subjects. Skin samples from donors were used for explant cultures before flow cytometry analysis. Our results depicted a higher proportion of CD4⁺ and a lower proportion of CD8⁺ among CD3⁺ T‐cells, a decreased proportion of CD45RA⁺ naive T‐cells (3.5 ± 1.9% vs 22.9 ± 11.1%, p≤0.007) and an upregulation of the expression of CD39 and PD1 on CD3⁺CD4⁺ T‐cells (25.1 ± 8.5% vs 12.5 ± 8.5%, p≤0.003, 68.8 ± 11.6% vs 50.0 ± 11.3%, p≤0.01, respectively) in the skin of old subjects. These findings could explain a reduced generation of long‐lived memory T‐cells and an impaired antitumoral response in the skin of the elderly.

This article is protected by copyright. All rights reserved.

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Melasma: Updates and Perspectives

Abstract

Management of melasma is highly challenging due to inconsistent treatment results and frequent relapses. However, recent studies revealed that melasma may not only be a disease of melanocytes, but also a photoaging skin disorder. Herein, we attempt to validate that melasma is indeed a photoaging disorder by presenting the histopathologic findings of melasma: solar elastosis, altered basement membrane, increased vascularization, and increased mast cell count. We also provide some therapeutic implications based on these findings and a discussion on the latest updates and perspectives regarding treatment.

This article is protected by copyright. All rights reserved.

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Randomized controlled trial of mechanical bowel preparation for laparoscopy‐assisted colectomy

Abstract

Introduction

The benefit of mechanical bowel preparation (MBP) before open colon surgery has been debated over the last decade. The aim of this randomized controlled trial was to evaluate the effect of MBP on the outcome of patients who underwent elective laparoscopic colectomy.

Methods

Patients who were scheduled to undergo elective laparoscopic colon resection with primary anastomosis were randomly allocated to a preoperative MBP group (either two bottles of sodium phosphate or 2‐L polyethylene glycol) or a no‐MBP group. Anastomotic leakage and other complications such as surgical‐site infection and extra‐abdominal complications were recorded postoperatively.

Results

In this study, 122 patients were recruited and randomly allocated to the MBP group (n = 62) or the no‐MBP group (n = 60). Demographic and clinical characteristics were not significantly different between the two groups. The rate of abdominal complications, including anastomotic leak and surgical‐site infection, was 16.2% in the MBP group and 18.3% in the no‐MBP group (P = 0.747). Anastomotic leakage occurred in four patients (6.5%) in the MBP group and in two patients (3.3%) in no‐MBP group (P = 0.680). About 29% of patients in the MBP group still had either liquid or solid content in the bowel. No significant difference was found between the length of hospital stay in the MBP group and the no‐MBP group (9.0 ± 2.9 vs 8.4 ± 1.9 days, P = 0.180).

Conclusions

Elective laparoscopic colectomy without MBP is safe and offers acceptable postoperative morbidity.

https://ift.tt/2qNtZ1Z

High long‐term mortality after incident status epilepticus in adults: Results from a population‐based study

Summary

Objective

To determine annual incidence, etiology, severity, and short‐ and long‐term mortality of first‐time, nonanoxic status epilepticus (SE) in adults in a population‐based retrospective cohort study.

Methods

We systematically identified all episodes of SE in the year 2014 on the island of Funen. Patients with SE due to anoxia, patients with recurrent SE, and patients <18 years old were excluded. Nonconvulsive SE in coma was diagnosed according to the Salzburg criteria. Etiology, semiology, modified Rankin Scale (mRS) at discharge, survival, and the Status Epilepticus Severity Score were retrospectively determined from patients' records. Patients with first‐time nonanoxic SE diagnosed during 2008‐2013 from our database (n = 88) were used to confirm the results.

Results

The incidence of first‐time, nonanoxic SE in 2014 was 10.7/100 000 persons at risk (n = 41). Median Status Epilepticus Severity Score was 3; in‐hospital mortality was 24.4%. After median follow‐up of 39.2 months, 53.7% of the patients had died (age‐ and gender‐adjusted mortality rate of 5.2/100 000). Mortality stabilized 2 years after diagnosis. Analysis of the cohort from 2008‐2013 confirmed stabilization of survival after 2‐3 years and the high mortality 2 years after discharge. When correcting for acute symptomatic causes, the in‐hospital mortality was 16.7% and 46.7% at follow‐up (crude mortality rate of nonhypoxic and nonacute symptomatic SE = 3.5/100 000). An exploratory multivariate analysis of pooled patients with SE from 2008 to 2014 revealed mRS ≥ 2 at discharge as a prognostic factor for long‐term mortality.

Significance

In this cohort, the overall mortality of first‐time nonhypoxic SE was >50%. Mortality of SE after discharge was substantially higher than in‐house mortality and stabilized after 2 years. The degree of disability as indicated by mRS at discharge was associated with long‐term mortality after discharge.

https://ift.tt/2qMJJCe

Corpus callosum low‐frequency stimulation suppresses seizures in an acute rat model of focal cortical seizures

Summary

Objective

Low‐frequency fiber‐tract stimulation has been shown to be effective in treating mesial temporal lobe epilepsies through activation of the hippocampal commissure in rodents and human patients. The corpus callosum is a major pathway connecting the two hemispheres of the brain; however, few experiments have documented corpus callosum stimulation. The objective is to determine the efficacy of corpus callosum stimulation at low frequencies to suppress cortical seizures.

Methods

4‐Aminopyridine was injected in the primary motor cortex of 24 rats under anesthesia. Recording electrodes were placed in the contralateral motor cortex and hippocampus. Three pairs of stimulating electrodes were inserted into the corpus callosum along its longitudinal axis. Local field potentials were recorded 1 hour before, during, and after stimulation to determine the effect of stimulation on seizure duration. Stimulation was delivered from each pair of electrodes independently in separate experiments. Furthermore, electrical stimulation was applied to the region of the corpus callosum with the highest degree of innervation of the seizure focus to compare the efficacy of different stimulation frequencies (1‐30 Hz) on seizure suppression.

Results

Corpus callosum stimulation was effective at suppressing seizures at 10 Hz by 76% (P < 0.05, n = 5) and at 20 Hz by 95% (P < 0.0001, n = 14). Stimulation at frequencies of 1 and 30 Hz did not have a significant effect on reducing the total time spent seizing (P > 0.9999, n = 5). Furthermore, stimulation was only effective at suppressing seizures when the pair of electrodes was placed within the section of corpus callosum containing fibers innervating the seizure focus. Secondarily generalized seizures in the hippocampus were eliminated when seizures in the cortical focus were suppressed.

Significance

Low‐frequency fiber‐tract stimulation of the corpus callosum suppresses both cortical and cortically induced hippocampal seizures in an acute model of focal cortical seizures. The stimulation paradigm is selective, as it is only effective when targeted to specific regions of the corpus callosum that project maximally to cortical regions generating the seizure activity. Selective placement of stimulation electrodes along the corpus callosum could be used as a patient‐specific treatment for cortical epilepsies.

https://ift.tt/2Fqv8qs

The repertoire of seizure onset patterns in human focal epilepsies: Determinants and prognostic values

Summary

Objective

In this study, we seek to analyze the determinants of the intracranial electroencephalography seizure onset pattern (SOP) and the impact of the SOP in predicting postsurgical seizure outcome.

Methods

To this end, we analyzed 820 seizures from 252 consecutive patients explored by stereo‐electroencephalography (total of 2148 electrodes), including various forms of focal refractory epilepsies. We used a reproducible method combining visual and time‐frequency analyses.

Results

We described eight SOPs: low‐voltage fast activity (LVFA), preictal spiking followed by LVFA, burst of polyspikes followed by LVFA, slow wave/DC shift followed by LVFA, sharp theta/alpha waves, beta sharp waves, rhythmic spikes/spike‐waves, and delta‐brush. LVFA occurred in 79% of patients. The seizure onset pattern was significantly associated with (1) underlying etiology (burst of polyspikes followed by LVFA with the presence of a focal cortical dysplasia, LVFA with malformation of cortical development, postvascular and undetermined epilepsies), (2) spatial organization of the epileptogenic zone (EZ; burst of polyspikes followed by LVFA with focal organization, slow wave/DC shift followed by LVFA with network organization), and (3) postsurgical seizure outcome (better outcome when LVFA present).

Significance

This study demonstrates that the main determinants of the SOP are the underlying etiology and the spatial organization of the EZ. Concerning the postsurgical seizure outcome, the main determinant factor is the spatial organization of the EZ, but the SOP plays also a role, conferring better prognosis when LVFA is present.

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Correction to: Trunk, head and pelvis interactions in healthy children when performing seated daily arm tasks

The authors inadvertently submitted a wrong figure part for publication. Figure 8b should be as follows.

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Perihilar Glissonian Approach for Anatomical Parenchymal Sparing Liver Resections: Technical Aspects The Taping Game Erratum

No abstract available

https://ift.tt/2FosTUz

Developing Safe Opioid Prescribing Practices Through Medical Student Education

No abstract available

https://ift.tt/2QxThwm

Retinal image analytics detects white matter hyperintensities in healthy adults

Abstract

Objective

We investigated whether an automatic retinal image analysis (ARIA) incorporating machine learning approach can identify asymptomatic older adults harboring high burden of white matter hyperintensities (WMH) using MRI as gold standard.

Methods

In this cross‐sectional study, we evaluated 180 community‐dwelling, stroke‐, and dementia‐free healthy subjects and performed ARIA by acquiring a nonmydriatic retinal fundus image. The primary outcome was the diagnostic performance of ARIA in detecting significant WMH on MRI brain, defined as age‐related white matter changes (ARWMC) grade ≥2. We analyzed both clinical variables and retinal characteristics using logistic regression analysis. We developed a machine learning network model with ARIA to estimate WMH and its classification.

Results

All 180 subjects completed MRI and ARIA. The mean age was 70.3 ± 4.5 years, 70 (39%) were male. Risk factor profiles were: 106 (59%) hypertension, 31 (17%) diabetes, and 47 (26%) hyperlipidemia. Severe WMH (global ARWMC grade ≥2) was found in 56 (31%) subjects. The performance for detecting severe WMH with sensitivity (SN) 0.929 (95% CI from 0.819 to 0.977) and specificity (SP) 0.984 (95% CI from 0.937 to 0.997) was excellent. There was a good correlation between WMH volume (log‐transformed) obtained from MRI versus those estimated from retinal images using ARIA with a correlation coefficient of 0.897 (95% CI from 0.864 to 0.922).

Interpretation

We developed a robust algorithm to automatically evaluate retinal fundus image that can identify subjects with high WMH burden. Further community‐based prospective studies should be performed for early screening of population at risk of cerebral small vessel disease.

https://ift.tt/2K6Bvhi

Remote ischemic conditioning for stroke: clinical data, challenges, and future directions

Abstract

Despite great improvement during the past several decades, the management of stroke is still far from satisfactory, which warrants alternative or adjunctive strategies. Remote ischemic conditioning (RIC), an easy‐to‐use and noninvasive therapy, can be performed in various clinical scenarios (e.g., prehospital transportation, intrahospital, and at home), and it has been widely investigated for stroke management. RIC has been demonstrated to be well tolerated in patients with acute ischemic stroke and aneurysm subarachnoid hemorrhage, and it may benefit these patients by improving clinical outcomes; in patients with intracranial atherosclerosis, long‐term repeated RIC could be safely performed and benefit patients by reducing recurrent ischemic stroke and transient ischemic attack, as well as improving cerebral perfusion status; long‐term repeated RIC may also benefit patients with cerebral small vessel disease by slowing cognitive decline and reducing volume of white matter hyperintensities on brain MRI; in patients with severe carotid atherosclerotic stenosis undergoing stenting, preprocedural RIC could reduce the odds of new brain lesions on postprocedural MRI. Previous clinical studies suggest broad future prospects of RIC in the field of cerebrovascular diseases. However, the optimal RIC protocol and the mechanisms that RIC protects the brain is not fully clear, and there is lack of sensitive and specific biomarkers of RIC, all these dilemmas prevent RIC from entering clinical practice. This review focuses on recent advances in clinical studies of RIC in stroke management, its challenges, and the potential directions of future studies.

https://ift.tt/2K5RTys

MYORG is associated with recessive primary familial brain calcification

Abstract

Objective

To investigate the genetic basis of the recessive form of primary familial brain calcification and study pathways linking a novel gene with known dominant genes that cause the disease.

Methods

Whole exome sequencing and Sanger‐based segregation analysis were used to identify possible disease causing mutations. Mutation pathogenicity was validated by structural protein modeling. Functional associations between the candidate gene, MYORG, and genes previously implicated in the disease were examined through phylogenetic profiling.

Results

We studied nine affected individuals from two unrelated families of Middle Eastern origin. The median age of symptom onset was 29.5 years (range 21–57 years) and dysarthria was the most common presenting symptom. We identified in the MYORG gene, a homozygous c.1233delC mutation in one family and c.1060_1062delGAC mutation in another. The first mutation results in protein truncation and the second in deletion of a highly conserved aspartic acid that is likely to disrupt binding of the protein with its substrate. Phylogenetic profiling analysis of the MYORG protein sequence suggests co‐evolution with a number of calcium channels as well as other proteins related to regulation of anion transmembrane transport (False Discovery Rate, FDR < 10⁻⁸) and with PDCD6IP, a protein interacting with PDGFRβ which is known to be involved in the disease.

Interpretation

MYORG mutations are linked to a recessive form of primary familial brain calcification. This association was recently described in patients of Chinese ancestry. We suggest the possibility that MYORG mutations lead to calcification in a PDGFRβ‐related pathway.

https://ift.tt/2Bc3oBT

Novel challenges in spinal muscular atrophy – How to screen and whom to treat?

Abstract

In recent years, disease‐modifying and life‐prolonging therapies for spinal muscular atrophy (SMA) have been developed. However, patients are currently diagnosed with significant delay and therapies are often administered in advanced stages of motor neuron degeneration, showing limited effects. Methods to identify children in presymptomatic stages are currently evaluated in newborn screening programs. Yet, not all children develop symptoms shortly after birth raising the question whom to treat and when to initiate therapy. Finally, monitoring disease progression becomes essential to individualize management. Here, we review the literature on screening approaches, strategies to predict disease severity, and biomarkers to monitor therapy.

https://ift.tt/2B9z2zZ

Long‐term follow‐up of single crowns supported by short, moderately rough implants – A prospective 10‐year cohort study

Abstract

Objectives

To evaluate prospectively the clinical and radiographic outcomes after ten years of short (6 mm) implants with a moderately rough surface supporting single crowns in the posterior region.

Material and Methods

Forty 6 mm modified sandblasted large‐grit acid‐etched (mod‐SLA), soft tissue level implants were installed in the distal segments of 35 consecutive patients. After 6 weeks of healing, abutments were tightened, and single porcelain fused‐to‐metal crowns were cemented. Implant survival, marginal bone loss and clinical crown/implant ratio were evaluated at various time intervals up to 10 years after loading.

Results

Two out of the 40 implants were lost before loading, one implant was lost after 7 years because of peri‐implantitis. One patient with two implants died and was excluded from analysis. Two patients did not come at the 10‐year follow‐up and were considered as drop out (2 implants). The survival rate was 91.7% (n=36). Thirty‐three implants were available for marginal bone loss evaluation. A mean marginal bone loss after 10 years of function was 0.8±0.7mm. Between 5 and 10 years the loss was 0.2±0.4 mm. No technical complications were registered during the 10‐year period. The clinical crown/implant ratio increased with time from 1.6 at the delivery of the prosthesis to 2.0 after 10 years of loading with no increase between 5 and 10 years.

Conclusion

Short (6mm) implants with a moderately rough surface supporting single crowns in the posterior region and loaded after 6‐7 weeks maintained full function for at least 10 years with low marginal bone resorption.

This article is protected by copyright. All rights reserved.

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Homozygous splicing mutation in NUP133 causes Galloway–Mowat syndrome

Objective

Galloway–Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early‐onset nephrotic syndrome. Biallelic mutations in WDR73 and the four subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107 kDa) mutation was identified in four GAMOS‐like families, although biallelic NUP107 mutations were originally identified in steroid‐resistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133 kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis.

Methods

Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid‐resistant nephrotic syndrome.

Results

We identified a homozygous NUP133 mutation, c.3335‐11T>A, which results in the insertion of 9 bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the three examined patients. A nup133‐knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wildtype NUP133 mRNA but not by mutant mRNA.

Interpretation

These data indicate that the biallelic NUP133 loss‐of‐function mutation causes GAMOS.

This article is protected by copyright. All rights reserved

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Ultrafast Sodium Full Batteries Derived from XFe (X = Co, Ni, Mn) Prussian Blue Analogs

Cubic‐like XFe (X = Co, Ni, Mn) Prussian blue analogs (PBAs) are designed through as‐tuned ionic bonding of XFe. Ni‐Fe PBAs as cathode show "zero‐strain" insertion traits with physical–chemical stability, and their derived binary metal‐selenide as anode displays strong metal‐like conductivity. Their matched sodium full‐cell systems deliver reasonably high and fast specific capacity.

Abstract

Exploring high‐rate electrode materials with excellent kinetic properties is imperative for advanced sodium‐storage systems. Herein, novel cubic‐like XFe (X = Co, Ni, Mn) Prussian blue analogs (PBAs), as cathodes materials, are obtained through as‐tuned ionic bonding, delivering improved crystallinity and homogeneous particles size. As expected, Ni‐Fe PBAs show a capacity of 81 mAh g⁻¹ at 1.0 A g⁻¹, mainly resulting from their physical–chemical stability, fast kinetics, and "zero‐strain" insertion characteristics. Considering that the combination of elements incorporated with carbon may increase the rate of ion transfer and improve the lifetime of cycling stability, they are expected to derive binary metal‐selenide/nitrogen‐doped carbon as anodes. Among them, binary Ni_0.67Fe_0.33Se₂ coming from Ni‐Fe PBAs shows obvious core–shell structure in a dual‐carbon matrix, leading to enhanced electron interactions, electrochemical activity, and "metal‐like" conductivity, which could retain an ultralong‐term stability of 375 mAh g⁻¹ after 10 000 loops even at 10.0 A g⁻¹. The corresponding full‐cell Ni‐Fe PBAs versus Ni_0.67Fe_0.33Se₂ deliver a remarkable Na‐storage capacity of 302.2 mAh g⁻¹ at 1.0 A g⁻¹. The rational strategy is anticipated to offer more possibilities for designing advanced electrode materials used in high‐performance sodium‐ion batteries.

https://ift.tt/2zfBL9o

Mobility Deception in Nanoscale Transistors: An Untold Contact Story

Mobility is a critical parameter that is routinely used for benchmarking the performance of field‐effect transistors (FETs) based on novel nanomaterials. In this article, it is demonstrated that contact interface, contact doping, and contact geometry play a pivotal role in mobility extraction and can lead to both underestimation and overestimation of its true value.

Abstract

Mobility is a critical parameter that is routinely used for benchmarking the performance of field‐effect transistors (FETs) based on novel nanomaterials. In fact, mobility values are often used to champion nanomaterials since high‐performance devices necessitate high mobility values. The current belief is that the contacts can only limit the FET performance and hence the extracted mobility is an underestimation of the true channel mobility. However, here, such misconception is challenged through rigorous experimental effort, backed by numerical simulations, to demonstrate that overestimation of mobility occurs in commonly used geometries and in nanomaterials for which the contact interface, contact doping, and contact geometry play a pivotal role. In particular, dual‐gated FETs based on multilayer MoS₂ and WSe₂ are used as case studies in order to elucidate and differentiate between intrinsic and extrinsic contact effects manifesting in the mobility extraction. The choice of 2D layered transition metal dichalcogenides (TMDCs) as the semiconducting channel is motivated by their potential to replace and/or coexist with Si‐based aging FET technologies. However, the results are equally applicable to nanotube‐ and nanowire‐based FETs, oxide semiconductors, and organic‐material‐based thin‐film FETs.

https://ift.tt/2OOqz8O

Hollow‐Structured Metal Oxides as Oxygen‐Related Catalysts

Offering flexible electronic structures, transition metal oxides are the optimal oxygen‐related catalysts. Rational design and precise synthesis of their hollow structures can greatly enhance their performance in energy‐related applications. Urgent challenges and further research directions are presented for hollow‐structured transition metal oxides toward oxygen‐related catalysis.

Abstract

Metal oxide hollow structures with large surface area, low density, and high loading capacity have received great attention for energy‐related applications. Acting as oxygen‐related catalysts, hollow‐structured transition metal oxides offer low overpotential, fast reaction rate, and excellent stability. Herein, recent progress in the oxygen‐related catalysis (e.g., oxygen evolution reaction (OER), oxygen reduction reaction (ORR), and metal–air batteries) of hollow‐structured transition metal oxides is discussed. Through a comprehensive outline of hollow‐structured spinels, perovskites, rutiles, etc., a rational design strategy is provided for an enhanced oxygen‐related catalysis performance from the viewpoint of crystal structures. Urgent challenges and further research directions are presented for hollow‐structured transition metal oxides toward excellent oxygen‐related catalysis.

https://ift.tt/2OLvdo3

Nanoscale Behavior and Manipulation of the Phase Transition in Single‐Crystal Cu2Se

In wedge‐shaped nanosized single‐crystal Cu₂Se, the significant surface and shape effects make the coexistence of the α and β phases thermodynamically stable over a large temperature range below the bulk transition temperature, and controllable at atomic level, which is difficult to achieve during a second‐order phase transition in a bulk single crystal.

Abstract

Phase transition is a fundamental physical phenomenon that has been widely studied both theoretically and experimentally. According to the Landau theory, the coexistence of high‐ and low‐temperature phases is thermodynamically impossible during a second‐order phase transition in a bulk single crystal. Here, the coexistence of two (α and β) phases in wedge‐shaped nanosized single‐crystal Cu₂Se over a large temperature range are demonstrated. By considering the surface free‐energy difference between the two phases and the shape effect, a thermodynamic model is established, which explicitly explains their coexistence. Intriguingly, it is found that with a precise control of the heating temperature, the phase boundary can be manipulated at atomic level. These discoveries extend the understanding of phase transitions to the nanoscale and shed light on rational manipulation of phase transitions in nanomaterials.

https://ift.tt/2zcyNCB

Ultrafast Sodium/Potassium‐Ion Intercalation into Hierarchically Porous Thin Carbon Shells

Exploitation of carbon as the anode for sodium‐ and potassium‐ion batteries is critical to develop inexpensive battery systems. Carbon material with relaxed graphitic layers (interlayer spacing reaching 0.375 nm) is developed for deep, fast, and reversible insertion of large metallic ions in the engineered lattice. The proposed methodology provides new ways of achieving high‐performing electrodes for new battery systems.

Abstract

The large‐scale application of sodium/potassium‐ion batteries is severely limited by the low and slow charge storage dynamics of electrode materials. The crystalline carbons exhibit poor insertion capability of large Na⁺/K⁺ ions, which limits the storage capability of Na/K batteries. Herein, porous S and N co‐doped thin carbon (S/N@C) with shell‐like (shell size ≈20–30 nm, shell wall ≈8–10 nm) morphology for enhanced Na⁺/K⁺ storage is presented. Thanks to the hollow structure and thin shell‐wall, S/N@C exhibits an excellent Na⁺/K⁺ storage capability with fast mass transport at higher current densities, leading to limited compromise over charge storage at high charge/discharge rates. The S/N@C delivers a high reversible capacity of 448 mAh g^‐1 for Na battery, at the current density of 100 mA g^‐1 and maintains a discharge capacity up to 337 mAh g^‐1 at 1000 mA g^‐1. Owing to shortened diffusion pathways, S/N@C delivers an unprecedented discharge capacity of 204 and 169 mAh g^‐1 at extremely high current densities of 16 000 and 32 000 mA g^‐1, respectively, with excellent reversible capacity for 4500 cycles. Moreover, S/N@C exhibits high K⁺ storage capability (320 mAh g^‐1 at current density of 50 mA g^‐1) and excellent cyclic life.

https://ift.tt/2OLv583

Caspase Recruitment Domain Protein 6 Protects Against Hepatic Steatosis and Insulin Resistance by Suppressing Apoptosis Signal–Regulating Kinase 1

The rapidly increasing prevalence of metabolic disorders associated with nonalcoholic fatty liver disease (NAFLD) warrants further study of the underlying mechanisms to identify key regulators as targets for the development of therapeutic interventions. Caspase recruitment domain protein 6 (Card6), as a member of the CARD family that regulates cell death and immunity, may potentially control this process. Indeed, Card6 down‐regulation was found to be closely associated with the fatty livers observed in NAFLD patients, obese mice, and a palmitate‐treated hepatocyte model. Gain‐of‐function and loss‐of‐function Card6 mouse models demonstrated that Card6 protected mice from insulin resistance, hepatic steatosis, and inflammatory responses upon high‐fat diet administration. Mechanistically, Card6 interacted with and inhibited apoptosis signal–regulating kinase 1 (Ask1) and its subsequent downstream c‐Jun N‐terminal kinase/p38 signaling. Furthermore, Ask1 was sufficient to mediate Card6 function, and the interaction between Ask1 and Card6 was absolutely required for Card6 function in vivo. Adenovirus‐mediated Card6 overexpression in the liver effectively ameliorated insulin resistance and hepatic steatosis in ob/ob mice. Therefore, we identified Card6 as an important negative regulator in NAFLD. Conclusion: Targeting Ask1 by Card6 may be a good strategy to develop a therapeutic method against NAFLD.

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Virtual Consultations Through the Veterans Administration SCAN‐ECHO Project Improves Survival for Veterans With Liver Disease

Access to specialty care has been associated with improved survival in patients with liver disease but universal access is not always feasible. Methods of care delivery using virtual modalities including the SCAN‐ECHO (Specialty Access Network‐Extension of Community Healthcare Outcome) program were implemented by the Veterans Health Administration (VHA) to address this need but limited data are available on patient outcomes. We sought to evaluate the efficacy of a SCAN‐ECHO visit within the context of a regional cohort of patients with liver disease in the VHA (n = 62,237) following implementation in the Ann Arbor SCAN‐ECHO Liver Clinic from June 1, 2011, to March 31, 2015. The effect of a SCAN‐ECHO visit on all‐cause mortality was compared with patients with no liver clinic visit. To adjust for the differences among patients who had a SCAN‐ECHO visit versus those with no visit, propensity score matching was performed on condition factors that affect the likelihood of a SCAN‐ECHO visit: demographics, geographic location, liver disease diagnosis, severity, and comorbidities. During the study period, 513 patients who had a liver SCAN‐ECHO visit were found within the cohort. Patients who had completed a virtual SCAN‐ECHO visit were more likely younger, rural, with more significant liver disease, and evidence for cirrhosis. Propensity‐adjusted mortality rates using the Cox Proportional Hazard Model showed that a SCAN‐ECHO visit was associated with a hazard ratio of 0.54 (95% confidence interval 0.36‐0.81, P = 0.003) compared with no visit. Conclusion: Improved survival in patients using SCAN‐ECHO suggests that this approach may be an effective method to improve access for selected patients with liver disease, particularly in rural and underserved populations where access to specialty care is limited.

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High Mobility Group Box‐1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice

High‐mobility group box‐1 (HMGB1) is a damage‐associated molecular pattern (DAMP) increased in response to liver injury. Because HMGB1 is a ligand for the receptor for advanced glycation endproducts (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis though RAGE cell‐specific signaling mechanisms. Liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus (HCV) infection, primary biliary cirrhosis (PBC), or alcoholic steatohepatitis (ASH). Hepatic HMGB1 protein expression and secretion increased in five mouse models of liver fibrosis attributed to drug‐induced liver injury (DILI), cholestasis, ASH, or nonalcoholic steatohepatitis (NASH). HMGB1 was up‐regulated and secreted mostly by hepatocytes and Kupffer cells (KCs) following CCl₄ treatment. Neutralization of HMGB1 protected, whereas injection of recombinant HMGB1 promoted liver fibrosis. Hmgb1 ablation in hepatocytes (Hmgb1 ^ΔHep) or in myeloid cells (Hmgb1 ^ΔMye) partially protected, whereas ablation in both (Hmgb1 ^ΔHepΔMye) prevented liver fibrosis in vivo. Coculture with hepatocytes or KCs from CCl₄‐injected wild‐type (WT) mice up‐regulated Collagen type I production by hepatic stellate cells (HSCs); yet, coculture with hepatocytes from CCl₄‐injected Hmgb1 ^ΔHep or with KCs from CCl₄‐injected Hmgb1 ^ΔMye mice partially blunted this effect. Rage ablation in HSCs (Rage ^ΔHSC) and RAGE neutralization prevented liver fibrosis. Last, we identified that HMGB1 stimulated HSC migration and signaled through RAGE to up‐regulate Collagen type I expression by activating the phosphorylated mitogen‐activated protein kinase kinase (pMEK)1/2, phosphorylated extracellular signal‐regulated kinase (pERK)1/2 and pcJun signaling pathway. Conclusion: Hepatocyte and KC‐derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling through RAGE in HSCs to activate the pMEK1/2, pERK1/2 and pcJun pathway and increase Collagen type I deposition.

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STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung

Type 2 immunity in the lung is promoted through the release of innate cytokines, including TSLP, from lung structural cells. These cytokines drive Type 2 immunity in part through upregulation of OX40L on dendritic cells (DCs). DCs expressing OX40L are potent inducers of Th2 differentiation. We have shown previously that STAT6 inhibitory peptide (STAT6‐IP), a cell penetrating peptide designed to inhibit the STAT6 transcription factor, reduces the induction of Th2 adaptive immunity in murine models of respiratory syncytial virus infection. Here we show that intranasal administration of STAT6‐IP at the time of antigen priming with ovalbumin (OVA), in conjunction with the Nod2 agonist, MDP, reduced frequencies of CD11b⁺ lung DCs expressing OX40L. Consistent with these reductions, fewer activated DCs were localized to the lung draining lymph nodes in STAT6‐IP‐treated mice. Upon OVA challenge four weeks later, mice treated with STAT6‐IP at the time of OVA/MDP priming did not develop airway hyperresponsiveness (AHR) and had reduced influx of eosinophils into the airways, mucus production, and serum OVA‐specific IgE levels. Our findings provide evidence that the long‐lasting inhibitory effects of STAT6‐IP are due in part to inhibition of DC responses that drive maladaptive Th2 adaptive immunity and allergic airways disease.

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Innate and adaptive stimulation of murine diverse NKT cells result in distinct cellular responses

Natural killer T (NKT) cells recognize glycolipids presented on CD1d. They share features of adaptive T lymphocytes and innate NK cells, and mediate immunoregulatory functions via rapid production of cytokines. Invariant (iNKT) and diverse (dNKT) NKT cell subsets are defined by their TCR. The immunological role of dNKT cells, that do not express the invariant TCRα‐chain used by iNKT cells, is less well explored than that of iNKT cells. Here, we investigated signals driving Toll‐like receptor (TLR) ligand activation of TCR‐transgenic murine dNKT cells. IFN‐γ production by dNKT cells required dendritic cells (DC), cell‐to‐cell contact and presence of TLR ligands. TLR‐stimulated DC activated dNKT cells to secrete IFN‐γ in a CD1d‐, CD80/86‐ and type I IFN‐independent manner. In contrast, a requirement for IL‐12p40, and a TLR ligand‐selective dependence on IL‐18 or IL‐15 was observed. TLR ligand/DC stimulation provoked early secretion of pro‐inflammatory cytokines by both CD62L⁺ and CD62L⁻ dNKT cells. However, proliferation was limited. In contrast, TCR/co‐receptor‐mediated activation resulted in proliferation and delayed production of a broader cytokine spectrum preferentially in CD62L⁻ dNKT cells. Thus, innate (TLR ligand/DC) and adaptive (TCR/co‐receptor) stimulation of dNKT cells resulted in distinct cellular responses that may contribute differently to the formation of immune memory.

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Elevated EGFL6 modulates cell metastasis and growth via AKT pathway in nasopharyngeal carcinoma

EGFL6 was detected overexpressed in NPC (tissue, serum, and cell). EGFL6 enhanced the metastasis and growth of NPC in vitro and vivo (nude mice, heat‐shock zebrafish model).

Abstract

Epidermal growth factor‐like domain multiple 6 (EGFL6) is a secreted protein, regulates maintenance and metastasis of cancer cells. Nevertheless, how EGFL6 participates in the progression and tumorigenesis of nasopharyngeal carcinoma (NPC) remains unclear. In our study, EGFL6 was detected highly expressed in 20 NPC tissues compared with normal tissues by IHC assay. Then, the level of EGFL6 in NPC serum and NPC cells was explored through enzyme‐linked immunosorbent assay and western blot, the results consistent with IHC. More interestingly, EGFL6 accelerated the migration and growth of NPC in vitro assays. Considering the mechanism of migration, NPC cells were cultured with AKT activator, revealing EGFL6 facilitated the progression of NPC via AKT. Moreover, the same effect of EGFL6 in promoting NPC growth was proved in nude mice. Furthermore, heat‐shock zebrafish model was established with EGFL6 overexpression. Then, CNE2 cells were injected into the model and cells mass was observed, showing that EGFL6 enhanced the migration and metastasis of NPC. Currently, as the prognosis of NPC is severely affected by distant metastasis, it might be a new therapeutic target toward EGFL6. Taken together, our results suggested that EGFL6 acts as a potential positive regulator in the migration and proliferation of NPC.

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Long non‐coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA‐106b‐5p in seminoma

Long non‐coding RNA H19 promotes the expression of TDRG1 through sequestering miRNA‐106b‐5p, and thus facilitates cell resistance to cisplatin in seminoma. The newly identified H19/miRNA‐106b‐5p/TDRG1 axis may serve as a potential target for the treatment of seminoma and the cisplatin‐resistant tumors.

Abstract

The role of TDRG1 in tumorigenesis and the progression of seminoma, as well as its role in regulating chemosensitivity of seminoma to cisplatin through the PI3K/Akt/mTOR signaling pathway, has been previously defined. However, the detailed mechanism underlying TDRG1 expression and concomitant chemoresistance conditions are unknown. Furthermore, it has been reported that non‐protein‐coding RNAs play an important role in a variety of vital processes including cellular chemosensitivity. However, the role of non‐protein‐coding RNAs in regulating the chemosensitivity of seminoma remains unknown. In this study, using microarray analysis, we found that long non‐coding RNA H19 was upregulated while miRNA‐106b‐5p was downregulated in an established cisplatin‐resistant TCam‐2 cell line. Moreover, H19 acts as a miRNA‐106b‐5p sponge and thus impairs the function of miRNA‐106b‐5p on its target gene, TDRG1. Based on these findings, we propose that H19 promotes the expression of TDRG1 by sequestering miRNA‐106b‐5p and uses this mechanism to facilitate cell survival in cisplatin‐based chemotherapeutic conditions. These findings elucidate the mechanisms, at least partially, applied to deregulate TDRG1 and cisplatin sensitivity, and may provide new therapeutic possibilities for chemoresistant seminoma.

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The power of tumor sizes in predicting the survival of solitary hepatocellular carcinoma patients

We explored the prognostic ability of tumor sizes in 18 591 patients with solitary HCC categorized as T1 and T2 classification. And we believed that AJCC TNM staging system for solitary HCC would be more comprehensive if the tumor size was integrated into T2 classification. Additionally, for T1 patients, the tumor size plays no role in the choice between resection and transplantation.

Abstract

Background

Vascular invasion, rather than tumor size, was applied into the 7th edition of the AJCC TNM staging system to predict survival of solitary hepatocellular carcinoma (HCC) patients. However, does this mean tumor size is of little value in prognostic prediction? The current study was designed to explore the prognostic ability of tumor sizes in solitary HCC.

Methods

A total of 18 591 patients with solitary HCC categorized as T1 and T2 were retrieved from the Surveillance Epidemiology and End Results (SEER) database. The Cox proportional hazards regression model was adopted to evaluate the impact of tumor sizes on overall survival (OS) and disease‐specific survival (DSS) in general and in subgroups stratified by vascular invasion and surgery type.

Results

Large tumor sizes (>39 mm) were associated with unfavorable clinicopathologic characteristics. Compared with tumors ≤30 mm, tumors between 31‐50 mm and tumors >50 mm showed significantly worse OS and DSS in general using multivariate analysis (all P < 0.001). In subgroup analyses, for patients without vascular invasion, tumor size was a notable prognostic indicator for OS in the radiofrequency ablation group (P < 0.001), rather than in the liver resection or transplantation group. Nevertheless, for patients with vascular invasion, tumor sizes exhibited a notable impact on OS in the liver resection and transplantation group.

Conclusions

The AJCC TNM staging system for solitary HCC would be more comprehensive if tumor sizes were integrated into the T2 classification. Additionally, for T1 patients, tumor sizes play no role in the choice between resection and transplantation.

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Issue Information ‐ Cover

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Reduction of Computed Tomography Use for Pediatric Closed Head Injury Evaluation at a Non‐pediatric Community Emergency Department

Abstract

Objective

The purpose of this study was to determine if implementation of a Pediatric Emergency Care Applied Research Network (PECARN)‐based closed head injury assessment tool could safely decrease computed tomography (CT) use for pediatric head injury evaluation at a non‐pediatric community emergency department (ED).

Methods

A quality improvement project was initiated at a non‐pediatric community ED to implement an institution‐specific, Pediatric Emergency Care Applied Research Network (PECARN)‐based Pediatric Closed Head Injury Assessment Tool. Baseline head CT use at the participating ED was determined for children with closed head injury through retrospective chart review from March 2014 through November 2015. Head injury patients were identified using International Classification of Disease (ICD)‐9 codes for head injury, unspecified (959.01) and concussion with and without loss of consciousness (850‐850.9) until October 2015, after which ICD‐9 was no longer used. To identify eligible patients after October 2015 lists of all pediatric patients evaluated at the participating ED were reviewed, and patients were included in the analysis if they had a physician‐assigned discharge diagnosis of head injury or concussion. Exclusion criteria were age ≥18 years, penetrating head trauma, history of brain tumor, ventriculoperitoneal shunt, or bleeding disorder, or presentation >24 hours post‐injury. Medical history, injury mechanism, symptoms, head CT use, and disposition were recorded. Implementation of the Pediatric Closed Head Injury Assessment Tool was achieved through provider education sessions beginning in December 2015 and ending in August 2016. Head CT use was monitored for 12 months post‐implementation, from September 2016 through August 2017. Patients were classified into low, intermediate, or high risk for clinically important traumatic brain injury (ciTBI) by chart review. ED length‐of‐stay (LOS), disposition, and ED returns within 72 hours were recorded. Categorical variables were compared using Chi‐Square test or Fisher's Exact test, and continuous variables using Kruskal‐Wallis test.

Results

A total of 252 children with closed head injury were evaluated pre‐implementation (March 2014 through November 2015), 132 children were evaluated during implementation (December 2015 through August 2016), and 172 children were evaluated post‐implementation (September 2016 through August 2017). Overall CT use decreased from 37.7% (95% CI, 31.7 ‐ 43.7) pre‐implementation to 16.9% (95% CI, 11.3 ‐ 22.5) post‐implementation (p <0.001). Only 1% (95% CI, 0 ‐ 2.9) of low risk patients received a head CT post‐implementation compared to 22.6% (95% CI, 16.1 ‐ 29.1) pre‐implementation (p <0.001). CT use among patients ≥24 months decreased from 42.9% (95% CI, 36.5 ‐ 49.6) to 19.6% (95% CI, 13.1 ‐ 26.1) (p <0.001) and remained low and unchanged for patients <24 months. Transfers to a pediatric trauma center and ED returns within 72 hours were unchanged, while median ED LOS improved from 1.5 hours to 1.3 hours (p = 0.03). There were no missed ciTBIs after implementation of the guideline.

Conclusion

Implementation of the PECARN‐based Pediatric Closed Head Injury Assesstment Tool reduced head CT use in a non‐pediatric ED. The greatest impact was seen among children aged ≥24 months at very low risk for ciTBI.

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Characteristics of metabolic stability and the cell permeability of 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activity

From the series of 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione, compound 4b behaved as antagonist of 5‐HT_1A with antidepressant‐and anxiolytic‐like activity. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.

Abstract

A series of 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT_1A, 5‐HT₇ and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione (4b) behaved as strong and selective antagonist of 5‐HT_1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5‐HT_1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes (MLM) system. Experimentally obtained value of apparent permeability coefficient P_app for 4b in parallel artificial permeability assay (PAMPA) indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐and anxiolytic‐like activity of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.

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Inter‐rater Reliability of the HEART Score

Abstract

Background

The HEART score is a risk stratification tool for suspected acute coronary syndrome and contains several subjective components. A single previous study found good inter‐rater reliability. Our objective was to assess the inter‐rater reliability of the HEART score in an external prospective cohort.

Methods

We prospectively collected paired, independent physician ratings of the HEART score for patients > 20 years of age presenting to the emergency department with chest pain for which an ECG and troponin were ordered. Two emergency physicians independently provided HEART scores for each unique patient. The primary outcome, the HEART score, was dichotomized by low risk (0‐3) vs non‐ low risk (4‐10). Additional outcomes included the HEART score across the entire scale (0‐10) and subcomponents of the HEART score (e.g., history, electrocardiogram, risk factors; score of 0‐2 for each).We calculated kappa statistics and percent agreement for all outcomes.

Results

We collected paired physician HEART score ratings on 311 patients from October 2017 to April 2018. The mean HEART score was 3.5 (SD 1.9). About half (49.2%) of our patients had a HEART score of ≤ 3, and 50.8% had a HEART score > 3. The kappa score for "low risk" (HEART ≤ 3) was 0.68 (95%CI: 0.60 ‐ 0.77). There was 84.2% agreement between physicians on this variable.

Conclusions

Our study demonstrates there is substantial inter‐rater reliability among emergency department physicians in identifying patients at low risk of acute coronary syndrome using the HEART score.

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Design, synthesis and biological evaluation of imidazo[1,2‐a]pyridine analogues or derivatives as anti‐helmintic drug

Albendazole was used as the leading compound, and its structure was optimized by structural transformation and alkyl modification. 18 compounds (4a‐4r) were designed and synthesized. The in vitro and in vivo activities of the 18 compounds were determined, and the results were analyzed

Abstract

The Albendazole was used as the lead compound, which was modified by structural transformation and with alkyl groups. A total of 18 compounds(4a‐4r) were designed and synthesized.The in vitro experiment results showed thatcompounds 4e, 4f, 4k, 4l, 4q and 4r had good inhibitory effect on egg and imago of roundworm. IC₅₀ of compound 4l to anti‐egg of roundworm was 0.65±0.01 μmol/L and to anti‐imago of roundworm was 1.04±0.01 μmol/L. At the same time, it showed thatcompound 4l had the best effect in vivo, and the rate of anti‐helmintic could reach more than 99%. The acute toxicity test results showed that the LD₅₀>2100 mg·kg⁻¹ was for these compounds by oral administration, and they were belong to low toxicity compounds. In a word, compound 4l was most likely to be a new anti‐helmintic drug through screening in vitro and in vivo.

This article is protected by copyright. All rights reserved.

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Improving nutritional status of children with Cerebral palsy: a qualitative study of caregiver experiences and community‐based training in Ghana

This is a qualitative study on feeding practices of caregivers of children with cerebral palsy (CP) in West Africa. We interviewed caregivers both before and after a 1‐year training intervention on caring for children with CP and found neither deterioration nor improvement in children's nutritional status, despite some improvements in feeding practices and a reduction in reported caregiver stress. The results also highlight the extent of severe undernutrition within this vulnerable group.

Abstract

Background

Cerebral palsy (CP) is the most common childhood disability worldwide, and evidence shows that children with CP are at an increased risk of malnutrition due to feeding difficulties. This qualitative study explores caregiver experiences of feeding before and after a community‐based training program in Ghana.

Methods

Thirteen caregivers of children with CP, who were severely undernourished, were interviewed at the start of the training program. Eleven of these were interviewed again after a year of monthly group trainings and home visits, which included guidance on feeding. Four additional caregivers were interviewed at end line. Interviews explored caregivers' mealtime experiences, as well as a 24‐hr dietary recall and a structured feeding observation checklist. Children's nutritional status was assessed by anthropometry.

Results

Caregivers found mealtimes stressful due to time demands, messiness, and the pressure of providing enough quality food. They felt that the training program had helped reduced this stress and dietary recall data suggested some improved dietary quality. However, there was neither improvement nor deterioration in anthropometric status of the children.

Conclusion

Group trainings were welcomed by caregivers and notably reduced stress around feeding times. However, future work is needed in order to improve anthropometric outcomes, including, but not limited to, greater focus on nutritional requirements during caregiver training interventions. Therapeutic feeding programs must also be better utilized and need to be better equipped to care for this group of children, including deviating from standard admission and treatment protocols.

https://ift.tt/2PuV210

PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. [Research Briefs]

Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than HCQ. Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR-Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.

https://ift.tt/2z9Vkjy

The Clinical Impact of the Genomic Landscape of Mismatch Repair-Deficient Cancers [Review]

The mismatch repair (MMR) system which detects and corrects base mismatches and insertions and deletions that occur during DNA synthesis is deregulated in approximately 20% of human cancers. MMR-deficient tumors have peculiar properties, including early-onset metastatic potential but generally favorable prognosis, and remarkable response to immune therapy. The functional basis of these atypical clinical features has recently started to be elucidated. Here, we discuss how the biological and clinical features of MMR-deficient tumors might be traced back to their ability to continuously produce new somatic mutations, leading to increased levels of neoantigens, which in turn stimulate immune surveillance.

Significance: Tumors carrying defects in DNA MMR accumulate high levels of mutations, a feature linked to rapid tumor progression and acquisition of drug resistance but also favorable prognosis and response to immune-checkpoint blockade. We discuss how the genomic landscape of MMR-deficient tumors affects their biological and clinical behaviors. Cancer Discov; 8(12); 1–11.©2018 AACR.

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Molecular Profiling of Cohorts of Tumor Samples to Guide Clinical Development of Pembrolizumab as Monotherapy

Purpose: Molecular profiling of large databases of human tumor gene expression profiles offers novel opportunities for informing decisions in clinical development programs.

Experimental Design: Gene expression profile of programmed death ligand 1 (PD-L1) was explored in a dataset of 16,000 samples, including approximately 4,000 metastatic tumors, across >25 tumor types prevalent in the United States, looking for new indications for the programmed death 1 (PD-1) inhibitor pembrolizumab. PD-L1 expression was highly concordant with several genomic signatures indicative of immune-inflamed tumor microenvironment. Prevalence of activated immune-inflamed tumors across all tumor types was explored and used to rank tumor types for potential response to pembrolizumab monotherapy.

Results: The analysis yielded 3 tiers of indications in which high levels of PD-L1 and immune-inflamed signatures were found in up to 40% to 60%, 20% to 40%, and 0% to 20% of tumors. Tier 1 contained novel indications known at the time of analysis to be responsive to PD-1 checkpoint blockade in the clinic (such as melanoma and non–small cell lung cancer), as well as indications not studied in the clinic previously, including microsatellite instability–high colorectal, head and neck, bladder, and triple-negative breast cancers. Complementary analysis of an Asian/Pacific cancer dataset (gastric cancer) revealed high prevalence of immune-inflamed tumors in gastric cancer. These data contributed to prioritization of these indications for clinical development of pembrolizumab as monotherapy.

Conclusions: Data highlight the value of molecular profiling in identifying populations with high unmet needs with potentially favorable response characteristics and accelerating development of novel therapies for these patients. Clin Cancer Res; 1–10. ©2018 AACR.

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