Cardiac and skeletal muscle effects of electrical weapons

Abstract

Conducted Electrical Weapons (CEWs) are being used as the preferred non-lethal force option for police and special forces worldwide. This new technology challenges an exposed opponent similarly to the way they would be challenged by physical exercise combined with emotional stress. While adrenergic and metabolic effects have been meta-analyzed and reviewed, there has been no systematic review of the effects of CEWs on skeletal and cardiac muscle. A systematic and careful search of the MedLine database was performed to find publications describing pathophysiological cardiac and skeletal muscle effects of CEWs. For skeletal muscle effects, we analyzed all publications providing changes in creatine kinase, myoglobin and potassium. For cardiac effects, we analyzed reported troponin changes and arrhythmias related to short dart-to-heart-distances. Conducted electrical weapons satisfy all relevant electrical safety standards and there are, to date, no proven electrocution incidents caused by CEWs. A potential cardiovascular risk has been recognized by some of the experimental animal data. The effects on the heart appear to be limited to instances when there is a short dart-to-heart-distance. The effect on the skeletal muscle system appears to be negligible. A responsible use of a CEW on a healthy adult, within the guidelines proposed by the manufacturer, does not imply a significant health risk for that healthy adult.

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Computer Simulations Predict High Structural Heterogeneity of Functional State of NMDA Receptors

NMDA receptors (NMDARs) – transmembrane proteins expressed in neurons – play the central role in the molecular mechanisms of learning and memory formation. It is unclear how the known atomic structures of NMDARs determined by X-ray crystallography and cryoEM (18 published PDB entries) relate to the functional states of NMDARs inferred from electrophysiological recordings (multiple closed, open, pre-open, etc. states). We address this problem by molecular dynamics (MD) simulations at atomic resolution, a method successfully applied in the past to much smaller biomolecules.

https://ift.tt/2IuJXEJ

The Management of Lower Urinary Tract Dysfunction in Multiple Sclerosis

Abstract

Purpose of Review

Multiple sclerosis (MS) is the most frequent neuroinflammatory disease of the central nervous system and is commonly associated with lower urinary tract (LUT) dysfunction. As a consequence, health-related quality of life is often impaired and the upper urinary tract might be at risk for damage. The aim of this review is to give an overview of current treatment options for LUT dysfunction in patients with MS.

Recent Findings

The treatment is tailored to the type of dysfunction—storage or voiding dysfunction—beginning with conservative treatment options and ending with invasive therapies and surgery. Additionally, alternative options, e.g., different intravesical therapies or cannabinoids, have been evaluated in recent years with promising results.

Summary

Current available therapies offer different possible treatments for LUT dysfunction in patients with MS. They address either voiding or storage dysfunction and therefore ameliorate LUT symptoms improve quality of life and protect the upper urinary tract.

https://ift.tt/2IzOm9h

Firearm Injuries and Violence Prevention — The Potential Power of a Surgeon General’s Report

In the aftermath of the mass shooting at a social services center in San Bernardino, California, in 2015, President Barack Obama suggested that the relationship between firearm ownership and gun injuries might be as strong as the connection between cigarette smoking and lung cancer. The full extent…

https://ift.tt/2KhPjZT

The pivotal role of DNA methylation in the radio‐sensitivity of tumor radiotherapy

Cancer Medicine, EarlyView.


https://ift.tt/2Kr9U9M

Profilometric changes of peri‐implant tissues over 5 years: A randomized controlled trial comparing a one‐ and two‐piece implant system

Clinical Oral Implants Research, EarlyView.


https://ift.tt/2tKl2rs

Genome-scale metabolic model analysis indicates low energy production efficiency in marine ammonia-oxidizing archaea

Marine ammonia-oxidizing archaea (AOA) play an important role in the global nitrogen cycle by obtaining energy for biomass production from CO2 via oxidation of ammonium. The isolation of Candidatus "Nitrosopumilu...

https://ift.tt/2Kh2zhd

Improvement During Inpatient Rehabilitation Among Older Adults with Guillain-Barré Syndrome, Multiple Sclerosis, Parkinson Disease, and Stroke

Objective To quantify the improvement in independence experienced by patients with the following diagnoses: Guillain-Barré Syndrome (GBS), Multiple Sclerosis (MS), Parkinson Disease (PD), and stroke following inpatient rehabilitation. Design Subjects who were admitted to inpatient rehabilitation hospitals in 2012-2013 with an incident diagnosis of: GBS (n = 1079), MS (n = 1438), PD (n = 11,834), or stroke (n = 131,313) were included. The main outcome measure was improvement in Functional Independence Measure® (FIM) scores on self-care, mobility, and cognition during inpatient rehabilitation. We estimated percent improvement from a linear mixed-effects model adjusted for patients' age, sex, race/ethnicity, comorbidity count, diagnostic group (GBS, MS, PD, and stroke), and admission score. Results All patient diagnostic groups receiving inpatient rehabilitation improved across all three domains. The largest adjusted percent improvements were observed in the mobility domain and the smallest in the cognition domain for all groups. Percent improvement in mobility ranged from 84.9% (MS) to 144.0% (GBS), self-care from 49.5% (MS) to 84.1% (GBS), and cognition from 34.0% (PD) to 51.7% (GBS). Patients with GBS demonstrated the greatest percent improvement across all three domains. Conclusions Patients with GBS, MS, PD, and stroke should improve during inpatient rehabilitation but anticipated outcomes for patients with GBS should be even higher. Author Disclosures: The study was supported by funding secured by Kenneth J. Ottenbacher, PhD, OTR through the National Institutes of Health (grant numbers R01 HD069443, P2C HD065702, and K12 HD055929) and the National Institute on Disability, Independent Living, and Rehabilitation Research (grant number 90AR5009). This work was also supported by the National Institute on Aging (grant number P30 AG024832) and the Foundation for Physical Therapy's Center of Excellence in Physical Therapy Health Services and Health Policy Research and Training Grant. We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated and we certify that all financial and material support for this research (eg, NIH or NIA grants) and work are clearly identified here in the title page of the manuscript. Neither author has financially benefitted from this research project or its dissemination. The results of this study are accepted as an abstract for the 2018 Combined Sections Meeting of the American Physical Therapy Association. To date, the results of this study have not been presented or published elsewhere. Corresponding author: A. Williams Andrews, Campus Box 2085, Elon, NC 27244. 336-278-6351. andrewsb@elon.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Pandemic influenza vaccines: what they have taught us about B cell immunology

David J Topham | Phuong Nguyen | Mark Y Sangster

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Editorial Board

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Firearm Injuries and Violence Prevention — The Potential Power of a Surgeon General’s Report

In the aftermath of the mass shooting at a social services center in San Bernardino, California, in 2015, President Barack Obama suggested that the relationship between firearm ownership and gun injuries might be as strong as the connection between cigarette smoking and lung cancer. The full extent…

https://ift.tt/2KhPjZT

Accreditation of Clinical Research Sites — Moving Forward

Accreditation is used in many fields, including education, travel, construction, and health care. When implemented correctly, it improves quality, performance, and safety, while signaling to the public that an accredited entity is committed to an agreed-on set of values. Key to its effectiveness is…

https://ift.tt/2tACC1y

Combined Ex Vivo Hypothermic and Normothermic Perfusion for Assessment of High-Risk Deceased Donor Human Kidneys for Transplantation

Background Despite careful clinical examination, procurement biopsy and assessment on hypothermic machine perfusion (HMP), a significant number of potentially useable deceased donor kidneys will be discarded because they are deemed unsuitable for transplantation. Ex vivo normothermic perfusion (EVNP) may be useful as a means to further assess high-risk kidneys to determine suitability for transplantation. Methods From June 2014 to October 2015, 7 kidneys (mean donor age 54.3 years and KDPI 79%) that were initially procured with the intention to transplant were discarded based on a combination of clinical findings, suboptimal biopsies, long cold ischemia time and/or poor hypothermic perfusion parameters. They were subsequently placed on EVNP using oxygenated packed red blood cells and supplemental nutrition for a period of 3 hours. Continuous hemodynamic and functional parameters were assessed. Results After a mean cold ischemia time (CIT) of 43.7 hours, all 7 kidneys appeared viable on EVNP with progressively increasing renal blood flow over the 3-hour period of perfusion. Five of the 7 kidneys had excellent macroscopic appearance, rapid increase in blood flow to 200-250 ml/min, urine output of 40-260 ml/hr and increasing creatinine clearance. Conclusions Favorable perfusion characteristics and immediate function after a 3 hour course of EVNP suggests that high-risk kidneys subjected to long CIT may have been considered for transplantation. The combined use of ex vivo hypothermic and normothermic perfusion may be a useful strategy to more adequately assess and preserve high-risk kidneys deemed unsuitable for transplantation. A clinical trial will be necessary to validate the usefulness of this approach. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. *Author contributed equally to the work presented in this paper Corresponding author: Richard V. Perez, MD, University of California, Davis Health, 2315 Stockton Blvd, OP 152, Sacramento, CA 95817. Phone: (703) 371 4330. Email: rvperez@ucdavis.edu Author contribution -Substantial contributions to the conception or design of the work: SKK, IPP, JS, RVP -Acquisition of data for the work: SKK, IPP, YS, IP, TB -Analysis and interpretation of data: SKK, IPP, YS, JS, MN, KYJ, RVP -Drafting of the work: SKK and IPP -Revising the work critically for important intellectual content: SKK, IPP, YS, JS, CT, CS, JPM, RVP -Final approval of the version to be published and agreement to be accountable for all aspects of the work: SKK, IPP, YS, TB, IP, JS, CT, CS, JPM, MN, KYJ, RVP Disclosures The authors declare no conflicts of interest Disclosures Dr. Perez is a member of the clinical advisory board for XOR Labs, Toronto, Canada. Funding No funding was received to complete this study Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies

S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies

S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies, Published online: 28 June 2018; doi:10.1038/s41416-018-0167-x

S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies

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Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study

Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study

Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study, Published online: 28 June 2018; doi:10.1038/s41416-018-0148-0

Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study

https://ift.tt/2IxOPc5

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-mutated Hepatocellular Carcinoma

Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS-mutant unresectable or metastatic HCC. Methods: Eligible patients with RAS mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Results: Of 1318 patients screened, 59 (4.4%) had a RAS mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and β-catenin (CTNNB1; 37.0%). Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, non-invasive approach for large-scale mutational testing in HCC patients. A median OS of 12.7 months with refametinib plus sorafenib in this small population of RAS-mutant patients may indicate a synergistic effect between sorafenib and refametinib - this preliminary finding should be further explored.

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The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy

Purpose: Although somatostatin analogues (SSA) and peptide receptor radionuclide therapy (PRRT) are validated therapies in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), it remains unclear whether SSA combined with PRRT or as maintenance therapy can provide prolonged survival compared to patients treated with PRRT alone. In this retrospective study, we aimed to investigate whether there is a survival benefit to adding SSA to PRRT as a combination therapy and/or maintenance therapy. Experimental Design: The investigation included 168 patients with unresectable GEP-NETs treated at the University Hospital Bonn, Germany. The patients were divided into two main groups: PRRT monotherapy (N=81, group 1) and PRRT plus SSA (N=87, group 2) as combined therapy with PRRT and/or as maintenance therapy after PRRT. Results: Data for overall survival (OS) were available from 168 patients, of whom 160 had data for progression-free survival (PFS). The median PFS was 27 months in group 1 vs. 48 months in group 2 (p = 0.012). The median OS rates were 47 months in group 1 and 91 months in group 2 (p < 0.001). The death-event rates were lower in group 2 (26%) than in group 1 (63%). SSA as a combination therapy with PRRT and/or as a maintenance therapy showed a clinical benefit rate (objective response or stable disease) of 95%, which was significantly higher than group 1 (79%). Conclusions: SSA as a combination therapy and/or maintenance therapy may play a significant role in tumor control in patients with GEP-NET who underwent a PRRT.

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IFN-{gamma}-induced chemokines are required for CXCR3-mediated T cell recruitment and anti-tumor efficacy of anti-HER2/CD3 bispecific antibody

Purpose: The response to cancer immune therapy is dependent on endogenous tumor reactive T cells. To bypass this requirement, CD3-bispecific antibodies have been developed to induce a polyclonal T cell response against the tumor. Anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody is highly efficacious in the treatment of HER2 over-expressing tumors in mice. Efficacy and immunological effects of anti-HER2/CD3 TDB were investigated in a mammary tumor model with very few T cells prior treatment. We further describe the mechanism for TDB-induced T cell recruitment to tumors. Experimental Design: Immunological effects and mechanism of CD3-bispecific antibody-induced T cell recruitment into spontaneous HER2 over-expressing mammary tumors was studied using human HER2 transgenic, immune-competent mouse models. Results: Anti-HER2/CD3 TDB treatment induced an inflammatory response in tumors converting them from poorly infiltrated to an inflamed, T cell abundant, phenotype. Multiple mechanisms accounted for the TDB-induced increase in T cells within tumors. TDB treatment induced CD8⁺ T cell proliferation. T cells were also actively recruited post-TDB treatment by IFN-g-dependent T cell chemokines mediated via CXCR3. This active T cell recruitment by TDB-induced chemokine signaling was the dominant mechanism and necessary for the therapeutic activity of anti-HER2/CD3 TDB. Conclusions: In summary, we demonstrate that the activity of anti-HER2/CD3 TDB was not dependent on high level baseline T cell infiltration. Our results suggest that anti-HER2/CD3 TDB may be efficacious in patients and indications that respond poorly to checkpoint inhibitors. An active T cell recruitment mediated by TDB-induced chemokine signaling was the major mechanism for T cell recruitment.

https://ift.tt/2lHOSJf

Therapeutic Immune Modulation Against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial

Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 (TLR3) and MDA-5 that can activate immune cells such as dendritic cells and trigger NK cells to kill tumor cells. Experimental Design: In this pilot study, eligible patients included those with recurrent metastatic disease who failed prior systemic therapy (head and neck squamous cell cancer (HNSCC), melanoma). Patients received 2 treatment cycles, each cycle consisting of 1mg Poly-ICLC 3x weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA Sequencing (RNASeq) in tumor and blood. Results: Two patients completed 2 cycles of IT treatments and one achieved clinical benefit (stable disease, PFS 6 months), while the remainder had progressive disease. Poly-ICLC was well tolerated with principal side effects of fatigue and inflammation at injection site (< grade 2). In the patient with clinical benefit, IHC analysis of tumor showed increased CD4, CD8, PD1 and PDL1 levels compared to patients with progressive disease. RNASeq analysis of the same patient's tumor and PBMC showed dramatic changes in response to Poly-ICLC treatment including upregulation of genes associated with chemokine activity, T cell activation and antigen presentation. Conclusions: Poly-ICLC was well tolerated in solid cancer patients, and generated local and systemic immune responses as evident in the patient achieving clinical benefit. These results warrant further investigation, and are currently being explored in a multicenter phase II clinical trial (NCT02423863).

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Mutational analysis identifies therapeutic biomarkers in inflammatory bowel disease-associated colorectal cancers

Purpose: Inflammatory bowel disease-associated colorectal cancers (IBD-CRCs) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection and treatment strategies. We aimed to identify biomarkers using whole exome sequencing of IBD-CRCs to guide individualised management. Experimental Design: Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined. Results: Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but 1 of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA POLE. Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified 6 distinct mutation signatures in IBD-CRCs, 3 of which corresponded with known mechanisms of mutagenesis. Driver genes were also identified. Conclusions:IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether immunohistochemistry to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualise surveillance and treatment programmes.

https://ift.tt/2lD3ucX

The Effect of Balancing Selection on Population Differentiation: A Study with HLA Genes

Balancing selection is defined as a class of selective regimes that maintain polymorphism above what is expected under neutrality. Theory predicts that balancing selection reduces population differentiation, as measured by FST. However, balancing selection regimes in which different sets of alleles are maintained in different populations could increase population differentiation. To tackle the connection between balancing selection and population differentiation, we investigated population differentiation at the HLA genes, which constitute the most striking example of balancing selection in humans. We found that population differentiation of single nucleotide polymorphisms (SNPs) at the HLA genes is on average lower than that of SNPs in other genomic regions. We show that these results require using a computation that accounts for the dependence of FST on allele frequencies. However, in pairs of closely related populations, where genome-wide differentiation is low, differentiation at HLA is higher than in other genomic regions. Such increased population differentiation at HLA genes for recently diverged population pairs was reproduced in simulations of overdominant selection, as long as the fitness of the homozygotes differs between the diverging populations. The results give insight into a possible "divergent overdominance" mechanism for the nature of balancing selection on HLA genes across human populations.

https://ift.tt/2Ke61ZU

Targeted Chromosomal Rearrangements via a Combinatorial Use of CRISPR/Cas9 and Cre/LoxP Technologies in Caenorhabditis elegans

Rearranged chromosomes have been applied to construct genetic balancers to manipulate essential genes in C. elegans. Although much effort has been put into constructing balancer chromosomes, approximately 6% (map units) of the C. elegans genome has not been covered, and this area lies mostly in pairing centers (PCs). Here, we developed a method for conditional chromosomal engineering through combinatorial use of the CRISPR/Cas9 and Cre/LoxP technologies. Functional DNA fragments containing LoxP sequences were inserted into designated genomic loci using a modified counterselection (cs)-CRISPR method. Then, heat-shock-induced Cre recombinase induced an inversion of the chromosomal region between the two LoxP sites. The chromosomal inversions were subsequently detected by the appearance of pharyngeal GFP. Through this method, we have successfully generated several chromosomal inversion lines, providing valuable resources for studying essential genes in pairing centers.

https://ift.tt/2KtReX9

Insights into the Structure of the Spruce Budworm (Choristoneura fumiferana) Genome, as Revealed by Molecular Cytogenetic Analyses and a High-Density Linkage Map

Genome structure characterization can contribute to a better understanding of processes such as adaptation, speciation, and karyotype evolution, and can provide useful information for refining genome assemblies. We studied the genome of an important North American boreal forest pest, the spruce budworm, Choristoneura fumiferana, through a combination of molecular cytogenetic analyses and construction of a high-density linkage map based on single nucleotide polymorphism (SNP) markers obtained through a genotyping-by-sequencing (GBS) approach. Cytogenetic analyses using fluorescence in situ hybridization methods confirmed the haploid chromosome number of n = 30 in both sexes of C. fumiferana and showed, for the first time, that this species has a WZ/ZZ sex chromosome system. Synteny analysis based on a comparison of the Bombyx mori genome and the C. fumiferana linkage map revealed the presence of a neo-Z chromosome in the latter species, as previously reported for other tortricid moths. In this neo-Z chromosome, we detected an ABC transporter C2 (ABCC2) gene that has been associated with insecticide resistance. Sex-linkage of the ABCC2 gene provides a genomic context favorable to selection and rapid spread of resistance against Bacillus thuringiensis serotype kurstaki (Btk), the main insecticide used in Canada to control spruce budworm populations. Ultimately, the linkage map we developed, which comprises 3586 SNP markers distributed over 30 linkage groups for a total length of 1720.41 cM, will be a valuable tool for refining our draft assembly of the spruce budworm genome.

https://ift.tt/2KrxqXC

LIN-12/Notch Regulates GABA Signaling at the Caenorhabditis elegans Neuromuscular Junction

The role of Notch signaling in cell-fate decisions has been studied extensively; however, this pathway is also active in adult tissues, including the nervous system. Notch signaling modulates a wide range of behaviors and processes of the nervous system in the nematode Caenorhabditis elegans, but there is no evidence for Notch signaling directly altering synaptic strength. Here, we demonstrate Notch-mediated regulation of synaptic activity at the C. elegans neuromuscular junction (NMJ). For this, we used aldicarb, an inhibitor of the enzyme acetylcholinesterase, and assessed paralysis rates of animals with altered Notch signaling. Notch receptors LIN-12 and GLP-1 are required for normal NMJ function; they regulate NMJ activity in an opposing fashion. Complete loss of LIN-12 skews the excitation/inhibition balance at the NMJ toward increased activity, whereas partial loss of GLP-1 has the opposite effect. Specific Notch ligands and co-ligands are also required for proper NMJ function. The role of LIN-12 is independent of cell-fate decisions; manipulation of LIN-12 signaling through RNAi knockdown or overexpression of the co-ligand OSM-11 after development alters NMJ activity. We demonstrate that LIN-12 modulates GABA signaling in this paradigm, as loss of GABA signaling suppresses LIN-12 gain-of-function defects. Further analysis, in vivo and in silico, suggests that LIN-12 may modulate transcription of the GABA_B receptor GBB-2. Our findings confirm a non-developmental role for the LIN-12/Notch receptor in regulating synaptic signaling and identify the GABA_B receptor GBB-2 as a potential Notch transcriptional target in the C. elegans nervous system.

https://ift.tt/2MvFcgi

Generation and Phenotype Identification of PAX4 Gene Knockout Rabbit by CRISPR/Cas9 System

Paired-homeodomain transcription factor 4 (PAX4) gene encodes a transcription factor which plays an important role in the generation, differentiation, development, and survival of insulin-producing β-cells during mammalian pancreas development. PAX4 is a key diabetes mellitus (DM) susceptibility gene, which is associated with many different types of DM, including T1DM, T2DM, maturity onset diabetes of the young 9 (MODY9), and ketosis prone diabetes. In this study, a novel PAX4 gene knockout (KO) model was generated through co-injection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) mRNA/sgRNA into rabbit zygotes. Typical phenotypes of growth retardation, persistent hyperglycemia, decreased number of insulin-producing β cells and increased number of glucagon-producing α cells were observed in the homozygous PAX4 KO rabbits. Furthermore, DM associated phenotypes including diabetic nephropathy, hepatopathy, myopathy and cardiomyopathy were also observed in the homozygous PAX4 KO rabbits but not in the wild type (WT) controls and the heterozygous PAX4 KO rabbits. In summary, this is the first PAX4 gene KO rabbit model generated by CRISPR/Cas9 system. This novel rabbit model may provide a new platform for function study of PAX4 gene in rabbit and gene therapy of human DM in clinical trails.

https://ift.tt/2KnQDtl

Erdafitinib Efficacious in Bladder Cancer [News in Brief]

FGFR inhibitor yields robust responses, even in those who did not respond to immunotherapy.

https://ift.tt/2yQNTQG

Trastuzumab Deruxtecan Targets HER2+ Cancers [News in Brief]

Antibody–drug conjugate generates many responses, shrinks high percentage of tumors in phase I trial.

https://ift.tt/2lCtaq9

The Dantastic Mr. Tox & Howard – Season 2 Episode 1 – Two Boards and a COWS

Activate your cerebral cortex exploring the determination of breath death with the world's greatest neurotoxicologist! Join Dan (@drusyniak) &Howard (@heshiegreshie) as they chat with Dr. Laura Tormoehlen about her experience as a neurologist and toxicologist. Dispel the myths and common misperceptions about the determination of brain death in the toxicology patient and learn the mimics […]

EMCrit Project by Tox & Hound.

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Effects of TNF-α in rheumatoid arthritis via attenuating α1 (I) collagen promoter

OBJECTIVE: To explore the role of TNF-α in the peripheral blood of patients with rheumatoid arthritis (RA) and its underlying mechanism.

PATIENTS AND METHODS: 32 patients diagnosed with RA in our hospital from July 2016 to March 2017 were selected in the experimental group. Meanwhile, 32 normal healthy people were selected in the healthy control group and 21 patients with other autoimmune diseases in the same period were selected in the disease control group. Serum samples of the subjects in the experimental group and the control group were collected. The content of serum tumor necrosis factor-α (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA), and the correlation between TNF-α and RA activity was analyzed. We then constructed rat RA model. The effect of different doses of TNF-α on the RA progression was evaluated by measuring the foot paw thickness of both hind limbs of rats. Fibroblast-like synoviocytes (FLS) were treated with different concentrations of TNF-α cytokine in vitro. Cell counting kit-8 (CCK-8) assay was carried out to detect the cell viability after TNF-α treatment. Serum levels of VEGF (vascular endothelial growth factor) and hydroxyproline were detected. Moreover, the α1 (I) collagen overexpression recombinant was constructed and transfected into MH7A cells. The activation of α1 (I) collagen promoter was reflected by the CAT reporter gene activity.

RESULTS: ELISA results showed higher content of TNF-α in the peripheral blood of the experimental group than that of the control group. In the RA rat model, the foot paw thickness of the hind limbs was increased with the increase of TNF-α concentration. CCK-8 and colony formation assay demonstrated that the proliferation of MH7A cells was elevated after TNF-α treatment. Higher levels of VEGF and IL-6 secreted by FLS and decreased collagen synthesis ability of MH7A cells were found after TNF-α treatment. Transfection of the α1 (I) collagen overexpression recombinant in MH7A cells led to the reduced activity of CAT after TNF-α treatment, suggesting that the activation of α1 (I) collagen promoter was inhibited.

CONCLUSIONS: TNF-α participates in RA by inhibiting the activation of the promoter of α1 (I) collagen, as well as enhancing the secretion of VEGF and IL-6 in MH7A cells.

L'articolo Effects of TNF-α in rheumatoid arthritis via attenuating α1 (I) collagen promoter sembra essere il primo su European Review.

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Two and a half years on: data and experiences establishing a ‘Virtual Clinic’ for joint replacement follow up

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2IBRtxK

Binge Drinking Linked to Increased Systolic BP in Men

WEDNESDAY, June 27, 2018 -- For men, binge drinking is associated with increased systolic blood pressure and any drinking is associated with an increased relative risk of hypertension, according to two studies published online June 27 in the Journal...

https://ift.tt/2IxSbvG

Few Hemodialysis Patients on Medicare Enroll in Hospice

WEDNESDAY, June 27, 2018 -- Among Medicare beneficiaries on hemodialysis, few patients are enrolled in hospice at the end of life, regardless of the spending trajectory during the last year of life, according to a study published in the June issue...

https://ift.tt/2Ksb0W9

Azithromycin Cuts Pulmonary Exacerbation in CF With Early Pa

WEDNESDAY, June 27, 2018 -- For children with cystic fibrosis (CF) and early Pseudomonas aeruginosa (Pa) infection, the risk of pulmonary exacerbation is significantly reduced with the addition of azithromycin to tobramycin inhalation solution...

https://ift.tt/2Mvu1Vc

Most Bleeding Events in Non-CVD Patients Are GI-Related

WEDNESDAY, June 27, 2018 -- Among a cohort of individuals without cardiovascular disease (CVD) not receiving antiplatelet therapy, most major bleeding events involved gastrointestinal bleeding and 7 percent of bleeding events were fatal, according...

https://ift.tt/2KgeOus

Half of CV Events Occur from Two to Five Years Post-TIA, -Stroke

WEDNESDAY, June 27, 2018 -- For patients who experienced a transient ischemic attack (TIA) or minor stroke, the rate of a composite of stroke, acute coronary syndrome, or death from cardiovascular causes is 12.9 percent at five years, with half of...

https://ift.tt/2IBNzF6

Reversible splenial lesion syndrome associated with dengue fever: a case report

Dengue virus infection in humans can lead to a wide range of clinical manifestations, from mild fever to potentially fatal dengue shock syndrome. The incidence of dengue fever is on the rise in tropical countr...

https://ift.tt/2KrGRGl

Effect of the dietary polyacetylenes falcarinol and falcarindiol on the gut microbiota composition in a rat model of colorectal cancer

(3R)-Falcarinol (FaOH) and (3R,8S)-falcarindiol (FaDOH) have previously been shown to reduce the number of neoplastic lesions and the growth rate of polyps in the colon of azoxymethane (AOM) treated rats. Based o...

https://ift.tt/2MtLfCp

Purifying Selection in the Toll-Like Receptors of Song Sparrows Melospiza melodia

Abstract

Variation in immune gene sequences is known to influence resistance to infectious diseases and parasites, and hence survival and mate choice, across animal taxa. Toll-like receptors (TLRs) comprise one essential gene family in the vertebrate innate immune system and recognize evolutionarily conserved structures from all major microorganism classes. However, the causes and consequences of TLR variation in passerine birds remain largely unexplored. We examined 7 TLR genes in song sparrows (Melospiza melodia), a species that is studied across North America. We then examined sequences from 4 unduplicated TLRs (TLR1LB, TLR3, TLR4, and TLR15) from birds in 2 parts of the species' range (N = 27, N = 6), tested for evidence of selection, and conducted pilot analyses of the role of TLR heterozygosity in survival. We identified 45 SNPs: 19 caused changes in amino acid sequences and 2 of these were likely deleterious. We found no evidence of codon-level episodic positive selection but detected purifying selection at codons in all TLRs. Contrary to expectations we found no strong correlation between heterozygosity at TLRs and inbreeding coefficient f (estimate ± standard error [SE] = −0.68 ± 0.37, Radj2 = 0.08, F_1,25 = 3.38, P = 0.08). In addition, pilot analyses revealed no relationship between TLR heterozygosity and survival (β ± SE: 0.09 ± 2.00, P = 0.96), possibly due to small sample size. Further analyses of genetic diversity in TLRs are likely to advance understanding of the effects of innate immune gene diversity on the fitness and persistence of wild populations.

https://ift.tt/2Krmhmx

Is the Red Wolf a Listable Unit Under the US Endangered Species Act?

Abstract

Defining units that can be afforded legal protection is a crucial, albeit challenging, step in conservation planning. As we illustrate with a case study of the red wolf (Canis rufus) from the southeastern United States, this step is especially complex when the evolutionary history of the focal taxon is uncertain. The US Endangered Species Act (ESA) allows listing of species, subspecies, or Distinct Population Segments (DPSs) of vertebrates. Red wolves were listed as an endangered species in 1973, and their status remains precarious. However, some recent genetic studies suggest that red wolves are part of a small wolf species (C. lycaon) specialized for heavily forested habitats of eastern North America, whereas other authors suggest that red wolves arose, perhaps within the last ~400 years, through hybridization between gray wolves (C. lupus) and coyotes (C. latrans). Using published genetic, morphological, behavioral, and ecological data, we evaluated whether each evolutionary hypothesis would lead to a listable unit for red wolves. Although the potential hybrid origin of red wolves, combined with abundant evidence for recent hybridization with coyotes, raises questions about status as a separate species or subspecies, we conclude that under any proposed evolutionary scenario red wolves meet both criteria to be considered a DPS: they are Discrete compared with other conspecific populations, and they are Significant to the taxon to which they belong. As population-level units can qualify for legal protection under endangered-species legislation in many countries throughout the world, this general approach could potentially be applied more broadly.

https://ift.tt/2tzM3i3

Nuclear Genetic Analysis of the Red Fox Across its Trans-Pacific Range

Abstract

The red fox (Vulpes vulpes) occurs on multiple continents in diverse habitats, making it an informative system for evolutionary genomic research. However, its phylogeography remains unclear. Previously, mitochondrial DNA and small numbers of nuclear loci provided discordant views. Both markers indicated deep divergence (~ 0.5 million years [MY]) between Eurasian and southern North American populations but differed in the apparent continental affinity of Alaskan red foxes, implying some degree of gene exchange during secondary contact (~0.1 MY). We assayed >173000 nuclear genomic sites in 52 red foxes, along with 2 Rueppell's foxes (Vulpes rueppellii) and a gray wolf (Canis lupus) using the Illumina CanineHD BeadChip. We obtained 5107 single nucleotide polymorphisms (SNPs) in the foxes. Consistent with the Afro-Eurasian origins of red foxes, genetic diversity was higher in Eurasian than North American samples. Phylogenetic trees indicated that Alaskan and southern North American red foxes formed a monophyletic group nested within the Eurasian clade. However, admixture models suggested Alaskan red foxes contained up to 40% Eurasian ancestry. We hypothesize that North American red foxes either hybridized with Eurasian foxes in Beringia at the start of the last glaciation or merged with a Beringian population after the last glaciation. Future work is needed to test between these scenarios and assess speciation.

https://ift.tt/2KqzWtM

Molecular Insights Into the Ctenophore Genus Beroe in Europe: New Species, Spreading Invaders

Abstract

The genus Beroe Browne, 1756 (Ctenophora, Beroidae) occurs worldwide, with 25 currently-described species. Because the genus is poorly studied, the definitive number of species is uncertain. Recently, a possible new Beroe species was suggested based on internal transcribed spacer 1 (ITS1) sequences from samples collected in Svalbard, Norway. Another species, Beroe ovata, was introduced to Europe from North America, initially in the Black Sea and subsequently (and possibly secondarily) into the Mediterranean and Baltic Seas. In areas where ctenophores have been introduced, they have often had significant detrimental ecological effects. The potential for other cryptic and/or undescribed Beroe species and history of spread of some species in the genus give reason for additional study. When alive, morphological hallmarks may be challenging to spot and photograph owing to the animals' transparency and near-constant motion. We sampled and analyzed 109 putative Beroe specimens from Europe, using morphological and molecular approaches. DNA analyses were conducted using cytochrome oxidase 1 and internal transcribed spacer sequences and, together with published sequences from GenBank, phylogenetic relationships of the genus were explored. Our study suggests the presence of at least 5 genetic lineages of Beroe in Europe, of which 3 could be assigned to known species: Beroe gracilis Künne 1939; Beroe cucumis Fabricius, 1780; and Beroe ovata sensu Mayer, 1912. The other 2 lineages (here provisionally named Beroe "norvegica" and Beroe "anatoliensis") did not clearly coincide with any known species and might therefore reflect new species, but confirmation of this requires further study.

https://ift.tt/2N4Embv

S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies

https://ift.tt/2tL8DU9

Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study

https://ift.tt/2N3zPGp

Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

Genes, Chromosomes and Cancer, Volume 57, Issue 8, Page 387-400, August 2018.


https://ift.tt/2Iva3aE

MCL1 gene co‐expression module stratifies multiple myeloma and predicts response to proteasome inhibitor‐based therapy

Genes, Chromosomes and Cancer, Volume 57, Issue 8, Page 420-429, August 2018.


https://ift.tt/2KrezIV

Correlation of TET2 SNP rs2454206 with improved survival in children with acute myeloid leukemia featuring intermediate‐risk cytogenetics

Genes, Chromosomes and Cancer, Volume 57, Issue 8, Page 379-386, August 2018.


https://ift.tt/2Kqw9QI

Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis

Genes, Chromosomes and Cancer, Volume 57, Issue 8, Page 401-408, August 2018.


https://ift.tt/2KtFqnU

Elucidation of the developmental mechanism of ovarian mature cystic teratomas using B allele‐frequency plots of single nucleotide polymorphism array data

Genes, Chromosomes and Cancer, Volume 57, Issue 8, Page 409-419, August 2018.


https://ift.tt/2Kg5G9a

Table of Content Volume 57, Number 8, August 2018

Genes, Chromosomes and Cancer, Volume 57, Issue 8, Page 377-378, August 2018.


https://ift.tt/2KrpAtQ

Cap-assisted double-lumen ERCP with forceps fixation for a tricky biliary access in periampullary diverticulum

https://ift.tt/2KeRfSz

Pancreatic disorders in children: new clues on the horizon

Pancreatic disorders in children represent a growing health problem in pediatric patients. In the past two decades, several advances have been made in the knowledge of pediatric pancreatic disorders, with better understanding of different etiologies and clinical manifestations of these disorders. Moreover, many efforts have been made in pancreatology, aiming to define guidelines in the management of pancreatitis in children, initially based on the available information in adults. A multidisciplinary and multicenter approach is necessary to better determine pancreatic disease pathways and treatment options in children.

https://ift.tt/2IB9sUK

Hospital admission for digestive diseases: gastroenterology units offer a more effective and efficient care

Digestive diseases imply a substantial burden for health care systems.Effectiveness of specialized gastroenterology care has been demonstrated in a few real life surveys.

https://ift.tt/2KtsilR

Erratum Regarding “Arteriovenous Fistula Maturation in Prevalent Hemodialysis Patients in the United States: A National Study” (Am J Kidney Dis. 2018;71[6]:793-801)

In the Original Investigation entitled "Arteriovenous Fistula Maturation in Prevalent Hemodialysis Patients in the United States: A National Study" that appeared in the June 2018 issue of AJKD (Woodside et al, volume 71, issue 6, page 793-801), some of the ESRD Networks listed in the last sections of Figure 2 and Table S1 were identified by the wrong numbers. A corrected version of Figure 2 is provided here, and Table S1 has been corrected online. The errors are confined to the numbers used for labeling purposes, and do not affect the data presented or the text of the article or its conclusions.

https://ift.tt/2Mw78AH

=Osteoradionecrosis of the Skull Base in Nasopharyngeal Carcinoma: Incidence and Risk Factors

Skull base ORN has been seldom reported, and it can be difficult to distinguish and easy to misdiagnose. In this study, we demonstrated the incidence of the skull base osteoradionecrosis(ORN) after one course of external beam radiotherapy (EBRT) in NPC patients. Complete medical records were reviewed; meanwhile, Magnetic Resonance Imaging (MRI) and nasopharyngeal endoscopy were performed during follow-up period after treatment. We analyzed the associated factors in an attempt to decrease the occurrence of ORN, promote the understanding of this condition and improve the quality of life in patients with ORN.

https://ift.tt/2MtDY5l

The Relationship Between Pre-residency Peer Reviewed Publications and Subsequent Citation-Based Scholarly Activity of United States Radiation Oncology Residents

Radiation oncology residents with at least one pre-residency peer-reviewed publication (PRP) are significantly more likely than those with no PRP to have higher h-index scores, as well as higher scores stratified by first and/or second authorship. More than 30% of graduates without PRP did not publish any cited manuscripts. These results allow for potential predictive evaluation of resident productivity during the radiation oncology residency applicancy process, and have potential utility in predicting career choices post-residency.

https://ift.tt/2KnukE9

Significance of Negative Post-Treatment 18-FDG PET/CT Imaging in Patients with p16/HPV-positive Oropharyngeal Cancer

Patients with HPV-associated oropharyngeal cancer have a favorable outcome after treatment. The optimal surveillance strategy and modality is not well established. A retrospective analysis of 327 patients with HPV-associated oropharyngeal cancer who received definitive (chemo)radiotherapy who had post-treatment PET/CT was performed. This study showed that patients who achieve a complete metabolic response on post-treatment PET imaging have excellent prognosis and the risk of developing a recurrence in the future is very low (8%).

https://ift.tt/2Mv9GPQ

Impact of Immunohistochemistry-Based Subtypes in Muscle-Invasive Bladder Cancer on Response to Chemoradiotherapy

Patients with muscle-invasive bladder cancer undergoing chemoradiotherapy (CRT) were analyzed to evaluate possible impact of immunohistochemistry-based subtypes on CRT response. Subtypes were determined using the model developed by Lund University; genomically unstable and squamous cell cancer-like subtypes, which have aggressive features and intrinsically poor prognoses, showed significantly more favorable CRT responses than urobasal subtype. In this series, cancer-specific mortalities (CSM) were equivalent among the subtypes, while favorable CRT response independently correlated with low CSM.

https://ift.tt/2KcUeel

Pre-, Perinatal, and Parental Predictors of Body Mass Index Trajectory Milestones

To assess associations of pre-, perinatal, and parental factors with age and magnitude at body mass index (BMI) peak and rebound.

https://ift.tt/2lCrOvv

Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial

To assess the acceptability and swallowability of several minitablets when administered as a unit dose compared with an equivalent dose of syrup in children aged 6 months to 5 years.

https://ift.tt/2tQ31In

Neurocognitive and Health Correlates of Overweight and Obesity among Ten-Year-Old Children Born Extremely Preterm

To assess the relationship between overweight (body mass index [BMI] percentile ≥85 and <95) and obesity (BMI ≥95 percentile) and developmental and health outcomes at 10 years of age in a cohort of individuals born extremely preterm.

https://ift.tt/2yQzfc2

Presenting Signs and Symptoms do not Predict Aspiration Risk in Children

To determine if any presenting symptoms are associated with aspiration risk, and to evaluate the reliability of clinical feeding evaluation (CFE) in diagnosing aspiration compared with videofluoroscopic swallow study (VFSS).

https://ift.tt/2lAglN4

The Impact of Being Born Preterm or Small for Gestational Age on Early Vascular Aging in Adolescents

To assess the impact of being born preterm or small for gestational age (SGA) on early vascular aging (EVA) in a cohort of healthy Tyrolean adolescents.

https://ift.tt/2tQ35rB

In Vitro Cell-free DNA Quantification: A Novel Method to Accurately Quantify Cell Survival after Irradiation

Radiation Research, Volume 190, Issue 1, Page 22-27, July 2018.


https://ift.tt/2lCE7bd

A Rapid Image-based Bacterial Virulence Assay Using Amoeba

Here, we present a protocol to measure the virulence of planktonic or surface-attached bacteria using D. discoideum (amoeba) as a host. Virulence is measured over a period of 1 h and host killing is quantified using fluorescence microscopy and image analysis. We demonstrate this protocol using the bacterium P. aeruginosa.

https://ift.tt/2lBjXye

The two cathepsin B-like proteases of Arabidopsis thaliana are closely related enzymes with discrete endopeptidase and carboxydipeptidase activities

Journal Name: Biological Chemistry
Issue: Ahead of print


https://ift.tt/2KdYRF8

Cold atmospheric plasma treatment inhibits growth in colorectal cancer cells

Journal Name: Biological Chemistry
Issue: Ahead of print


https://ift.tt/2KqU9Qt

h-Type Membrane Current Shapes the Local Field Potential from Populations of Pyramidal Neurons

In cortex, the local field potential (LFP) is thought to mainly stem from correlated synaptic input to populations of geometrically aligned neurons. Computer models of single cortical pyramidal neurons showed that subthreshold voltage-dependent membrane conductances can also shape the LFP signal, in particular the hyperpolarization-activated cation current (I_h; h-type). This ion channel is prominent in various types of pyramidal neurons, typically showing an increasing density gradient along the apical dendrites. Here, we investigate how I_h affects the LFP generated by a model of a population of cortical pyramidal neurons. We find that the LFP from populations of neurons that receive uncorrelated synaptic input can be well predicted by the LFP from single neurons. In this case, when input impinges on the distal dendrites, where most h-type channels are located, a strong resonance in the LFP was measured near the soma, whereas the opposite configuration does not reveal an I_h contribution to the LFP. Introducing correlations in the synaptic inputs to the pyramidal cells strongly amplifies the LFP, while maintaining the differential effects of I_h for distal dendritic versus perisomatic input. Previous theoretical work showed that input correlations do not amplify LFP power when neurons receive synaptic input uniformly across the cell. We find that this crucially depends on the membrane conductance distribution: the asymmetric distribution of I_h results in a strong amplification of the LFP when synaptic inputs to the cell population are correlated. In conclusion, we find that the h-type current is particularly suited to shape the LFP signal in cortical populations.

SIGNIFICANCE STATEMENT The local field potential (LFP), the low-frequency part of extracellular potentials recorded in neural tissue, is often used for probing neural circuit activity. While the cortical LFP is thought to mainly reflect synaptic inputs onto pyramidal neurons, little is known about the role of subthreshold active conductances in shaping the LFP. By means of biophysical modeling we obtain a comprehensive, qualitative understanding of how LFPs generated by populations of cortical pyramidal neurons depend on active subthreshold currents, and identify the key importance of the h-type channel. Our results show that LFPs can give information about the active properties of neurons and that preferred frequencies in the LFP can result from those cellular properties instead of, for example, network dynamics.

https://ift.tt/2N40a77

Copine-6 Binds to SNAREs and Selectively Suppresses Spontaneous Neurotransmission

Recent studies suggest that spontaneous and action potential-evoked neurotransmitter release processes are independently regulated. However, the mechanisms that uncouple the two forms of neurotransmission remain unclear. In cultured mouse and rat neurons, we show that the two C2 domain-containing protein copine-6 is localized to presynaptic terminals and binds to synaptobrevin2 as well as other SNARE proteins in a Ca²⁺-dependent manner. Ca²⁺-dependent interaction of copine-6 with synaptobrevin2 selectively suppresses spontaneous neurotransmission in a reaction that requires the tandem tryptophan residues at the C-terminal region of synaptobrevin2. Accordingly, copine-6 loss of function augmented presynaptic Ca²⁺ elevation-mediated neurotransmitter release. Intracellular Ca²⁺ chelation, on the other hand, occluded copine-6-mediated suppression of release. We also evaluated the molecular specificity of the copine-6-dependent regulation of spontaneous release and found that overexpression of copine-6 did not suppress spontaneous release in synaptobrevin2-deficient neurons. Together, these results suggest that copine-6 acts as a specific Ca²⁺-dependent suppressor of spontaneous neurotransmission.

SIGNIFICANCE STATEMENT Synaptic transmission occurs both in response to presynaptic action potentials and spontaneously, in the absence of stimulation. Currently, much more is understood about the mechanisms underlying action potential-evoked neurotransmission compared with spontaneous release. However, recent studies have shown selective modulation of spontaneous neurotransmission process by several neuromodulators, suggesting specific molecular regulation of spontaneous release. In this study, we identify copine-6 as a specific regulator of spontaneous neurotransmission. By both gain-of-function and loss-of-function experiments, we show that copine-6 functions as a Ca²⁺-dependent suppressor of spontaneous release. These results further elucidate the mechanisms underlying differential regulation of evoked and spontaneous neurotransmitter release.

https://ift.tt/2yMMD0D

Lrfn2-Mutant Mice Display Suppressed Synaptic Plasticity and Inhibitory Synapse Development and Abnormal Social Communication and Startle Response

SALM1 (SALM (synaptic adhesion-like molecule), also known as LRFN2 (leucine rich repeat and fibronectin type III domain containing), is a postsynaptic density (PSD)-95-interacting synaptic adhesion molecule implicated in the regulation of NMDA receptor (NMDAR) clustering largely based on in vitro data, although its in vivo functions remain unclear. Here, we found that mice lacking SALM1/LRFN2 (Lrfn2^–/– mice) show a normal density of excitatory synapses but altered excitatory synaptic function, including enhanced NMDAR-dependent synaptic transmission but suppressed NMDAR-dependent synaptic plasticity in the hippocampal CA1 region. Unexpectedly, SALM1 expression was detected in both glutamatergic and GABAergic neurons and Lrfn2^–/– CA1 pyramidal neurons showed decreases in the density of inhibitory synapses and the frequency of spontaneous inhibitory synaptic transmission. Behaviorally, ultrasonic vocalization was suppressed in Lrfn2^–/– pups separated from their mothers and acoustic startle was enhanced, but locomotion, anxiety-like behavior, social interaction, repetitive behaviors, and learning and memory were largely normal in adult male Lrfn2^–/– mice. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, and social communication and startle behaviors in mice.

SIGNIFICANCE STATEMENT Synaptic adhesion molecules regulate synapse development and function, which govern neural circuit and brain functions. The SALM/LRFN (synaptic adhesion-like molecule/leucine rich repeat and fibronectin type III domain containing) family of synaptic adhesion proteins consists of five known members for which the in vivo functions are largely unknown. Here, we characterized mice lacking SALM1/LRFN2 (SALM1 KO) known to associate with NMDA receptors (NMDARs) and found that these mice showed altered NMDAR-dependent synaptic transmission and plasticity, as expected, but unexpectedly also exhibited suppressed inhibitory synapse development and synaptic transmission. Behaviorally, SALM1 KO pups showed suppressed ultrasonic vocalization upon separation from their mothers and SALM1 KO adults showed enhanced responses to loud acoustic stimuli. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, social communication, and acoustic startle behavior.

https://ift.tt/2N6XANY

Blocking Autophagy in Oligodendrocytes Limits Functional Recovery after Spinal Cord Injury

Autophagy mechanisms are well documented in neurons after spinal cord injury (SCI), but the direct functional role of autophagy in oligodendrocyte (OL) survival in SCI pathogenesis remains unknown. Autophagy is an evolutionary conserved lysosomal-mediated catabolic pathway that ensures degradation of dysfunctional cellular components to maintain homeostasis in response to various forms of stress, including nutrient deprivation, hypoxia, reactive oxygen species, DNA damage, and endoplasmic reticulum (ER) stress. Using pharmacological gain and loss of function and genetic approaches, we investigated the contribution of autophagy in OL survival and its role in the pathogenesis of thoracic contusive SCI in female mice. Although upregulation of Atg5 (an essential autophagy gene) occurs after SCI, autophagy flux is impaired. Purified myelin fractions of contused 8 d post-SCI samples show enriched protein levels of LC3B, ATG5, and BECLIN 1. Data show that, while the nonspecific drugs rapamycin (activates autophagy) and spautin 1 (blocks autophagy) were pharmacologically active on autophagy in vivo, their administration did not alter locomotor recovery after SCI. To directly analyze the role of autophagy, transgenic mice with conditional deletion of Atg5 in OLs were generated. Analysis of hindlimb locomotion demonstrated a significant reduction in locomotor recovery after SCI that correlated with a greater loss in spared white matter. Immunohistochemical analysis demonstrated that deletion of Atg5 from OLs resulted in decreased autophagic flux and was detrimental to OL function after SCI. Thus, our study provides evidence that autophagy is an essential cytoprotective pathway operating in OLs and is required for hindlimb locomotor recovery after thoracic SCI.

SIGNIFICANCE STATEMENT This study describes the role of autophagy in oligodendrocyte (OL) survival and pathogenesis after thoracic spinal cord injury (SCI). Modulation of autophagy with available nonselective drugs after thoracic SCI does not affect locomotor recovery despite being pharmacologically active in vivo, indicating significant off-target effects. Using transgenic mice with conditional deletion of Atg5 in OLs, this study definitively identifies autophagy as an essential homeostatic pathway that operates in OLs and exhibits a direct functional role in SCI pathogenesis and recovery. Therefore, this study emphasizes the need to discover novel autophagy-specific drugs that specifically modulate autophagy for further investigation for clinical translation to treat SCI and other CNS pathologies related to OL survival.

https://ift.tt/2N2Io4l

Increased Microglial Activity, Impaired Adult Hippocampal Neurogenesis, and Depressive-like Behavior in Microglial VPS35-Depleted Mice

Vacuolar sorting protein 35 (VPS35) is a critical component of retromer, which is essential for selective endosome-to-Golgi retrieval of membrane proteins. VPS35 deficiency is implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, exactly how VPS35 loss promotes AD pathogenesis remains largely unclear. VPS35 is expressed in various types of cells in the brain, including neurons and microglia. Whereas neuronal VPS35 plays a critical role in preventing neurodegeneration, the role of microglial VPS35 is largely unknown. Here we provide evidence for microglial VPS35's function in preventing microglial activation and promoting adult hippocampal neurogenesis. VPS35 is expressed in microglia in various regions of the mouse brain, with a unique distribution pattern in a brain region-dependent manner. Conditional knocking out of VPS35 in microglia of male mice results in regionally increased microglial density and activity in the subgranular zone of the hippocampal dentate gyrus (DG), accompanied by elevated neural progenitor proliferation, but decreased neuronal differentiation. Additionally, newborn neurons in the mutant DG show impaired dendritic morphology and reduced dendritic spine density. When examining the behavioral phenotypes of these animals, microglial VPS3S-depleted mice display depression-like behavior and impairment in long-term recognition memory. At the cellular level, VPS35-depleted microglia have grossly enlarged vacuolar structures with increased phagocytic activity toward postsynaptic marker PSD95, which may underlie the loss of dendritic spines observed in the mutant DG. Together, these findings identify an important role of microglial VPS35 in suppressing microglial activation and promoting hippocampal neurogenesis, which are both processes involved in AD pathogenesis.

SIGNIFICANCE STATEMENT The findings presented here provide the first in vivo evidence that Vacuolar sorting protein 35 (VPS35)/retromer is essential for regulating microglial function and that when microglial retromer mechanics are disrupted, the surrounding brain tissue can be affected in a neurodegenerative manner. These findings present a novel, microglial-specific role of VPS35 and raise multiple questions regarding the mechanisms underlying our observations. These findings also have myriad implications for the field of retromer research and the role of retromer dysfunction in neurodegenerative pathophysiology. Furthermore, they implicate a pivotal role of microglia in the regulation of adult hippocampal neurogenesis and the survival/integration of newborn neurons in the adult hippocampus.

https://ift.tt/2N64we3

Preferential Targeting of Lateral Entorhinal Inputs onto Newly Integrated Granule Cells

Mature dentate granule cells in the hippocampus receive input from the entorhinal cortex via the perforant path in precisely arranged lamina, with medial entorhinal axons innervating the middle molecular layer and lateral entorhinal cortex axons innervating the outer molecular layer. Although vastly outnumbered by mature granule cells, adult-generated newborn granule cells play a unique role in hippocampal function, which has largely been attributed to their enhanced excitability and plasticity (Schmidt-Hieber et al., 2004; Ge et al., 2007). Inputs from the medial and lateral entorhinal cortex carry different informational content. Thus, the distribution of inputs onto newly integrated granule cells will affect their function in the circuit. Using retroviral labeling in combination with selective optogenetic activation of medial or lateral entorhinal inputs, we examined the functional innervation and synaptic maturation of newly generated dentate granule cells in the mouse hippocampus. Our results indicate that lateral entorhinal inputs provide the majority of functional innervation of newly integrated granule cells at 21 d postmitosis. Despite preferential functional targeting, the dendritic spine density of immature granule cells was similar in the outer and middle molecular layers, which we speculate could reflect an unequal distribution of shaft synapses. However, chronic blockade of neurotransmitter release of medial entorhinal axons with tetanus toxin disrupted normal synapse development of both medial and lateral entorhinal inputs. Our results support a role for preferential lateral perforant path input onto newly generated neurons in mediating pattern separation, but also indicate that medial perforant path input is necessary for normal synaptic development.

SIGNIFICANCE STATEMENT The formation of episodic memories involves the integration of contextual and spatial information. Newly integrated neurons in the dentate gyrus of the hippocampus play a critical role in this process, despite constituting only a minor fraction of the total number of granule cells. Here we demonstrate that these neurons preferentially receive information thought to convey the context of an experience. Each newly integrated granule cell plays this unique role for ~1 month before reaching maturity.

https://ift.tt/2N5PftB

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant liver donor shortage, and criteria for liver donors have been expanded. Normothermic ex vivo liver perfusion (NEVLP) has been developed to evaluate and modify organ function. This study demonstrates a rat model of NEVLP and tests the ability of pegylated-catalase, to mitigate liver preservation injury.

https://ift.tt/2KulNf9

Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy

Here, we present a robust and optimized protocol for the production of milligram quantities of native, tag-free monomers and fibrils of the exon1 of the Huntingtin protein (Httex1) based on the transient fusion of small ubiquitin related modifier (SUMO).

https://ift.tt/2N4P1mK

LncRNA SNHG16 predicts poor prognosis in ESCC and promotes cell proliferation and invasion by regulating Wnt/β-catenin signaling pathway

OBJECTIVE: Increasing evidence indicated that small nucleolar RNA host gene 16 (SNHG16) acted as a key regulator in the proliferation and metastasis of several cancers, including esophageal squamous cell carcinoma (ESCC). In this research, we aimed to explore biological functions, clinical significance and the underlying molecular mechanisms of SNHG16 in ESCC.

PATIENTS AND METHODS: qRT-PCR was performed to examine the expression of SNHG16 in ESCC cell lines and clinical ESCC tissue samples. The association of SNHG16 expression with clinicopathological factors and prognosis was statistically analyzed. Cell Counting Kit-8, flow cytometry, and transwell invasion assays were performed to determine the effect of SNHG16 in the regulation of biological behaviors of ESCC cells. Luciferase assay and Western blot were performed to determine the activation of Wnt/β-catenin signaling pathway

RESULTS: We observed that SNHG16 expression levels were significantly upregulated in ESCC tissues and cell lines compared with the corresponding normal tissues and normal esophageal cell line, respectively. In addition, increased expression of SNHG16 were strongly linked to tumor stage (p = 0.019), lymph nodes metastasis (p = 0.007) and clinical stage (p = 0.026). Kaplan-Meier assay showed that the survival time of patients with high SNHG16 expression was significantly shorter than those with low SNHG16 expression (p = 0.0017). Univariate and multivariate analyses showed that high SNHG16 expression in ESCC was an independent predictor of poor survival. Loss-of-function experiments revealed that knockdown of SNHG16 suppressed proliferation and invasion and induced apoptosis of ESCC cells. Mechanistically, Wnt/β-catenin signaling pathways were actively modulated by SNHG16 in ESCC cells.

CONCLUSIONS: Our findings reveal that SNHG16 plays an important role in ESCC proliferation/metastasis via modulating Wnt/β-catenin signaling pathways and could represent a novel biomarker for predicting poor survival as well a promising therapeutic target.

L'articolo LncRNA SNHG16 predicts poor prognosis in ESCC and promotes cell proliferation and invasion by regulating Wnt/β-catenin signaling pathway sembra essere il primo su European Review.

https://ift.tt/2MuKI2K

Effect of the rs1862513 variant of resistin gene on insulin resistance and resistin levels after two hypocaloric diets with different fat distribution in subjects with obesity

OBJECTIVE: Polymorphisms of a single nucleotide in resistin gene (RETN) have been associated with insulin resistance. We decide to investigate the role of this polymorphism on insulin resistance and resistin levels after two hypocaloric diets.

PATIENTS AND METHODS: A sample of 361 obese non-diabetic Caucasian was enrolled. Biochemical evaluation and anthropometric data were measured at the start of the trial and repeated after 3 months of both diets (Diet P, Polyunsaturated vs. diet M, Monounsaturated).

RESULTS: With both diets and in both genotype groups, BMI, weight, fat mass, waist circumference, systolic blood pressure, and diastolic blood pressure decreased. After diet P, insulin levels (GG vs. GC+CC genotypes) (-1.2±3.8 UI/L vs. -0.7±2.1 UI/L; p<0.05), HOMA-IR (-0.6±1.0 units vs. -0.4±0.9 units; p<0.05), total cholesterol (-10.5±20.1 mg/dl vs. -6.1±15.1 mg/dl; p<0.05) and LDL-total cholesterol (-8.6±10.1 mg/dl vs. -2.2±9.1 mg/dl; p<0.05) decreased in subjects with GG genotype. After diet M, insulin levels (-1.8±2.1 UI/L vs. -0.6±3.0 UI/L: p>0.05), HOMA-IR (-0.5±1.0 units vs. -0.3±1.1 units: p>0.05), total cholesterol (-9.5±13.1 mg/dl vs. -4.4±8.1 mg/dl; p<0.05) and LDL-total cholesterol (-8.1±6.1 mg/dl vs. -2.9±9.1 mg/dl; p<0.05) decreased, too.

CONCLUSIONS: We suggest that GG genotype of RETN rs1862513 could be a predictor of the reduction of HOMA-IR, insulin, and LDL cholesterol secondary to two hypocaloric diet in obese subjects.

L'articolo Effect of the rs1862513 variant of resistin gene on insulin resistance and resistin levels after two hypocaloric diets with different fat distribution in subjects with obesity sembra essere il primo su European Review.

https://ift.tt/2Kp2FCJ

Global seasonal occurrence of middle east respiratory syndrome coronavirus (MERS-CoV) infection

OBJECTIVE: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an evolving global health crisis. Despite recent efforts, there are numerous notable gaps in the understanding of MERS-CoV seasonal diversity. We aimed at investigating the global seasonal occurrence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) outbreaks.

MATERIALS AND METHODS: We obtained the data on the prevalence and occurrence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection from the World Health Organization (WHO) for all the MERS cases reported from the various countries and their allied ministries. We also recorded the research documents published in various global scientific journals on the seasonal occurrence of MERS-CoV infection during the period 2012-2017.

RESULTS: Worldwide 2048 laboratory confirmed cases of MERS-CoV infection were reported from June 2012 to the Dec 2017. 1680 (82.03%) cases were from the Saudi Arabia and 368 (17.96%) cases were reported from the other countries of the world. The maximum number of cases reported in June was 474 (23.14%). 287 (14.01%) cases were reported from Saudi Arabia and remaining 187 (9.13%) cases were reported from all over the world. The number of cases reported from April to June was 396 (19.33%) while the cases encountered from October to December were 231 (11.27%).

CONCLUSIONS: The highest global seasonal occurrence of Middle East Respiratory Syndrome coronavirus-MERS-CoV outbreak cases were found in the month of June, while the lowest was found in the month of January during the period of 2012 to 2017. The pattern of MERS-CoV infections has been observed to have seasonal variations. It is suggested that the health officials should highlight the seasonal occurrence of MERS-CoV outbreak and take better preventive measures to minimize the disease burden nationally and globally.

L'articolo Global seasonal occurrence of middle east respiratory syndrome coronavirus (MERS-CoV) infection sembra essere il primo su European Review.

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Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway

OBJECTIVE: Osteoporosis is the most common bone metabolic disease. Exosome exerts a crucial role in the development of multiple diseases. The aim of the study was to investigate the role of exosome derived from bone marrow mesenchymal stem cells (MSCs) in osteoporosis and its underlying mechanism.

MATERIALS AND METHODS: MSCs were first isolated from rat bone marrow. After the surface antigen of MSCs was identified by flow cytometry, MSCs-derived exosomes (MSC-Exo) was extracted. The osteogenic and lipid differentiation abilities of BMSCs were determined by alizarin red staining and oil red staining, respectively. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to detect the mRNA expressions of genes. Cell counting kit-8 (CCK-8) assay was used to detect the viability of hFOB 1.19 cells. Western blot was used to measure expressions of the specific surface markers in exosomes and the MAPK pathway-related proteins in hFOB 1.19 cells. Moreover, cell cycle of hFOB 1.19 was detected by flow cytometry.

RESULTS: We observed a positive identification of surface antigens in MSCs, which presented good multidirectional differentiation ability. The isolated MSC-Exo exhibited typical morphology and particle size of exosomes, and the detection of specific surface labeled protein was positive under an electron microscope. After co-culture of MSC-Exo and osteoblast cell line hFOB 1.19, we found that MSC-Exo could promote the proliferation of hFOB 1.19 cells. Moreover, mRNA and protein expressions of GLUT3 in cells were increased, and the cell cycle was also promoted. The expressions of related proteins in the MAPK signaling pathway were found to be promoted. Rescue experiments demonstrated that MSC-Exo could promote the growth and cell cycle of hFOB 1.19, which were reversed by p-JNK knockdown.

CONCLUSIONS: MSC-derived exosomes improve osteoporosis by promoting the proliferation of osteoblasts via MAPK pathway.

L'articolo Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway sembra essere il primo su European Review.

https://ift.tt/2yObnWr

Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis

Objective

In patients with pancreatitis, early persisting organ failure is believed to be the most important cause of mortality. This study investigates the relation between the timing (onset and duration) of organ failure and mortality and its association with infected pancreatic necrosis in patients with necrotising pancreatitis.

Design

We performed a post hoc analysis of a prospective database of 639 patients with necrotising pancreatitis from 21 hospitals. We evaluated the onset, duration and type of organ failure (ie, respiratory, cardiovascular and renal failure) and its association with mortality and infected pancreatic necrosis.

Results

In total, 240 of 639 (38%) patients with necrotising pancreatitis developed organ failure. Persistent organ failure (ie, any type or combination) started in the first week in 51% of patients with 42% mortality, in 13% during the second week with 46% mortality and in 36% after the second week with 29% mortality. Mortality in patients with persistent multiple organ failure lasting <1 week, 1–2 weeks, 2–3 weeks or longer than 3 weeks was 43%, 38%, 46% and 52%, respectively (p=0.68). Mortality was higher in patients with organ failure alone than in patients with organ failure and infected pancreatic necrosis (44% vs 29%, p=0.04). However, when excluding patients with very early mortality (within 10 days of admission), patients with organ failure with or without infected pancreatic necrosis had similar mortality rates (28% vs 34%, p=0.33).

Conclusion

In patients with necrotising pancreatitis, early persistent organ failure is not associated with increased mortality when compared with persistent organ failure which develops further on during the disease course. Furthermore, no association was found between the duration of organ failure and mortality.

https://ift.tt/2MsnNoP

Implantation of Electrospun Vascular Grafts with Optimized Structure in a Rat Model

Here, we present a modified electrospinning method to fabricate PCL vascular grafts with thick fibers and large pores, and describe a protocol to evaluate the in vivo performance in a rat model of abdominal aorta replacement.

https://ift.tt/2Krw3YV

Preparation of Aligned Steel Fiber Reinforced Cementitious Composite and Its Flexural Behavior

This protocol describes an approach for manufacturing aligned steel fiber reinforced cementitious composite by applying a uniform electromagnetic field. Aligned steel fiber reinforced cementitious composite exhibits superior mechanical properties to ordinary fiber reinforced concrete.

https://ift.tt/2KucFXV

National HIV Testing Day Is on June 27

WEDNESDAY, June 27, 2018 -- In honor of National HIV Testing Day, health care providers should encourage people to get an HIV test. About 1 in 7 people in the United States who have HIV don't know that they are infected, according to the U.S....

https://ift.tt/2yJaDSq

Missed Opportunities for HIV Diagnosis Among Those at Risk

WEDNESDAY, June 27, 2018 -- Considerable numbers of men who have sex with men (MSM) and persons who inject drugs (PWID) who are unaware of their HIV infection report missed opportunities for diagnosis, according to a research letter published online...

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Sleep Disruption Increases Risk of Atrial Fibrillation

WEDNESDAY, June 27, 2018 -- Sleep disruption consistently predicts risk of atrial fibrillation (AF) before and after adjusting for obstructive sleep apnea, according to a study published online June 25 in Heart Rhythm. Matthew A. Christensen, M.D.,...

https://ift.tt/2tHBWHe

Clotting Time in Transfemoral PCI Linked to Bleeding Risk

WEDNESDAY, June 27, 2018 -- Higher maximal activated clotting time (ACT) is associated with a greater risk of major bleeding after transfemoral (TF) percutaneous coronary intervention (PCI) than after transradial (TR) PCI, according to a study...

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Mercury Released From Amalgam Fillings After High-Power MRI

WEDNESDAY, June 27, 2018 -- Mercury is released from amalgam fillings after exposure to 7.0 Tesla (T) magnetic resonance imaging (MRI), according to a study published online June 26 in Radiology. Selmi Yilmaz, Ph.D., from Akdeniz University and M....

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Intervention Programs Prevent Diabetes Distress in Teens

WEDNESDAY, June 27, 2018 Intervention programs that start before psychological symptoms develop can prevent diabetes distress (DD) in teens with type 1 diabetes, according to a study published in the June issue of Diabetes Care. Korey K. Hood,...

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Sodium Thiosulfate Post-Cisplatin May Lessen Hearing Loss

WEDNESDAY, June 27, 2018 -- Delayed administration of sodium thiosulfate after cisplatin chemotherapy may prevent treatment-related hearing loss in children with standard-risk hepatoblastoma without affecting survival outcomes, according to a study...

https://ift.tt/2yKdb2N

Abortion Complication Rates Similar Between Facility Type

WEDNESDAY, June 27, 2018 There is no significant difference in abortion-related morbidities and adverse events following induced abortions, whether the procedure is performed in an ambulatory surgical center (ASC) or an office-based setting,...

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Decline in Medicare Patients Who Die in Acute Care Hospitals

WEDNESDAY, June 27, 2018 -- Medicare fee-for-service beneficiaries were less likely to die in acute care hospitals in 2015 than in 2000, according to a study published online June 25 in the Journal of the American Medical Association. Joan M. Teno,...

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Higher Rates of Cancers Observed Among Flight Attendants

WEDNESDAY, June 27, 2018 -- Flight attendants have higher rates of specific cancers compared with the general population, according to a study published online June 25 in Environmental Health. Eileen McNeely, Ph.D., from the Harvard T.H. Chan School...

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Apelin-12 exerts neuroprotective effect against ischemia-reperfusion injury by inhibiting JNK and P38MAPK signaling pathway in mouse

OBJECTIVE: Cerebral ischemia is a common neurological disease, and its pathological process remains elusive. This study focused on the protective mechanism of Apelin-12 protein on the nervous system of mice during cerebral ischemia-reperfusion injury through JNK and P38MAPK signaling pathway.

MATERIALS AND METHODS: The mouse model with an ischemia-reperfusion injury in middle cerebral artery was prepared by the modified thread-occlusion method and divided into 4 groups randomly. Before implantation of the mice, we assessed the neurological function and evaluated the cerebral edema by the wet-dry weight method. Lactate dehydrogenase (LDH) kit was used to assess the degree of cell injury. Malondialdehyde (MDA) kit was used to measure the level of neuron MDA. Immunohistochemistry was performed to evaluate the neuronal cell in the ischemic brain. Protein expressions of JNK and P38MAPK and apoptosis-related molecules, including Bax, Bcl-2, caspase-3, and cleaved caspase-3, were measured by Western blot assay.

RESULTS: After focal cerebral ischemia-reperfusion, a significant decrease in neurobehavioral score, brain edema and neuron injury in mice occurred. Apelin-12 significantly improved the neurobehavioral score of the mice with ischemia-reperfusion injury, alleviated brain edema and the damage to neurons. In addition, Apelin-12 inhibited the morphological changes and apoptosis of neuronal cells in the ischemic penumbra of mice. Apelin-12 could downregulate the expression of Bax and caspase-3, inhibit the activity of caspase-3 and upregulate the expression of Bcl-2, an anti-apoptotic protein. A significant reduction in the protein expression of p-JNK and p-p38 was observed in the Apelin-12 group compared with that in the I/R or Vehicle group (p<0.05).

CONCLUSIONS: When an ischemia-reperfusion injury occurred, Apelin-12 can inhibit the JNK and P38MAPK signaling pathway of the apoptosis-related MAPKs family, thus offering protection to neurons.

L'articolo Apelin-12 exerts neuroprotective effect against ischemia-reperfusion injury by inhibiting JNK and P38MAPK signaling pathway in mouse sembra essere il primo su European Review.

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Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.


https://ift.tt/2KrIT68

Radiological findings in ancient Egyptian canopic jars

Examination of ancient Egyptian canopic jars through clinical imaging modalities.

Read the research: https://eurradiolexp.springeropen.com/articles/10.1186/s41747-018-0048-3

DOI: 10.1186/s41747-018-0048-3

Video courtesy of Patrick Eppenberger

https://www.youtube.com/watch?v=Q7r4zX_oaTQ

Erratum to “Fat Embolism Syndrome: A Case Report and Review Literature”

https://ift.tt/2tHmieM

Brown-Vialetto-Van Laere syndrome: a novel diagnosis to a common presentation

Brown-Vialetto-Van Laere syndrome (BVVLS) or riboflavin transporter deficiency (OMIM 211530) is a rare treatable autosomal recessive neurodegenerative disorder. This condition is associated with progressive pontobulbar palsy. We describe the clinical course of a 16-month-old boy with BVVLS and a novel homozygous mutation from Pakistan. Our patient presented with stridor and respiratory insufficiency. Hearing loss which is the most common sign of this condition was absent, making it an unusual presentation of BVVLS. His examination revealed ptosis and tongue fasciculation. His riboflavin receptor mutational analysis showed the homozygous mutation in the SLC52A3 gene. Per oral riboflavin was administered, and subsequently, he was able to be weaned off the ventilator. Now the child is improving and attaining developmental milestones.

https://ift.tt/2N56KKD

New headaches with normal inflammatory markers: an early atypical presentation of giant cell arteritis

An 80-year-old man presented repeatedly to his general practitioner with 3 months of unexplained persistent frontal headaches. CT head revealed no diagnosis. His dentist diagnosed his co-existing jaw pain as bruxism. Three months later, the patient happened to attend a routine ophthalmology follow-up appointment. During this routine appointment, features of giant cell arteritis (GCA) including worrying visual complications were first noted. His inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) were not significantly raised—contrary to the norm. A temporal artery ultrasound and biopsy were performed, in light of the history. This confirmed GCA. He was commenced on high-dose oral prednisolone and was managed by ophthalmology and rheumatology. At 4 weeks, symptoms resolved with no permanent visual loss despite a prolonged initial symptomatic period. Multiple symptomatic presentations to different specialties should therefore alert clinicians to a unifying diagnosis, for example, vasculitis. Serious illnesses may present with severe symptoms despite normal screening investigations.

https://ift.tt/2KnSY43

Perioperative continuous glucose monitoring in a preterm infant

Surgery in the neonatal period presents challenges, especially in preterm infants weighing <1 kg. Their small size, minimal reserves and physiological immaturity means attention to detail and careful monitoring is critical to avoid cardiovascular instability; maintaining fluid balance and metabolic stability is also problematic due to often limited vascular access and small blood volumes. Developments in technology have meant that cardiovascular parameters such as heart rate, blood pressure and oxygen saturations are all routinely and continuously monitored before and during surgery.

We have been exploring the role of continuous glucose monitoring (CGM) for metabolic monitoring and management of glucose control in very preterm infants (24–32 weeks gestation). In this paper, we report on a preterm infant who uniquely underwent surgery while wearing a continuous glucose monitor, blinded to the clinical team. This case highlights the metabolic vulnerability of these babies and a possible role for real-time CGM during surgical procedures.

https://ift.tt/2txHXa2

Possible SAMe-induced mania

This paper describes a patient who presented with mania with psychotic features in the context of concomitant use of S-adenosyl-L-methionine (SAMe) and selective serotonin reuptake inhibitor (SSRI). The aim of this case report is to provide medical practitioners with a greater awareness of the possibility of a psychotic episode and/or mania manifesting with concurrent use of SAMe and SSRI.

https://ift.tt/2Iv781L

Correction: Primary malignant melanoma of the ascending colon

Miliaras S, Ziogas IA, Mylonas KS, et al. Primary malignant melanoma of the ascending colon. BMJ Case Rep 2018. doi: 10.1136/bcr-2017-223282. 

In the 'Summary' and 'Discussion' sections, it is stated that 36 previous cases have been reported, while in fact this number is incorrect: the correct number of cases that have been previously reported is 15.

https://ift.tt/2txsVBa

Intravenous immunoglobulin for severe thrombocytopenia in secondary dengue

A 30-year-old woman with severe dengue presented on the sixth day of her illness with life-threatening thrombocytopenia, refractory to multiple platelet transfusions. Dengue IgM antibody and the non-structural-1 antigen tests as of day 3 were negative. The IgG antibody against the same was positive, suggesting a past episode of dengue. Since she had a history of menorrhagia prior to the current illness, a working diagnosis of idiopathic thrombocytopenic purpura was made, for which intravenous immunoglobulin (IVIg) was administered that led to a rapid rise in the platelet count with no adverse events. Subsequently, dengue IgM antibody repeated on day 6 came back positive, confirming dengue. This case report re-emphasises the potential use of IVIg in patients with severe thrombocytopenia in dengue.

https://ift.tt/2KsOuZY

Pyopericardium presenting with echocardiographic features of pericardial tamponade in an elderly man

A 72-year-old Chinese man presented with mild symptoms of heart failure. Transthoracic echocardiography showed signs of cardiac tamponade though clinically he was relatively well. The option of pericardiocentesis was not carried out due to a narrow window for aspiration with only a thin layer of effusion seen surrounding the apex and right ventricle on subcostal view.

Pericardial window was done via a left anterolateral thoracotomy. Intraoperatively, 500 cm³ of purulent fluid was drained. Microbiology screens were all negative. We present the atypical clinical course of this elderly man presenting with a large pyopericardium.

https://ift.tt/2twsWVM

Cloudy Cornea with Arcus Juvenilis in a Case of Dense Deposit Disease

A 25-year-old male patient presented with complaints of blurred vision in both eyes since 2 years. The patient was a known case of nephrotic syndrome with dyslipidaemia for which he was on diuretics and lipid-lowering agents for 3 years. On examination, his visual acuity was 6/9 in both eyes with cloudy cornea and arcus juvenilis. Fundus examination was within normal limits. On systemic work-up, his lipid profile was deranged with increased serum total cholesterol, very low density lipoprotein, low density lipoprotein and triglyceride. The serum high density lipoprotein was decreased. Renal function test revealed elevated serum creatinine with significant proteinuria. Renal biopsy was suggestive of dense deposit disease on immunofluorescence and transmission electron microscopy. Ocular manifestation of dense deposit disease is characterised by retinal drusen, pigmentary atrophy, choroidal neovascular membrane and atypical serous retinopathy. To the best of our knowledge, anterior segment changes in dense deposit disease has not been reported. This is the first case reporting cloudy cornea with arcus juvenilis in a case of dense deposit disease.

https://ift.tt/2Kq5Pmu

Craniovertebral junction cord compression due to neurofibroma

Description

A 26-year-old man with premorbid cutaneous neurofibromatosis presented with history of insidious onset, slowly progressive, bilaterally asymmetrical quadriparesis along with incontinence of urine since 4 weeks. Simultaneous to the onset of motor symptoms, he also complained of paraesthesias in all four limbs. On examination, multiple cutaneous neurofibromas were noticed all over his trunk, abdomen and all the limbs (figure 1). The upper and lower limbs were spastic. Motor power as per Medical Research Council grading was 3/5 in all four limbs. The deep tendon reflexes were brisk. The plantar response on both sides was extensor. The sensory level was clinically around C3/C4 dermatome.

Figure 1

Multiple cutaneous neurofibromas of varying sizes on the lower chest and abdomen (red arrows).

In view of the premorbid neurofibromata, a possibility of compressive cervical myelopathy was thought of. MRI of cervical spine T2-weighted sagittal view...

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Dural arteriovenous fistula presenting with acute subdural haematoma showing impending cerebral herniation

A dural arteriovenous fistula (DAVF) presenting with acute subdural haematoma (ASDH), which were not related to head injury, is rare. A 61-year-old woman was transported by ambulance because of deterioration of consciousness. On admission, she was comatose with anisocoria. Emergent CT demonstrated a severe midline shift associated with a left ASDH and an additional left occipital intracerebral haematoma, both of which had no continuity with each other. MRI showed flow void signs in the left occipital lobe. Because of the impending cerebral herniation, an emergent evacuation of the ASDH and external decompression was performed. Subsequent evaluation revealed a DAVF at the left occipital convexity near the confluence with retrograde leptomeningeal venous reflux and venous ectasia (Cognard type III DAVF). The patient underwent endovascular treatment for the DAVF involving transarterial embolisation using coils and N-butyl cyanoacrylate with complete obliteration. Her further clinical course was uneventful and discharged after cranioplasty.

https://ift.tt/2Ixbk0G

The microRNA signatures: aberrantly expressed miRNAs in prostate cancer

Abstract

MicroRNAs (miRNAs) are short, non-coding, conserved, oligonucleotides that are regulatory in nature and are often dysregulated in many cancers including prostate cancer. Depending on the level of complementarity between the miRNA and mRNA target, they can either inhibit translation or degrade the target mRNA. MiRNAs expression is specific to the type of cancer, its stage and level of metastasis, making miRNAs potential stage-specific biomarkers of cancer. Recent research has shown that these miRNAs have the potential to be a diagnostic and prognostic non-invasive biomarker for various cancers including prostate cancer. Various miRNAs have been reported as novel biomarkers for prostate cancer therapy. However, there is inconsistency in the data reported and no overlapping expression pattern could be found. In this review, we have highlighted the most consistently reported dysregulated miRNAs in prostate cancer from the existing literature and discussed the currently available data on their role in regulating the hallmarks of prostate cancer. These four most consistently reported dysregulated miRNAs viz. miRNA-141, miRNA-375, miRNA-221 and miRNA-21 need to be further validated in terms of their regulatory potential in regulating various pathways important for prostate cancer management.

https://ift.tt/2tyGaBw

Effect of Freeze-Thaw on a Midtemperate Soil Bacterial Community and the Correlation Network of Its Members

Freeze-thaw (FT) events can influence soil functions. However, the overall impact of FTs on soil bacterial communities, especially in temperate regions, remains unclear. In this study, soil samples were collected from a midtemperate region in the northeast of China, and three incubation tests were then designed with varied FT amplitudes (i.e., at a freezing temperature of −15, −9, and −3°C, respectively), frequencies of FT cycles (i.e., under one, six, and 15 FT cycles, respectively) and soil water content (SWC) values (i.e., at 10 and 30% SWC, respectively). High-throughput sequencing of 16S rRNA gene amplicons was performed and the functional profile was further predicted based on these data, in addition to examinations of bulk microbial properties. Data analyses suggested that, first of all, the FT amplitude significantly influenced the bulk microbial properties and bacterial community (composition and function); certain taxa showed a nonlinear response to the three amplitudes. Next, compared to a single FTC, multiple FT cycles had only minor effects on the bacterial functional capabilities, although the bulk microbial properties changed significantly after multiple FT cycles. In addition, the bacterial response to FTs was influenced by the SWC, characterized by the significantly different bacterial community structures (composition and function) and the opposite trends of enzyme activities. Finally, RDA plots and a correlation network assembled data from all soil samples across the three tests and suggested that bacterial response trajectories changed because some species were influenced mainly by other species (i.e., biotic environment) during FT processes.

https://ift.tt/2tAqv4L

Do Different LED Colours Influence Sand Fly Collection by Light Trap in the Mediterranean?

Light traps represent the most used attractive system to collect and monitor phlebotomine sand flies. Recent studies have suggested that light traps can be easily upgraded by the use of light-emitting diode (LED) with positive effects on trap design, weight, and battery life. However, scant data on the effect of different LED colours on the attractiveness to phlebotomine sand fly species are available in literature. In this study, the capture performances of light traps equipped with different LED colours on phlebotomine sand fly species indigenous in the Mediterranean area were evaluated. Phlebotomine sand fly collections were performed using a classical light trap (CLT), equipped with a traditional incandescent lamp, and five Laika 4.0 light traps supplied, each with LED of different colours and wavelengths: (i) white; (ii) red; (iii) green; (iv) blue; (v) UV. Light traps were set for three consecutive nights fortnightly from May to October 2017 and climate data recorded using a meteorological station. A total of 411 phlebotomine sand flies (191 males and 220 females), belonging to three different species, namely, Phlebotomus perniciosus (n= 298, 141 males and 157 females), Sergentomyia minuta (n=110, 48 males and 62 females), and Phlebotomus neglectus (n=3, 2 males and 1 females) were collected. Abundance of capture was influenced by colours of LED and time. The highest number of phlebotomine sand flies was captured on June (P0.05) or LED colour (P>0.05) was recorded for S. minuta and P. neglectus. According to the results of the present study light trap equipped with UV LED can represent an effective tool for the capture of sand fly species in the Mediterranean area.

https://ift.tt/2tzkeX6

Lumbosacral Defects in a 16th–18th-Century Joseon Dynasty Skeletal Series from Korea

Paleopathological evidence for congenital and degenerative disorders of the lumbosacral vertebrae is informative about ancient individual lifeways and physical conditions. However, very few studies have focused on the paleopathology of the lumbosacral vertebrae in ancient skeletal series from East Asia. One reason for the lack of studies is that skeletal samples from East Asia are typically insufficient in size to represent populations for comparative studies within the continent. Here, we present the first comprehensive analysis of lumbosacral defects in an East Asian human skeletal sample, examining occurrences of spina bifida occulta (SBO), lumbosacral transitional vertebrae (LSTV), and spondylolysis in remains from Joseon tombs dating to the 16–18th centuries in Korea. In this study, we present an alternative methodology for understanding activities of daily life among ancient Koreans through paleopathological analysis.

https://ift.tt/2KmuITn

Simvastatin Improves the Jaw Bone Microstructural Defect Induced by High Cholesterol Diet in Rats by Regulating Autophagic Flux

Objective. The objective of this study is to evaluate the effect of simvastatin on the jaw bone microstructural defect and autophagy in rats with high cholesterol diet (HCD). Methods. Male Sprague-Dawley rats were fed a standard rodent chow (NC group) or a high cholesterol diet for 32 weeks and the HCD-fed rats were treated with vehicle (HC group) or simvastatin (5 mg/kg orally daily for 8 weeks, HC + SIM group, and /group). The static histomorphometric changes in the jaw bone tissues in individual rats were evaluated. The relative levels of OPG, RANKL, NF-κB, LC3, and p62 in the jaw bone tissues were determined by quantitative RT-PCR and/or immunohistochemistry. Results. Compared with the NC group, the HC groups had lower trabecular bone volume, trabecular thickness and trabecular number, and increased ratios of RANKL/OPG in the jaw bone, accompanied by enhanced NF-κB activation and autophagy. Simvastatin treatment inhabited these changes, including the decreased levels of serum proinflammatory cytokines and increased autophagy. Conclusion. Simvastatin treatment could inhibit the hyperlipidemia-induced jaw bone microstructural defect in rats by increasing autophagic flux.

https://ift.tt/2Mu4iMJ