Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation

Summary

Background

Functional constipation is a common clinical presentation in primary care. Functional defaecation disorders are defined as the paradoxical contraction or inadequate relaxation of the pelvic floor muscles during attempted defaecation (dyssynergic defaecation) and/or inadequate propulsive forces during attempted defaecation. Prompt diagnosis and management of dyssynergic defaecation is hindered by uncertainty regarding nomenclature, diagnostic criteria, pathophysiology and efficacy of management options such as biofeedback therapy.

Aim

To review the evidence pertaining to the pathophysiology of functional defaecation disorders and the efficacy of biofeedback therapy in the management of patients with dyssynergic defaecation and functional constipation.

Methods

Relevant articles addressing functional defaecation disorders and the efficacy of biofeedback therapy in the management of dyssynergic defaecation and functional constipation were identified from a search of Pubmed, MEDLINE Ovid and the Cochrane Library.

Results

The prevalence of dyssynergic defaecation in patients investigated for chronic constipation is as many as 40%. Randomised controlled trials have demonstrated major symptom improvement in 70%-80% of patients undergoing biofeedback therapy for chronic constipation resistant to standard medical therapy and have determined it to be superior to polyethylene glycol laxatives, diazepam or sham therapy. Long-term studies have shown 55%-82% of patients maintain symptom improvement.

Conclusions

Dyssynergic defaecation is a common clinical condition in patients with chronic constipation not responding to conservative management. Biofeedback therapy appears to be a safe, successful treatment with sustained results for patients with dyssynergic defaecation. Further studies are required to standardise the diagnosis of dyssynergic defaecation in addition to employing systematic protocols for biofeedback therapy.

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Anionic Redox in Rechargeable Lithium Batteries

The extraordinarily high capacities delivered by lithium-rich oxide cathodes, compared with conventional layered oxide electrodes, are a result of contributions from both cationic and anionic redox processes. This phenomenon has invoked a lot of research exploring new kinds of lithium-rich oxides with multiple-electron redox processes. Though proposed many years ago, anionic redox is now regarded to be crucial in further developing high-capacity electrodes. A basic overview of the previous work on anionic redox is given, and issues related to electronic and geometric structures are discussed, including the principles of activation, reversibility, and the energy barrier of anionic redox. Anionic redox also leads to capacity loss and structural degradation, as well as voltage hysteresis, which shows the importance of controlling anionic redox reactions. Finally, the techniques used for characterizing anionic redox processes are reviewed to aid the rational choice of techniques in future studies. Important perspectives are highlighted, which should instruct future work concerning anionic redox processes.

Anionic redox plays an important role in obtaining high capacities in lithium-rich layered oxide cathodes. Previous studies on anionic redox and related electronic- and geometric-structure issues, as well as problems induced by anionic-redox and suitable characterization techniques, are reviewed, in order to direct future work on high-capacity electrodes that utilize anionic redox processes and widen the scope of these materials.

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3D Printed Photoresponsive Devices Based on Shape Memory Composites

Compared with traditional stimuli-responsive devices with simple planar or tubular geometries, 3D printed stimuli-responsive devices not only intimately meet the requirement of complicated shapes at macrolevel but also satisfy various conformation changes triggered by external stimuli at the microscopic scale. However, their development is limited by the lack of 3D printing functional materials. This paper demonstrates the 3D printing of photoresponsive shape memory devices through combining fused deposition modeling printing technology and photoresponsive shape memory composites based on shape memory polymers and carbon black with high photothermal conversion efficiency. External illumination triggers the shape recovery of 3D printed devices from the temporary shape to the original shape. The effect of materials thickness and light density on the shape memory behavior of 3D printed devices is quantified and calculated. Remarkably, sunlight also triggers the shape memory behavior of these 3D printed devices. This facile printing strategy would provide tremendous opportunities for the design and fabrication of biomimetic smart devices and soft robotics.

3D printed photoresponsive devices are successfully fabricated through combining fused deposition modeling and photoresponsive shape memory composites based on polyurethane and carbon black. This study demonstrates the shape memory behavior of these 3D printed devices is well triggered by sunshine. This development provides tremendous opportunities for customized stimuli-responsive devices with complex geometry structure, which have potentials in soft robots, selectively pliable tools, and orthopedic surgery.

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Prognostic Significance of IgG4+ Plasma Cell Infiltrates Following Neoadjuvant Chemoradiation Therapy for Esophageal Adenocarcinoma

Lymphoplasmacytic infiltrates in esophageal adenocarcinoma (EAC) tissue following chemoradiotherapy (CRT) reflect alterations in the tumor immunoenvironment. The presence and role of plasma cells in this process are poorly understood. Our aim was to characterize the IgG4+ plasma cell population in EAC following CRT. Seventy-one esophagectomy specimens post CRT were compared to a surgery only group of 31 EACs. The distribution, density, and ratio of IgG4+ and IgG+ plasma cells were evaluated by immunohistochemistry and correlated with clinicopathologic features, treatment response, and survival.

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Palliative Care Access for Hospitalized Patients with End Stage Liver Disease Across the United States

Abstract

Objective:

Patients with end-stage liver disease (ESLD) often have a high symptom burden. Historically, palliative care (PC) services have been underutilized in this population. We investigated the use of PC services in patients with ESLD hospitalized across the United States.

Methods:

We utilized the Nationwide Inpatient Sample (NIS) to conduct a retrospective nationwide cohort analysis. All patients >18 years of age admitted with ESLD, defined as those with at least two liver decompensation events, were included in the analysis. A multivariate logistic regression model predicting referral to PC was created.

Results:

55,208,382 hospitalizations from the 2006-2012 NIS samples were analyzed with 39,349 (0.07%) patients meeting study inclusion. PC consultation was performed in 1,789 (4.5%) ESLD patients. The rate of PC referral in ESLD increased from 0.97% in 2006 to 7.1% in 2012 (p<0.01). In multivariate analysis, factors associated with lower referral to PC were Hispanic race (OR 0.77; 95% CI 0.66-0.89; p<0.01) and insurance coverage (OR 0.74; 95% CI 0.65-0.84; p<0.01). Factors associated with increased referral to PC were: age (per 5-year increase, OR 1.05; 95% CI 1.03-1.08; p<0.01), DNR status (OR 16.24; 95% CI 14.20-18.56; p<0.01), treatment in a teaching hospital (OR 1.25; 95% CI 1.12-1.39; p<0.01), presence of HCC (OR 2.00; 95% CI 1.71-2.33; p<0.01), and presence of metastatic cancer (OR 2.39; 95% CI 1.80 -3.18; p<0.01). PC referral was most common in West coast hospitals (OR 1.81; 95% CI 1.53-2.14; p<0.01) as well as large sized hospitals (OR 1.49; 95% CI 1.22-1.82; p<0.01).

Conclusions:

From 2006-2012 the use of PC in ESLD patients increased substantially. Socioeconomic, geographical and ethnic barriers to accessing PC were observed. This article is protected by copyright. All rights reserved.

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Prospective measurement of quality of life in myotonic dystrophy type 1

Introduction

Generic patient reported outcome measures have had varied success in tracking QoL in myotonic dystrophy type 1 (DM1).

Aim

To analyze changes of Individualized Neuromuscular Quality of Life questionnaire (INQoL) scores in clinic patients with DM1 over a 6-year period.

Method

Patients completed the INQoL at baseline and after a 6-year period through their attendance in a neurology outpatient clinic. Severity of muscular involvement in DM1 was analyzed using the Muscular Impairment Rating Scale (MIRS).

Results

Ninety-nine DM1 patients completed a baseline visit. Sixty-seven of these patients were retested at an interval time. The overall INQoL score improved in our sample of patients (P<.05) as did the following subscales: myotonia (P<.05), pain (P<.05), activities (P<.01), social relationships (P<.01), and body image (P<.05). No changes were observed for the independence and emotions scales. There were no differences in mean change of INQoL scores between patients with worsened MIRS and those with no change in MIRS scale after follow-up (P>.05).

Conclusion

Individualized Neuromuscular Quality of Life questionnaire scores improved in our cohort of DM1 patients during a 6-year period. INQoL score did not correlate with progression of muscle weakness. This must be better understood before the selection of the instrument for use in trials to measure therapeutic benefit in DM1 patients.

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An ultrasound transient elastography system with coded excitation

Ultrasound transient elastography technology has found its place in elastography because it is safe and easy to operate. However, it's application in deep tissue is limited. The aim of this study is to design ...

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Are we reproducible in measurement of NET liver metastasis?

Accurate measurement of well-differentiated neuroendocrine tumours (NET) liver metastases is critical to determine tumour slope and to assess treatment efficacy.Our objectives were to determine which CT or MRI sequence is the most reproducible to measure NET liver metastases and to assess the percentage of variability of measurements.Intra and inter-observer variability were studied on triphasic abdominal CT or liver MRI in 22 and 32 NET patients respectively. Patients were treatment-naïve or under somatostatin analogues.

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Sustained attention ability in schizophrenia: investigation of conflict monitoring mechanisms

Amongst the main cognitive deficits in schizophrenia, impairments in sustained attention have been considered to be characteristic since the first descriptions and definition of the disorder (Kraepelin, 1919; Bleuler, 1950; Shakow, 1962; Nuechterlein et al., 1984). Nowadays, they are still considered as a hallmark of schizophrenia (Green, 1996; Green et al., 2000; Nuechterlein et al., 2004) and recognized as a probable causal explanation of multiple impairments observed in these patients (Green, 1996; Green et al., 2000; Green et al., 2004).

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Celiac disease and a novel association with a multifocal acquired motor axonopathy (MAMA)

Human rights

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Propriospinal cutaneous-induced EMG suppression is unaltered by anodal tDCS of healthy motor cortex

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with potential application as an adjuvant to neuro-rehabilitation of the upper limb. Anodal tDCS (a-tDCS) is expected to increase corticomotor excitability and cathodal tDCS (c-tDCS) decrease corticomotor excitability (Nitsche et al., 2000; Nitsche et al., 2008; Stagg et al., 2011). The exact mechanisms of tDCS are yet to be elucidated, however corticomotor excitability may be modulated via acute subthreshold shifts in the membrane potential that mediates polarity-specific changes in synaptic plasticity (Stagg et al., 2011).

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Temporal-spatial characteristics of phase-amplitude coupling in electrocorticogram for human temporal lobe epilepsy

Abnormal discharge of neurons in the epileptic human brain causes the specificity of the neural oscillations of the cerebral cortex. The low-frequency and high-frequency neural oscillations of some frequency bands have been known as the essential biomarkers of the epileptogenicity and epileptic seizure-onset zones. The dynamic process of very low frequency oscillations (LFOs) in the intracranial electroencephalographic recordings has been found to occur during the preictal state in the refractory epilepsy patients (Ren et al., 2011).

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Febrile headache and leg weakness as the initial symptoms of tickborne encephalitis

Description

A 61-year-old woman presented to the emergency department (ED) with a 1-week fever associated with progressive headache. She also reported weakness and paraesthesias in both legs. In the ED, the patient had normal vital parameters and reported no other medical history. Clinical examination showed a slight neck stiffness; the rest of the examination was normal. Laboratory findings showed a mild inflammatory syndrome. The patient had a lumbar punction; the cerebrospinal fluid (CSF) showed moderate pleocytosis (140 leucocytes/μL with a mononuclear cell dominance). After a normal CT scan, an MRI examination was performed (figures 1and 2). Several days later, intrathecal IgM and IgG antibodies came back positive.

Figure 1

T2-weighted transverse MRI. Localised hyperintense band involving the tegmentum pontis (arrow heads) and the cerebellar vermis (arrow).

Figure 2

Coronal MRI, fluid attenuation inversion recovery...

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The impact of oral probiotics on vaginal Group B Streptococcal colonisation rates in pregnant women: A pilot randomised control study

Publication date: Available online 28 June 2017
Source:Women and Birth
Author(s): Paula Olsen, Moira Williamson, Victoria Traynor, Chris Georgiou
ObjectiveTo perform a pilot project to determine if this research design was appropriate to explore potential causal relationships between oral probiotic use and vaginal Group B Streptococcal (GBS) colonisation rates in pregnant women.MethodThirty-four GBS-positive women at 36 weeks pregnant were recruited. The participants were randomly allocated to the control group, who received standard antenatal care, or to the intervention group, who received standard antenatal care and a daily oral dose of probiotics for three weeks or until they gave birth. A vaginal GBS swab was collected three weeks post consent or during labour.FindingsNo significant difference was found in vaginal GBS rates between the control and intervention groups. Only seven of 21 women in the intervention group completed the entire 21days of probiotics. A subgroup analysis, including only those who had completed 14days or more of probiotics (n=16), also showed no significant difference in vaginal GBS when compared to the control. The findings did show significantly more vaginal commensals in the probiotics group (p=0.048).DiscussionFive possible reasons for the lack of significant results are: the length of the intervention was too short; the dosage of the probiotics was too low; the wrong strains of probiotics were used; the sample size was inadequate; or oral probiotics are ineffective in impacting vaginal GBS.ImplicationsThe finding of a significant increase of vaginal commensals in women who completed 14days or more of probiotics supports the potential of probiotics to impact vaginal GBS in pregnancy.



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Paroxysmal freezing of gait in a patient with mesial frontal transient ischemic attacks

Rare patients have been reported who developed a mixture of gait disturbances following a focal lesion in the frontal lobe. Thus, the exact location of frontal lesion responsible for a specific gait disturbanc...

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Critical Ischemia Times and The Effect of Novel Preservation Solutions HTK-N and TiPROTEC on Tissues of a Vascularized Tissue Isograft.

Background: We herein investigate critical ischemia times and the effect of novel preservation solutions HTK-N and TiProtec on the individual tissues of a rat limb isograft. Methods: Orthotopic hind-limb transplantations were performed in male Lewis rats following 2h, 6h or 10h of cold ischemia. Limbs were flushed and stored in either HTK-N, TiProtec, HTK or saline solution. Muscle, nerve, vessel, skin and bone samples were procured on day 10 for histology, immunohistochemistry, confocal and electron microscopy and RTqPCR analysis. Results: Histomorphology of the muscle showed a mainly perivascular inflammatory infiltrate, fibrotic degeneration and neovascularization after 6h and 10h of cold ischemia. However, centrally aligned nuclei observed in muscle fibers suggest for muscle regeneration in these samples. In addition to Wallerian degeneration, nerve injury was significantly (p=0.032) aggravated after prolonged cold ischemia. Proinflammatory and regulatory cytokines were most significantly upregulated after 2h cold ischemia. Our data suggest no superiority of novel perfusates HTK-N and TiProtec in terms of tissue preservation, compared to HTK and saline. Conclusions: Limiting cold ischemia time below 6h is the most significant factor to reduce tissue damage in vascularized tissue transplantation. Signs of muscle regeneration give rise that ischemic muscle damage in limb transplantation might be reversible to a certain extent. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Targeted Next-generation Sequencing in Brazilian Children With Nephrotic Syndrome Submitted to Renal Transplant.

Background: The aims of this study were to identify the genetic mutations profile in Brazilian children with nephrotic syndrome and to determine a genotype-phenotype correlation in this disease. Methods: Next generation sequencing (NGS) and mutation analysis were performed on 24 genes related to nephrotic syndrome in a cross-sectional study involving 95 children who underwent kidney transplantation due to nephrotic syndrome, excluding congenital cases. Results: A total of 149 variants were identified in 22 out of 24 sequenced genes. The mutations were classified as pathogenic, likely pathogenic, likely benign and benign per the chance of causing the disease. NPHS2 was the most common mutated gene. We identified 8 patients (8.4%) with hereditary NS and 5 patients (5%) with probably genetically caused NS. COL4A3-5 variants were found as well, but it is not clear whether they should be considered isolated FSGS or simply a misdiagnosed type of the Alport spectrum. Considering the clinical results, hereditary NS patients presented a tendency to early disease onset when compared to the other groups (p=0.06) and time to end stage renal disease (ESRD) was longer in this group (p=0.03). No patients from hereditary NS group had NS recurrence after transplantation. Conclusions: This is the first study in children with steroid resistant nephrotic syndrome who underwent kidney transplantation using NGS. Considering our results, we believe this study has shed some light to the uncertainties of genotype-phenotype correlation in NS, where several genes cooperate to produce or even to modify the course of the disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Pharmacokinetics and Clinical Outcomes of Generic Tacrolimus (Hexal) Versus Branded Tacrolimus in De Novo Kidney Transplant Patients: A Multicenter, Randomized Trial.

Background: Scrupulous comparison of the pharmacokinetic and clinical characteristics of generic tacrolimus formulations versus the reference drug (Prograf) is essential. Pharmacokinetics of the TacHexal formulation are similar to Prograf in stable renal transplant patients but data in de novo patients is lacking. Methods: De novo kidney transplant patients were randomized to generic tacrolimus (Tacrolimus Hexal [TacHexal]) or Prograf in a 6-month open-label study. Results: The primary endpoint, the dose-normalized AUC0-12h ratio at month 1 posttransplant, was similar with TacHexal or Prograf: back-transformed geometric means of adjusted log-transformed values (ANOVA) were 18.99 ng*h/L (TacHexal) and 20.48 ng*h/L (Prograf) (ratio 1.08 [90% CI 0.84; 1.38]; p=0.605). The dose-normalized peak concentration (Cmax) geometric means at month 1 was also comparable between treatments (ratio 1.16 [90% CI 0.88; 1.54], p=0.377). There were no relevant differences in other pharmacokinetic parameters at month 1, or in AUC0-4 and trough concentration when measured at months 3 and 6. The adjusted change in mean estimated GFR from baseline to month 6 (Nankivell) was noninferior for TacHexal versus Prograf using observed values (47.7 versus 38.6mL/min/1.73m2, p

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Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation.

Background: Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African-American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. Methods: Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. Results: 1411 recipients were included (54.4% AA) with 39 521 concentrations utilized to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs vs non-AAs (39.9+/-19.8 % vs. 34.8+/-15.8% p40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. Conclusions: These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Image distortions on a plastic interstitial CT/MR brachytherapy applicator at 3 T MRI and their dosimetric impact

To quantify magnetic resonance image (MRI) distortions on a plastic intracavitary/interstitial applicator with plastic needles at a field strength of 3 T and to determine the dosimetric impact, using patient data.

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Postmastectomy Radiation in Breast Cancer Patients with Pathologically Positive Lymph Nodes After Neoadjuvant Chemotherapy: Utilization Rates and Survival Trends

To analyze postmastectomy radiation therapy (PMRT) utilization and its association with overall survival (OS) in breast cancer patients with pathologically positive lymph nodes after neoadjuvant chemotherapy (NAC).

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Relapse Rates with Surgery Alone in HPV-related Intermediate and High Risk Group Oropharynx Squamous Cell Cancer, A Multi-Institutional Review

Indications for adjuvant therapy including radiation therapy (RT) and chemotherapy after surgery for oropharyngeal squamous cell cancer (OPSCC) were defined prior to the predominance of human papilloma virus-related (HPV+) disease. Risk factors for relapse were likewise determined prior to the development of Transoral Surgery (TOS) such as transoral robotic surgery (TORS) and transoral laser microsurgery (TLM). This study aimed to evaluate whether historic risk categories and indications for adjuvant therapy in the pre-HPV and pre-TOS era were associated with clinically significant relapse rates in HPV+ OPSCC patients undergoing TOS.

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Panitumumab in combination with preoperative radiotherapy in patients with locally advanced RAS wildtyp rectal cancer. Results of the multicenter explorative single-arm phase II study NEORIT

Studies investigating combinations of anti-epidermal growth factor receptor monoclonal antibodies such as panitumumab or cetuximab with standard chemoradiotherapy protocols in rectal cancer yielded disappointing results. Because of the supposed negative interaction of EGFR-inhibition and chemoradiotherapy we conducted a phase II-study using single agent panitumumab in combination with RT in patients with RAS wildtype with locally advanced rectal cancer.

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“Ethics in the Legal and Business Practices of Radiation Oncology”

Ethical issues arise when a professional endeavor such as medicine, which seeks to place the well-being of others over the self interest of the practitioner, meets granular business and legal decisions involved in making a livelihood out of a professional calling. The use of restrictive covenants, involvement in self referral patterns and maintaining appropriate comity among physicians while engaged in the marketplace are common challenges in radiation oncology practice. A paradigm of analysis is presented to help navigate these management challenges

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ICU Outcomes Among Patients With Cancer After Palliative Radiation Therapy

Many patients with advanced cancer treated with palliative radiation therapy (RT) are subsequently admitted to an intensive care unit (ICU) with acute critical illness. We sought to characterize ICU outcomes for patients treated with palliative RT prior to ICU admission, compared to other metastatic cancer patients, to inform goals of care discussions at the time of palliative RT consultation.

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Necrotising coronaritis with fatal outcome

A 56-year-old woman presented with acute onset of typical chest pain. She was diagnosed with acute coronary syndrome with ST-segment elevation myocardial infarction. Although significant obstructive coronary artery disease was ruled out by coronary angiography, cardiac MRI showed transmural necrosis of the lateral free wall with extensive microvascular obstruction consistent with ischaemic heart disease. Within 48 hours after initial presentation, the patient suddenly arrested due to pulseless electrical activity with futile resuscitation efforts. Autopsy revealed myocardial perforation with extensive haematothorax due to pericardial laceration, caused by the mechanical chest compressions. Eventually, histology identified diffuse necrotising coronary vasculitis as a rare cause of ischaemic heart disease.

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Clinical Effect of Electroacupuncture on Lung Injury Patients Caused by Severe Acute Pancreatitis

This study aimed to investigate the effects of electroacupuncture at the Lieque, Chize, and Zusanli points in patients with lung injury caused by severe acute pancreatitis. Patients with acute respiratory distress syndrome (ARDS) induced by severe acute pancreatitis (SAP) were randomly divided into three groups based on the treatment: conventional therapy alone (group A), electroacupuncture of nonacupoints with conventional therapy (group B), and electroacupuncture at the Lieque (LU7), Chize (LU5), and Zusanli (ST36) points (group C) once a day for 5 days. Arterial blood samples were obtained for blood gas analysis before electroacupuncture () and 3 () and 5 () days after electroacupuncture. The oxygenation index was significantly higher in all groups at and than that at , while the APACHE-II scores were decreased significantly. The expression of TNF-α was significantly decreased and the IL-10 was significantly increased in all groups at . The oxygenation index at and was significantly higher in group C than that in group B. Electroacupuncture at Lieque, Chize, and Zusanli can lessen the lung injury induced by SAP, and the mechanism may be related to the decreased TNF-α and increased IL-10 value. Clinical Registration Number is ChiCTR-ICR-15006850.

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Update on afatinib-based combination regimens for the treatment of EGFR mutation-positive non-small-cell lung cancer

Future Oncology Ahead of Print.


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Community Practice Implementation of a Self-administered Version of PREMM1,2,6 to Assess Risk for Lynch Syndrome

Lynch syndrome is a genetic disorder that greatly increases risk for colorectal and other cancers, though it is underdiagnosed. PREMM1,2,6 is a web-based tool that analyzes individuals' personal/family histories of cancer to quantify their likelihood of carrying a germline mutation associated with Lynch syndrome. We investigated the feasibility of systematic risk assessment for Lynch syndrome in a community gastroenterology practice using a patient-completed version of PREMM1,2,6.

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A Diet Low in Fermentable Oligo-, Di-, and Mono-saccharides and Polyols Improves Quality of Life and Reduces Activity Impairment in Patients with Irritable Bowel Syndrome and Diarrhea

We investigated the effects of a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs) vs traditional dietary recommendations, on health-related quality of life (QOL), anxiety and depression, work productivity, and sleep quality in patients with IBS and diarrhea (IBS-D).

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Reply: Gastrointestinal safety profiles differ among non-vitamin K antagonist anticoagulants?

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Upregulation of circulating myomiR following short-term energy restriction is inversely associated with whole-body protein synthesis

The objective of the present investigation was to determine whether energy restriction (ER) influences expression of skeletal muscle specific microRNA in circulation (c-myomiR), and if changes in c-myomiR are associated with rates of whole-body protein synthesis. Sixteen older (64 ± 2 yrs) overweight (28.5 ± 1.2 kg·m^-2) males enrolled in this 35-day controlled feeding trial. A 7-day weight maintenance (WM) period was followed by 28 days of 30% ER. Whole-body protein turnover was determined from ¹⁵N-glycine enrichments in 24-hr urine collections, and c-myomiR (miR-1-3p, miR-133a-3p, miR-133b, and miR-206) expressions were assessed from serum samples using RT-qPCR at the conclusions of WM and ER. Participants lost 4.4 ± 0.3 kg body mass during ER (P < 0.05). Following 28 days of ER miR-133a and miR-133b expression was upregulated (P < 0.05) compared to WM. When all four c-myomiR were grouped as a c-myomiR Score (sum of the median fold change of all myomiR), overall expression of c-myomiR was higher (P < 0.05) at ER versus WM. Backward linear regression analysis of whole-body protein synthesis, breakdown, and carbohydrate, fat and protein oxidation determined protein synthesis to be the strongest predictor of c-myomiR Score. An inverse association (P < 0.05) was observed with ER c-myomiR Scores and whole-body protein synthesis (r = -0.729, r² = -0.530). Findings from the present investigation provide evidence that upregulation in c-myomiR expression profiles in response to short-term ER are associated with lower rates of whole-body protein synthesis.

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Renal Vascular and Glomerular Pathologies Associated with Spontaneous Hypertension in the Nonhuman Primate Chlorocebus aethiops sabaeus

Hypertension is a complex disease affecting 78 million adults in the United States. The etiology of essential hypertension is unknown and current experimental models do not recapitulate all behavioral and physiological characteristics of the pathology. Researchers should assess the translational capacity of these models and look to other animal models for the discovery of new therapies. Chlorocebus aethiops sabaeus, the African Green Monkey (AGM), is a nonhuman primate that develops spontaneous hypertension and is a novel translational model for the study of hypertension and associated diseases. In a group of 424 adult AGMs, 37% (157/424) exhibited systolic blood pressures (SBP) >140 mmHg (SBP: 172.0±2.2 mmHg) and were characterized as hypertensive (HT). 44% (187/424) were characterized as normotensive with SBP <120 mmHg (NT, SBP: 99.6±1.0 mmHg) and the remaining 18% (80/424) as borderline hypertensive (BHT, SBP: 130.6±0.6 mmHg). Compared to NT animals, HT AGMs are older (8.7±0.6 vs 12.4±0.7 years, p<0.05) with elevated heart rates (121.3±1.91 vs 34.3±2.1 BPM, p<0.05). BHT animals had average heart rates of 138.2±3.1 BPM (p<0.05 vs. NT) and were 11.00±0.9 years old. NT and HT animals had similar levels of angiotensinogen gene expression, plasma renin activity, and renal cortical renin content (p>0.05). HT monkeys exhibit renal vascular remodeling (wall/lumen ratio NT 0.11±0.01 vs HT 0.15±0.02, p<0.05) and altered glomerular morphology (Bowman's capsular space: NT 30.9±1.9% vs HT 44.4±3.1%, p<0.05). The hypertensive AGM is an animal model that is highly similar to humans and may help identify novel, effective targets for the treatment of hypertension.

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MEMORY T CELLS EXPRESSING AN NKG2D-CAR EFFICIENTLY TARGET OSTEOSARCOMA CELLS

Purpose: NKG2D ligands (NKG2DL) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. Various immune cells express NKG2D receptors, including natural killer (NK) cells and CD8+ T cells. Interactions between NKG2DL and NKG2D receptors are essential for NK cell elimination of osteosarcoma tumor initiating cells. In this report, we used NKG2D-NKG2DL interactions to optimize an immunotherapeutic strategy against osteosarcoma. We evaluated in vitro and in vivo the safety and cytotoxic capacity against osteosarcoma cells of CD45RA- memory T cells expressing an NKG2D-4-1BB-CD3z chimeric antigen receptor (CAR).<br /><br />Experimental Design: CD45RA- cells from healthy donors were transduced with NKG2D CARs containing 4-1BB and CD3z signaling domains. NKG2D CAR expression was analyzed by flow cytometry. In vitro cytotoxicity of NKG2D-CAR+ CD45RA- T cells against osteosarcoma was evaluated by performing conventional 4-hour europium-TDA release assays. For the in vivo orthotopic model, 531MII YFP-luc osteosarcoma cells were used as targets in NOD-scid IL2Rgnull mice. <br /><br />Results: Lentiviral transduction of NKG2D-4-1BB-CD3z markedly increased NKG2D surface expression in CD45RA- cells. Genetic stability was preserved in transduced cells. In vitro, NKG2D-CAR+ memory T cells showed significantly increased cytotoxicity than untransduced cells against osteosarcoma cell lines, while preserving the integrity of healthy cells. NKG2D-CAR+ memory T cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas untransduced T cells were ineffective.<br /><br />Conclusions:Our results demonstrate NKG2D-4-1BB-CD3z CAR-redirected memory T cells target NKG2DL-expressing osteosarcoma cells in vivo and in vitro and could be a promising immunotherapeutic approach for patients with osteosarcoma.

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DNA-methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-like factor 4 Expression

Purpose: The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the underlying molecules remain unknown. We investigated the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment.<br /><br />Experimental Design: Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by immunohistochemistry and the genetic and epigenetic alterations of KLF4 in and KLF4's impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3'-diindolylmethane (DIM) on miR-152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal model.<br /><br />Results: Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently, reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. Additionally, DIM treatment caused significant inhibition of cell growth in vitro and tumorigenesis in animal model of pancreatic cancer.<br /><br />Conclusions: This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers.

http://ift.tt/2tmNLEr

Radiosensitization of adenoid cystic carcinoma with MDM2 inhibition

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACC contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition. <p>Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient derived xenograft (PDX) which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiation (RT).</p> <p>Results: AMG 232 monotherapy induced modest tumor growth inhibition and RT monotherapy induced a transient tumor growth delay in a dose dependent fashion. Strikingly, combination treatment of AMG 232 with RT (including low dose RT of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates three months following treatment. Post treatment analysis revealed that while both AMG 232 and RT alone induced TP53 tumor suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.</p> <p>Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC.  In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/RT combination may be warranted to improve local control in this challenging malignancy. 

http://ift.tt/2trdM69

Recognizing Sepsis as a Global Health Priority — A WHO Resolution

"Some very important clinical issues, some of them affecting life and death, stay largely in a backwater which is inhabited by academics and professionals and enthusiasts, dealt with very well at the clinical and scientific level but not visible to the public, political leaders, leaders of…

http://ift.tt/2tmMVad

Insomnia and Its Temporal Association with Academic Performance among University Students: A Cross-Sectional Study

Introduction. Studies show that 9.4% to 38.2% of university students are suffering from insomnia. However, research data in developing countries is limited. Thus, the aim of the study was to assess insomnia and its temporal association with academic performance. Methods and Materials. Institution based cross-sectional study was conducted with 388 students at Debre Berhan University. Data were collected at the nine colleges. Logistic and linear regression analysis was performed for modeling insomnia and academic performance with a value threshold of 0.05, respectively. Data were entered using EPI-data version 3.1 and analyzed using SPSS version 20. Results. The prevalence of insomnia was 61.6%. Field of study ( value = 0.01), worshiping frequency ( value = 0.048), marital status ( value = 0.03), and common mental disorder ( value

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A Deep Morphological Characterization and Comparison of Different Dental Restorative Materials

Giomer is a relatively new class of restorative material with aesthetics, handling and physical properties of composite resins, and benefits of glass ionomers: high radiopacity, antiplaque effect, fluoride release, and recharge. To verify the superior properties of Giomers, in this study, a deep morphological characterization has been performed with an in vitro comparative study among a Giomer (Beautifil® II by Shofu Dental Corporation, Osaka, Japan), a Compomer (Dyract Extra by Dentsply, Caulk, Germany), glass ionomer cement (Ketac fil plus by 3M ESPE), and a composite resin (Tetric Evoceram by Ivoclar). In particular, mechanical and optical properties and ageing effects have been compared to investigate materials similarities and differences. Indentation tests, UV-Visible spectroscopy, Raman spectroscopy, and weight loss after storage in saliva or sugary drink have been carried out to analyze materials behavior in real conditions. The results confirm the high quality of Giomer material and indicate possible improvements in their usage.

http://ift.tt/2s3Julo

Recombinant Immunotoxin Therapy of Glioblastoma: Smart Design, Key Findings, and Specific Challenges

Recombinant immunotoxins (RITs) refer to a group of recombinant protein-based therapeutics, which consists of two components: an antibody variable fragment or a specific ligand that allows RITs to bind specifically to target cells and an engineered toxin fragment that kills the target cells upon internalization. To date, over 1,000 RITs have been generated and significant success has been achieved in the therapy of hematological malignancies. However, the immunogenicity and off-target toxicities of RITs remain as significant barriers for their application to solid tumor therapy. A group of RITs have also been generated for the treatment of glioblastoma multiforme, and some have demonstrated evidence of tumor response and an acceptable profile of toxicity and safety in early clinical trials. Different from other solid tumors, how to efficiently deliver the RITs to intracranial tumors is more critical and needs to be solved urgently. In this article, we first review the design and expression of RITs, then summarize the key findings in the preclinical and clinical development of RIT therapy of glioblastoma multiforme, and lastly discuss the specific issues that still remain to forward RIT therapy to clinical practice.

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Body, Make Thy Own Bispecific Antibody [News in Brief]

Injections of RNA encoding bispecific antibodies rid mice of advanced tumors.

http://ift.tt/2sTfyeN

Positive First Trial of Enasidenib for AML [News in Brief]

Study of drug for patients with IDH2 mutations indicates that it can induce complete remissions.

http://ift.tt/2soxdr5

Dissecting the Satellite DNA Landscape in Three Cactophilic Drosophila Sequenced Genomes

Eukayote genomes are replete with repetitive DNAs. This class includes tandemly repeated satellite DNAs (satDNA) which are among the most abundant, fast evolving (yet poorly studied) genomic components. Here, we used high throughput sequencing data from three cactophilic Drosophila species, D. buzzatii, D. seriema and D. mojavensis, to access and study their whole satDNA landscape. In total, the RepeatExplorer software identified five satDNAs, three previously described (pBuM, DBC-150 and CDSTR198) and two novel ones (CDSTR138 and CDSTR130). Only pBuM is shared among all three species. The satDNA repeat length falls within only two classes, between 130-200bp or between 340-390bp. FISH on metaphase and polytene chromosomes revealed the presence of satDNA arrays in at least one of the following genomic compartments: centromeric, telomeric, subtelomeric or dispersed along euchromatin. The chromosomal distribution ranges from a single chromosome to almost all chromosomes of the complement. Fiber-FISH and sequence analysis of contigs revealed interspersion between pBuM and CDSTR130 in the microchromosomes of D. mojavensis. Phylogenetic analyses showed that the pBuM satDNA underwent concerted evolution at both interspecific and intraspecific levels. Based on RNAseq data, we found transcription activity for pBuM (in D. mojavensis) and CDSTR198 (in D. buzzatii) in all five analyzed developmental stages, most notably in pupae and adult males. Our data revealed that cactophilic Drosophila present the lowest amount of satDNAs (1.9% to 2.9%) within the Drosophila genus reported so far. We discuss how our findings on the satDNA location, abundance, organization and transcription activity may be related to functional aspects.

http://ift.tt/2tmP2LV

Characterizing the Pyrenophora teres f. maculata - Barley Interaction Using Pathogen Genetics

Pyrenophora teres f. maculate is the cause of the foliar disease spot form net blotch (SFNB) on barley. To evaluate pathogen genetics underlying the P. teres f. maculate- barley interaction, we developed a 105-progeny population by crossing two globally diverse isolates, one from North Dakota, USA and the other from Western Australia. Progeny were phenotyped on a set of four barley genotypes showing a differential reaction to the parental isolates, then genotyped using a restriction-site associated - genotype by sequencing (RAD-GBS) approach. Genetic maps were developed for use in quantitative trait locus (QTL) analysis to identify virulence-associated QTL. Six QTL were identified on five different linkage groups and individually accounted for 20 to 37% of the disease variation with the number of significant QTL ranging from two to four for the barley genotypes evaluated. The data presented demonstrates the complexity of virluence involved in the P. teres f. maculate-barley interaction and begins to lay the foundation for understanding this important interaction.

http://ift.tt/2s3MfmT

Highly Accurate Detection of Cancer In Situ with Intraoperative, Label-Free, Multimodal Optical Spectroscopy

Effectiveness of surgery as a cancer treatment is reduced when all cancer cells are not detected during surgery, leading to recurrences that negatively impact survival. To maximize cancer cell detection during cancer surgery, we designed an in situ intraoperative, label-free, optical cancer detection system that combines intrinsic fluorescence spectroscopy, diffuse reflectance spectroscopy, and Raman spectroscopy. Using this multimodal optical cancer detection system, we found that brain, lung, colon, and skin cancers could be detected in situ during surgery with an accuracy, sensitivity, and specificity of 97%, 100%, and 93%, respectively. This highly sensitive optical molecular imaging approach can profoundly impact a wide range of surgical and noninvasive interventional oncology procedures by improving cancer detection capabilities, thereby reducing cancer burden and improving survival and quality of life. Cancer Res; 77(14); 1–9. ©2017 AACR.

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Hepatocellular Malignant Neoplasm-NOS: A Clinicopathologic Study of 11 Cases from a Single Institution

Abstract

Aims

The primary aim of this study is to characterize hepatocellular malignant neoplasm, NOS (HEMNOS), a new provisional entity describing a subset of paediatric hepatocellular tumours, which have histological features of neither typical hepatoblastoma (HB) nor hepatocellular carcinoma (HCC).

Methods and results

The clinicopathological features of 11 patients with HEMNOS were analyzed retrospectively. The median age and serum alpha-fetoprotein level at diagnosis was 7 years and 182,000 ng/mL respectively. Ten patients presented with PRETEXT stage III/IV multifocal tumours, eight with major vascular involvement, three with lung metastases, and three with extrahepatic extension. The original pathology diagnoses were: HB in seven patients, HCC in two and HEMNOS in two. Our pathology review of pre-chemotherapy specimens showed that six tumours had equivocal/overlapping histological features of HB and HCC, four had predominant HB histology along with focal HCC-like histology, and one had HB histology. Seven of nine post-chemotherapy resection specimens showed predominant HCC-like histology. Beta-catenin, glypican 3 and spalt-like transcription factor 4 immunostaining showed that all the tumours had a mixed HB/HCC immunophenotype. Telomerase reverse-transcriptase immunostaining showed nuclear staining in nine of the eleven tumours. All patients received chemotherapy and achieved gross total primary tumor resection. Nine of the eleven patients were treated with established HB chemotherapy regimens. After a median follow-up of 6.1 years (range, 1.2 to 11.8 years), all patients were in remission.

Conclusions

HEMNOS is a subtype of HB with focal HCC-like histology, a high-risk clinical profile but favorable outcome following chemotherapy and complete tumor resection.

This article is protected by copyright. All rights reserved.

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Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy

To the Editor: Protein-losing enteropathy usually manifests as peripheral and visceral edema due to hypoalbuminemia. We followed a large consanguineous Muslim–Arab family that included six patients who had protein-losing enteropathy associated with hypercoagulability (Fig. S1A in the Supplementary…

http://ift.tt/2t2A4YS

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis

Genetic inquiry has contributed to our understanding of gastrointestinal diseases, associating at least 64 genes with early-onset or very-early-onset inflammatory bowel disease. Deleterious gene variants affect the intestinal epithelial barrier, phagocytosis processes, immune regulation, and…

http://ift.tt/2sjkA5t

Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy

To the Editor: Protein-losing enteropathy usually manifests as peripheral and visceral edema due to hypoalbuminemia. We followed a large consanguineous Muslim–Arab family that included six patients who had protein-losing enteropathy associated with hypercoagulability (Fig. S1A in the Supplementary…

http://ift.tt/2t2A4YS

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis

Genetic inquiry has contributed to our understanding of gastrointestinal diseases, associating at least 64 genes with early-onset or very-early-onset inflammatory bowel disease. Deleterious gene variants affect the intestinal epithelial barrier, phagocytosis processes, immune regulation, and…

http://ift.tt/2sjkA5t

Recognizing Sepsis as a Global Health Priority — A WHO Resolution

"Some very important clinical issues, some of them affecting life and death, stay largely in a backwater which is inhabited by academics and professionals and enthusiasts, dealt with very well at the clinical and scientific level but not visible to the public, political leaders, leaders of…

http://ift.tt/2tmMVad

Analysis of Neanderthal teeth grooves uncovers evidence of prehistoric dentistry

A discovery of multiple toothpick grooves on teeth and signs of other manipulations by a Neanderthal of 130,000 years ago are evidence of a kind of prehistoric dentistry, according to a new study researcher.

http://ift.tt/2snjuRh

A multicentre double-blind randomised controlled trial evaluating the efficacy of daily use of antibacterial mouthwash against oropharyngeal gonorrhoea among men who have sex with men: the OMEGA (Oral Mouthwash use to Eradicate GonorrhoeA) study protocol

Gonorrhoea is one of the most common sexually transmissible infections in men who have sex with men (MSM). Gonorrhoea rates have increased substantially in recent years. There is concern that increasing gonorr...

http://ift.tt/2ukuSPw

Small-Sized Thyroid Cancers—a Single Institutional Experience in India

Abstract

The incidence of small differentiated thyroid carcinomas is increasing worldwide in the recent years, especially tumours of size less than 2 cm in diameter. In this study, we have analysed the patterns of behaviour of small-sized thyroid carcinomas (<2 cm, T1 tumours) in comparison with large-sized thyroid carcinomas. This is a retrospectively analysed data of patients with thyroid carcinoma. The following parameters were analysed: distribution with regard to age, sex and the presence of metastasis based on radioiodine scan. The following histopathological details were collected: maximal tumour diameter, extrathyroidal extension and lymphovascular invasion. Out of 152 patients, 39 patients were excluded due to the non-availability of complete details. Among the 113 patients of thyroid carcinomas, 43 patients (28%) were presented with small-sized tumours (measuring less than 2 cm). In small-sized thyroid tumours, 21.6% showed extrathyroidal extension. 2.7% of the small-sized thyroid carcinomas showed perineural invasion as compared to 6.3% of the large-sized thyroid carcinomas. Twenty percent of the small-sized thyroid carcinomas showed lymphovascular emboli. 51.2% of the small-sized thyroid carcinomas were presented with nodal metastasis as compared to 40% of the large-sized thyroid carcinomas. 57.5% of the small-sized thyroid carcinomas showed extracapsular extension as compared to 57.8% of the large-sized thyroid carcinomas. Despite small size, thyroid carcinomas have properties to behave aggressively as comparable to large-sized thyroid carcinomas. Taking the above facts into account, the small thyroid cancers should be treated with considerable caution as large thyroid cancers, especially since we have limited tools to predict the preoperative poor prognostic factors.

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Authors' Response to a Letter to the Editor on Radial Extracorporeal Shockwave in the Management of Lateral Epicondylitis.

No abstract available

http://ift.tt/2ujUtI0

Patient Registry of Spasticity Care World: Data Analysis Based on Physician Experience.

Objective: The aim of the study was to report physician experience-based "real-world" treatment patterns with botulinum toxin type A in patients with stroke and traumatic brain injury. Design: A prospective, multicenter, international observational registry design was used. Results: Six hundred twenty-seven participants with stroke and 132 participants with traumatic brain injury were assessed and treated by 17 more experienced physicians and 12 less experienced physicians. Due to the limited usage of abobotulinumtoxinA Dysport and incobotulinumtoxinA Xeomin, data were reported on onabotulinumtoxinA BOTOX only. Based on physician experience, onabotulinumtoxinA doses were statistically different with larger mean doses injected by more experienced physicians in the upper limb (59.9 [39.0], P = 0.001) and in the lower limb (101.8 [69.2], P

http://ift.tt/2tmyPpB

Neuro- and nephrotoxicity of subchronic cadmium chloride exposure and the potential chemoprotective effects of selenium nanoparticles

Abstract

Cadmium (Cd) exposure leads to production of reactive oxygen species (ROS), which are associated with Cd-induced neurotoxicity and nephrotoxicity. Selenium nanoparticles (Se-NPs) have high bioavailability and antioxidant activities so it attracted wide spread attention. The present study examined the possible ameliorative effect of Se-NPs with diameters of 3–5 nm and 10–20 nm against cadmium chloride (CdCl₂)-induced neuro- and nephrotoxicity in rats. Rats were treated with Se-NPs (0 or 0.5 mg/kg BW, s.c.) one hour prior to the CdCl₂ (0 or 5 mg/kg BW, p.o.). Pretreatment with Se-NPs significantly decreased CdCl₂-induced elevation of serum kidney and brain damage biomarkers; lipid peroxidation; the percent of DNA fragmentation and nearly normalized the activity of acetylcholinesterase (AchE) and significantly increased the activity and expression of antioxidant biomarkers in the RNA and protein levels. Se-NPs also attenuated CdCl₂-induced upregulation of kidney and brain pro-apoptotic B-cell CLL/lymphoma 2 associated X (Bax) RNA and protein levels with preventing the increased body burden of Cd and the altered Fe and Cu homeostasis. Histopathological analysis confirmed the biochemical and molecular outcomes. Our data stated that Se-NPs appear to be effective in ameliorating the adverse neurological and nephrotoxic effects induced by CdCl₂ partially through the scavenging of free radicals, metal ion chelation, averting apoptosis and altering the cell-protective pathways. The results indicated that Se-NPs could potentially included as an additive to Cd-based industries to control Cd-induced brain and renal injury.

http://ift.tt/2sSLq2V

Microfluidic Imaging Flow Cytometry by Asymmetric-detection Time-stretch Optical Microscopy (ATOM)

This protocol describes the implementation of an asymmetric-detection time-stretch optical microscopy system for single-cell imaging in ultrafast microfluidic flow and its applications in imaging flow cytometry.

http://ift.tt/2snyG0J

Measuring the Densities of Aqueous Glasses at Cryogenic Temperatures

A protocol for determining the vitreous phase densities of micro- to pico-liter size drops of aqueous mixtures at cryogenic temperatures is described.

http://ift.tt/2tlSA0w

Non-alcoholic Wernicke’s encephalopathy with cortical involvement and polyneuropathy following gastrectomy

Abstract

In this study, we present the clinical manifestations, brain magnetic resonance imaging (MRI) and concurrent polyneuropathies in two patients with non-alcoholic Wernicke's encephalopathy (WE) after gastrojejunostomy (Billroth II) anastomosis procedures. These patients developed sub-acute onset of disorientation and disturbance of consciousness following several weeks of poor intake. Peripheral neuropathy of varying severity was noted before and after the onset of WE. Brain MRI of the patients showed cerebellar vermis and symmetric cortical abnormalities in addition to typical WE changes. Electrophysiological studies demonstrated axonal sensorimotor polyneuropathy. Prompt thiamine supplement therapy was initiated and both patients gradually recovered, however mild amnesia was still noted 6 months later. We reviewed non- alcoholic WE with atypical cortical abnormalities in English language literatures and identified 29 more cases. Eight out of 31 (25.8%) patients died during follow-up. Nine patients with gait disturbance or motor paresis had showed hyporeflexia in neurological examinations. In addition to classic triad, seizure was recorded in seven patients. Dietary deprivation is a risk factor for non-alcoholic WE among elderly patients receiving gastrointestinal surgery. The prognosis is good after thiamine supplement therapy. Recognizing the MRI features and predisposing factors in patients who have undergone gastrectomy can aid in the diagnosis and management.

http://ift.tt/2siz0Tw

Aspartame and Soft Drink-Mediated Neurotoxicity in Rats: Implication of Oxidative Stress, Apoptotic Signaling Pathways, Electrolytes and Hormonal Levels

Abstract

A significant association between fructose corn syrup in sweetened beverages consumption and increased risk of detrimental central nervous system effects has been recently reported. We hypothesized that the aspartame and soft drink induced disturbances in energy production and endocrine function, which play a role in the induction of brain damage. Therefore, we aimed to assess the effect of aspartame and soft drink on brain function and the link between energy status in the brain, oxidative stress and molecular pathways of apoptosis. Thirty rats were randomly assigned to drink water, aspartame (240 mg/kg orally) and cola soft drinks (free access) daily for two months. Subchronic intake of aspartame and soft drink significantly disrupted the brain energy production, as indicated by inhibited serum and brain creatine kinase, specifically in soft drink-received rats. Moreover, they substantially altered serum electrolytes (increased Ca and Na, and depleted Cu, Fe, Zn and K levels), and accordingly the related hormonal status (increased T4 and PTH, and lowered T3 and aldosterone levels), particularly in soft drink-received rats reflecting brain damage. Additionally, significant increment of acetylcholine esterase activity concomitant with the reduction of antioxidant molecules (SOD, CAT, GSH-Px and GSH), and induction of malondialdehyde level are precisely indicative of oxidative brain damage. Brain mRNA transcripts of target genes showed that aspartame and soft drink induced upregulation of BAX, Casp3, P27 and Mdm2 (1.5-fold) and down-regulation of Bcl2, suggesting an activation of cellular apoptosis. Collectively, subchronic aspartame and soft drink-induced brain damage in rats may be driven via a mechanism that involves energy production disruption, electrolytes and hormonal imbalance, increased oxidative stress and activation of molecular pathway of neuronal apoptosis.

http://ift.tt/2t1ZlCf

Hereditary pancreatic cancer: related syndromes and clinical perspective

Abstract

Pancreatic cancer is a very aggressive disease with a poor prognosis. The majority of them are attributed to sporadic causes, especially to many modifiable risk factors such as tobacco or alcohol abuse. The principal histologic subtype of pancreatic cancer is ductal adenocarcinoma. Pancreatic neuroendocrine tumors, which constitute a more indolent entity, represent second type of pancreatic cancer in terms of incidence. Individuals with a family history of pancreatic cancer carry an increased risk of developing the disease, which may be related to an underlying hereditary component. Unfortunately, in the majority of these families the suspected germline genetic cause responsible of the disease will not be identified, but approximately in a 20% of the cases a hereditary cancer predisposition syndrome with increased risk of pancreatic cancer development can be recognized. This review will be focused on the leading hereditary cancer syndromes related to pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Additionally, we will try to explain clinical aspects related to the identification of germline mutations in pancreatic cancer patients and their potential implications in oncologic treatment decisions.

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An Oncolytic Adenovirus Expressing SNORD44 and GAS5 Exhibits Antitumor Effect in Colorectal Cancer Cells

Human Gene Therapy , Vol. 0, No. 0.


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Human Bocavirus Type-1 Capsid Facilitates the Transduction of Ferret Airways by Adeno-Associated Virus Genomes

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2uj2GfR

RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma

Abstract

Background

Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types.

Methods

RERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2'-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines.

Results

RERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818–0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts.

Conclusions

Our results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy.

http://ift.tt/2si5cWZ

CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model

Abstract

Background

GPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species.

Methods

We determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a "humanized" mouse GPRC6A containing the K..Y sequence by immunofluorescence. We assessed functions of GPRC6A in PC-3 cells expressing endogenous GPRC6A and in GPRC6A-deficient PC-3 cells created using CRISPR/Cas9 technology. The effect of GPRC6A on basal and ligand stimulated cell proliferation and migration was evaluated in vitro in wild-type and PC-3-deficient cell lines. The effect of editing GPRC6A on prostate cancer growth and progression in vivo was assessed in a Xenograft mouse model implanted with wild-type and PC-3 deficient cells and treated with the GPRC6A ligand osteocalcin.

Results

We found that all of the human prostate cancer cell lines tested endogenously express the "K..Y" polymorphism in the 3rd IL. Comparison of mouse wild-type GPRC6A with a "humanized" mouse GPRC6A construct created by replacing the "RKLP" with the "K..Y" sequence, found that both receptors were predominantly expressed on the cell surface. The transfected "humanized" GPRC6A receptor, however, preferentially activated mTOR compared to ERK signaling in HEK-293 cells. In contrast, in PC-3 cells expressing the endogenous GPRC6A with the "K..Y" polymorphism, the ligand osteocalcin stimulated ERK, AKT and mTOR phosphorylation, promoted cell proliferation and migration, and upregulated genes regulating testosterone biosynthesis. Targeting GPRC6A in PC-3 cells by CRISPR/Cas9 significantly blocked these responses in vitro. In addition, GPRC6A deficient PC-3 xenografts exhibited significantly less growth and were resistant to osteocalcin-induced prostate cancer progression compared to control PC-3 cells expressing GPRC6A.

Conclusions

Human GPRC6A is a functional osteocalcin and testosterone sensing receptor that promotes prostate cancer progression. GPRC6A may contribute to racial disparities in prostate cancer, and is a potential therapeutic target to develop antagonists to treat prostate cancer.

http://ift.tt/2t1lSiQ

Antibody targeting of claudin-1 as a potential colorectal cancer therapy

Abstract

Background

Metastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti-CLDN1 monoclonal antibody (mAb).

Methods

Gene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells.

Results

Compared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit-ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation.

Conclusion

Our data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target.

http://ift.tt/2sikieY

Randomised controlled trial of transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND Study)

Objective

Non-randomised studies suggest that endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM), but EMR might be more cost-effective and safer. This trial compares the clinical outcome and cost-effectiveness of TEM and EMR for large rectal adenomas.

Design

Patients with rectal adenomas ≥3 cm, without malignant features, were randomised (1:1) to EMR or TEM, allowing endoscopic removal of residual adenoma at 3 months. Unexpected malignancies were excluded postrandomisation. Primary outcomes were recurrence within 24 months (aiming to demonstrate non-inferiority of EMR, upper limit 10%) and the number of recurrence-free days alive and out of hospital.

Results

Two hundred and four patients were treated in 18 university and community hospitals. Twenty-seven (13%) had unexpected cancer and were excluded from further analysis. Overall recurrence rates were 15% after EMR and 11% after TEM; statistical non-inferiority was not reached. The numbers of recurrence-free days alive and out of hospital were similar (EMR 609±209, TEM 652±188, p=0.16). Complications occurred in 18% (EMR) versus 26% (TEM) (p=0.23), with major complications occurring in 1% (EMR) versus 8% (TEM) (p=0.064). Quality-adjusted life years were equal in both groups. EMR was approximately 3000 cheaper and therefore more cost-effective.

Conclusion

Under the statistical assumptions of this study, non-inferiority of EMR could not be demonstrated. However, EMR may have potential as the primary method of choice due to a tendency of lower complication rates and a better cost-effectiveness ratio. The high rate of unexpected cancers should be dealt with in further studies.

http://ift.tt/2t1wT3y

Endothelial dysfunction: what is the role of the microbiota?

In this issue, Catry et al described a study in which inulin-type fructans (ITF) improved endothelial dysfunction in mice.1 They demonstrated that the supplementation of ITF reverses endothelial dysfunction in mesenteric and carotid arteries of apolipoprotein E (apoE) gene knockout mice that were fed an n-3 polyunsaturated fatty acid-depleted diet. They further showed that improvement of endothelial dysfunction was accompanied with a change in microbiota composition and key gut peptides.

Endothelial dysfunction is a pathological state of the inner lining of the blood vessels which is characterised by a reduction in vasodilation in response to endothelial stimuli and considered an early key marker of cardiovascular disease.2 Impaired synthesis and release of nitric oxide (NO) by the endothelium is considered one of the important mechanisms associated with endothelial dysfunction.

A wide variety of risk factors associated with cardiovascular disease have been identified. These include general lifestyle factors such as...

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Non-coding regulatory variations: the dark matter of pancreatic cancer genomics

Pancreatic ductal adenocarcinoma (PDAC) is the seventh cause of death for cancer worldwide and the third in the USA, where it is expected to become the second by year 2030. Unlike other cancers, little progress has been made when it comes to therapeutic options other than surgery, which is possible only for a small fraction (~20%) of patients presenting with localised disease.1 2

For the above reasons, large efforts have been undertaken to get a deeper understanding of the molecular alterations and their effects on cancer cells and tumour microenvironment, by exploiting both innovative disease models and high-throughput studies for genomic and transcriptomic profiling of PDAC.3 4 In the meanwhile, genome-wide association studies, and the study of familial pancreatic cancer, have been looking for and found genetic variations associated to PDAC onset and outcome.5 6

At the genomic level, mutations...

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The effect of geriatric intervention in frail elderly patients receiving chemotherapy for colorectal cancer: a randomized trial (GERICO)

Abstract

Background

Better surgical techniques, chemotherapy and biological therapy have improved survival in patients with colorectal cancer (CRC), most markedly in younger patients. About half of patients over 70 years receive dose reductions or early treatment discontinuation of the planned adjuvant or first-line treatment due to side effects. The Comprehensive Geriatric Assessment (CGA) is a multidisciplinary evaluation of an elderly individual's health status. This assessment in older patients with cancer can predict survival, chemotherapy toxicity and morbidity.

Methods

This randomized phase II trial (GERICO) is designed to investigate whether comprehensive geriatric assessment and intervention before and during treatment with chemotherapy in frail elderly patients with stages II–IV CRC will increase the number of patients completing chemotherapy. All patients ≥70 years in whom chemotherapy for CRC is planned to start at Herlev and Gentofte Hospital are screened for frailty using the G8 questionnaire at the first visit to the outpatient clinic. The G8 questionnaire is a multi-domain screening tool to identify frail or vulnerable patients at risk of increased toxicity and morbidity. Frail patients are offered inclusion and are then randomized to two groups (the intervention group and the control group). Patients in the intervention group receive a full geriatric assessment of comorbidity, medication, psycho-cognitive function, physical, functional and nutrition status, and interventions are undertaken on identified health issues. Simultaneously, they are treated for their cancer according to international guidelines. Patients in the control group receive the same chemotherapy regimens and standard of care. Primary outcome is number of patients completing scheduled chemotherapy at starting dose. Secondary outcomes are dose reductions, treatment delays, toxicity, time to recurrence, survival, cancer-related mortality and quality of life.

Discussion

This ongoing trial is one of the first to evaluate the effect of geriatric intervention in frail elderly patients with CRC. The trial will provide new and valuable knowledge about whether it is beneficial for the elderly patient undergoing chemotherapy to be treated simultaneously by a geriatrician.

Trial registration

ClinicalTrials.gov ID: NCT02748811. The trial was registered retrospectively; registration date 04/28/2016.

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Prognostic and predictive factors in patients with metastatic or recurrent cervical cancer treated with platinum-based chemotherapy.

Abstract

Background

Recognizing resistance or susceptibility to the current standard cisplatin and paclitaxel treatment could improve therapeutic outcomes of metastatic or recurrent cervical cancer.

Methods

Forty-five tissue samples from patients participating in a phase II trial of cisplatin and ifosfamide, with or without paclitaxel were collected for retrograde analysis. Immunohistochemistry and genotyping was performed to test ERCC1, III β-tubulin, COX-2, CD4, CD8 and ERCC1 (C8092A and N118 N) and MDR1 (C3435T and G2677 T) gene polymorphisms, as possible predictive and prognostic markers. Results were statistically analyzed and correlated with patient characteristics and outcomes.

Results

Patients with higher levels of ERCC1 expression had shorter PFS and OS than patients with low ERCC1 expression (mPFS:5.1 vs 10.2 months, p = 0.027; mOS:10.5 vs. 21.4 months, p = 0.006). Patients with TT in the site of ERCC1 N118 N and GT in the site of MDR1 G2677 T polymorphisms had significantly longer PFS (p = 0.006 and p = 0.027 respectively). ERCC1 expression and the ERCC1 N118 N polymorphism remained independent predictors of PFS. Interestingly, high III beta tubulin expression was associated with chemotherapy resistance and fewer responses [5/20 (25%)] compared to lower III β-tubulin expression [15/23 (65.2%)] (p = 0.008). Finally, ΙΙΙ β-tubulin levels and chemotherapy regimen were independent predictors of response to treatment.

Conclusions

ERCC1 expression proved to be a significant prognostic factor for survival in our metastatic or recurrent cervical cancer population treated with cisplatin based chemotherapy. ERCC1 N118 N and MDR1 G2677 T polymorphism also proved of prognostic significance for disease progression, while overexpression of III β-tubulin was positively correlated with chemotherapy resistance.

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Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed.

Methods

We used reverse transcription-RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin.

Results

The present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage.

Conclusions

The current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression.

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CMISG1701: a multicenter prospective randomized phase III clinical trial comparing neoadjuvant chemoradiotherapy to neoadjuvant chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced resectable esophageal squamous cell carcinoma (cT 3-4a N 0-1 M 0 ) (NCT03001596)

Abstract

Background

Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT_3-4aN_0-1M₀).

Methods/design

CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT_3-4aN_0-1M₀) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment-related complications, postoperative mortality as well as quality of life.

Discussion

The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE.

Trial registration

NCT03001596 (December 17, 2016).

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Electrospinning of Photocatalytic Electrodes for Dye-sensitized Solar Cells

The overall goal of this project was to use electrospinning to fabricate a photoanode with improved performance for dye-sensitized solar cells.

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PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation

Abstract

BRAF inhibitors (BRAFi) are standard of care for the treatment of BRAF V600 mutation-driven metastatic melanoma, but can lead to paradoxical activation of the mitogen-activated protein kinase (MAPK) signalling pathway. This can result in the promotion of precancerous lesions and secondary neoplasms, mainly (but not exclusively) associated with pre-existing mutations in RAS genes. We previously reported a patient with synchronous BRAF-mutated metastatic melanoma and BRAF ^wt /KRAS ^G12D-metastatic colorectal cancer (CRC), whose CRC relapsed and progressed when treated with the BRAF inhibitor dabrafenib (GSK2118436). We used tissue from the resected CRC metastasis to derive a cell line, LM-COL-1, which directly and reliably mimicked the clinical scenario including paradoxical activation of the MAPK signalling pathway resulting in increased cell proliferation upon dabrafenib treatment. Novel BRAF inhibitors (PLX8394 and PLX7904), dubbed as "paradox breakers", were developed to inhibit V600 mutated oncogenic BRAF without causing paradoxical MAPK pathway activation. In this study we used our LM-COL-1 model alongside multiple other CRC cell lines with varying mutational backgrounds to demonstrate and confirm that the paradox breaker PLX8394 retains on-target inhibition of mutated BRAF V600 without paradoxically promoting MAPK signalling.

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Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment

Hearing loss leads to a host of cellular and synaptic changes in auditory brain areas that are thought to give rise to auditory perception deficits such as temporal processing impairments, hyperacusis, and tinnitus. However, little is known about possible changes in synaptic circuit connectivity that may underlie these hearing deficits. Here, we show that mild hearing loss as a result of brief noise exposure leads to a pronounced reorganization of local excitatory and inhibitory circuits in the mouse inferior colliculus. The exact nature of these reorganizations correlated with the presence or absence of the animals' impairments in detecting brief sound gaps, a commonly used behavioral sign for tinnitus in animal models. Mice with gap detection deficits (GDDs) showed a shift in the balance of synaptic excitation and inhibition that was present in both glutamatergic and GABAergic neurons, whereas mice without GDDs showed stable excitation–inhibition balances. Acoustic enrichment (AE) with moderate intensity, pulsed white noise immediately after noise trauma prevented both circuit reorganization and GDDs, raising the possibility of using AE immediately after cochlear damage to prevent or alleviate the emergence of central auditory processing deficits.

SIGNIFICANCE STATEMENT Noise overexposure is a major cause of central auditory processing disorders, including tinnitus, yet the changes in synaptic connectivity underlying these disorders remain poorly understood. Here, we find that brief noise overexposure leads to distinct reorganizations of excitatory and inhibitory synaptic inputs onto glutamatergic and GABAergic neurons and that the nature of these reorganizations correlates with animals' impairments in detecting brief sound gaps, which is often considered a sign of tinnitus. Acoustic enrichment immediately after noise trauma prevents circuit reorganizations and gap detection deficits, highlighting the potential for using sound therapy soon after cochlear damage to prevent the development of central processing deficits.

http://ift.tt/2tpcwjA

Axonal Conduction Delays, Brain State, and Corticogeniculate Communication

Thalamocortical conduction times are short, but layer 6 corticothalamic axons display an enormous range of conduction times, some exceeding 40–50 ms. Here, we investigate (1) how axonal conduction times of corticogeniculate (CG) neurons are related to the visual information conveyed to the thalamus, and (2) how alert versus nonalert awake brain states affect visual processing across the spectrum of CG conduction times. In awake female Dutch-Belted rabbits, we found 58% of CG neurons to be visually responsive, and 42% to be unresponsive. All responsive CG neurons had simple, orientation-selective receptive fields, and generated sustained responses to stationary stimuli. CG axonal conduction times were strongly related to modulated firing rates (F1 values) generated by drifting grating stimuli, and their associated interspike interval distributions, suggesting a continuum of visual responsiveness spanning the spectrum of axonal conduction times. CG conduction times were also significantly related to visual response latency, contrast sensitivity (C-50 values), directional selectivity, and optimal stimulus velocity. Increasing alertness did not cause visually unresponsive CG neurons to become responsive and did not change the response linearity (F1/F0 ratios) of visually responsive CG neurons. However, for visually responsive CG neurons, increased alertness nearly doubled the modulated response amplitude to optimal visual stimulation (F1 values), significantly shortened response latency, and dramatically increased response reliability. These effects of alertness were uniform across the broad spectrum of CG axonal conduction times.

SIGNIFICANCE STATEMENT Corticothalamic neurons of layer 6 send a dense feedback projection to thalamic nuclei that provide input to sensory neocortex. While sensory information reaches the cortex after brief thalamocortical axonal delays, corticothalamic axons can exhibit conduction delays of <2 ms to 40–50 ms. Here, in the corticogeniculate visual system of awake rabbits, we investigate the functional significance of this axonal diversity, and the effects of shifting alert/nonalert brain states on corticogeniculate processing. We show that axonal conduction times are strongly related to multiple visual response properties, suggesting a continuum of visual responsiveness spanning the spectrum of corticogeniculate axonal conduction times. We also show that transitions between awake brain states powerfully affect corticogeniculate processing, in some ways more strongly than in layer 4.

http://ift.tt/2tp5Kut

Keeping control by letting it go

While we are on duty, anything and everything can happen. I used to let the responsibility of being one of the people that other people call when things are out of control overwhelm me. I would sit frozen in place waiting for the bell to tip, hoping it was for something easy. Eventually I realized that I could handle anything and allowed myself the luxury of relaxing while on duty, but only between ...

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Loss of Doc2-Dependent Spontaneous Neurotransmission Augments Glutamatergic Synaptic Strength

Action potential-evoked vesicle fusion comprises the majority of neurotransmission within chemical synapses, but action potential-independent spontaneous neurotransmission also contributes to the collection of signals sent to the postsynaptic cell. Previous work has implicated spontaneous neurotransmission in homeostatic synaptic scaling, but few studies have selectively manipulated spontaneous neurotransmission without substantial changes in evoked neurotransmission to study this function in detail. Here we used a quadruple knockdown strategy to reduce levels of proteins within the soluble calcium-binding double C2 domain (Doc2)-like protein family to selectively reduce spontaneous neurotransmission in cultured mouse and rat neurons. Activity-evoked responses appear normal while both excitatory and inhibitory spontaneous events exhibit reduced frequency. Excitatory miniature postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), increase in amplitude after quadruple knockdown. This increase in synaptic efficacy correlates with reduced phosphorylation levels of eukaryotic elongation factor 2 and also requires the presence of elongation factor 2 kinase. Together, these data suggest that spontaneous neurotransmission independently contributes to the regulation of synaptic efficacy, and action potential-evoked and spontaneous neurotransmission can be segregated at least partially on a molecular level.

SIGNIFICANCE STATEMENT Action potential-evoked and spontaneous neurotransmission have been observed in nervous system circuits as long as methods have existed to measure them. Despite being well studied, controversy still remains about whether these forms of neurotransmission are regulated independently on a molecular level or whether they are simply a continuum of neurotransmission modes. In this study, members of the Doc2 family of presynaptic proteins were eliminated, which caused a reduction in spontaneous neurotransmission, whereas action potential-evoked neurotransmission remained relatively normal. This protein loss also caused an increase in synaptic strength, suggesting that spontaneous neurotransmission is able to communicate independently with the postsynaptic neuron and trigger downstream signaling cascades that regulate the synaptic state.

http://ift.tt/2toWjLs

Enlargement of Ribbons in Zebrafish Hair Cells Increases Calcium Currents But Disrupts Afferent Spontaneous Activity and Timing of Stimulus Onset

In sensory hair cells of auditory and vestibular organs, the ribbon synapse is required for the precise encoding of a wide range of complex stimuli. Hair cells have a unique presynaptic structure, the synaptic ribbon, which organizes both synaptic vesicles and calcium channels at the active zone. Previous work has shown that hair-cell ribbon size is correlated with differences in postsynaptic activity. However, additional variability in postsynapse size presents a challenge to determining the specific role of ribbon size in sensory encoding. To selectively assess the impact of ribbon size on synapse function, we examined hair cells in transgenic zebrafish that have enlarged ribbons, without postsynaptic alterations. Morphologically, we found that enlarged ribbons had more associated vesicles and reduced presynaptic calcium-channel clustering. Functionally, hair cells with enlarged ribbons had larger global and ribbon-localized calcium currents. Afferent neuron recordings revealed that hair cells with enlarged ribbons resulted in reduced spontaneous spike rates. Additionally, despite larger presynaptic calcium signals, we observed fewer evoked spikes with longer latencies from stimulus onset. Together, our work indicates that hair-cell ribbon size influences the spontaneous spiking and the precise encoding of stimulus onset in afferent neurons.

SIGNIFICANCE STATEMENT Numerous studies support that hair-cell ribbon size corresponds with functional sensitivity differences in afferent neurons and, in the case of inner hair cells of the cochlea, vulnerability to damage from noise trauma. Yet it is unclear whether ribbon size directly influences sensory encoding. Our study reveals that ribbon enlargement results in increased ribbon-localized calcium signals, yet reduces afferent spontaneous activity and disrupts the timing of stimulus onset, a distinct aspect of auditory and vestibular encoding. These observations suggest that varying ribbon size alone can influence sensory encoding, and give further insight into how hair cells transduce signals that cover a wide dynamic range of stimuli.

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Preparation, calibration and evaluation of the First International Standard for human C-peptide

Authors: Moore, Melanie / Dougall, Thomas / Ferguson, Jackie / Rigsby, Peter / Burns, Chris


http://ift.tt/2roZjqf

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

New England Journal of Medicine, Ahead of Print.


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Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2sRhxjK

The relationship between serum CXCL16 level and carotid vulnerable plaque in patients with ischemic stroke

OBJECTIVE: We investigated the relationship between the serum macrophage chemokine ligand 16 (CXCL16) levels and the vulnerable carotid plaque in patients with ischemic stroke.

PATIENTS AND METHODS: We successively selected 118 cases of patients with an initial diagnosis of acute ischemic stroke (time of onset <72h), recorded risk factors, including gender, age, family history, smoking, body mass index, blood glucose levels, blood lipid levels, average systolic pressure and diastolic blood pressure (DBP) and homocysteine levels. ELISA was used to detect the levels of serum CXCL16. GE-3000 color Doppler ultrasound diagnostic instrument was applied for the detection of the cervical artery (including a bilateral common carotid artery, internal carotid artery and external carotid artery) intima-media thickness (IMT), plaque number, size, nature (stable and vulnerable) and luminal stenosis rate. Delica EMS-9EBx2P type transcranial Doppler ultrasound (TCD) was used to detect micro-arterial micro-embolic signals (MES). Stroke, according to etiologic type, was divided into large artery atherosclerosis (LAA), small artery occlusion (SAA) and others.

RESULTS: Serum CXCL16 levels were not significantly correlated with sex, age, family history, smoking, BMI, blood glucose levels, blood lipid levels, mean systolic blood pressure, diastolic blood pressure, and homocysteine levels. Serum CXCL16 levels increased with an increase of IMT, plaque area and lumen stenosis rate. Serum CXCL16 levels of vulnerable plaques were significantly higher than those of stable plaques; differences were statistically significant (p<0.05).

It has nothing to do with the number of atherosclerotic plaques. The levels of serum CXCL16 in MES positive group were significantly higher than that in MES negative group; differences were statistically significant (p<0.05). The serum CXCL16 levels of LAA patients were significantly higher than that of SAA and other types of patients; differences were statistically significant (p<0.05).

CONCLUSIONS: The levels of serum CXCL16 are not related to high-risk factors for acute stroke and closely related to characteristics of atherosclerotic plaque, micro-embolic signals and stroke subtypes.

L'articolo The relationship between serum CXCL16 level and carotid vulnerable plaque in patients with ischemic stroke sembra essere il primo su European Review.

http://ift.tt/2uiQc7V

The relationship between serum CXCL16 level and carotid vulnerable plaque in patients with ischemic stroke

OBJECTIVE: We investigated the relationship between the serum macrophage chemokine ligand 16 (CXCL16) levels and the vulnerable carotid plaque in patients with ischemic stroke.

PATIENTS AND METHODS: We successively selected 118 cases of patients with an initial diagnosis of acute ischemic stroke (time of onset <72h), recorded risk factors, including gender, age, family history, smoking, body mass index, blood glucose levels, blood lipid levels, average systolic pressure and diastolic blood pressure (DBP) and homocysteine levels. ELISA was used to detect the levels of serum CXCL16. GE-3000 color Doppler ultrasound diagnostic instrument was applied for the detection of the cervical artery (including a bilateral common carotid artery, internal carotid artery and external carotid artery) intima-media thickness (IMT), plaque number, size, nature (stable and vulnerable) and luminal stenosis rate. Delica EMS-9EBx2P type transcranial Doppler ultrasound (TCD) was used to detect micro-arterial micro-embolic signals (MES). Stroke, according to etiologic type, was divided into large artery atherosclerosis (LAA), small artery occlusion (SAA) and others.

RESULTS: Serum CXCL16 levels were not significantly correlated with sex, age, family history, smoking, BMI, blood glucose levels, blood lipid levels, mean systolic blood pressure, diastolic blood pressure, and homocysteine levels. Serum CXCL16 levels increased with an increase of IMT, plaque area and lumen stenosis rate. Serum CXCL16 levels of vulnerable plaques were significantly higher than those of stable plaques; differences were statistically significant (p<0.05).

It has nothing to do with the number of atherosclerotic plaques. The levels of serum CXCL16 in MES positive group were significantly higher than that in MES negative group; differences were statistically significant (p<0.05). The serum CXCL16 levels of LAA patients were significantly higher than that of SAA and other types of patients; differences were statistically significant (p<0.05).

CONCLUSIONS: The levels of serum CXCL16 are not related to high-risk factors for acute stroke and closely related to characteristics of atherosclerotic plaque, micro-embolic signals and stroke subtypes.

L'articolo The relationship between serum CXCL16 level and carotid vulnerable plaque in patients with ischemic stroke sembra essere il primo su European Review.

http://ift.tt/2uiQc7V

Astragalus polysaccharides inhibits cell growth and pro-inflammatory response in IL-1β-stimulated fibroblast-like synoviocytes by enhancement of autophagy via PI3K/AKT/mTOR inhibition

Abstract

The hyperplastic growth of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and inflammatory response are pathological hallmarks of RA. It has been reported that Astragalus polysaccharides (APS) possess appreciable anti-inflammatory activity against adjuvant-induced arthritis. Nevertheless, little is known about the role and detailed mechanism underlying the therapeutic effects of APS in RA. This study demonstrated that administration of APS dose-dependently impaired cell viability, increased cell apoptosis by decreasing Bcl-2 expression, increasing Bax expression and Caspase3 activity in IL-1β-stimulated RSC-364 cells and RA-FLS. Simultaneously, IL-1β-induced production of pro-inflammatory cytokines IL-6 and TNF-α was significantly decreased after APS treatment. Furthermore, preconditioning with APS dramatically enhanced autophagy activity by increasing Beclin-1 and LC3II/LC3I expression coupled with decreasing p62 expression and augmenting the number of LC3 puncta in IL-1β-stimulated RSC-364 cells. More importantly, autophagy inhibitor 3-methyladenine (3-MA) partly abolished APS-triggered inhibitory effects on cell growth and production of pro-inflammatory cytokines. APS also repressed the activation of PI3K/Akt/mTOR signaling pathway in IL-1β-stimulated RSC-364 cells. Moreover, treatment with insulin-like growth factor-1 (IGF-1), an activator of PI3K/Akt signaling, partly reversed the therapeutic effects of APS in IL-1β-stimulated RSC-364 cells. Collectively, we concluded that APS might attenuate the pathological progression of RA by exerting the pro-apoptotic and anti-inflammatory effects in IL-1β-stimulated FLSs by regulating the PI3K/AKT/mTOR-autophagy pathway.

http://ift.tt/2tpgc59

Next generation deep sequencing corrects diagnostic pitfalls of traditional molecular approach in a patient with prenatal onset of Pompe disease

Pompe disease is a rare inherited metabolic disorder of glycogen metabolism caused by mutations in the GAA gene, encoding the acid α-1,4 glucosidase. Successful diagnosis of Pompe disease is achieved by clinical and biochemical evaluation followed by confirmation with DNA testing. Here, we report a male infant with a prenatal onset of cardiac symptoms and enzyme testing consistent with Pompe disease, but DNA testing by Sanger sequencing revealed no pathogenic variants. Due to the strong indication from clinical, enzymatic, and histological studies (despite the absence of molecular confirmation by traditional Sanger sequencing), enzyme replacement therapy (ERT) for Pompe disease was initiated. Reanalysis of the patient's DNA sample using next generation sequencing (NGS) of a panel of target genes causing glycogen storage disorders demonstrated compound heterozygosity for a point mutation and an exonic deletion in the GAA gene. This case illustrates the value of astute clinical judgement in patient management as well as the power of target capture deep NGS in the simultaneous detection of both a point mutation and a heterozygous exonic deletion by correcting pitfalls of the traditional PCR based sequencing, namely; allele dropout and the inability to detect exonic deletions.

http://ift.tt/2smqa24