Systematic review and meta‐analysis: portal vein recanalisation and transjugular intrahepatic portosystemic shunt for portal vein thrombosis

Summary

Background

Transjugular intrahepatic portosystemic shunt has been increasingly used in patients with portal vein thrombosis to obtain patency, but evidenced‐based decisions are challenging.

Aim

To evaluate published data on efficacy and safety of endovascular therapy in portal vein thrombosis.

Methods

Systematic search of PubMed, ISI, Scopus, and Embase for studies (in English, until October 2017) reporting feasibility, safety, 12‐month portal vein recanalisation, transjugular intrahepatic portosystemic shunt patency, and survival in patients with benign portal vein thrombosis undergoing endovascular treatment. An independent extraction of articles using predefined data fields and quality indicators was used; pooled analyses based on random‐effects models; heterogeneity assessment by Cochran's Q, I ² statistic, subgroup analyses, and meta‐regression.

Results

Thirteen studies including 399 patients (92% cirrhosis; portal vein thrombosis: complete 46%, chronic 87%, cavernous transformation 17%, superior mesenteric vein involvement 55%) were included. Transjugular intrahepatic portosystemic shunt was technically feasible in 95% (95% CI: 89%‐98%) with heterogeneity (I ² = 57%, P < 0.001) explained by cavernous transformation. Major complications occurred in 10% (95% CI: 6.0%‐18.0%; I ² = 52%, P = 0.55). Additional catheter‐directed thrombolysis was associated with more complications compared to transjugular intrahepatic portosystemic shunt alone or plus thrombectomy (17.6% vs 3.3%). Twelve‐month portal vein recanalisation was 79% (95% CI: 67%‐88%; I ² = 78%, P < 0.01). Shunt patency at 12 months was 84% (95% CI: 76%‐90%; I ² = 62%, P < 0.01). Overall 12‐month survival rate was 89%, with no heterogeneity.

Conclusions

Transjugular intrahepatic portosystemic shunt for portal vein thrombosis recanalisation was highly feasible, effective, and safe. Cavernous transformation was the main determinant of technical failure. Additional catheter‐directed thrombolysis was associated with higher risk of severe complications.

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Propofol sedation and colonoscopy: a perspective from endoscopists [Letters]

https://ift.tt/2PDUJ3V

Ending overly broad criminalization of nondisclosure of human immunodeficiency virus infection [Commentary]

https://ift.tt/2QUoFVU

Risk of sexual transmission of human immunodeficiency virus with antiretroviral therapy, suppressed viral load and condom use: a systematic review [Research]

Background:

The Public Health Agency of Canada reviewed sexual transmission of HIV between serodiscordant partners to support examination of the criminal justice system response to HIV nondisclosure by the Department of Justice of Canada. We sought to determine HIV transmission risk when an HIV-positive partner takes antiretroviral therapy, has a suppressed viral load or uses condoms.

Methods:

We conducted an overview and systematic review update by searching MEDLINE and other databases (Jan. 1, 2007, to Mar. 13, 2017; and Nov. 1, 2012, to Apr. 27, 2017, respectively). We considered reviews and studies about absolute risk of sexual transmission of HIV between serodiscordant partners to be eligible for inclusion. We used A Measurement Tool to Assess Systematic Reviews (AMSTAR) for review quality, Quality in Prognosis Studies (QUIPS) instrument for study risk of bias and then the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence across studies. We calculated HIV incidence per 100 person-years with 95% confidence intervals (CIs). We assigned risk categories according to potential for and evidence of HIV transmission.

Results:

We identified 12 reviews. We selected 1 review to estimate risk of HIV transmission for condom use without antiretroviral therapy (1.14 transmissions/100 person-years, 95% CI 0.56–2.04; low risk). We identified 11 studies with 23 transmissions over 10 511 person-years with antiretroviral therapy (0.22 transmissions/ 100 person-years, 95% CI 0.14–0.33; low risk). We found no transmissions with antiretroviral therapy and a viral load of less than 200 copies/mL across consecutive measurements 4 to 6 months apart (0.00 transmissions/100 person-years, 95% CI 0.00–0.28; negligible risk regardless of condom use).

Interpretation:

Based on high-quality evidence, there is a negligible risk of sexual transmission of HIV when an HIV-positive sex partner adheres to antiretroviral therapy and maintains a suppressed viral load of less than 200 copies/mL measured every 4 to 6 months. Sexual transmissions of HIV have occurred when viral load was more than 200 copies/mL with antiretroviral therapy or condoms alone were used, although the risk remains low. These findings will help to support patient and clinician decision-making, affect public health case management and contact tracing, and inform justice system responses to HIV nondisclosure.

https://ift.tt/2PDCQ55

Canadian medical residents report pervasive harassment, crushing workloads [News]

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What is Your Call: Brain natriuretic peptide and shortness of breath in the emergency department [Practice]

https://ift.tt/2PGweD5

Diagnostic accuracy in the presence of a rare outcome [Letters]

https://ift.tt/2QScVmX

Moyamoya disease [Practice]

https://ift.tt/2PFhowM

Was euthanasia dispute behind CMA-WMA split? [News]

https://ift.tt/2QPSNln

Ronald Epstein: from awkward moments to mindful practice [Humanities]

https://ift.tt/2PzAcgR

Physicians not immune to intimate partner violence [News]

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Radical Trachelectomy for Early Stage Cervical Cancer

Opinion Statement

In patients with early-stage cervical cancer, radical hysterectomy and pelvic lymphadenectomy is the gold standard. However, this disease commonly affects women of childbearing age; thus an option to spare fertility is ideal. This option came to fruition in the early 90s when the Dargent procedure or radical trachelectomy was first reported. The procedure has subsequently been modified as technology has improved and now may be performed via minimally invasive techniques. Additionally, with the advent of the sentinel lymph node procedure, the morbidity in this usually young patient population has continued to improve. There is a multitude of data to show that oncologic outcomes, concerning recurrence and mortality, are comparable to radical hysterectomy, as well as obstetrical outcomes are favorable. Data to support its acceptance within the gynecologic oncology community has led to radical trachelectomy being implemented into governing body guidelines and should be offered to appropriate candidates with early-stage cervical cancer who wish to preserve fertility.

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Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Abstract

Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as "TDP-43 pathology" in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43^A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.

https://ift.tt/2FGRxQD

Final Results of the RHAPSODY trial: A multi‐center, Phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A‐APC, a Recombinant Variant of Human Activated Protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke

Abstract

Objective

Agonism of the protease activated receptor (PAR) 1 by activated protein C (APC) provides neuroprotection and vasculoprotection in experimental neuro‐injury models. The pleiotropic PAR1 agonist, 3K3A‐APC, reduces neurologic injury and promotes vascular integrity; 3K3A‐APC proved safe in human volunteers. We performed a randomized, controlled, blinded, trial to determine the maximally tolerated dose (MTD) of 3K3A‐APC in ischemic stroke patients.

Methods

The NeuroNEXT trial RHAPSODY used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360 and 540μg/kg 3K3A‐APC. After intravenous tissue plasminogen activator, intraarterial mechanical thrombectomy, or both, patients were randomized to one of the four doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates.

Results

Between January 2015 and July 2017 we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest dose 3K3A‐APC tested, 540μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A‐APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p=0.046), and total hemorrhage volume from an average of 2.1±5.8 mL in placebo to 0.8±2.1 mL in the combined treatment arms (p=0.066).

Interpretation

RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540μg/kg for the PAR1 active cytoprotectant 3K3A‐APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation.

This article is protected by copyright. All rights reserved.

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Production of nutrient‐enhanced millet‐based composite flour using skimmed milk powder and vegetables

The aim of this study was to develop a nutrient‐enhanced millet‐based composite flour using skimmed milk powder and vegetables for children aged 6–59 months. The product has the potential to make a significant contribution to the RDA for children aged 6–69 months and to help in reduction in malnutrition among children in Uganda and other developing countries.

Abstract

The aim of this study was to develop a nutrient‐enhanced millet‐based composite flour incorporating skimmed milk powder and vegetables for children aged 6–59 months. Two processing methods were tested to optimize nutrient content and quality of millet‐based composite flour, namely germination for 0, 24 and 48 hr and roasting at 80, 100, and 140°C. The amount of ingredients in the formulation was determined using Nutri‐survey software. Germinating millet grains for 48 hr at room temperature significantly (p < 0.05) increased protein content (9.3%–10.6%), protein digestibility (22.3%–65.5%), and total sugars (2.2%–5.5%), while phytate content (3.9–3.7 mg/g) decreased significantly (p < 0.05). Roasting millet grains at 140°C significantly (p < 0.05) increased the protein digestibility (22.3%–60.1%) and reduced protein (9.3%–7.8%), phytate (3.9–3.6 mg/g), and total sugar content (2.2%–1.9%). Germinating millet grains at room temperature for 48 hr resulted in millet flour with the best nutritional quality and was adopted for the production of millet‐based composite flour. Addition of vegetables and skimmed milk powder to germinated millet flour significantly (p < 0.05) increased the macro‐ and micronutrient contents and the functional properties of millet‐based composite flour. The study demonstrated that the use of skimmed milk powder and vegetables greatly improves the protein quality and micronutrient profile of millet‐based complementary foods. The product has the potential to make a significant contribution to the improvement of nutrition of children in developing countries.

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Mesomelia‐synostoses syndrome: Description of a patient presenting a monoallelic expression of SULF1 without alterations in the SLCOA1 gene

https://ift.tt/2A6zhtx

Analyses of LMNA -negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann–Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

Abstract

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson–Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann–Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

https://ift.tt/2zitpy5

An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells

Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ε on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP-BiTE–encoding virus induced activation of tumor-infiltrating PD1+ T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF-mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment.Significance: An engineered oncolytic adenovirus that encodes a bispecific antibody combines direct virolysis with endogenous T-cell activation to attack stromal fibroblasts, providing a multimodal treatment strategy within a single therapeutic agent. Cancer Res; 1–14. ©2018 AACR.

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Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases

Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases

Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases, Published online: 19 November 2018; doi:10.1038/s41416-018-0321-5

Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases

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Distinct Nasopharyngeal and Oropharyngeal Microbiota of Children with Influenza A Virus Compared with Healthy Children

Background. Influenza A virus (IAV) has had the highest morbidity globally over the past decade. A growing number of studies indicate that the upper respiratory tract (URT) microbiota plays a key role for respiratory health and that a dysfunctional respiratory microbiota is associated with disease; but the impact of microbiota during influenza is understudied. Methods. We recruited 180 children, including 121 IAV patients and 59 age-matched healthy children. Nasopharyngeal (NP) and oropharyngeal (OP) swabs were collected to conduct 16S rDNA sequencing and compare microbiota structures in different individuals. Results. Both NP and OP microbiota in IAV patients differed from those in healthy individuals. The NP dominated genera in IVA patients, such as Moraxella, Staphylococcus, Corynebacterium, and Dolosigranulum, showed lower abundance than in healthy children. The Streptococcus significantly enriched in patients' NP and Phyllobacterium could be generally detected in patients' NP microbiota. The most abundant genera in OP microbiota showed a decline tendency in patients, including Streptococcus, Neisseria, and Haemophilus. The URT's bacterial concurrence network changed dramatically in patients. NP and OP samples were clustered into subgroups by different dominant genera; and NP and OP microbiota provided the precise indicators to distinguish IAV patients from healthy children. Conclusion. This is the first respiratory microbiome analysis on pediatric IAV infection which reveals distinct NP and OP microbiota in influenza patients. It provides a new insight into IAV research from the microecology aspect and promotes the understanding of IAV pathogenesis.

https://ift.tt/2DvUaSh

Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases

https://ift.tt/2QOde22

Experimental Study of the Effectiveness of Phenolic Antioxidants in Male Infertility Caused by Pathospermia

The effect of phenolic antioxidants (dihydroquercetin, p-tyrosol, dibornol) on the morphology, functions, and redox processes in the reproductive cells of male rats was studied on the model of experimental pathospermia. All antioxidants reduced the percentage of degenerative forms of spermatozoa. Dibornol was most effective. Dihydroquercetin and p-tyrosol did not increase the total number of spermatozoa and the percentage of their mobile forms. These indicators were improved only by dibornol. After administration of all test drugs, the antioxidant potential of spermatozoa increased and did not significantly differ from the baseline values.

https://ift.tt/2PBxrMa

Effect of Silver Nanoparticles on Protein Composition of Rat Liver Microsomal Fraction

We studied the effect of oral administration of metallic silver nanoparticles to rats on the proteome of the liver microsomal fraction. Nanoparticles (5-80 nm) were administered daily to growing Wistar male rats over 92 days. Controls received pure water. To control the effect of the carrier, the rats were administered aqueous solution of a stabilizer polyvinylpyrrolidone. The protein composition (proteome) of the liver microsomal fraction was analyzed by 2D-electrophoresis with identification of variable protein spots using the high-resolution nanoHPLC-MS/MS. Eight, 6, and 8 proteins absent in the control groups appeared in the microsomal fraction under the action of nanoparticles in doses of 0.1, 1, and 10 mg/kg body weight, among these, proteasome activator complex subunit 1 (Psme1 gene), and the heat shock protein HSP60 (Hspd1 gene) were reliably identified. The consumption of silver nanoparticles led to disappearance of protein of β2a tubulin chain (Tuba1b gene) from the microsomal fraction. The expression of catalase, present in the proteome of the liver microsomal fraction in animals of all groups was significantly decreased after consumption of silver nanoparticles in doses of 0.1 and 10 mg/kg. The observed changes in the proteome are considered as manifestations of hepatotoxicity of silver nanoparticles and can be related to the antagonistic effect of silver on the status of the essential trace element selenium.

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Discoordination of Autonomic Support of Functions in the Pathogenesis Gastroesophageal Reflux Disease

A cross-sectional study performed on a continuous sample of 32 patients (mean age 46.36±3.31 years) with gastroesophageal reflux disease and excess body weight showed that the disturbance of sympathetic/parasympathetic relationships, disruption of segmental and compensatory increase in the suprasegmental mechanisms of autonomic regulation determines the course of gastroesophageal reflux disease in these patients.

https://ift.tt/2PE824a

A Study of the Cytotoxic Effect of Microcapsules and Their Constituent Polymers on Macrophages and Tumor Cells

We studied the effect of different concentrations of polyelectrolytes poly(allylamine hydrochloride) (PAH) and polystyrene sulfonate (PSS) as well as the effects of microcapsules coated with these polymers on survival of Ehrlich ascites carcinoma cells and mouse peritoneal macrophages and on ROS production by phagocytes. PAH reduced viability of Ehrlich ascites carcinoma in a concentration-dependent manner (LD₅₀=12-15 μg/ml). This effect was presumably determined by its ability to bind phosphates, thereby depleting the culture medium. At the same time, PAH did not affect the viability of macrophages. PSS produced no cytotoxic effect on the examined cells. Polyelectrolyte capsules with the shell architectonics (PAH/PSS)₃ and (PAH/PSS)₃PAH in the examined concentration range had no effect on the viability of macrophages and tumor cells. PAH microcapsules with positively charged surface much more rapidly and more intensively activated macrophages. The chemiluminescence response directly depended on the amount of capsules in the solution.

https://ift.tt/2QTj4zj

Mechanisms of Granulocytopoiesis Recovery Stimulation with Filgrastim in Breast Cancer Patients Receiving Chemotherapy

We studied myelotoxicity of modern schemes of chemotherapy for breast cancer (docetaxel/doxorubicin and cyclophosphamide/doxorubicin/5-fluorouracil) towards granulocytopoiesis, the mechanisms determining the differences of hematological effects of these schemes, and the efficiency of correction of the observed changes with granulocyte CSF (filgrastim). Granulocytopoiesis stimulation with filgrastim during the treatment with docetaxel/doxorubicin combination was more pronounced than during cyclophosphamide/doxorubicin/5-fluorouracil therapy. The observed differences were found at all levels of granulocyte lineage organization (central and peripheral), which is related to different effects of the cytostatic substances used in the proposed protocols on the structures controlling hemopoiesis.

https://ift.tt/2PDIa8w

New Experimental Facts on the Influence of Secondary Immunodeficiency on the Morphology and Biological Activity of Colorectal Tumor

Colorectal tumors were studied 5 months after carcinogen injection to outbred albino rats with secondary immunodeficiency by common histological and immunobiochemical methods with the use of monoclonal and polyclonal antibodies to Ki-67, Bcl-2, p53, and VEGF. Injection of carcinogen to intact animals led to the formation of adenocarcinomas with high and moderate cell differentiation in the colon, while injection of carcinogen to animals with immunodeficiency was associated with a 1.5-fold higher incidence of GRADE 2 and GRADE 3 adenocarcinomas with more aggressive morphological phenotype and appearance of distant metastases.

https://ift.tt/2QYw9Yh

Effect of Vasopressin V1b Receptor Blockade on Activity of the Hypothalamic—Pituitary—Adrenal Axis in Old Monkeys with Depression-Like and Anxious Behavior Subjected to Stress or Injected with Vasopressin

The effect of selective antagonist of the arginine vasopressin (AVP) V1b receptors on the secretion of ACTH and corticosteroids in response to insulin-induced hypoglycemia and injection of AVP is studied in old Macaca mulatta females with depression-like and anxious behavior. Intravenous antagonist in a dose of 1.1-1.7 μg/kg inhibits the increase of ACTH concentration, induced by hypoglycemia or injection of AVP. The degree of increase in the concentrations of hydrocortisone and dehydroepiandrosterone sulfate has not changed or increased. The effects of AVP antagonist prove that previously detected disorders in the reaction of the hypothalamic—pituitary—adrenal system in old Macaca mulatta with depression-like and anxious behavior could be caused by excessive activation of vasopressin V1b receptors on the pituitary corticotrophs, while the use of V1b receptor antagonists seems to be a promising method for prevention of these disorders.

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Relationship between Cell Receptors and Tumor Cell Sensitivity to Oncolytic Enteroviruses

Replicative ability of 5 oncolytic enterovirus strains was evaluated on a panel of 18 human normal and tumor cells. The capacity of each cell line to support replication of enterovirus strains varied. Cell lines weakly replicating one virus could be highly sensitive to another viral strain. Differences in the expression of CXADR cell receptor did not correlate with susceptibility to infection and replication of Coxsackie B virus, but complete inactivation of CXADR gene and poliovirus receptor gene (PVR) led to loss of the sensitivity to Coxsackie B5 and poliovirus, respectively. Detection of additional expression markers will contribute to understanding the causes of different sensitivity of tumor cells to viruses.

https://ift.tt/2A27Ktm

Postgenomic Properties of Natural Micronutrients

Modern medical approaches to the therapy of various diseases, including cancer, are based on the use of toxic drugs. The unfavorable side effects of traditional medicine could be counterbalanced by addition of natural bioactive substances to conventional therapy due to their mild action on cells combined with the multitargeted effects. To elucidate the real mechanisms of their biological activity, versatile approaches including a number of "omics" such as genomics, transcriptomics, proteomics, and metabolomics are used. This review highlights inclusion of bioactive natural compounds into the therapy of chronic diseases from the viewpoint of modern omics-based nutritional biochemistry. The recently accumulated data argue for necessity to employ nutrigenetic and nutrimetabolomic analyses to prevent or diminish the risk of chronic diseases.

https://ift.tt/2TpJnPo

Studying of the Mechanisms of Combined Effect of Dexamethasone, Doxorubicin, and Docetaxel on Breast Cancer Cells

The sensitivity of MDA-MB231 breast cancer cells to the effects of pharmacological agents was evaluated by their motility and viability. Dexamethasone, doxorubicin, or docetaxel administered separately in their effective concentration suppressed cell motility (in 16 h) and caused cell death (in 48 h). The strength of the effects increased in the following order: dexa methasone<doxorubicin≤docetaxel. The combined effects of the drugs were multidirectional: the total effect of dexamethasone and doxorubicin combination was inferior to their separate effect, while the effect of dexamethasone and docetaxel surpassed their individual effects. The combination of dexamethasone, doxorubicin, and docetaxel allowed negating the negative reciprocal interactions between dexamethasone and doxorubicin. The studying of the mechanisms underlying the observed phenomena attested to a potential role of S100A4 in the regulation of MDA-MB231 cells to the studied drugs.

https://ift.tt/2A4Kye7

A Protocol for Transcranial Photobiomodulation Therapy in Mice

Photobiomodulation therapy is an innovative noninvasive modality for the treatment of a wide range of neurological and psychiatric disorders and can also improve healthy brain function. This protocol includes a step-by-step guide to performing brain photobiomodulation in mice by transcranial light delivery, which can be adapted for use in other laboratory rodents.

https://ift.tt/2qSpGCs

Left Atrial Stenosis Induced Pulmonary Venous Arterialization and Group 2 Pulmonary Hypertension in Rat

Left atrial stenosis (LAS) is a novel surgical technique used for studying group 2 pulmonary hypertension (PH) and mechanisms underlying pulmonary venous arterialization. Here, we present a protocol to constrict the left atrium using a titanium clip to cause pulmonary venous arterialization and moderate PH in a rat.

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Subclavian Vein Puncture As an Alternative Method of Blood Sample Collection in Rats

Here, we present a protocol to collect blood samples from the rat subclavian vein.

https://ift.tt/2zhia8N

Production and Measurement of Organic Particulate Matter in the Harvard Environmental Chamber

This paper describes operation procedures for the Harvard Environmental Chamber (HEC) and related instrumentation for measuring gaseous and particle species. The environmental chamber is used to produce and study secondary organic species produced from the organic precursors, especially related to atmospheric organic particulate matter.

https://ift.tt/2Tmpqc1

Correction: The Effects of Melatonin Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Horm Metab Res 2018; 50: e6-e6
DOI: 10.1055/a-0792-1864

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Future Trends in Demand for Liver Transplant: Birth-Cohort Effects among Patients with NASH and HCC

Background With increasing U.S. adiposity, NASH is now a leading liver transplant (LT) indication. Given its association with hepatocellular carcinoma (HCC), the burden of NASH is substantial. We analyzed birth-cohort effects among NASH LT registrants, with and without HCC. Methods All new LT registrants in UNOS (1995-2015) were identified. Birth-cohorts were: 1936-1940, 1941-1945, 1946-1950, 1951-1955, 1956-1960, 1961-1965, 1966-1970, 1971-2015. Poisson regression examined trends in LT registration, by disease etiology (NASH, HCV, OTHER), and HCC. Results We identified 182,368 LT registrants with median age 52 years (range 0-86). Nine-percent (n=16,160) had NASH, 38% (n=69,004) HCV, 53% (n=97,204) OTHER. HCC was present in: 13% (n=2,181), 27% (n=18,295), and 11% (n=10,902), of NASH, HCV, and OTHER, respectively. LT registration for HCC increased significantly from 2002-2015 across all etiologies (NASH 6%➔18%; HCV 19%➔51%; OTHER 9%➔16%, p

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Societal and Professional Obligation in the Care of the Living Organ Donor

No abstract available

https://ift.tt/2ToyRHR

mTOR Inhibitor Everolimus in Regulatory T cell Expansion for Clinical Application in Transplantation

Background Experimental and pre-clinical evidence suggest that adoptive transfer of regulatory T cells (Tregs) could be an appropriate therapeutic strategy to induce tolerance and improve graft survival in transplanted patients. The University of Kentucky Transplant Service Line is developing a novel Phase I/II clinical trial with ex vivo expanded autologous Tregs as an adoptive cellular therapy in renal transplant recipients who are using everolimus (EVR)-based immunosuppressive regimen. Methods The aim of this study was to determine the mechanisms of action and efficacy of EVR for the development of functionally competent Treg cell-based adoptive immunotherapy in transplantation to integrate a common EVR-based regimen in vivo (in the patient) and ex vivo (in the expansion of autologous Treg cells). CD25+ Treg cells were selected from leukapheresis product with a GMP-compliant cell separation system and placed in 5-day (short) or 21-day (long) culture with EVR or rapamycin (RAPA). Multi-parametric flow cytometry analyses were used to monitor the expansion rates, phenotype, autophagic flux and suppressor function of the cells. PI3K/AKT/mTOR signaling pathway profiles of treated cells were analyzed by western blot and cell bioenergetic parameters by extracellular flux analysis. Results EVR-treated cells showed temporary slower growth, lower metabolic rates, and reduced phosphorylation of AKT compared to RAPA-treated cells. In spite of these differences, the expansion rates, phenotype, and suppressor function of long-term Treg cells in culture with EVR were similar to those with RAPA. Conclusions Our results support the feasibility of EVR to expand functionally competent Treg cells for their clinical use. *Both authors contributed equally to this manuscript #Corresponding Authors: Roberto Gedaly, MD and Francesc Marti, PhD, University of Kentucky Transplant Center, 740 South Limestone, K301, Lexington, KY, 40536-0284, USA, Email: rgeda2@uky.edu & fmart3@uky.edu. Tel: 1-859-323-4661, FAX: 1-859-257-3644 Clinical Trial Notation: National Cancer Trial Registry; # NCT03284242 Authorship: Designed research: RG and FM Collected data: FDS, LT, GH, MIM, MCA, HCM and FM Contributed analytic tools: MH, DAB, JH, CDJ Analyzed data: RG, AAT and FM Wrote the manuscript: RG and FM Critical editing of content: all authors Approval of final version: all authors Disclosure: The authors declare no commercial or financial conflicts of interest Funding sources: This research was supported by the National Institute of Allergy and Infectious Diseases (NIAID) NIH grant R03-AI135592 to FM, and by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1TR001998 to RG and FM. The Redox Metabolism Shared Resource (RMSR) and the University of Kentucky Flow Cytometry and Immune Monitoring (FCIM) core facilities received support from the National Cancer Institute (NCI) NIH Cancer Center Support Grant P30CA177558 awarded to the University of Kentucky Markey Cancer Center. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Reevaluation of the Kidney Donor Risk Index (KDRI)

Background The Kidney Donor Risk Index (KDRI) is a score applicable to deceased kidney donors which reflects relative graft failure risk associated with deceased donor characteristics. The KDRI is widely used in kidney transplant outcomes research. Moreover, an abbreviated version of KDRI is the basis, for allocation purposes, of the "top 20%" designation for deceased donor kidneys. Data upon which the KDRI model was based used kidney transplants performed between 1995 and 2005. Our purpose in this report was to evaluate the need to update the coefficients in the KDRI formula, with the objective of either (a) proposing new coefficients or (b) endorsing continued used of the existing formula. Methods Using data obtained from the Scientific Registry of Transplant Recipients (SRTR), we analyzed n=156,069 deceased donor adult kidney transplants occurring from 2000 to 2016. Cox regression was used to model the risk of graft failure. We then tested for differences between the original and updated regression coefficients, and compared the performance of the original and updated KDRI formulas with respect to discrimination and predictive accuracy. Results In testing for equality between the original and updated KDRIs, few coefficients were significantly different. Moreover, the original and updated KDRI yielded very similar risk discrimination and predictive accuracy. Conclusions Overall, our results indicate that the original KDRI is robust and is not meaningfully improved by an update derived through modeling analogous to that originally employed. *Corresponding author: Douglas Schaubel, University of Michigan, 1415 Washington Hts., Ann Arbor, MI, 48109-2029; email: deschau@umich.edu Author Contributions: Yingchao Zhong: research design; literature review; database management; data analysis; writing manuscript; statistical computing. Douglas Schaubel: research design; database management; data analysis; writing manuscript. Jack Kalbfleisch: research design; data analysis; writing manuscript. Valarie Ashby: research design; literature review; data analysis; writing manuscript. Pandu Rao: research design; literature review; writing manuscript. Randall Sung: research design; literature review; writing manuscript. Disclosure: The authors have no conflicts of interest to disclose. Funding: This work was supported in part by National Institutes of Health Grant R01 DK070869, and by a Michigan Institute for Clinical and Health Research (MICHR). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Donor Urinary C5a Levels Independently Correlate With Posttransplant Delayed Graft Function

Background Accumulating evidence implicates the complement cascade as pathogenically contributing to ischemia-reperfusion injury and delayed graft function (DGF) in human kidney transplant recipients. Building upon observations that kidney injury can initiate in the donor before nephrectomy, we tested the hypothesis that anaphylatoxins C3a and C5a in donor urine prior to transplantation associate with risk of post-transplant injury. Methods We evaluated the effects of C3a and C5a in donor urine on outcomes of 469 deceased donors and their corresponding 902 kidney recipients in a subset of a prospective cohort study. Results We found a 3-fold increase of urinary C5a concentrations in donors with stage 2 and 3 AKI compared donors without AKI (p

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Accelerated Hypofractionated Radiation Therapy for Elderly Frail Bladder Cancer Patients Unfit for Surgery or Chemotherapy

Purpose/Objectives: The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy. Materials and Methods: Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes. Results: Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index ≥3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002). Conclusions: Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT. Support for the database manager was from the Parasol Foundation. The authors declare no conflicts of interest. Reprints: Zvi Symon, MD, Department of Radiation Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel. E-mail: Zvi.Symon@sheba.health.gov.il. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Essentials of Anesthesia for Infants and Neonates

No abstract available

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Systematic Review of the Efficacy and Safety of Gabapentin and Pregabalin for Pain in Children and Adolescents

The barriers to opioid use in some countries necessitate the need to identify suitable alternatives or adjuncts for pain relief. The gabapentinoids (gabapentin and pregabalin) are approved for the management of persistent pain in adults, but not in children. Searches were conducted in Embase, Medline, Scopus, and Web of Science up until November 2017, for randomized controlled trials that investigated the analgesic effects of gabapentin or pregabalin in children and adolescents

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Comment on “Race/Ethnicity and Sex Both Affect Opioid Administration in the Emergency Room”

No abstract available

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Glycocalyx Degradation Is Independent of Vascular Barrier Permeability Increase in Nontraumatic Hemorrhagic Shock in Rats

BACKGROUND: Glycocalyx shedding after traumatic hemorrhagic or septic shock, as well as different resuscitation fluids, has been causally linked to increased vascular barrier permeability (VBP) resulting in tissue edema. In nontraumatic hemorrhagic shock (NTHS), it remains questionable whether glycocalyx degradation in itself results in an alteration of VBP. The composition of fluids can also have a modulatory effect on glycocalyx shedding and VBP. We hypothesized that the shedding of the glycocalyx during NTHS has little effect on VBP and that the composition of fluids can modulate these effects. METHODS: Fully instrumented Wistar-albino rats were subjected to a pressure-controlled NTHS (mean arterial pressure of 30 mm Hg) for 60 minutes. Animals were fluid resuscitated with Ringer's acetate, balanced hydroxyethyl starch (HES) solution, or 0.9% normal saline to a mean arterial pressure of 80 mm Hg and compared with shams or nonresuscitated NTHS. Glycocalyx shed products were determined at baseline and 60 minutes after fluid resuscitation. Skeletal muscle microcirculation was visualized using handheld vital microscopy. VBP changes were assessed using plasma decay of 3 fluorescent dyes (40- and 500-kDa dextran and 70-kDa albumin), Evans blue dye exclusion, intravital fluorescence microscopy, and determination of tissue edema (wet/dry weight ratio). RESULTS: All glycocalyx shedding products were upgraded as a result of NTHS. Syndecan-1 significantly increased in NTHS (mean difference, −1668; 95% confidence interval [CI], −2336 to −1001; P

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In Response

No abstract available

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Progressive Increase in Scholarly Productivity of New American Board of Anesthesiology Diplomates From 2006 to 2016: A Bibliometric Analysis

BACKGROUND: Improving research productivity is a common goal in academic anesthesiology. Initiatives to enhance scholarly productivity in anesthesiology were proposed more than a decade ago as a result of emphasis on clinical work. We hypothesized that American Board of Anesthesiology diplomates certified from 2006 to 2016 would be progressively more likely to have published at least once during this time period. METHODS: A complete list of 17,332 new diplomates was obtained from the American Board of Anesthesiology for the years 2006 to 2016. These names were queried using PubMed, and the number of publications up to and including the diplomate's year of primary certification was recorded. Descriptive statistics and logistic regression analysis were used to analyze the association of the year of primary certification and whether a diplomate had published at least once. RESULTS: The percentage of American Board of Anesthesiology diplomates with ≥1 publication at the time of primary certification increased from 14.9% to 29.3% from 2006 to 2016. The mean number of publications per diplomate more than doubled from 0.31 to 0.79. Logistic regression analysis revealed the year of primary certification as significantly associated with having ≥1 publication (P

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Intraluminal Pulmonary Vein Stenosis in Children: A “New” Lesion

Pulmonary vein stenosis (PVS) is a rare disorder that leads to progressive narrowing of the extrapulmonary veins. PVS has been reported in both children and adults and in its worse iteration leads to pulmonary hypertension, right ventricular failure, and death. Multiple etiologies of PVS have been described in children and adults. This review will focus on intraluminal PVS in children. Intraluminal PVS has an estimated incidence ranging from 0.0017% to 0.03%. It is associated with conditions such as prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, Smith-Lemli-Opitz syndrome, and Down syndrome. Cardiac catheterization and pulmonary vein angiography are the gold standard for diagnosis and anatomic delineation. Other imaging modalities including magnetic resonance imaging, chest tomography, and transesophageal echocardiography are increasingly being used. Mortality of PVS in children is approximately 50%. Predictors of mortality include involvement of ≥3 pulmonary veins, bilateral pulmonary vein involvement, onset of PVS in infancy, elevated pulmonary artery pressure or systolic pulmonary artery-to-aortic pressure ratio, right ventricular dysfunction, restenosis after surgery, distal/upstream disease, and disease progression to previously uninvolved pulmonary veins. Treatment includes catheter-based pulmonary vein dilations with or without stenting, surgical interventions, medical therapy, and in some instances, lung transplantation. Cardiac catheterization for PVS involves a comprehensive hemodynamic and anatomic assessment of the pulmonary veins as well as therapeutic transcatheter interventions. Several surgical strategies have been used. Sutureless repair is currently most commonly used, but patch venoplasty, endarterectomy, ostial resection, and reimplantation are used in select circumstances as well. Medical therapies such as imatinib mesylate and bevacizumab are increasingly being used in an effort to suppress the myofibroblastic proliferation seen in PVS patients. Lung transplantation has been used as an alternative treatment strategy for end-stage, refractory PVS. Nonetheless, despite the different innovative approaches used, morbidity and mortality remain high. At present, the preferred treatment strategy is frequent reassessment of disease progression to guide use of catheter-based and surgical interventions in conjunction with medical therapy. Accepted for publication October 8, 2018. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Viviane G. Nasr, MD, Department of Anesthesiology, Critical Care and Pain Medicine, Division of Cardiac Anesthesia, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115. Address e-mail to viviane.nasr@childrens.harvard.edu. © 2018 International Anesthesia Research Society

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A Review of Complementary and Alternative Medicine Therapies on Muscular Atrophy: A Literature Review of In Vivo/In Vitro Studies

Objective. The objective of this review is to evaluate the recent treatment and study trends of complementary and alternative medicine (CAM) treatments on muscular atrophy by reviewing in vivo/in vitro studies. Materials and Methods. The searches were conducted via electronic databases including PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang MED, and five Korean databases. Only in vivo and in vitro studies were included in this study. Results. A total of 44 studies (27 in vivo studies, 8 in vitro studies, and 9 in vivo with in vitro) were included. No serious maternal or fetal complications occurred. There were various animal models induced with muscular atrophy through "hindlimb suspension", "nerve damage", 'alcohol or dexamethasone treatment', "diabetes", "CKD", "stroke", "cancer", "genetic modification", etc. In 28 of 36 articles measuring muscle mass, CAM significantly increased the mass. Additionally, 10 of them showed significant improvement in muscle function. In most in vitro studies, significant increases in both the diameter of myotubes and muscle cell numbers were reported. The mechanisms of action of protein synthesis, degradation, autophagy, and apoptotic markers were also investigated. Conclusions. These results demonstrate that CAM could prevent muscular atrophy. Further studies about CAM on muscular atrophy are needed.

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Restless legs syndrome and its variants in acute ischemic stroke

Abstract

Background

The clinical–radiological correlation between restless legs syndrome (RLS) or its variants and acute ischemic stroke remains unclear.

Methods

This study prospectively included 104 consecutive patients with acute ischemic stroke, confirmed by diffusion‐weighted imaging. The frequency and clinical characteristics of RLS or RLS variants were evaluated according to the International RLS Study Group criteria, as was the topography of the associated lesions.

Results

Among 104 patients with acute ischemic stroke, 6 (5.8%) and 2 patients (1.9%) had RLS and RLS variants, respectively, for a total of 8 patients (7.7%). Three (3.3%) had poststroke RLS/RLS variants: 2 (66.7%) had bilateral symptoms, and 1 (33.3%) had unilateral symptoms contralateral to the lesion. RLS symptoms developed within 2 days after the onset of stroke. Forty percent of prestroke RLS/RLS variant patients experienced exacerbation of their symptoms after stroke onset, and two‐thirds of poststroke RLS/RLS variant patients required treatment for their RLS/RLS variants. Patients positive for RLS/RLS variants tended to have difficulty falling asleep, but there was no difference in daytime sleepiness, sleep quality, depressive symptoms, stroke subtypes, comorbid diseases, laboratory data or modified Rankin Scale scores at admission or discharge between patients with and without RLS/RLS variants. RLS/RLS variants were most frequently observed to accompany lesions in the medulla (25%), followed by the pons (15.4%), the corona radiata (14.8%), the basal ganglia (3.8%) and the cortex (3.8%).

Conclusion

RLS/RLS variants were found in 8% of acute ischemic stroke patients. Adequate screening and management are needed to improve patients' quality of life.

This article is protected by copyright. All rights reserved.

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Colquhounia Root Tablet Protects Rat Pulmonary Microvascular Endothelial Cells against TNF--Induced Injury by Upregulating the Expression of Tight Junction Proteins Claudin-5 and ZO-1

Background. There are currently limited effective pharmacotherapy agents for acute lung injury (ALI). Inflammatory response in the lungs is the main pathophysiological process of ALI. Our preliminary data have shown that colquhounia root tablet (CRT), a natural herbal medicine, alleviates the pulmonary inflammatory responses and edema in a rat model with oleic acid-induced ALI. However, the potential molecular action mechanisms underlining its protective effects against ALI are poorly understood. This study aimed to investigate the effects and mechanism of CRT in rat pulmonary microvascular endothelial cells (PMEC) with TNF-α-induced injury. Methods. PMECs were divided into 6 groups: normal control, TNF-α (10 ng/mL TNF-α), Dex (1× M Dex + 10 ng/mL TNF-α), CRT high (1000 ng/mL CRT + 10 ng/mL TNF-α), CRT medium (500 ng/mL CRT + 10 ng/mL TNF-α), and CRT low group (250 ng/mL CRT + 10 ng/mL TNF-α). Cell proliferation and apoptosis were detected by MTT assay and flow cytometry. Cell micromorphology was observed under transmission electron microscope. The localization and expression of tight junction proteins Claudin-5 and ZO-1 were analyzed by immunofluorescence staining and Western blot, respectively. Results. TNF-a had successfully induced an acute endothelial cell injury model. Dex and CRT treatments had significantly stimulated the growth and reduced the apoptosis of PMECs (all p

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Colorectal Cancer and Mitochondrial Dysfunctions of the Adjunct Adipose Tissues: A Case Study

Excess body weight has been causally linked to an increased risk of different cancer types, including colorectal cancer (CRC) but the mechanisms underlying this association are practically unknown. We investigate redox state-superoxide (SO) generation rate, activity of complex I in electron transport chain (ETC) of mitochondria and of dinitrosyl iron complexes by electron paramagnetic resonance; activity of matrix metalloproteinase (gelatinase) MMP-2 and MMP-9 by gel zymography of adipose tissues (AT) from 46 patients (64.0 ± 1.6 y.o.) with CRC (II–III stages, pT2–3N0–2M0) in the AT adjacent to tumor (ATAT) and at a distance of 3 cm from the tumor (ATD) to follow the connection of the AT redox state with some of the tumor microenvironment indicators. We have incubated the AT species with the tumor necrosis factor α (TNF-α) to follow its influence on the measured values. As a control, normal AT (NAT) obtained during the liposuction is used. Tumor-induced changes in mitochondrial ETC of ATAT, particularly for Complex I, lead to the enhanced SO generation and consequent oxidative modifications of DNA in ATAT (up to 6.1 times higher than that in NAT and 3.7 times higher than that in ATD, p

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Role of Double-Carbapenem Regimen in the Treatment of Infections due to Carbapenemase Producing Carbapenem-Resistant Enterobacteriaceae: A Single-Center, Observational Study

Purpose. (i) To compare infections caused by carbapenem-susceptible (CS) and carbapenemase producing carbapenem-resistant Enterobacteriaceae (CP-CRE); (ii) to evaluate the clinical effectiveness of the double-carbapenem (DC) regimen in comparison with the best available treatment (BAT) in infections caused by CP-CRE; and (iii) to determine the exact minimal inhibitory concentrations (MICs) of meropenem/ertapenem (MEM/ETP) and the degree of in vitro ETP+MEM synergism in subjects receiving the DC. Methodology. Over a 3-year period (2014-2017), patients with infections due to Enterobacteriaceae were included in a single-center, retrospective, observational study. According to the susceptibility to carbapenems, subjects were divided into CSE and CP-CRE groups. CP-CRE group was further divided into subjects receiving the DC regimen and those treated with other regimens (BAT group). Clinical characteristics and the presence of 5th-day response and 60-day outcome were evaluated for DC and BAT groups. The determination of MEM and ETP actual MICs and the MEM+ETP synergistic activity were performed on strains obtained from subjects receiving the DC regimen. Results. A total of 128 patients were included in the study: 55/128 (43%) with infections due to CP-CRE and 73/128 (57%) with infections due to CSE. Among CP-CRE (n=55), 21 subjects (39%) were treated with the DC regimen whereas 34 (61%) received BAT. No differences in terms of severity of infection, presence/absence of concomitant bacteremia, type of infection, and resolution of infection were found; in contrast, DC group tended to have a higher rate of sepsis or septic shock at the onset of infection and a higher rate of 5th-day response. MICs 50/90 were 256/512 and 256/256 μg/mL for MEM and ETP, respectively. Overall, complete in vitro synergism was found in 6/20 strains (30%). Conclusion. The DC regimen is a valid and effective therapeutic option in patients with infections due to KPC producing CRE, including those with bacteremic infection and more severe clinical conditions. The clinical effectiveness is maintained even in the presence of extremely high MEM MICs.

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Development of a Rat Model of Sick Sinus Syndrome Using Pinpoint Press Permeation

Objective. Sick sinus syndrome (SSS) is one of the most common causes of cardiac impairment necessitating pacemaker implantation. However, studies of SSS pathogenesis are neither comprehensive nor conclusive due to limited success in achieving a stable rat SSS model. Here, we modified pinpoint press permeation to establish a stable rat SSS model. Methods. We randomly assigned 138 male Sprague-Dawley rats into three groups: normal control (n = 8), sham (n = 10), and SSS (n = 120). Postoperatively, the SSS group was further divided into SSSA (n = 40), SSSB (n = 40), and SSSC (n = 40), based on reduction in heart rates by 20–30%, 31–40%, and 41–50%, respectively. We also assessed histomorphological characteristics and hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4) expression in the sinoatrial node (SAN) at 1, 2, 3, and 4 weeks after surgery. Results. Mortality was statistically higher in SSSC compared to SSSA and SSSB (7.5% versus 90.0% and 87.5%; P

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Future Prospective and Current Trend of Biomaterials and Growth Factor Used for Maxillofacial Hard and Soft Tissue Reconstruction

https://ift.tt/2Q3le25

Stay-Green QTLs Response in Adaptation to Post-Flowering Drought Depends on the Drought Severity

Stay-green trait enhances sorghum adaptation to post-flowering drought. Six stay-green backcross introgression lines (BILs) carrying one or more stay-green QTLs (Stg1-4) and their parents were characterized under non-stress (W100: 100% of soil field capacity (FC)) and two levels of post-flowering drought (W75: 75% FC; W50: 50% FC) in a controlled condition. We aimed to study the response and identify the drought threshold of these QTLs under different levels of post-flowering drought and find traits closely contributing to grain yield (GY) under different drought severity. W50 caused the highest reduction in BILs performance. From W100 to W50, the GY of the recurrent parent reduced by 70%, whereas that of the BILs reduced by only 36%. W75 and W50 induce different behavior/response compared to W100. Harvest index contributed to the GY under the three water regimes. For high GY under drought transpiration rate at the beginning of drought and mid-grain filling was important at W75, whereas it was important at mid-grain filling and late-grain filling at W50. Stay-green trait can be scored simply with the relative number of green leaves/plants under both irrigated and stress environments. QTL pyramiding might not always be necessary to stabilize or increase the GY under post-flowering drought. The stay-green QTLs increase GY under drought by manipulating water utilization depending on drought severity.

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A Rare Case of Monophasic Synovial Sarcoma of Thoracic Vertebra

Synovial sarcoma of spine is an extremely rare malignancy with poor prognosis. It is often metastatic at the time of presentation. Its relative rarity and histological resemblance to other tumors make it diagnostically challenging, requiring the need of immunohistochemistry and cytogenetics for definite diagnosis. Surgery is the mainstay of therapy with adjunct chemotherapy, although survival rates are very low.

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Differential Gene Expression Profile of Renin-Angiotensin System in the Left Atrium in Mitral Regurgitation Patients

Background. Left atrial enlargement is a mortality and heart failure risk factor in primary mitral regurgitation (MR) patients. Pig models of MR have shown differential expression of genes linked to the renin-angiotensin system. Therefore, the aim of this study was to investigate the key genes of the renin-angiotensin that are expressed differentially in the left atrial myocardium in MR patients. Methods. Quantitative RT-PCR was used to compare gene expression in the renin-angiotensin system in the left atrium in MR patients, aortic valve disease patients, and normal subjects. Results. Plasma angiotensin II concentrations did not significantly differ between MR patients and aortic valve disease patients (). Compared to normal controls, however, MR patients had significantly downregulated expressions of angiotensin-converting enzyme, angiotensin I converting enzyme 2, type 1 angiotensin II receptor, glutamyl aminopeptidase, angiotensinogen, cathepsin A (CTSA), thimet oligopeptidase 1, neurolysin, alanyl aminopeptidase, cathepsin G, leucyl/cystinyl aminopeptidase (LNPEP), neprilysin, and carboxypeptidase A3 in the left atrium. The MR patients also had significantly upregulated expressions of MAS1 oncogene (MAS1) and mineralocorticoid receptor compared to normal controls. Additionally, in comparison with aortic valve disease patients, MR patients had significantly downregulated CTSA and LNPEP expression and significantly upregulated MAS1 expression in the left atrium. Conclusions. Expressions of genes in the renin-angiotensin system, especially CTSA, LNPEP, and MAS1, in the left atrium in MR patients significantly differed from expressions of these genes in aortic valve disease patients and normal controls. Notably, differences in expression were independent of circulating angiotensin II levels. The results of this study provide a rationale for pharmacological therapies or posttranslational regulation therapies targeting genes expressed differentially in the renin-angiotensin system to remedy structural remodeling associated with atrial enlargement and heart failure progression in patients with MR.

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The Clinical Utility of Circulating Epstein-Barr Virus DNA Concentrations in NK/T-Cell Lymphoma: A Meta-Analysis

Background. Circulating Epstein-Barr virus (EBV) DNA concentrations were reported to have prognostic value for NK/T-cell lymphoma patients in limited small-scale studies. In this study, we aimed to evaluate the clinical utility of circulating EBV-DNA concentrations to a large sample of NK/T-cell lymphoma patients. Methods. We conducted this meta-analysis, which included a total of 15 prospective and retrospective comparable studies to assess the association between pretreatment EBV-DNA (pre-DNA), posttreatment EBV-DNA (post-DNA), and clinical outcomes of NK/T-cell lymphoma patients. We chose overall survival (OS) as the primary endpoint and progression-free survival (PFS), complete response (CR), and overall response rate (ORR) as secondary endpoints. Results. High pre-DNA and detectable post-DNA were both significantly correlated with poorer OS in NK/T-cell lymphoma patients (), with hazard radios (HRs) equal to 3.45 and 2.30, respectively. High pre-DNA and detectable post-DNA also predicted poorer PFS. Additionally, high pre-DNA was found to be significantly correlated with both worse CR and ORR, which indicated worse treatment response. Conclusion. Circulating EBV-DNA concentrations provides prognostic values of survival and treatment response in NK/T-cell lymphoma patients.

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Metabarcoding successfully tracks temporal changes in eukaryotic communities in coastal sediments

Abstract

Metabarcoding is a method that combines high-throughput DNA sequencing and DNA based identification. Previously, this method has been successfully used to target spatial variation of eukaryote communities in marine sediments, however, the temporal changes in these communities remain understudied. Here, we follow the temporal changes of the eukaryote communities in Baltic Sea surface sediments collected from two coastal localities during three seasons of two consecutive years. Our study reveals that the structure of the sediment eukaryotic ecosystem was primarily driven by annual and seasonal changes in prevailing environmental conditions, whereas spatial variation was a less significant factor in explaining the variance in eukaryotic communities over time. Therefore, our data suggests that shifts in regional climate regime or large-scale changes in the environment are the overdriving factors in shaping the coastal eukaryotic sediment ecosystems rather than small-scale changes in local environmental conditions or heterogeneity in ecosystem structure. More studies targeting temporal changes are needed to further understand the long-term trends in ecosystem stability and response to climate change. Furthermore, this work contributes to the recent efforts in developing metabarcoding applications for environmental biomonitoring, proving a comprehensive option for traditional monitoring approaches.

https://ift.tt/2Q88szi

Klebsiella pneumoniae infection biology: living to counteract host defences

Abstract

Klebsiella species cause a wide range of diseases including pneumonia, UTIs, bloodstream infections, and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals. Klebsiella is also responsible for a significant number of community-acquired infections. A defining feature of these infections is their morbidity and mortality, and the Klebsiella strains associated with them are considered hypervirulent. The increasing isolation of multidrug resistant strains has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Not surprisingly, this pathogen has then been singled out as an 'urgent threat to human health' by several organizations. This review summarizes the tremendous progress has been made to uncover the sophisticated immune evasion strategies of K. pneumoniae. The co-evolution of Klebsiella in response to the challenge of an activated immune has made Klebsiella a formidable pathogen exploiting stealth strategies and actively suppressing innate immune defences to overcome host responses to survive in the tissues. A better understanding of Klebsiella immune evasion strategies in the context of the host-pathogen interactions is pivotal to develop new therapeutics, which can be based on antagonizing the anti-immune strategies of this pathogen.

https://ift.tt/2Dvx9yP

A Newly Authenticated Compound from Traditional Chinese Medicine Decoction Induces Melanogenesis in B16-F10 Cells by Increasing Tyrosinase Activity

Vitiligo is a kind of skin dysfunction on melanogenesis. The highly prevalent, chronic, and distinctive complexion changes on patients have imposed enormous psychic and economic burden on both individuals and society. Traditional Chinese Medicine (TCM) is a kind of precious source on chronic disease treatment, including skin dysfunctional diseases. In our previous study, a new compound named apigenin-7-butylene glucoside has been authenticated and purified from a prescription of Chinese traditional medicine formula which has been used clinically in vitiligo treatment. The aim of this work is to evaluate the effects of this compound on melanogenesis using melanoma cell B16-F10 in vitro. The results showed that apigenin-7-butylene glucoside had almost no cytotoxicity on B16-F10 cells within a lower dose of 5.0 μg and enhanced the melanin level to about 41% and tyrosinase activity to 1.32-fold when compared with controls. The compound showed minor cytotoxicity to B16-F10 cells at the higher concentration of 10 μg and 50 μg , the inhibition rate was 8.4% and 11.8%, and the melanin level and tyrosinase activity showed a decreased trend because of the lower cell number at the higher concentrations. The results indicated that apigenin-7-butylene glucoside was safe to B16-F10 cells within a lower concentration,

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Xiaoyao Kangai Jieyu Fang, a Chinese Herbal Formulation, Ameliorates Cancer-Related Depression Concurrent with Breast Cancer in Mice via Promoting Hippocampal Synaptic Plasticity

Diagnosis with breast cancer is a major life event that elicits increases in depressive symptoms for up to 50% of women. Xiaoyao Kangai Jieyu Fang (XYKAJY) is derived from a canonical TCM formula, Xiaoyao San (XYS), which has a history of nearly 1000 years for treating depression. The aim of this study was to investigate whether XYKAJY alleviates depression-like behavior and breast tumor proliferation in breast cancer mice then explore the mechanisms underlying its action on HPA axis and hippocampal plasticity further. XYKAJY was treated at the high dose of 1.95 g/mL and 0.488 g/mL, after 21 days of administration. Different behaviors, monoamine neurotransmitters, tumor markers, and the index of HPA axis were detected to evaluate depressive-like symptoms of breast cancer mice. Also, the pathological changes of the tumor, hippocampus, and the expressions of GR, NR2A, NR2B, CAMKII, CREB, and BDNF were detected. In this study, XYKAJY formulation significantly improved the autonomic behavior, reduced the incubation period of feeding, and reversed the typical depressive-like symptoms in breast cancer mice. Also, it reduced the content of CORT, ACTH, CRH, and CA125, CA153, CEA in the blood, protected the pathological changes of the hippocampus and tumor, upregulated the expression of GR, CREB, and BDNF in the hippocampus, and significantly decreased the expression of NR2A, NR2B, and CaMKII. These results provide direct evidence that XYKAJY effectively alleviates depression-like behaviors and tumor proliferation in vehicle mice with ameliorates hippocampus synaptic plasticity dysfunctions.

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HO-1 Induction by Selaginella tamariscina Extract Inhibits Inflammatory Response in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

Selaginella Herba is the dried, aerial part of Selaginella tamariscina (P.Beauv.) Spring and has been used to treat amenorrhea, abdominal pain, headaches, and hematuria in Korea. However, scientific evidence regarding the anti-inflammatory activity and action mechanism of Selaginella tamariscina is lacking. Thus, the present study was performed to investigate the anti-inflammatory and antioxidant activities of Selaginella tamariscina ethanol extract (STE) against lipopolysaccharide (LPS)-induced inflammatory responses and identify the molecular mechanism responsible. STE was prepared by heating in 70% ethanol and its quality was confirmed by HPLC. STE dose-dependently inhibited the productions of inflammatory mediators (NO and PGE2) and proinflammatory cytokines (IL-1β and IL-6) in LPS-stimulated RAW 264.7 cells. STE markedly suppressed the phosphorylations of MAPKs, IκB-α, and NF-κB and the nuclear translocation of NF-κB induced by LPS stimulation. In addition, STE exhibited good free radical scavenging activity and prevented ROS generation by LPS. STE also upregulated the expression of Nrf2 and HO-1 and promoted the nuclear translocation of Nrf2. Taken together, STE was found to have anti-inflammatory and antioxidant effects on RAW 264.7 macrophages and the mechanism appeared to involve the MAPK, NF-κB, and Nrf2/HO-1 signaling pathways. These results suggest that STE might be useful for preventing or treating inflammatory diseases and provide scientific evidence that supports the developments of herbal prescriptions or novel natural products.

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The Antitumor and Immunomodulatory Effect of Yanghe Decoction in Breast Cancer Is Related to the Modulation of the JAK/STAT Signaling Pathway

Background. Yanghe decoction (YHD) has been used in the treatment of breast cancer for hundreds of years in Asia. However, the underlying mechanisms are currently unknown. The present study aims to evaluate the efficacy of YHD on antitumor and immune system enhancement in a 4T1 mouse breast cancer model and to clarify the antitumor mechanisms of YHD in breast cancer. Materials and Methods. The YHD was orally administrated for 2 weeks after inoculation. Tumor tissues were then removed, weighed, and homogenized. Flow cytometry was used to detect the number of Myeloid-Derived Suppressor Cells (MDSCs), Natural Killer T Cells (NKTs), and T cell subsets. Quantitative real-time PCR was used to detect the expression of inducible nitric oxide synthase (iNOS) and arginase-1 (ARG-1). Western blot was used to detect the protein expression of signal transducers and the activator of transcription 1 (STAT1), phosphorylated-signal transducers and the activator of transcription 1 (p-STAT1), signal transducers and the activator of transcription 3 (STAT3), and phosphorylated-signal transducers and the activator of transcription 3 (p-STAT3). The expression levels of interleukin-6 (IL-6), transforming growth factor-β (TGF-β), and interferon-γ (IFN-γ) were detected using an enzyme linked immunosorbent assay. Results. We found that the tumor weight of YHD high-dose group was significantly lower compared with the control group (p

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Apoptosis of Platelets Inhibited By Herba Sarcandrae Extract through the Mitochondria Pathway

The purpose of the present study is to decode the underlying mechanism of Herba Sarcandrae that indicated antipurpuric effect and to unveil one of its primary components, flavonoids, which play an important role. An immune mediated bone marrow failure (BMF) model in mouse was established by infusion thymus suspension cells after radiation in vivo. Platelets isolated in vitro were prepared from normal mice and BMF mice, respectively. The expressions of PS, P-selectin, PAC-1, Bax, Bad, Bid, and caspase-9 were examined by flow cytometry, and alteration of morphology of platelets under different conditions was observed. Our results indicated that the number of platelets was increased by addition of total flavonoids, and some of apoptotic markers such as Bax, Bad, Bid, and Caspase-9 were downregulated. In addition, the phosphatidylserine (PS) exposure on platelets was inhibited by total flavonoids, and the expressions of PAC-1 and P-selectin were decreased. In conclusion, it is suggested that the total flavonoids of Herba Sarcandrae may inhibit the excessive platelet apoptosis through mitochondrial pathway. In addition, activation of platelets may be also involved in mediating apoptosis of platelets.

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Extra-Intestinal Fluoroquinolone-Resistant Escherichia coli Strains Isolated from Meat

Extra-intestinal E. coli are emerging as a global threat due to their diffusion as opportunistic pathogens and, above all, to their wide set of antibiotic resistance determinants. There are still many gaps in our knowledge of their origin and spread pathways, although food animals have been adjudicated vehicles for passing mult-drug resistant bacteria to humans. This study analyzed 46 samples of meat purchased from retail stores in Palermo in order to obtain quinolone-resistant E. coli isolates. Strains were screened for their phylogenetic groups, ST131-associated single nucleotide polymorphisms (SNPs), and then typed by ERIC-PCR. Their set of virulence factors, namely, kpsMII, papA, sfaS, focG, iutA, papC, hlyD, and afa genes, were investigated and their fluoroquinolone-resistance determinants evaluated. The data obtained show a dramatically high prevalence of multidrug resistance patterns in the Palermo area, with 28% of the isolates having virulence factor genes typical of ExPEC strains. No B2 group or ST131 strains were detected. Moreover, 20% of our isolates showed positivity to all the plasmid-mediated quinolone resistance (PMQR) determinants, showing a potential to transfer these genes among other bacteria. Therefore, these data underline the possibility that food animals and, specifically, poultry in particular may be a significant source of resistant bacterial strains, posing a potential zoonotic risk.

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Adding Handles to Optimize Manual Box Handling

The risk factors for developing musculoskeletal disorders in material handling tasks are well known. Among strategies for controlling risks, modifying boxes by adding handles is suggested. However, there are no clear recommendations regarding box modification as an approach to improve musculoskeletal health. In this study, we investigated the main literature databases to identify effects of box modification on reducing physical load. Electronic and manual searches were performed to identify studies that evaluated effects of boxes handles on physical exposure during handling tasks. The included studies were very heterogeneous (methods of assessment, types of handles used, and methodological quality), jeopardizing synthesis of evidence. Despite the mentioned limitations, we could suggest some features that could improve manual handling in practical settings, like the use of cylindrical handles forms with intermediate diameters (between 31 and 51 mm) and 30° inclination. Those characteristics demonstrated positive results on physical exposure. Regular cut-outs were indicated as a beneficial approach when boxes are handled in high surfaces. When handling occurs in medium heights or in the floor level, handles positioned on the top of the box might bring better results. Efforts to standardize methods are important to support both objective and subjective assessment of box handle design, as well to improve the internal validity of studies.

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Infections Caused by Extended-Spectrum β-Lactamase Producing Escherichia Coli in Systemic Lupus Erythematosus Patients: Prevalence, Risk Factors, and Predictive Model

Objective. To investigate the prevalence and risk factors of infections caused by Extended-Spectrum β-Lactamase (ESBL) producing Escherichia coli (E. coli) in systemic lupus erythematosus (SLE) patients and develop a predictive model. Methods. Three hundred and eighty-four consecutive SLE patients with E. coli infection were enrolled in this retrospective case control study from January 2012 to December 2017. Prevalence and antimicrobial susceptibility pattern of ESBL producing E. coli were analyzed. Multivariate analysis was performed to determine the risk factors. Sensitivity and specificity were obtained at various point cutoffs and area under the receiver operator characteristic curve (AuROC) was determined to confirm the prediction power of the model. Results. Of the total 384 E. coli strains tested, 212 (55.2%) produced ESBL. The majority of these isolates were from urine (44.3%). Carbapenems (>80%) and amikacin (89.6%) had good activity against ESBL producing E. coli. Eleven variables were identified as independent risk factors for ESBL producing E. coli infection including Enterobacteriaceae colonization or infection in preceding year (OR=8.15, 95%CI 5.12–21.71), daily prednisone dose > 30mg (OR=5.48, 95%CI 3.12–13.72), low C3 levels (OR=2.17, 95%CI 1.62–6.71), nosocomial acquired infection (OR=4.12, 95%CI 1.98–8.85), etc. The model developed to predict ESBL producing E. coli infection was effective, with the AuROC of 0.840 (95% CI 0.799-0.876). Conclusions. The prevalence of ESBL producing E. coli was increasing with high antibiotics resistance in patients with SLE. The model revealed excellent predictive performance and exhibited a good discrimination.

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The Role of Endothelium in Physiological and Pathological States: New Data

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Endoscopic submucosal dissection of superficial esophageal cancer expanding into the diverticulum

Abstract

Endoscopic submucosal dissection (ESD) is standard treatment for early esophageal cancer (EEC). Cancer located within the diverticulum, which has a thin or nonexistent muscular coating, is extremely rare. We describe successful ESD of esophageal diverticular cancer with a high risk of perforation. A 20‐mm EEC lesion expanding into the diverticulum was detected in the middle thoracic esophagus of a 73‐year‐old man. Positive‐pressure ventilation under general anesthesia and carbon dioxide insufflation were performed.

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EUS‐guided coil and cyanoacrylate embolization for gastric varices and the roles of endoscopic Doppler and Endosonographic varicealography in vascular targeting

Abstract

Objectives

To report the results of endoscopic‐ultrasound guided injection of coils with cyanoacrylate using a less‐expensive coil, with an emphasis on the roles of Doppler and Endosonographic varicealography in identifying the feeder vessel in gastric varix treatment.

Methods

An observational, descriptive study with prospectively collected data. Patients with gastric varices were included and were treated by the endoscopic‐ultrasound guided injection of cyanoacrylate and a less‐expensive coil. Technical success, complete and immediate variceal obliteration, rebleeding, complication and survival rates were evaluated.

Results

Thirty patients with gastric varices, with a mean age of 62 years (range 44‐76 years), were treated. The median number of coils used was 2 (range 1‐3), and the median volume of cyanoacrylate was 1.8 ml (1.2‐2.4 ml). The technical success rate was 100%. Endosonographic varicealography technical success was observed in 26/30 patients. Complete variceal obliteration was observed in 96.6%of patients, and the immediate disappearance of the varix was observed in 24 (80%) patients. The complication rate was 6.7%.

Conclusions

Endoscopic‐ultrasound guidance for gastric varix treatment with the addition of endosonographic varicealography and the use of a less‐expensive coil is a safe and effective technique that results in the immediate disappearance of gastric varices after targeting the feeding vessel.

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