Effects of speed and direction of perturbation on electroencephalographic and balance responses

Abstract

The modulation of perturbation-evoked potential (PEP) N1 as a function of different biomechanical characteristics of perturbation has been investigated before. However, it remains unknown whether the PEP N1 modulation contributes to the shaping of the functional postural response. To improve this understanding, we examined the modulation of functional postural response in relation to the PEP N1 response in ten healthy young subjects during unpredictable perturbations to their upright stance—translations of the support surface in a forward or backward direction at two different amplitudes of constant speed. Using independent components from the fronto-central region, obtained from subject-specific head models created from the MRI, our results show that the latency of onset of the functional postural response after the PEP N1 response was faster for forward than backward perturbations at a constant speed but was not affected by the speed of perturbation. Further, our results reinforce some of the previous findings that suggested that the N1 peak amplitude and peak latency are both modulated by the speed of perturbation but not by the direction of the perturbation. Our results improve the understanding of the relation between characteristics of perturbation and the neurophysiology of reactive balance control and may have implications for the design of brain–machine interfaces for populations with a higher risk of falls.

https://ift.tt/2IdW49Y

Increased adiponectin is associated with cerebral white matter lesions in the elderly with cognitive impairment

Abstract

Adiponectin is an adipocyte-derived peptide that increases with age and is thought to protect against atherosclerotic vascular changes and organ damage. However, paradoxically, higher adiponectin levels are associated with increased risk for cardiovascular events and mortality. We investigated whether this adiponectin paradox occurs in elderly people with cognitive impairment. Fifty-two elderly participants with mild cognitive impairment or dementia (20 male and 32 female, aged 60–93 years, mean 80.0) were recruited. We evaluated serum adiponectin levels and cerebral white matter lesions (WML), which are involved in cognitive decline and dementia, by computed tomography. Body mass index (BMI), Mini-Mental State Examination score, history of hypertension (HT), chronic kidney disease, and diabetes mellitus were also assessed. Stepwise multiple regression analysis was used to reveal the relationships between serum adiponectin and age, sex, BMI, HT, diabetes mellitus, chronic kidney disease, Mini-Mental State Examination, and WML scores. High serum adiponectin levels correlated with more severe WML (P = 0.013). Low BMI (P < 0.001), female sex (P = 0.025), and high WML scores (P = 0.039) were significant determinants of high serum adiponectin. HT (P = 0.032) and high adiponectin levels (P = 0.021) were independent risk factors for WML. Overall, we observed an association between serum adiponectin levels and WML severity in elderly people with cognitive decline. Our findings reveal that the adiponectin paradox occurs in this population, and this study may help guide future treatments for elderly people with mild cognitive impairment or dementia.

https://ift.tt/2G6sql0

Cytoplasmic FMRP interacting protein 1/2 ( CYFIP1/2 ) expression analysis in autism

Abstract

Cytoplasmic FMRP interacting proteins 1 and 2 (CYFIP1/2) have been previously shown to be associated with central nervous system (CNS) disorders such as autism spectrum disorder (ASD). Moreover, dysregulation of their expression levels results in disturbances in CNS maturation and neuronal interconnections. In the present study, we compared expression levels of CYFIP1/2 in peripheral blood of 30 ASD patients and 41 healthy subjects by means of real time PCR. Expression analysis showed significant over-expression of CYFIP1/2 in ASD patients compared with healthy subjects (Fold change = 3.252, P < 0.0001 and Fold change = 4.14, P = 0.001 respectively). Such over-expression was also seen for CYFIP1 in male and female patients when compared with the corresponding control subjects. In addition, a significant correlation was found between CYFIP1 transcript levels and age in female subjects. A significant correlation was detected between expression levels of these genes in control subjects. The current study provides further supports for contribution of CYFIP1/2 in the pathogenesis of ASD and potentiates it as a peripheral marker for ASD diagnosis. Future studies in larger sample sizes are needed to confirm the results of the current study.

https://ift.tt/2KUK1jp

Editorial Board

https://ift.tt/2ryTBjW

Author Index

https://ift.tt/2wuUrTH

Table of Contents

https://ift.tt/2rzj4d0

The Quest for Off-the-Shelf CAR T Cells [News in Depth]

To improve patient access, companies are exploring this therapy in allogeneic form, but challenges remain.

https://ift.tt/2KTfGlx

The acceptability of high resolution anoscopy examination in patients attending a tertiary referral centre

Abstract

Background

High resolution anoscopy (HRA) examination is regarded as the best method for the management of anal high grade squamous intraepithelial lesions to prevent anal squamous carcinoma. However, little is known about the acceptability of this procedure. This analysis looks at patient experience of HRA examination and ablative treatment under local anaesthetic.

Methods

Patients took part in anonymised feedback of their experience immediately after their HRA examinations and/or treatments. A standard questionnaire was used that included assessment of pain and overall satisfaction scores as well as willingness to undergo future HRA examinations.

Results

Four hundred four (89.4%) responses were received and all responses were analysed. The group consisted of 119 females (29.4%) and 261 males (64.6%) with median age of 45 years (IQR = 19) and 45 years (IQR = 21) respectively, and included 58 new cases, 53 treatment cases and 202 surveillance cases. 158 patients (39.1%) had at least one biopsy during their visits. The median pain score was 2 [Inter Quartile Range (IQR) 3] on a visual analogue scale of 0 to 10, where 0 indicated no pain / discomfort and 10 indicated severe pain. The median pain score was 2 (IQR 2) in men and 4 (IQR = 3) in women [Dunn's Test = 4.3, p < 0.0001] and 3 (IQR 4.5) in treatment cases. Problematic pain defined as a pain score of ≥7 occurred more frequently in women (14%) than in men (6%), [Chi square test (chi²) = 5.6, p = 0.02]. Patient satisfaction with the care they received, measured on a scale of 0 (not happy) to 10 (very happy) found the median score to be 10 with 76% reporting a score of 10. Out of 360 responses, 98% of women and 99% of men said that they would be willing to have a future HRA examination.

Conclusions

In this cohort, the overall pain scores were low and similar across appointment types. However, women had a higher pain score, including troublesome pain levels. Despite this, both women and men were equally satisfied with their care and were willing to have a future examination. The results of the analysis show that the procedure is acceptable to patient groups. A small number of women may need general anaesthesia for their examinations/treatment.

https://ift.tt/2KRWFQ8

Novel Thirdhand Smoke Exposure Route Identified

THURSDAY, May 10, 2018 -- Thirdhand smoke (THS), the chemical residue from cigarette smoke that attaches to anything and anyone in the vicinity of a smoke cloud, can still make its way into the air of buildings that currently have a non-smoking...

https://ift.tt/2wuzBnr

Recent Oral Antibiotics Use Tied to Higher Risk of Nephrolithiasis

THURSDAY, May 10, 2018 -- Recent use of oral antibiotics is associated with increased odds of nephrolithiasis, according to a study published online May 10 in the Journal of the American Society of Nephrology. Gregory Tasian, M.D., from Children's...

https://ift.tt/2rzm5Kw

FDA Targets Clinics Offering Unapproved Stem Cell Therapies

THURSDAY, May 10, 2018 -- The U.S. Food and Drug Administration has launched legal action to stop two stem cell clinics from providing unapproved treatments that have caused serious, long-term harm to some patients. On Wednesday, the FDA filed...

https://ift.tt/2KaCMCH

Uveal Effusion Reported After Initiation of Anti-PD-1, -PD-L1

THURSDAY, May 10, 2018 -- Patients receiving immunotherapy with antiprogrammed cell death protein-1 (anti-PD-1) and antiprogrammed cell death ligand-1 (anti-PD-L1) monoclonal antibodies may develop uveal effusion, according to a report published...

https://ift.tt/2ryBeM0

Many Oncologists Discuss, Recommend Medical Marijuana

THURSDAY, May 10, 2018 -- Many oncologists recommend medical marijuana (MM) clinically despite not feeling sufficiently knowledgeable about its utility, according to a study published online May 10 in the Journal of Clinical Oncology. Ilana M....

https://ift.tt/2wBZUYO

Does the Anatomy of the Transected Pancreatic Neck Influence Post Whipple’s Operation Pancreatic Fistula?

Abstract

Few studies correlate anatomical parameters of the transected pancreatic neck to occurrence of the dangerous complication—post Whipple's pancreaticoduodenectomy pancreatic fistula. To evaluate the correlation between anatomical details of the transected neck of the pancreas and post-operative pancreatic fistula (POPF) following Whipple's pancreaticoduodenectomy. Observational study. The study included 66 patients undergoing Whipple's pancreaticoduodenectomy with pancreaticojejunostomy at tertiary care centre between December 2009 and December 2014. Student's t test, Fisher's exact test, Pearson's chi-squared test and forward stepwise. Clinically relevant POPF (grade B and C) was noted in 12 patients. Morbidity/mortality was 30.30% and 4.54% respectively. Among the fistula v/s no fistula groups, (a) mean thickness of the pancreatic stump was 12.17 ± 1.40 mm v/s 14.94 ± 1.87 mm (P = 0.000), (b) mean width of the pancreatic stump was 24.33 ± 4.14 mm v/s 25.87 ± 4.02 mm (P = 0.238) and (c) mean pancreatic duct (PD) diameter was 2.92 ± 0.79 mm v/s 4.27 ± 1.39 mm (P = 0.001). Mean distances of PD from anterior, posterior, superior and inferior pancreatic borders in the fistula group v/s no fistula group were 6.08 ± 1.62 mm, 3.17 ± 0.72 mm, 9.92 ± 2.15 mm, and 11.42 ± 3.45 mm v/s 5.93 ± 1.71 mm, 4.83 ± 1.26 mm, 11.83 ± 2.79 mm and 9.96 ± 3.25 mm respectively. Eleven of 38 patients (28.9%) with soft pancreas developed POPF. Pancreatic duct < 3 mm diameter, < 3 mm from posterior border, < 12 mm from superior border, pancreatic neck thickness < 12 mm and soft pancreas consistency were significantly associated with POPF.

https://ift.tt/2jRBJfL

Dual suppressive effect of microRNA-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion

Purpose - Recent studies indicated that dysregulation of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC). Experimental Design- We performed in vitro functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a. Results- In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3`-untranslated region (3`-UTR) of eEF2K and FOXM1 mRNAs and suppresses its expression, leading to inhibition of TNBC cell proliferation, motility, and invasion.  Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis and inducing apoptosis. Conclusions- Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC.

https://ift.tt/2KRV2lu

Aberrant Lck signal via CD28 co-stimulation augments antigen-specific functionality and tumor control by redirected T cells with PD-1 blockade in humanized mice

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast Activation Protein (FAP)-specific CARs with different co-stimulatory domains including CD28, -CD28 (lacking lck binding moiety) or 4-1BB were established. CAR-T cells were characterized in vitroand anti-tumor efficacy was tested in vivoin a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a MPM patient. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the -CD28 CAR including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a MPM patient, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a MPM patient. Therefore, further clinical investigation of this optimized CAR is warranted.

https://ift.tt/2G4WmOw

A PDX/organoid biobank of advanced prostate cancers captures genomic and phenotypic heterogeneity for disease modeling and therapeutic screening

Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models   that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested > 20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results:All PDX models proliferated as organoids in culture. Greater than fifty percent could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously-reported conditions. Additionally, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs, was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling, was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2^-/- organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically-characterized platform to investigate mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC.

https://ift.tt/2KVpYBg

Clonal Hematopoiesis: A new layer in the liquid biopsy story in lung cancer

Cell free DNA (cfDNA) is a unique biospecimen that contains multiple sources of DNA including tumor, germline, fetal, and others. Clonal hematopoiesis, a process that leads to expansion of mutations in peripheral blood cells, is an additional source of DNA that adds a layer of complexity when interpreting results

https://ift.tt/2G517HC

GWAS by GBLUP: Single and Multimarker EMMAX and Bayes Factors, with an Example in Detection of a Major Gene for Horse Gait

Bayesian models for genomic prediction and association mapping are being increasingly used in genetics analysis of quantitative traits. Given a point estimate of variance components, the popular methods SNP-BLUP and GBLUP result in joint estimates of the effect of all markers on the analyzed trait; single and multiple marker frequentist tests (EMMAX) can be constructed from these estimates. Indeed, BLUP methods can be seen simultaneously as Bayesian or frequentist methods. So far there is no formal method to produce Bayesian statistics from GBLUP. Here we show that the Bayes Factor, a commonly admitted statistical procedure, can be computed as the ratio of two normal densities: the first, of the estimate of the marker effect over its posterior standard deviation; the second of the null hypothesis (a value of 0 over the prior standard deviation). We extend the BF to pool evidence from several markers and of several traits. A real data set that we analyze, with ours and existing methods, analyzes 630 horses genotyped for 41711 polymorphic SNPs for the trait "outcome of the qualification test" (which addresses gait, or ambling, of horses) for which a known major gene exists. In the horse data, single marker EMMAX shows a significant effect at the right place at Bonferroni level. The BF points to the same location although with low numerical values. The strength of evidence combining information from several consecutive markers increases using the BF and decreases using EMMAX, which comes from a fundamental difference in the Bayesian and frequentist schools of hypothesis testing. We conclude that our BF method complements frequentist EMMAX analyses because it provides a better pooling of evidence across markers, although its use for primary detection is unclear due to the lack of defined rejection thresholds.

https://ift.tt/2IeNAPE

Dynamic Changes in Yeast Phosphatase Families Allow for Specialization in Phosphate and Thiamine Starvation

Convergent evolution is often due to selective pressures generating a similar phenotype. We observe relatively recent duplications in a spectrum of Saccharomycetaceae yeast species resulting in multiple phosphatases that are regulated by different nutrient conditions - thiamine and phosphate starvation. This specialization is both transcriptional and at the level of phosphatase substrate specificity. In Candida glabrata, loss of the ancestral phosphatase family was compensated by the co-option of a different histidine phosphatase family with three paralogs. Using RNA-seq and functional assays, we identify one of these paralogs, CgPMU3, as a thiamine phosphatase. We further determine that the 81% identical paralog CgPMU2 does not encode thiamine phosphatase activity; however, both are capable of cleaving the phosphatase substrate, 1-napthyl-phosphate. We functionally demonstrate that members of this family evolved novel enzymatic functions for phosphate and thiamine starvation, and are regulated transcriptionally by either nutrient condition, and observe similar trends in other yeast species. This independent, parallel evolution involving two different families of histidine phosphatases suggests that there were likely similar selective pressures on multiple yeast species to recycle thiamine and phosphate. In this work, we focused on duplication and specialization, but there is also repeated loss of phosphatases, indicating that the expansion and contraction of the phosphatase family is dynamic in many Ascomycetes. The dynamic evolution of the phosphatase gene families is perhaps just one example of how gene duplication, co-option, and transcriptional and functional specialization together allow species to adapt to their environment with existing genetic resources.

https://ift.tt/2I8pWIy

Risk Factors for Umbilical Cord Prolapse at the Time of Artificial Rupture of Membranes

AJP Rep 2018; 08: e89-e94
DOI: 10.1055/s-0038-1649486

Objective The aim of the study was to examine the association between cervical exam at the time of artificial rupture of membranes (AROM) and cord prolapse. Study Design We conducted a retrospective cohort study using the data from the Consortium on Safe Labor. We included women with cephalic presentation and singleton pregnancies at ≥ 23 weeks' gestation who underwent AROM during the course of labor. Multivariable logistic regression was used to calculate the adjusted odds ratio (aOR) with 95% confidence interval (95% CI), controlling for prespecified covariates. Results Of 57,204 women who underwent AROM, cord prolapse occurred in 113 (0.2%). Compared with dilation 6 to 10 cm + station ≥ 0 at the time of AROM, <6 cm + any station and 6–10 cm + station ≤ −3 were associated with increased risks of cord prolapse (<6 cm + station ≤ −3 [aOR, 2.29; 95% CI, 1.02–5.40]; <6 cm + station −2.5 to −0.5 [aOR, 2.34; 95% CI, 1.23–4.97]; <6 cm + station ≥ 0 [aOR, 3.31; 95% CI, 1.39–8.09]; and 6–10 cm + station ≤ −3 [aOR, 5.47; 95% CI, 1.35–17.48]). Conclusion Cervical dilation < 6 cm with any station and 6 to 10 cm with station ≤ −3 were associated with a higher risk of cord prolapse.
[...]

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Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Gastric cancer: French Intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO)

This document is a summary of the French Intergroup guidelines regarding the management of gastric cancer published in October 2016, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org), updated in October 2017.

https://ift.tt/2ryyzSB

Role of HNF1β in the differential diagnosis from other germ cell tumors

Identification of the yolk sac tumor (YST) component in germ cell tumors (GCT) may prove challenging, and highly sensitive and specific immunohistochemical markers are still lacking. Preliminary data from the literature suggest that HNF1β may represent a sensitive marker of YST. The specificity of HNF1β has not been addressed in GCT. A cohort of 49 YST specimens from 45 patients was designed, occurring either as pure tumors, or as a component of a mixed GCT. Immunohistochemistry was conducted on whole tumor sections using HNF1β.

https://ift.tt/2rwWD8w

Motor unit number estimation (MUNE): where are we now?

Counting the number of motor units (MUs) in a muscle appears a deceptively simple task. Count the number of muscle fibers and count the number of motor axons supplying the muscle, then divide the former by the latter. But there's a problem. This erroneously assumes that each MU is approximately the same size. However, the innervation ratio varies between muscles (Feinstein et al., 1955). Also, type II MUs are larger than type I MUs and the proportions of these two basic MU types varies between muscles (Brooke and Engel, 1969; McComas et al., 1971).

https://ift.tt/2rzWzEN

Medline Remedy Essentials No-Rinse Cleansing Foam: Avoid Using - Multistate Outbreak of Burkholderia Cepacia Complex

[Posted 05/10/2018] AUDIENCE: Consumer, Health Professional, Patient ISSUE: CDC reports that there are 10 confirmed cases of infection caused by bacteria within the Burkholderia cepacia complex, also commonly called B. cepacia, in three states:...

https://ift.tt/2G2Sei3

PTBP1 enhances miR-101-guided AGO2 targeting to MCL1 and promotes miR-101-induced apoptosis

PTBP1 enhances miR-101-guided AGO2 targeting to MCL1 and promotes miR-101-induced apoptosis

PTBP1 enhances miR-101-guided AGO2 targeting to <i>MCL1</i> and promotes miR-101-induced apoptosis, Published online: 10 May 2018; doi:10.1038/s41419-018-0551-8

PTBP1 enhances miR-101-guided AGO2 targeting to MCL1 and promotes miR-101-induced apoptosis

https://ift.tt/2Ie4hed

Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury

Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury

Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury, Published online: 10 May 2018; doi:10.1038/s41419-018-0531-z

Hepatic steatosis associated with decreased β-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury

https://ift.tt/2jP1oWI

Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration

Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration

Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration, Published online: 10 May 2018; doi:10.1038/s41419-018-0597-7

Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration

https://ift.tt/2IcNeJB

microRNA-501-3p suppresses metastasis and progression of hepatocellular carcinoma through targeting LIN7A

microRNA-501-3p suppresses metastasis and progression of hepatocellular carcinoma through targeting LIN7A

microRNA-501-3p suppresses metastasis and progression of hepatocellular carcinoma through targeting LIN7A, Published online: 10 May 2018; doi:10.1038/s41419-018-0577-y

microRNA-501-3p suppresses metastasis and progression of hepatocellular carcinoma through targeting LIN7A

https://ift.tt/2I6PLJ1

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair, Published online: 10 May 2018; doi:10.1038/s41419-018-0575-0

Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair

https://ift.tt/2IcN84H

Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis

Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis

Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis, Published online: 10 May 2018; doi:10.1038/s41419-018-0568-z

Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis

https://ift.tt/2jLGvvg

Fructose fuels lung adenocarcinoma through GLUT5

Fructose fuels lung adenocarcinoma through GLUT5

Fructose fuels lung adenocarcinoma through GLUT5, Published online: 10 May 2018; doi:10.1038/s41419-018-0630-x

Fructose fuels lung adenocarcinoma through GLUT5

https://ift.tt/2Ifdm6F

The long noncoding RNA GAS5 negatively regulates the adipogenic differentiation of MSCs by modulating the miR-18a/CTGF axis as a ceRNA

The long noncoding RNA GAS5 negatively regulates the adipogenic differentiation of MSCs by modulating the miR-18a/CTGF axis as a ceRNA

The long noncoding RNA GAS5 negatively regulates the adipogenic differentiation of MSCs by modulating the miR-18a/CTGF axis as a ceRNA, Published online: 10 May 2018; doi:10.1038/s41419-018-0627-5

The long noncoding RNA GAS5 negatively regulates the adipogenic differentiation of MSCs by modulating the miR-18a/CTGF axis as a ceRNA

https://ift.tt/2jLjFUG

Medline Remedy Essentials No-Rinse Cleansing Foam: Avoid Using - Multistate Outbreak of Burkholderia Cepacia Complex

[Posted 05/10/2018] AUDIENCE: Consumer, Health Professional, Patient ISSUE: CDC reports that there are 10 confirmed cases of infection caused by bacteria within the Burkholderia cepacia complex, also commonly called B. cepacia, in three states:...

https://ift.tt/2G2Sei3

A case report of granulomatous amoebic encephalitis by Group 1 Acanthamoeba genotype T18 diagnosed by the combination of morphological examination and genetic analysis

The diagnosis of granulomatous amoebic encephalitis is challenging for clinicians because it is a rare and lethal disease. Previous reports have indicated that Acanthamoeba with some specific genotypes tend to ca...

https://ift.tt/2KR5hGI

Epithelioid cell histiocytoma with SQSTM1-ALK fusion: a case report

Epithelioid cell histiocytoma (ECH), which is also known as epithelioid benign fibrous histiocytoma, has been classified as a rare variant of fibrous histiocytoma (FH). However, the recent detection of ALK pro...

https://ift.tt/2G3PUHz

The Use of a Fitbit Device for Assessing Physical Activity and Sedentary Behavior in Preschoolers

To determine the accuracy of the Fitbit Flex (FF) activity monitor for assessing preschoolers' physical activity (PA) and sedentary behavior (SED) in free-living conditions.

https://ift.tt/2ryA8jf

Adherence to Polyethylene Glycol Treatment in Children with Functional Constipation Is Associated with Parental Illness Perceptions, Satisfaction with Treatment, and Perceived Treatment Convenience

To assess treatment adherence in children with functional constipation and to evaluate the association with parental beliefs about medication, illness perceptions, treatment satisfaction, and satisfaction with information about medication.

https://ift.tt/2rA8ySM

Incidence Trends and Risk Factor Variation in Severe Intraventricular Hemorrhage across a Population Based Cohort

To quantify the current burden of severe intraventricular hemorrhage (IVH), describe time trends in severe IVH, identify IVH-associated risk factors, and determine the contribution of mediating factors.

https://ift.tt/2KaORb4

Attitudes Surrounding the Management of Neonates with Severe Necrotizing Enterocolitis

To assess providers' recommendations as to comfort care versus medical and surgical management in clinical scenarios of newborns with severe bowel loss and to assess how a variety of factors influence providers' decision making.

https://ift.tt/2wtTMBU

Assessing Ethics Knowledge: Development of a Test of Ethics Knowledge in Neonatology

To develop and validate the Test of Ethics Knowledge in Neonatology (TEK-Neo) with good internal consistency reliability, item performance, and construct validity that reliably assesses interprofessional staff and trainee knowledge of neonatal ethics.

https://ift.tt/2rzNbRD

Relationships of Anxiety and Depression with Cardiovascular Health in Youth with Normal Weight to Severe Obesity

To evaluate the relationships of depression and anxiety symptoms with cardiovascular disease (CVD) risk factors and measures of vascular health in youth. Major depressive disorder and bipolar disorder are considered CVD risk factors in youth.

https://ift.tt/2KePMan

Adolescent Health, Confidentiality in Healthcare, and Communication with Parents

Ensuring the health of adolescents is an important social priority that requires the engagement of parents, healthcare providers, schools, and young people themselves. Although schools provide key information through health and sex education classes and adolescents' peers represent major influences on their health behaviors, it is also clear that healthcare providers and parents play critical roles. In this volume of The Journal, these roles are examined in studies by Gilbert et al1 and Edwards et al,2 which both offer instructive insights for a more nuanced understanding of issues long recognized as important factors in promoting adolescents' health and well-being: confidential communications in healthcare settings and parent–adolescent communication about sensitive issues such as sexual behavior.

https://ift.tt/2ry0eTs

A Modular Microfluidic Technology for Systematic Studies of Colloidal Semiconductor Nanocrystals

Detailed herein are the operation and assembly protocols of a modular microfluidic screening platform for the systematic characterization of colloidal semiconductor nanocrystal syntheses. Through fully adjustable system arrangements, highly efficient spectra collection may be carried out across 4 orders of magnitude reaction time scales within a mass transfer-controlled sampling space.

https://ift.tt/2KNe38F

Inside EMS Podcast: What it takes to work in the EMS field

Co-hosts Chris Cebollero and Kelly Grayson discuss Chris' latest project — writing a book

https://ift.tt/2G2eOY0

General practitioners providing non-urgent care in emergency department: a natural experiment

Objective

To examine whether care provided by general practitioners (GPs) to non-urgent patients in the emergency department differs significantly from care provided by usual accident and emergency (A&E) staff in terms of process outcomes and A&E clinical quality indicators.

Design

Propensity score matched cohort study.

Setting

GPs in A&E colocated within the University Hospitals Coventry and Warwickshire NHS Trust between May 2015 and March 2016.

Participants

Non-urgent attendances visits to the A&E department.

Main outcomes

Process outcomes (any investigation, any blood investigation, any radiological investigation, any intervention, admission and referrals) and A&E clinical indicators (spent 4 hours plus, left without being seen and 7-day reattendance).

Results

A total of 5426 patients seen by GPs in A&E were matched with 10 852 patients seen by emergency physicians (ratio 1:2). Compared with standard care in A&E, GPs in A&E significantly: admitted fewer patients (risk ratio (RR) 0.28, 95% CI 0.25 to 0.31), referred fewer patients to other specialists (RR 0.31, 95% CI 0.24 to 0.40), ordered fewer radiological investigations (RR 0.38, 95% CI 0.34 to 0.42), ordered fewer blood tests (0.57, 95% CI 0.52 to 0.61) and ordered fewer investigations (0.93, 95% CI 0.90 to 0.96). However, they intervened more, offered more primary care follow-up (RR 1.78, 95% CI 1.67 to 1.89) and referred more patients to outpatient and other A&E clinics (RR 2.29, 95% CI 2.10 to 2.49). Patients seen by GPs in A&E were on average less likely to spend 4 hours plus in A&E (RR 0.37, 95% CI 0.30 to 0.45) compared with standard care in A&E. There was no difference in reattendance after 7 days (RR 0.96, 95% CI 0.84 to 1.09).

Conclusion

GPs in A&E tended to manage self-reporting minor cases with fewer resources than standard care in A&E, without increasing reattendance rates.

https://ift.tt/2Ic5piq

IMPACT: Investigating the impact of Models of Practice for Allied health Care in subacuTe settings. A protocol for a quasi-experimental mixed methods study of cost effectiveness and outcomes for patients exposed to different models of allied health care

Introduction

This protocol considers three allied health staffing models across public health subacute hospitals. This quasi-experimental mixed-methods study, including qualitative process evaluation, aims to evaluate the impact of additional allied health services in subacute care, in rehabilitation and geriatric evaluation management settings, on patient, health service and societal outcomes.

Methods and analysis

This health services research will analyse outcomes of patients exposed to different allied health models of care at three health services. Each health service will have a control ward (routine care) and an intervention ward (additional allied health). This project has two parts. Part 1: a whole of site data extraction for included wards. Outcome measures will include: length of stay, rate of readmissions, discharge destinations, community referrals, patient feedback and staff perspectives. Part 2: Functional Independence Measure scores will be collected every 2–3 days for the duration of 60 patient admissions.

Data from part 1 will be analysed by linear regression analysis for continuous outcomes using patient-level data and logistic regression analysis for binary outcomes. Qualitative data will be analysed using a deductive thematic approach. For part 2, a linear mixed model analysis will be conducted using therapy service delivery and days since admission to subacute care as fixed factors in the model and individual participant as a random factor. Graphical analysis will be used to examine the growth curve of the model and transformations. The days since admission factor will be used to examine non-linear growth trajectories to determine if they lead to better model fit.

Ethics and dissemination

Findings will be disseminated through local reports and to the Department of Health and Human Services Victoria. Results will be presented at conferences and submitted to peer-reviewed journals. The Monash Health Human Research Ethics committee approved this multisite research (HREC/17/MonH/144 and HREC/17/MonH/547).

https://ift.tt/2jQSnw1

Validation of the health assets index in the Australian inpatient setting: a multicentre prospective cohort protocol study

Introduction

It is well known that frail older adults are at increased risk for mortality and functional decline on admission to hospital. Systematic review demonstrates that health assets are associated with improved outcomes for hospitalised older adults. The health assets index (HAI) has been developed to measure health assets in the hospital setting. A protocol has been developed to determine the predictive validity of the HAI for frail older adults.

Methods and analysis

The HAI was developed based on a systematic review and secondary analysis of the interRAI-Acute Care (interRAI-AC) dataset. A pilot study was undertaken to refine the tool.

The validation study will be a multicentre prospective cohort. Participants will be adults aged 70 years and older with an unplanned admission to hospital. Frailty, illness severity and demographic data will also be recorded. The primary outcomes are mortality at 28 days postdischarge and functional decline at the time of discharge from hospital. The primary hypothesis is that a higher score on the HAI will mitigate the effects of frailty for hospitalised older adults. The secondary outcomes to be recorded are length of stay, readmission at 28 days and functional status at 28 days postdischarge. The correlation between HAI and frailty will be explored. A multivariate analysis will be undertaken to determine the relationship between the HAI and the outcomes of interest.

Ethics and dissemination

Ethical approval has been obtained from Austin Health Human High Risk Ethics Committee. The results will be disseminated in peer-reviewed journals and research conferences. This study will determine whether the HAI has predictive validity for mortality and functional decline for hospitalised, frail older adults.

https://ift.tt/2IcMfJo

Physical activity among HIV-positive patients receiving antiretroviral therapy in Hanoi and Nam Dinh, Vietnam: a cross-sectional study

Objectives

Antiretroviral therapy (ART) has facilitated the transition of HIV infection into a chronic disease, where adherence to medications is required along with keeping a healthy lifestyle. Therefore, an increase in physical activity has been recommended for patients with HIV in order to maintain their health status. This study looked to determine the physical activity level and its associated factors among patients with HIV receiving ART treatment.

Settings

Eight outpatient clinic sites across different levels of the health systems in both rural and urban settings in Hanoi and Nam Dinh, Vietnam.

Study design and participants

A cross-sectional study was performed among 1133 patients with HIV receiving ART treatment from January to August 2013.

Primary and secondary outcome measures

Physical activity level was measured using the International Physical Activity Questionnaire (IPAQ). Socioeconomic, health-related quality of life, ART adherence and ART-related characteristics were self-reported.

Results

16% of participants were inactive, and 68% were reported active via health-enhancing physical activity. Rural participants reported a higher level of physical activity compared with urban participants. Participants having a longer duration of ART were less likely to be physically active. Participants who were female and self-employed, who had higher CD4 cell count, higherEuroQol - 5 dimensions - 5levels (EQ-5D-5L) index/EQ-Visual Analogue Scale, and shared their health status with their peers were more likely to have a higher IPAQ score or be physically active. A lower IPAQ score was associated with participants living in urban areas and being at the symptomatic stage. Participants having poor adherence and longer duration of ART were more likely to be physically inactive.

Conclusion

The majority of participants who received ART were physically active. There is a need for interventions to promote physical activity among patients with HIV in urban areas and in the later ART treatment phases. Other potential interventions to increase the level of physical activity include peer support and job guidance.

https://ift.tt/2jOirIp

Parents experience when their child has chronic abdominal pain: a qualitative study in Norway

Objective

Functional abdominal pain occurs frequently in children and adolescents. It is an exclusion diagnosis; somatic diseases have to be ruled out. However little explanation is given for why the child is experiencing pain. The aim was to explore the experiences of parents of children with chronic abdominal pain discharged from hospital without a somatic explanation.

Design

The study has a qualitative design. The open questions concerned pain experiences and management. Interviews were conducted at the hospital, at the parents' workplace or in their homes, audiotape recorded and transcribed. A descriptive content analysis was used to analyse the transcribed text.

Setting

Parents of children referred from general practice located in urban and rural areas in two municipals in Norway.

Participants

Fourteen parents of children with functional abdominal pain aged 5–15 years.

Results

Fourteen parents participated. Some explained that their child's disability glued the parents together on a common project to help the child. Other parents could tell that siblings got less attention and complained about too much fuss during pain. Parents wished for diagnosis that could be treated efficiently. Some were still anxious that an undetected condition triggered pain. They prompted their doctor to do further examinations. However, some parents knew that social factors could inflict pain and were concerned that their child was unable to distinguish sensations like anxiety and 'butterfly' tensions from physical pain. The parents and children needed professional guidance on how to manage the pain .

Conclusion

The doctor's consultation should not end at the diagnosis of functional abdominal pain. Doctors may help these families further by focusing on pain management strategies.

https://ift.tt/2I8JMiW

The China Patient-centered Evaluative Assessment of Cardiac Events (China PEACE) retrospective heart failure study design

Introduction

Heart failure (HF) is a leading cause of hospitalisation in China, which is experiencing a rapid increase in cardiovascular disease prevalence. Yet, little is known about current burden of disease, quality of care and treatment outcomes of HF in China. The objective of this paper is to describe the study methodology, data collection and abstraction, and progress to date of the China Patient-centered Evaluative Assessment of Cardiac Events 5 Retrospective Heart Failure Study (China PEACE 5r-HF).

Methods and analysis

The China PEACE 5r-HF Study will examine a nationally representative sample of more than 10 000 patient records hospitalised for HF in 2015 in China. The study is a retrospective cohort study. Patients have been selected using a two-stage sampling design stratified by economic–geographical regions. We will collect patient characteristics, diagnostic testing, treatments and in-hospital outcomes, including death and complications, and charges of hospitalisation. Data quality will be monitored by a central coordinating centre and will address case ascertainment, data abstraction and data management. As of October 2017, we have sampled 15 538 medical records from 189 hospitals, and have received 15 057 (96.9%) of these for data collection, and completed data abstraction and quality control on 7971.

Ethics and dissemination

The Central Ethics Committee at the Chinese National Center for Cardiovascular Diseases approved the study. All collaborating hospitals accepted central ethics committee approval with the exception of 15 hospitals, which obtained local approval by internal ethics committees. Findings will be disseminated in future peer-reviewed papers and will serve as a foundation for improving the care for HF in China.

Trial registration number

NCT02877914.

https://ift.tt/2I3nTpc

Prognosis of oesophageal adenocarcinoma and squamous cell carcinoma following surgery and no surgery in a nationwide Swedish cohort study

Objectives

To assess the recent prognostic trends in oesophageal adenocarcinoma and oesophageal squamous cell carcinoma undergoing resectional surgery and no such surgery. Additionally, risk factors for death were assessed in each of these patient groups.

Design

Cohort study.

Setting

A population-based, nationwide study in Sweden.

Participants

All patients diagnosed with oesophageal adenocarcinoma and oesophageal squamous cell carcinoma in Sweden from 1 January 1990 to 31 December 2013, with follow-up until 14 May 2017.

Outcome measures

Observed and relative (to the background population) 1-year , 3-year and 5-year survivals were analysed using life table method. Multivariable Cox regression provided HR with 95% CI for risk factors of death.

Results

Among 3794 patients with oesophageal adenocarcinoma and 4631 with oesophageal squamous cell carcinoma, 82% and 63% were men, respectively. From 1990–1994 to 2010–2013, the relative 5-year survival increased from 12% to 15% for oesophageal adenocarcinoma and from 9% to 12% for oesophageal squamous cell carcinoma. The corresponding survival following surgery increased from 27% to 45% in oesophageal adenocarcinoma and from 24% to 43% in oesophageal squamous cell carcinoma. In patients not undergoing surgery, the survival increased from 3% to 4% for oesophageal adenocarcinoma and from 3% to 6% for oesophageal squamous cell carcinoma. Women with oesophageal squamous cell carcinoma had better prognosis than men both following surgery (HR 0.71, 95% CI 0.61 to 0.83) and no surgery (HR 0.86, 95% CI 0.81 to 0.93).

Conclusions

The prognosis has improved over calendar time both in oesophageal adenocarcinoma and oesophageal squamous cell carcinoma in Sweden that did and did not undergo surgery. Women appear to have better prognosis in oesophageal squamous cell carcinoma than men, independent of treatment.

https://ift.tt/2Ico1yM

Association of ambient particulate matter with heart failure incidence and all-cause readmissions in Tasmania: an observational study

Objectives

We sought to investigate the relationship between air quality and heart failure (HF) incidence and rehospitalisation to elucidate whether there is a threshold in this relationship and whether this relationship differs for HF incidence and rehospitalisation.

Methods

This retrospective observational study was performed in an Australian state-wide setting, where air pollution is mainly associated with wood-burning for winter heating. Data included all 1246 patients with a first-ever HF hospitalisation and their 3011 subsequent all-cause readmissions during 2009–2012. Daily particulate matter <2.5 µm (PM_2.5), temperature, relative humidity and influenza infection were recorded. Poisson regression was used, with adjustment for time trend, public and school holiday and day of week.

Results

Tasmania has excellent air quality (median PM_2.5=2.9 µg/m³ (IQR: 1.8–6.0)). Greater HF incidences and readmissions occurred in winter than in other seasons (p<0.001). PM_2.5 was detrimentally associated with HF incidence (risk ratio (RR)=1.29 (1.15–1.42)) and weakly so with readmission (RR=1.07 (1.02–1.17)), with 1 day time lag. In multivariable analyses, PM_2.5 significantly predicted HF incidence (RR=1.12 (1.01–1.24)) but not readmission (RR=0.96 (0.89–1.04)). HF incidence was similarly low when PM <4 µg/m³ and only started to rise when PM_2.5≥4 µg/m³. Stratified analyses showed that PM_2.5 was associated with readmissions among patients not taking beta-blockers but not among those taking beta-blockers (p_interaction=0.011).

Conclusions

PM_2.5 predicted HF incidence, independent of other environmental factors. A possible threshold of PM_2.5=4 µg/m³ is far below the daily Australian national standard of 25 µg/m³. Our data suggest that beta-blockers might play a role in preventing adverse association between air pollution and patients with HF.

https://ift.tt/2I3nMdg

Androgen receptor expression in endometrial carcinoma and its correlation with clinicopathologic features

Recent evidence suggests a role of androgen receptor expression as a prognostic and therapeutic biomarker in endometrial carcinoma, therefore in the present study we aimed to evaluate the frequency of androgen...

https://ift.tt/2IbKdZY

Characterization of the first complete genome sequence of an Impatiens necrotic spot orthotospovirus isolate from the United States and worldwide phylogenetic analyses of INSV isolates

Impatiens necrotic spot orthotospovirus (INSV) can impact economically important ornamental plants and vegetables worldwide. Characterization studies on INSV are limited. For most INSV isolates, there are no comp...

https://ift.tt/2I69ysn

Incidence and predictors of loss to follow up among HIV-infected adults at Pawi General Hospital, northwest Ethiopia: competing risk regression model

This study was aimed at assessing the incidence of lost-to-follow-up and its predictors among HIV-positive adults after initiation into antiretroviral therapy at Pawi General Hospital, northwest Ethiopia.

https://ift.tt/2IaTAJr

Finding the Right Balance

When I was a young resident in the 1990s, surgical patients received so much intravenous saline on the day of surgery that they often gained 4 to 6 kg, and by postoperative day 2 or 3, pulmonary congestion and cardiac arrhythmias were commonplace. That was the basis for a 2003 trial of restrictive…

https://ift.tt/2wxX7Qy

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery

Each year, at least 310 million patients undergo major surgery worldwide, procedures that involve the administration of intravenous fluids. Clinicians have traditionally administered generous amounts of intravenous fluids perioperatively to correct for preoperative fasting and other fluid deficits,…

https://ift.tt/2wvAyvK

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion

Here, we present homogeneous time resolved FRET (HTRF) as an efficient method for rapid detection of insulin secreted from cells.

https://ift.tt/2Iauom8

Gestational Diabetes May Indicate Future Subclinical Renal Issues

THURSDAY, May 10, 2018 -- Gestational diabetes mellitus (GDM) may be an early indicator of subsequent subclinical renal dysfunction, according to a study published online May 4 in Diabetes Care. Shristi Rawal, Ph.D., from the National Institutes of...

https://ift.tt/2I9TT73

Ob-Gyns Should Play Role in Reducing CVD Risk for Women

THURSDAY, May 10, 2018 -- Obstetrician-gynecologists (ob-gyns) can help promote risk identification and reduction of cardiovascular disease among women at well-women visits, according to an American Heart Association/American College of Obstetrics...

https://ift.tt/2jP1i1l

Much International Consensus Regarding Employment in Autism

THURSDAY, May 10, 2018 -- There is international consensus as to the importance of work experience and vocational training for helping individuals with autism spectrum disorder (ASD) obtain employment, according to a study presented at the annual...

https://ift.tt/2Ic0RbQ

Pivotal Response Treatment Plus NAO Robot Effective in Autism

THURSDAY, May 10, 2018 -- Parent-mediated pivotal response treatment (PRT) using a humanoid (NAO) robot may be effective for reducing autism spectrum disorder (ASD)-related symptoms in young children, according to a study presented at the annual...

https://ift.tt/2jNrTvF

Restricting Fluids Post Abdominal Surgery Doesn't Up Survival

THURSDAY, May 10, 2018 -- A restrictive fluid regimen is not associated with increased disability-free survival for patients at increased risk of complications during major abdominal surgery, but is associated with increased acute kidney injury,...

https://ift.tt/2IcHuzw

Extended Range of Vision Lens Found Superior to Monofocal

THURSDAY, May 10, 2018 -- Extended range of vision (ERV) intraocular lens (IOL) targeted to achieve micro-monovision shows superior range of visual acuity and independence from glasses compared to the monofocal IOL targeted to achieve emmetropia,...

https://ift.tt/2jP14av

Low-Dose Vaginal Estradiol Improves Menopause-Linked QOL

THURSDAY, May 10, 2018 -- For menopausal women with moderate-severe vulvovaginal symptoms, treatment with low-dose vaginal estradiol is associated with improved menopause-related quality of life, according to a study published online May 7 in...

https://ift.tt/2IeLwHH

Nodal Metastasis Risk Up When Cancer Is Directly on the Lip

THURSDAY, May 10, 2018 -- The risk of nodal metastasis is five-fold greater for skin cancer on the vermilion lip versus the cutaneous lip, according to a study published online May 2 in JAMA Dermatology. David M. Wang, from Case Western Reserve...

https://ift.tt/2jP0WYz

Age of First Football Tackles Tied to Neuro Symptom Onset

THURSDAY, May 10, 2018 -- Younger age of exposure to tackle football predicts earlier neurobehavioral symptom onset among players with chronic traumatic encephalopathy (CTE), according to a study published online April 30 in the Annals of...

https://ift.tt/2Ic6c2I

Vertebroplasty Does Not Up Pain Relief in Osteoporotic Fracture

THURSDAY, May 10, 2018 -- For patients with acute osteoporotic vertebral compression fractures, percutaneous vertebroplasty does not result in significantly greater pain relief than a sham procedure at 12 months, according to a study published...

https://ift.tt/2I8fili

Mycotic aneurysm caused by Edwardsiella tarda successfully treated with stenting and suppressive antibiotic therapy: a case report and systematic review

Mycotic aneurysm is an uncommon disease which could be fatal without appropriate treatment. Although standard therapy for mycotic aneurysms consists of resection of the infected aorta and in situ graft replace...

https://ift.tt/2wu05FM

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery

Each year, at least 310 million patients undergo major surgery worldwide, procedures that involve the administration of intravenous fluids. Clinicians have traditionally administered generous amounts of intravenous fluids perioperatively to correct for preoperative fasting and other fluid deficits,…

https://ift.tt/2wvAyvK

The 2017 Nobel Peace Prize and the Doomsday Clock — The End of Nuclear Weapons or the End of Us?

The awarding of the 2017 Nobel Peace Prize to the International Campaign to Abolish Nuclear Weapons (ICAN) may mark a turning point in efforts to ensure that humanity survives the nuclear-weapons era. The urgency of ICAN's work was recently highlighted when the Bulletin of the Atomic Scientists…

https://ift.tt/2Iefyej

Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs

Toeprinting aims to measure the ability of in vitro transcribed RNA to form translation initiation complexes with ribosomes under a variety of conditions. This protocol describes a method for toeprinting mammalian RNA and can be used to study both cap-dependent and IRES-driven translation.

https://ift.tt/2rxWkKs

Patient and provider perspectives on adherence to and care coordination of lynch syndrome surveillance recommendations: findings from qualitative interviews

Abstract

Background

Patients with a genetic variant associated with Lynch syndrome (LS) are recommended to undergo frequent and repeated cancer surveillance activities to minimize cancer-related morbidity and mortality. Little is known about how patients and primary care providers (PCPs) track and manage these recommendations. We conducted a small exploratory study of patient and PCP experiences with recommended LS surveillance activities and communication with family members in an integrated health care system.

Methods

We used in-depth interviews with patients and providers to understand how surveillance is coordinated and monitored following confirmation of LS. We recruited patients with a range of ages/gender, and providers with at least at least one patient with a molecular diagnosis of LS. All interviews were recorded, transcribed, and content analyzed by a trained qualitative methodologist.

Results

Twenty-two interviews were completed with 12 patients and 10 providers. Most patients (10) had detailed knowledge of surveillance recommendations, but were less sure of time intervals. While all patients reported receiving initial education about their surveillance recommendations from a genetic counselor, seven did not follow-up with a genetic counselor in subsequent years. A third of patients described taking sole responsibility for managing their LS surveillance care. Lack of routine communication from the health system (e.g., prompts for surveillance activities), and provider engagement were surveillance barriers. PCPs were generally aware of LS, but had limited familiarity with surveillance recommendations. Most PCPs (7) viewed LS as rare and relied on patient and specialist expertise and support. Providers typically had 1 patient with LS in a panel of 1800 patients overall. Providers felt strongly that management of LS should be coordinated by a dedicated team of specialists. Most patients (92%) had at least one family member that sought LS testing, and common barriers for family members included lack of insurance, affordability, and fear of result.

Conclusion

The maximal benefits of screening for confirmation of LS will only be realized with adherence to recommended preventive care. Important factors to ensure patients receive recommended LS care include a comprehensive and coordinated monitoring program that includes reminder prompts, and increased PCP education of LS and associated surveillance recommendations.

https://ift.tt/2jNjZT1

Synthesis of Multi-walled Carbon Nanotubes Modified with Silver Nanoparticles and Evaluation of Their Antibacterial Activities and Cytotoxic Properties

In this study, antimicrobial nanomaterials were synthesized by acidic oxidation of multiwalled carbon nanotubes and subsequent reductive deposition of silver nanoparticles. Antimicrobial activity and cytotoxicity tests were performed with the as-prepared nanomaterials.

https://ift.tt/2rzftLc

R-spondin3 is associated with basal-progenitor behavior in normal and tumor mammary cells

R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo. Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among breast cancer patients. Thus we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers.

https://ift.tt/2I8s674

The microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different CRC cell lines and recently established primary cultures enriched in colon cancer stem cells (CSCs) - also known as tumor-initiating cells (TICs) - to identify genes and microRNAs (miRNAs) with regulatory functions in CRC progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, transforming growth factor beta (TGF-β) signaling activity, and reduced expression of the miR-371~373 cluster compared to non-metastatic cultures. TGF-β receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371~373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371~373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor-initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371~373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371~373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371~373 and ID1. Altogether, our results establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.

https://ift.tt/2I6webW

slan+ monocytes and macrophages mediate CD20-dependent B cell lymphoma elimination via ADCC and ADCP

Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extra-nodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in DLBCL patients that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient Rituximab (RTX)-mediated antibody dependent cellular cytotoxicity (ADCC), almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression and became very efficient in RTX-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient RTX-mediated ADCP, however using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in DLBCL patients.

https://ift.tt/2IavluV

TRAF1 is critical for regulating the BRAF/MEK/ERK pathway in non-small cell lung carcinogenesis

Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) is a unique TRAF protein that can interact directly or indirectly with multiple TNFR family members, regulatory proteins, kinases, and adaptors that contribute to its diverse functions in specific tissues. However, the role of TRAF1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we report that TRAF1 is overexpressed in human lung cancer cells and tissues. TRAF1 expression level inversely correlated with patient survival probability. Loss of TRAF1 decelerated tumor invasion in a urethane-induced lung carcinogenesis mouse model. Furthermore, TRAF1 expression affected TRAF2-mediated BRAF Lys48-linked ubiquitination, which was followed by the inhibition of growth and differentiation, and the induction of death in lung cancer cells. Overall, our work suggests that TRAF1 plays a novel role in the regulation of the BRAF/MEK/ERK signaling pathway in NSCLC and offers a candidate molecular target for lung cancer prevention and therapy.

https://ift.tt/2jN9yij

miRNA-590-3p promotes ovarian cancer growth and metastasis via a novel FOXA2-versican pathway

MicroRNAs (miRNAs) play important roles in gene regulation, and their dysregulation is associated with many diseases including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared to low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in EOC patients than in subjects with benign gynecological disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion. In vivo studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3' UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, while knockout of FOXA2 increased, VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2-VCAN pathway.

https://ift.tt/2Iez1eQ

Blood hyperviscosity identification with reflective spectroscopy of tongue tip based on principal component analysis combining artificial neural network

With spectral methods, noninvasive determination of blood hyperviscosity in vivo is very potential and meaningful in clinical diagnosis. In this study, 67 male subjects (41 health, and 26 hyperviscosity accord...

https://ift.tt/2rxtM3A

Differentiation of neuropsychological features between posterior cortical atrophy and early onset Alzheimer’s disease

Posterior cortical atrophy (PCA) is a group of clinical syndromes characterized by visuospatial and visuoperceptual impairment, with memory relatively preserved. Although PCA is pathologically almost identical...

https://ift.tt/2jOwDBg

Axonal chronic injury in treatment-naïve HIV+ adults with asymptomatic neurocognitive impairment and its relationship with clinical variables and cognitive status

HIV is a neurotropic virus, and it can bring about neurodegeneration and may even result in cognitive impairments. The precise mechanism of HIV-associated white matter (WM) injury is unknown. The effects of mu...

https://ift.tt/2IbvzBV

In vitro evaluation of the synergistic antioxidant and anti-inflammatory activities of the combined extracts from Malaysian Ganoderma lucidum and Egyptian Chlorella vulgaris

Since oxidative stress and inflammation are two linked factors in the pathogenesis of several human diseases. Thus identification of effective treatment is of great importance. Edible mushroom and microalgae a...

https://ift.tt/2IafgoQ

FDA Approves Nivolumab and Ipilimumab Combination for Advanced Kidney Cancer

FDA has approved the combination of two immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), as an initial treatment for some patients with advanced kidney cancer. Learn how this approval will affect patient care.

https://ift.tt/2KPIxXG

Mother-to-child transmission of HIV infection and its associated factors in Ethiopia: a systematic review and meta-analysis

Mother-to-child transmission (MTCT) is the main mode of HIV transmission in children under 15 years old. This problem is significant in the Sub-Saharan African countries, where more than 80% of children living...

https://ift.tt/2KduJVF

Correction to: Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

In the original publication of the article, there is an error in one of the citations in the Discussion section.

https://ift.tt/2rA5Onx

The Dantastic Mr Tox & Howard Podcast 4 – Foraging For Sex Organs

Join Dan (@drusyniak) & Howard (@heshiegreshie) as they welcome Dr. Bryan Judge to discuss the problems with the sex organs of the world's largest organism. Also, Bryan shares his very special recipe for "sun tea". https://ift.tt/2IuvL2w   Thanks as always to @shelovj and Julia Helene of @prettysimpleduo. Comments, questions, suggestions, mushroom recipes? – @dantastictox. Subscribe to listen […]

EMCrit Project by Tox & Hound.

https://ift.tt/2wrAWM0

Predicting multi-level drug response with gene expression profile in multiple myeloma using hierarchical ordinal regression

Abstract

Background

Multiple myeloma (MM), like other cancers, is caused by the accumulation of genetic abnormalities. Heterogeneity exists in the patients' response to treatments, for example, bortezomib. This urges efforts to identify biomarkers from numerous molecular features and build predictive models for identifying patients that can benefit from a certain treatment scheme. However, previous studies treated the multi-level ordinal drug response as a binary response where only responsive and non-responsive groups are considered.

Methods

It is desirable to directly analyze the multi-level drug response, rather than combining the response to two groups. In this study, we present a novel method to identify significantly associated biomarkers and then develop ordinal genomic classifier using the hierarchical ordinal logistic model. The proposed hierarchical ordinal logistic model employs the heavy-tailed Cauchy prior on the coefficients and is fitted by an efficient quasi-Newton algorithm.

Results

We apply our hierarchical ordinal regression approach to analyze two publicly available datasets for MM with five-level drug response and numerous gene expression measures. Our results show that our method is able to identify genes associated with the multi-level drug response and to generate powerful predictive models for predicting the multi-level response.

Conclusions

The proposed method allows us to jointly fit numerous correlated predictors and thus build efficient models for predicting the multi-level drug response. The predictive model for the multi-level drug response can be more informative than the previous approaches. Thus, the proposed approach provides a powerful tool for predicting multi-level drug response and has important impact on cancer studies.

https://ift.tt/2wuL3jb

The search for a melanoma-tailored chemotherapy in the new era of personalized therapy: a phase II study of chemo-modulating temozolomide followed by fotemustine and a cooperative study of GOIM (Gruppo Oncologico Italia Meridionale)

Abstract

Background

It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6–11 months. Therefore, a need for other therapeutic options is still very much apparent.

We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients.

Methods

A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21–81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m² on days 1 and 2 and FM iv 100 mg/m² on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients.

Results

We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status.

Conclusion

This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed.

Trial registration

EUDRACT 2009–016487-36l; date of registration 23 June 2010.

https://ift.tt/2rtRHBd

VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma

Abstract

Background

Vascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant.

Methods

We assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients' clinical outcome.

Results

In athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively).

Conclusions

Quantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.

https://ift.tt/2wpME9I

Inactivation of the tight junction gene CLDN11 by aberrant hypermethylation modulates tubulins polymerization and promotes cell migration in nasopharyngeal carcinoma

Abstract

Background

Aberrant hypermethylation of cellular genes is a common phenomenon to inactivate genes and promote tumorigenesis in nasopharyngeal carcinoma (NPC).

Methods

Methyl binding domain (MBD)-ChIP sequencing of NPC cells, microarray data of NPC biopsies and gene ontology analysis were conducted to identify a potential tumor suppressor gene CLDN11 that was both hypermethylated and downregulated in NPC. Bisulfite sequencing, qRT-PCR, immunohistochemistry staining of the NPC clinical samples and addition of methylation inhibitor, 5'azacytidine, in NPC cells were performed to verify the correlation between DNA hypermethylation and expression of CLDN11. Promoter reporter and EMSA assays were used to dissect the DNA region responsible for transcription activator binding and to confirm whether DNA methylation could affect activator's binding, respectively. CLDN11 was transiently overexpressed in NPC cells followed by cell proliferation, migration, invasion assays to characterize its biological roles. Co-immunoprecipitation experiments and proteomic approach were carried out to identify novel interacting protein(s) and the binding domain of CLDN11. Anti-tumor activity of the CLDN11 was elucidated by in vitro functional assay.

Results

A tight junction gene, CLDN11, was identified as differentially hypermethylated gene in NPC. High methylation percentage of CLDN11 promoter in paired NPC clinical samples was correlated with low mRNA expression level. Immunohistochemistry staining of NPC paired samples tissue array demonstrated that CLDN11 protein expression was relatively low in NPC tumors. Transcription activator GATA1 bound to CLDN11 promoter region − 62 to − 53 and its DNA binding activity was inhibited by DNA methylation. Re-expression of CLDN11 reduced cell migration and invasion abilities in NPC cells. By co-immunoprecipitation and liquid chromatography-tandem mass spectrometry LC-MS/MS, tubulin alpha-1b (TUBA1B) and beta-3 (TUBB3), were identified as the novel CLDN11-interacting proteins. CLDN11 interacted with these two tubulins through its intracellular loop and C-terminus. Furthermore, these domains were required for CLDN11-mediated cell migration inhibition. Treatment with a tubulin polymerization inhibitor, nocodazole, blocked NPC cell migration.

Conclusions

CLDN11 is a hypermethylated and downregulated gene in NPC. Through interacting with microtubules TUBA1B and TUBB3, CLDN11 blocks the polymerization of tubulins and cell migration activity. Thus, CLDN11 functions as a potential tumor suppressor gene and silencing of CLDN11 by DNA hypermethylation promotes NPC progression.

https://ift.tt/2KbhyVu

Gadolinium-based contrast agents induce gadolinium deposits in cerebral vessel walls, while the neuropil is not affected: an autopsy study

Abstract

Recent studies showed gadolinium depositions following serial administrations of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging examinations in various parts of the brain with the dentate nucleus (DN) being most affected. Even though no clinical correlates of the deposits are known yet, an intensive debate developed if this might be harmful. The aim of the current study was to specify the gadolinium distribution in brain tissue of patients who received serial injections of GBCAs in the low-µm range and to explore any potential pathological tissue changes caused by gadolinium deposits. Thirteen autopsy cases—eight receiving GBCA administrations, five serving as controls—were identified and analyzed. For all patients, total gadolinium quantification after acidic digestion by means of inductively coupled plasma-mass spectrometry (ICP-MS) was performed. Six cases were utilized for the spatially resolved quantification of gadolinium within the cerebellum and the basal ganglia by means of high-resolution laser ablation (LA)-ICP-MS. Histopathological and immunohistochemical examinations were performed to determine tissue reactions. LA-ICP-MS revealed gadolinium depositions in the walls of small blood vessels of the DN in all GBCA exposed patients, while no gadolinium was found in the control group. Additionally, the detection of phosphorus and metals like copper, zinc and iron provides evidence that transmetalation reactions might have occurred. No significant pathological changes of the brain tissue in the vicinity of the DN with respect to micro-/astrogliosis and neuronal loss were found in any of the patients. This notably holds true even for a patient who died from nephrogenic systemic fibrosis exhibiting extremely high gadolinium concentrations within the DN. The findings show that gadolinium depositions in the brain are restricted to blood vessel walls, while the neuropil is spared and apparent cellular reactions are absent.

https://ift.tt/2rw2JWI

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project

Abstract

Background

Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time.

Methods

BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease.

The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy.

Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31.

Results

After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain.

Conclusions

In this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

https://ift.tt/2jKtimG

Single-Cell Transcriptomics Meets Lineage Tracing

In this Review, Kester and van Oudenaarden discuss transcriptome-based lineage trajectory prediction algorithms, single-cell genetic lineage tracing, and the promising combination of these techniques for stem cell and cancer research.

https://ift.tt/2I83Y4u

A Linc1405/Eomes Complex Promotes Cardiac Mesoderm Specification and Cardiogenesis

Kang and colleagues identify linc1405 as a crucial regulator of cardiac differentiation via its interaction with Eomes. Linc1405 mediates an Eomes/WDR5/GCN5 regulatory complex at the Mesp1 enhancer, which coordinates Mesp1 expression and cardiac specification. They also show that linc1405 depletion results in impaired heart development and function in vivo.

https://ift.tt/2I4iOgx

Membrane Potential Distinctly Modulates Mobility and Signaling of IL-2 and -15 Receptors in T Cells

The high electric field across the plasma membrane might influence the conformation and behavior of transmembrane proteins that have uneven charge distributions in or near their transmembrane regions. Membrane depolarization of T cells occurs in the tumor microenvironment and in inflamed tissues because of K+ release from necrotic cells and hypoxia affecting the expression of K+ channels. However, little attention has been given to the effect of membrane potential (MP) changes on membrane receptor function.

https://ift.tt/2IbgkJd

Assembly Kinetics of Vimentin Tetramers to Unit-Length Filaments: A Stopped-Flow Study

Intermediate filaments (IFs) are principal components of the cytoskeleton, a dynamic integrated system of structural proteins that provides the functional architecture of metazoan cells. They are major contributors to the elasticity of cells and tissues due to their high mechanical stability and intrinsic flexibility. The basic building block for the assembly of IFs is a rod-like, 60-nm-long tetrameric complex made from two antiparallel, half-staggered coiled coils. In low ionic strength, tetramers form stable complexes that rapidly assemble into filaments upon raising the ionic strength.

https://ift.tt/2I4kzKy

Delayed Cerebral Injury in Adults With Bacterial Meningitis: A Novel Complication of Adjunctive Steroids?

Objectives: To report the prevalence of delayed cerebral injury in adults with bacterial meningitis and explore its association with adjunctive steroids. Design: Retrospective analysis of adults with bacterial meningitis between 2005 and 2016. Setting: Ten hospitals in the Greater Houston area. Patients: Consecutive subjects with culture proven community-acquired bacterial meningitis. Intervention: Subjects were categorized as receiving or not adjunctive steroids within 4 hours. Measurements and Main Results: A total of 120 patients were identified who were admitted with community-acquired bacterial meningitis. Delayed cerebral injury was seen in five of 120 patients (4.1%); all five patients had fever and abnormal neurologic examinations. Adjunctive steroids within 4 hours were more likely given to those with delayed cerebral injury (5/5,100% vs 43/115, 37.5%; p = 0.01). Of the patients who developed delayed cerebral injury, three had Streptococcus pneumoniae, one had methicillin-resistant Staphylococcus aureus, and one had Listeria monocytogenes isolated. We observed an adverse clinical outcome as defined by the Glasgow Outcome Scale in four of the five patients (80%). Conclusions: Delayed cerebral injury occurred in 4.1% of adults with bacterial meningitis, and it was associated with the use of adjunctive steroids. Future studies should explore the etiology and prevention of this devastating complication. Drs. Gallegos, Nigo, and Tobowlosky screened the patients and did the data collection. Dr. Gallegos created the first draft of the article. Dr. Hasbun designed the study. Dr. Hasbun participated in the data interpretation and edited the article. Dr. Hasbun wrote the final draft of the article and made all the changes suggested by the coauthors. Supported, in part, by Grant A Starr Foundation. Dr. Hasbun is a consultant for bioMérieux and a speaker for Pfizer, Merck, Medicines Company, and BioFire. Dr. Hasbun received funding from BioFire Diagnostics, Biomeriaux, and Merck. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Rodrigo.Hasbun@uth.tmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2rAHEt4

Lingual Tonsillectomy Likely does not Improve Outcomes for Squamous Cell Carcinoma of the Head and Neck From an Unknown Primary Site

Objective: Patients with mucosal squamous cell carcinoma (SCC) of the head and neck almost always have a primary site in the base of tongue or tonsillar fossa. Lingual tonsillectomy has recently been advocated as part of the diagnostic evaluation as opposed to directed biopsies of the base of tongue and thought to possibly result in an increased likelihood or cure. The purpose of this project is to determine whether this is probable. Materials and Methods: We reviewed the medical records of patients treated with primary radiotherapy (RT) between January 1983 and March 2013. The outcomes were compared following RT in consecutively treated patients with either T1-2 base of tongue or unknown primary (cancer of unknown primary) SCC with predominantly level 2 adenopathy. Results: At 10 years, there were no clinically significant differences in the 2 groups, in local control, regional control, freedom from distant metastases, disease-specific, or cause-specific survival. Overall survival at 10 years was improved with T1-2 base of tongue cancers but not for those with T0 N3 disease. The reasons for this are unclear. Conclusions: Tongue base biopsy (or lingual tonsillectomy) likely increases the probability of identifying an unknown primary in the base of tongue, but it does not improve outcome following RT for patients with cancer of unknown primary SCC with predominantly level 2 adenopathy. The authors declare no conflicts of interest. Reprints: William M. Mendenhall, MD, 2000 SW Archer Rd, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: mendwm@shands.ufl.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2KS3b9B

In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide

Abstract

Glioblastoma is an aggressive brain cancer that is very difficult to treat. Clinically, it is important to be able to distinguish aggressive from non-aggressive brain tumors. Previous studies have shown that some drugs can induce a rapid change in intracellular pH that could help to identify aggressive cancer. The sodium proton exchanger (NHE1) plays a significant role in maintaining pH balance in the tumor microenvironment. Cariporide is a sodium proton exchange inhibitor that is well tolerated by humans in cardiac applications. We hypothesized that cariporide could selectively acidify brain tumors. The purpose of this study was to determine whether amine/amide concentration-independent detection (AACID) chemical exchange saturation transfer (CEST) MRI measurement of tumor pH_i could detect acidification after cariporide injection. Using a 9.4T MRI scanner, CEST spectra were acquired in six mice approximately 14 days after implanting 10⁵ U87 human glioblastoma multiforme cells in the brain, before and after administration of cariporide (dose: 6 mg/kg) by intraperitoneal injection. Three additional mice were studied as controls and received only vehicle injection (DMSO + PBS). Repeated measures t test was used to examine changes in tumor and contralateral tissue regions of interest. Two hours after cariporide injection, there was a significant 0.12 ± 0.03 increase in tumor AACID value corresponding to a 0.48 decrease in pH_i and no change in AACID value in contralateral tissue. A small but significant increase of 0.04 ± 0.017 in tumor AACID value was also observed following vehicle injection. This study demonstrates that acute CEST MRI contrast changes, indicative of intracellular acidification, after administration of cariporide could help localize glioblastoma.

https://ift.tt/2ItDGNz

Clinical and Biological Predictors of Plasma Levels of Soluble RAGE in Critically Ill Patients: Secondary Analysis of a Prospective Multicenter Observational Study

Rationale. Although soluble forms of the receptor for advanced glycation end products (RAGE) have been recently proposed as biomarkers in multiple acute or chronic diseases, few studies evaluated the influence of usual clinical and biological parameters, or of patient characteristics and comorbidities, on circulating levels of soluble RAGE in the intensive care unit (ICU) setting. Objectives. To determine, among clinical and biological parameters that are usually recorded upon ICU admission, which variables, if any, could be associated with plasma levels of soluble RAGE. Methods. Data for this ancillary study were prospectively obtained from adult patients with at least one ARDS risk factor upon ICU admission enrolled in a large multicenter observational study. At ICU admission, plasma levels of total soluble RAGE (sRAGE) and endogenous secretory (es)RAGE were measured by duplicate ELISA and baseline patient characteristics, comorbidities, and usual clinical and biological indices were recorded. After univariate analyses, significant variables were used in multivariate, multidimensional analyses. Measurements and Main Results. 294 patients were included in this ancillary study, among whom 62% were admitted for medical reasons, including septic shock (11%), coma (11%), and pneumonia (6%). Although some variables were associated with plasma levels of RAGE soluble forms in univariate analysis, multidimensional analyses showed no significant association between admission parameters and baseline plasma sRAGE or esRAGE. Conclusions. We found no obvious association between circulating levels of soluble RAGE and clinical and biological indices that are usually recorded upon ICU admission. This trial is registered with NCT02070536.

https://ift.tt/2KRpoov

Dissecting the heterogeneity of localized prostate cancer risk groups through integration of percent of positive cores

Future Oncology, Ahead of Print.


https://ift.tt/2KPjXX2

Role of inhibitory control in modulating focal seizure spread

Abstract

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2–3-mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

https://ift.tt/2wvH2L5

MiR-23b-3p induces the proliferation and metastasis of esophageal squamous cell carcinomas cells through the inhibition of EBF3

Abstract

MicroRNAs (miRNAs), some small non-coding RNAs that regulate gene expression at the posttranscriptional level, are always aberrantly expressed in carcinomas. In this study, we found that miR-23b-3p was remarkably up-regulated in human esophageal squamous cell carcinoma cells and tissues. Moreover, miR-23b-3p could induce the proliferation, invasion, and metastasis in vitro. EBF3 was identified as the direct downstream target gene of miR-23b-3p and ectogenic EBF3 could strongly inhibit the proliferation, invasion, and metastasis in vitro. Furthermore, it was found that miR-23b-3p could regulate epithelial-to-mesenchymal transition progress by blocking EBF3. Therefore, it was concluded that miR-23b-3p targeted EBF3 to accelerate the proliferation, invasion, and metastasis in ESCC.

https://ift.tt/2I8ELGZ

Yang DD, Krasnova A, Nead KT et al. Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer

https://ift.tt/2jPdzCO

Latest clinical evidence and further development of PARP inhibitors in ovarian cancer

Abstract

Background

For several decades, the systemic treatment of ovarian cancer has involved chemotherapy, with the relatively recent addition of anti-angiogenic strategies given with chemotherapy and in the maintenance setting. In the past decade, numerous poly(ADP-ribose) polymerase (PARP)-inhibiting agents have been assessed.

Design

We review key trials that have led to the approval of three PARP inhibitors – olaparib, niraparib and rucaparib – as maintenance therapy for platinum-sensitive recurrent ovarian cancer. We discuss the efficacy and safety of these agents in the populations studied in clinical trials. We then provide an overview of the numerous avenues of ongoing research for PARP inhibitors in different treatment settings: as treatment rather than maintenance strategies and in combination with other anti-cancer approaches, including anti-angiogenic and immunotherapeutic agents.

Results

Three phase III trials (NOVA, SOLO2 and ARIEL3) demonstrated remarkable improvement in progression-free survival (PFS) with PARP inhibitors given as maintenance therapy in patients with complete or partial response after platinum-based therapy for platinum-sensitive ovarian cancer. Differences in trial design and patient populations influence the conclusions that can be drawn from these trials. Overall survival data are pending and there is a limited experience regarding long-term safety.

Conclusions

PARP inhibitors have transformed the management of ovarian cancer and have changed the course of disease for many patients. Although recent approvals are irrespective of BRCA mutation or homologous repair deficiency status, genetic profiles, as well as dosing schedules, tolerability and affordability, may influence patient selection and the setting in which PARP inhibitors are used. The development and evolution of PARP inhibitors continue, with new agents, strategies, combinations and indications under intensive evaluation.

https://ift.tt/2G5cVcW

Increased mortality in patients aged 75 years or over with pyogenic vertebral osteomyelitis

.


https://ift.tt/2KPc1Fe

Predictors of one-year all-cause mortality and infection-related mortality in patients with Staphylococcus aureus bacteraemia

.


https://ift.tt/2G3yomF

Overexpression of TRIM24 Stimulates Proliferation and Glucose Metabolism of Head and Neck Squamous Cell Carcinoma

TRIM24 (Tripartite Motif Containing 24) is a recently identified oncogene overexpressed in various cancers. However, the molecular mechanism of TRIM24 in the progression of head and neck squamous cell carcinoma (HNSCC) remains ambiguous. In the present study, we analyzed the expression pattern of TRIM24 in 100 HNSCC tissues and found that TRIM24 was overexpressed in 43/100 HNSCC cases. Significant association was found between TRIM24 overexpression and tumor-node-metastasis (TNM) stage () and T stage (). Furthermore, we overexpressed and knocked down TRIM24 in Detroit 562 and FaDu cell lines, respectively. TRIM24 overexpression promoted proliferation, colony formation, and invasion, while TRIM24 depletion inhibited proliferation, colony formation, and invasion. Further studies showed that TRIM24 facilitated cell cycle transition and upregulated cyclin D1 and p-Rb. In addition, we found that GLUT3, a key protein involved in regulating glucose metabolism, was altered in HNSCC cells overexpressing TRIM24. We demonstrated that TRIM24 overexpression increased glucose uptake ATP production. Overexpression of TRIM24 increases cell sensitivity to glucose deprivation in Detroit cells. Depleting TRIM24 in FaDu cells demonstrated the opposite results. We also showed that TRIM24 could bind to the promoter region of cyclin D1. In conclusion, TRIM24 is upregulated in HNSCC and promotes HNSCC cell growth and invasion through modulation of cell cycle, glucose metabolism, and GLUT3, making TRIM24 a potential oncoprotein in HNSCC.

https://ift.tt/2K8WHlw

A pharmacy-led United States Pharmacopeia (USP) chapter 800 compliance collaborative at an academic medical center [Descriptive Research Report]

Purpose

One academic medical center's efforts to move toward compliance with requirements of United States Pharmacopeia (USP) chapter 800 through a multidepartmental collaborative initiative are described.

Summary

Requirements of USP general chapter 800 (enforceable as of December 2019) address the handling of hazardous drugs (HDs) throughout the entire operational and clinical cycle, from receiving to compounding, administration, and waste disposal. Due to the variety of pharmacy operational areas in which HDs are encountered at University of North Carolina Medical Center (UNCMC), multiple pharmacy managers oversee the safe handling of HDs. To determine baseline compliance with USP chapter 800 requirements, a common assessment tool was developed to ensure a standardized approach to compliance assessment in all areas. An interdepartmental workgroup was created to ensure institutionwide support for a collaborative compliance initiative, a uniform understanding of compliance risks, and robust action planning. UNCMC has taken a number of steps toward USP chapter compliance in areas such as engineering controls, environmental quality and controls, use of personal protective equipment, hazard communication programs, personnel training, spill control, and medical surveillance.

Conclusion

Achieving USP chapter 800 compliance presented several operational, clinical, and financial challenges for the medical center, requiring months of preparation and diligence by the hospital leadership. The pharmacy department–led compliance collaborative allowed departments to proactively align while implementing practice and quality standards to foster safety for patients, workers, and the environment.

https://ift.tt/2G25C61

Designing an emergency medicine pharmacy rotation [New Practitioners Forum]

https://ift.tt/2jLKpV9

Professional Policies Approved by the 2018 ASHP March Virtual House of Delegates [ASHP Report]

https://ift.tt/2G3u7j8

Mitigating risk of bloodstream infection related to inpatient probiotic use [Letters]

https://ift.tt/2KNtOMO

Report projects continued increase in drug spending at clinics this year [News]

https://ift.tt/2G2zPSs

At homeless clinic, Alabama pharmacy students gain experience and serve local need [News]

https://ift.tt/2G25Aep

Actions of the ASHP Board of Directors--Meeting of January 18-19, 2018 [ASHP Report]

https://ift.tt/2KNtEFc

Former ASHP VP Dwight R. Tousignaut dies at 84 [News]

https://ift.tt/2G3pW6S

Establishment of outpatient rounds by an interprofessional chronic care management team [Frontline Pharmacist]

https://ift.tt/2jMTv3N

News brief [News]

https://ift.tt/2G1mdH9

Drug interaction screening in SWOG clinical trials [Practice Research Report]

Purpose

The frequency and process for drug interaction (DI) screening at sites enrolling patients into SWOG clinical trials were studied.

Methods

Survey invitations were e-mailed to 180 SWOG head clinical research associates to determine the frequency of and personnel involved in DI assessment in subjects who were screened for and enrolled in clinical trials at their sites. Descriptive statistics were performed to evaluate the data.

Results

A total of 83 surveys recorded a response to at least 1 question, yielding an overall response rate of 46.1%. At least 72 completed surveys were submitted, for a completion rate of 40.0%. The majority of sites (51%) reported that DI screening only occurred during eligibility assessment when a DI was included in the protocol exclusion criteria. The pharmacist was "always" involved in DI screening during eligibility assessment at 17% of sites. Clinical research coordinators (56%) and research nurses (45%) were the predominant personnel who performed DI screening to assess eligibility for trial enrollment. A subset of sites (3–6%) reported not having access to a pharmacist. Fewer than 10% of sites reported that they "always" use drug information services, websites, resources, or literature searches, though many tools were used "often" or "sometimes" by more than 20% of sites.

Conclusion

A survey revealed that DI screening was not being systematically conducted within SWOG clinical trials. When DI screening did occur, it was primarily conducted by clinical research coordinators or study nurses. Pharmacist-led DI screening was not the current practice within SWOG sites surveyed and was precluded by a lack of pharmacists' availability or involvement.

https://ift.tt/2jMTuNh

Pharmacists critical role in cancer clinical trials [Editorials]

https://ift.tt/2G40JsX

Stability of isoniazid injection in i.v. solutions [Practice Research Report]

Purpose

Results of an assessment of the chemical stability of isoniazid injection in 0.9% sodium chloride injection and 5% dextrose injection are reported.

Methods

Triplicate solutions of isoniazid (0.5 and 6.0 mg/mL) in the 2 diluents were prepared in ethylene and propylene copolymer i.v. containers and stored under light protection at room temperature (20–25 °C) or under refrigeration (2–8 °C). Standard aliquots were removed from each solution at time points up to 72 hours and analyzed via high-performance liquid chromatography (HPLC). Stability was defined as retention of >90% of the initial isoniazid concentration; pH, osmolality, and visual appearance were assessed.

Results

Isoniazid 0.5- and 6.0-mg/mL solutions in 0.9% sodium chloride injection were stable for up to 72 hours at room temperature or under refrigeration. HPLC analysis of isoniazid 0.5-mg/mL solutions in 5% dextrose injection revealed a decrease to less than 90% of the initial concentration at 8 hours at room temperature and at 30 hours under refrigeration. Isoniazid 6.0-mg/mL solutions in 5% dextrose injection were stable for 24 hours at room temperature and for 48 hours under refrigeration. The pH, osmolality, and visual appearance of the solutions were not affected.

Conclusion

Isoniazid solutions of 0.5 and 6.0 mg/mL in 0.9% sodium chloride injection were stable under light protection for up to 72 hours when stored at room temperature or under refrigeration. Isoniazid injection was less stable in 5% dextrose injection, especially at a concentration of 0.5 mg/mL at room temperature.

https://ift.tt/2KSBayO