Bariatric Surgery Ameliorates Diabetic Cardiac Dysfunction by Inhibiting ER Stress in a Diabetic Rat Model

Abstract

Background

Cardiac dysfunction is a severe complication of diabetes, with no effective treatment. Currently, bariatric surgery is more and more widely used to attenuate diabetes-associated diseases. The mechanism is not clear. Endoplasmic reticulum (ER) stress-dependent apoptosis has been observed in the progression of diabetic myocardium damage. Therefore, this research was designed to investigate the effects of different bariatric procedures on cardiac dysfunction via ER stress-induced cardiomyocyte apoptosis pathway in a diabetic rat model.

Methods

Duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham surgery were performed in diabetic rats. Echocardiographic examination, H&E staining, Masson staining, and TUNEL staining were performed to measure the diabetes-caused heart damages. ER stress-associated signaling molecules like glucose-regulated protein 78 (GRP78), protein kinase RNA (PKR)-like ER protein kinase (PERK), p-PERK, inositol-requiring enzyme 1ɑ (IRE1ɑ), p-IRE1ɑ, activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), and caspase 12 were measured and compared among DJB group, SG group, and sham group.

Results

Compared with sham group, DJB and SG groups both had significantly lower GRP78, PERK, p-PERK, CHOP, and caspase 12, though there was no statistical change on IRE1ɑ, p-IRE1ɑ, and ATF6. DJB and SG groups also showed improved heart function and lower cardiomyocyte apoptosis in diabetic rats.

Conclusion

DJB and SG ameliorated cardiac dysfunction by inhibiting PERK-mediated pathway. And no difference was observed on the effects of DJB and SG on ER stress-dependent myocardium damage in diabetic rats.

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Bariatric Surgery or Non-surgical Weight Loss for Idiopathic Intracranial Hypertension? A Systematic Review and Comparison of Meta-analyses

Abstract

Background

Idiopathic intracranial hypertension (IIH) is associated with obesity and weight loss by any means is considered beneficial in this condition.

Objectives

This study aims to appraise bariatric surgery vs. non-surgical weight-loss (medical, behavioural and lifestyle) interventions in IIH management.

Methods

A systematic review and meta-analyses of surgical and non-surgical studies.

Results

Bariatric surgery achieved 100% papilloedema resolution and a reduction in headache symptoms in 90.2%. Non-surgical methods offered improvement in papilloedema in 66.7%, visual field defects in 75.4% and headache symptoms in 23.2%. Surgical BMI decrease was 17.5 vs. 4.2 for non-surgical methods.

Conclusions

Whilst both bariatric surgery and non-surgical weight loss offer significant beneficial effects on IIH symptomatology, future studies should address the lack of prospective and randomised trials to establish the optimal role for these interventions.

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HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Abstract

Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.

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Comment on: “Challenges in Individualizing Drug Dosage for Intensive Care Unit Patients: Is Augmented Renal Clearance What We Really Want to Know? Some Suggested Management Approaches and Clinical Software Tools”

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Acute methotrexate toxicity presenting with bullous lesions: an unusual presentation

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Impact of genetic and nongenetic factors on interindividual variability in 4 β -hydroxycholesterol concentration

Abstract

Purpose

Individual variability in the endogenous CYP3A metabolite 4β-hydroxycholesterol (4βOHC) is substantial, but to which extent this is determined by genetic and nongenetic factors remains unclear. The aim of the study was to evaluate the explanatory power of candidate genetic variants and key nongenetic factors on individual variability in 4βOHC levels in a large naturalistic patient population.

Methods

We measured 4βOHC concentration in serum samples from 655 patients and used multiple linear regression analysis to estimate the quantitative effects of CYP3A4*22, CYP3A5*3, and POR*28 variant alleles, comedication with CYP3A inducers, inhibitors and substrates, sex, and age on individual 4βOHC levels.

Results

4βOHC concentration ranged >100-fold in the population, and the multiple linear regression model explained about one fourth of the variability (R ² = 0.23). Only comedication with inducers or inhibitors, sex, and POR genotype were significantly associated with individual variability in 4βOHC level. The estimated quantitative effects on 4βOHC levels were greatest for inducer comedication (+>313%, P < 0.001), inhibitor comedication (−34%, P = 0.021), and female sex (+30%, P < 0.001), while only a modestly elevated 4βOHC level was observed in carriers vs. noncarriers of POR*28 (+11%, P = 0.023).

Conclusions

These findings suggest that the CYP3A4*22, CYP3A5*3, and POR*28 variant alleles are of limited importance for overall individual variability in 4βOHC levels compared to nongenetic factors.

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Identification and characterization of protein coding genes in monsonia ( Monsonia burkeana Planch. ex harv) using a combination of approaches

Abstract

The advent of next generation sequencing has made possible massive availability of sequence information for in-depth structural and functional analysis of the genes and their encoded biological state in model and non-model organisms. In this study, we demonstrate a combinatorial approach for finding protein coding genes using ab initio and extrinsic evidence-based methods in monsonia (Monsonia burkeana Planch. ex harv). This is an important herbal tea crop, yet little is known about its coding genes. To our knowledge, this is the first description of protein coding genes with detailed functional annotation in M. burkeana. This study demonstrates that (1) regions of transcript assembly potentially encode protein coding genes, (2) homologous evidence with known functions reliably assigns functions to the identified genes (3) conserved domains suggest evolutionary and functional relationship of the crop with other lineage and (4) accuracy of finding coding genes in alignment free models and in RNA-seq alignment based transcript assembly performs well. This study provides a glimpse of functional information of the protein coding region at the transcriptome level and can be used as the basis for further investigation of the underlying genetic composition and molecular functions associated with M. burkeana.

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