Cholesterol deficiency as a mechanism for autism: A valproic acid model.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

Cancer-Related Stigmatization, Quality of Life, and Fear of Death Among Newly Diagnosed Cancer Patients.

The purpose of the study is to investigate the gender differences among newly diagnosed cancer patients from the cultural perspective of Pakistan. The data comprised two equal groups: men (50%) and women (50%). Most participants were 31-45 years old, and the duration of the cancer diagnosis was less than 6 months (74.6%). The data was collected on the following scales: the discrimination and stigma scale, the internalized stigma scale, the WHO-quality of life scale, and the fear of death scale. Data was analyzed using SPSS v.25; descriptive statistics, an independent sample t-test, and simple linear regression were applied to the data. The results revealed that men and women are both experiencing cancer-related stigmatization in Pakistan. However, women face a higher level of stigmatization, lower quality of life, and higher fear of death than men. Furthermore, the regression analysis result confirms that the cancer-related stigma faced by the diagnosed patients decreases the patient's quality of life and induces the fear of death.

Hydroxychloroquine Effects on THP-1 Macrophage Cholesterol Handling: Cell Culture Studies Corresponding to the TARGET Cardiovascular Trial.

Background and Objectives: Cardiovascular (CV) risk is elevated in rheumatoid arthritis (RA). RA patient plasma causes pro-atherogenic derangements in cholesterol transport leading to macrophage foam cell formation (FCF). The TARGET randomized clinical trial compares CV benefits of 2 RA drug regimens. Hydoxychloroquine (HCQ) is a key medication used in TARGET. This study examines effects of HCQ on lipid transport to elucidate mechanisms underlying TARGET outcomes and as an indicator of likely HCQ effects on atherosclerosis in RA. Materials and Methods: THP1 human macrophages were exposed to media alone, IFNγ (atherogenic cytokine), HCQ, or HCQ + IFNγ. Cholesterol efflux protein and scavenger receptor mRNA levels were quantified by qRT-PCR and corresponding protein levels were assessed by Western blot. FCF was evaluated via Oil-Red-O and fluorescent-oxidized LDL. Intracellular cholesterol and efflux were quantified with Amplex Red assay. Results: With the exception of a decrease in the efflux protein cholesterol 27-hydroxylase in the presence IFNγ at all HCQ concentrations, no significant effect on gene or protein expression was observed upon macrophage exposure to HCQ and this was reflected in the lack of change in FCF and oxidized LDL uptake. Conclusions: HCQ did not significantly affect THP1 macrophage cholesterol transport. This is consistent with TARGET, which postulates superior effects of anti-TNF agents over sulfasalazine + HCQ.

Methotrexate effects on adenosine receptor expression in peripheral monocytes of persons with type 2 diabetes and cardiovascular disease.

The Cardiovascular Inflammation Reduction Trial (CIRT) was designed to assess whether low-dose methotrexate (LD-MTX) would reduce future cardiac events in patients with metabolic syndrome or type 2 diabetes (T2DM) who are post-myocardial infarction (MI) or have multivessel disease. Our previous work indicates that MTX confers atheroprotection via adenosine A2A receptor (A2AR) activation. In order for A2AR ligation to reduce cardiovascular events, A2AR levels would need to be preserved during MTX treatment. This study was conducted to determine whether LD-MTX alters peripheral blood mononuclear cell (PBMC) adenosine receptor expression in persons at risk for cardiovascular events. Post-MI T2DM CIRT patients were randomized to LD-MTX or placebo (n=10/group). PBMC isolated from blood drawn at enrollment and after 6 weeks were evaluated for expression of adenosine receptors and reverse cholesterol transporters by real-time PCR. Fold change between time points was calculated using factorial analyses of variance. Compared with placebo, the LD-MTX group exhibited a trend toward an increase in A2AR (p=0.06), while A3R expression was significantly decreased (p=0.01) after 6 weeks. Cholesterol efflux gene expression did not change significantly. Persistence of A2AR combined with A3R downregulation indicates that failure of MTX to be atheroprotective in CIRT was not due to loss of adenosine receptors on PBMC (ClinicalTrials.gov identifier: NCT01594333).

Immediate changes in hemodynamics and gas exchange after initiation of noninvasive ventilation in cardiac surgical patients.

Introduction: Cardiac surgery is associated with pulmonary dysfunction and complications such as prolonged intubation and reintubation. Bilevel positive airway pressure (BiPAP) machine has been used in the clinical settings to improve oxygenation, reduce work of breathing, and avoid reintubation. The effect of BiPAP on cardiovascular parameters is not well established, and very few studies have targeted hemodynamic changes. The aim of the study was to assess the immediate effect of BiPAP on respiratory and hemodynamic parameters in post-cardiac surgery patients. Materials and Methods: This quasi-experimental study was done on 33 adult cardiac surgery patients. Ethical review committee approval was sought and consent was taken. All patients who were in respiratory distress with respiratory rate of >30/min and/or PaO2:FiO2 ratio of <200 were included. Hemodynamic and respiratory parameters were recorded just before and 15 min after BiPAP application. Sample size was determined on the basis of BiPAP effect on one of the variables, PaO2:FiO2 ratio. Results: A total of 33 patients were included in the study. The average age of the patients was 60.97 ± 10.8, of which 23 (69.7%) were males and 10 (30.7%) females. BiPAP application leads to statistically significant improvement in ventilator parameters including SaO2 29 (87.7%), PaO2 29 (87.8%), PaCO2 21 (63.6%), and PaO2:FiO2 ratio in 27 (81.8%). Conclusion: Ventilatory parameters were significantly improved after BiPAP application in this study, but hemodynamic parameters showed no statistically significant change. BiPAP application was also able to decrease the need for reintubation in post-cardiac surgery patients.

Atlastins remodel the endoplasmic reticulum for selective autophagy.

Specific receptors are required for the autophagic degradation of endoplasmic reticulum (ER), known as ER-phagy. However, little is known about how the ER is remodeled and separated for packaging into autophagosomes. We developed two ER-phagy-specific reporter systems and found that Atlastins are key positive effectors and also targets of ER-phagy. Atlastins are ER-resident GTPases involved in ER membrane morphology, and Atlastin-depleted cells have decreased ER-phagy under starvation conditions. Atlastin's role in ER-phagy requires a functional GTPase domain and proper ER localization, both of which are also involved in ER architecture. The three Atlastin family members functionally compensate for one another during ER-phagy and may form heteromeric complexes with one another. We further find that Atlastins act downstream of the FAM134B ER-phagy receptor, such that depletion of Atlastins represses ER-autophagy induced by the overexpression of FAM134B. We propose that during ER-phagy, Atlastins remodel ER membrane to separate pieces of FAM134B-marked ER for efficient autophagosomal engulfment.

Commotio cordis: A review.

Commotio cordis is an increasingly reported fatal mechano-electric syndrome and is the second most common cause of sudden cardiac death in young athletes. It is most commonly associated with a sports-related injury, wherein, there is a high-velocity impact between a projectile and the precordium. By virtue of this impact, malignant arrhythmias consequently develop leading to the individual's immediate demise, accompanied by a relatively normal post-mortem analysis. The importance of an autopsy remains paramount to exclude other causes of sudden death. With increasing awareness and reporting, survival rates are beginning to improve; however, prevention of the development of this condition remains the best approach for survival.

Systemic Mastocytosis as an Unconventional Cause of Variceal Bleeding: Think Outside the Box.

Systemic mastocytosis is a rare infiltrative disease involving the skin, bone marrow, digestive system, and liver. We report a case of a 59-year-old male who presented with a massive variceal bleed without any evidence of cirrhosis; however was later found to have severe perisinusoidal fibrosis with mast cells in portal tracts on liver biopsy and hypercellular mast cell infiltrated bone marrow. This rare case describes an out-of-the-ordinary reason of variceal bleeding with preserved liver function due to non-cirrhotic portal hypertension.

Repositioning of drugs using open-access data portal DTome: A test case with probenecid (Review).

The one gene-one enzyme hypothesis, first introduced by Beadle and Tatum in the 1940s and based on their genetic analysis and observation of phenotype changes in Neurospora crassa challenged by various experimental conditions, has witnessed significant advances in recent decades. Much of our understanding of the association between genes and their phenotype expression has benefited from the completion of the human genome project, and has shown continual transformation guided by the effort directed at the annotation and characterization of human genes. Similarly, the idea of one drug­one primary disease indication that traditionally has been the benchmark for the labeling and usage of drugs has also undergone evident progressive refinements; in recent years the science and practice of pharmaceutical development has notable success in the strategy of drug repurposing. Drug repurposing is an innovative approach where, instead of de novo synthesis and discovery of new drugs with novel indications, drug candidates with the desired usage are identified by a process of re­profiling using an open­source database or knowledge of known or failed drugs already in existence. In the present study, the repurposing drug strategy employing open­access data portal drug­target interactome (DTome) is applied to the uncovering of new clinical usage for probenecid.