PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells

Background

Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells.

Methods and results

Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers.

Conclusion

Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.     

A functionally dominant mitochondrial DNA mutation

Mutations in mitochondrial DNA (mtDNA) tRNA genes can be considered functionally recessive because they result in a clinical or biochemical phenotype only when the percentage of mutant molecules exceeds a critical threshold value, in the range of 70-90%. We report a novel mtDNA mutation that contradicts this rule, since it caused a severe multisystem disorder and respiratory chain (RC) deficiency even at low levels of heteroplasmy. We studied a 13-year-old boy with clinical, radiological and biochemical evidence of a mitochondrial disorder. We detected a novel heteroplasmic C>T mutation at nucleotide 5545 of mtDNA, which was present at unusually low levels (<25%) in affected tissues. The pathogenic threshold for the mutation in cybrids was between 4 and 8%, implying a dominant mechanism of action. The mutation affects the central base of the anticodon triplet of tRNA(Trp) and it may alter the codon specificity of the affected tRNA. These findings introduce the concept of dominance in mitochondrial genetics and pose new diagnostic challenges, because such mutations may easily escape detection. Moreover, similar mutations arising stochastically and accumulating in a minority of mtDNA molecules during the aging process may severely impair RC function in cells.     

Genetic landscape of human platelet antigen variants in the Indian population analysed from 1029 whole genomes

Genetic variants in human platelet antigens (HPAs) considered allo- or auto antigens are associated with various disorders, including neonatal alloimmune thrombocytopenia, platelet transfusion refractoriness and post-transfusion purpura. Although global differences in genotype frequencies were observed, the distributions of HPA variants in the Indian population are largely unknown. This study aims to explore the landscape of HPA variants in India to provide a basis for risk assessment and management of related complications. Population-specific frequencies of genetic variants associated with the 35 classes of HPAs (HPA-1 to HPA-35) were estimated by systematically analysing genomic variations of 1029 healthy Indian individuals as well as from global population genome datasets. Allele frequencies of the most clinically relevant HPA systems in the Indian population were found as follows, HPA-1a – 0.884, HPA-1b – 0.117, HPA-2a – 0.941, HPA-2b – 0.059, HPA-3a – 0.653, HPA-3b – 0.347, HPA-4a – 0.999, HPA-4b – 0.0010, HPA-5a – 0.923, HPA-5b – 0.077, HPA-6a – 0.998, HPA-6b – 0.002, HPA-15a – 0.582 and HPA-15b – 0.418. This study provides the first comprehensive analysis of HPA allele and genotype frequencies using large scale representative whole genome sequencing data of the Indian population.     

Neurochemical correlates of caudate atrophy in Huntington's disease

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy (¹H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous ¹H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two ¹H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized ¹H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N‐acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease‐related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches. © 2014 International Parkinson and Movement Disorder Society     

Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease

BACKGROUND: Mutations in the SCO2 gene have been associated with fatal cardioencephalomyopathy. OBJECTIVE: To report a novel SCO2 mutation with prominent spinal cord involvement mimicking spinal muscular atrophy (Werdnig-Hoffmann disease). PATIENT AND METHODS: An infant girl presented at birth with generalized weakness, hypotonia, and lactic acidosis. At 1 month of age she developed hypertrophic cardiomyopathy and died of heart failure 1 month later. Neuroradiological studies were unremarkable. Muscle biopsy specimens showed groups of atrophic and hypertrophic fibers, but mutation screening of the SMN gene was negative. Histochemical and biochemical studies of respiratory chain complexes were performed, and the whole coding region of the SCO2 gene was sequenced. RESULTS: Findings from muscle histochemistry studies showed virtually undetectable cytochrome c oxidase activity, but normal succinate dehydrogenase reaction. Biochemical analysis in muscle confirmed a severe isolated cytochrome c oxidase deficiency. Pathologic findings of the brain were unremarkable, but the ventral horns of the spinal cord showed moderate-to-severe loss of motor neurons and astrocytosis. Sequencing of the SCO2 gene showed the common E140K mutation, and a novel 10 base-pair duplication of nucleotides 1302 to 1311, which disrupts the reading frame of the messenger RNA and gives rise to a truncated protein. CONCLUSION: The SCO2 mutations should be considered in the differential diagnosis of children with spinal muscular atrophy without mutations in the SMN gene.     

CDC''s National Violent Death Reporting System: background and methodology

OBJECTIVES: This paper describes a new surveillance system called the National Violent Death Reporting System (NVDRS), initiated by the United States Centers for Disease Control and Prevention. NVDRS's mission is the collection of detailed, timely information on all violent deaths. DESIGN: NVDRS is a population based, active surveillance system designed to obtain a complete census of all resident and occurrent violent deaths. Each state collects information on its own deaths from death certificates, medical examiner/coroner files, law enforcement records, and crime laboratories. Deaths occurring in the same incident are linked. Over 270 data elements can be collected on each incident. SETTING: The 13 state health departments of Alaska, Colorado, Georgia, Maryland, Massachusetts, New Jersey, North Carolina, Oklahoma, Oregon, Rhode Island, South Carolina, Virginia, and Wisconsin. SUBJECTS: Cases consist of violent deaths from suicide, homicide, undetermined intent, legal intervention, and unintentional firearm injury. Information is collected on suspects as well as victims. INTERVENTIONS: None. OUTCOME MEASURES: The quality of surveillance will be measured in terms of its acceptability, accuracy, sensitivity, timeliness, utility, and cost. RESULTS: The system has just been started. There are no results as yet. CONCLUSIONS: NVDRS has achieved enough support to begin data collection efforts in selected states. This system will need to overcome the significant barriers to such a large data collection effort. Its success depends on the use of its data to inform and assess violence prevention efforts. If successful, it will open a new chapter in the use of empirical information to guide public policy around violence in the United States.     

Anemia and clinical outcomes

This article discusses the impact of anemia in the context of the perioperative setting. Relevant data from animal and human studies, the adaptive mechanisms in anemia, and current views on transfusion triggers are evaluated. Recommendations are provided for the anesthesiologist for transfusion of red blood cells.