Alcohol-related brain damage in humans

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann’s area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

A population-based phenome-wide association study of cardiac and aortic structure and function

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart–brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers

Global, regional, and national prevalence of adult overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021

Background: Overweight and obesity is a global epidemic. Forecasting future trajectories of the epidemic is crucial for providing an evidence base for policy change. In this study, we examine the historical trends of the global, regional, and national prevalence of adult overweight and obesity from 1990 to 2021 and forecast the future trajectories to 2050. Methods: Leveraging established methodology from the Global Burden of Diseases, Injuries, and Risk Factors Study, we estimated the prevalence of overweight and obesity among individuals aged 25 years and older by age and sex for 204 countries and territories from 1990 to 2050. Retrospective and current prevalence trends were derived based on both self-reported and measured anthropometric data extracted from 1350 unique sources, which include survey microdata and reports, as well as published literature. Specific adjustment was applied to correct for self-report bias. Spatiotemporal Gaussian process regression models were used to synthesise data, leveraging both spatial and temporal correlation in epidemiological trends, to optimise the comparability of results across time and geographies. To generate forecast estimates, we used forecasts of the Socio-demographic Index and temporal correlation patterns presented as annualised rate of change to inform future trajectories. We considered a reference scenario assuming the continuation of historical trends. Findings: Rates of overweight and obesity increased at the global and regional levels, and in all nations, between 1990 and 2021. In 2021, an estimated 1·00 billion (95% uncertainty interval [UI] 0·989–1·01) adult males and 1·11 billion (1·10–1·12) adult females had overweight and obesity. China had the largest population of adults with overweight and obesity (402 million [397–407] individuals), followed by India (180 million [167–194]) and the USA (172 million [169–174]). The highest age-standardised prevalence of overweight and obesity was observed in countries in Oceania and north Africa and the Middle East, with many of these countries reporting prevalence of more than 80% in adults. Compared with 1990, the global prevalence of obesity had increased by 155·1% (149·8–160·3) in males and 104·9% (95% UI 100·9–108·8) in females. The most rapid rise in obesity prevalence was observed in the north Africa and the Middle East super-region, where age-standardised prevalence rates in males more than tripled and in females more than doubled. Assuming the continuation of historical trends, by 2050, we forecast that the total number of adults living with overweight and obesity will reach 3·80 billion (95% UI 3·39–4·04), over half of the likely global adult population at that time. While China, India, and the USA will continue to constitute a large proportion of the global population with overweight and obesity, the number in the sub-Saharan Africa super-region is forecasted to increase by 254·8% (234·4–269·5). In Nigeria specifically, the number of adults with overweight and obesity is forecasted to rise to 141 million (121–162) by 2050, making it the country with the fourth-largest population with overweight and obesity. Interpretation: No country to date has successfully curbed the rising rates of adult overweight and obesity. Without immediate and effective intervention, overweight and obesity will continue to increase globally. Particularly in Asia and Africa, driven by growing populations, the number of individuals with overweight and obesity is forecast to rise substantially. These regions will face a considerable increase in obesity-related disease burden. Merely acknowledging obesity as a global health issue would be negligent on the part of global health and public health practitioners; more aggressive and targeted measures are required to address this crisis, as obesity is one of the foremost avertible risks to health now and in the future and poses an unparalleled threat of premature disease and death at local, national, and global levels. Funding: Bill & Melinda Gates Foundation

Antithrombin Perfluorocarbon Nanoparticles Improve Renal Allograft Function in a Murine Deceased Criteria Donor Model

Background. Over 100 000 patients await renal transplantation and 4000 die per year. Compounding this mismatch between supply and demand is delayed graft function which contributes to short-term and long-term graft failures. Previously, we reported that thrombin-targeted perfluorocarbon nanoparticles (PFC-NP) protect kidneys from ischemic renal injury after transient arterial occlusion. Here we hypothesize that perfusion of renal allografts with PFC-NP similarly can protect graft function after an ischemic interval. Methods. After 60 minutes of warm ischemia, male Lewis rats underwent left renal explantation followed by renal perfusion with 5 mL of standard perfusate alone (N = 3) or with 0.3 mL of untargeted PFC-NP (N = 5) or 0.3 mL thrombin-targeted of PFC NP functionalized with phenylalanine-proline-arginine-chloromethylketone (PPACK) (PFC-PPACK), an irreversible thrombin inhibitor (N = 5). Kidneys underwent 6 hours of cold storage, followed by transplantation into recipients and native nephrectomy. Animals were euthanized at 24 hours for tissue collection or at 48 hours for blood and renal tissue collection. A survival experiment was performed using the same protocol with saline control (N = 3), PFC-NP (N = 3) or PFC-PPACK (N = 6). Results. Serum creatinine was improved for the PFC-PPACK groups as compared with control groups (P < 0.04). Kaplan-Meier survival curves also indicated increased longevity (P < 0.05). Blinded histologic scoring revealed markedly attenuated renal damage in the PFC-PPACK group compared to untreated animals (2.75 ± 1.60 versus 0.83 ± 3.89; P = 0.0001) and greater preservation of renal vasculature. Conclusions. These results validate an NP-based approach to improve renal graft function as antithrombin NPs improved allograft function, decreased renal damage, protected vasculature, and improved longevity