Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated ...synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.
Administration of intravenous crystalloid solutions is a fundamental therapy for sepsis, but the effect of crystalloid composition on patient outcomes remains unknown.
To compare the effect of ...balanced crystalloids versus saline on 30-day in-hospital mortality among critically ill adults with sepsis.
Secondary analysis of patients from SMART (Isotonic Solutions and Major Adverse Renal Events Trial) admitted to the medical ICU with an
code for sepsis, using multivariable regression to control for potential confounders.
Of 15,802 patients enrolled in SMART, 1,641 patients were admitted to the medical ICU with a diagnosis of sepsis. A total of 217 patients (26.3%) in the balanced crystalloids group experienced 30-day in-hospital morality compared with 255 patients (31.2%) in the saline group (adjusted odds ratio aOR, 0.74; 95% confidence interval CI, 0.59-0.93;
= 0.01). Patients in the balanced group experienced a lower incidence of major adverse kidney events within 30 days (35.4% vs. 40.1%; aOR, 0.78; 95% CI, 0.63-0.97) and a greater number of vasopressor-free days (20 ± 12 vs. 19 ± 13; aOR, 1.25; 95% CI, 1.02-1.54) and renal replacement therapy-free days (20 ± 12 vs. 19 ± 13; aOR, 1.35; 95% CI, 1.08-1.69) compared with the saline group.
Among patients with sepsis in a large randomized trial, use of balanced crystalloids was associated with a lower 30-day in-hospital mortality compared with use of saline.Clinical trial registered with www.clinicaltrials.gov (NCT02444988).
Eukaryotic 2-Cys peroxiredoxins (Prx) are abundant antioxidant enzymes whose thioredoxin peroxidase activity plays an important role in protecting against oxidative stress, aging, and cancer. ...Paradoxically, this thioredoxin peroxidase activity is highly sensitive to inactivation by peroxide-induced Prx hyperoxidation. However, any possible advantage in preventing Prx from removing peroxides under oxidative stress conditions has remained obscure. Here we demonstrate that, in cells treated with hydrogen peroxide, the Prx Tpx1 is a major substrate for thioredoxin in the fission yeast Schizosaccharomyces pombe and, as such, competitively inhibits thioredoxin-mediated reduction of other oxidized proteins. Consequently, we reveal that the hyperoxidation of Tpx1 is critical to allow thioredoxin to act on other substrates ensuring repair of oxidized proteins and cell survival following exposure to toxic levels of hydrogen peroxide. We conclude that the inactivation of the thioredoxin peroxidase activity of Prx is important to maintain thioredoxin activity and cell viability under oxidative stress conditions.
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► Tpx1, Pap1, and Mxr1 are all substrates for S. pombe thioredoxin Trx1 ► In H2O2-treated cells, Tpx1 competitively inhibits reduction of Pap1 and Mxr1 ► H2O2-induced hyperoxidation of Tpx1 allows Trx1 to reduce other oxidized proteins ► Inhibition of Tpx1 by H2O2 is essential for Trx1-mediated repair and cell survival
Background: The 10-yr survival rate of patients with differentiated thyroid cancer exceeds 90%. These patients may be at elevated risk for secondary cancers.
Methods: The risk of nonthyroid second ...primary malignancies after differentiated thyroid cancer was determined in 30,278 patients diagnosed between 1973 and 2002 from centers participating in the National Cancer Institute’s Surveillance, Epidemiology, and End Results program. Median follow-up was 103 months (range, 2–359 months). Risk was further assessed for the addition of radioisotope therapy, gender, latency to development of secondary cancer, and age at thyroid cancer diagnosis.
Results: There were 2158 patients who developed a total of 2338 nonthyroid second primary malignancies, significantly more than that expected in the general population observed/expected (O/E) = 1.09; 95% confidence interval (CI), 1.05–1.14; P < 0.05; absolute excess risk per 10,000 person-years (AER) = 6.39. A significantly greater risk of second primary malignancies over that expected in the general population was for patients treated with radioisotopes (O/E = 1.20; 95% CI, 1.07–1.33; AER = 11.8) as well as for unirradiated patients (O/E = 1.05; 95% CI, 1.00–1.10; AER = 3.53). However, the increased risk was greater for the irradiated vs. the unirradiated cohort (relative risk = 1.16; 95% CI, 1.05–1.27; P < 0.05). Gender did not affect risk. The greatest risk of second primary cancers occurred within 5 yr of diagnosis and was elevated for younger patients.
Conclusions: The overall risk of second primary malignancies is increased for thyroid cancer survivors and varies by radioisotope therapy, latency, and age at diagnosis.
Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with ...recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.
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•BET bromodomains coactivate cardiac gene expression programs•BET inhibition blocks pathologic cardiac remodeling in vitro and in vivo•BRD4 occupies active cardiac enhancers and promoters•BET inhibition blocks pathologic transcriptional elongation in the adult heart
Small-molecule inhibition of BET bromodomain proteins that recognize acetylated histones blocks release of paused polymerase at genes induced during cardiac stress. This inhibition protects against heart failure.
Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method ...for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800–4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We ...demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the ...atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
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•Activated NF-κB prompts rapid formation of super enhancers in endothelial cells•Super enhancer-bound BRD4 coactivates inflammatory genes•Redistribution of BRD4 results in eviction from basal super enhancers•BET bromodomain inhibition attenuates atherogenic responses and atherosclerosis
Activation of NF-κB underlies many chronic diseases including atherosclerosis. Brown et al. show that TNFα-mediated activation of NF-κB forms de novo super enhancers in endothelial cells by reallocation of the BET bromodomain protein BRD4 away from basal super enhancers. In a preclinical model of atherosclerosis, BET bromodomain inhibition can suppress atherogenesis.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, ...adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (alpha, gamma, and delta, also known as beta or beta/delta) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPARalpha, and thiazolidinediones, which activate PPARgamma, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology.
Objective:This study examined the availability of primary care and wellness services in community mental health centers (CMHCs) and outpatient mental health facilities (OMHFs).Methods:This study used ...data from the 2016 National Mental Health Services Survey to examine the proportion of facilities that reported offering integrated primary care and wellness services (smoking and tobacco cessation counseling, diet and exercise counseling, and chronic disease and illness management). The study used logistic regression to model the odds that a facility offered integrated primary care as a function of facility characteristics.Results:Across states, 23% of CMHCs and 19% of OMHFs offered integrated primary care. The odds of offering integrated primary care were significantly higher among facilities that reported more quality improvement practices, prohibited smoking, or offered wellness services. Less than one third offered smoking and tobacco cessation counseling or other wellness services.Conclusions:Integrated primary care remains uncommon in CMHCs and OMHFs and is more likely among facilities with certain characteristics.
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