P2X7, inflammation and gastrointestinal disease

The inflammatory bowel diseases, ulcerative colitis and Crohn's disease are characterised by spontaneously relapsing and remitting inflammation, associated with increased mucosal levels of the inflammatory cytokine, interleukin-1 (IL-1)β. IL-1β processing and release is mediated by ATP stimulation of the purine receptor, P2X7. P2X7 is a membrane ion channel highly expressed in immune cells. Signal transduction occurs via rapid cation exchange, plasma membrane depolarisation and increased intracellular calcium. Additionally, prolonged or repeated P2X7 stimulation leads to formation of a non-selective membrane pore permeable to small molecules, and ultimately to cell death. The aim of this project was to investigate the properties of the P2X7 receptor in mononuclear cells, to show that it is associated with IL-1β release in the colon, and that this release can be modified by P2X7 antagonists. Studies of ethidium bromide uptake, a functional assay, showed that P2X7 receptors are present on LPMCs and displayed properties similar to those of PBMCs and THP-1 cells. P2X7 receptor-stimulation released mature IL-1β from LPMCs in a dose-dependent manner that, in IBD patients, matched the severity of their inflammation, and could be markedly reduced by P2X7 antagonists. P2X7 stimulation also results in increased exposure of phosphatidylserine on the outer cell membrane (PS flip), often considered to be a marker of apoptotic cell death. P2X7-stimulated PS flip however is reversible and is not associated with cell death following brief stimulation times. Cell death caused by longer stimulation did not have features of apoptosis, was more evident in monocytes than lymphocytes, with LPMCs being less susceptible than PBMCs and THP-1 cells. These studies have shown that the P2X7 receptor is intimately involved in the release of IL-1β from human colonic mononuclear cells, that the release is greater in cells from IBD tissue and can be markedly inhibited by P2X7 antagonists

P2X7, inflammation and gastrointestinal disease

The inflammatory bowel diseases, ulcerative colitis and Crohn's disease are characterised by spontaneously relapsing and remitting inflammation, associated with increased mucosal levels of the inflammatory cytokine, interleukin-1 (IL-1)β. IL-1β processing and release is mediated by ATP stimulation of the purine receptor, P2X7. P2X7 is a membrane ion channel highly expressed in immune cells. Signal transduction occurs via rapid cation exchange, plasma membrane depolarisation and increased intracellular calcium. Additionally, prolonged or repeated P2X7 stimulation leads to formation of a non-selective membrane pore permeable to small molecules, and ultimately to cell death. The aim of this project was to investigate the properties of the P2X7 receptor in mononuclear cells, to show that it is associated with IL-1β release in the colon, and that this release can be modified by P2X7 antagonists. Studies of ethidium bromide uptake, a functional assay, showed that P2X7 receptors are present on LPMCs and displayed properties similar to those of PBMCs and THP-1 cells. P2X7 receptor-stimulation released mature IL-1β from LPMCs in a dose-dependent manner that, in IBD patients, matched the severity of their inflammation, and could be markedly reduced by P2X7 antagonists. P2X7 stimulation also results in increased exposure of phosphatidylserine on the outer cell membrane (PS flip), often considered to be a marker of apoptotic cell death. P2X7-stimulated PS flip however is reversible and is not associated with cell death following brief stimulation times. Cell death caused by longer stimulation did not have features of apoptosis, was more evident in monocytes than lymphocytes, with LPMCs being less susceptible than PBMCs and THP-1 cells. These studies have shown that the P2X7 receptor is intimately involved in the release of IL-1β from human colonic mononuclear cells, that the release is greater in cells from IBD tissue and can be markedly inhibited by P2X7 antagonists

Viral Dynamics of Acute HIV-1 Infection

Viral dynamics were intensively investigated in eight patients with acute HIV infection to define the earliest rates of change in plasma HIV RNA before and after the start of antiretroviral therapy. We report the first estimates of the basic reproductive number (R0), the number of cells infected by the progeny of an infected cell during its lifetime when target cells are not depleted. The mean initial viral doubling time was 10 h, and the peak of viremia occurred 21 d after reported HIV exposure. The spontaneous rate of decline (α) was highly variable among individuals. The phase 1 viral decay rate (δI = 0.3/day) in subjects initiating potent antiretroviral therapy during acute HIV infection was similar to estimates from treated subjects with chronic HIV infection. The doubling time in two subjects who discontinued antiretroviral therapy was almost five times slower than during acute infection. The mean basic reproductive number (R0) of 19.3 during the logarithmic growth phase of primary HIV infection suggested that a vaccine or postexposure prophylaxis of at least 95% efficacy would be needed to extinguish productive viral infection in the absence of drug resistance or viral latency. These measurements provide a basis for comparison of vaccine and other strategies and support the validity of the simian immunodeficiency virus macaque model of acute HIV infection

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism

The Iso2k Database: A global compilation of paleo-δ18O and δ2H records to aid understanding of Common Era climate

Reconstructions of global hydroclimate during the Common Era (CE; the past ~ 2000 years) are important for providing context for current and future global environmental change. Stable isotope ratios in water are quantitative indicators of hydroclimate on regional to global scales, and these signals are encoded in a wide range of natural geologic archives. Here we present the Iso2k database, a global compilation of previously published datasets from a variety of natural archives that record the stable oxygen (δ18O) or hydrogen (δ2H) isotopic composition of environmental waters, which reflect hydroclimate changes over the CE. The Iso2k database contains 756 isotope records from the terrestrial and marine realms, including: glacier and ground ice (205); speleothems (68); corals, sclerosponges, and mollusks (145); wood (81); lake sediments and other terrestrial sediments (e.g., loess) (158); and marine sediments (99). Individual datasets have temporal resolutions ranging from sub-annual to centennial, and include chronological data where available. A fundamental feature of the database is its comprehensive metadata, which will assist both experts and non-experts in the interpretation of each record and in data synthesis. Key metadata fields have standardized vocabularies to facilitate comparisons across diverse archives and with climate model simulated fields. This is the first global-scale collection of water isotope proxy records from multiple types of geological and biological archives. It is suitable for evaluating hydroclimate processes through time and space using large-scale synthesis, model-data intercomparison and (paleo)data assimilation. The Iso2k database is available for download at: https://doi.org/10.6084/m9.figshare.11553162 (McKay and Konecky, 2020)

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Spiritual Well-Being and Depression in Patients with Heart Failure

BACKGROUND: In patients with chronic heart failure, depression is common and associated with poor quality of life, more frequent hospitalizations, and higher mortality. Spiritual well-being is an important, modifiable coping resource in patients with terminal cancer and is associated with less depression, but little is known about the role of spiritual well-being in patients with heart failure. OBJECTIVE: To identify the relationship between spiritual well-being and depression in patients with heart failure. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty patients aged 60 years or older with New York Heart Association class II–IV heart failure. MEASUREMENTS: Spiritual well-being was measured using the total scale and 2 subscales (meaning/peace, faith) of the Functional Assessment of Chronic Illness Therapy—Spiritual Well-being scale, depression using the Geriatric Depression Scale—Short Form (GDS-SF). RESULTS: The median age of participants was 75 years. Nineteen participants (32%) had clinically significant depression (GDS-SF > 4). Greater spiritual well-being was strongly inversely correlated with depression (Spearman’s correlation −0.55, 95% confidence interval −0.70 to −0.35). In particular, greater meaning/peace was strongly associated with less depression (r = −.60, P < .0001), while faith was only modestly associated (r = −.38, P < .01). In a regression analysis accounting for gender, income, and other risk factors for depression (social support, physical symptoms, and health status), greater spiritual well-being continued to be significantly associated with less depression (P = .05). Between the 2 spiritual well-being subscales, only meaning/peace contributed significantly to this effect (P = .02) and accounted for 7% of the variance in depression. CONCLUSIONS: Among outpatients with heart failure, greater spiritual well-being, particularly meaning/peace, was strongly associated with less depression. Enhancement of patients’ sense of spiritual well-being might reduce or prevent depression and thus improve quality of life and other outcomes in this population