Background and Aims
Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome‐wide association and candidate ...gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population‐based samples, and (2) the genetic covariance across these measures.
Participants
A total of 2596 unrelated subjects from the Study of Addiction: Genetics and Environment provided information on alcohol, tobacco, cocaine, cannabis and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM‐IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e. 1+ DSM‐IV symptoms) and (3) dependence vulnerability (DV; a ratio of DSM‐IV symptoms to the number of substances used).
Findings
Univariate and bivariate genome‐wide complex trait analyses of this selected sample indicated that common SNPs explained 25–36% of the variance across measures, with DD and DV having the largest effects h2SNP (standard error) = 0.36 (0.13) and 0.33 (0.13), respectively; PU = 0.25 (0.13). Genetic effects were shared across the three phenotypic measures of comorbid drug problems rDD‐PU = 0.92 (0.08), rDD‐DV = 0.97 (0.08) and rPU‐DV = 0.96 (0.07).
Conclusion
At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems.
Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity ...associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.
Abstract Objectives Comorbid depression and anxiety are common in inflammatory bowel disease (IBD), but few population-based estimates of the burden of depression and anxiety exist. Methods to ...support population-based studies are needed. We aimed to test the performance of administrative case definitions for depression and anxiety in IBD and to understand what the prevalence estimated using such definitions reflects. Methods We linked administrative (health claims) data from the province of Manitoba, Canada with clinical data for 266 persons in the Manitoba IBD Cohort Study. We compared the performance of administrative case definitions for depression and anxiety with (a) diagnoses of depression and anxiety as identified based on the Composite International Diagnostic Interview (CIDI), which identifies disorders meeting formal diagnostic criteria, and (b) participant report of physician-diagnosed depression or anxiety. Results Administrative definitions for depression showed moderate agreement with the CIDI (κ = 0.39–0.42). Agreement was higher with participant report of physician-diagnosed depression (κ = 0.54). The lifetime prevalence of depression was 29.3% based on the CIDI, 17.7% based on participant report of physician-diagnosed depression, and 21.8–22.5% based on administrative data. Compared to the CIDI, administrative definitions for anxiety showed fair agreement (κ = 0.21–0.25). The lifetime prevalence of anxiety was 31.2% based on the CIDI, 9.7% based on participant report of physician-diagnosed anxiety, and 24.4–31.9% based on administrative data. Conclusions Administrative data may be used for population-level surveillance of depression and anxiety in IBD, although they will not capture undiagnosed or untreated cases.
Objective. To investigate the use of the six-minute walk test (6MWT) for stroke survivors, including adherence to 6MWT protocol guidelines and distances achieved. Methods. A systematic search was ...conducted from inception to March 2014. Included studies reported a baseline (intervention studies) or first instance (observational studies) measure for the 6MWT performed by stroke survivors regardless of time after stroke. Results. Of 127 studies (participants n = 6,012) that met the inclusion criteria, 64 were also suitable for meta-analysis. Only 25 studies made reference to the American Thoracic Society (ATS) standards for the 6MWT, and 28 reported using the protocol standard 30 m walkway. Thirty-nine studies modified the protocol walkway, while 60 studies did not specify the walkway used. On average, stroke survivors walked 284 ± 107 m during the 6MWT, which is substantially less than healthy age-matched individuals. The meta-analysis identified that changes to the ATS protocol walkway are associated with reductions in walking distances achieved. Conclusion. The 6MWT is now widely used in stroke studies. The distances achieved by stroke patients indicate substantially compromised walking ability. Variations to the standard 30 m walkway for the 6MWT are common and caution should be used when comparing the values achieved from studies using different walkway lengths.
GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These ...mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.
•In mice, loss of GNA13 in GC B cells protects against cell death and may promote genetic instability via ongoing somatic hypermutation.•Gna13 loss, in combination with MYC overexpression, promotes lymphoma in mice.
Covid 19 and Surgical training: Carpe Diem Hennessy, O; Fowler, AL; Hennessy, C ...
British journal of surgery,
November 2020, Letnik:
107, Številka:
12
Journal Article
We search for single-photon decays of the Υ(1S) resonance, Υ → γ + invisible, where the invisible state is either a particle of definite mass, such as a light Higgs boson A⁰, or a pair of dark matter ...particles, χχ. Both A⁰ and χ are assumed to have zero spin. We tag Υ(1S) decays with a dipion transition Υ(2S) → π⁺π⁻Υ(1S) and look for events with a single energetic photon and significant missing energy. We find no evidence for such processes in the mass range m(A⁰) ≤ 9.2 GeV and m(χ) ≤ 4.5 GeV in the sample of 98 × 10⁶ Υ(2S) decays collected with the BABAR detector and set stringent limits on new physics models that contain light dark matter states.
The synovial fluid (SF) of joints normally functions as a biological lubricant, providing low-friction and low-wear properties to articulating cartilage surfaces through the putative contributions of ...proteoglycan 4 (PRG4), hyaluronic acid (HA), and surface active phospholipids (SAPL). These lubricants are secreted by chondrocytes in articular cartilage and synoviocytes in synovium, and concentrated in the synovial space by the semi-permeable synovial lining. A deficiency in this lubricating system may contribute to the erosion of articulating cartilage surfaces in conditions of arthritis. A quantitative intercompartmental model was developed to predict in vivo SF lubricant concentration in the human knee joint. The model consists of a SF compartment that (a) is lined by cells of appropriate types, (b) is bound by a semi-permeable membrane, and (c) contains factors that regulate lubricant secretion. Lubricant concentration was predicted with different chemical regulators of chondrocyte and synoviocyte secretion, and also with therapeutic interventions of joint lavage and HA injection. The model predicted steady-state lubricant concentrations that were within physiologically observed ranges, and which were markedly altered with chemical regulation. The model also predicted that when starting from a zero lubricant concentration after joint lavage, PRG4 reaches steady-state concentration approximately 10-40 times faster than HA. Additionally, analysis of the clearance rate of HA after therapeutic injection into SF predicted that the majority of HA leaves the joint after approximately 1-2 days. This quantitative intercompartmental model allows integration of biophysical processes to identify both environmental factors and clinical therapies that affect SF lubricant composition in whole joints.
Abstract Purpose Agriculture and food production contribute to climate change. There is mounting pressure to transition to diets with less environmental impact while maintaining nutritional adequacy. ...MyPlanetDiet aimed to reduce diet-related greenhouse gas emissions (GHGE) in a safe, nutritionally adequate, and acceptable manner. This paper describes the trial protocol, development, and testing of personalised nutrition feedback in the MyPlanetDiet randomised controlled trial (RCT). Methods MyPlanetDiet was a 12-week RCT that provided standardised personalised nutrition feedback to participants based on new sustainable healthy eating guidelines (intervention) or existing healthy eating guidelines (control) using decision trees and corresponding feedback messages. To test the personalised nutrition feedback, we modelled a sample of 20 of the MyPlanetDiet participants baseline diets. Diets were modelled to adhere to control and intervention decision trees and feedback messages. Modelled nutrient intakes and environmental metrics were compared using repeated measure one-way analysis of covariance. Results Intervention diets had significantly lower ( p < 0.001) diet-related GHGE per 2500 kilocalories (kcal) (4.7 kg CO 2 -eq) relative to control (6.6 kg CO 2 -eq) and baseline (7.1 kg CO 2 -eq). Modelled control and intervention diets had higher mean daily intakes of macronutrients (carbohydrates, fibre, and protein) and micronutrients (calcium, iron, zinc, and iodine). Modelled control and intervention diets had lower percent energy from fat and saturated fat relative to baseline. Conclusions Adherence to the MyPlanetDiet personalised nutrition feedback would be expected to lead to better nutrient intakes and reduced diet-related GHGE. The MyPlanetDiet RCT will test the effectiveness and safety of personalised feedback for a more sustainable diet. Trial registration number and date of registration: Clinical trials registration number: NCT05253547, 23 February 2022
Bipolar disorder (BD) has been associated with abnormalities of brain structure. Specifically, in vivo volumetric MRI and/or post mortem studies of BD have reported abnormalities of gray matter (GM) ...volume in the medial prefrontal cortex (PFC), amygdala, hippocampal subiculum and ventral striatum. These structures share anatomical connections with each other and form part of a “visceromotor” network modulating emotional behavior. Areas of the lateral orbital, superior temporal and posterior cingulate cortices project to this network, but morphometric abnormalities in these areas have not been established in BD. The current study assessed tissue volumes within these areas in BD using MRI and voxel-based morphometry (VBM).
MRI images were obtained from 36 BD subjects and 65 healthy controls. To account for possible neurotrophic and neuroprotective effects of psychotropic medications, BD subjects were divided into medicated and unmedicated groups. Images were segmented into tissue compartments, which were examined on a voxel-wise basis to determine the location and extent of morphometric changes.
The GM was reduced in the posterior cingulate/retrosplenial cortex and superior temporal gyrus of unmedicated BD subjects relative to medicated BD subjects and in the lateral orbital cortex of medicated BD subjects relative to controls. White matter (WM) was increased in the orbital and posterior cingulate cortices, which most likely reflected alterations in gyral morphology resulting from the reductions in the associated GM.
The morphometric abnormalities in the posterior cingulate, superior temporal and lateral orbital cortices in BD support the hypothesis that the extended network of neuroanatomical structures subserving visceromotor regulation contains structural alterations in BD. Additionally, localization of morphometric abnormalities to areas known to exhibit increased metabolism in depression supports the hypothesis that repeated stress and elevated glucocorticoid secretion may result in neuroplastic changes in BD.
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