OBJECTIVE:microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role ...in vascular disease is not understood.
APPROACH AND RESULTS:We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk.
CONCLUSIONS:Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.
Objective
An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and ...previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.
Method
Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task.
Results
Impairments were found for all 11 test‐measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26–0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test‐measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression.
Conclusion
This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta‐analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.
Previous cross-sectional studies report that cognitive impairment is associated with poor psychosocial functioning in euthymic bipolar patients. There is a lack of long-term studies to determine the ...course of cognitive impairment and its impact on functional outcome. Method A total of 54 subjects were assessed at baseline and 6 years later; 28 had DSM-IV TR bipolar I or II disorder (recruited, at baseline, from a Lithium Clinic Program) and 26 were healthy matched controls. They were all assessed with a cognitive battery tapping into the main cognitive domains (executive function, attention, processing speed, verbal memory and visual memory) twice over a 6-year follow-up period. All patients were euthymic (Hamilton Rating Scale for Depression score lower than 8 and Young mania rating scale score lower than 6) for at least 3 months before both evaluations. At the end of follow-up, psychosocial functioning was also evaluated by means of the Functioning Assessment Short Test.
Repeated-measures multivariate analysis of covariance showed that there were main effects of group in the executive domain, in the inhibition domain, in the processing speed domain, and in the verbal memory domain (p<0.04). Among the clinical factors, only longer illness duration was significantly related to slow processing (p=0.01), whereas strong relationships were observed between impoverished cognition along time and poorer psychosocial functioning (p<0.05).
Executive functioning, inhibition, processing speed and verbal memory were impaired in euthymic bipolar out-patients. Although cognitive deficits remained stable on average throughout the follow-up, they had enduring negative effects on psychosocial adaptation of patients.
Major Depressive Disorder (MDD) entails cognitive dysfunction in many cognitive domains, but it is still uncertain whether such deficits are present in the early stages. The purpose of the study is ...to determine the cognitive performance in first episode depression (FED) exploring the presence of different cognitive profiles, and the role of cognition in FED at baseline and long-term. Ninety subjects (18–50 years) were included, 50 patients with a FED and 40 healthy controls. Participants were assessed with a neuropsychological battery, covering language, attention, verbal memory, processing speed and executive domains. Neuropsychological group comparisons were performed with MANOVAs. A hierarchical cluster analysis was run to identify clusters of patients with similar neuropsychological performance. Two generalized linear models were built to predict baseline HDRS-17 and changes at 12 months. Patients performed significantly worse than healthy controls in language, attention/working memory, verbal memory, processing speed and executive functioning, with moderate to large effect sizes (0.5 - 1). Two clusters were found: cognitively preserved patients (n=37) and cognitively impaired patients (n=13). Large effect sizes of cognitive impairment in FED were observed between the two cognitive clusters (preserved and impaired). Depressive symptoms at baseline were predicted by verbal memory (p=0.003), while 12-month changes were predicted by executive function (p=0.041) and language (p=0.037). Cognitive performance predicted depressive symptoms at baseline and at follow-up, pointing to the usefulness of cognitive assessment even at the commencement of the illness.
Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) ...genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome translocations and off-target SHM, however, the exact contribution of AID activity to lymphoma generation and progression is not completely understood. Here we show using a conditional knock-in strategy that AID supra-activity alone is not sufficient to generate B cell transformation. In contrast, in the absence of UNG, AID supra-expression increases SHM and promotes lymphoma. Whole exome sequencing revealed that AID heavily contributes to lymphoma SHM, promoting subclonal variability and a wider range of oncogenic variants. Thus, our data provide direct evidence that UNG is a brake to AID-induced intratumoral heterogeneity and evolution of B cell lymphoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate radiology residents' opinions about breast imaging and the possibility of choosing this subspecialty after completing their residency.
We elaborated a 15-question survey aimed at ...radiology residents in Spain. The survey was approved by the Spanish Society of Breast Imaging (SEDIM) and the Spanish Society of Medical Radiology (SERAM), and it was disseminated by the SERAM through links to Google Forms via social networks and emails. Responses sent between February 21, 2020 and July 31, 2020 were accepted.
A total of 72 residents responded to the survey (7.83% response rate); 69.44% of these were third- or fourth-year residents. Of the respondents, 73.61% knew about the SEDIM, and 18.06% knew about the European Society of Breast Imaging. The duration of training programs was three months for 70.83% of respondents. In 7.84% of the responses, residents stated that their supervision was less than 50%, and 70.59% of the residents stated that the rotation exceeded their expectations. One-third of the respondents would consider a fellowship in breast imaging. In all hospitals, residents did diagnostic mammography and breast ultrasound; not all did interventional procedures. Aspects of breast imaging that were rated negatively included the lack of CT studies and the possible legal repercussions of errors. Aspects that were rated positively were dynamics, interventionism, and the role of the radiologist in the process of care for patients with breast cancer.
Most residents considered that their rotations in breast imaging exceeded their expectations; however, only a small percentage of residents would consider specializing in the field.
Abstract Background Neurocognitive dysfunction in bipolar disorder represents a possible marker of underlying pathophysiology, but to date, most studies are cross-sectional and heterogeneous with ...regard to pharmacological treatments. In the present study we investigated the 6-year cognitive and functional outcome of a sample of euthymic excellent lithium responders (ELR). Method A total sample of twenty subjects was assessed at baseline and 6 years later: ten diagnosed of bipolar disorder according to DSM-IV criteria and ten healthy matched controls. The sample size was enough to find statistical differences between groups, with a statistical power of 0.8. Bipolar patients were on lithium treatment during all this follow-up period and fulfilled ELR criteria as measured by the Alda scale. A neuropsychological test battery tapping into the main cognitive domains was used at baseline and at after 6-year of follow-up. Functional outcome was evaluated by means of the Functioning Assessment Short Test at study endpoint. Results Repeated measures multivariate analyses of variance showed that bipolar patients were cognitively impaired in the executive functioning, inhibition, processing speed and verbal memory domains (p < 0.03) compared to controls and such deficits were stable over time. Longer duration of illness and lower psychosocial outcome were significantly related to cognitive impairment (p < 0.05). Conclusions Cognitive dysfunction was present even in euthymic ELR. These deficits remain stable over the long term, and are basically associated with greater symptoms and poorer psychosocial adjustment.
Vacuum-packaged cooked sausages were treated at 500 MPa for 5 or 15 min at mild temperature (65 °C). Colour, texture and yield of pressure-treated sausages were evaluated, and compared to those of ...sausages treated with a conventional heat pasteurisation (80–85 °C for 40 min). Colour attributes did not change. Pressurised sausages were more cohesive and less firm than heat-treated sausages. Pressure treatment induced higher yield than heat treatment. Sensory analysis was also carried out. In some cases, the sensory panel did not detect differences between both types of sausages; and when there were differences, pressurised samples were preferred in more occasions because of their better appearance, taste and, especially, texture. High pressure processing can replace the second industrial heat treatment of cooked sausages.
Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and ...cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies
, and there is a connection between atherosclerosis and autoimmunity
. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood
. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr
and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr
mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD.
To assess the use of prescribed antipsychotic treatments in the Spanish prison population in order to determine whether there are differences in efficacy and cost between the different long-acting ...antipsychotic injectables (LAIs).
An observational, retrospective study was carried out in twelve prisons and in two prison psychiatric hospitals. To assess efficacy, all the clinical histories of patients with some kind of LAI were reviewed and only those who were in a situation of therapeutic stability were selected, defined as those treatments that had not undergone any change in the three last months, both in doses and in the association of another antipsychotic.
Of the 11,953 inmates included in the study, 1,851 (15.5%) received prescriptions for an antipsychotic, 415 in penitentiary psychiatric hospitals (87%) and 1,436 in prisons (12%), which is a much higher prevalence than that found in the population. Regarding the prescription pattern of LAIs, paliperidone is the most widely prescribed in prison psychiatric hospitals and prisons, followed by aripiprazole, zuclopenthixol and risperidone. Finally flufenazine, olanzapine and paliperidone quarterly, which are scarcely represented. Of the 292 patients with LAI, 41% (121 patients) are with monotherapy and 59% (171 patients) are with polytherapy, which is similar to the data found in the bibliography.
The use of prescribed LAIs amongst inmates is widespread. Polytherapy is also a common phenomenon, although there is a downward trend due to the use of more recently marketed drugs. Since the use of LAI is long-term, with numerous side effects and a wide range of prices, it is essential to consider the patient's risk factors and the cost of treatment alongside the therapeutic efficacy.
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