206 research outputs found

    Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

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    Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction

    Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

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    Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strateg

    Serous cystic neoplasm of the pancreas: A multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

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    OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58\u2005years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40\u2005mm (2-200)), 9% had resection beyond 1\u2005year of follow-up (3\u2005years (1-20), size at diagnosis: 25\u2005mm (4-140)) and 39% had no surgery (3.6\u2005years (1-23), 25.5\u2005mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1\u2005year (n=1271), size increased in 37% (growth rate: 4\u2005mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN

    TRH: Pathophysiologic and clinical implications

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    Thyrotropin releasing hormone is thought to be a tonic stimulator of the pituitary TSH secretion regulating the setpoint of the thyrotrophs to the suppressive effect of thyroid hormones. The peptide stimulates the release of normal and elevated prolactin. ACTH and GH may increase in response to exogenous TRH in pituitary ACTH and GH hypersecretion syndromes and in some extrapituitary diseases. The pathophysiological implications of extrahypothalamic TRH in humans are essentially unknown. The TSH response to TRH is nowadays widely used as a diganostic amplifier in thyroid diseases being suppressed in borderline and overt hyperthyroid states and increased in primary thyroid failure. In hypothyroid states of hypothalamic origin, TSH increases in response to exogenous TRH often with a delayed and/or exaggerated time course. But in patients with pituitary tumors and suprasellar extension TSH may also respond to TRH despite secondary hypothyroidism. This TSH increase may indicate a suprasellar cause for the secondary hypothyroidism, probably due to portal vessel occlusion. The TSH released in these cases is shown to be biologically inactive

    The reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) checklist: a joint statement by the ERAS® and ERAS® USA societies

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    Background: Enhanced Recovery After Surgery (ERAS) programs are multimodal care pathways designed to minimize the physiologic and psychological impact of surgery for patients. Increased compliance with ERAS guidelines is associated with improved patient outcomes across surgical types. As ERAS programs have proliferated, an unintentional effect has been significant variation in how ERAS-related studies are reported in the literature. Methods: To improve the quality of ERAS reporting, the ERAS® USA and the ERAS® Society launched an effort to create an instrument to assist authors in manuscript preparation. Criteria to include were selected by a combination of literature review and expert opinion. The final checklist was refined by group consensus. Results: The Societies present the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. The tool contains 20 items including best practices for reporting clinical pathways, compliance auditing, and formatting guidelines. Conclusions: The RECOvER Checklist is intended to provide a standardized framework for the reporting of ERAS-related studies. The checklist can also assist reviewers in evaluating the quality of ERAS-related manuscripts. Authors are encouraged to include the RECOvER Checklist when submitting ERAS-related studies to peer-reviewed journals

    Low-dose aspirin does not improve ovarian stimulation, endometrial response, or pregnancy rates for in vitro fertilization

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    BACKGROUND: The purpose of this study is to determine if low-dose aspirin improved ovarian stimulation, endometrial response, or IVF pregnancy rates in our program. METHODS: Retrospective analysis of 316 consecutive IVF cycles from 1995 through 2001. Aspirin 80 mg daily was initiated at the start of luteal leuprolide in 72 cycles. The 244 controls received no aspirin during treatment. RESULTS: The live birth rate in aspirin users was 29%, slightly lower compared to 41% in the no aspirin control group (p = 0.07). Implantation rates were 21% with aspirin and 30% in the control population (p = 0.01). There was no difference in the maximal endometrial thickness between aspirin and non-aspirin groups. The two groups were similar regarding age, gonadotropin ampules, embryos, number of embryos transferred, prior parity, diagnosis, use of intracytoplasmic sperm injection, and stimulation protocol. CONCLUSION: Low-dose aspirin was not beneficial to IVF patients in our program. Aspirin does not enhance endometrial thickness, augment the ovarian response, or improve pregnancy rates

    Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis.

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    BACKGROUND: There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO2) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO2, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO2 in context with a meta-analysis of published estimates of the association. METHODS AND FINDINGS: Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9-10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV1 in CHASE to estimate the prevalence of children with abnormal lung function (FEV1<80% of predicted value) expected under different scenarios of NO2 exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 μg/m3 increase in NO2 was associated with an 8 ml lower FEV1 (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 μg/m3 increase in NO2 level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function. CONCLUSIONS: Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function

    A multi-centre randomised controlled study of pre-IVF outpatient hysteroscopy in women with recurrent IVF implantation failure: Trial of Outpatient Hysteroscopy - [TROPHY] in IVF

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    <p>Abstract</p> <p>Background</p> <p>The success rate of IVF treatment is low. A recent systematic review and meta-analysis found that the outcome of IVF treatment could be improved in patients who have experienced recurrent implantation failure if an outpatient hysteroscopy (OH) is performed before starting the new treatment cycle. However, the trials were of variable quality, leading to a call for a large and high-quality randomised trial. This protocol describes a multi-centre randomised controlled trial to test the hypothesis that performing an OH prior to starting an IVF cycle improves the live birth rate of the subsequent IVF cycle in women who have experienced two to four failed IVF cycles.</p> <p>Methods and design</p> <p>Eligible and consenting women will be randomised to either OH or no OH using an internet based trial management programme that ensures allocation concealment and employs minimisation for important stratification variables including age, body mass index, basal follicle stimulating hormone level and number of previous failed IVF cycles. The primary outcome is live birth rate per IVF cycle started. Other outcomes include implantation, clinical pregnancy and miscarriage rates.</p> <p>The sample size for this study has been estimated as 758 participants with 379 participants in each arm. Interim analysis will be conducted by an independent Data Monitoring Committee (DMC), and final analysis will be by intention to treat. A favourable ethical opinion has been obtained (REC reference: 09/H0804/32).</p> <p>Trail Registration</p> <p>The trial has been assigned the following ISRCTN number: ISRCTN35859078</p

    The reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) checklist: a joint statement by the ERAS® and ERAS® USA societies

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    Background: Enhanced Recovery After Surgery (ERAS) programs are multimodal care pathways designed to minimize the physiologic and psychological impact of surgery for patients. Increased compliance with ERAS guidelines is associated with improved patient outcomes across surgical types. As ERAS programs have proliferated, an unintentional effect has been significant variation in how ERAS-related studies are reported in the literature.Methods: To improve the quality of ERAS reporting, the ERAS® USA and the ERAS® Society launched an effort to create an instrument to assist authors in manuscript preparation. Criteria to include were selected by a combination of literature review and expert opinion. The final checklist was refined by group consensus.Results: The Societies present the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. The tool contains 20 items including best practices for reporting clinical pathways, compliance auditing, and formatting guidelines.Conclusions: The RECOvER Checklist is intended to provide a standardized framework for the reporting of ERAS-related studies. The checklist can also assist reviewers in evaluating the quality of ERAS-related manuscripts. Authors are encouraged to include the RECOvER Checklist when submitting ERAS-related studies to peer-reviewed journals
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