Free fatty acids,insulin resistance,and pregnancy

Acute elevation of plasma free fatty acid (FFA) levels causes insulin resistance to rise dose dependently in pregnant and nonpregnant women. Plasma FFA levels are commonly elevated during late pregnancy, partly due to rising blood levels of lipolytic placental hormones, and are a likely cause for much of the increase in insulin resistance occurring at that time in all pregnant women. Plasma FFA levels are similar or higher and the insulin resistance is comparable or more severe in women with gestational diabetes mellitus (GDM) than in nondiabetic pregnant women. In contrast to healthy pregnant women, insulin secretion in women with GDM is defective and, therefore, is unable to rise adequately to compensate for the insulin resistance; the result is hyperglycemia. The mechanism by which elevated plasma FFA levels cause insulin resistance in skeletal muscle includes intramyocellular accumulation of diacylglycerol, which activates protein kinase C (the β II and δ isoforms). This results in reduction of tyrosine phosphorylation of the insulin receptor substrate-1 and inhibits activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake.     

Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis

BACKGROUND & AIMS: We tested whether the attenuation of experimental colitis by live probiotic bacteria is due to their immunostimulatory DNA, whether toll-like receptor (TLR) signaling is required, and whether nonviable probiotics are effective. METHODS: Methylated and unmethylated genomic DNA isolated from probiotics (VSL-3), DNAse-treated probiotics and Escherichia coli (DH5 alpha) genomic DNA were administered intragastrically (i.g.) or subcutaneously (s.c.) to mice prior to the induction of colitis. Viable or gamma-irradiated probiotics were administered i.g. to wild-type mice and mice deficient in different TLR or in the adaptor protein MyD88, 10 days prior to administration of dextran sodium sulfate (DSS) to their drinking water and for 7 days thereafter. RESULTS: Intragastric and s.c. administration of probiotic and E. coli DNA ameliorated the severity of DSS-induced colitis, whereas methylated probiotic DNA, calf thymus DNA, and DNase-treated probiotics had no effect. The colitis severity was attenuated to the same extent by i.g. delivery of nonviable gamma-irradiated or viable probiotics. Mice deficient in MyD88 did not respond to gamma-irradiated probiotics. The severity of DSS-induced colitis in TLR2 and TLR4 deficient mice was significantly decreased by i.g. administration of gamma-irradiated probiotics, whereas, in TLR9-deficient mice, gamma-irradiated probiotics had no effect. CONCLUSIONS: The protective effects of probiotics are mediated by their own DNA rather than by their metabolites or ability to colonize the colon. TLR9 signaling is essential in mediating the anti-inflammatory effect of probiotics, and live microorganisms are not required to attenuate experimental colitis because nonviable probiotics are equally effective.     

Utilization,Patient Characteristics,and Longitudinal Improvements among Patients from a Provincially Funded Transdiagnostic Internet-delivered Cognitive Behavioural Therapy Program: Observational Study of Trends over 6 Years

Objective:There is strong evidence supporting internet-delivered cognitive behaviour therapy (iCBT) and consequently growing demand for iCBT in Canada. Transdiagnostic iCBT that addresses both depression and anxiety is particularly promising as it represents an efficient method of delivering iCBT in routine care. The Online Therapy Unit, funded by the Saskatchewan government, has been offering transdiagnostic iCBT for depression and anxiety since 2013. In this article, to broadly inform implementation efforts, we examined trends in utilization, patient characteristics, and longitudinal improvements for patients receiving transdiagnostic iCBT over 6 years.Methods:Patients who completed telephone screening between November 2013 and December 2019 were included in this observational study. Patients provided demographics and mental health history at screening and completed measures at pre-treatment, post-treatment and at 3- to 4-month follow-up. Treatment engagement and satisfaction were assessed.Results:A total of 5,321 telephone screenings were completed and 4,283 of patients were accepted for treatment over the 6-year period (80.5% acceptance). The most common reason for referral to another service was high suicide risk/severe symptoms (47.1%). Examination of trends showed growing use of transdiagnostic iCBT over time (37% increase per year). There was remarkable stability in patient characteristics across years. Most patients were concurrently using medication (57.3%) with 11.9% reporting using iCBT while on a waiting list for face-to-face treatment highlighting the importance of integrating iCBT with other services. Consistent across years, large improvements in depression and anxiety symptoms were found and maintained at 3- to 4-month follow-up. There was strong patient engagement with iCBT and positive ratings of treatment experiences.Conclusions:As there is growing interest in iCBT in Canada, this large observational study provides valuable information for those implementing iCBT in terms of likely user characteristics, patterns of use, and improvements. This information has potential to assist with resource allocation and planning in Canada and elsewhere.     

Evaluation of the clinical significance of sonographic perinephric fluid in patients with renal colic

ObjectiveTo evaluate the significance of sonographic perinephric fluid collection on the emergent management of patients with acute urinary stone obstruction.MethodsWe conducted a prospective study with retrospective analysis. Since January 2016 through July 2017, patients admitted to our tertiary hospital's emergency department (ED) with suspected symptomatic urinary stones underwent ultrasound evaluation. Images were prospectively interpreted by experienced radiologist who analyzed each case for the following imaging features: hydronephrosis, perinephric fluid and urethral stone identification. The presence and measurements of perinephric fluid were re-evaluated by second radiologist who was blinded for the first reader's measurements. Retrospective analysis was conducted to evaluate for an association between perinephric fluid collection and the following outcome variables: need for analgesics, the number of doses of analgesics and the amount of morphine (mg) in the ED, elevation of creatinine levels, hospitalization and need for urological interventions.ResultsThe need for analgesics, the number of doses of analgesics and the amount of morphine were significantly associated with the presence of perinephric fluid (p < 0.05). The odds ratio for the need for analgesics was 3.8 in the presence of any perinephric fluid, and 8.9 in the presence of moderate/severe perinephric fluid. No other patient outcome variables were found to be significantly associated with the presence of perinephric fluid (p > 0.05).ConclusionsThis study shows a correlation between sonographic evidence of perinephric fluid and more severe pain. Therefore, an emergency physician can consider the evidence of perinephric fluid, in acute urethral stone obstruction, a predictor for more severe pain.     

Olanzapine vs. haloperidol in the treatment of elderly chronic schizophrenia patients

OBJECTIVE: Most of the data supporting the use of atypical antipsychotics (AA) is based on studies in young adult patients. The present study is an open-label naturalistic follow-up study of olanzapine treatment vs. haloperidol for elderly chronic schizophrenia patients. MEHTOD: 20 patients (mean age 72.7+/-5.9 years, mean disease duration 33.1+/-12.0 years) who met the DSM-IV criteria for schizophrenia were randomly assigned to olanzapine (n=10) or haloperidol (n=10) treatment during acute exacerbation. Primary outcome measure was rating on the Clinical Global Impression (CGI) scale and the Positive and Negative Symptom Scale (PANSS). RESULTS: Between-group differences were computed using analysis of covariance. PANSS Total score decreased from 84 at baseline to 65 after treatment with olanzapine while decreased only from 79 to 74 with haloperidol treatment (F= 6.66, P=.02). PANSS Negative subscale decreased from 19 at baseline to 15 with olanzapine treatment while increased (deteriorated) from 18 to 20 with haloperidol treatment (F=23.37, P=.0003). CGI decreased from baseline with both olanzapine and haloperidol treatments (1.1 vs. 0.4) but the decrease in the olanzapine group was significantly greater (F=4.63, P=.05). Mean weight increased in both groups but without statistical difference between groups. CONCLUSIONS: In elderly chronic schizophrenia patients, olanzapine treatment is superior to haloperidol in reducing negative symptoms as well as less induction of extrapyramidal symptoms (EPS).     

Involvement of microparticles in diabetic vascular complications

Type 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipid-bearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients (<0.7) but high in patients with coronary artery disease and foot ulcers (>1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the pro- coagulant state and vascular pathology in patients with T2DM.