Increased transforming growth factor-beta1circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin

AbstractObjectivesWe sought to determine whether inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase with pravastatin affects transforming growth factor-beta1(TGF-beta1) circulating levels and its production in the monocytes of hypercholesterolemic patients.BackgroundTransforming growth factor-beta1is a multifunctional growth factor/cytokine involved in many physiologic and pathologic processes, such as vascular remodeling and atherogenesis. Statins have been reported to have a modulatory role in cytokine expression in the monocytes of hyperlipidemic patients.MethodsWe evaluated, in a cross-over study design, plasma TGF-beta1levels and ex vivo TGF-beta1production in the monocytes of hypercholesterolemic patients before and after four to six weeks of lipid-lowering treatment with diet or diet plus 40 mg/day of pravastatin. In addition, isolated blood monocytes were subjected to pravastatin treatment and evaluated for TGF-beta1messenger ribonucleic acid (mRNA) expression and TGF-beta1in vitro production.ResultsLipid-lowering treatment significantly decreased total cholesterol and low-density lipoprotein cholesterol plasma levels. Pravastatin, but not a low lipid diet, induced a significant increase in TGF-beta1plasma levels (from 1.7 ± 0.5 ng/ml to 3.1 ± 1.1 ng/ml, p < 0.001) and in ex vivo monocyte production (from 1.8 ± 0.8 ng/ml to 3.9 ± 1.0 ng/ml, p < 0.001). The increase in TGF-beta1levels was not related to the changes in the lipid profile observed with pravastatin. An increase of approximately twofold in TGF-beta1production and in mRNA expression was also observed after in vitro treatment of human monocytes with pravastatin (5 μM). Co-incubation with mevalonate reversed the in vitro effect of pravastatin.Conclusions3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition with pravastatin increases TGF-beta1plasma levels, as well as monocyte production, in hypercholesterolemic patients. The mevalonate pathway plays a role in the regulation of TGF-beta1expression in human monocytes. A possible implication in the biologic and clinical effects of statins can be suggested

Splanchnic vein thrombosis : current perspectives

Splanchnic vein thrombosis (SVT) including portal, mesenteric, splenic vein thrombosis and the Budd-Chiari syndrome, is a manifestation of unusual site venous thromboembolism. SVT presents with a lower incidence than deep vein thrombosis of the lower limbs and pulmonary embolism, with portal vein thrombosis and Budd-Chiari syndrome being respectively the most and the least common presentations of SVT. SVT is classified as provoked if secondary to a local or systemic risk factor, or unprovoked if the causative trigger cannot be identified. Diagnostic evaluation is often affected by the lack of specificity of clinical manifestations: the presence of one or more risk factors in a patient with a high clinical suspicion may suggest the execution of diagnostic tests. Doppler ultrasonography represents the first line diagnostic tool because of its accuracy and wide availability. Further investigations, such as computed tomography and magnetic resonance angiography, should be executed in case of suspected thrombosis of the mesenteric veins, suspicion of SVT-related complications, or to complete information after Doppler ultrasonography. Once SVT diagnosis is established, a careful patient evaluation should be performed in order to assess the risks and benefits of the anticoagulant therapy and to drive the optimal treatment intensity. Due to the low quality and large heterogeneity of published data, guidance documents and expert opinion could direct therapeutic decision, suggesting which patients to treat, which anticoagulant to use and the duration of treatment.peer-reviewe

Inhibition of P-glycoprotein-mediated multidrug resistance by unfractionated heparin: a new potential chemosensitizer for cancer therapy.

Anticoagulant treatment with heparins is frequently used to prevent venous thromboembolism in cancer patients. In the present study, we investigated the ability of unfractionated heparin (UFH) to inhibit P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) on human breast cancer cell line (MDA-MB231) and its doxo-resistant subline. Results were a compared to the classic reversing agent, Verapamil (Ver), used, as reference at 50 microM concentration. We analysed the Pgp function by calcein acetoxymethylester (calcein-AM) uptake, a fluorescent marker substrate, before and after in vitro exposure to UFH at clinically achievable dose of 20 U/ml. The mean percentage of calcein-AM retained into cancer cells after 3 and 12 h were 32 +/- 10.9 and 45 +/- 12.3, respectively, for UFH pretreated cells and 25.3 +/- 8.7 and 29.4 +/- 10.4, respectively, for Ver pretreated cells when compared to control cells, receiving only medium. Pgp activity was studied by measuring intracellular drug accumulation in doxo-resistant subline, treated (2 h) with either UFH or Ver, prior exposure (2 h) at different doxo concentrations (2, 4 and 8 microM). The mean percentage of remaining intracellular doxo were 55.4 +/- 4.5 , 51.4 +/- 3.9 and 50 +/- 1.8 percent, respectively for UFH treated cells, and 44.1 +/- 5.8, 39.3 +/- 4.4 and 19.4 +/- 8.6%, respectively, for Ver treated cells as compared with control cells, receiving only doxo. These results were consistent with the increase of sensitivity to doxo of the same doxo-resistant subline resulting in a 2.2, 2.6 and 2.2-fold increase, respectively, for UFH-doxo combination and 2.2, 2.5 and 2.0-fold respectively, for Ver-doxo combination respect to cells receiving doxo alone, as assessed by MTT test. In conclusion, these findings demonstrate the potentiating effect in vitro of UFH on doxo accumulation and cytotoxicity in the MDA-231 cell line and its doxo-resistant subline and suggest that UFH could to be used, as an potential chemosensitizer, in clinical chemotherapy for increasing in vivo, the efficacy of the anticancer treatment

Effects of Obesity and Thrombophilia on the Risk of Abortion in Women Undergoing In Vitro Fertilization.

Introduction Obesity is associated with a higher risk of abortion in women undergoing in vitro fertilization (IVF). Whether thrombophilia amplifies this risk is currently unclear. The aim of this study was to evaluate the effects of thrombophilia on the risk of abortion in obese women treated with IVF. Methods Patient characteristics, presence of inherited or acquired thrombophilia, and comorbidities were prospectively collected before the procedure in consecutive women undergoing IVF. The primary outcome was the incidence of abortion among women who achieved a clinical pregnancy. Results A total of 633 non-obese and 49 obese Caucasian women undergoing IVF were included. 204 (32%) women achieved clinical pregnancy, of whom six had an ectopic pregnancy and 63 experienced an abortion. The incidence of abortion was higher in obese women compared to non-obese women after adjusting for age (64.3% vs. 29.3%, odds ratio [OR] 4.41; 95% CI 1.41 to 13.81). Women with one or more thrombophilia were at increased risk of abortion relative to those without thrombophilia (OR 2.70; 95% CI 1.34 to 5.45), and the risk seemed to be higher with hereditary (OR 5.12; 95% CI 1.77 to 14.8) than acquired thrombophilia (OR 1.92; 95% CI 0.52 to 5.12; p for interaction 0.194). Among obese women, the presence of one or more thrombophilia seemed associated with a substantially increased risk of abortion (unadjusted OR 14.00; 95% CI 0.94 to 207.6). Conclusions Obese women undergoing IVF have a high risk of abortion which seems further amplified by the concomitant presence of thrombophilia

Antithrombotic treatment of retinal vein occlusion: a position statement from the Italian Society on Thrombosis and Haemostasis (SISET)

Retinal vein occlusion (RVO) represents a common cause of visual impairment and blindness. RVO may be associated with both local (e.g., hyperopia, glaucoma) and systemic (e.g., hypertension, diabetes, smoking, obesity, and dyslipidaemia) risk factors. The association with thrombophilia remains controversial. Data on the use of antithrombotic therapy for RVO are poor and inconsistent with most of the information being derived from observational studies. Here we provide a position statement from the Italian Society on Thrombosis and Haemostasis (SISET) to guide the clinical and therapeutic management of patients with RVO based on the available evidence and expert opinion

Cannabinoids for Medical Use A Systematic Review and Meta-analysis

Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Data Sources Twenty-eight databases from inception to April 2015. Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.36 [95% CI, −0.69 to −0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.This funded by the Swiss Federal Office of Public Health (FOPH) under grant agreement 14.001443/204.0001/-1257Revisión por pare

Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life

Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life

The Khorana score for prediction of venous thromboembolism in cancer patients:a systematic review and meta-analysis

We aimed to evaluate the performance of the Khorana score in predicting venous thromboembolic events in ambulatory cancer patients. Embase and MEDLINE were searched from January 2008 to June 2018 for studies which evaluated the Khorana score. Two authors independently screened studies for eligibility, extracted data, and assessed risk of bias. Additional data on the 6-month incidence of venous thromboembolism were sought by contacting corresponding authors. The incidence in each Khorana score risk group was estimated with random effects meta-analysis. A total of 45 articles and eight abstracts were included, comprising 55 cohorts enrolling 34,555 ambulatory cancer patients. For 27,849 patients (81%), 6-month follow-up data were obtained. Overall, 19% of patients had a Khorana score of 0 points, 64% a score of 1 or 2 points, and 17% a score of 3 or more points. The incidence of venous thromboembolism in the first six months was 5.0% (95% CI: 3.9-6.5) in patients with a low-risk Khorana score (0 points), 6.6% (95% CI: 5.6-7.7) in those with an intermediate-risk Khorana score (1 or 2 points), and 11.0% (95% CI: 8.8-13.8) in those with a high-risk Khorana score (3 points or higher). Of the patients with venous thromboembolism in the first six months, 23.4% (95% CI: 18.4-29.4) had been classified as high risk according to the Khorana score. In conclusion, the Khorana score can be used to select ambulatory cancer patients at high risk of venous thromboembolism for thromboprophylaxis; however, most events occur outside this high-risk group