Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up.
The orphan nuclear hormone receptor small heterodimer partner (SHP) regulates the expression of several genes involved in bile acid homeostasis in the liver. Because bile acid toxicity is a major source of liver injury in cholestatic disease, we explored the role of SHP in liver damage induced by common bile duct ligation (BDL). Shp ؊/؊ mice show increased sensitivity in this model of acute obstructive cholestasis, with greater numbers of bile infarcts and higher mortality than wild-type C57BL/6 mice. This increased sensitivity could not be accounted for by differences in expression of bile acid homeostatic genes 2 or 5 days after BDL. Instead, higher basal expression of such genes, including the key biosynthetic enzyme cholesterol 7␣ hydroxylase (Cyp7A1) and the bile salt export pump, is associated with both an increase in bile flow prior to BDL and an increase in acute liver damage at only 1.5 hours after BDL in Shp ؊/؊ mice, as shown by bile infarcts. At 3 hours, Cyp7A1 expression still remained elevated in Shp ؊/؊ with respect to wild-type mice, and the hepatic and serum bile acid levels and total hepatobiliary bile acid pool were significantly increased. The increased sensitivity of mice lacking SHP contrasts with the decreased sensitivity of mice lacking the farnesoid X receptor (FXR; nuclear receptor subfamily 1, group H, member 4) to BDL, which has been associated with decreased intraductal pressure and fewer bile infarcts. Conclusion: We propose that differences in acute responses to BDL, particularly the early formation of bile infarcts, are a primary determinant of the differences in longer term sensitivity of the Fxr ؊/؊ and Shp ؊/؊ mice to acute obstructive cholestasis. (HEPATOLOGY 2008;
Diabetic nephropathy (DN) is a serious complication of both type 1 and type 2 diabetes mellitus. The disease is now the most common cause of end-stage kidney disease (ESKD) in developed countries, and both the incidence and prevalence of diabetes mellitus is increasing worldwide. Current treatments are directed at controlling hyperglycemia and hypertension, as well as blockade of the renin angiotensin system with angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers. Despite these therapies, DN progresses to ESKD in many patients. As a result, much interest is focused on developing new therapies. It has been over two decades since ACEIs were shown to have beneficial effects in DN independent of their blood pressure-lowering actions. Since that time, our understanding of disease mechanisms in DN has evolved. In this review, we summarize major cell signaling pathways implicated in the pathogenesis of diabetic kidney disease, as well as emerging treatment strategies. The goal is to identify promising targets that might be translated into therapies for the treatment of patients with diabetic kidney disease.
Rationale: The coronavirus disease (COVID-19) pandemic struck an immunologically naive, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates. Objectives: To assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19. Methods: We performed a randomized clinical trial of hydroxychloroquine versus azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID ordinal outcomes scale at Day 14. Secondary endpoints included hospital-, intensive care unit–, and ventilator-free days at Day 28. The trial was stopped early after the enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective. Results: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine versus azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithromycin. Secondary outcomes displayed a similar slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The 20 safety outcomes were similar between arms, with the possible exception of postrandomization-onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than those in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury. Conclusions: Although early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation. Clinical trial registered with www.clinicaltrials.gov (NCT04329832).
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.
Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current “off-label” treatments for COVID-19—hydroxychloroquine and azithromycin—in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered ( ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient. Clinical trial registered with www.clinicaltrials.gov (NCT04329832).
Radiofrequency catheter ablation is being used with increasing frequency as a strategy to manage atrial fibrillation. Patients undergoing this procedure are at increased short-term risk of thromboembolism for several days and up to 4 weeks or longer after their ablation, and anticoagulation management surrounding the ablation procedure remains controversial. Although no conclusive recommendations can be made, published guidelines and data support therapeutic anticoagulation with warfarin for 3 weeks prior and intravenous heparin during the ablation. Warfarin may either be continued through the ablation or stopped 2–5 days prior. If the latter approach is chosen, a pre-ablation bridging strategy of enoxaparin 1 mg/kg twice daily is reasonable in selected patients unless the patient’s bleeding risk dictates using a lower dose regimen (0.5 mg/kg twice daily) or avoiding bridging altogether. Fewer data are available for post-ablation management strategies, and current practice patterns are based largely on single-center experiences in smaller, non-randomized studies. For lower risk patients (CHADS2 0–1), either warfarin or aspirin may be utilized without bridging. In higher thromboembolic risk patients (CHADS2 ≥ 2), either enoxaparin (1 mg/kg twice daily) or heparin may be started within the first 12–24 h post-procedure. For patients with bleeding risk factors, enoxaparin may be subsequently reduced to 0.5 mg/kg until the INR is therapeutic, although the efficacy of this lower dosing regimen has not been well studied. In accordance with national guidelines, warfarin should be continued post-ablation for a minimum of 2 months and then indefinitely in patients with a CHADS2 score ≥ 2.
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