Compared with control intervention, transcutaneous electrical nerve stimulation supplementation intervention was found to significantly reduce pain and morphine requirement over a period of 24 h and to promote functional recovery in patients who have undergone total knee arthroplasty.

BNP and NT-proBNP display closely equivalent overall diagnostic accuracies in distinguishing cardioembolic stroke from non-cardioembolic stroke in adult ischemic stroke patients, with BNP showing a superior sensitivity and NT-proBNP showing a superior specificity.

BackgroundAntihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease.MethodsMEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed.ResultsA total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria.ConclusionsTrandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively.

Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPARγ’s co-regulators during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPARγ co-regulator that directly binds to and suppresses PPARγ activity in murine cerebrovascular endothelial cells. Moreover, IRF6 was also revealed to be a transcriptional target of PPARγ suppression, with PPARγ silencing significantly promoting IRF6 expression in cerebrovascular endothelial cells. In addition, IRF6 silencing significantly promoted pioglitazone’s cytoprotective effects in ischemic murine cerebrovascular endothelial cells. Mechanistically, IRF6 significantly suppressed PPARγ’s transcriptional inhibition of the ischemia-induced, pro-apoptotic microRNA miR-106a. In conclusion, we identified IRF6 as a novel PPARγ co-suppressor that serves a key role in suppressing PPARγ-mediated cerebrovascular endothelial cytoprotection following ischemia. Further investigation into IRF6 and other PPARγ co-regulators should provide additional insights into PPARγ’s cytoprotective role in the cerebrovascular endothelium following stroke.

Toll-like receptor 2 and 4 (TLR2, TLR4) signaling is implicated in atherosclerotic plaque formation. The two-stage master regulator Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis of macrophage TLR2 and TLR4 signature genes integrated with coexpression network genes derived from 371 patient-derived carotid specimens identifies activated RNA polymerase II transcriptional coactivator p15 (SUB1/Sub1, PC4) as a master regulon in the atherogenic TLR response. It is found that TLR2 and TLR4 signaling is proinflammatory and proatherosclerotic in chow-fed apolipoprotein E-deficient (ApoE −/− ) mice. Through transgenic myeloid-specific Sub1 knockout in ApoE −/− mice, it is discovered that these proatherosclerotic effects of TLR2 and TLR4 signaling are mediated by Sub1. Sub1 knockout in macrophages enhances anti-inflammatory M2 macrophage polarization and cholesterol efflux. Irradiated low density lipoprotein receptor-deficient (Ldlr −/− ) mice transplanted with Sub1 −/− murine bone marrow display reduced atherosclerosis. Promoter analysis reveals Sub1-dependent activation of interferon regulatory factor 1 (Irf1) transcription in a casein kinase 2 (Ck2)-dependent manner, and Sub1-knockout macrophages display decreased Irf1 expression. Artificial Irf1 overexpression in Sub1-knockout macrophages enhances proinflammatory M1 skewing and lowers cholesterol clearance. In conclusion, the TLR master regulon Sub1, and its downstream effect on the transcription factor Irf1, promotes a proinflammatory M1 macrophage phenotype and enhances atherosclerotic burden in vivo.