Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors.

BACKGROUND: Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. METHODS: We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. RESULTS: Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. CONCLUSION: We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

Impact of statin on long-term outcome among patients with end-stage renal disease with acute myocardial infarction (AMI): a nationwide case-control study.

BACKGROUND: Use of statin has been associated with reduced risk of cardiovascular diseases events and mortality. However, in patients with end-stage renal disease (ESRD), the protective effects of statin are controversial. To evaluate the impact of chronic statin use on clinical outcomes of patients with acute myocardial infarction (AMI) with ESRD. METHODS: We enrolled 8056 patients with ESRD who were initially diagnosed and admitted for first AMI from Taiwan's National Health Insurance Research Database. Of which, 2134 patients underwent statin therapy. We randomly selected and use age, sex, hypertension, diabetes mellitus (DM), peripheral vascular diseases (PVD), heart failure (HF), cerebrovascular accidents (CVA), chronic obstructive pulmonary disease, matched with the study group as controls (non-stain user). We compared the effects of statin use in term of all-cause death among patients with AMI with ESRD. RESULTS: Statin use resulted in a significantly higher survival rate in patients ith AMI with ESRD compared with non-statin users. After adjusted the comorbidities the male patients and patients with DM, PVD, HF and CVA had lower long-term survival rate (all p<0.001). Patients who underwent percutaneous coronary intervention (p<0.001), ACE inhibitors/angiotensin II receptor blockers (p<0.001), ß receptor blockers (p<0.001) and statin therapy (p=0.007) had better long-term survival rate. Patients with AMI with ESRD on statin therapy exhibited a significantly lower risk of mortality compared with non-statin users (p<0.0001). CONCLUSION: Among patients with ESRD with AMI, statin therapy was associated with reduced all-cause mortality.

Safety and Cumulative Incidence of Major Cardiovascular Events with Ticagrelor in Taiwanese Patients with Non-ST-Segment Elevation Myocardial Infarction: A 12-Month, Prospective, Phase IV, Multicenter, Single-Arm Study.

BACKGROUND: Ticagrelor, an oral, direct-acting, and reversible P2Y12 receptor antagonist, inhibits platelet activation and aggregation. This phase IV, single-arm study analyzed the safety and tolerability of ticagrelor in Taiwanese patients with non-ST-segment elevation myocardial infarction (NSTEMI) during 1 year of follow-up. METHODS: Patients aged ≥ 20 years with an index event of NSTEMI received ticagrelor (180 mg loading and 90 mg doses twice daily thereafter) plus low-dose aspirin (100 mg/day) for up to 1 year. Safety was evaluated according to adverse events (AEs), serious AEs (SAEs), and PLATO-defined bleeding events. The cumulative incidence of major cardiovascular (CV) events including CV death, myocardial infarction, and stroke was also evaluated. RESULTS: The safety population included 108 patients across 13 centers in Taiwan. During treatment, 32 (29.6%) patients had ≥ one PLATO-defined bleeding event. Major bleeding events occurred in seven (6.5%) patients with a Kaplan-Meier (KM) estimated event risk [95% confidence interval (CI)] of 7.1% (3.4%-14.4%), including life-threatening bleeding [four (3.7%) patients] and other major bleeding [three (2.8%) patients]. No PLATO-defined fatal bleeding was observed. SAEs were reported in 23 (21.3%) patients. Six (5.6%) patients experienced major CV events during the 1-year follow-up period, with a KM-estimated event risk (95% CI) of 5.6% (2.6%-12.0%). CONCLUSIONS: Ticagrelor for up to 1 year was associated with a low rate of major bleeding events and a low incidence of major CV events in Taiwanese patients with NSTEMI. The overall safety of ticagrelor was in accordance with the known safety profile of ticagrelor.

Influence of Contact Stress on Surface Microstructure and Wear Property of D2/U71Mn Wheel-Rail Material.

To investigate the relationship between surface microstructure and wear mechanism in D2/U71Mn wheel-rail material under different contact stress conditions, rolling wear tests using a GPM-40 wear machine to simulate the wheel-rail operation was performed. After wear tests, an optical microscope (OM), scanning electron microscope (SEM) and micro-hardness testers were used to characterize the microstructure and fatigue wear cracks. The results show that the thickness of the plastic deformation layer and surface hardness is increased with the increase of contact stress. Under high contact stress condition (1200 MPa), the severe plastic deformation layer led to the formation of fatigue wear of wheel-rail samples. Under a contact stress of 700 MPa, the wear mechanism of samples is adhesive wear and wear rate is low. With the increase of contact stress, the fatigue cracks are gradually severe. Under a contact stress of 1200 MPa, the wear mechanism of samples becomes fatigue wear and the fatigue wear cracks cause the increase of wear rate. The fatigue wear can accelerate the wear failure of wheel-rail samples. The fatigue wear cracks of wheel samples are severer than that of rail samples due to both the rate of plastic strain and the content of proeutectoid ferrite.

Caffeic Acid Phenethyl Ester Rescues Pulmonary Arterial Hypertension through the Inhibition of AKT/ERK-Dependent PDGF/HIF-1α In Vitro and In Vivo.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.

Improving outcomes in chronic obstructive pulmonary disease by taking beta-blockers after acute myocardial infarction: a nationwide observational study.

ß-Blockers are a standard therapy for acute myocardial infarction (AMI) due to their better short-term and long-term outcomes. However, ß-blockers are often under-prescribed in chronic obstructive pulmonary disease (COPD) patients with AMI, since they are thought be related to bronchospasm. The aim of this study was to investigate the association between the usage of ß-blockers and the risk of mortality in COPD patients after first AMI via a nationwide, population-based cohort study. In this retrospective study, we identified 186,326 patients with AMI diagnosed between January 2000 and December 2012, 23,116 of whom had COPD, from the National Health Insurance Research Database. A total of 7609 patients (32.92%) were prescribed ß-blockers, while 15,507 were not. The ß-blocker patients were stratified into selective and non-selective ß-blocker groups. Multivariate Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) with 95% confidence intervals (95% CI). Selective ß-blocker use showed a reduced risk of mortality, as compared with patients without ß-blockers (HR 0.93; 95% CI 0.89-0.98; p < 0.01) while non-selective ß-blocker groups did not increase the risk of mortality compared to the patients without ß-blockers (HR 0.98; 95% CI 0.94-1.02; p = 0.38). In addition, the use of ß-blockers was found to be associated with a reduced risk of mortality in most stratified analyses which was seen particularly in males, patients aged 65 years and above, and in individuals with an array of comorbidities. These findings suggest that ß-blockers improve overall survival among COPD patients after first AMI.

Combination Therapy with Dipyridamole and Clopidogrel for Secondary Stroke Prevention in Aspirin-Intolerant Patients After Myocardial Infarction: Results of a Nationwide Case-Control Study.

BACKGROUND AND PURPOSE: Combination therapy with dipyridamole and clopidogrel in stroke prevention and long-term outcomes in aspirin-intolerant patients with acute myocardial infarction (AMI) and previous stroke are unknown. This nationwide study analyzed the impact of dipyridamole and clopidogrel on secondary stroke prevention and long-term outcomes in aspirin-intolerant stroke patients after AMI. METHODS: This was a nationwide, case-control study involving 186,112 first AMI patients, 78,607 of whom had a previous history of stroke. In the final analysis, we included 4637 patients taking clopidogrel alone and 208 patients using a combination of clopidogrel and dipyridamole. RESULTS: The 12-year survival rate was not different between clopidogrel and clopidogrel-dipyridamole groups (log-rank p = 0.6247). Furthermore, there were no differences in event-free survival after stroke (log-rank p = 0.6842), gastrointestinal (GI) bleeding (log-rank p = 0.9539), or intracerebral hemorrhage (ICH; log-rank p = 0.6191) between the two groups. Dipyridamole did not contribute significantly to AMI survival (hazard ratio 0.98, 95% confidence interval 0.84-1.15), and did not show benefits in any of the subgroups regardless of sex, age (younger or older than 75 years), comorbidities, percutaneous coronary intervention, or medications. CONCLUSION: No differences were observed in the 12-year survival rate between clopidogrel and clopidogrel-dipyridamole groups. The two groups had balanced event-free survival in recurrent stroke, ICH, GI bleeding, and myocardial infarction.

Comparison of long-term mortality in patients with acute myocardial infarction associated with or without sepsis.

OBJECTIVES: Although the association between systemic infection and cardiovascular events has been identified, uncertainty remains regarding the incidence and prognosis of sepsis in acute myocardial infarction (AMI). The purpose of this research was to assess the impact of sepsis on survival after first AMI. METHODS: This was a nationwide cohort study involving the analysis of data from the Taiwan National Health Insurance Research Database for the period 2000-2012, for patients with a primary diagnosis of first AMI. Among the 186112 prospective patients, sepsis was diagnosed in 13065 (7.0%). The propensity score matching technique was used to match 13065 controls to the patients with sepsis and AMI with similar baseline characteristics. Cox proportional hazards regression models, including sepsis, percutaneous coronary intervention (PCI), and comorbidities, were performed to further evaluate the different influences on the mortality risk in patients hospitalized for first AMI. RESULTS: Overall, the 12-year survival rate was lower in AMI patients with sepsis than in those without sepsis (log rank p-value <0.001); this was also shown in the different age and sex groups. The AMI patients with sepsis had a longer length of hospital stay than those without sepsis (32.5days vs. 11.74 days, p<0.001). In the Cox proportional hazards regression analysis, sepsis was an independent risk factor for mortality in patients after AMI (hazard ratio 1.78; 95% confidence interval 1.72-1.83). Interventional management with PCI or coronary artery bypass grafting improved survival in both the sepsis and non-sepsis patients after first AMI. CONCLUSIONS: In conclusion, sepsis significantly increased the mortality risk of patients after first AMI. PCI may improve the long-term survival of patients in comparison to those managed conservatively.

The Dipyridamole Added to Dual Antiplatelet Therapy in Cerebral Infarction After First Acute Myocardial Infarction: A Nationwide, Case-Control Study.

Background and Purpose: No previous study has compared the impact of dipyridamole-based triple antiplatelet therapy on secondary stroke prevention and long-term outcomes to that of dual antiplatelet therapy (DAPT) in patients with acute myocardial infarction (AMI) and previous stroke. This study aimed to evaluate the impact of dipyridamole added to DAPT on stroke prevention and long-term outcomes in patients with cerebral infarction after first AMI. Methods: This nationwide, case-control study included 75,789 patients with cerebral infarction after first AMI. A 1:4 propensity score matching ratio was adopted based on multiple variables. Finally, the data of 4,468 patients included in the DAPT group and 1,117 patients included in the Dipyridamole-DAPT group were analyzed. Primary outcome was overall survival. Secondary outcomes were cumulative event rate of recurrent MI or stroke, and cumulative intracerebral hemorrhage (ICH) and gastrointestinal bleeding rate. Results: Long-term survival rate was comparable between the two groups (log-rank P = 0.1117), regardless of sex analyses. However, after first year, DAPT subgroup revealed better survival over DAPT-dipyridamole subgroup (log-rank P = 0.0188). In age subgroup analysis, a lower survival rate was detected in younger patients from the Dipyridamole-DAPT group after first year (log-rank P = 0.0151), but no survival difference for older patients. No benefit of Dipyridamole-DAPT was detected for patients after AMI, regardless of the myocardial infarction type. DAPT was superior to Dipyridamole-DAPT in patients who underwent percutaneous coronary intervention (PCI) (log-rank P = 0.0153) and ST elevation myocardial infarction after first year (log-rank P = 0.0019). Dipyridamole-DAPT did not reduce cumulative event rate of recurrent MI or stroke in patients after AMI. Moreover, Dipyridamole-DAPT increased the cumulative ICH rate (log-rank P = 0.0026), but did not affect the cumulative event rate of gastrointestinal bleeding. In Cox analysis, dipyridamole did not improve long-term survival. Conclusions: This nationwide study showed that Dipyridamole-DAPT, compared with DAPT, did not improve long-term survival in patients with stroke after AMI, and was related to poor outcomes after 1 year. Dipyridamole-DAPT did not reduce recurrent rate of MI or stroke, but increased the ICH rate without impacting the incidence of gastrointestinal bleeding.

A novel clinical multidimensional transcriptome signature predicts prognosis in bladder cancer.

A number of studies has shown that long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and protein coding genes (PCGs) are involved in various pathophysiological processes and can be used as prognostic biomarkers in cancer patients. The purpose of this study was to find a multidimensional transcriptome signature to predict clinical outcomes in bladder cancer. Using Cox's proportional hazards regression analysis and the random survival forest algorithm, we mined the expression profile data of 239 bladder cancer patients derived from The Cancer Genome Atlas (TCGA) public database. A signature comprised of two PCGs (ACADS and C1QTNF9B), two lncRNAs (RP11­60L3.1 and CTD­3195I5.3) and two microRNAs (has­miR­3913­1 and has­miR­891a) with highest accuracy prediction (AUC=0.79 in the training dataset and 0.64 in the test dataset) was selected. The signature had an ability to stratify patients into high­ and low­risk groups with significantly different survival rates (median 16.9 vs. 54.9 months, log­rank test P<0.001) in the training dataset, and its performance was validated for risk stratification in the test dataset (median 18.2 vs. 58.9 months, log­rank test P=0.002). Multivariable Cox regression analysis revealed that the signature was an independent prognostic factor for patients with bladder urothelial carcinoma (BLCA). A comparison of tumour node metastasis (TNM) stage and the signature indicated that the signature had better survival prediction power (AUCsignature=0.79/0.64 vs. AUCTNM=0.67/0.60, P<0.05). Functional analyses indicated that these prognostic genes from the signature may be involved in tumourigenesis­related biological processes and pathways. In conclusion, the multidimensional PCG­lncRNA­microRNA signature can be a novel prognostic marker to predict the survival of bladder cancer patients.

Impact of hepatitis C virus infection on long-term mortality after acute myocardial infarction: a nationwide population-based, propensity-matched cohort study in Taiwan.

INTRODUCTION: The influence of hepatitis C virus (HCV) infection on long-term outcomes of patients with acute myocardial infarction (AMI) is unclear. Therefore, this study aimed to analyse the impact of HCV infection on 12-year mortality rates after AMI using data from the Taiwan National Health Insurance Research Database (NHIRD). METHODS: NHIRD data for approximately 23 000 000 patients between January 2000 and December 2012 were analysed. A total of 186 112 cases of first AMI admission were identified. A total of 4659 patients with HCV infection not receiving interferon therapy were enrolled and divided into those with (n=107) or without (n=4552) cirrhosis. Using one-to-one matching, 4552 matched controls were included in the final analysis. RESULTS: The 12-year mortality rate was significantly higher in patients with AMI with HCV infection and cirrhosis than in those with HCV infection but without cirrhosis (P<0.0001) or controls (P<0.0001). Patients with HCV infection but without cirrhosis had significantly higher long-term mortality rates than the matched controls (P<0.0001). The HR for mortality was higher in patients with HCV infection (HR 1.12; 95% CI 1.06 to 1.18). HCV influenced outcomes among the subgroups of patients who were male (HR 1.15) and those who had hypertension (HR 1.14). CONCLUSIONS: HCV infection influenced the 12-year mortality rates of patients with AMI, especially those who were male and those who had hypertension. Cirrhosis further increased the long-term mortality rates of patients with AMI with HCV infection.

Risk Factors For Radiation-Induced Skin Ulceration in Percutaneous Coronary Interventions of Chronic Total Occluded Lesions: A 2-Year Observational Study.

Relationship between radiation-induced skin ulceration (RSU) and variables in percutaneous coronary interventions (PCI) was rarely reported. RSU is a severe complication in PCIs, especially for chronic total occlusion (CTO) lesions. We investigated the RSUs and their risk factors in patients receiving CTO PCIs over a 2-year period. Data were analyzed using chi-square tests, t-tests and receiver operating characteristic (ROC) curve. Of 238 patients, 11 patients (4.6%) had RSUs all at right upper back. RSUs were significantly associated with use of left anterior oblique (LAO) views (100% vs. 47.1%, p < 0.001), retrograde techniques (36.3% vs. 7.9%, p = 0.012), or a procedure time (PT) defined as a time duration between the first and last angiograms of > 120, 180, or 240 minutes (p < 0.05). ROC analysis showed a long PT was an accurate predictor of RSUs (AUC = 0.88; p < 0.001) at a cut-off of 130 minutes (sensitivity = 0.91, specificity = 0.81). The results showed risk factors for RSUs containing use of large LAO views, retrograde techniques, and prolonged PTs. This study suggests that, to minimize RSU, interventionalists should limit PT to roughly 2 hours in fixed LAO views.

The impact of DPP-4 inhibitors on long-term survival among diabetic patients after first acute myocardial infarction.

BACKGROUND: Previous studies regarding the cardioprotective effects of dipeptidyl peptidase 4 (DPP-4) inhibitors have not provided sufficient evidence of a relationship between DPP-4 inhibition and actual cardiovascular outcomes. This study aimed to evaluate the impact of DPP-4 inhibitors on the survival of diabetic patients after first acute myocardial infarction (AMI). METHODS: This was a nationwide, propensity score-matched, case-control study of 186,112 first AMI patients, 72,924 of whom had diabetes. A propensity score, one-to-one matching technique was used to match 2672 controls to 2672 patients in the DPP-4 inhibitor group for analysis. Controls were matched based on gender, age, and a history of hypertension, dyslipidemia, diabetes, peripheral vascular disease, heart failure, cerebrovascular accident, end-stage renal disease, chronic obstructive pulmonary disease, and percutaneous coronary intervention. RESULTS: DPP-4 inhibitors improve the overall 3-year survival rate (log rank P < 0.0001), whether male or female. Cox proportional hazard regression showed DPP-4 inhibitor is beneficial in diabetes patients after AMI (HR = 0.86; 95% CI 0.78-0.95), especially in those patients with hypertension (HR = 0.87; 95% CI 0.78-0.97; P = 0.0103) and cerebrovascular disease (HR = 0.83; 95% CI 0.72-0.97; P = 0.018), but without dyslipidemia (HR = 0.78; 95% CI 0.67-0.92; P = 0.0029), without peripheral vascular disease (HR = 0.86; 95% CI 0.78-0.96; P = 0.0047), without heart failure (HR = 0.84; 95% CI 0.73-0.96; P = 0.0106), without end stage renal disease (HR = 0.86; 95% CI 0.77-0.95; P = 0.0035), and without chronic obstructive pulmonary disease (HR = 0.87; 95% CI 0.78-0.97; P = 0.0096). CONCLUSIONS: DPP-4 inhibitor therapy improved long-term survival in diabetic patients after first AMI, regardless of gender.

Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance.

Type 2 diabetes are at a high risk of complications related to hypertension, and reports have indicated that insulin levels may be associated with blood pressure (BP). Fructose intake has recently been reported to promote insulin resistance and superoxide formation. The aim of this study is to investigate whether fructose intake can enhance superoxide generation and impair insulin signaling in the NTS and subsequently elevate BP in rats with fructose-induced hypertension. Treatment with fructose for 4 weeks increased the BP, serum fasting insulin, glucose, homeostatic model assessment-insulin resistance, and triglyceride levels and reduced the serum direct high-density lipoprotein level in the fructose group. The Tempol treatment recovered the fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that fructose increased the p38- and fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1S307) and suppressed AktS473 and neuronal nitric oxide synthase phosphorylation. Similarly, fructose was able to impair insulin sensitivity and increase insulin levels in the NTS. Fructose intake also increased the production of superoxide in the NTS. The results of this study suggest that fructose might induce central insulin resistance and elevate BP by enhancing superoxide production and activating p38 phosphorylation in the NTS.

Histamine-2 Receptor Antagonist Cannot Prevent Recurrent Peptic Ulcers in Patients With Atherosclerotic Diseases Who Receive Platelet ADP Receptor Antagonist Monotherapy: A Randomized-Controlled, Double-Blind, and Double-Dummy Trial.

OBJECTIVES: Proton pump inhibitor can effectively prevent recurrent peptic ulcers among atherosclerotic patients receiving clopidogrel monotherapy. However, the interaction between proton pump inhibitors and clopidogrel has raised concerns over the safety of combined use of the two medicines in clinical practice. The aims of this randomized-controlled, double-blind and double-dummy trial were to investigate the efficacy of histamine-2 receptor antagonist (H2RA) in the prevention of recurrent peptic ulcer in patients undergoing thienopyridine monotherapy. METHODS: From January 2012 to 2016, long-termed thienopyridine users with a peptic ulcer history who did not have peptic ulcers at initial endoscopy were randomly assigned to receive either famotidine (40 mg, before bedtime) or placebo (before bedtime) for 6 months. Follow-up endoscopy was performed at the end of the 6th month and whenever dyspepsia, hematemesis, or melena occurred. RESULTS: The cumulative incidence of recurrent peptic ulcer during the 6-month period was 7.0% in famotidine group (n=114) and 11.4% in the placebo group (n=114). The two patient groups had comparable cumulative incidence of peptic ulcer (difference, 4.4%; 95% confidence interval (CI), -11.7 to 2.9%; P=0.239). Additionally, there was no difference in the cumulative incidence of ulcer bleeding (2.6% vs. 1.8%; difference, 0.8%; 95% CI, -0.6 to 2.4%, P=1.000) between famotidine and placebo groups. However, the former had a lower incidence of gastroduodenal erosion than the latter (21.1% vs. 36.8%; difference, 15.7%; 95% CI, -27.3 to -4.1%; P=0.013). CONCLUSIONS: Famotidine cannot decrease the incidence of peptic ulcer or ulcer bleeding in thienopyridine users with atherosclerotic disease and a history of peptic ulcer.

Renal Denervation Improves the Baroreflex and GABA System in Chronic Kidney Disease-induced Hypertension.

Hypertensive rats with chronic kidney disease (CKD) exhibit enhanced gamma-aminobutyric acid (GABA)B receptor function and regulation within the nucleus tractus solitarii (NTS). For CKD with hypertension, renal denervation (RD) interrupts the afferent renal sympathetic nerves, which are connecting to the NTS. The objective of the present study was to investigate how RD improves CKD-induced hypertension. Rats underwent 5/6 nephrectomy for 8 weeks, which induced CKD and hypertension. RD was induced by applying phenol to surround the renal artery in CKD. RD improved blood pressure (BP) by lowering sympathetic nerve activity and markedly restored the baroreflex response in CKD. The GABAB receptor expression was increased in the NTS of CKD; moreover, the central GABA levels were reduced in the cerebrospinal fluid, and the peripheral GABA levels were increased in the serum. RD restored the glutamic acid decarboxylase activity in the NTS in CKD, similar to the effect observed for central treatment with baclofen, and the systemic administration of gabapentin reduced BP. RD slightly improved renal function and cardiac load in CKD. RD may improve CKD-induced hypertension by modulating the baroreflex response, improving GABA system dysfunction and preventing the development and reducing the severity of cardiorenal syndrome type 4 in CKD rats.

Application of whole-body FDG-PET for cancer screening in a cohort of hospital employees.

Whole-body positron emission tomography/computed tomography with the glucose analog 2-[F]fluoro-2-deoxy-D-glucose (FDG-PET/CT) has been extensively used to screen for underlying malignancies in asymptomatic individuals. We were able to survey a cohort of hospital employees using FDG-PET/CT and to report the results herein.A total of 116 hospital employees older than 55 years old were offered whole-body FDG-PET in our hospital. Ninety-seven employees (83.6%) completed the assessment from February 2014 to August 2014 in our PET center. The final confirmation of cancer was based on pathologic examination and follow-up after more than 1 year.Among the 97 participants, 92 were asymptomatic and 5 presented with previously diagnosed cancers. Six of the 92 asymptomatic participants (6.6%) with significant nodular lesions were referred for histological or cytological evaluation of the possibility of malignancy, and 1 case was considered clinically important and required surgical resection. The cancer discovery rate was 3.3% (3/92) with positive predictive value of 50% (3/6). In the 5 participants with previously identified cancers, no recurrence or metastasis was detected.The offer of whole-body FDG-PET for cancer screening was welcomed with enthusiasm by most of the hospital employees. PET/CT combines the merits of PET and CT and can be administered to and provide benefits to a select group of hospital employees.

Resveratrol Inhibition of Rac1-Derived Reactive Oxygen Species by AMPK Decreases Blood Pressure in a Fructose-Induced Rat Model of Hypertension.

Recent studies have reported that the activation of AMP-activated protein kinase (AMPK) suppressed oxidative stress. The aim of this study was to examine whether the activation of AMPK in the brain decreased Rac1-induced ROS generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The inhibition of ROS by treatment with an AMPK activator (oral resveratrol, 10 mg/kg/day) for 1 week decreased the BP and increased the NO production in the rostral ventrolateral medulla (RVLM) of fructose-fed rats but not in control Wistar-Kyoto (WKY) rats. In addition, resveratrol treatment abolished the Rac1-induced increases in the activity of the NADPH oxidase subunits p22-phox and reduced the activity of SOD2, while treatment with an AMPK inhibitor (compound C, 40 µM/day) had the opposite effect, in the fructose-fed rats. Interestingly, the activation of AMPK abolished Rac1 activation and decreased BP by inducing the activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and nNOS phosphorylation in the fructose-fed rats. We conclude that the activation of AMPK decreased BP, abolished ROS generation, and enhanced ERK1/2-RSK-nNOS pathway activity by negatively regulating Racl-induced NADPH oxidase levels in the RVLM during oxidative stress-associated hypertension.

Risk of Chronic Low Back Pain Among Parturients Who Undergo Cesarean Delivery With Neuraxial Anesthesia: A Nationwide Population-Based Retrospective Cohort Study.

To investigate the risk of chronic low back pain (LBP) in parturients undergoing cesarean delivery (CD) with neuraxial anesthesia (NA). LBP is common during pregnancy and also after delivery, but its etiology is poorly understood. Previous studies that investigated the correlation between epidural labor analgesia and chronic low back pain were inconclusive. These studies lacked objective diagnostic criteria for LBP and did not exclude possible confounders. We performed this nationwide population-based retrospective cohort study to explore the relationship between CD with NA and subsequent LBP. From the Taiwan National Health Insurance Research Database (NHIRD), we identified all primiparas who had given birth between January 1, 2000 and December 31, 2013. Using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes, we identified the women who had vaginal delivery (VD) and those who had CD. The mode of anesthesia was ascertained by the NHI codes. Multivariable logistic regression was used to estimate the odds of postpartum LBP in women undergoing CD with NA compared with those having VD. The outcome was a diagnosis of LBP according to the first ICD-9-CM diagnosis code. The patients were observed for 3 years after delivery or until diagnosis of postpartum LBP, withdrawal from the NHI system, death, or December 31, 2013. Of the 61,027 primiparas who underwent delivery during the observation period, 40,057 were eligible for inclusion in the study. Of these women, 27,097 (67.6%) received VD, 8662 (21.6%) received CD with spinal anesthesia, and 4298 (10.7%) received CD with epidural anesthesia (EA). Women who received CD with EA were found to have higher risk of LBP than did women who received VD, with the adjusted OR being 1.26 (95% CI: 1.17-1.34). CD with EA might increase the risk of subsequent chronic LBP.

Paricalcitol Attenuates Cardiac Fibrosis and Expression of Endothelial Cell Transition Markers in Isoproterenol-Induced Cardiomyopathic Rats.

OBJECTIVES: Acute cardiomyopathy is a health problem worldwide. Few studies have shown an association between acute cardiomyopathy and low vitamin D status. Paricalcitol, a vitamin D receptor activator, clinically benefits patients with advanced kidney disease. The effect of paricalcitol supplement on cardiac remodeling in cardiomyopathic rats is unknown. This experimental study investigated the effect of paricalcitol in rats with cardiomyopathy induced by isoproterenol. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Hospital-affiliated animal research institution. SUBJECTS: Eight-week-old male Wistar-Kyoto rats. INTERVENTIONS: Male Wistar-Kyoto rats were first injected intraperitoneally with isoproterenol to create a rat model of acute cardiomyopathy. Then paricalcitol was administered intraperitoneally to isoproterenol-injected rats at a dosage of 200 ng three times a week for 3 weeks. Relevant cardiomyopathy-related variables were measured regularly in three groups of rats, controls, isoproterenol, and isoproterenol plus paricalcitol. Rat hearts were obtained for evaluation of cardiac fibrosis using Masson trichrome staining and commercially available software, and evaluation of cell transition using immunofluorescence staining analysis. MEASUREMENTS AND MAIN RESULTS: Isoproterenol infusions generated significant cardiac fibrosis (p < 0.001). Subsequent paricalcitol treatment attenuated the isoproterenol-induced cardiac fibrosis (p = 0.006). Fluorescence showed colocalization of endothelial and fibroblast cell markers (cluster differentiation 31 and α-smooth muscle actin, respectively) in the isoproterenol-treated hearts. Paricalcitol injections attenuated the isoproterenol-induced fluorescence intensity of two cell markers (p < 0.01). CONCLUSIONS: Paricalcitol injections may ameliorate isoproterenol-induced cardiac fibrosis possibly through regulating cell transition.