Vidhu Anand

Vascular Endothelial Growth Factor Signaling in Hypoxia and Inflammation

Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by re-programming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions.

Continuous Dose-Response Association Between Sedentary Time and Risk for Cardiovascular Disease: A Meta-analysis

IMPORTANCE Prior studies suggest that higher sedentary time is associated with a greater risk for cardiovascular disease (CVD). However, the quantitative, dose-response association between sedentary time and CVD risk is not known. OBJECTIVE To determine the categorical and quantitative dose-response association between sedentary time and CVD risk. DATA SOURCES Two independent investigators searched the MEDLINE and EMBASE databases for all studies published before July 6, 2015, that evaluated the association between sedentary time and incident CVD. STUDY SELECTION Prospective cohort studies with participants 18 years or older that reported the association between sedentary time and incident CVD were included. DATA EXTRACTION AND SYNTHESIS Two independent investigators performed the data extraction and collection using a standardized form. The study quality was assessed using the Newcastle-Ottawa Scale. The categorical dose-response association was evaluated by comparing the pooled hazard ratio (HR) for incident CVD associated with different levels of sedentary time (vs lowest sedentary time) across studies. The continuous dose-response association was assessed using random-effects generalized least squares spline models. Data were collected from April 5 to July 6, 2015. MAIN OUTCOMES AND MEASURES Incident CVD (coronary heart disease, including nonfatal myocardial infarction, stroke, and cardiovascular mortality). RESULTS Nine prospective cohort studies with 720 425 unique participants (57.1% women; 42.9% men; mean age, 54.5 years) and 25 769 unique cardiovascular events and a median follow-up of 11 years were included. In categorical analyses, compared with the lowest sedentary time category (median, 2.5 h/d), participants in the highest sedentary time category (median, 12.5 h/d) had an increased risk for CVD (HR, 1.14; 95% CI, 1.09-1.19). However, no apparent risk associated with intermediate levels of sedentary time (HR for 7.5 h/d, 1.02; 95% CI, 0.96-1.08) was found. In continuous analyses, a nonlinear association between sedentary time and incident CVD was found (P for nonlinearity < .001), with an increased risk observed for more than 10 hours of sedentary time per day (pooled HR, 1.08; 95% CI, 1.00-1.14). CONCLUSIONS AND RELEVANCE The association between sedentary time and the risk for CVD is nonlinear with an increased risk only at very high levels. These findings could have implications for guideline recommendations regarding the risks related to sedentary behavior.

Trends and Outcomes of Pulmonary Arterial Hypertension–Related Hospitalizations in the United States: Analysis of the Nationwide Inpatient Sample Database From 2001 Through 2012

Importance Recent trends and outcomes of pulmonary arterial hypertension (PAH)-related hospitalization in adults in the United States are unknown. Objective To examine the characteristics of PAH-related hospitalizations. Design, Setting, and Participants We analyzed the National Inpatient Sample database for all adult patients (≥18 years old) with PAH as the principal discharge diagnosis from January 1, 2001, through December 31, 2012. Main Outcomes and Measures We analyzed the temporal trends in hospitalization rate, hospital charges, in-hospital mortality, length of hospitalization, and comorbidities pertaining to PAH-related hospitalizations. We also evaluated the predictors of in-hospital mortality and length of hospitalizations. Results The number of PAH-related hospitalizations per year in adults decreased significantly from 2001 through 2012 (3177 vs 1345, P for trend <.001). However, the mean hospital charge per admission increased 2.7-fold from 2001 through 2012 (

Morphine potentiates LPS-induced autophagy initiation but inhibits autophagosomal maturation through distinct TLR4-dependent and independent pathways

29 507 vs

Hashimoto encephalopathy presenting as progressive myoclonus epilepsy syndrome.

79 607, P for trend <.001). There was a significant increase in each of these associated comorbid conditions: diabetes (4.6%-7.8%), hypertension (5.1%-17.1%), coronary artery disease (15.6%-22.3%), chronic obstructive pulmonary disease (14.4%-20.1%), anemia (12.4%-20.4%), cardiac dysrhythmias (21.7%-29.0%), congestive heart failure (40.7%-56.1%), acute (5.9%-20.1%) or chronic kidney disease (1.1%-16.4%), fluid and electrolyte imbalance (18.9%-35.3%), pneumonia (4.4%-6.3%), cardiogenic shock (0.5%-1.5%), and acute respiratory failure (4.3%-20.8%) from 2001 through 2012. The length of hospitalization increased (mean [SE], 7.0 [0.5] days in 2001 vs 7.6 [0.6] days in 2012, P for trend = .009), but in-patient mortality remained unchanged (7.8% [1.1%] in 2001 vs 6.3% [1.7%] in 2012, P for trend = .54). Admission to a teaching hospital (β coefficient for length of hospitalization, 2.0; 95% CI, 1.3-1.6; odds ratio [OR] for mortality, 1.5; 95% CI, 1.1-2.1), cardiac dysrhythmias (β coefficient, 1.8; 95% CI, 1.1-2.6; OR, 1.8; 95% CI, 1.4-2.4), acute kidney injury (β coefficient, 5.0; 95% CI, 3.9-6.1; OR, 2.3; 95% CI, 1.7-3.2), acute cerebrovascular accident (β coefficient, 6.6; 95% CI, 1.9-11.3; OR, 6.7; 95% CI, 2.1-21.1), and acute respiratory failure (β coefficient, 6.2; 95% CI, 5.1-7.4; OR, 5.6; 95% CI, 4.2-7.5) were associated with increased length of hospitalization and in-hospital mortality. Congestive heart failure (OR, 1.7; 95% CI, 1.3-2.2), cardiogenic shock (OR, 5.4; 95% CI, 2.7-10.9), and fluid and electrolyte imbalance (OR, 1.9; 95% CI, 1.5-2.4) were associated with increased in-hospital mortality but not length of hospitalization. Conclusions and Relevance Analyses of temporal changes in PAH care reveal a significant decrease in PAH-related hospitalizations in the United States, but hospital charges have increased substantially and are increasingly being borne by Medicare. In-hospital mortality remains unchanged, but length of hospitalization has increased. This study should help identify the characteristics of patients with PAH that are associated with increased risk of in-hospital mortality and longer length of hospitalization.

Hematopoietic Cell Transplantation for Mantle Cell Lymphoma: Predictive Value of Pretransplant Positron Emission Tomography/Computed Tomography and Bone Marrow Evaluations for Outcomes

Opioids are the most prescribed analgesics for moderate and severe pain management; however, chronic use impairs host innate immune response and increases susceptibility to infection. Recently, autophagy has been shown to be an innate defence mechanism against bacterial infection. The effect of autophagy‐induced bacterial clearance following morphine treatment has not been previously investigated.

A systematic review and meta-analysis of trials using statins in pulmonary arterial hypertension

We report an 11 year old girl with multi-focal spontaneous myoclonus, generalized seizures and behavioural changes. She was found to have sub-clinical hypothyroidism and elevated anti-thyroid peroxidase antibodies. A diagnosis of Hashimoto encephalopathy (or Steroid Responsive Encephalopathy with Autoimmune Thyroiditis) was made in view of consistent clinical and laboratory features. The patient showed and maintained significant improvement with valproate, clonazepam and long term prednisolone. Other findings included mild cerebral cortical grey matter atrophy on brain magnetic resonance imaging and intermittent slowing with generalized poly-spike-and-wave discharges on electroencephalography. Other causes of progressive myoclonus epilepsy (PME) syndrome including subacute sclerosing panencephalitis, Lafora body disease, Juvenile Neuronal Ceroid Lipofuscinosis, Late onset gangliosidosis, Sialidosis, mitochondrial disorders and coeliac disease were ruled out by appropriate investigations. No other auto-immune abnormality was detected. This case emphasizes that Hashimoto encephalopathy should be considered in the etiologies of PME syndrome in adolescents since it is a treatable entity.

Outcomes of sudden cardiac arrest in a state-wide integrated resuscitation program: Results from the Minnesota Resuscitation Consortium

BACKGROUND The prognostic roles of 18F-fludeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging and marrow involvement evaluation on outcomes following autologous and allogeneic hematopoietic cell transplantation (HCT) for mantle cell lymphoma (MCL) are uncertain and require more data. PATIENTS AND METHODS We categorized 66 patients with MCL who received HCT (38 autologous and 28 allogeneic) on the basis of pre-HCT residual disease (RD) status as assessed by marrow MCL morphology and flow/molecular analysis and PET/CT imaging to RD positive (RD(+)) (either or both measures positive) and RD(-) (both negative). We analyzed the predictive value of these RD detection methods on transplant outcomes. RESULTS The 2-year relapse rate after autograft was significantly higher in pre-HCT RD(+) patients (46% [95% CI 16-77%]) than in patients who were RD(-) (19% [95% CI 0-42%]; P = .02), leading to worse 5-year disease-free survival (DFS) in RD(+) patients (46% [95% CI 14%-73%] vs. 68% [95% CI 33-87%], P = .04). In multivariate analysis, RD(+) status was associated with a reduction in DFS (hazard ratio, 5.6; P = .02). Most allogeneic HCT recipients had advanced disease and most were RD(+) (12 PET/CT(+); 5 marrow-positive). The 5-year DFS and relapse rates after allogeneic HCT were 34% and 25% for all patients and 40% and 33% for RD(+) recipients, suggesting that active disease at the time of allograft does not preclude long-term remissions in advanced MCL. CONCLUSION Both autologous and allogeneic HCT lead to promising long-term survival. RD detected prior to autograft was associated with increased relapse and worse 5 year DFS. Allograft recipients had favorable long-term outcomes even in presence of pre-HCT detectable disease.

Challenges of managing elderly men with prostate cancer

Statins improve pulmonary vascular remodeling and right ventricular hypertrophy in animal models of pulmonary arterial hypertension (PAH). However, clinical trials assessing the efficacy of statins in patients with PAH have reported mixed results. In this systematic review and meta-analysis, we assess the efficacy of statins in patients with PAH. We included randomized controlled clinical trials (RCTs) that evaluated the efficacy of statins in patients with PAH. Primary outcomes were mortality and change in 6-minute walk distance (6MWD). Data are presented as odds ratio (OR) and weighted mean difference (WMD), with 95% confidence intervals (CIs), for binary and continuous variables, respectively. We included 4 RCTs of high quality. The mean age of participants was 42 ± 13 years, and 70% were women. The statins used were simvastatin at 40–80 mg in two trials, atorvastatin 10 mg in one trial, and rosuvastatin 10 mg in the other. In the pooled-data analysis, there was no statistically significant improvement in mortality (OR: 0.75 [95% CI: 0.32–1.74]), 6MWD (WMD: −9.27 [95% CI: −27.73 to 9.20]), or cardiac index (WMD: 0.11 [95% CI: −0.04 to 0.27]) with statin therapy when compared to placebo. There was no difference in adverse events leading to withdrawal of therapy between statin and placebo groups. These data suggest that statins are not beneficial in the treatment of PAH. There is a need for large, well-conducted clinical trials assessing the effects of statins in patients with PAH. Future trials should include homogeneous patient populations and should be long-term, event-driven trials with combined morbidity and mortality end points.

Intravenous versus inhalational techniques for rapid emergence from anaesthesia in patients undergoing brain tumour surgery: A Cochrane systematic review

BACKGROUND Despite many advances in resuscitation science the outcomes of sudden cardiac arrest (SCA) remain poor. The Minnesota Resuscitation Consortium (MRC) is a statewide integrated resuscitation program, established in 2011, to provide standardized, evidence-based resuscitation and post-resuscitation care. The objective of this study is to assess the outcomes of a state-wide integrated resuscitation program. METHODS We examined the trends in resuscitation metrics and outcomes in Minnesota since 2011 and compared these to the results from the national Cardiac Arrest Registry to Enhance Survival (CARES) program. Since 2011 MRC has expanded significantly providing service to >75% of Minnesotas population. RESULTS A total of 5192 SCA occurred in counties covered by MRC from 2011 to 2014. In this period, bystander cardiopulmonary resuscitation (CPR) and use of hypothermia, automatic CPR device and impedance threshold device increased significantly (p<0.0001 for all). Compared to CARES, SCA cases in Minnesota were more likely to be ventricular fibrillation (31% vs. 23%, p<0.0001) but less likely to receive bystander CPR (33% vs. 39%, p<0.0001). Survival to hospital discharge with good or moderate cerebral performance (12% vs. 8%, p<0.0001), survival in SCA with a shockable rhythm (Utstein survival) (38% vs. 33%, p=0.0003) and Utstein survival with bystander CPR (44% vs. 37%, p=0.003) were greater in Minnesota than CARES. CONCLUSIONS State-wide integration of resuscitation services in Minnesota was feasible. Survival rate after cardiac arrest is greater in Minnesota compared to the mean survival rate in CARES.