Avash Das

Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury

Extracellular vesicles (EVs) serve an important function as mediators of intercellular communication. Exercise is protective for the heart, although the signaling mechanisms that mediate this cardioprotection have not been fully elucidated. Here using nano-flow cytometry, we found a rapid increase in plasma EVs in human subjects undergoing exercise stress testing. We subsequently identified that serum EVs were increased by ~1.85-fold in mice after 3-week swimming. Intramyocardial injection of equivalent quantities of EVs from exercised mice and non-exercised controls provided similar protective effects against acute ischemia/reperfusion (I/R) injury in mice. However, injection of exercise-induced EVs in a quantity equivalent to the increase seen with exercise (1.85 swim group) significantly enhanced the protective effect. Similarly, treatment with exercise-induced increased EVs provided additional anti-apoptotic effect in H2O2-treated H9C2 cardiomyocytes mediated by the activation of ERK1/2 and HSP27 signaling. Finally, by treating H9C2 cells with insulin-like growth factor-1 to mimic exercise stimulus in vitro, we found an increased release of EVs from cardiomyocytes associated with ALIX and RAB35 activation. Collectively, our results show that exercise-induced increase in circulating EVs enhances the protective effects of endogenous EVs against cardiac I/R injury. Exercise-derived EVs might serve as a potent therapy for myocardial injury in the future.

Cameron Ulcer Causing Severe Anemia in a Patient with Diaphragmatic Hernia.

Patient: Female, 51 Final Diagnosis: Cameron’s ulcer Symptoms: — Medication: — Clinical Procedure: Endoscopy Specialty: Gastroenterology and Hepatology Objective: Rare co-existance of disease or pathology Background: Cameron lesions are linear gastric erosions on the mucosal folds at the diaphragmatic impressions found in patients with large hiatal hernias. While usually asymptomatic, hiatal hernias can result in serious sequelae, as this case report will clearly illustrate. Cameron lesions are clinically significant because of their ability to cause significant acute, chronic, or obscure gastrointestinal bleeding, often requiring blood transfusions. Case Report: In this report, we present the case of a 51-year-old white woman who originally presented to the Emergency Department with complaints of a runny nose, dry cough, generalized weakness, and muscle cramping ascribed to a viral infection. However, closer examination revealed substantial pallor with pale conjunctiva prompting further workup that revealed substantial anaemia. Upon further inquiry of her past medical history, she revealed the need for previous blood transfusions, and meticulous review of her medical record indicated a previous diagnosis of hiatal hernia with the presence of Cameron lesions based on esophagogastroduodenoscopy 2 years prior. Conclusions: This case emphasizes the need for a high index of suspicion for Cameron lesions as a causative agent of substantial blood loss in patients with hiatal hernias after other common causes of gastrointestinal bleeding have been ruled out.

Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer–related Mortality: A Systematic Review and Meta-Analysis

Objective: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. Materials and Methods: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m2) and overweight (BMI, 25 to 29.9 kg/m2) individuals with normal BMI individuals using random-effects model. Results: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. Conclusions: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy.

Selexipag in Pulmonary Arterial Hypertension: Most Updated Evidence From Recent Preclinical and Clinical Studies

Pulmonary arterial hypertension (PAH) is a relatively rare disease that, due to its chronic nature, has always been difficult to treat effectively. Selexipag is an oral prostacyclin (PGI2) agonist that was approved by US Food and Drug Administration (US FDA) in December 2015 for the treatment of PAH. After its success in phase 1 and phase 2 clinical trials regarding the convenient oral twice‐daily dosing and low side‐effect profile, selexipag raised the hope of controlling the disease progression in PAH patients. In the recently completed multicentered phase 3 study (GRIPHON), selexipag has been shown to reduce death and hospitalization due to PAH significantly, an effect that was consistent across different ranges of maintenance dose. In the same study selexipag use was also associated with an increase in 6‐minute walk distance (a measure of symptom severity) from baseline, but no significant improvement in all‐cause mortality could be observed. The results of the ongoing phase 3 studies (TRITON and TRANSIT‐1) are expected to throw some more light on the safety and efficacy of this novel molecule across various treatment scenarios. Hence, our article aims to summarize all the available information from preclinical and clinical studies published to date on the pharmacodynamics, pharmacokinetics, efficacy, safety (in general and in scenarios such as hepatic and renal function impairment), significant drug interactions (with warfarin and antiretroviral drugs), and clinical significance of oral selexipag in patients with PAH.

Cardiometabolic disease in South Asians: A global health concern in an expanding population

Cardiovascular disease (CVD) is one of the main causes of mortality and morbidity worldwide. As an emerging population, South Asians (SAs) bear a disproportionately high burden of CVD relative to underlying classical risk factors, partly attributable to a greater prevalence of insulin resistance and diabetes and distinct genetic and epigenetic influences. While the phenotypic distinctions between SAs and other ethnicities in CVD risk are becoming increasingly clear, the biology of these conditions remains an area of active investigation, with emerging studies involving metabolism, genetic variation and epigenetic modifiers (e.g., extracellular RNA). In this review, we describe the current literature on prevalence, prognosis and CVD risk in SAs, and provide a landscape of translational research in this field toward ameliorating CVD risk in SAs.

Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report

Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health.NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community.

Cytomegalovirus-Induced Hepatitis in an Immunocompetent Patient

Patient: Female, 20 Final Diagnosis: Cytomegalovirus-induced hepatitis Symptoms: Chills • cough dry • decreased appetite • fever Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: Hepatitis is a descriptive term given for any inflammation of the liver. It can be characterized as inflammatory cells infiltrating normal hepatic parenchyma, which destroys their ability to perform normal physiologic functions. Hepatitis is a common disorder in immunocompetent populations, mainly attributed to viruses, alcohol, drugs, or autoimmune causes. Case Report: Cytomegalovirus is a virus mostly affecting immunocompromised patients, resulting in infectious mononucleosis-like symptoms as well as hepatitis in liver transplant patients, but is generally benign in immunocompetent hosts. This report presents an unusual case of hepatitis caused by Cytomegalovirus in an immunocompetent patient with previous Herpes Simplex virus infection. A 20-year-old African-American woman presenting with intermittent subjective fevers and chills, sore throat, non-productive cough, and decreased appetite 1 month ago was diagnosed with a case of Cytomegalovirus-induced hepatitis. Conclusions: This report clearly emphasizes the need for investigation of other disease entities such as Cytomegalovirus as a potential cause of hepatitis in an immunocompetent patient after more common causes of hepatitis have been ruled out.

Cholecystitis as the initial presentation of acute myeloid leukaemia

A 52-year-old man with no past medical history presented with a one-month history of right upper quadrant pain and postprandial discomfort. Physical examination was notable for right upper quadrant focal tenderness. A full blood count showed haemoglobin concentration 123 g/l, white cell count 5 2 9 10/l with a normal differential and platelet count 373 9 10/l. Alkaline phosphatase was elevated to 418 iu/l (reference range 30–126). Ultrasound of the abdomen showed a normal gallbladder with a small amount of sludge. A computed tomography (CT) scan of the abdomen showed focal thickening along the fundus of the gall bladder without biliary dilation. A diagnosis of chronic cholecystitis was made and the patient underwent an elective laparoscopic cholecystectomy. The gall bladder showed a bluish white infiltrate at the fundus giving it a cartilaginous texture. Histopathology showed a diffuse infiltrate of large cells with high mitotic activity and scanty cytoplasm (top left). Immunohistochemistry showed the neoplastic cells to be positive for myeloperoxidase and CD45 (top right and bottom left), consistent with a granulocytic sarcoma. A subsequent review of the peripheral blood film showed 75% segmented neutrophils, 1 5% metamyelocytes, 2 5% myelocytes, 12% lymphocytes, 6% monocytes, 2% eosinophils and 1% blasts. Bone marrow examination showed 14% myeloblasts (bottom right). The bone marrow findings in association with the granulocytic sarcoma indicated a diagnosis of acute myeloid leukaemia (AML). Cytogenetic analysis was normal. Surgical removal of the gall bladder was accepted as adequate local therapy and standard AML induction chemotherapy (cytarabine and daunorubicin) was initiated, but he had refractory disease requiring re-induction with high dose cytarabine and, ultimately, allogeneic stem cell transplantation. Granulocytic sarcoma is a rare neoplastic condition, characterized by infiltration of extramedullary tissues by immature myeloid cells. Rarely it is a presenting isolated manifestation of AML. Gall bladder involvement is extremely uncommon. The diagnosis can be made with adequate pathological evaluation that includes comprehensive immunohistochemistry. The discovery of a granulocytic sarcoma should always prompt an investigation for AML. This diagnosis can be made with less than 20% bone marrow blast cells when a granulocytic sarcoma is present.

Trends in Outcomes of Patients With Metastatic Cancer Undergoing Intubation and Mechanical Ventilation: Results of the National Hospital Discharge Survey

Background: There has been an overall decline in intensive care unit mortality over the past 2 decades, including in patients undergoing intubation and mechanical ventilation (MV). Whether this decline extends to patients with metastatic cancer remains unknown. We analyzed the outcomes of patients with metastatic cancer undergoing intubation/MV using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis and procedure codes were used to identify patients with metastatic cancer who underwent intubation/MV. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study trends in outcomes. Results: During the 10-year study period, 200,350 patients with metastatic cancer and who underwent intubation/MV were identified; the mean age was 65.3 years and 46.2% were men. There was an increase in the total number of patients with metastatic cancer who underwent intubation/MV during the study period, from 36,881 in 2001-2002 to 51,003 in 2009-2010 (P<.001). The overall inpatient mortality rate was 57.3%, discharge to a care facility (DTCF) rate was 40.9% among patients alive at discharge, and mean LOS was 11.1 days. No significant trends were seen in rates of mortality, DTCF, or LOS from 2001 to 2010. Conclusions: In this national database, there was an increase in the number of patients with metastatic cancer who underwent intubation/MV. These patients had high rates of inpatient mortality and DTCF, which did not improve during the study period. Therefore, novel solutions are required to improve outcomes for these patients.

Comparison of treatment options for depression in heart failure: A network meta-analysis

BACKGROUND Depression independently predicts poor outcomes in heart failure (HF) patients, including increased mortality, morbidity and 30-day re-hospitalization. In this network meta-analysis, we compared different interventions designed to treat depression in HF. MATERIALS AND METHODS Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and PsycINFO up to November 2016. Included randomized clinical trials (RCTs) compared interventions (Exercise therapy (ET), cognitive behavioral therapy (CBT) or antidepressant (AD) medications) for depression in heart failure patients. The primary outcome was change in depressive symptoms based on validated measures of depression. Network meta-analysis based on random effects model estimating standardized mean difference (SMD) with 95% confidence interval (CI), compared the effects of the 3 classes of interventions with respect to usual care or placebo control conditions. RESULTS A total of 21 RCTs (including 4563 HF patients) reporting the effects of treating depression in HF patients were included in the analysis. In comparison to placebo or usual standard of care, ET (SMD -0.38; 95% CI -0.54 to -0.22) and CBT (SMD -0.29; 95% CI -0.58 to -0.01) were associated with reduction in depressive symptoms whereas AD (SMD -0.16; 95% CI -0.44 to 0.11) was less effective. CONCLUSIONS This meta-analysis is suggestive of therapeutic benefit of ET and CBT in comparison to usual standard of care in treating depression in HF patients. However, comparison among the three interventions was not conclusive. Future randomized clinical trials are warranted to compare the therapeutic effects of ET, CBT and AD in such patients.