Cerebral uptake of microvesicles occurs in normocapnic but not hypocapnic passive hyperthermia in young healthy male adults.

Passive hyperthermia causes cerebral hypoperfusion primarily from heat-induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro-inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water-perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet-poor plasma via cells expressing CD62E (activated endothelial cells), CD31+ /CD42b- (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan-leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P-values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+ /CD42b- (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2 /pH-mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. KEY POINTS: The hyperthermia-induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow. We tested the hypothesis that the respiratory-induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow. At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross-brain microvesicle kinetics. However, when core temperature was increased by 2°C with CO2 /pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2 /pH-mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia. These new findings suggest that the heat-induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain.

Circulating Notch1 in response to altered vascular wall shear stress in adults.

NEW FINDINGS: What is the central question of this study? Is the plasma concentration of Notch1 extracellular domain altered in response to decreased and increased vascular wall shear stress in the forearm in humans? What is the main finding and its importance? Notch1 extracellular domain is increased with acute increases in antegrade shear rate but does not change with 20 min of decreased shear rate caused by distal forearm occlusion. A novel and integral endothelial mechanosensor in humans that can help explain vascular endothelial adjustments in response to increases in antegrade shear stress was characterized. ABSTRACT: Notch1 has been proposed as a novel endothelial mechanosensor that is central for signalling adjustments in response to changes in vascular wall shear stress. However, there remains no controlled in vivo study in humans. Accordingly, we sought to address the question of whether plasma concentrations of Notch1 extracellular domain (ECD) is altered in response to transient changes in vascular wall shear stress. In 10 young healthy adults (6M/4F), alterations in shear stress were induced by supra-systolic cuff inflation around the wrist. The opposite arm was treated as a time control with no wrist cuff inflation. Plasma was collected from an antecubital vein of both arms at baseline, 20 min of wrist cuff inflation (low shear), as well as 1-2 min (high shear) and 15 min following (recovery) wrist cuff release. The Notch1 ECD was quantified using a commercially available ELISA. Duplex ultrasound was used to confirm alterations in shear stress. In the experimental arm, concentrations of Notch1 ECD remained statistically similar to baseline at all time points except for immediately following cuff release where it was elevated by ∼50% (P = 0.033), coinciding with the condition of high antegrade shear rate. Concentrations of Notch1 ECD remained unchanged in the control arm through all time points. These data indicate that Notch1 is a viable biomarker for quantifying mechanotransduction in response to increased shear stress in humans, and it may underlie the vascular adaptations or mal-adaptations associated with conditions that impact antegrade shear.

Adverse drug reactions and risk factors for discontinuation of multidrug-resistant tuberculosis regimens in Gujarat, western India.

Background: The predictors for discontinuation of multidrug-resistant tuberculosis (MDR-TB) regimens have not been studied in Gujarat. We aimed to find out the adverse drug reactions (ADRs) and predictors for discontinuation of MDR-TB regimens. Methods: We conducted this cross-sectional study in Bhavnagar district of Gujarat from September to November 2016 through home visits and personal interviews of 94 patients with MDR-TB. Results: Sixty-nine patients with MDR-TB (73%) reported ADRs. Tingling (42.6%), headache (37.2%), numbness (36.2%), dizziness (34%) and nausea (33%) were the most common ADRs. Of the 94 patients, 7.4% were compelled to think of discontinuing their treatment due to ADRs; 8.5% had discontinued Cat-I/Cat-II regimen in the past; 11.7% had discontinued their MDR-TB regimen in the past; 13.8% had their drug regimen changed due to ADRs and 94.7% had good adherence to their current regimen (took at least 80% of their doses till date). ADRs were the reason for 75% of the patients who discontinued their Cat-I/Cat-II regimen in the past and 64% of the patients who discontinued their MDR-TB regimen in the past. Tobacco chewing, poor adherence and thought of discontinuing an MDR-TB regimen due to ADRs were significant predictors for discontinuation on bivariate analysis. On multiple logistic regression, none of the predictors were significant. Conclusions: The frequency of ADRs among patients with MDR-TB is high. ADRs were the primary reason for discontinuing MDR-TB drugs.

Cross-sectional study on smokeless tobacco use, awareness and expenditure in an urban slum of Bhavnagar, western India.

Background: Data are sparse on smokeless tobacco (SLT) use in Bhavnagar. We assessed the prevalence and awareness of and expenditure on SLT use in Bhavnagar. Methods: We conducted a community-based, cross- sectional study in an urban slum of Bhavnagar on a sample of 260 SLT users for a period of three months in 2017. Results: The prevalence of SLT use in Bhavnagar was 27.3% (95% CI 25%-30%). Mawa, a preparation of tobacco flakes mixed with areca nut and lime, was the most commonly chewed form of tobacco; commonly kept in the buccal mucosa. The mean age ofstarting SLT use was 25 years; the mean number of years since chewing was 15 years; the mean time tobacco was kept in the mouth per consumption was 5 minutes and the mean number of packets of tobacco consumed per day was five. The mean expenditure on SLT use per month was ?536. All SLT users were aware that tobacco consumption led to oral cancer. Peer influence was the most common (75%) reason for starting SLT use, and addiction was the most common (74%) reason for its continued use. Among SLT users, 47% had made at least one attempt to quit; of them, 98% had tried self-control for quitting but did not succeed. The most common (72%) reason given by those not able to quit (n=119) was addiction to SLT use. Among the 260 study participants, 72% had read the warnings on packets of tobacco; 59% wished to chew tobacco even after reading the warnings and 62% opined on banning the sale and consumption of tobacco. Ninety-two per cent of SLT users were not comfortable with the idea that imitating them, their children too would start chewing tobacco. Conclusions: Every third person in the urban slum of Bhavnagar was a SLT user. Even though SLT users knew about the harmful effects of tobacco, only a handful were able to quit due to addiction to it. This burden on health services, in addition to the expenditure on purchase of tobacco, requires a comprehensive tobacco cessation programme at the community level.

Cross-sectional study to assess the need to commence opportunistic screening of women for cervical cancer presenting with sexually transmitted disease in Western India.

This study examines the prevalence of suspected cervical cancer (established through the use of visual inspection with Lugol's Iodine - VILI) among outpatients attending Surat Municipal Institute of Medical Education & Research Hospital, India. A cross-sectional study was conducted on 356 patients; 178 with an established sexually transmitted disease (STD) and 178 patients without. Patients with positive results were investigated with cervical biopsy; out of 356 patients, 21.91% patients with STD and 12.35% patients without STD tested positive for VILI respectively (p = .017). The factors found to be significantly associated with a positive VILI test were STD, marital status, oral contraceptive pill use, a complaint of PV bleeding, white discharge on speculum examination (PS) and cervical erosion on PS. On applying multiple logistic regression, STD, age of patient in years, parity, OC pill use, a complaint of PV bleeding and cervical erosion on PS were found to be significant predictors of VILI positivity among the patients. STD patients are 2.5 times more likely to test positive for VILI than patients without STD. In Indian populations comparable to ours, opportunistic screening should be considered in gynaecology outpatient clinics for women presenting with complaints related to STDs.

Cross-sectional study on socio-demographic and clinical correlates of depression among human immunodeficiency virus-positive patients in Surat City, Western India.

INTRODUCTION: Surat has the highest incidence of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) in Gujarat, the main reason being its large migrant population. Mental health in HIV/AIDS has most often been a topic of neglect all over the world. This study attempts to assess the magnitude of depression and the socio-demographic and clinical variables associated with it in HIV-positive patients. METHODS: A cross-sectional study was conducted in 270 HIV-positive patients using Beck Depression Inventory (BDI; translated and validated in Gujarati and Hindi) along with a questionnaire for eliciting information on socio-demographic and clinical variables. RESULTS: The prevalence of depression among HIV-positive patients was 30% with 12.22% having mild depression; 14.07% with moderate depression and 3.7% with severe depression. Bivariate analysis showed that physical pain, physical illness, Cluster of Differentiation 4 (CD4)<300 cells/mm3, HIV positive spouse, discrimination at hospital, discrimination in society, government setup as the first place of HIV test and broken relationship with spouse after HIV disclosure were significantly associated with depression among the patients. On multiple logistic regression, discrimination at hospital, physical pain and CD4<300 cells/mm3 were found to be the significant predictors of depression among the patients. DISCUSSION: HIV-positive patients can be screened by counselors using easy-to-administer scales like BDI, which can be translated and validated into any regional language. A trained psychiatrist should be appointed at the Anti-Retroviral Therapy (ART) center to take care of the mental health issues of the patients.

Application of nanotechnology in cancer: a review.

Cancer nanotechnology is an interdisciplinary area with broad applications. The basic rationale is that nanometre-sized particles, when linked with tumour-targeting ligands, can be used to target tumour antigens. It is difficult to target the abnormal cells in cancer by the conventional method of the drug delivery. Nanotechnology is probably the only method that can be used for site-specific action without causing the side effects. Different cancer detection techniques like Carbon Nanotubes (CNTs), nanorods and biosensors are available. This review paper gives an idea about the possible potential of nanotechnology in drug delivery, drug targeting and diagnosis of cancer.