Role of Reactive Oxygen Species in Mercapto-Methylimidazole-Induced Gastric Acid Secretion and Stress-Induced Gastric Ulceration

The objective of the present study is to delineate the role of reactive oxygen species in drug-induced gastric hyperacidity and stress-induced gastric ulceration. We reported earlier that mercaptomethylimidazole (MMI), an antithyroid drug, induces gastric acid (HCl) secretion partially through H2receptor activation of the parietal cell by histamine release and partially through an intracellular mechanism. While studying the latter, MMI-induced acid secretion was found to correlate well with the inactivation of the peroxidase, an important H2O2metabolizing enzyme of the mucosa. MMI activates the isolated parietal cell for acid secretion, which is sensitive to omeprazole. Peroxidase and catalase activity of the isolated cell is also irreversibly inactivated by MMI. It thus creates a favourable condition for endogenous accumulation of H2O2. Acid secretion by gastric gland preparation or isolated gastric mucosa is stimulated by exogenous H2O2, which is inhibited by omeprazole. Studies indicate that H2O2inactivates the prostaglandin synthetase and removes the inhibitory influence of prostaglandin on acid secretion. MMI thus stimulates acid secretion not only through H2, receptor activation but also through the stimulation of the parietal cell by intracellular generation of H2O2following inactivation of the peroxidase-catalase system. Among the various factors responsible for gastric ulceration, stress was found to cause severe haemorrhagic lesions mainly through oxidative damage of the mucosa as indicated by increased lipid peroxidation, increased protein carbonyl content, and decreased glutathione level. The severity of ulcer correlates well with the time-dependent induction of superoxide dismutase and inactivation of peroxidase, a condition favourable for accumulation of endogenous H2O2. Desferrioxamine prevents stress ulcer, indicating involvement of transition metal ion in the process. Studies indicate that severity of stress ulcer is dependent on the concurrent generation of hydroxyl radical (•OH) formed through metal-catalysed Haber-Weiss reaction between O2-and H2O2

Stimulation and inhibition by bicarbonate of stomatal opening in epidermal strips of Commelina benghalensis

The effect of 0 to 100 μM bicarbonate on stomatal opening in epidermal strips of Commelina benghalensis was examined in the presence or absence of fusicoccin in light or darkness. Low concentrations of bicarbonate (up to 10 μM in the absence and 25 μM in presence of fusicoccin) stimulated stomatal opening while higher concentrations inhibited. The enhancement of opening by low concentrations of bicarbonate and phosphoenol pyruvate (PEP), and prevention of bicarbonate stimulation by malate or oxaloacetate suggested PEP carboxylase as a CO2 sensor in the guard cells. However, the inhibition of PEP carboxylase did not completely suppress the opening caused by fusicoccin. The action of fusicoccin therefore appears to involve a site other than CO2 fixation, presumably through the stimulation of proton excretion

Second-line failure and first experience with third-line antiretroviral therapy in Mumbai, India

Background: There are limited data on the failure of second-line antiretroviral therapy (ART) and the use of third-line ART in people living with HIV in resource-limited settings. Since 2011, the Médecins Sans Frontières (MSF) HIV/tuberculosis programme in Mumbai, India, has been providing third-line ART to patients in care. Objective: To describe the experiences and programmatic challenges during management of suspected second-line ART failure and third-line ART therapy for patients living with HIV, including the use of HIV viral load (VL) testing. Design: This was a retrospective, observational cohort study of patients with suspected second-line ART treatment failure, who were followed for at least 12 months between January 2011 and March 2014. Results: A total of 47 patients with suspected second-line failure met the inclusion criteria during the study period. Twenty-nine of them (62%) responded to enhanced adherence support, had a subsequent undetectable VL after a median duration of 3 months and remained on second-line ART. The other 18 patients had to be initiated on a third-line ART regimen, which consisted of darunavir–ritonavir, raltegravir, and one or more appropriate nucleoside or nucleotide reverse transcriptase inhibitors, based on the results of HIV genotype testing. Of the 13 patients for whom follow-up VL results were available, 11 achieved virological suppression after a median duration of 3 months on third-line ART (interquartile range: 2.5–3.0). No serious treatment-related adverse events were recorded. Conclusions: With intensive counselling and adherence support in those suspected of failing second-line ART, unnecessary switching to more expensive third-line ART can be averted in the majority of cases. However, there is an increasing need for access to third-line ART medications such as darunavir and raltegravir, for which national ART programmes should be prepared. The cost of such medications and inadequate access to VL monitoring and HIV genotype testing are currently major barriers to optimal management of patients failing second-line ART

“When treatment is more challenging than the disease” : a qualitative study of MDR-TB patient retention.

CAPRISA, 2016.Abstract available in PDF file

Low Incidence of Renal Dysfunction among HIV-Infected Patients on a Tenofovir-Based First Line Antiretroviral Treatment Regimen in Myanmar.

BACKGROUND: Since 2004, Médecins Sans Frontières-Switzerland has provided treatment and care for people living with HIV in Dawei, Myanmar. Renal function is routinely monitored in patients on tenofovir (TDF)-based antiretroviral treatment (ART), and this provides an opportunity to measure incidence and risk factors for renal dysfunction. METHODS: We used routinely collected program data on all patients aged ≥15 years starting first-line TDF-based ART between January 2012 and December 2013. Creatinine clearance (CrCl) was assessed at base line and six-monthly, with renal dysfunction defined as CrCl < 50 ml/min/1.73 m2. We calculated incidence of renal dysfunction and used Cox regression analysis to identify associated risk factors. RESULTS: There were 1391 patients, of whom 1372 had normal renal function at baseline. Of these, 86 (6.3%) developed renal dysfunction during a median time of follow-up 1.14 years with an incidence rate of 5.4 per 100 person-years: 78 had CrCl between 30-50 ml/min/1.73 m2 and were maintained on TDF-based ART, but 5 were changed to another regimen: 4 because of CrCl <30 ml/min/1.73 m2. Risk factors for renal dysfunction included age ≥45 years, diagnosed diabetes, underlying renal disease, underweight and CD4 count <200 cells/mm3. There were 19 patients with baseline renal dysfunction and all continued on TDF-based ART: CrCl stayed between 30-49 ml/min/1.73 m2 in five patients while the remainder regained normal renal function. CONCLUSIONS: In a resource-poor country like Myanmar, the low incidence of renal toxicity in our patient cohort suggests that routine assessment of CrCl may not be needed and could be targeted to high risk groups if resources permit

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India.

Adverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients

Hydroxyl radical is the major causative factor in stress-induced gastric ulceration

The role of the metal-catalyzed production of hydroxyl radicals (OH.) on gastric ulceration caused by restraint-cold stress in rat was studied. Stress causes a 50% increase in the thiobarbituric acid reactive species (TBARS) as a measure of the lipid peroxidation, nearly 70% increase in protein oxidation as measured by its carbonyl content and about 40% decrease in the glutathione content of the fundic stomach, suggesting oxidative damage by stress. Stress also causes a time-dependent increase in the mitochondrial superoxide dismutase activity and a decrease in the peroxidase activity, both of which correlate well with the increase in the severity of ulceration as measured by the ulcer index. Specific OH scavengers such as benzoate or dimethylsulfoxide (DMSO) and the free radical trap such as &#945;-phenyl N-tert-butyl nitrone (PBN) significantly inhibit gastric ulceration suggesting the role of OH in this oxidative damage. Desferrioxamine (DFO), a nontoxic transition metal ion chelator, protects the mucosa against stress-ulceration dose dependently. Increased level of TBARS and the inactivation of gastric peroxidase are also prevented by DFO or by antioxidants such as glutathione or vitamin E, suggesting the critical role of metal ion and OH in the oxidative damage. A metal-catalyzed OH generating system constituted by Cu2+, H2O2 and ascorbate (reducing equivalent of O2-) causes inactivation of the purified gastric peroxidase in vitro, which can be effectively prevented by DFO. The stress-induced activation of the superoxide dismutase is completely blocked by pretreatment with a-amanitin indicating an increased synthesis of the enzyme by increased transcription of its m-RNA. Quantitative measurement indicates that stress causes a fivefold increase in the generation of OH, which correlates well with the increase in ulcer index with the progress of stress. The results indicate that the stress-induced gastric ulceration is a consequence of the oxidative damage of the gastric mucosa. This is caused by the OH generated through the metal-catalyzed Haber-Weiss reaction between O2- and H2O2, the latter being formed by the stimulation of the superoxide dismutase and inactivation of the gastric peroxidase

Clinical and Radiological Features of Seizures in Children Admitted in the PICU at a Tertiary Care Hospital in North-eastern India: A Retrospective Study

Introduction: A seizure is a brief change in normal electrical brain activity resulting in alterations in awareness, perception, behaviour, or movement, which affect persons of all ages, but are particularly common in childhood. Seizure is a serious neurological symptom in the Paediatric Intensive Care Unit (PICU), yet data on the clinical spectrum of seizures occurring in the PICU setting in India are scarce. Aim: To determine the aetiology, clinical and radiological features of seizures in critically ill children admitted to PICU at a tertiary care hospital. Materials and Methods: This retrospective study was conducted at Gauhati Medical College and Hospital, Guwahati, Assam, India, from April 2017 to September 2018. A total of 253 children aged between 29 days to 12 years, admitted to PICU with seizures were enrolled in the study. Data regarding demographics, diagnosis, clinical seizures, associated diagnosis, Electroencephalogram (EEG) features, imaging, length of stay in PICU, and in-hospital mortality were collected. Data was presented in frequencies, mean, standard deviation. Results: In present study, male to female ratio was 1.5:1 with mean age of 48.9±44.5 months. The most common causes of seizures in PICU setting were acute symptomatic in 185 (73.1%) and epileptic in 68 (26.9%) patients. Central Nervous System (CNS) infections constituted 15.8% of the PICU admissions following seizures. Most frequent co-existent diagnosis at admission was infectious diseases in 96 (38%) patients, followed by pulmonary diseases in 28 (11%) and cardiologic diseases in 14 (5.5%). Conclusion: CNS infections are the most common cause of acute symptomatic seizure, while non infectious diseases such as metabolic disorders, epilepsy and immune disorders also contribute to seizure occurrence in PICU. Identification of common seizure aetiologies in PICU is important step for a prompt and effective treatment

Role of reactive oxygen species in mercaptomethylimidazole-induced gastric acid secretion and stress-induced gastric ulceration

The objective of the present study is to delineate the role of reactive oxygen species in drug-induced gastric hyperacidity and stress-induced gastric ulceration. We reported earlier that mercaptomethylimidazole (MMI), an antithyroid drug, induces gastric acid (HCl) secretion partially through H2 receptor activation of the parietal cell by histamine release and partially through an intracellular mechanism. While studying the latter, MMI-induced acid secretion was found to correlate well with the inactivation of the peroxidase, an important H2O2 metabolizing enzyme of the mucosa. MMI activates the isolated parietal cell for acid secretion, which is sensitive to omeprazole. Peroxidase and catalase activity of the isolated cell is also irreversibly inactivated by MMI. It thus creates a favourable condition for endogenous accumulation of H2O2. Acid secretion by gastric gland preparation or isolated gastric mucosa is stimulated by exogenous H2O2, which is inhibited by omeprazole. Studies indicate that H2O2 inactivates the prostaglandin synthetase and removes the inhibitory influence of prostaglandin on acid secretion. MMI thus stimulates acid secretion not only through H2, receptor activation but also through the stimulation of the parietal cell by intracellular generation of H2O2 following inactivation of the peroxidase-catalase system. Among the various factors responsible for gastric ulceration, stress was found to cause severe haemorrhagic lesions mainly through oxidative damage of the mucosa as indicated by increased lipid peroxidation, increased protein carbonyl content, and decreased glutathione level. The severity of ulcer correlates well with the time-dependent induction of superoxide dismutase and inactivation of peroxidase, a condition favourable for accumulation of endogenous H2O2. Desferrioxamine prevents stress ulcer, indicating involvement of transition metal ion in the process. Studies indicate that severity of stress ulcer is dependent on the concurrent generation of hydroxyl radical (&#8226;OH) formed through metal-catalysed Haber-Weiss reaction between O2- and H2O2