A Study of Dopaminergic Pathway in Neurologic Wilson Disease with Movement Disorder.

Movement disorder (MD) is an important manifestation of neurologic Wilson disease (NWD), but there is a paucity of information on dopaminergic pathways. We evaluate dopamine and its receptors in patients with NWD and correlate the changes with MD and MRI changes. Twenty patients with NWD having MD were included. The severity of dystonia was assessed using BFM (Burke-Fahn-Marsden) score. The neurological severity of NWD was categorized as grades I to III based on the sum score of 5 neurological signs and activity of daily living. Dopamine concentration in plasma and CSF was measured using liquid chromatography-mass spectrometry, and D1 and D2 receptor expression at mRNA by reverse transcriptase polymerase chain reaction in patients and 20 matched controls. The median age of the patients was 15 years and 7 (35%) were females. Eighteen (90%) patients had dystonia and 2 (10%) had chorea. The CSF dopamine concentration (0.08 ± 0.02 vs 0.09 ± 0.017 pg/ml; p = 0.42) in the patients and controls was comparable, but D2 receptor expression was reduced in the patients (0.41 ± 0.13 vs 1.39 ± 1.04; p = 0.01). Plasma dopamine level correlated with BFM score (r = 0.592, p < 0.01) and D2 receptor expression with the severity of chorea (r = 0.447, p < 0.05). The neurological severity of WD correlated with plasma dopamine concentration (p = 0.006). Dopamine and its receptors were not related to MRI changes. The central nervous system dopaminergic pathway is not enhanced in NWD, which may be due to structural damage to the corpus striatum and/or substantia nigra.

Effect of Exercise on ß-Endorphin and Its Receptors in Myasthenia Gravis Patients.

This is a prospective observational study evaluating the change in ß-endorphin (BE) and its receptors following exercise in patients with myasthenia gravis (MG) and their association with clinical improvement. Fifteen patients with mild to moderate MG, aged 16-70 years, who were able to do 6-Minute Walk Test (6-MWT) and had MG Quality of Life-15 (MGQoL-15) ≤ 45 without any contraindication for exercise were included. The patients walked 30 min daily for 3 months. The primary outcome at 3 months was > 50% improvement in MGQoL-15 from the baseline, and the secondary outcomes were MG Activities of Daily Living (MGADL), Hospital Anxiety and Depression Scale (HADS), number of steps, and distance covered on 6-MWT and adverse events. Plasma BE level, µ-opioid receptor (MOR), and δ-opioid receptor (DOR) were measured on admission and at 1 and 3 months. Twelve age- and gender-matched healthy controls who were not on regular exercise were included for comparison of BE, MOR, and DOR levels. Plasma BE level (P = 0.007) and DOR expression (P = 0.001) were lower in MG patients compared to the healthy controls. After 3 months of exercise, 6 patients improved. Plasma BE, MOR, and DOR levels increased in the first and decreased in the third month. MGQoL-15 (P < 0.001), HADS (P < 0.0001), number of steps (P < 0.007), distance (P = 0.030), and MGADL (P < 0.001) significantly improved compared to baseline. At 3 months, MGQoL-15 was associated with HADS score (P = 0.001), reduced depression (P = 0.013), MGADL (P = 0.035), and distance travelled on the 6-WMW test (P = 0.050). The improvement in depression was associated with higher BE level.

A Comparative Study of Diagnosis and Treatment of Pott's Spine Amongst Specialists and Super Specialists in India.

Background and Objective: There is a paucity of guidelines about the diagnosis and management of Pott's spine. In this study, we report the pattern of practice of diagnosis and treatment of Pott's spine among the specialists and super-specialists in India. Subject and Methods: Response to a 22-item questionnaire regarding the diagnosis and treatment of Pott's spine has been reported. The responses were compared between medical and surgical specialists, residents and consultants, and specialists and super-specialists. There were 84 responders: 42 physicians and 42 surgeons; 48 residents and 36 faculty or consultants; 53 specialists and 31 super-specialists. Results: Thirty-eight responders rarely recommended biopsy whereas others recommended biopsy more frequently, especially the surgeons (P < 0.007). Twenty-five responders recommended immobilization even in an asymptomatic patient whereas 38 would immobilize those with neurological involvement only. All but 4 responders would repeat imaging at different time points. The response of medical treatment was judged at 1 month by 53, and 3 months by 26 responders. Surgery was recommended in a minority of patients-in those with neurological involvement or abscess. Surgeons more frequently biopsied, immobilized the patients, and recommended surgery compared to the physicians. The residents also recommended biopsy and recommended immobilization more frequently compared to consultants or faculty members. Super-specialists more frequently recommended biopsy compared to specialists. Conclusion: There is marked variation in investigations and treatment of Pott's spine patients, suggesting the need for consensus or evidence-based guidelines.

Treatment response and complications during management of Pott's spine.

The global incidence of TB in 2016 was 10.4 million and India accounts for a quarter of the global burden of TB. It is estimated that there are 2.79 million people with TB in India. About 10% of extra pulmonary TB involves bone and joints. Spinal TB accounts for half the cases of skeletal TB. The incidence of spinal TB is 1-4% of total TB cases, then it is estimated that only in India approximately 60,000 spinal TB cases exist. To report the pattern of recovery and predictors of outcome of Pott's spine. The intervention comprised of four drug antitubercular treatment, rest, immobilization, and ultrasonography or computerized tomography guided aspiration or biopsy as indicated outcome measures were six months Nurick grade, and mRS and complications like drug induced hepatitis (DIH) and paradoxical worsening. Seventy-three patients with Pott's spine, median age 36 (11-73) years, 32 (43.8%) females were included. The neurological signs were present in 44 (64.4%) patients. At six months, median Nurick grade improved from 4 to 2 and;and 70% patients had a good outcome as defined by mRS.The predictors of poor outcome were weight loss, non-ambulatory state on admission and paradoxical worsening. It is concluded that neurological involvement in Pott's spine was present in 64% patients, paradoxical worsening (deterioration in symptoms after one month of ATT) in 11% and DIH in 16%. Weight loss, non-ambulatory state on admission and paradoxical worsening predicted poor outcome.

Oxidative stress and ER stress are related to severity of tubercular infection.

To report the markers of oxidative stress and endoplasmic reticulum (ER) stress in tuberculosis of differing severity. Ninety patients with tuberculosis, 30 each with pulmonary tuberculosis (PTB), Pott's spine (PS) and tuberculous meningitis (TBM) were included. The diagnosis and severity of the respective group was based on pre-defined criteria. Six-months outcome and complications (Hyponatremia, paradoxical worsening and Drug induced hepatitis(DIH)) were recorded. Serum Melanodehyde (MDA) , glutathione (GSH), total antioxidant capacity (TAC), ER stress markers ATF-4,GRP-78 and CHOP, were measured using spectrophotometry and real time PCR. The oxidative and ER stress markers were correlated with different subgroups, severity of TBM, complications and outcome. The severity of TBM correlated with alteration in oxidative and ER stress markers. MDA was related to hyponatremia (P = 0.045), paradoxical worsening (P = 0.035) and DIH (P = 0.038), TAC correlated with paradoxical worsening (P = 0.047) and DIH (P = 0.015). In PS, MDA correlated with paradoxical worsening (P = 0.032) and DIH (P = 0.032); and in PTB, MDA correlated with hyponatremia (P = 0.025) and DIH (P = 0.037). Changes in stress marker levels were more marked in TBM compared to PS and PTB. Outcome of TBM correlated with MDA (P = 0.002), PS to MDA(P = 0.004), TAC(P = 0.05) CHOP(P = 0.004), GRP78(P = 0.001), ATF4(P = 0.045) and PTB to MDA(P = 0.0450), TAC(P = 0.014), CHOP(P = 0.025) and GRP78(P = 0.035). Oxidative and ER stress markers seem to be related to severity of TB, its complications and outcome.

Role of Caspase- 3, TNF-α, and IL6 mRNA Expression in Intracranial Tuberculoma.

The development of tuberculoma is a process of inflammation, necrosis, and apoptosis. Therefore, the pro-inflammatory cytokines and apoptosis biomarkers are likely to play an important role. In this study, we report the expression of TNFα, IL6, and caspase-3 at the mRNA level in the patients with tuberculous meningitis (TBM) and compare these biomarkers in the patients with and without tuberculoma. A total of 134 patients with TBM and 35 matched healthy controls were included. The clinical, cerebrospinal fluid (CSF), and cranial magnetic resonance imaging (MRI) findings were noted. The mRNA expression of TNFα, IL6, and caspase-3 in peripheral blood mononuclear cells was evaluated by reverse transcriptase polymerase chain reaction. On cranial MRI, 89 (64.2%) patients had tuberculoma, and their level of consciousness, severity of meningitis, CSF findings, and blood counts were not significantly different from those without tuberculoma. Patients with tuberculoma had a higher expression of TNFα and IL6 compared to the controls, but had lower expression compared to the patients without tuberculoma. TNFα expression positively correlated with the expression of caspase-3, but not with IL6. Twenty-five (18.6%) patients died: 12 (13.5%) in tuberculoma and 13 (28.9%) in the non-tuberculoma group. Death was related to higher expression of TNFα and caspase-3. The lower expression of TNFα and IL6 in intracranial tuberculoma suggests that these patients are unlikely to be benefited with TNFα blockers.

A Study of Catecholamine Levels in Acute ICH Patients and its Clinical Significance.

ICH is one of the most serious neurological emergency which can result in high mortality which may be related to catecholamine release. We aim to evaluate serum catecholamine levels in acute ICH and correlate their levels with clinical parameters of stress and outcome. MATERIAL: Consecutive patients with CT proven ICH within 7 days of ictus were included and their clinical finding, SIRS Parameters, GCS, NIH score, laboratory parameters (ESR, CRP) were evaluated. Serum Catecholamine (DA, NE, E) levels were measured by LCMS. The patients were followed up at discharge and one month, the outcome was defined by mortality and 1 month modified Rankin scale (good 0-2, poor >2). OBSERVATION: There were 31 patients of acute ICH. Patients were admitted 1 to 2 days after ictus. Among the patients 19 were male and 12 were female.Their age ranged from 31 to 86 with mean 53.3+- 16.7. History of hypertension was present in 27.3% of patients. Their average GCS was median 12 (6.0, 15.0) and NIHSS was 12.5 (8.5, 22) Their average ESR was 30 (13,56) and average CRP was 1.8 (1.1, 5.9). Almost all pateints had raised SIRS parameters. There was an increase in levels of Dopamine (63.2 pg/ml), Epinephrine (73.5 pg/ml) and Norepinephrine (390pg/ml) on admission as compared to their levels 1 week after ictus or on discharge (Dopamine 35.6, Epinephrine 52.1, and Norepinephrine 241 pg/ml). CONCLUSION: CA surge is common in ICH pateints and it correlates with severity and outcome of patient. 6 pateints died in the hospital 72 % of patients had poor outcome. Catecholamine levels were higher in poor outcome patients.

Renin, antidiuretic hormone (ADH), and ADH receptor levels in cerebral salt wasting associated with tuberculous meningitis.

BACKGROUND: To evaluate serum antidiuretic hormone (ADH), its receptors, and renin levels in cerebral salt wasting (CSW) in tuberculous meningitis (TBM). METHODS: Patients diagnosed with definite (n = 30) or probable TBM (n = 47) who developed hyponatremia (CSW, SIADH, or miscellaneous causes) were included. Sequential measurement of serum ADH, ADH-R, and renin activity by enzyme-linked immunosorbent assay was done and correlated with serum sodium level, urinary output, and fluid balance. RESULTS: Out of 79 TBM patients, CSW was observed in 36, SIADH in four, and miscellaneous hyponatremia in eight patients. CSW patients had a longer hospital stay (P < 0.001), lower GCS score (P < 0.007), higher MRC grade (P < 0.007), and a lower serum Na (P < 0.001) compared to non-CSW TBM patients. In severe CSW patients, serum ADH and ADH-R were correlated with hyponatremia and returned to baseline on correction; however, serum renin levels remained elevated. Serum ADH was related to hyponatremia but ADH-R and renin were not. ADH-R and renin levels did not significantly differ in CSW and SIADH. CONCLUSION: CSW is the commonest cause of hyponatremia in TBM and correlates with disease severity. ADH is related to hyponatremia, but ADH receptor and renin are not.

A study of glutamate excitotoxicity in seizures related to tuberculous meningitis.

BACKGROUND AND PURPOSE: Glutamate is a neurotransmitter that regulates approximately half of the nervous system, along with the sensory system. Glutamate excitotoxicity is related to seizures but its role in TBM-related seizure has not been reported to our best knowledge. It is proposed to report plasma glutamate level and its receptors in TBM patients with seizures and correlate with the type of seizures, Magnetic Resonance Imaging (MRI) findings, and outcome. METHODS: TBM was diagnosed clinically with MRI as well as cerebrospinal fluid examination. TBM-related seizures have been categorized into early (< 1 month) or late (> 1 month) seizures. Six months outcome was defined using modified Rankin Scale as good (mRS ≤ 2) or poor (mRS > 2). Plasma glutamate was measured by ELISA, along with NR1, NR2A, and NR2B receptors using Real Time Polymerase Chain Reaction (RT-PCR) and have been correlated with seizure, MRI abnormalities, and outcome. RESULTS: A total of 29 (53.7%) patients developed seizures (early-09, late-20). Glutamate (P < 0.0001), NR1 (p ≤ 0.0001), NR2A (p ≤ 0.0001), and NR2B (p ≤ 0.0001) were higher than the controls. In TBM patients with seizures, plasma glutamate (p = 0.01), NR1 (p = 0.03) and NR2A (p = 0.001) were significantly higher than those without seizures. Plasma glutamate level and all three receptor genes expression were higher during seizures and improved on cessation of seizure compared to the baseline. These markers correlated well with MRI findings and determined the outcome. ROC curve was used to estimate the diagnostic accuracy of the markers. The result indicated that NR2A gene was the best predictor followed by glutamate and NR1 gene. CONCLUSION: Our results highlight the role of glutamate and its receptors in TBM-related seizures and outcomes.

Rest or 30-Min Walk as Exercise Intervention (RESTOREX) in Myasthenia Gravis: A Randomized Controlled Trial.

INTRODUCTION: There is a lack of evidence about the usefulness of exercise or rest in myasthenia gravis (MG). This study is aimed to evaluate the efficacy and safety of exercise or rest in MG. METHODS: In a single-center open-labeled randomized controlled trial, the patients with mild to moderate MG were randomized to 30-min walk or rest in addition to the standard treatment. The primary endpoint was 50% improvement in the MG Quality of Life (MG-QOL15), and secondary endpoints were change in the Myasthenic Muscle Score (MMS), MG Activities of Daily Living (MGADL), grip strength, dose of acetylcholine esterase inhibitor and prednisone, 6-min walk test (6MWT), decrement in trapezius on the low-rate repetitive nerve stimulation test, and adverse events. The outcomes were defined at 3 months, by >50% improvement in these outcome parameters. RESULTS: Forty patients with MG were randomized to the exercise or rest arm. The 2 arms were matched for demographic and clinical parameters. The patients in the exercise arm had significantly better QOL evidenced by MG-QOL15 (p = 0.02). The secondary endpoints, distance covered in 6MWT (p = 0.007), were also better in the exercise arm without any adverse event. CONCLUSION: Regular exercise for 30 min in mild and moderate MG improves quality of life and walking distance compared to rest and is safe. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is CTRI/2019/11/021869.

Impact of COVID-19 pandemic on cancer surgery: Patient's perspective.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has impacted cancer care globally. The aim of this study is to analyze the impact of COVID-19 on cancer healthcare from the perspective of patients with cancer. METHODS: A cross-sectional survey was conducted between June 19, 2020, to August 7, 2020, using a questionnaire designed by patients awaiting cancer surgery. We examined the impact of COVID-19 on five domains (financial status, healthcare access, stress, anxiety, and depression) and their relationship with various patient-related variables. Factors likely to determine the influence of COVID-19 on patient care were analyzed. RESULTS: A significant adverse impact was noted in all five domains (p = < 0.05), with the maximal impact felt in the domain of financial status followed by healthcare access. Patients with income levels of INR < 35 K (adjusted odds ratio [AOR] = 1.61, p < 0.05), and 35K- 100 K (AOR = 1.96, p < 0.05), married patients (AOR = 3.30, p < 0.05), and rural patients (AOR = 2.82, p < 0.05) experienced the most adverse COVID-19-related impact. CONCLUSION: Delivering quality cancer care in low to middle-income countries is a challenge even in normal times. During this pandemic, deficiencies in this fragile healthcare delivery system were exacerbated. Identification of vulnerable groups of patients and strategic utilization of available resources becomes even more important during global catastrophes, such as the current COVID-19 pandemic. Further work is required in these avenues to not only address the current pandemic but also any potential future crises.

Is cerebral salt wasting related to sympathetic dysregulation in tuberculous meningitis?

BACKGROUND: Cerebral Salt wasting (CSW) is common in Tuberculous Meningitis (TBM) and is suggested to be due to sympathetic dysregulation of renal blood supply but has not been proven. OBJECTIVE: To evaluate plasma Catecholamines in TBM patients with CSW and correlate with the markers of stress. MATERIALS AND METHODS: The diagnosis of TBM was based on clinical, CSF and MRI criteria. Catecholamines level was measured by LC-MS on admission, at the time of hyponatremia and on correction of hyponatremia. Catecholamine levels were correlated with clinical and laboratory markers of stress, hyponatremia and severity of CSW using pre-defined criteria. RESULTS: There were 24 patients with TBM (12 with CSW) and 12 controls. The median age of patients was 31 (18-75) years and 12 (50 %) were females. TBM patients with CSW had significantly higher levels of catecholamines compared to controls (p < 0.001). TBM patients with CSW had higher levels of norepinephrine than those without CSW (p = 0.034). Sequential studies revealed that dopamine and epinephrine increased at the time of hyponatremia and declined on its correction. Severity of TBM was related to dopamine (p = 0.04) and severity of CSW was related to epinephrine (p = 0.016). CONCLUSION: CSW in TBM seems to be related to catecholamine dysregulation.

Impact of COVID-19 pandemic and lockdown in a cohort of myasthenia gravis patients in India.

OBJECTIVE: Myasthenia gravis (MG) is characterized by fluctuating muscle weakness due to immune mediated damage of acetylcholine receptor (AchR). COVID-19 infection, mental stress and non-availability of drugs following lockdown may worsen myasthenic symptoms. We report the impact of COVID 19, and lockdown on the physical and mental health, and quality of sleep in a cohort of MG. METHODS: Thirty-eight MG patients were telephonically interviewed 2months after the declaration of lockdown in India. The difficulty in procuring drugs, complications, and worsening in the MG Foundation of America (MGFA) stage were noted. The patients were enquired about MG Quality of Life 15 (MGQOL15), MG Activity of Daily Living (MGADL), Hospital Anxiety and Depression Scale (HADS) and Pittsburgh Sleep Quality Index (PSQI) using a prefixed questionnaire. Their pre-COVID parameters were retrieved from our earlier trial data, which was completed 4months back. The scores of the above mentioned parameters before and after COVID were compared. RESULTS: Their median age was 45 years, and the median duration of treatment for MG was 4.5years. Eleven (28.9 %) patients were hypertensive and 3(7.9 %) diabetic. All were on prednisolone and 18(47.4 %) received azathioprine. None developed COVID, but three had other infections. Two patients needed hospitalization because of wrong medication in one and severe anxiety-insomnia in another. Following COVID19 and lockdown, MG patients had worsening in MGQOL15, MGADL, HADS and PSQI scores. Pittsburgh Sleep Quality Index score correlated with MGQOL15 and dose of acetylcholine esterase inhibitors. CONCLUSION: COVID-19 and lockdown were associated with anxiety, depression, poor MGQOL and sleep especially in severe MG patients.

Mitochondrial Stress-Mediated Targeting of Quiescent Cancer Stem Cells in Oral Squamous Cell Carcinoma.

INTRODUCTION: Despite improved therapeutics in oral squamous cell carcinoma (OSCC), tumor cells that are either quiescent and/or endowed with stem cell-like attributes usually survive treatment and recreate tumor load at relapse. Through this study, we aimed strategically to eliminate these stem cell-like cancer cells using a combination drug approach. METHODS: Primary cultures from 15 well-moderately differentiated OSCC were established, and the existence of cancer cells with stem cell-like characteristics using five cancer stem cell (CSC) specific markers - CD44, CD133, CD147, C166, SOX2 and spheroid assay was ascertained. Next, we assessed quiescence in CSCs under normal and growth factor-deprived conditions using Ki67. Among several gene signatures regulating quiescent cellular state, we evaluated the effect of inhibiting Dyrk1b in combination with topoisomerase II and histone deacetylase inhibitors in targeting quiescent CSCs. Multiple drug-effect analysis was carried out with CompuSyn software to determine combination-index values. RESULTS: We observed that CD44+CD133+ showed the highest level of SOX2 expression. CSCs showed varying degrees of quiescence, and inhibition of Dyrk1b decreased quiescence and sensitized CSCs to apoptosis. In the drug-combination study, Dyrk1b inhibitor was combined with topoisomerase II and histone deacetylase inhibitors to target quiescent CSCs. In combination, a synergistic effect was seen even at a 16-fold lower dose than IC50. Furthermore, combined treatment decreased glutathione levels and increased ROS and mitochondrial stress, leading to increased DNA damage and cytochrome c in CSCs. CONCLUSION: We report marker-based identification of CSC subpopulations and synergy of Dyrk1b inhibitor with topoisomerase II and HDAC inhibitors in primary OSCC. The results provide a new therapeutic strategy to minimize quiescence and target oral CSCs simultaneously.

Oxidative stress and ER stress may contribute to drug-induced hepatitis in tuberculous meningitis.

BACKGROUND: Study of oxidative stress and endoplasmic reticulum (ER) stress markers in drug induced hepatitis (DIH) associated with tuberculous meningitis (TBM) has not been done. Such a study may provide information on the role of stress in DIH. OBJECTIVE: To report the role of oxidative stress and ER stress in DIH associated with TBM and their effect on outcome of patients. METHOD: Demographic and clinical information about TBM patients including stage of TBM, duration of illness, Magnetic Resonance Imaging (MRI) findings, laboratory markers, oxidative and ER stress markers were recorded. These markers were compared in patients with and without DIH. Survival analysis between DIH and no DIH patients was done using Kaplan - Meier analysis and the predictors of outcome were evaluated using Cox regression analysis. RESULTS: Out of 92 patients with TBM, 36 (39.1%) developed DIH. There was significant alteration in oxidative stress and ER stress markers compared to baseline and following recovery from DIH. At the time of discharge 58.3% patients with DIH had poor outcome (mRS >2). Kaplan-Meier analysis of survival revealed that the proportion of the patient's survival was significantly higher in non DIH group as compared to DIH group (89.3% vs. 61.1%, p = .006). CONCLUSION: Oxidative stress and ER stress are related with the severity of TBM, its outcome and mortality.

Challenges, opportunities and progress in solid waste management during COVID-19 pandemic.

At the end of December 2019, Wuhan City became the epicenter of the highly contagious virus known as the novel coronavirus. Now that mid-2020 has already passed, almost every country is adversely affected by Corona Virus Disease (COVID-19). The routine activities of people of all ages are overturned, which has led to a shift in the trends of waste created by households, streets, and most importantly, medical facilities and quarantine centers. Compulsive use of personal protection equipment such as masks, gloves, sanitizers, etcetera by the frontline workers from the medical sector, banks, daily need stores, waste collection industries, etc. and the use of masks by every common man stepping out has skewed the trend of waste generation to a different direction. Recently, the replacement of single-use plastic was accepted by the masses, and the pandemic suddenly rebounded to the previous situation, it is expected to be worse in the long run. Another secondary outcome is reduced waste collection and recycling due to lockdown, leading to a pile-up of wastes. But several nations are adopting strategies to break the transmission chain of the virus by trying to minimize human contact. The study discusses the effect of COVID-19 on the generation, recycling, and disposal of solid waste. A brief collection of different countries' efforts to restrict the transmission of virus through solid waste is also discussed.

Oxidative and endoplasmic reticulum stress in tuberculous meningitis related seizures.

BACKGROUND AND PURPOSE: High oxygen consumption and high polyunsaturated fatty acid content in the brain may render it vulnerable to oxidative stress and endoplasmic reticulum (ER) stress. We report the role of these parameters in tuberculous meningitis (TBM) patients with seizures and correlate these with clinical radiological, and laboratory findings. METHODS: Serum oxidative stress markers ; Catalase, Superoxide dismutase (SOD), Glutathione (GSH), Protein-carbonyl, Malonaldehyde (MDA) were measured using spectrophotometer and ER stress markers-ATF4, CHOP, XBP1 and GRP-78 using RT-PCR in TBM patients, 29 with seizures, 20 without seizures and 20 matched controls. In 10 patients, sequential estimation of oxidative stress and ER stress markers was also measured. RESULTS: In comparison to controls, TBM patients had significant difference in the expression of oxidative stress and ER stress markers. Serum MDA (P=0.02), protein-carbonyl (P < 0.01) were significantly higher and SOD (P=0.02) and GSH (P < 0.01) significantly lower in the patients with seizures compared to those without seizures. The ER stress markers were insignificantly elevated in TBM patients with seizures. On sequential evaluation, oxidative stress and ER stress markers increased following seizures and returned to baseline at the time of discharge. CONCLUSION: The results suggest some role of oxidative stress and ER stress in TBM, but do not predict its outcome.

ROS-dependent Bax/Bcl2 and caspase 3 pathway-mediated apoptosis induced by zineb in human keratinocyte cells.

There are a large number of agricultural workers who are exposed to pesticides through skin and inhalation. The best approach to identify altered molecular pathways during dermal exposure to pesticides is relevant to risk-associated concern about skin safety. In this study, we investigated the cytotoxic effect of zineb, a fungicide, in human keratinocyte (HaCaT) cells. HaCaT cells were treated with zineb (1-40 µg/mL) for 24 hours. Cellular and molecular mechanisms of cell toxicity were investigated through MTT and neutral red-uptake assays. Zineb reduced viability of HaCaT cells and induced apoptosis in a concentration-dependent manner. Zineb increased levels of Bax and caspase 3 and inhibited the level of Bcl2, which subsequently induced apoptosis via the Bax/Bcl2 and caspase pathway. Therefore, zineb could have induced apoptosis through the mitochondrial pathway in HaCaT cells. Our study suggests that zineb is cytotoxic to HaCaT cells via the induction of apoptosis and oxidative stress in vitro.

Is drug-induced hepatitis related to the severity of tuberculous meningitis?

Background: Drug-induced hepatitis (DIH) occurs more commonly in tuberculous meningitis (TBM) than non-CNS tuberculosis. We evaluate DIH in TBM and its relationship with disease severity and surrogate markers of stress. Methods: Sixty-seven patients with TBM were included prospectively. The diagnosis of DIH was based on five times elevation of alanine amino transferase (ALT) in asymptomatic and three times in symptomatic patients, serum bilirubin 1.5 mg/dL or more occurring after 3 days of antitubercular drugs without any other cause of liver dysfunction; and improvement in liver function upon drug withdrawal. Stage of TBM, Glasgow Coma Scale (GCS) score, signs of raised intracranial pressure (ICP), ESR, C-reactive protein (CRP), systemic inflammatory response syndrome (SIRS), serum cortisol and MRI findings were noted on admission and during DIH. Results: A total of 32.8% (22/67) patients with TBM developed DIH that was associated with worsening in GCS score (p=0.01), stage TBM (p=0.02), SIRS parameters (p=0.04), ESR (p=0.04) and CRP (p<0.01) compared with their baseline. Stage of TBM independently predicted DIH (OR=0.42, 95% CI, 0.18-1.0; p=0.04)]. Drug-induced hepatitis occurred with paradoxical worsening in 11 patients and had higher mortality (32% vs 7%; p=0.01). Conclusion: DIH occurred in 32.8% (22/67) of patients with TBM, and was related to the severity of TBM and possibly to the accompanying 'physiological stress'.