Prevalence and predictors of hypocalcaemia in severe acute malnutrition.

OBJECTIVE: To determine the prevalence and predictors of hypocalcaemia in under-five children (1-59 months) hospitalised with severe acute malnutrition (SAM). DESIGN: A cross-sectional study was designed to determine the prevalence of hypocalcaemia among children hospitalised with SAM. Serum Ca and 25-hydroxycholecalciferol (25-(OH)D) were estimated. Hypocalcaemia was defined as serum Ca (albumin-adjusted) <2·12 mmol/l. To identify the clinical predictors of hypocalcaemia, a logistic regression model was constructed taking hypocalcaemia as a dependent variable, and sociodemographic and clinical variables as independent variables. SETTING: A tertiary care hospital in Delhi, between November 2017 and April 2019. PARTICIPANTS: One-hundred and fifty children (1-59 months) hospitalised with SAM were enrolled. RESULTS: Hypocalcaemia was documented in thirty-nine (26 %) children hospitalised with SAM, the prevalence being comparable between children aged <6 months (11/41, 26·8 %) and those between 6 and 59 months (28/109, 25·7 %) (P = 0·887). Vitamin D deficiency (serum 25-(OH)D <30 nmol/l) and clinical rickets were observed in ninety-eight (65·3 %) and sixty-three (42 %) children, respectively. Hypocalcaemia occurred more frequently in severely malnourished children with clinical rickets (OR 6·6, 95 % CI 2·54, 17·15, P < 0·001), abdominal distension (OR 4·5, 95 % CI 1·39, 14·54, P = 0·012) and sepsis (OR 2·6, 95 % CI 1·00, 6·57, P = 0·050). CONCLUSION: Rickets and hypocalcaemia are common in children with SAM. Routine supplementation of vitamin D should be considered for severely malnourished children. Ca may be empirically prescribed to severely malnourished children with clinical rickets, abdominal distension and/or sepsis.

Cardiac autonomic tone, plasma BDNF levels and paroxetine response in newly diagnosed patients of generalised anxiety disorder.

Objective: The study examined the effect on cardiac autonomic tone via heart rate variability (HRV), brain derived neurotrophic factor (BDNF) in newly diagnosed generalised anxiety disorder (GAD) cases with paroxetine-controlled release (PX) CR intervention.Methods: Fifty GAD cases using DSM-5 criteria, matched with healthy controls (HC) were assessed with clinical measures (Hamilton Anxiety Scale (HAM-A), Clinical Global Impression- Severity Scale (CGI-Severity), General Health Questionnaire -12 (GHQ-12), HRV, plasma BDNF levels initially and 6 weeks postintervention with paroxetine CR.Results: HRV parameters were significantly lower in GAD vs HC at baseline for standard deviation of normal to normal intervals (SDNN) and proportion of differences in consecutive NN intervals that are longer than 50 ms (pNN50). Significantly higher plasma BDNF levels were noted between HC versus GAD at baseline. Postintervention HAM-A, CGI scores, GHQ-12 item scores showed significant reduction. Significant differences also noted in square root of mean squared difference of successive NN intervals (RMSSD), (SDNN), pNN50 and in plasma BDNF levels after intervention within GAD group. Significant negative correlation observed between HAM-A scores and SDNN parameter after taking PX CR in GAD.Conclusion: GAD showed cardiac autonomic dysfunction, lowered plasma BDNF levels and their improvement with paroxetine CR.Key messageGAD is associated with significantly lower HRV, suggestive of cardiac autonomic dysfunction and lowered plasma BDNF levels, an indicator of stress.Therapeutic intervention with Paroxetine in GAD patients showed clinically significant improvement reflecting restoration of the cardiac autonomic tone and BDNF levels, thus implying their role as potential biomarkers.

Association of organochlorine pesticides with the mRNA expression of tumour necrosis factor-alpha (TNF-α) & cyclooxygenase-2 (COX-2) genes in idiopathic preterm birth.

BACKGROUND & OBJECTIVES: Preterm birth (PTB) is an important cause of prenatal death, neonatal morbidity and mortality and adult illness. Increased inflammation occurs in normal parturition, and inflammatory cytokines and oxidative stress are found to be higher in PTB cases. The present study was planned to investigate the association of organochlorine pesticides (OCPs) with mRNA expression of inflammatory pathway genes such as tumour necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2) in preterm delivery (PTD) cases. METHODS: Maternal blood samples of PTD (n=30) cases and equal number of term delivery (n=30) were collected at the time of labour. Women occupationally exposed to OCPs and other high risk factors such as anaemia, hypertension, bacterial vaginosis, renal and heart disease, diabetes, etc. were excluded. The OCP levels were estimated by gas chromatography, and mRNA expressions of TNF-α and COX-2 genes were analysed using real-time PCR (qPCR). RESULTS: Significantly higher levels of ß-HCH (beta-hexachlorocyclohexane, 95% CI=2.08-4.633, p0 =0.001), p'p'-DDE (para, para-dichlorodiphenyldichloroethylene, 95% CI=0.546-2.551, p0 =0.003), and o'p'-DDD (ortho, para-dichlorodiphenyldichloroethane, 95% CI=0.004-0.690, P=0.047) were observed in maternal blood of PTB cases as compared to term delivery. The mRNA expressions of COX-2 and TNF-α genes were 3.13 and 2.31 folds higher in PTB cases in comparison to term delivery. l0 inear positive correlations were observed between period of gestation (POG) and ΔCt of COX-2 and TNF-α genes. INTERPRETATION & CONCLUSIONS: Environmental factors such as OCPs may be associated with inflammatory events showing gene-environment interaction in PTB cases. Evaluating the molecular control of inflammation along with gene environment interaction may be used as a model to explore the aetiology of idiopathic PTB cases and may be considered for the prognosis of adverse reproductive outcomes.

Profile of oxidative stress in response to treatment for type 1 leprosy reaction.

OBJECTIVE: To measure oxidative stress in Type 1 leprosy reaction, and to document the effect of anti-leprosy multidrug therapy (MDT) and anti-reaction drugs on measures of oxidative stress. MATERIALS AND METHODS: A prospective study was carried out at a teaching hospital involving consecutive patients with Type 1 reaction. MDA (malondialdehyde), FRAP (ferric reducing ability of plasma) and GSH (reduced glutathione) were measured in venous blood samples as measures of oxidative stress and compared at inclusion, after 4 weeks of initial therapy (following standard guidelines including MDT, NSAIDS, and systemic steroids), and 4 weeks after clinical remission. RESULTS: The final study cohort included 40 patients with Type 1 reaction (different treatment arms) after excluding for confounding factors such as prior treatment, smoking, NSAID use or concurrent illness requiring therapy. Measures of lipid derived oxidative stress assessed by MDA showed a significant rise with 4 weeks of therapy and a trend towards decline after clinical resolution. In contrast, the other two measures of anti-oxidants namely GSH and FRAP, showed a significant decrease (P < 0.05) at 4 weeks of treatment followed by a significant increase after 4 weeks of clinical remission of reaction. CONCLUSION: MDT and anti-reactional treatment is associated with significant increases in FRAP and GSH levels, reflecting a reduction in the oxidative stress in patients treated for Type 1 reaction. However, lipid peroxidation as measured by MDA is only partially controlled with treatment.

Gene-environment interaction in preterm delivery with special reference to organochlorine pesticides.

We investigated the association between glutathione S-transferases mu1 (GSTM1), theta 1 (GSTT1), Cytochrome P450IA1-T6235C (rs4646903, CYP1A1m1) and CYP1A1-1462V (rs1048943, CYP1A1m2) gene polymorphisms, and organochlorine pesticides (OCPs) level with risk of preterm delivery (PTD). Maternal and cord blood samples of PTD (n = 156) cases and subjects of full-term delivery (FTD, n = 151) were collected at the time of delivery/after delivery. Women occupationally exposed to OCPs and other high-risk factors such as anemia, hypertension and dietary habit were excluded. The OCP levels were estimated by gas chromatography, and polymorphic analysis of GSTM1/GSTT1 and CYP450 genes was carried out using multiplex PCR and PCR-restriction fragment length polymorphism, respectively. The frequency of GSTM1/GSTT1 (null) genotype was significantly higher in PTD cases than in the controls. Significantly high levels of α-hexachlorocyclohexane (HCH), γ-HCH and Dichlorodiphenyldichloroethylene (p'p'-DDE) were observed in maternal blood, while significantly high levels of p,p'-dichlorodiphenyltrichloroethane and p'p'-DDE were found in the cord blood of PTD cases compared with the controls. A significant association was seen between ß-HCH and GSTM1 genotype when interaction between GSTM1 gene polymorphism, maternal blood OCP levels and period of gestation (POG) was ascertained. A significant reduction in POG was observed. Similarly, cord blood dieldrin levels were significantly associated with CYP1A1m2 (Aa/aa) with reduction in POG. Our observations indicate that higher levels of OCPs in pregnant women may be associated with increased risk of 'idiopathic' PTD. Furthermore, this study shows that the interaction between high OCPs levels and polymorphism in CYP1A1m2 and GSTM1 null genotypes may magnify the risk of PTD, thus providing evidence for a gene-environment interaction in pregnant women.

A randomized, prospective study of efficacy and safety of oral tramadol in the management of post-herpetic neuralgia in patients from north India.

OBJECTIVE: To evaluate the safety and efficacy of oral tramadol therapy (50 to 200 mg/day) in the treatment for post-herpetic neuralgia (PHN). METHODS: The study was a prospective, single-blind, non-responder vs. responder, randomized trial conducted in 100 outpatients of PHN after oral administration of tramadol for 4 weeks. Those patients who had achieved 50% or greater pain relief after 14 days of oral tramadol treatment were categorized as responders and those reporting < 50% pain relief were categorized as non-responders. Rescue analgesia was provided by the topical application of a cream consisting of the combination of 3.33% doxepin and 0.05% capsaicin to the affected areas of PHN patients of both groups for at least 14 days, along with tramadol therapy. The rescue analgesia was extended to 4 weeks in patients of the non-responder group. The primary endpoints were measured using a numerical rating scale (NRS) at rest and with movement. Secondary endpoints included additional pain ratings such as global perceived effect (GPE), Neuropathic Pain Symptom Inventory scores (NPSI), daily sleep interference score (DSIS), quality of life (QOL) as per WHO QOL-BREF Questionnaire scores, patient and clinician ratings of global improvement. The 2 groups were compared on the basis of pain intensity scores, encompassing primary as well as secondary endpoints, and QOL after 28 days of the treatment regimen. RESULTS: Pain intensity scores measured by NRS (at resting and with movement), NPSI, and DSIS were consistently reduced (P < 0.001) over 28 days at varying intervals in both the groups, but the magnitude of reduction was higher in responders than non-responders. A concomitant improvement (P < 0.001) was observed in GPE on days 3, 14, and 28 as compared to the respective baseline scores in both the groups. Although the WHO QOL-BREF scores showed significant (P < 0.001) improvement in QOL of PHN patients at days 14 and 28 in both the groups, the magnitude of improvement was higher in responders as compared to non-responders. Significant improvement in pain intensity scores and QOL in non-responders is mainly attributed to the use of rescue analgesia for 28 days rather than recommended tramadol therapy. CONCLUSIONS: Treatment with tramadol 50 to 200 mg per day was associated with significant pain reduction in terms of enhanced pain relief, reduced sleep interference, greater global improvement, diminished side-effect profile, and improved QOL in PHN patients from North India. Further categorization of PHN patients may be helpful so that additional or alternative therapy may be prescribed to non-responders.

Serological Response to COVID-19 and Its Association With Measles-Rubella (MR)-Containing Vaccines.

BACKGROUND AND OBJECTIVES:  Epidemiological studies suggest that coronavirus disease 2019 (COVID-19) has a less severe disease course and a more favorable prognosis among children. Childhood vaccines and heterologous immunity have been suggested as reasons for this. Additionally, the structural similarity between the measles, rubella, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus particles may affect immune responses. The objective of this study was to compare COVID-19 antibody titers and disease severity between measles-rubella (MR) vaccinated and unvaccinated children. Additionally, we aimed to evaluate and compare the antibody response in recipients of a single dose and two doses of the MR vaccine. METHODS:  The study was prospective and comparative and included 90 COVID-19-positive children aged nine months to 12 years. The study was registered under the clinical trials registry of India (CTRI/2021/01/030363). COVID-19 antibody titers were measured at two weeks, six weeks, and 12 weeks, along with the assessment of MR antibody titers. COVID-19 antibody titers and disease severity were compared between MR-vaccinated and MR-unvaccinated children. The comparison of COVID-19 antibody titers between recipients of a single dose and two doses of MR vaccine was also conducted. RESULTS: The results showed significantly higher median COVID-19 antibody titers at all time points during follow-up in the MR-vaccinated group (P<0.05). However, the two groups had no significant difference in the disease severity. Moreover, there was no difference in the antibody titers of MR one dose and two dose recipients. CONCLUSION: Exposure to even a single dose of MR-containing vaccine enhances the antibody response against COVID-19. However, randomized trials are necessary to further explore this subject.

Efficacy of Oral vs. Intravenous Calcium Supplementation for Continuation Therapy in Hypocalcemic Seizures: A Randomized, Controlled Trial.

OBJECTIVE: To evaluate efficacy of oral vs. intravenous calcium supplementation for continuation therapy in hypocalcemic seizures. METHODS: Sixty children between 1 mo and 5 y presenting with hypocalcemic seizures without any other underlying febrile, chronic systemic disease, or acute neurological illness were included. Participants were randomized to receive either intravenous (IV) 10% calcium gluconate (n = 30) or oral elemental calcium (n = 30) for 48 h following initial seizure control with intravenous calcium. RESULTS: Seizures recurred in 3 (10%) children in IV group as compared to 4 (13.3%) in oral calcium group (p = 0.278) within 48 h. Serum calcium levels achieved in the two treatment groups at 24 h [7.96 (1.32) vs. 8.23 (1.58) mg/dL; p = 0.476] and 48 h [8.5 (1.01) vs. 8.63 (1.39) mg/dL; p = 0.681] were comparable. CONCLUSION: Oral calcium may be as efficacious as intravenous calcium during continuation phase of treating hypocalcemic seizures; however, further studies are needed for definite recommendations. TRIAL REGISTRATION: Trial Registration number: CTRI/2017/12/011042.

Chemotherapy-Induced Oxidative Stress in Pediatric Acute Lymphoblastic Leukemia.

Introduction Plasma antioxidant capacity in children receiving chemotherapy decreases due to the effect of the disease and chemotherapy. Increased oxidative stress (OS) predisposes to an increased risk for chemotherapy-related toxicity and febrile neutropenic episodes. Materials and methods We conducted this case-control study in the hematology-oncology unit of the department of pediatrics of a tertiary hospital in Delhi, India, from November 2017 to March 2019 to compare OS between children with acute lymphoblastic leukemia (ALL) and healthy controls. We estimated the trends in OS as measured by the plasma total antioxidant capacity (TAC) and thiobarbituric acid reactive substance (TBARS) levels at baseline and at the completion of induction I (four weeks), induction II (eight weeks), and induction IIA-consolidation (16 weeks) phases of chemotherapy in children with ALL. We also assessed the change in OS during different phases of initial treatment and studied the association between OS and the hematological toxicity of chemotherapy (determined by the need for blood component therapy and the number of febrile neutropenic episodes) and serum cobalamin and folate levels. Results OS was significantly higher in children with ALL at diagnosis (n=23) compared to controls (n=19). The median (interquartile range (IQR)) TAC levels (mM) were significantly lower (1.21 (1.05-1.26) versus 1.28 (1.26-1.32), P=0.006), and TBARS levels (nmol/mL) were significantly higher (312.0 (216.6-398.0) versus 58.5 (46.2-67.2), P<0.001) in children with ALL at diagnosis compared to controls. OS was highest at the end of the induction I phase (four weeks) despite the patients being in clinical and hematological remission. OS at the completion of intensive chemotherapy (16 weeks) was higher than at diagnosis. A significant correlation was found between serum folate levels and TAC levels at baseline (P=0.03). Serum cobalamin levels, the need for blood component therapy, and the number of febrile neutropenic episodes did not have any association with OS. Conclusion Children with ALL had significantly higher OS compared to controls, indicating that underlying disease affects the oxidative balance unfavorably. Chemotherapy itself increases oxidative stress.

Ameliorating effect of N-acetylcysteine and curcumin on pesticide-induced oxidative DNA damage in human peripheral blood mononuclear cells.

Endosulfan, malathion, and phosphamidon are widely used pesticides. Subchronic exposure to these contaminants commonly affects the central nervous system, immune, gastrointestinal, renal, and reproductive system. There effects have been attributed to increased oxidative stress. This study was conducted to examine the role of oxidative stress in genotoxicity following pesticide exposure using peripheral blood mononuclear cells (PBMC) in vitro. Further possible attenuation of genotoxicity was studied using N-acetylcysteine (NAC) and curcumin as known modulators of oxidative stress. Cultured mononuclear cells was isolated from peripheral blood of healthy volunteers, and exposed to varying concentrations of different pesticides: endosulfan, malathion, and phosphamidon for 6, 12, and 24 h. Lipid peroxidation was assessed by cellular malondialdehyde (MDA) level and DNA damage was quantified by measuring 8-hydroxy-2'-deoxyguanosine (8-OH-dG) using ELISA. Both MDA and 8-OH-dG were significantly increased in a dose-dependent manner following treatment with these pesticides. There was a significant decrease in MDA and 8-OH-dG levels in PBMC when co-treated with NAC or/and curcumin as compared to pesticide alone. These results indicate that pesticide-induced oxidative stress is probably responsible for the DNA damage, and NAC or curcumin attenuate this effect by counteracting the oxidative stress.

Oxidative Stress in Cerebrospinal Fluid During Treatment in Childhood Acute Lymphoblastic Leukemia.

Introduction Central nervous system (CNS) treatment using intrathecal chemotherapy and cranial radiation to enable long-term disease-free survival from childhood acute lymphoblastic leukemia (ALL) comes at the cost of neurotoxic side effects and long-term sequelae. We investigated oxidative stress as a possible mechanism of chemotherapy-induced neurotoxicity in children with ALL. Materials and methods In this case-control study, we estimated the cerebrospinal fluid (CSF) levels of 8-hydroxy-deoxyguanosine (8-OH-dG), a DNA damage product, in children with B-cell ALL and control children. CSF samples were collected at diagnosis, at end of Induction 1, Induction 2, and Induction 2A - consolidation phase. CSF 8-OH-dG levels were compared in children with and without neurotoxicity. Results Children with ALL (n=23) at diagnosis had significantly higher median (interquartile range, IQR) CSF 8-OH-dG levels (ng/mL) compared to controls (n=19) [1.97 (1.59-2.56) Vs 0.65 (0.59-0.82), P<0.001]. CSF 8-OH-dG levels at the end of four weeks, eight weeks, and 16 weeks of chemotherapy were [3.96 (2.85-5.44) ng/mL], 1.00 (0.89-1.09), and 3.73 (2.80-4.39) ng/mL, respectively. Out of 23 children with ALL, 12 developed neurotoxicity; the CSF levels of 8-OH-dG in them were only marginally higher compared to those who did not develop neurotoxicity. The CSF 8-OH-dG levels did not show a significant correlation with the number of doses of methotrexate or vincristine received. Conclusion Chemotherapy increases the CNS oxidative stress as measured by CSF 8-OH-dG levels, with the levels being proportional to the intensity of chemotherapy. Children with neurotoxicity had only marginally higher CSF 8-OH-dG levels as compared to children without neurotoxicity.

Assessment of phosphamidon-induced apoptosis in human peripheral blood mononuclear cells: protective effects of N-acetylcysteine and curcumin.

The molecular mechanism for noncholinergic toxicity of phosphamidon, an extensively used organophosphate pesticide, is still not clear. The aim of the present study is to find the possible molecular mechanism of this pesticide to induce apoptosis and the role of different drugs for attenuation of such effects. Human peripheral blood mononuclear cells (PBMC) were incubated with increasing concentrations of phosphamidon (0-20 µM) for 6-24 h. The MTT assay reveals that phosphamidon induces cytotoxicity in a dose-dependent manner. Cellular glutathione (GSH) is depleted in a dose-dependent manner from 55% to 70% at concentrations between 10 and 20 µM. The percentage of cells that bind to Annexin-V, which is a representative of cells either undergoing apoptosis or necrosis during 24 h incubation, increases in a dose-dependent manner. Above 5 µM, significant necrosis of cells was observed. DNA fragmentation assay revealed that at low concentration of phosphamidon (1 µM), no appreciable change in DNA fragmentation was seen; however, distinct fragmentation was observed beyond 2.5 µM. Phosphamidon was found to cause significant depletion of GSH, which correlates well with the percentage of cells undergoing apoptosis. An increasing trend in levels of cytochrome c was observed with increasing concentration of phosphamidon, indicating that the apoptotic effect of phosphamidon is mediated through cytochrome c release. Coadministration of the antioxidants N-acetylcysteine and curcumin attenuated phosphamidon-induced apoptosis. This further supports our hypothesis that oxidative stress, as indicated by GSH depletion, results in the induction of apoptosis by release of cytochrome c.

Association of glutathione S-transferase M1 and T1 gene polymorphism with oxidative stress in diabetic and nondiabetic chronic kidney disease.

BACKGROUND AND OBJECTIVE: Glutathione S-transferases (GSTs) belong to a family of ubiquitous and multifunctional enzymes that work as one of the endogenous antioxidants in our body. This study was designed to look into the association of GST polymorphism with oxidative stress in both diabetic and nondiabetic chronic kidney disease (CKD). DESIGN AND METHODS: Three groups of patients (50 in each): diabetics without CKD (DM), diabetic CKD (DM-CKD), and nondiabetic CKD (NDM-CKD) and 50 age- and sex-matched healthy controls were recruited. Genotyping was done for GSTM1 and GSTT1 genes using a multiplex polymerase chain reaction. Serum GST and malondialdehyde (MDA) as a marker of oxidative stress were measured spectrophotometrically. RESULTS: Based on genotyping, subjects were categorized as GSTM1+/GSTT1+, GSTM1-/GSTT1+, GSTM1+/GSTT1-, and GSTM1-/GSTT1-. Serum GST levels were lower among subjects with deletion in one/both GST genes, whereas MDA levels were found to be correspondingly raised. A negative correlation for MDA versus GST levels was observed among genotypes with one/both gene deletions. Presence of GSTM1+/GSTT1- and GSTM1-/GSTT1- was significantly higher among patients with CKD in both diabetics and nondiabetics. INTERPRETATIONS AND CONCLUSIONS: GSTM1 and GSTT1 deletions singly or together were associated with lower GST levels and higher oxidative stress in both diabetic and nondiabetic CKD. Interestingly, GSTT1 deletion appears to be associated with both diabetic and nondiabetic CKD irrespective of the GSTM1 status.

Maternal and cord blood levels of aldrin and dieldrin in Delhi population.

Aldrin and dieldrin, structurally similar organochlorine pesticides belong to cyclodiene family and were widely used for agriculture and public health program in India. Although the manufacturing, use and import of aldrin and dieldrin have been banned in India since 2003, these pesticides are still persistent in environment and may be associated with adverse neurological and reproductive effects. The aim of this study is to assess the recent exposure level of aldrin and dieldrin and their placental transfer to fetus in normal healthy full-term pregnant women belonging to north Indian population undergoing normal delivery at Obstetrics and Gynecology department of UCMS and GTB hospital, Delhi. Quantitative analysis of aldrin and dieldrin residues in maternal and cord blood samples were carried out by gas chromatography system equipped with electron capture detector. The results of our study clearly revealed that maternal and cord blood levels of aldrin and dieldrin of pregnant women are age and dietary habit dependent. The aldrin level in maternal blood and dieldrin level in cord blood are higher in women in the age group 25-30 years than in women in age group of 19-24 years. Similarly, aldrin level in maternal blood is significantly higher in women with non-vegetarian dietary habit than in women with vegetarian dietary habit. No significant association is found for maternal and cord blood level. The results of the present study clearly demonstrate prenatal uptake of aldrin and dieldrin and provide recent information on the subsequent transplacental transfer.

Induction of oxidative stress and histopathological changes by sub-chronic doses of triazophos.

The effect of triazophos (O, O-diethyl O-1-phenyl-1 H-1, 2, 4-triazol-3-yl phosphorothioate), a widely used insecticide was studied on the induction of oxidative stress and histological alterations at sub-chronic doses in male albino rats. Oral administration of triazophos at concentrations of 1.64, 3.2 and 8.2 mg/kg body wt for 30 days produced dose as well as time-dependent increase in the lipid peroxidation (determined by malondialdehyde levels) and glutathione-S-transferase (GST) activity in serum with aconcomitant decrease in ferric reducing ability of plasma (FRAP) and blood glutathione (GSH) content. Histopathological examination of liver of triazophos-treated rats showed significant and progressive degenerative changes as compared to control, which could be due to induction of oxidative stress. However, no significant histopathological changes were observed in spleen, kidney and brain at either dose of triazophos with respect to control. These results indicated that oral administration of triazophos was associated with enhanced lipid peroxidation and compromised antioxidant defence in rats in dose and time-dependent manner. Thus the present study demonstrated for the first time the role of oxidative stress as the important mechanism involved in the stimulation of hepatic histoarchitectural alterations at sub-chronic doses of triazophos in rats.

Effect of GSTM1 and GSTT1 double deletions in the development of oxidative stress in diabetic nephropathy patients.

Association of diabetic nephropathy (DN) with the deletion of GSTT1 and GSTM1 genes is well reported. Oxidative stress (OS) has also been associated with the development of DN. The present study was conducted to find out, whether these deletions had any contributory role in the development of OS in patients with DN. Pre-dialysis venous blood samples were obtained from 60 patients with diabetic end-stage renal disease (stages 4 and 5). Reduced-glutathione (GSH), glutathione S-transferase (GST) activity and malondialdehyde (MDA) levels were measured for the assessment of OS. Genetic polymorphism analysis of DN patients revealed the following distribution pattern: GSTM1 null 46.7%; GSTT1 null 55%; both null 30% and both positive 28.3%. Patients with both null genotypes were found to have significantly increased levels of MDA and low GST activity as compared to other genotypic groups. Lower GSH levels were observed in all the genotypic groups as compared to both positives. Double deletions involving GSTT1 and GSTM1 may result in decreased GST levels, leading to increased OS as reflected by increased MDA levels. As GST is a multi-functional enzyme involved in xenobiotic metabolism, this double null genotype population has a greater risk of development of DN. Further studies using increased sample size to find out the allelic distribution and their role in the development of DN are in progress.

Chemokines: A Potential Therapeutic Target to Suppress Autoimmune Arthritis.

BACKGROUND: Chemokines are a family of low molecular weight proteins that induce chemotaxis of inflammatory cells, which mainly depends on the recognition of a chemo-attractant gradient and interaction with the substratum. In Rheumatoid Arthritis (RA), abundant chemokines are expressed in synovial tissue, cause inflammatory cells migration into the inflamed joint that necessitates the formation of new blood vessels i.e. angiogenesis. Over the decades, studies showed that continuous inflammation may lead to the loss of tissue architecture and function, causing severe disability and cartilage destruction. In spite of the advancement of modern drug therapy, thousands of arthritic patients suffer mortality and morbidity globally. Thus, there is an urgent need for the development of novel therapeutic agents for the treatment of RA. METHODS: This review is carried out throughout a non-systematic search of the accessible literature, will provide an overview of the current information of chemokine in RA and also exploring the future perspective of the vital role of targeting chemokine in RA treatment. RESULTS: Since, chemokines are associated with inflammatory cells/leucocyte migration at the site of inflammation in chronic inflammatory diseases and hence, blockade or interference with chemokines activity showing a potential approach for the development of new anti-inflammatory agents. Currently, results obtained from both preclinical and clinical studies showed significant improvement in arthritis. CONCLUSION: This review summarizes the role of chemokines and their receptors in the pathogenesis of RA and also indicates possible interactions of chemokines/receptors with various synthetic and natural compounds that may be used as a potential therapeutic target in the future for the treatment of RA.

Endosulfan-induced apoptosis and glutathione depletion in human peripheral blood mononuclear cells: Attenuation by N-acetylcysteine.

Present study investigated whether endosulfan, an organochlorine pesticide is able to deplete glutathione (GSH) and induce apoptosis in human peripheral blood mononuclear cells (PBMC) in vitro. The role of oxidative stress in the induction of apoptosis was also evaluated by the measurement of the GSH level in cell lysate. The protective role of N-acetylcysteine (NAC) on endosulfan-induced apoptosis was also studied. Isolated human PBMC were exposed to increasing concentrations (0-100 microM) of endosulfan (alpha/beta at 70:30 mixture) alone and in combination with NAC (20 microM) up to 24 h. Apoptotic cell death was determined by Annexin-V Cy3.18 binding and DNA fragmentation assays. Cellular GSH level was measured using dithionitrobenzene. Endosulfan at low concentrations, i.e., 5 and 10 microM, did not cause significant death during 6 h/12 h incubation, whereas a concentration-dependent cell death was observed at 24 h. DNA fragmentation analysis revealed no appreciable difference between control cells and 5 microM/10 microM endosulfan treated cells, where only high molecular weight DNA band was observed. Significant ladder formation was observed at higher concentration, which is indicative of apoptotic cell death. Intracellular GSH levels decreased significantly in endosulfan-treated cells in a dose-dependent manner, showing a close correlation between oxidative stress and degree of apoptosis of PBMC. Cotreatment with NAC attenuated GSH depletion as well as apoptosis. Our results provide experimental evidence of involvement of oxidative stress in endosulfan-mediated apoptosis in human PBMC in vitro.

Protective effects of dietary ginger (Zingiber officinales Rosc.) on lindane-induced oxidative stress in rats.

The protective effect of dietary feeding of Zingiber officinales Rosc. (ginger) against lindane-induced oxidative stress was investigated in male albino rats. Oxidative stress was monitored by estimating the extent of lipid peroxidation, activities of the oxygen free radical (OFR) scavenging enzymes superoxide dismutase (SOD) and catalase (CAT) and the status of the glutathione redox cycle antioxidants. Lindane administration (30 mg/kg bw orally for 4 weeks) was associated with enhanced lipid peroxidation and compromised antioxidant defenses in rats fed a normal diet. Concomitant dietary feeding of ginger (1%w/w) significantly attenuated lindane-induced lipid peroxidation, accompanied by modulation of OFR scavenging enzymes as well as reduced glutathione (GSH) and the GSH dependent enzymes glutathione peroxidase (Gpx), glutathione reductase (GR) and glutathione-S-transferase (GST) in these rats. These findings suggest that a diet containing naturally occurring compounds is effective in exerting protective effects by modulating oxidative stress.

Melatonin treatment prevents modulation of cell-mediated immune response induced by propoxur in rats.

The effect of melatonin, a major secretory product of the pineal gland, in attenuation of propoxur (2-isopropoxy phenyl N-methyl carbamate)-induced modulation of cell-mediated immune (CMI) response was studied in rats. Male Wistar albino rats were exposed to propoxur (a widely used pesticide) orally (10 mg/kg) and/or melatonin (10 mg/kg) orally for 4 weeks. CMI was measured by delayed-type hypersensitivity (DTH), leucocyte and macrophage migration inhibition (LMI and MMI) responses and estimation of cytokines TNF-alpha and IFN-gamma levels. Rats exposed to propoxur for 4 weeks showed significant decrease in DTH, LMI and MMI responses. Propoxur also suppressed TNF-alpha and IFN-gamma production significantly. Administration of melatonin alone caused a significant increase in DTH response. Although there were no changes in the LMI and MMI response, the cytokine levels were significantly increased, as compared to control. Co-administration of melatonin along with propoxur significantly nullified the effect of the pesticide on the CMI response, except DTH and reversed levels of cytokines to near control/normal values. Thus, melatonin treatment considerably attenuated immunomodulation caused by sub-chronic treatment of propoxur in experimental animals.