Phosalone-Induced Changes in Regional Cholinesterase Activities in Rat Brain during Behavioral Tolerance

Organophosphate pesticides exert their toxic effects by cholinesteraseinhibition and the consequent prolongation of the undesirable effects ofaccumulation of acetylcholine. The signs of toxicity include tremors,convulsions, lachrymation, defecation etc. However, sustained cholinesterase inhibition through sustained administration of organophosphates would lead to the gradual disappearance of the initial signs of toxicity over time, termed behavioral tolerance. The present study was undertaken to examine the activity levels of cholinesterases in different regions of rat brain during the development of behavioral tolerance to the organophosphate phosalone. Male albino rats were given a daily oral dose of phosalone (41.35 mg, equivalent to ¼ of LD50) every day for 15 days and the activities of acetylcholinesterase (AChE) butyrylcholinesterase (BuChE) and pseudocholinesterase (PChE) were estimated at intervals at 1, 3, 9 and 15 days of treatment. All the cholinesterases were inhibited, and this inhibition was found to vary among different brain regions at different times. Greater inhibition of AChE and BuChE activities was observed at 9 days, while for PChE it was recorded at 3 days. Recovery trend to normalcy was observed earlier in PChE compared to AChE and BuChE. The signs and symptoms of pesticide toxicity were mainly cholinergic. Inhibition of cholinesterases was well correlated with the appearance and severity of signs and symptoms. Tremors and convulsions in particular were more after 9 days. After 9 days, decline followed by disappearance of majority of the signs and symptoms wasnoticed while reduction in cholinesterase activities still continued, indicatingthe development of behavioral tolerance to phosalone. Among the brainregions, striatum recorded a greater decrease in cholinesterase activity.Earlier recovery of pseudocholinesterase activity seems to be an interestingphenomenon in regulating homeostasis of cholinesterases and in thedevelopment of symptomatic tolerance of phosalone.Key words: Phosalone, Cholinesterases, Rat brain, Behavioraltolerance

HEPATOPROTECTIVE EFFECT OF HEDYOTIS LESCHENAULTIANA DC, ETHANOL EXTRACT IN CCL 4 INDUCED HEPATOTOXICITY IN WISTAR RATS

ABSTRACT Objective: The intention of this study is to explore the hepatoprotective potential of hepatoprotective potential of ethanol extract of Hedyotis leschenaultiana whole plant in carbon tetrachloride (CCl 4 ) induced hepatoprotective rats. Methods: Hepatotoxicity was induced in male wistar rats by intraperitoneal infection of CCl (2.5 ml/kg body weight for 14 days). The ethanol extract of H. leschenaultiana whole plant was administered to the experimental rats (100, 200, and 300 mg/kg body weight for 14 days). Silymarin (100 mg/kg) was given as a reference standard drug. In hepatotoxic rats, liver damage was studied by assessing parameters such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), serum alkaline phosphatase (ALP), total, conjugated and unconjugated bilirubin, gamma-glutamyl transferase, concentration of proteins, and antioxidants in serum. Results: Administration of hepatotoxins (CCl 4 4 ) showed significant elevation of SGOT, SGPT, serum ALP, total bilirubin, conjugated, unconjugated, and lipid peroxidation. Treatment with H. leschenaultiana (100, 200 and 300 mg/kg) significantly reduced the above-mentioned parameters. Regarding antioxidant activity, the ethanol extract of H. leschenaultiana exhibited a significant effect showing increasing levels of superoxide dismutase, catalase, glutathione peroxidase, reduced and glutathione, and glutathione reductase by reducing malondialdehyde levels. Conclusion: The ethanol extract of H. leschenaultiana have a significant effect on the CCl induced hepatotoxic animal models. Moreover, it is suggested that H. leschenaultiana can be used as a safe, cheap and effective alternative chemopreventive and protective against in the management of liver diseases. 4 Keywords: H. leschenaultiana, Bilirubins, Hepatotoxicity, Gamma-glutamyl transferase, Carbon tetrachloride, Melondialdehyde

Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation

The Drosophila IAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophila midgut, but not in the fat body. Drice is a Drosophila effector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine

Lack of significant association of an insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene with tropical calcific pancreatitis

BACKGROUND: The genetic basis of tropical calcific pancreatitis (TCP) is different and is explained by mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene. However, mutated SPINK1 does not account for the disease in all the patients, neither does it explain the phenotypic heterogeneity between TCP and fibro-calculous pancreatic diabetes (FCPD). Recent studies suggest a crucial role for pancreatic renin-angiotensin system during chronic hypoxia in acute pancreatitis and for angiotensin converting enzyme (ACE) inhibitors in reducing pancreatic fibrosis in experimental models. We investigated the association of ACE gene insertion/deletion (I/D) polymorphism in TCP patients using a case-control approach. Since SPINK1 mutations are proposed a modifier role, we also investigated its interaction with the ACE gene variant. METHODS: We analyzed the I/D polymorphism in the ACE gene (g.11417_11704del287) in 171 subjects comprising 91 TCP and 80 FCPD patients and compared the allelic and genotypic frequency in them with 99 healthy ethnically matched control subjects. RESULTS: We found 46% and 21% of TCP patients, 56% and 19.6% of FCPD patients and 54.5% and 19.2% of the healthy controls carrying the I/D and D/D genotypes respectively (P>0.05). No significant difference in the clinical picture was observed between patients with and without the del allele at the ACE in/del polymorphism in both categories. No association was observed with the presence or absence of N34S SPINK1 mutation in these patients. CONCLUSION: We conclude that the ACE insertion/deletion variant does not show any significant association with the pathogenesis, fibrosis and progression of tropical calcific pancreatitis and the fibro-calculous pancreatic diabetes

Telomere shortening occurs in Asian Indian Type 2 diabetic patients

Aim: Telomere shortening has been reported in several diseases including atherosclerosis and Type 1 diabetes. Asian Indians have an increased predilection for Type 2 diabetes and premature coronary artery disease. The aim of this study was to determine whether telomeric shortening occurs in Asian Indian Type 2 diabetic patients. Methods: Using Southern‐blot analysis we determined mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leucocyte DNA. Type 2 diabetic patients without any diabetes‐related complications (n = 40) and age‐ and sex‐matched control non‐diabetic subjects (n = 40) were selected from the Chennai Urban Rural Epidemiology Study (CURES). Plasma level of malondialdehyde (MDA), a marker of lipid peroxidation, was measured by TBARS (thiobarbituric acid reactive substances) using a fluorescence method. Results: Mean (± SE) TRF lengths of the Type 2 diabetic patients (6.01 ± 0.2 kb) were significantly shorter than those of the control subjects (9.11 ± 0.6 kb) (P = 0.0001). Among the biochemical parameters, only levels of TBARS showed a negative correlation with shortened telomeres in the diabetic subjects (r = −0.36; P = 0.02). However, telomere lengths were negatively correlated with insulin resistance (HOMA‐IR) (r = −0.4; P = 0.01) and age (r = −0.3; P = 0.058) and positively correlated with HDL levels (r = 0.4; P = 0.01) in the control subjects. Multiple linear regression (MLR) analysis revealed diabetes to be significantly (P < 0.0001) associated with shortening of TRF lengths. Conclusions: Telomere shortening occurs in Asian Indian Type 2 diabetic patients

Quantitative analysis of dynamic 18F-FDG PET/CT for measurement of lung inflammation

$\textbf{Background:}$ An inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, is present in some patients with chronic obstructive pulmonary disease (COPD). Thoracic fluorodeoxyglucose $^{18}$F-FDG) positron emission tomography (PET) has been proposed as a promising imaging biomarker to assess this inflammation. We sought to introduce a fully quantitative analysis method and compare this with previously published studies based on the Patlak approach using a dataset comprising $^{18}$F-FDG PET scans from COPD subjects with elevated circulating inflammatory markers (fibrinogen) and matched healthy volunteers (HV). Dynamic $^{18}$F-FDG PET scans were obtained for high-fibrinogen (>2.8 g/l) COPD subjects (N = 10) and never smoking HV (N = 10). Lungs were segmented using co-registered computed tomography images and subregions (upper, middle and lower) were semi-automatically defined. A quantitative analysis approach was developed, which corrects for the presence of air and blood in the lung (qABL method), enabling direct estimation of the metabolic rate of FDG in lung tissue. A normalised Patlak analysis approach was also performed to enable comparison with previously published results. Effect sizes (Hedge's g) were used to compare HV and COPD groups. $\textbf{Results:}$ The qABL method detected no difference (Hedge's g = 0.15 [-0.76 1.04]) in the tissue metabolic rate of FDG in the whole lung between HV (μ = 6.0 ± 1.9 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$) and COPD (μ = 5.7 ± 1.7 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$). However, analysis with the normalised Patlak approach detected a significant difference (Hedge's g = -1.59 [-2.57 -0.48]) in whole lung between HV (μ = 2.9 ± 0.5 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$) and COPD (μ = 3.9 ± 0.7 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$). The normalised Patlak endpoint was shown to be a composite measure influenced by air volume, blood volume and actual uptake of $^{18}$F-FDG in lung tissue. $\textbf{Conclusions:}$ We have introduced a quantitative analysis method that provides a direct estimate of the metabolic rate of FDG in lung tissue. This work provides further understanding of the underlying origin of the $^{18}$F-FDG signal in the lung in disease groups and helps interpreting changes following standard or novel therapies.JC and IBW acknowledge the funding support from the Cambridge Comprehensive Biomedical Research Centre. MIP’s contribution to this work was funded by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College who part fund his salary. EVOLUTION and EVOLVE studies were funded by Innovate UK under the ERICA consortium grant with in kind contributions from GSK

Transcultural Diabetes Nutrition Therapy Algorithm: The Asian Indian Application

India and other countries in Asia are experiencing rapidly escalating epidemics of type 2 diabetes (T2D) and cardiovascular disease. The dramatic rise in the prevalence of these illnesses has been attributed to rapid changes in demographic, socioeconomic, and nutritional factors. The rapid transition in dietary patterns in India—coupled with a sedentary lifestyle and specific socioeconomic pressures—has led to an increase in obesity and other diet-related noncommunicable diseases. Studies have shown that nutritional interventions significantly enhance metabolic control and weight loss. Current clinical practice guidelines (CPGs) are not portable to diverse cultures, constraining the applicability of this type of practical educational instrument. Therefore, a transcultural Diabetes Nutrition Algorithm (tDNA) was developed and then customized per regional variations in India. The resultant India-specific tDNA reflects differences in epidemiologic, physiologic, and nutritional aspects of disease, anthropometric cutoff points, and lifestyle interventions unique to this region of the world. Specific features of this transculturalization process for India include characteristics of a transitional economy with a persistently high poverty rate in a majority of people; higher percentage of body fat and lower muscle mass for a given body mass index; higher rate of sedentary lifestyle; elements of the thrifty phenotype; impact of festivals and holidays on adherence with clinic appointments; and the role of a systems or holistic approach to the problem that must involve politics, policy, and government. This Asian Indian tDNA promises to help guide physicians in the management of prediabetes and T2D in India in a more structured, systematic, and effective way compared with previous methods and currently available CPGs

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes

Management of chronic obstructive pulmonary disease in India: a systematic review.

OBJECTIVES: Chronic diseases are fast becoming the largest health burden in India. Despite this, their management in India has not been well studied. We aimed to systematically review the nature and efficacy of current management strategies for chronic obstructive pulmonary disease (COPD) in India. METHODS: We used database searches (MEDLINE, EMBASE, IndMED, CENTRAL and CINAHL), journal hand-searches, scanning of reference lists and contact with experts to identify studies for systematic review. We did not review management strategies aimed at chronic diseases more generally, nor management of acute exacerbations. Due to the heterogeneity of reviewed studies, meta-analysis was not appropriate. Thus, narrative methods were used. SETTING: India. PARTICIPANTS: All adult populations resident in India. MAIN OUTCOME MEASURES: 1. Trialled interventions and outcomes 2. Extent and efficacy of current management strategies 3. Above outcomes by subgroup. RESULTS: We found information regarding current management - particularly regarding the implementation of national guidelines and primary prevention - to be minimal. This led to difficulty in interpreting studies of management strategies, which were varied and generally of positive effect. Data regarding current management outcomes were very few. CONCLUSIONS: The current understanding of management strategies for COPD in India is limited due to a lack of published data. Determination of the extent of current use of management guidelines, availability and use of treatment, and current primary prevention strategies would be useful. This would also provide evidence on which to interpret existing and future studies of management outcomes and novel interventions

Dietary Intake and Rural-Urban Migration in India: A Cross-Sectional Study

BACKGROUND: Migration from rural areas of India contributes to urbanisation and lifestyle change, and dietary changes may increase the risk of obesity and chronic diseases. We tested the hypothesis that rural-to-urban migrants have different macronutrient and food group intake to rural non-migrants, and that migrants have a diet more similar to urban non-migrants. METHODS AND FINDINGS: The diets of migrants of rural origin, their rural dwelling sibs, and those of urban origin together with their urban dwelling sibs were assessed by an interviewer-administered semi-quantitative food frequency questionnaire. A total of 6,509 participants were included. Median energy intake in the rural, migrant and urban groups was 2731, 3078, and 3224 kcal respectively for men, and 2153, 2504, and 2644 kcal for women (p<0.001). A similar trend was seen for overall intake of fat, protein and carbohydrates (p<0.001), though differences in the proportion of energy from these nutrients were <2%. Migrant and urban participants reported up to 80% higher fruit and vegetable intake than rural participants (p<0.001), and up to 35% higher sugar intake (p<0.001). Meat and dairy intake were higher in migrant and urban participants than rural participants (p<0.001), but varied by region. Sibling-pair analyses confirmed these results. There was no evidence of associations with time in urban area. CONCLUSIONS: Rural to urban migration appears to be associated with both positive (higher fruit and vegetables intake) and negative (higher energy and fat intake) dietary changes. These changes may be of relevance to cardiovascular health and warrant public health interventions