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Adult male rats receiving 10 or 30 ppm chlordecone (Kepone) in the diet for 90 days exhibited decreased binding of [3H]spiroperidol in membranes prepared from the striatum. [3H]Muscimol and [3H]quinuclidinyl benzilate binding in the cerebellum were also depressed. The binding of [3H]diazepam and [3H]serotonin to cortical membranes was unaltered in treated animals. The areas of brain of exposed animals which exhibited a reduced ability to bind several ligands for specific neurotransmitter-receptor sites also possessed an increased amount of membrane protein. The frontal cortex of chlordecone-dosed rats where ligand binding was not altered, showed no significant change in membrane protein content. Thus chlordecone-induced alterations in receptor properties could be accounted for in terms of a region-specific hyperplastic increase in nonreceptor proteins. Thirty days after cessation of dosing ligand-binding properties and membrane protein from regions of treated animals did not differ significantly from controls, suggesting that these effects were reversible at the dose levels used. Male and female rats exposed indirectly throughout gestation and lactation showed no abnormal concentrations of membrane protein at 30 days of age after a maternal diet of 1 or 6 ppm chlordecone. No decrease in cerebellar binding of muscimol or quinuclidinyl benzilate, in frontal cortical binding of serotonin, or in striatal binding of spiroperidol was observed. At the 6-ppm dose level, male rats had an elevation of striatal dopamine binding. These data illustrate that gestational exposure to chlordecone can have effects that are in an opposite direction than those observed after exposure of adults to a higher dose level. © 1981.

A single oral dose of acrylamide (25 or 50 mg/kg) increased the level of striatal 3H-spiroperidol binding in six week old male rats. This enhanced dopamine receptor activity was specific since treatment caused no significant changes in glycine, serotonin, and muscarinic cholinergic binding. At the highest acrylamide dose tested (100 mg/kg), elevations of the medullary glycine and frontal cortical serotonin receptors were also found. Pretreatment of animals with a blocker of hepatic mixed function oxidase (SKF 525a) or a thiol blocker (methylmercuric chloride) prevented the acrylamide-induced elevation of striatal spiroperidol binding, indicating that the causative agent was a secondary metabolite of acrylamide. Apomorphine-induced motility was significantly attenuated by 24 hr predosing with acrylamide, suggesting a change in the sensitivity of the dopamine receptor. The behavioral relevance of observed biochemical changes was thus shown by the altered response of treated animals to apomorphine.

Purpose: To study the different subtypes of glaucoma and to analyze the demographic and clinical profile of glaucoma patients along with associated risk factors in a multi-locational North Indian study., Methods: Newly diagnosed and known glaucoma patients on treatment were enrolled in the study. Complete history was taken, and clinical evaluation was done by senior glaucoma experts., Results: Five hundred and eighty-six patients (1121 eyes) were included with 383 males (65.4%) and 203 females (34.6%). Of these, 508 (86.7%) had primary glaucoma and 78 (13.3%) had secondary glaucoma. Also, 263 (44.9%) patients had primary open angle glaucoma (POAG) and 172 (29.4%) had primary angle closure glaucoma. Four hundred and fifty-one (77%) were graduates or postgraduates and 293 (50%) were dependents on family income. One hundred and forty-one (24%) had a positive family history. Secondary glaucoma patients had a lower average age (52.6 ± 16.8 years) and higher average intraocular pressure (IOP; 34.23 ± 13 mm) compared to primary glaucoma patients (26.6 ± 9.7 mm) (P < 0.0001). Thirty-three (47.8%) out of 78 secondary glaucoma patients had advanced disease. Seventy-four (12.6%) were first-time diagnosed and 18 had advanced disease. In addition, 161 eyes had one or more glaucoma surgeries done (128 trabeculectomy and 28 phacotrabeculectomy). Ninety-five (16.2%) patients were advised surgery at our centers (46 trab, 26 phacotrab, 15 phaco, five Ahmed glaucoma valve implantation, and three pars plana vitrectomy). Disease progression was noted in 62 patients reporting good compliance to medicines., Conclusion: POAG was the most common variant in this study. Secondary glaucoma patients were youngest in age and had the highest IOP. Trabeculectomy was the most performed surgery. A good literacy rate did not prevent late presentations., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Purpose: To describe the clinical profile and relative prevalence of subtypes of glaucoma presenting to a tertiary care center in India., Methods: This cross-sectional hospital-based study included 6,120 new patients (>16 years) presenting between January 2016 and December 2017. The data were collected using an electronic medical record system., Results: A total of 11,016 eyes of 6,120 new patients were diagnosed with glaucoma. Sixty-one percent were male and 79% had a bilateral affliction. Primary glaucoma was present in 4,352 (71.1%) and secondary glaucoma in 1,063 (17.4%) subjects. Glaucoma was primary open-angle (POAG) in 4,015 (36.4%) eyes and primary angle closure disease (PACD) in 3,806 (34.5%) eyes. Commonest among secondary glaucoma was post-cataract surgery glaucoma (3.1%), neovascular glaucoma (2.4%), pseudoexfoliation glaucoma (PXG) (2.1%), and steroid-induced glaucoma (SIG) (1.4%). Patients with primary glaucoma were older than secondary (56.6 ± 0.2 vs 54.1 ± 0.4; P < 0.0001). Mean IOP was higher in secondary glaucoma compared to primary (26.9 ± 0.3 vs 18.9 ± 0.1; P < 0.0001). Secondary glaucoma had greater mean CDR compared to primary glaucoma (0.77 ± 0.007 vs 0.70 ± 0.003; P < 0.0001). The prevalence of blindness (visual acuity <20/200) was 16.2% of eyes. Mean deviation (MD) 20db or worse was noted in 39.5% of eyes at presentation including 47.8% of PACG, 37.3% of POAG, 51% of JOAG, 58% of PXG, and 45% of SIG, suggesting disease severity., Conclusion: At the presentation to a tertiary care center, 40% of all eyes with glaucoma had advanced disease with MD worse than - 20D. PACG and JOAG had the worse disease among primary; among secondary, PXG and SIG had the worse disease at presentation., Competing Interests: None

Background & Objectives: The massive outbreak of Novel Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has turned out to be a serious global health issue worldwide. Currently, no drugs or vaccines are available for the treatment of COVID-19. The current computational study was attempted to identify a novel therapeutic inhibitor against novel SARS-CoV-2 using in silico drug discovery pipeline., Methods: In the present study, the human angiotensin-converting enzyme 2 (ACE2) receptor was the target for the designing of drugs against the deadly virus. The 3D structure of the receptor was modeled & validated using a Swiss-model, Procheck & Errat server. A molecular docking study was performed between a group of natural & synthetic compounds having proven anti-viral activity with ACE2 receptor using Autodock tool 1.5.6. The molecular dynamics simulation study was performed using Desmond v 12 to evaluate the stability and interaction of the ACE2 receptor with a ligand., Results: Based on the lowest binding energy, confirmation, and H-bond interaction, cinnamic acid (-5.20 kcal/mol), thymoquinone (-4.71 kcal/mol), and andrographolide (Kalmegh) (-4.00 kcal/mol) were screened out showing strong binding affinity to the active site of ACE2 receptor. MD simulations suggest that cinnamic acid, thymoquinone, and andrographolide (Kalmegh) could efficiently activate the biological pathway without changing the conformation in the binding site of the ACE2 receptor. The bioactivity and drug-likeness properties of compounds show their better pharmacological property and safer to use., Interpretation & Conclusions: The study concludes the high potential of cinnamic acid, thymoquinone, and andrographolide against the SARS-CoV-2 ACE2 receptor protein. Thus, the molecular docking and MD simulation study will aid in understanding the molecular interaction between ligand and receptor binding site, thereby leading to novel therapeutic intervention., Competing Interests: The authors declare that they have no competing interests., (© 2021 Srivastava et al.)

Dopamine (D2) receptors are known drug targets for various antipsychotics used in Schizophrenia. Therefore, it is of interest to analyze the binding features of D2 receptors with known olanzapine derivatives for further consideration using molecular docking and QSAR analysis. A 2D QSAR model was built using energy-based descriptors generated by docking as independent variable and known Ki value of Olanzapine derivatives with D2 Receptor as dependent variable. QSAR model provided coefficient of determination of r2 of 0.7 in multiple linear regression analysis. The predictive performance of QSAR model was assessed using different cross-validation procedures. Thus, data shows that a ligand-receptor binding interaction for D2 Receptor using a QSAR model is promising approach to design novel and potent inhibitors of D2 Receptor., Competing Interests: The authors declare that they have no conflict of interest., (© 2020 Biomedical Informatics.)

The primary sensory molecule underlying light-dependent magnetic compass orientation in migratory birds has still not been identified. The cryptochromes are the only known class of vertebrate proteins which could mediate this mechanism in the avian retina. Cryptochrome 4 of the night-migratory songbird the European robin (Erithacus rubecula; erCry4) has several of the properties needed to be the primary magnetoreceptor in the avian eye. Here, we report on the identification of a novel isoform of erCry4, which we named erCry4b. Cry4b includes an additional exon of 29 amino acids compared to the previously described form of Cry4, now called Cry4a. When comparing the retinal circadian mRNA expression pattern of the already known isoform erCry4a and the novel erCry4b isoform, we find that erCry4a is stably expressed throughout day and night, whereas erCry4b shows a diurnal mRNA oscillation. The differential characteristics of the two erCry4 isoforms regarding their 24-h rhythmicity in mRNA expression leads us to suggest that they might have different functions. Based on the 24-h expression pattern, erCry4a remains the more likely cryptochrome to be involved in radical-pair-based magnetoreception, but at the present time, an involvement of erCry4b cannot be excluded.

A one-eyed 67-year-old man with 20/400 vision, dense cataract, previously failed trabeculectomy and medically uncontrolled advanced glaucoma underwent a single-site phacoemulsification with repeat trabeculectomy and mitomycin C. One-week postoperatively, vision in the right eye improved to 20/120, good bleb and intraocular pressure (IOP) of 14 mm Hg. By third postoperative week, patient presented to the emergency with diminished vision, pain and redness in right eye of 2 days duration and was diagnosed to have bleb-related endophthalmitis (BRE). Vitreous biopsy, smear from the bleb were taken and underwent pars plana vitrectomy with intraocular antibiotic injection. Smears and cultures were negative however, aqueous DNA-PCR was positive for Mycobacterium tuberculosis Revisited history revealed treated pulmonary tuberculosis 3 years ago with a positive Mantoux test (17 mm) and hilar prominence on chest X-ray. One month after starting anti-tubercular therapy (ATT), the BRE resolved and vision improved to 20/60 with IOP of 14 mm Hg and the ATT was continued., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Long non-coding RNAs (lncRNAs) have emerged as an important regulatory control in biological systems. Though the field of lncRNA has been progressing rapidly, a complete understanding of the role of lncRNAs in neuroblastoma pathogenesis is still lacking. To identify the abrogated lncRNAs in primary neuroblastoma and in the metastasized as well as the relapsed form of neuroblastoma, we analyzed an RNA-seq dataset on neuroblastoma that is available online to identify the lncRNAs that could potentially be contributing to the biology of neuroblastoma. The identified lncRNAs were further scrutinized using a publicly available epigenetic dataset of neuroblastoma and a cancer database. After this cross-sectional study, we were able to identify three significant lncRNAs, CASC15 , PPP1R26-AS1 , and USP3-AS1 , which could serve as potential biomarkers in clinical studies of neuroblastoma pathogenesis., (Copyright © 2019 Prajapati, Fatma, Fatima, Khan, Sinha and Seth.)

Several Genome Wide Association Studies (GWASs) have reported that PARK16 gene locus possibly regulate the risk of Parkinson's disease (PD). It contains functionally interesting candidate genes for PD, regulated by number of SNPs. In present study rs823093 polymorphism in NUCKS1 gene has been evaluated as significant performer in PD though its mechanism is not yet known. Here various regulatory and functional analyses were performed using computational tools and information from databases. The rs823093 variant was predicted to locate in enhancer histone marks in blood and have strong transcription in various parts of brain, heart, kidney and liver. PhenoScanner (a database of human genotype-phenotype associations) identified significant associations of this variant with many other diseases and phenotypic conditions as well. Gene expression analysis shows significant association with multiple human tissues and multiple genes together with NUCKS1. Further, the post mortem brain samples showed diverse expressions of NUCKS1 gene in PD patients compared to healthy samples. Besides, the metabolite analysis shows significant association with serotonin a known neurotransmitter, and other 15 metabolites. In addition, NUCKS1 also showed co-expression with ZNF43 and PLIN1 genes involved in cell cycle regulation presume their association in PD. Thus, these data links NUCKS1 gene as a potential disease susceptibility biomarker for PD., (© 2019 Biomedical Informatics.)

Strain RT1 was isolated from root nodules of Lens culinaris (a lentil) and characterized as Rhizobium etli (a Gram-negative soil-borne bacterium) by 16S rDNA sequencing and phylogenetic analysis. The signaling molecules produced by R. etli (RT1) were detected and identified by high-performance liquid chromatography coupled with mass spectrometry. The most abundant and biologically active N-acyl homoserine lactone molecules (3-oxo-C 8 -HSL and 3-OH-C 14 -HSL) were detected in the ethyl acetate extract of RT1. The biological role of 3-oxo-C 8 -HSL was evaluated in RT1. Bacterial motility and biofilm formation were affected or modified on increasing concentrations of 3-oxo-C 8 -HSL. Results confirmed the existence of cell communication in RT1 mediated by 3-oxo-C 8 -HSL, and positive correlations were found among quorum sensing, motility and biofilm formation in RT1., (Copyright © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.)

In this work, 3D model of D2 dopamine receptor was determined by comparative homology modeling program MODELLER. The computed model's energy was minimized and validated using PROCHECK and Errat tool to obtain a stable model structure and was submitted in Protein Model Database (PMDB-ID: PM0079251). Stable model was used for molecular docking against Risperidone and their 15 derivatives using AutoDock 4.2, which resulted in energy-based descriptors such as Binding Energy, Ligand Efficiency, Inhib Constant, Intermol energy, vdW + Hbond + desolv Energy, Electrostatic Energy, Total Internal Energy and Torsional Energy. After that, we have built quantitative structure activity relationship (QSAR) model, which was trained and tested on Risperidone and their 15 derivatives having activity value pKi in µM. For QSAR modeling, Multiple Linear Regression model was engendered using energy-based descriptors yielding correlation coefficient r2 of 0.513. To assess the predictive performance of QSAR models, different cross-validation procedures were adopted. Our results suggests that ligand-receptor binding interactions for D2 employing QSAR modeling seems to be a promising approach for prediction of pKi value of novel antagonists against D2 receptor.

White spot disease is a devastating disease of shrimp Penaeus monodon in which the shrimp receptor protein PmRab7 interacts with viral envelop protein VP28 to form PmRab7-VP28 complex, which causes initiation of the disease. The molecular mechanism implicated in the disease, the dynamic behavior of proteins as well as interaction between both the biological counterparts that crafts a micro-environment feasible for entry of virus into the shrimp is still unknown. In the present study, we applied molecular modeling (MM), molecular dynamics (MD) and docking to compute surface mapping of infective amino acid residues between interacting proteins. Our result showed that α-helix of PmRab7 (encompassing Ser74, Ile143, Thr184, Arg53, Asn144, Thr184, Arg53, Arg79) interacts with β-sheets of VP28 (containing Ser74, Ile143, Thr184, Arg53, Asn144, Thr184, Arg53, Arg79) and Arg69-Ser74, Val75-Ile143, Leu73-Ile143, Arg79-Asn144, Ala198-Ala182 bonds contributed in the formation of PmRab7-VP28 complex. Further studies on the amino acid residues and bonds may open new possibilities for preventing PmRab7-VP28 complex formation, thus reducing chances of WSD. The quantitative predictions provide a scope for experimental testing in future as well as endow with a straightforward evidence to comprehend cellular mechanisms underlying the disease.

Hepatitis D is a liable reason of mortality and morbidity worldwide. It is caused by an RNA virus known as Hepatitis Delta Virus (HDV). Genetic studies of HDV have shown that delta antigen protein is responsible for replication of genome and play a foremost role in viral infection. Therefore, delta antigen protein may be used as suitable target for disease diagnosis. Viral activity can be restrained through RNA interference (RNAi) technology, an influential method for post transcriptional gene silencing in a sequence specific manner. However, there is a genetic variability in different viral isolates; it is a great challenge to design potential siRNA molecules which can silence the respective target genes rather than any other viral gene simultaneously. In current study two effective siRNA molecules for silencing of HDV were rationally designed and validated using computational methods, which may lead to knockdown the activity of virus. Thus, this approach may provide an insight for the chemical synthesis of antiviral RNA molecule for the treatment of hepatitis D, at genome level.

Protein-protein interactions play an important role in regulating the expression of huntingtin protein (htt). Expansion of polyglutamine tracts in htt results in neurodegenerative Huntington disease. Huntingtin interacting protein (HIP14) is an important interacting partner of htt and the altered interactions have been proposed to play an important role in disease progression. In the present study, an attempt has been made to explore the potential of several known Huntington inhibitors to inhibit HIP14. The docking studies have resulted in the identification of a novel binding site for these inhibitors distinct from the previously known ankyrin repeat domain. The results have been validated using geometry based docking transformations against the other binding pocket. The specificity of binding has been determined with high values of both accuracy and precision. Nine potential inhibitors obtained after screening belong to three distinct classes of compounds viz, carbohydrates (deoxy-glucose), alcohols (including phenolic scaffold) and tetracycline. The compounds form stable complex with protein exhibiting optimal intermolecular and Gibbs free energy. The hydrogen bonding and hydrophobic interactions predominantly contribute to the stability of these complexes. The present study identifies metoprolol, minocyclines and 18 F fluorodeoxyglucose as the best inhibitors that bind specifically to the new site. Therefore, these compounds can further be exploited for their potential to serve in the diagnosis and treatment of Huntington disease. The quantitative predictions provide a scope for experimental testing in future.

Background: The small delta antigen protein of hepatitis delta virus (HDV) has been shown to be important for replication of the virus and essential for the viral life cycle. Therefore, it may be an appropriate target for designing biological experiments for drug development to identify the potential inhibitors of hepatitis D., Objectives: To identify a novel molecule as possible drug candidate for the treatment of Hepatitis D., Materials and Methods: In the present study, a computational approach was used for the identification of novel small-molecule inhibitors against HDV replication using docking studies. An Autodock tool was used for docking and identifying the active binding sites in target proteins. The Lipinski filter and preADMET program were also used for determining the pharmacokinetic properties in order to filter out potential ligand molecules to restrain virus replication., Results: Our results suggest that pyridinone (3-[(4,7-dichloro-1,3-benzoxazol-2-yl) methylamino]-5-ethyl-6-methyl-pyridin-2(1H)-one) is a validated potential inhibitor of HDV replication and could be as a novel antiviral drug for the treatment of hepatitis D. COUNCLUSIONS: We have identified a novel antiviral drug by using innovative computational approaches. The results provide a basis to experimentally develop into drug which can be used for the treatment of delta hepatitis.

Rationale: Mutations in MYBPC3 encoding cardiac myosin binding protein C are common genetic cause of hereditary cardiac myopathies. An intronic 25-bp deletion in MYBPC3 at 3' region is associated with dilated (DCM) and hypertrophic (HCM) cardiomyopathies in Southeast Asia. However, the frequency of MYBPC3 25 bp deletion and associated clinical presentation has not been established in an unrelated cohort of left ventricular dysfunction (LVD) secondary to coronary artery disease (CAD) patients., Objective: We sought to determine the role of MYBPC3 25 bp polymorphism on LVD in two cohorts of CAD patients., Methods and Results: The study included 265 consecutive patients with angiographically confirmed CAD and 220 controls. MYBPC3 25 bp polymorphism was determined by polymerase chain reaction. Our results showed that carrier status of MYBPC3 25 bp deletion was associated with significant compromised left ventricle ejection fraction (LVEF ≤45) in CAD patients (p value  =  <0.001; OR = 4.49). To validate our results, we performed a replication study in additional 140 cases with similar clinical characteristics and results again confirmed consistent findings (p = 0.029; OR = 3.3). Also, presence of the gene deletion did not have significant association in CAD patients with preserved ejection fraction (LVEF>45) (p value  = 0.1; OR  = 2.3)., Conclusion: The frequency of MYBPC3 DW genotype and D allele was associated with compromised LVEF implying that genetic variants of MYBPC3 encoding mutant structural sarcomere protein could increase susceptibility to left ventricular dysfunction. Therefore, 25 bp deletion in MYBPC3 may represent a genetic marker for cardiac failure in CAD patients from Southeast Asia.

Unlabelled: A number of plants have been described in Ayurveda and other traditional medicine for the management of diabetes. However, information about them is not easily available. Active constituents of any medicinal plant define the efficacy and safety of treatment to control hyperglycemia. We describe the database to maintain the record of medicinal plants having anti-hyperglycemic or anti-diabetic activity. The database contains information such as plant name, its geographical distribution, useful plant part, known dosage, active constituents, mechanism of action and clinical/experimental data. The database also includes information about plant raw material suppliers or manufacturers in India. The current database includes 238 plants species and 123 Indian industries using them., Availability: The database is freely available at http://www.biotechpark.org.in/antidia/index.html.

Dengue fever, dengue hemorrhagic fever and dengue shock syndrome are the prevalent mosquito borne viral infections worldwide. The dengue virus belongs to the genus flavivirus with conserved RNA domains peptidase&#95;S7 and dexHc among its members. The secondary structures for RNA domains peptidase&#95;S7 and DexHc are hence predicted and discussed with other known viral RNA structures to glean structural insights through comparison.

The avian influenza is an important infectious disease of birds. The genome of influenza A virus was segmented, single-stranded, negative-sense RNA molecules, which encodes many proteins. The significant surface proteins are hemagglutinin and neuraminidase for the pathogenicity of birds to humans. The prediction of epitopes in protein provides a suitable primary immunodiagnostic antigen for the detection of the influenza A virus H5N1. It was further used in the development and approval of epitopes, which were used as antigens, and the peptides can be used for vaccines in the potential control of an emerging pandemic of this pathogen. The conserved epitopes may be useful for the diagnosis of animals infected with the influenza virus. These might be helpful to prevent the spreading of influenza in animal to animal and also in the prevention and monitoring of its spread in the newer region. The epitopes provide the support for serodiagnosis or as a protective immunogen in novel vaccines. In this study, the preliminary data from the in silico analysis of hemagglutinin and neuraminidase was done to find potential T-cell epitopes. The determined peptides were beneficial for vaccine development, as they can reduce time by minimizing the number of required tests to find the possible selected epitopes, which target for vaccine development. T-cell recognition of the peptide-major histocompatible complex (MHC) is a prerequisite for cellular immunity. This work examines existing computational strategies for the study of peptide-MHC interactions. We have also provided guidelines for predicting antigenic peptides based on the availability of existing experimental data.

The genus Flavivirus comprises medically significant pathogenic virus; causing several infections in humans worldwide. Flavivirus genomes are 10-11 kb approximately and encode both structural and non structural region. The non structural region plays fundamental role in the stability, regulation and cell cycle of virus. The complete genomes of 26 Flavivirus were used for identification of promoter motifs through in silico approaches. The promoter sequences were encoded in merely 16 viruses and 10 viruses could not encode it. All these in silico identified promoter motifs was confirmed and verified with the known experimental data. This analysis suggests that presence of promoter may play a crucial role in the pattern of gene expression, regulation networks, cell specificity and development. It may also be useful for designing efficient expression vector and target specific delivery system in the gene therapy.

The present study was undertaken to investigate the spectrum of bacteria present in the River Gomti water before and after chlorination for drinking purposes. We observed that the strains of Pseudomonas aeruginosa that survived chlorination on three out of seven occasions were resistant to almost all the antibiotics tested. The chlorine-resistant bacteria had mucoid colonies and grew better at 24 degrees C. All attempts to isolate the plasmid responsible for chlorine resistance were unsuccessful. Laboratory experiments using different strains of the P. aeruginosa in distilled water showed that only the resistant strain survived chlorine treatment at a dose of < or =500 microg/L. Similar results were obtained when water collected from seven different sites on the River Gomti was treated with graded doses of chlorine. At the higher dose of chlorine, all the bacteria died in 30 min, whereas with lower doses all the bacteria survived. The present study underscores the importance of measuring water chlorine concentrations to assure they are sufficiently high to remove pathogenic bacteria from drinking water. To our knowledge, this is the first report in the literature of the selection of multidrug-resistant bacteria by suboptimal chlorine treatment of water.

Objective: To investigate the effect of Lead (Pb) acetate exposure on Semliki forest virus (SFV) pathogenesis in mice., Methods: Different doses (62.5, 125, 250 and 500 mg/Kg body weight) of Pb dissolved in normal saline were given to mice by oral intubation in a sub-acute (28 days) and sub-chronic (90 days) regimen followed by SFV infection. Morbidity, mortality, clinical symptoms, mean survival time (MST), changes in body and organ weight, accumulation of lead in soft tissues, virus titre in brain and histopathological alterations were compared between lead exposed and infected groups., Results: Early appearance of virus symptoms, increased mortality, decreased MST, enhanced SFV titre and greater tissue damage were observed in lead exposed-SFV-infected mice., Conclusion: Pre-exposure to lead increases the susceptibility of mice towards SFV infection. Further studies are suggested in view of the persistence of lead in the environment and the possibility of infection by microbial pathogens.

Oral administration of lindane (2.5, 5, 10 and 15 mg/kg, body weight) for 5 days was found to produce a dose-dependent increase in the activity of P450 dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in rat brain and liver. A significant increase in the hepatic and brain P450 monooxygenases was also observed when the duration of exposure of low dose (2.5 mg/kg) of lindane was increased from 5 days to 15 or 21 days. As observed with different doses, the magnitude of induction in the activity of P450 monooxygenases was several fold higher in liver microsomes when compared with the brain. Western blotting studies have indicated that the increase in the P450 enzymes could be due to the increase in the expression of P450 1A1/1A2, 2B1/2B2 and 2E1 isoenzymes. In vitro studies using organic inhibitors specific for individual P450 isoenzymes and antibody inhibition experiments have further demonstrated that the increase in the activity of PROD, EROD and NDMA-d are due to the increase in the levels of P450 2B1/2B2, 1A1/1A2 and 2E1 isoenzymes, respectively. Induction studies have further shown that while pretreatment of 3-methylcholanthrene (MC), an inducer of P4501A1/1A2, did not produce any significant effect in the incidence of lindane induced convulsions, pretreatment with phenobarbital (PB), an inducer of P450 2B1/2B2 or ethanol, an inducer of P450 2E1 catalysed reactions, significantly increased the incidence of lindane induced convulsions. Similarly, when the P450-mediated metabolism of lindane was blocked by cobalt chloride incidence of convulsions was increased in animals treated with lindane indicating that lindane per se or its metabolites formed by PB or ethanol inducible P450 isoenzymes are involved in its neurobehavioral toxicity.

To investigate the involvement of cytochrome P450 (P450) enzyme induction and the effect of different P450 modifiers in the neurobehavioral toxicity of deltamethrin, deltamethrin (10 mg/kg; orally for 1 day) was administered to young male albino Wistar rats, or in rats pretreated with phenobarbital (PB; 80 mg/kg, ip for 5 days), an inducer of P450 2B1/2B2 or 3-methylcholanthrene (MC; 30 mg/kg, ip for 5 days), an inducer of P450 1A1/1A2 or cobalt chloride (CoCl(2); sc for 2 days), a depletor of P450s. The administration of PB or MC or CoCl(2) alone did not produced any symptoms of neurobehavioral toxicity. While a single oral administration of deltamethrin produced tremors in two out of 10 rats and decreased the spontaneous locomotor activity, pretreatment with MC or PB potentiated the deltamethrin induced neurobehavioral toxicity with 50% of the treated rats exhibiting tremors. Half of the animals pretreated with MC prior to exposure to deltamethrin also exhibited choreoathetosis. The decrease in the spontaneous locomotor activity was found to be much more significant in PB- or MC-pretreated animals exposed to deltamethrin. In contrast to the pretreatment with inducers, rats pretreated with CoCl(2) exhibited no symptoms of tremors or choreoathetosis, indicating that a reactive metabolite of deltamethrin is formed by P450 catalysed reactions which is involved in the neurobehavioral toxicity of deltamethrin.

Iron deficiency evolves, slowly through several stages. Early iron deficiency caused a depletion in iron stores as shown by a reduction in the levels of hepatic non heme iron (44%) in the 7 days old pups born to iron deficient mothers. The hemoglobin levels and PCV (packed cell volume) were significantly reduced only after the age of three weeks. The activities of GABA (γ-amino butyric acid) shunt enzymes viz. GDH, GAD and GABA-T (glutamate dehydrogenase, glutamate decarboxylase and GABA-transaminase, respectively) and GABA content were found to decrease during gestation and/or lactation iron deficiency at 1 week (wk), 2wk, 3wk and 4wk of age in the developing rat brains. However GABA binding showed a significant increase at different age groups. The iron deficiency during lactational exposure showed significant alteration in most of the parameters only at the age of 3 weeks onwards. On rehabilitation with iron supplemented diet for 2 weeks, these altered parameters could not attain corresponding control values. A prolonged iron deficiency causing alterations in GABA may lead to neurological and behavioral alterations.

Background: Platelets are an elective site for oxidative stress owing to their high content of polyunsaturated fatty acid. Increased lipid peroxidation and elevated platelet thiobarbituric acid-reacting substances (TBARS) signal oxidative stress. This possibly leads to retinal neovascularization in Eales' disease., Methods: TBARS levels were estimated in consecutive cases of Eales' disease with neovascularisation (n = 26), Eales' disease without neovascularisation (n = 17) and healthy controls (n = 17)., Results: Platelet TBARS levels in the cases of Eales' disease with neovascularisation, Eales' disease without neovascularisation, and healthy controls were 0.66 +/- 0.1, 0.57 +/- 0.11 and 0.42 +/- 0.14 n moles TBARS formed/hour/10(8) platelets respectively. Student's t-test showed a significant increase in platelet TBARS levels in cases with neovascularisation as compared to cases without neovascularization (p < 0.05) and healthy controls (p < 0.01)., Conclusion: The increase in platelet TBARS levels in proliferative Eales' disease is consistent with an emerging view that lipid peroxides may be associated with retinal neovascularisation.

The therapeutic efficacy of a combination of meso 2,3-dimercaptosuccinic acid (DMSA) and calcium disodium EDTA in protecting testicular disorders in chronic lead intoxication was investigated. The results indicate that two five-days courses of the combined therapy produced a more effective recovery in the lead induced biochemical and histopathological disorders compared to conventional single 5 days therapy. No adverse effect of the chelators, when administered individually or in combination, was noticed in the testes of control (without lead exposure) animals.

Deltamethrin, an α-cyano type II pyrethroid, administered orally (5, 10 and 15 mg/kg body weight for 7 consecutive days or at 5 mg/kg for further 15 and 21 days) to young albino Wistar rats (approximately 8 weeks old) produced a dose- and time-dependent increase in the activity of cytochrome P450-dependent 7-ethoxyresorufin-O-dealkylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) in rat liver and brain. However, significant induction in the enzyme activities was observed at higher doses or prolonged exposure. The magnitude of induction in rat liver microsomes was less at 15 mg/kg dose as compared to 10 mg/kg dose. Western blot analysis revealed a similar dose-related and time-dependent increase in the expression of P450 2B1/2B2 and 1A1 isoenzymes as indicated by the increased cross-reactivity of liver microsomes isolated from deltamethrin-treated animals with anti-P450 2B1/2B2 and 1A1. Inhibition of EROD and PROD observed after in vitro addition of anti-P450 2B1/2B2 and 1A1/1A2 or organic inhibitors, metyrapone and α-naphthoflavone, to the brain and liver microsomes of deltamethrin-pretreated animals (5 mg/kg×21 days), further provided support that the induction observed in the EROD and PROD activity in brain is due to the increased expression of P450 2B1/2B2 and 1A1/1A2, while, in the liver, isoenzymes other than these are also involved.

First-generation adenovirus (Ad) vectors that had been rendered replication defective by removal of the E1 region of the viral genome (DeltaE1) or lacking the Ad E3 region in addition to E1 sequences (DeltaE1DeltaE3) induced G2 cell cycle arrest and inhibited traverse across G1/S in primary and immortalized human bronchial epithelial cells. Cell cycle arrest was independent of the cDNA contained in the expression cassette and was associated with the inappropriate expression and increase in cyclin A, cyclin B1, cyclin D, and cyclin-dependent kinase p34(cdc2) protein levels. In some instances, infection with DeltaE1 or DeltaE1 DeltaE3 Ad vectors produced aneuploid DNA histogram patterns and induced polyploidization as a result of successive rounds of cell division without mitosis. Cell cycle arrest was absent in cells infected with a second-generation DeltaE1Ad vector in which all of the early region E4 except the sixth open reading frame was also deleted. Consequently, E4 viral gene products present in DeltaE1 or DeltaE1 DeltaE3 Ad vectors induce G2 growth arrest, which may pose new and unintended consequences for human gene transfer and gene therapy.

The cyclin-dependent kinase inhibitor p21(Cip1/WAF1) has been implicated as an inducer of differentiation. However, although expression of p21 is increased in postmitotic cells immediately adjacent to the proliferative compartment, its expression is decreased in cells further along the differentiation program. Expression of the p21 protein was decreased in terminally differentiated primary keratinocytes of mice, and this occurred by a proteasome-dependent pathway. Forced expression of p21 in these cells inhibited the expression of markers of terminal differentiation at both the protein and messenger RNA levels. These inhibitory effects on differentiation were not observed with a carboxyl-terminal truncation mutant or with the unrelated cyclin-dependent kinase inhibitor p16(INK4a), although all these molecules exerted similar inhibition of cell growth. These findings reveal an inhibitory role of p21 in the late stages of differentiation that does not result from the effects of p21 on the cell cycle.

The therapeutic potential of meso 2,3-dimercaptosuccinic acid (DMSA) and calcium disodium ethylenediamine tetraacetic acid (CaNa(2)EDTA) alone or in combination in reducing levels of lead in blood and other soft organs and reversing lead induced biochemical and immunological alterations were investigated after chronic low level lead exposure. Lead exposure produced a significant adverse effect on few selected haematopoietic, nervous, testicular and immunological variables. Conventional 5-day treatment with both DMSA and CaNa(2)EDTA individually was effective in inducing elimination of lead but the recovery of the altered biochemical and clinical indices was moderate. When given in combination for 5 days, (DMSA was administered orally twice daily before intraperitoneal CaNa(2)EDTA administration) they were more effective in depleting body lead burden and providing recoveries in the altered biochemical parameters. Along with the rapid removal of lead from body stores after combined treatment, the immunological variables also recovered spontaneously. However, the altered CNS disorders remained practically unchanged following 5 days of chelation therapy. Lead induced testicular alterations also showed some recoveries after combined treatment. The results indicate that combined DMSA and CaNa(2)EDTA treatment could be more beneficial than individual treatment with any of these agents.

Several studies have reported decreased platelet 5-HT uptake in patients of major depression. The present study was undertaken with the aim to study the active platelet 5-HT uptake in depressed patients and effect of treatment with imipramine/ECT on platelet 5-HT uptake in these patients. 30 patients of major depression and equal number of age and sex-matched controls were included in the study. The depressives received imipramine (N=15) or ECT (N=15). Pretreatment active platelet 5-HT uptake was lower in depressives. Treatment with imipramine resulted in significant decrease in 5-HT uptake while with ECT there was significant increase. The serotonergic mechanisms are discussed.

Several studies have reported decreased platelet 5-HT uptake in patients of major depression. The mechanism of antidepressant action of ECT is not clear. The present work was undertaken with the aim to study the active platelet 5-HT uptake and the effect of ECT on it in patients of major depression. 15 patients of major depression (DSM-lll-R) and equal number of age and sex-matched controls were included in the study. Active platelet 5-HT uptake was determined before ECT, after a course of ECT and 7 days after last ECT. Platelet 5-HT uptake was. significantly lower in der essives than normal controls. After ECT treatment there was significant increase in 5-HT uptake which came down to pretreatment level after 1 week of last ECT. The effect of ECT on serotonergic system is discussed.

We studied the quality of water obtained using a new method of tapping underground water seepages by digging shallow water collection chambers in the Almora Hills of the state of Uttar Pradesh, India; quality of this water was compared with that of water obtained using traditional water sources in this region, namely naulas (surface seepages) and springs.Water from both the new and the traditional water sources had an excess of chromium and, in some samples, of iron and lead. Microbiological analysis showed that water from new water sources was safer than that obtained from tradional sources; however, only 40% of the shallow seepages provided water conforming to WHO standards on water quality.We conclude that tapping of underground water seepages may be a useful method of providing potable water to populations living in the hills. However, further improvement is necessary in the maintenance of the clean catchment area and in disposal of waste water from these water sources to ensure water quality.

During in vitro transformation, Leishmania donovani promastigotes converted into amastigote-like forms and underwent several changes in membrane parameters. They exhibited significantly increased microviscosity comparable to true amastigotes. Activities of several functionally important membrane bound enzymes were also altered, thereby indicating a change in their orientation. Peanut agglutinin was found to be specific for agglutination of stationary phase promastigotes whereas wheat-germ agglutinin was specific for the amastigote-like forms as well as for pure amastigotes, implying the presence of specific glycoconjugates on the parasite surface.

Glucose-6-phosphate dehydrogenase (G6PD) and hemoglobin E (HbE) were studied among 708 malarial patients and control groups of Ao Nagas from the Mokokchung District of Nagaland in the extreme northeast of India. The data suggest that malaria is an important ecologic factor in maintaining the high frequency of G6PD deficiency and HbE among the Ao Nagas. Although migrations from adjoining populations that have a high frequency of both these traits could have contributed to the presence of these genes in the Ao Nagas, malaria also could be an essential determinant in maintaining the current high frequency in present-day Ao Nagas.

Six weeks of daily intraperitoneal injection with manganese chloride (15 mg/kg body wt) reduced the normal weight gain of male Fischer-344 rats. This treatment depressed plasma testosterone and corticosterone levels, but prolactin levels were unaffected. The only significant changes in the levels of a variety of neuropeptides assayed in several regions were increases in the levels of hypothalamic substance P and pituitary neurotensin. Striatal serotonin, dopamine, and their metabolites were unchanged in manganese-exposed rats relative to saline-injected controls. However, the stress of injection combined with the effect of manganese appeared to significantly increase concentrations of striatal monoamines relative to uninjected controls.

Lipid peroxidation, glutathione level and activity of glutathione-S-transferase were studied in liver and brain of rats 4 and 3 h after a single i.p. administration of 0, 25, 75, 100 mg/kg acrylamide or 0, 50, 100, 200, 600 mg/kg styrene, respectively. In liver both acrylamide and styrene caused an increase in lipid peroxidation and decrease in glutathione contents and activity of glutathione-S-transferase in a dose dependent manner, while in brain only acrylamide produced a decrease in glutathione content. The decrease in glutathione content was not always associated with increase of lipid peroxidation. The enhancement of lipid peroxidation occurred only when glutathione contents were depleted to certain critical levels. No effect of acrylamide or styrene was seen on lipid peroxidation under in vitro conditions. The addition of glutathione in the incubation mixture significantly inhibited the rate of lipid peroxidation of liver homogenates of acrylamide and styrene treated animals. The results suggest that enhancement of lipid peroxidation in liver on exposure to acrylamide or styrene is a consequence of depletion of glutathione to certain critical levels. The inhibition of glutathione-S-transferase activity by acrylamide and styrene suggests that detoxication of these neurotoxic compounds could be suppressed following acute exposure.

Single exposure of endosulfan (5 mg/kg) to pigeons (Columbia livia) caused neuronal hyperexcitability as evidenced by spike discharges of 200-500 microV in the electroencephalograms (EEG) from the telencephalon and hyperstriatum, but there was no effect on the ectostriatal area. Cholinergic (muscarinic) receptor binding study using [3H]quinuclidinyl benzilate ([3H]QNB) as a specific ligand indicated that a single exposure to 5 mg/kg of endosulfan caused a significant increase (P less than 0.05) in [3H]QNB binding to the striatal membrane. Behavioral study further indicated that a single dose of 200 micrograms/kg of oxotremorine produced a significant induction in the tremor (P less than 0.01) in endosulfan-pretreated pigeons. The results of this behavioral and biochemical study indicate the involvement of a cholinergic (muscarinic) transmitter system in endosulfan-induced neurotoxicity.

The binding of acrylamide (ACR) with purified bovine serum albumin (BSA) was studied. Binding of ACR with BSA was characterized by equilibrium dialysis, fluorescence studies, and ultraviolet spectroscopy. ACR was quantitated by high-pressure liquid chromatography. Equilibrium dialysis studies on the binding of ACR with BSA showed that more than 25% of the added ligand was bound to the protein at equilibrium. ACR produced a concentration-dependent decrease in uv absorbance of BSA, indicating reactivity of ACR with BSA. Fluorescence quenching studies of ACR binding showed a concentration-dependent quenching of the fluorescence of BSA. ACR also caused a concentration-dependent decrease in the fluorescence of sulfhydryl (-SH) groups present on BSA, implicating a role of protein -SH groups in the binding of ACR. Prior blocking of -SH groups by N-ethylmaleimide resulted in 16% inhibition of the initial binding of ACR, suggesting involvement of -SH groups. Our results demonstrate that ACR binds to BSA through both aromatic amino acids and -SH groups and that such binding may play an important role in pharmacodynamics and toxicity of ACR.