Virendra P. Singh

Status of antioxidant defense system and expression of toxicant responsive genes in striatum of maneb- and paraquat-induced parkinson's disease phenotype in mouse : Mechanism of neurodegeneration

Parkinsons disease (PD) is a progressive neurodegenerative disorder contributed by the combination of age, genetic and environmental factors. Several studies have clearly shown increase in the incidences of PD in the rural environments and hypothesized the involvement of pesticides such as paraquat and maneb in neurodegeneration. These studies have prompted researchers to develop paraquat and maneb models to study the effect of co-treatment of maneb and paraquat on neuronal toxicity; however, the mechanism underlying maneb and paraquat co-treatment induced neuronal toxicity has not yet been clearly understood. The involvement of cytochrome P4502E1 and glutathione S-transferases A4-4 enzymes in the detoxification of several pesticides such as atrazine, fenamirol, organophosphorous insecticide parathion, methoxychlor, diethyl dithiocarbamate and paraquat has been known. The contribution of CYP2E1 and GSTA4-4 in neuronal toxicity has also been reported. The present study was therefore undertaken to investigate the mechanism of maneb- and paraquat-induced neurodegeneration by estimating the level of antioxidant defense enzymes in the striatum and measuring the differential expressions of CYP2E1 and GSTA4-4 genes. Animals were treated with and without maneb (30 mg/kg, i.p.) or paraquat (10 mg/kg, i.p.) either alone or in combination in exposure time-dependent manner. A significant increase in catalase, glutathione S-transferase and lipid peroxidation in the striatum was found following 3, 6 and 9 weeks of co-treatment as compared with individual treatment or controls. Individual treatment of maneb or paraquat did not exhibit any significant alteration in CYP2E1 and GSTA4-4 expression up to 6 weeks; however, an augmentation in CYP2E1 and GSTA4-4 expression was observed in the animals exposed to maneb or paraquat for 9 weeks. Augmentation in the expression of CYP2E1 and GSTA4-4 was more pronounced in the animals treated with maneb and paraquat in combination for nine weeks. A significant reduction in the augmented lipid peroxidation in the striatum was observed when the striatum was pre-administered with CYP2E1 inhibitors; however, glutathione pre-administration induced lipid peroxidation. Results obtained from the present investigation suggest the involvement of CYP2E1 and GSTA4-4 in the augmentation of the lipid peroxidation thereby enhancing neurodegeneration.

A Study on the Association of Cytochrome-P450 1A1 Polymorphism and Breast Cancer Risk in North Indian Women

Cytochrome P-450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogens and mammary carcinogens into 2-hydroxy catechol metabolites. Many commonly occurring single nucleotide polymorphism (SNP) are reported in CYP1A1 in various populations that include, isoleucine to valine substitution at 462 codon in heme binding region in exon 7 (A to G transition at position 2455; M2), threonine to asparagine substitution at codon 461 (C to A transversion at position 2453; M4), T to C transition at 3801 position (M1) and T to C transition at position 3205 (M3) in 3′ non-coding region. Epidemiological studies have shown inconsistent patterns between CYP1A1 polymorphism and breast cancer risk among various populations. Most of the studies have shown significant association between CYP1A1 genotype polymorphism and breast cancer risk. The present investigation was therefore undertaken to investigate the association of M1, M2, M3 and M4 polymorphisms and their subsequent contribution in premenopausal and postmenopausal women with breast cancer risk in north Indian women. Genomic DNA was isolated from case controls and breast cancer patients, specific segments of genomic DNA were amplified and restriction fragment length polymorphism (RFLP) was performed. CYP1A1 expression and catalytic activity were also assessed in premenopausal and postmenopausal case controls and patients. Polymorphism at M1, M2 and M4 alleles was detected and odds ratio for W/M1 and␣M1/M1 was calculated as 1.07 (95% CI, 0.59–1.87) and 0.74 (95% CI, 0.28–1.96) respectively. Odds ratio for W/M1 and M1/M1 alleles in premenopausal and postmenopausal women was 1.09 (95% CI, 0.45–2.49)/0.62 (95% CI, 0.10–2.66) and 1.60 (95% CI, 0.60–4.22)/1.06 (95% CI, 0.22–7.33) respectively. Odds ratio for W/M4 and M4/M4 allele was 1.20 (95% CI, 0.65–2.24)/4.55 (95% CI, 0.44–226.2) and 0.96 (95% CI, 0.36–2.64)/4.51 (95% CI, 0.23–273.0) respectively in total and premenopausal women. In postmenopausal women odds ratio was calculated as 1.16 (95% CI, 0.45–2.94) for M4/W but it could not be detected for M4/M4 since this genotype was not found in any postmenopausal case controls. Odds ratio for W/M2 genotype was calculated 0.57 (95% CI, 0.28–1.02), 1.06 (95% CI, 0.40–2.47) and 0.33 (95% CI, 0.12–0.89) respectively for total, premenopausal and postmenopausal women, however, in any group the odds ratio for M2/M2 could not be detected as M2/M2 genotype was not found in breast cancer patients. Polymorphism at M1 and M4 alleles was not found significantly associated with breast cancer risk and only wild type genotype was found in case controls and patients for M3 allele. Lack of protective association between CYP1A1 M2 genotype was also observed, however, in postmenopausal women a significant protective association with breast cancer risk was found (odds ratio, 0.33; 95% CI, 0.12–0.89; P-value 0.03). Similarly, no significant alteration in CYP1A1 expression and catalytic activity was observed in wild type and variant genotypes both in premenopausal and postmenopausal patients as compared with their respective controls. The results obtained from the present investigation thus suggest that probably CYP1A1 (M1, M2, M3, and M4) polymorphism alone does not play a significant role in the breast cancer risk in north Indian women.

Association of single nucleotide polymorphisms in CYP1B1 and COMT genes with breast cancer susceptibility in Indian women

Cytochrome P450 1B1 (CYP1B1) and catechol-

Do Single Nucleotide Polymorphisms in Xenobiotic Metabolizing Genes Determine Breast Cancer Susceptibility and Treatment Outcomes

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Polymorphism of xenobiotic-metabolizing genes and breast cancer susceptibility in North Indian women.

-methyltransferase (COMT) enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu) to valine (Val) at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met) at codon 158 decreases the catalytic activity of COMT. The present study was performed to evaluate the associations of CYP1B1 Leu432Val and/or COMT Val158Met polymorphisms with total, premenopausal and postmenopausal breast cancer risks in Indian women. COMT and CYP1B1 polymorphisms in controls and breast cancer patients were analyzed employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by gel electrophoresis. Although CYP1B1 and COMT genotypes did not exhibit statistically significant association with breast cancer risks when analyzed individually, COMT wild type (Val158Val) in combination with CYP1B1 heterozygous variant (Leu432Val) [OR: 0.21; 95% CI (0.05–0.82), p value; 0.021] and COMT heterozygous variant (Val158Met) in combination with CYP1B1 wild type (Leu432Leu) [OR: 0.29; 95% CI (0.08–0.96), p value; 0.042] showed significant protective association with premenopausal breast cancer risk. The results demonstrate that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.

Non-steroidal immunosuppressive drugs for non-neoplastic ocular disorders

SNPs in CYP1A1, CYP2A1, CYP2B6, CYP2C, CYP2D6, CYP3A, GSTM1, GSTT1, GSTP1, SULT1A1, SULT1A2, UGT, and MTHFR are associated with breast cancer susceptibility; however, lack of such associations are also reported in some populations. The contradictory findings are explained on the basis of ethnic variation among populations and due to lack of proper sample size, detailed genotype-phenotype combinations and validation of gene expression studies at protein level. In this review, SNPs in these genes that have tremendous potential in identification of susceptible individuals, development of preventive strategies, treatment outcomes and their limitations are discussed.

Traumatic Subconjunctival Dislocation of Fractured Posterior Chamber Intraocular Lens by Cow Horn Injury

NAD(P)H:quinone oxidoreductase 1 (NQO1) and cytochrome P450 1A2 (CYP1A2) are involved in the metabolism of estrogens. Genetic polymorphisms in these genes may lead to interindividual variation in breast cancer susceptibility. This study was undertaken to investigate the association of NQO1 exon 6 proline187serine (C609T) and CYP1A2 exon 2 phenylalanine21leucine (C63G) polymorphisms with breast cancer susceptibility in North Indian women. Polymorphisms were analyzed by polymerase chain reaction amplification of the desired segment of NQO1 and CYP1A2 genes followed by restriction fragment length polymorphism. NQO1 mRNA expression was analyzed by semiquantitative reverse transcription-polymerase chain reaction and its enzyme activity was estimated spectrofluorophotometrically. Odds ratios for NQO1 C609T heterozygous and homozygous variants were 0.66 (95% confidence interval: 0.39-1.13; p-value: 0.141) and 1.07 (95% confidence interval: 0.46-2.46; p-value: 0.976). All cases and controls were monomorphic for the CYP1A2 exon 2 phenylalanine21leucine (C63G) genotype. NQO1 mRNA expression and its catalytic activity among wild-type genotype, homozygous variant, and heterozygous variant were not significantly altered, except for catalytic activity of the NQO1 homozygous variant, which was observed extremely low. The results of the study suggest that NQO1 exon 6 proline187serine (C609T) and CYP1A2 exon 2 phenylalanine21leucine (C63G) polymorphisms do not play a significant role in breast cancer susceptibility in North Indian women.

Orbital Myiasis (Dermatobia Hominis)Complicating Secondary Squamous Cell Carcinoma of Medial Rectus Muscle

Introduction Immunomodulatory or immunosuppressive drugs have an ability to suppress the immune drive by producing certain soluble bioactive molecules like cytokines and chemokines thus decreasing the tissue damage resulting from the inflammatory mediators. The use of immunosuppressives in ophthalmology follow their extensive use as anticancer chemotherapeutic agents. Nonneoplastic use of immunosuppressive agents by ophthalmologists has greatly increased over the past three decades because of better knowledge of the immunopathology of immune mediated, noninfectious ocular inflammatory disorders, affecting conjunctiva, cornea, sclera, uveal tissue etc.. Most of the uveal disorders such as non-infectious uveitis associated with arthritis and collagen vascular diseases e.g. Vogt-koyanagi-Haradas disease, Behecets disease, sympathetic ophthalmitis, pars planitis etc are immune mediated and require immunosuppressive agents if corticosteroids fail or are not tolerated or contraindicated. Allergic eye diseases like vernal keratoconjunctivitis and atopic keratoconjunctivitis are characterized by complex immunopathology. Immunomodulating agents like cyclosporine A and tacrolimus can be used to inhibit T-cell activation among the patients with severe allergic eye diseases. Other immune mediated ocular conditions which require immunosuppressive drugs are thyroid associated ophthalmopathy (TAO), dry eye disease, necrotizing scleritis, moorener’s ulcer, limbal cell transplantation and peripheral ulcerative keratitis (PUK). Earlier, the use of immunosuppressives were limited to treatment of corticosteroid resistant, sight threatening ocular inflammation , but now a days these drugs are considered as first line of treatment for Wegeners granulomatosis, Behcetss disease etc. Most of the immunosuppressive agents are extremely potent and have significant adverse effects. The purpose of this review is to briefly summarize the management of various ocular inflammatory disorders by using immunosuppressive agents, with focus on use of newer immunosuppressive drugs. A review of the literature in the PubMed, MedLine, and Cochrane database was conducted to identify clinical trials, comparative studies, case series and case reports describing the use of immunosuppressive therapy.

Association of Polymorphism in MDM-2 and p53 Genes with Breast Cancer Risk in Indian Women

Traumatic sub-conjunctival dislocation of posterior chamber intraocular lens is a rare and emergency condition. This communication is to report a rare ocular trauma by cow horn. A 52 year old male farmer presented with history of cow horn injury to his right eye. He had pain redness and decreased vision in his right eye. His posterior chamber IOL which was implanted two years back,was found dislocated to superiotemporal sub-conjunctival space with one broken haptic in anterior chamber and was removed surgically. Such a dislocation has not yet been reported in Indan literature and rarely reported in international literature to the best of our knowledge.

A live cysticercosis in anterior chamber leading to glaucoma secondary to pupilary block.

Background: Myiasis is an infestation of living tissue of human and other vertebrate animals by larvae of flies of the order Diptera. Aim: To present a case of destructive squamous cell carcinoma complicated by orbital myiasis. Case report: Here is a rare case report of ocular myiasis from the species sarcophaga in an elderly patient belonging to rural India having neglected secondary squamous cell carcinoma of medial rectus muscle, one month after excision of conjunctival intraepithelial neoplasia. Computerized tomography imaging of orbit and brain revealed multiple bony erosions with intracranial extension. The pathogenesis, clinical presentations, findings of investigations and treatment of orbital myiasis in squamous cell carcinoma are discussed here under.