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author:("Thomas, bena")
1.  A novel method for detecting 7-methyl guanine reveals aberrant methylation levels in Huntington disease 
Analytical biochemistry  2013;436(2):112-120.
Guanine methylation is a ubiquitous process affecting DNA and various RNA species. N-7 guanine methylation (7-MG), though relatively less studied, could have a significant role in normal transcriptional regulation as well as in the onset and development of pathological conditions. The lack of a sensitive method to accurately quantify trace amounts of altered bases like 7-MG, has been a major deterrent in delineating its biological function(s). Here we report the development of methods to detect trace amounts of 7-MG in biological samples using electrochemical detection combined with HPLC separation of compounds. We further sought to assess global alterations in DNA methylation in Huntington's disease (HD) in which transcriptional dysregulation, is a major factor in pathogenesis. The developed method was used to study guanine methylation in cytoplasmic and nuclear nucleic acids from human and transgenic mouse HD brain and controls. Significant differences were observed in the guanine methylation levels in mouse and human samples, consistent with the known transcriptional pathology of HD. The sensitivity of the method makes it capable of detecting subtle aberrations. Identification of changes in methylation pattern will provide insights into the molecular mechanisms changes that translate into onset and/or development of symptoms in diseases like HD.
PMCID: PMC4090024  PMID: 23416183
7-methyl guanine (7-MG); Guanine (G); Huntington disease (HD); electrochemical detection (ECD)
2.  The influence of stigma on HIV risk behavior among men who have sex with men in Chennai, India 
AIDS care  2012;24(11):1401-1406.
Stigma has been shown to increase vulnerability to HIV acquisition in many settings around the world. However, limited research has been conducted examining its role among men who have sex with men (MSM) in India, whose HIV prevalence is far greater than the general population. In 2009, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about stigma, sexual-risk, demographics, and psychosocial variables. More than one fifth of the MSM reported unprotected anal sex (UAS) in the past three months. Logistic regression procedures were used to examine correlates of having experienced stigma. The 11-item stigma scale had high internal consistency reliability (Cronbach's alpha=0.99). Almost 2/5ths (39%) reported a high-level of experienced stigma (≥12 mean scale-score) in their lifetime, and the mean stigma scale score was 12 (SD=2.0). Significant correlates of having experienced prior stigma, after adjusting for age and educational attainment, included: identifying as a kothi (feminine acting/appearing and predominantly receptive in anal sex) compared to a panthi (masculine appearing, predominantly insertive) (AOR= 63.23; 95% CI: 15.92, 251.14; p<0.0001); being “out” about one's MSM behavior (AOR=5.63; 95% CI: 1.46, 21.73; p=0.01); having clinically significant depressive symptoms (AOR=2.68; 95% CI: 1.40, 5.12; p=0.003); and engaging in sex work in the prior 3 months (AOR=4.89; 95% CI: 2.51, 9.51; p<0.0001). These findings underscore the need to address psychosocial issues of Indian MSM. Unless issues such as stigma are addressed, effective HIV prevention interventions for this hidden population remain a challenge.
PMCID: PMC3634562  PMID: 22519945
men who have sex with men; MSM; depression; India; HIV; stigma
In India men who have sex with men (MSM) are stigmatized, understudied, and at high risk for HIV. Understanding the impact of psychosocial issues on HIV risk behavior and HIV infection can help shape culturally relevant HIV prevention interventions. Peer outreach workers recruited 210 MSM in Chennai who completed an interviewer-administered psychosocial assessment battery and underwent HIV testing and counseling. More than one fifth (46/210) reported unprotected anal intercourse in the past 3 months, 8% tested positive for HIV, and 26% had previously participated in an HIV prevention intervention. In a multivariable logistic-regression model controlling for age, MSM subpopulation (kothi, panthi, or double-decker), marital status, and religion, significant predictors of any unprotected anal intercourse were being less educated (adjusted odds ratio [AOR] = .54; p = .009), not having previously participated in an HIV prevention program (AOR = 3.75; p = .05), having clinically significant depression symptoms (AOR = 2.8; p = .02), and lower self-efficacy (AOR = .40; p < .0001). Significant predictors of testing positive for HIV infection were: being less educated (AOR = .53; .05) and not currently living with parent(s) (AOR = 3.71; p = .05). Given the prevalence of HIV among MSM, efforts to reach hidden subpopulations of MSM in India are still needed. Such programs for MSM in India may need to address culturally-relevant commonly co-occurring psychosocial problems to maximize chances of reducing risk for infection.
PMCID: PMC3623672  PMID: 19670971
Men who have sex with men (MSM) in India have an HIV seroprevalence 22 times greater than the country’s general population and face unique challenges that may hinder the effectiveness of current HIV prevention efforts. To obtain an understanding of the logistical and sociocultural barriers MSM experience while accessing HIV prevention services, focus groups and key informant interviews were conducted with 55 MSM in Chennai, India. Qualitative data were analyzed using descriptive qualitative content analysis. Sixty-five percent of participants identified as kothi (receptive partners), 9% as panthi (insertive partners), 22% as double decker (receptive and insertive), and 4% did not disclose. Themes included: (a) fatigue with current HIV risk reduction messages; (b) increased need for non-judgmental and confidential services; and (c) inclusion of content that acknowledges individual and structural-level determinants of risk such as low self-esteem, depression, and social discrimination. MSM interventions may benefit from approaches that address multilevel psychosocial factors, including skills building and strategies to foster self-acceptance and increased social support.
PMCID: PMC3613222  PMID: 23206199
5.  HIV in Indian MSM: Reasons for a concentrated epidemic & strategies for prevention 
Men who have sex with men (MSM) in India are disproportionately likely to be HIV-infected, and face distinct psychosocial challenges. Understanding the unique socio-cultural issues of MSM in India and how they relate to HIV risk could maximize the utility of future prevention efforts. This review discusses: (i) the importance of addressing co-occurring mental health issues, such as depression, which may interfere with MSM's ability to benefit from traditional risk reduction counselling, (ii) reducing HIV-related stigma among health providers, policymakers and the lay public, and (iii) the role for non-governmental organizations that work with the community to play in providing culturally relevant HIV prevention programmes for MSM.
PMCID: PMC3284100  PMID: 22310824
HIV; India; men who have sex with men; MSM; mental health; stigma
6.  Feasibility of an Alcohol Intervention Programme for TB Patients with Alcohol Use Disorder (AUD) - A Qualitative Study from Chennai, South India 
PLoS ONE  2011;6(11):e27752.
The negative influences of alcohol on TB management with regard to delays in seeking care as well as non compliance for treatment has been well documented. This study is part of a larger study on the prevalence of AUD (Alcohol Use Disorder) among TB patients which revealed that almost a quarter of TB patients who consumed alcohol could be classified as those who had AUD. However there is dearth of any effective alcohol intervention programme for TB patients with Alcohol Use Disorder (AUD).
This qualitative study using the ecological system model was done to gain insights into the perceived effect of alcohol use on TB treatment and perceived necessity of an intervention programme for TB patients with AUD. We used purposive sampling to select 44 men from 73 TB patients with an AUDIT score >8. Focus group discussions (FGDs) and interviews were conducted with TB patients with AUD, their family members and health providers.
TB patients with AUD report excessive alcohol intake as one of the reasons for their vulnerability for TB. Peer pressure has been reported by many as the main reason for alcohol consumption. The influences of alcohol use on TB treatment has been elaborated especially with regard to the fears around the adverse effects of alcohol on TB drugs and the fear of being reprimanded by health providers. The need for alcohol intervention programs was expressed by the TB patients, their families and health providers. Suggestions for the intervention programmes included individual and group sessions, involvement of family members, audiovisual aids and the importance of sensitization by health staff.
The findings call for urgent need based interventions which need to be pilot tested with a randomized control trial to bring out a model intervention programme for TB patients with AUD.
PMCID: PMC3221662  PMID: 22132134
7.  Alcohol Use Disorders (AUD) among Tuberculosis Patients: A Study from Chennai, South India 
PLoS ONE  2011;6(5):e19485.
Alcohol Use Disorders (AUDs) among tuberculosis (TB) patients are associated with nonadherence and poor treatment outcomes. Studies from Tuberculosis Research Centre (TRC), Chennai have reported that alcoholism has been one of the major reasons for default and mortality in under the DOTS programme in South India. Hence, it is planned to conduct a study to estimate prevalence of alcohol use and AUDs among TB patients attending the corporation health centres in Chennai, India.
This is a cross-sectional cohort study covering 10 corporation zones at Chennai and it included situational assessment followed by screening of TB patients by a WHO developed Alcohol Use Disorders Identification Test AUDIT scale. Four zones were randomly selected and all TB patients treated during July to September 2009 were screened with AUDIT scale for alcohol consumption.
Out of 490 patients, 66% were males, 66% were 35 years and above, 57% were married, 58% were from the low monthly income group of 8. Age (>35 years), education (less educated), income (
AUD among TB patients needs to be addressed urgently and the findings suggest the importance of integrating alcohol treatment into TB care.
PMCID: PMC3096635  PMID: 21611189
AIDS Patient Care and STDs  2009;23(11):981-986.
India has the greatest number of HIV infections in Asia and the third highest total number of infected persons globally. Men who have sex with men (MSM) are considered by the Government of India's National AIDS Control Organization (NACO) a “core risk group” for HIV in need of HIV prevention efforts. However there is a dearth of information on the frequency of participation in HIV prevention interventions and subsequent HIV risk and other correlates among MSM in India. Recruited through peer outreach workers, word of mouth and snowball sampling techniques, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about participating in any HIV prevention interventions in the past year, sexual risk taking, demographics, MSM identities, and other psychosocial variables. Bivariate and multivariable logistic regression procedures were used to examine behavioral and demographic correlates with HIV prevention intervention participation. More than a quarter (26%) of the sample reported participating in an HIV prevention intervention in the year prior to study participation. Participants who reported engaging in unprotected anal sex (UAS; odds ratio [OR] = 0.28; p = 0.01) in the 3 months prior to study enrollment were less likely to have participated in an HIV prevention program in the past year. MSM who were older (OR = 1.04; p = 0.05), kothis (feminine acting/appearing and predominantly receptive partners in anal sex) compared to panthis (masculine appearing, predominantly insertive partners; OR = 5.52, p = 0.0004), those with higher educational attainment (OR = 1.48, p = 0.01), being “out” about having sex with other men (OR = 4.03, p = 0.0001), and MSM who reported ever having been paid in exchange for sex (OR = 2.92, p = 0.001) were more likely to have reported participation in an HIV prevention intervention in the preceding year. In a multivariable model, MSM reporting UAS in the prior 3 months were less likely to have participated in an HIV prevention intervention (AOR = 0.34, p = 0.04). MSM who were older (AOR = 1.05, p = 0.05), those with higher educational attainment (AOR = 1.92, p = 0.0009), and MSM who were “out” about having sex with other men (AOR = 2.71, p = 0.04) were more likely to have reported participating in an HIV prevention program. Findings suggest that exposure to HIV prevention interventions may be protective against engaging in UAS for some MSM in India. Understanding predictors of participation in an HIV prevention intervention is helpful for identifying Indian MSM who might have had no exposure to HIV prevention information and skills building, hence allowing researchers and prevention workers to focus efforts on individuals at greatest need.
PMCID: PMC2859779  PMID: 19821722
AIDS and behavior  2008;13(5):989-996.
The purpose of this study is to explore the perceptions and needs of mothers living with HIV to gain greater insights into the challenges they face in relation to their health seeking behavior, fears around disclosure, and issues related to stigma and discrimination. This qualitative study utilized focus groups consisting of a sample of 60 HIV-infected mothers recruited from a large maternity hospital and STD clinic in Chennai, India. Discrimination by physicians and other health care workers has been a major impediment expressed by mothers living with HIV in accessing quality health care. Mothers living with HIV are increasingly concerned about how and when to disclose their HIV status to their children and the repercussions which could result from disclosure. The findings of this study call for urgent intervention strategies taking into consideration these various concerns and needs of mothers living with HIV and their children.
PMCID: PMC2949417  PMID: 18941883
HIV; Mothers; India; Qualitative research
PLoS ONE  2010;5(9):e12379.
With the creation of the Revised National TB Control Programme (RNTCP), tuberculosis services have become decentralized and more accessible. A 1997 study prior to RNTCP implementation reported that most chest symptomatics accessed first private health care facilities and a general dissatisfaction with government health facilities. The study was repeated post-RNTCP implementation to gain insight into the current care seeking behavior of chest symptomatics.
A cross-sectional community-based study carried out between March-August 2008 in 4 sites (2 rural [R] and 2 urban [U]) from the same two districts of Chennai and Madurai, southern India, as in the 1997 study. Six hundred and forty chest symptomatics were identified (R 314; U 326), and detailed interviews were done for 606 (R311; U295).
Prevalence of chest symptomatics in the urban and rural areas were 2.7% and 4.9% respectively (p<0.01), and was found to increase with age (Chi-square for trend, p<0.01). Longer delays in seeking care were seen amongst symptomatics above 45 years of age (p 0.01), and those who had taken previous TB treatment (p = 0.05). Overall, 50% (222/444) of the chest symptomatics approached a government health care facility first (R 142 (61%); U 80 (38%), p = <0.001). This was significantly (p<0.001) more than were observed in the 1997 study, where only 38.4% approached a government facility first. Sixty two (28%) of the 222 made a second visit to a government facility (R26%; U31%), while 17% shifted to a private facility (R14%; U21%). Dissatisfaction with the health care facility was one of the major reasons expressed.
It appears that the RNTCP has had an impact in the community with regard to the availability and accessibility of TB services in government health facilities. However the relatively high levels of subsequent shifting to private health facilities calls for urgent action to make government facilities more patients friendly with quality care facilities in the delivery of RNTCP services.
PMCID: PMC2942833  PMID: 20862219
PLoS ONE  2009;4(12):e8389.
The acceptability and feasibility of provider-initiated HIV testing and counseling (PITC) in many settings across Asia with concentrated HIV epidemics is not known. A pilot study of the PITC policy undertaken within the public health care systems in two districts in India offered the opportunity to understand patient's perspectives on the process of referral for HIV testing and linking to HIV treatment and care.
We conducted a cross-sectional study of randomly selected TB patients registered by the TB control program between July and November 2007 in two districts in south India. Trained interviewers met patients shortly after TB diagnosis and administered a structured questionnaire. Patients were assessed regarding their experience with HIV status assessment, referral for counseling and testing, and for HIV-infected patients the counseling itself and subsequent referral for HIV treatment and care.
Of the 568 interviewed TB patients, 455 (80%) reported being referred for HIV testing after they presented to the health facility for investigations or treatment for TB. Over half the respondents reported having to travel long distances and incurred financial difficulties in reaching the Integrated Counselling and Testing Centre (ICTC) and two-thirds had to make more than two visits. Only 48% reported having been counseled before the test. Of the 110 HIV-infected patients interviewed, (including 43 with previously-known positive HIV status and 67 detected by PITC), 89 (81%) reported being referred for anti-retroviral treatment (ART); 82 patients reached the ART centre but only 44 had been initiated on ART.
This study provides the first evidence from India that routine, provider-initiated voluntary HIV testing of TB patients is acceptable, feasible and can be achieved with very high efficiency under programmatic conditions. While PITC is useful in identifying new HIV-infected patients so that they can be successfully linked to ART, the convenience and proximity of testing centres, quality of HIV counseling, and efficiency of ART services need attention.
PMCID: PMC2791227  PMID: 20041167
PLoS ONE  2009;4(11):e7899.
Provider-initiated HIV testing and counselling (PITC) is internationally recommended for tuberculosis (TB) patients, but the feasibility, effectiveness, and impact of this policy on the TB programme in India are unknown. We evaluated PITC of TB patients across two districts in India considered to have generalized HIV epidemics, Tiruchirappalli (population 2.5 million) and Mysore (population 2.8 million).
Methodology/Principal Findings
Starting June 2007, healthcare providers in both districts were instructed to ascertain HIV status for all TB patients, and refer those with unknown HIV status to the nearest Integrated Counselling and Testing Centre (ICTC)—often in the same facility—for counselling and voluntary HIV testing. All TB patients registered from June 2007 to March 2008 were followed prospectively. Field investigators assessed PITC practices and abstracted data from routine TB programme records and HIV counselling registers to determine the proportion of TB patients appropriately evaluated for HIV infection. Patient records were traced to determine the efficiency of referral links to HIV care and antiretroviral treatment (ART). Between July 2007 and March 2008, 5299 TB patients were registered in both study districts. Of the 4701 with unknown HIV status at the time of TB treatment initiation, 3368 (72%) were referred to an ICTC, and 3111 (66%) were newly tested for HIV. PITC implementation resulted in the ascertainment of HIV status for 3709/5299 (70%) of TB patients, and detected 200 cases with previously undiagnosed HIV infection. Overall, 468 (8.8%) of all registered TB patients were HIV-infected; 177 (37%) were documented to have also received any ART.
With implementation of PITC in India, HIV status was successfully ascertained for 70% of TB patients. Previously undiagnosed HIV-infection was detected in 6.4% of those TB patients newly tested, enabling referral for life-saving anti-retroviral treatment. ART uptake, however, was poor, suggesting that PITC implementation should include measures to strengthen and support ART referral, evaluation, and initiation.
PMCID: PMC2774514  PMID: 19936067
Biochemistry  2008;47(22):5889-5895.
Efforts to elucidate the nature of the bimolecular interaction of parathyroid hormone (PTH) with its cognate receptor, the PTH receptor type 1 (PTHR1), have relied heavily on benzoylphenylalanine- (Bpa-) based photoaffinity cross-linking. However, given the flexibility, size, and shape of Bpa, the resolution at the PTH–PTHR1 interface appears to be reaching the limit of this technique. Here we employ a disulfide-trapping approach developed by others primarily for use in screening compound libraries to identify novel ligands. In this method, cysteine substitutions are introduced into a specific site within the ligand and a region in the receptor predicted to interact with each other. Upon ligand binding, if these cysteines are in close proximity, they form a disulfide bond. Since the geometry governing disulfide bond formation is more constrained than Bpa cross-linking, this novel approach can be employed to generate a more refined molecular model of the PTH–PTHR1 complex. Using a PTH analogue containing a cysteine at position 1, we probed 24 sites and identified 4 in PTHR1 to which cross-linking occurred. Importantly, previous photoaffinity cross-linking studies using a PTH analogue with Bpa at position 1 only identified a single interaction site. The new sites identified by the disulfide-trapping procedure were used as constraints in molecular dynamics simulations to generate an updated model of the PTH–PTHR1 complex. Mapping by disulfide trapping extends and complements photoaffinity cross-linking. It is applicable to other peptide–receptor interfaces and should yield insights about yet unknown sites of ligand–receptor interactions, allowing for generation of more refined models.
PMCID: PMC2570702  PMID: 18459800
Molecular Biology of the Cell  2004;15(10):4347-4355.
Human angiotensin type 1 receptor (hAT1R) gene is regulated by hormones, second messengers, and both pathophysiological and developmental states. The focus of the present study was to determine the role of glucose in the trans-repression of hAT1R gene transcription and to identify the functional cis-acting response element(s). Serial deletions of the hAT1R promoter region indicated that an area between –1717 and –1543 base pairs upstream of the 5′ end of the cDNA sequence has a glucose responsive regulatory element (GluRE) to down-regulate the gene expression. Further analysis revealed a putative 29-bp (5′-AACTGATTTTTGTATATTGATCTTGTATT-3′) repressor element located between –1582 and -1610 bp was necessary for transcriptional repression. Removal of this region from promoter construct abolished repression of the hAT1R gene transcription in human proximal tubule epithelial cells (hPTECs). Using mobility shift assays, we demonstrated DNA binding activity to the labeled repressor element in hPTEC nuclear extracts. Additional studies demonstrated increased DNA binding activity to the labeled repressor element in nuclear extracts treated with high glucose (25 mM). Southwestern analysis identified two GluRE binding proteins of 34 and 36 kDa in glucose-treated extracts. Glucose-induced activity of the repressor trans-acting factor(s) reached a maximum at 4 h, which correlated with decreased transcriptional activity of the hAT1R gene, suggesting that glucose can down-regulate the transcription of the hAT1R gene through the repressor element. Furthermore, insertion of the glucose response element into heterologous SV40 promoter (SV40) chloramphenicol acetyl transferase (CAT) vector showed orientation/distance-independent repression of SV40 promoter-mediated CAT activity in hPTECs. Our results show that the glucose response factor(s) acts as trans-acting factor(s) binding to the cis-acting repressor element in the hAT1R promoter, which may participate in the control of basal transcription as well as glucose-mediated transcriptional inhibition of the hAT1R gene.
PMCID: PMC519131  PMID: 15269283
Indian Journal of Clinical Biochemistry  2000;15(Suppl 1):83-100.
The dramatic advancements in the field of vaccinology has led to the formulation of chemically well defined vaccines composed of synthetic peptides and recombinant proteins derived from the immunologically dominant regions of the pathogens. Though these subunit vaccines are safer compared to the traditional vaccines they are known to be poorly immunogenic. This necessitates the use of adjuvants to enhance the immunogenicity of these vaccine formulations. The most common adjuvant for human use is alum. Research in the past has focused on the development of systemic immunity using conventional immunization protocols. In the present are, the emphasis is on the development and formulation of alternative adjuvants and delivery systems in generating systemic as well as mucosal immunity. This review mainly focuses on a variety of adjuvants (particulate as well as non-particulate) used with protective antigens of HIV, malaria, plague, leprosy using modified delivery vehicles. The experience of our laboratory and other researchers in this field clearly proves that these new age adjuvants and delivery systems undoubtedly generate enhanced immune response-both humoral and cell mediated. The choice of antigens, the nature of adjuvant used and the mode of delivery employed have a profound effect on the type of immune response generated. Besides the quantity, the quality of the antibodies generated also play a vital role in protection against these diseases. Some of the adjuvants and delivery systems used promoted high titre and affinity antibodies, which were shown to be cytophilic in nature, an important criteria in providing protection to the host. Thus the studies on these adjuvants/delivery systems with respect to various infectious diseases indicate their active role in efficient modulation of immune response along with safety and permissibility.
PMCID: PMC3454077  PMID: 23105272
vaccine; subunit; adjuvants; delivery systems

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