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Biomedical subjects

N K Mehra

Publications and source records attributed to N K Mehra.

At least 19 recordsLinked to original sources
PubMed2006

Polymorphism in L-selectin, E-selectin and ICAM-1 genes in Asian Indian pediatric patients with celiac disease.

Celiac disease (CD) follows an autoimmune course in which both genetic and environmental factors contribute to its development. A strong association with HLA class II molecules, predominantly HLA-DQ2, has been reported in most ethnic groups with CD. The aim of this study was to determine if genetic polymorphisms in L-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) have any correlation with CD. We investigated 5 mutations, namely F206L in L-selectin, S128R and L554F in E-selectin, and G241R and K469E in ICAM-1, in 37 North Indian pediatric patients with CD. A significant increase in allele frequencies of 128R of E-selectin and the associated genotype SR was observed in patients. No significant differences were observed in the F206L polymorphism of L-selectin, or the G241R and E469K polymorphisms in the ICAM-1 gene in CD. This study illustrates that selectin gene polymorphism might contribute to the genetic background of CD and invites further investigation relevant to understanding the mechanisms underlying the immunopathogenesis of this autoimmune disease.

Alleles↗
PubMed2006

Fludarabine, cyclophosphamide and horse antithymocyte globulin conditioning regimen for allogeneic peripheral blood stem cell transplantation performed in non-HEPA filter rooms for multiply transfused patients with severe aplastic anemia.

Multiply transfused patients of severe aplastic anemia are at increased risk of graft rejection. Five such patients underwent peripheral blood stem cell transplantation from HLA-identical siblings with a fludarabine-based protocol. The conditioning consisted of fludarabine 30 mg/m(2)/day x 6 days, cyclophosphamide 60 mg/kg/day x 2 days and horse antithymocyte globulin (ATG) x 4 days. Two different ATG preparations were used: ATGAM (dose 30 mg/kg/day x 4 days) or Thymogam (dose 40 mg/kg/day x 4 days). Engraftment: median time to absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range: 8-17) and median time to platelet count >20 x 10(9)/l was 11 days (range: 9-17). At a median follow-up of 171 days (range: 47-389), there has been no graft rejection and all patients are in complete remission. Acute GVHD (grade 1) occurred in one patient only. Chronic GVHD developed in two patients (extensive in one and limited in another). The transplants were performed in non-HEPA filter rooms. In only one patient, systemic antifungal therapy (voriconazole) was used. The use of Thymogam brand of ATG for conditioning is being reported for the first time. Our experience suggests that this fludarabine-based protocol allows rapid sustained engraftment in high-risk patients without significant immediate toxicity.

Adolescent↗
PubMed2006

Immunogenetic association and thyroid autoantibodies in juvenile autoimmune thyroiditis in North India.

OBJECTIVES: Autoimmune thyroid diseases (AITD) encompass a number of conditions that have in common cellular and humoral responses targeting the thyroid gland. Interactions between susceptibility genes and environmental triggers are thought to initiate an autoimmune response to thyroid antigens leading to disease manifestation. Commencement of the disease in childhood leads to the presumption that genetics may have an important role in the causation of the disease. DESIGN: The present study was aimed at evaluating the human leucocyte antigen (HLA) encoded susceptibility to develop juvenile autoimmune thyroiditis (JAT) in patients from North India. PATIENTS: We studied 48 consecutive patients of JAT along with 176 first-degree relatives for their thyroid function (FT4, TSH) and anti-thyroid peroxidase antibody status (AbTPO). MEASUREMENTS: HLA studies were carried out using serology for HLA-class I antigens and DNA analysis of HLA-class II alleles. The data were compared with a cohort of 308 ethnically matched healthy individuals. RESULTS: We observed overt hypothyroidism in 50% and AbTPO positivity in 70.8% of the index cases. Among the first-degree relatives, goitre was observed in 51.7%, thyroid dysfunction in 28.4% and AbTPO in 29.5% of individuals. Of the 37 relatives who underwent fine-needle aspiration cytology (FNAC), 60% had evidence of chronic lymphocytic thyroiditis (CLT). A strong positive association of HLA-DRB1*1404 was observed with the JAT (35.4%vs. 10.4%, chi2 = 19.8, Pc = 0.0001). We also observed a higher (72%, P = 0.03) paternal transmission of HLA-DRB1*1404 to affected offspring in comparison to unaffected offspring. HLA-DRB1*03 was also increased among JAT patients but did not reach statistical significance. CONCLUSION: These studies point towards an important role of immune modifying genes, such as HLA, in influencing susceptibility to juvenile-onset AITD.

Adolescent↗
PubMed2004

Immunological monitoring of posttransplant allograft sensitization following living related donor renal transplantation.

A better understanding of the immunobiological processes and predictors of graft rejection holds promise for development of new therapeutic strategies and also for individualization of immunosuppression. The objective of this study was to analyze the clinical relevance of immune parameters, such as recipient sensitization status, donor-specific antibodies, and anti-HLA antibodies, which are major predictors of graft outcome following renal transplantation. Sera from 264 renal recipients at different posttransplant period were included for detection of anti-donor antibodies (by flowcytometry); anti-HLA, antibody (by ELISA), and panel-reactive antibodies (PRA) by complement-dependent cytotoxicity (CDC) methods. Graft survival was analyzed in relation to posttransplant PRA at 2 years follow-up time: overall survival was significantly compromised in the highly sensitized group (group III) compared to the other two groups (overall chi2 = 24.20, P = 5.5 x 10(-06)). Flow cytometric cross-matches revealed the presence of anti-donor class I antibodies (T+) in 39 patients who had a poor graft survival of 51% compared with 85% survival in 225 antibody-negative patients. (chi2 = 22.260, P = 2.381 x 10(-.06)). Further analysis was performed based on the presence or absence of FCXM and ELISA-detected antibodies. Recipients belonging to group I (ELISA+/FCXM+) showed significantly lower graft survival (43%) compared with that observed in group II, which were essentially nonsensitized individuals (90%; P = 3.1 x 10(-08)). The graft survival in the ELISA-/FCXM+ group was 63%, which was significantly lower than that in group II (P = 5.14 x 10(-03)). Group IV (ELISA+/FCXM-) including 38 (14%) serum samples with nondonor but HLA-specific antibodies was associated with significantly poorer graft survival (63%) compared with group II (P = 6.6 x 10(-05)). Our data also show that while FCXM is the most sensitive test to detect donor-specific antibodies, the ELISA method offers the additional advantage of detecting anti-HLA class-I antibodies, which are detrimental for renal graft survival. Thus the use of multiple parameters to assess recipient immune profile can predict graft outcome more accurately thus helping the individualization and optimization of immunosuppression.

Follow-Up Studies↗
PubMed2003

Development and characterization of a novel immobilized microbial membrane for rapid determination of biochemical oxygen demand load in industrial waste-waters.

The rapid determination of waste-water quality of waste-water treatment plants in terms of pollutional strength, i.e. biochemical oxygen demand (BOD) is difficult or even impossible using the chemical determination method. The present study reports the determination of BOD within minutes using microbial BOD sensors, as compared to the 5-day determination using the conventional method. Multiple criteria establish the basis for the development of a BOD biosensor useful for rapid and reliable BOD estimation in industrial waste-waters. Of these, preparation of a suitable novel immobilized microbial membrane used in conjunction with an apt transducer is discussed. As a result, a microbial biosensor based on a formulated, synergistic, pre-tested microbial consortium has been developed for the measurement of BOD load of various industrial waste-waters. The sensor showed maximum response in terms of current difference, when a cell concentration of 2.25 x 10(10) CFU, harvested in their log phase of growth were utilized for microbial membrane construction. The sensor showed a stability of 180 days when the prepared membranes were stored at a temperature of 4 degrees C in 50 mM phosphate buffer of pH 6.8. The reusability of the immobilized membranes was up to 200 cycles without appreciable loss of their response characteristics. A linear relationship between the current change and a glucose-glutamic acid (GAA) concentration up to 60 mg l(-1) was observed (r=0.999). The lower detection limit was 1.0 mg l(-1) BOD. The sensor response was reproducible within +/-5% of the mean in a series of ten samples having 44 mg l(-1) BOD using standard a GGA solution. When used for the BOD estimation of industrial waste-waters, a relatively good agreement was found between the two methods, i.e. 5-day BOD and that measured by the developed microbial sensor.

Bacteria↗
PubMed2003

Clinical and genetic risk factors for the development of multi-drug resistant tuberculosis in non-HIV infected patients at a tertiary care center in India: a case-control study.

Genetic susceptibility of the host to multi-drug resistant tuberculosis (MDR-TB) is not fully understood. We undertook a case-control study at a tertiary care center at New Delhi, India to identify the clinical and genetic predictors of MDR-TB as compared to the drug sensitive TB cases. Patients with multi-drug resistant tuberculosis were identified on the basis of drug sensitivity testing by the proportion method. Treatment was initiated according to standard norms and all patients were followed up during the period. Genomic DNA extracted from the peripheral blood mononuclear cell pellet was used for amplification of HLA class II region (second exon) with a set of forward (5') and reverse (3') primers. A sequence specific 5' biotinylated probes were used to determine 12 DRB1, 8 DQA1 and 13 DQB1 alleles by the PCR-SSOP method. Past history of disease, higher severity of illness, inadequacy of drug treatment and presence of HLA-DRB1*14, DQB1*0503 and DQB1*0502 alleles were found to be significant risk factors for MDR-TB. Multivariate analysis identified poor past compliance to treatment (odds ratio, OR=6.6; 95% confidence interval, CI [2.0-21.5]), higher number of cavities (OR=6; 95% CI [2.1-17.3]) in chest radiographs and the presence of the HLA-DRB1*14 allele (OR=8.2; 95% CI [2.1-31.3]) as independent predictors of MDR-TB. Our results suggest that a combination of clinical and immunogenetic parameters could provide better information on drug resistance in tuberculosis with implications in therapy.

Adult↗
PubMed2002

Reconstitution of naïve T cells and type 1 function after autologous peripheral stem cell transplantation: impact on the relapse of original cancer.

BACKGROUND: Phenotypic and functional reconstitution of T cells after peripheral blood stem cell transplantation (PBSCT) and its influence on posttransplant immune status is important in terms of immune surveillance and relapse of original cancer. We investigated the relationship between the dominant immune reconstitution pathway and the immune surveillance. We also tested the cytokine bias acquired by T cells after transplantation and its possible influence on relapse of original malignancy. METHODS: Immunophenotyping of naïve and memory T cells was performed by flow cytometry on patients who underwent PBSCT for various cancers. Cytokine production by peripheral memory helper (CD4) and cytotoxic (CD8) T cells was investigated at various pretransplant and posttransplant time points with fluorescein isothiocyanate-based intracellular cytokine assay after short-term in vitro mitogenic stimulation (phorbol myristate acetate + ionomycin). Data on T-cell subsets and polarized cytokines gamma-interferon (Ifn) and interleukin 4 produced by memory T cells were compared with that of healthy controls. RESULTS: The reconstitution of naïve T cells and gamma-Ifn-producing memory cells was significantly lower in patients who experienced relapse of original cancer within 1 year of PBSCT compared to those who showed no signs of relapse even after 2 years and compared to normal subjects. The results indicate that efficient reconstitution of naïve T cells and type 1 function of memory T cells are important in maintaining T-cell repertoire diversity after PBSCT. It also confers appropriate levels of immune surveillance against diverse neoantigens that evolve from residual tumor burden. The data reveal that chemotherapy-induced thymic injuries may impair regeneration of naïve cells that result in a naivopenic state in a susceptible host. CONCLUSIONS: The study highlights the importance of naïve T-cell reconstitution and points towards cell replacement strategies for improving immune surveillance after PBSCT.

Adult↗
PubMed2002

Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes.

The role of human leukocyte antigen (HLA) DQ2 heterodimer (DQA1*0501-DQB1*0201) in presenting gluten peptides to effector T cells in celiac disease (CD) has been well documented. Because HLA-DQ2 is carried on DR3 haplotypes due to linkage disequilibrium, such haplotypes are encountered more frequently in patients with autoimmune disease. This study analyzed 35 North Indian children below 15 years of age and diagnosed to have CD as per the ESPGAN criteria, which included histopathologic alterations in duodenal biopsies, clinical response to gluten withdrawal, and presence of antiendomysial antibodies. The HLA class I and class II alleles were determined by polymerase chain reaction-sequence-specific primers, sequence-specific oligonucleotide probe, and reverse line strip molecular techniques. A statistically significant positive association of the disease with HLA-DRB1*03 (94.2% versus 22.1% in controls, chi(2) = 73.4, p = 7.54E-11), and a negative association with DRB1*15 (chi(2) = 7.4, p = 6.5E-03) and DRB1*13 alleles was observed. The HLA-DQB1*0201 was observed in all the 35 patients (100%), whereas the DQ2 heterodimer alpha(0)beta(0) occurred in 97.1% of CD patients (31.4% in double dose, 65.7% in single dose) and revealed significant deviation from healthy controls (chi(2) = 102.08, p = 7.56E-11). Further analysis revealed involvement of multiple DR3+ve haplotypes with CD in Indians, of which A26-B8-DR3 was the most common DR3 haplotype among patients (34.28%, chi(2) = 40.57, p = 2.65E-10) followed by Ax-B21-DR3 (11.4%) (chi(2) = 13.8, p = 2E-04) and the classical Caucasian haplotype A1-B8-DR3 (5.7%). The former two haplotypes are characteristic of Asian Indians and are involved in the development of CD. We conclude that the high risk DR3 haplotypes that play a crucial role in the development of CD are unique in Asian Indians. Detailed analysis of these haplotypes in Indian patients with autoimmune diseases may help understand the influence of other intervening genes within the major histocompatibility complex.

Adolescent↗
PubMed2002

Molecular diversity of the HLA-A*19 group of alleles in North Indians: possible oriental influence.

The present study aims to determine the genetic diversity of the HLA-A19 allelic family in the North Indian and Japanese populations. The HLA-A*19 group of alleles occurred at similar frequencies in North Indians and Japanese as in Caucasians. All the known serological splits of HLA-A19 were observed among the North Indians, i.e. A*33 (15.6%), A*32 (8.6%), A*31 (3.5%), A*30 (3%), A*29 (1.2%) and A*74 (0.77%), while only A*30 (0.7%), A*31 (17.6%) and A*33 (11.7%) were observed in the Japanese. High resolution analysis indicated that the A*29, A*30, A*31 and A*32 alleles were represented by only single subtypes among the North Indians while the HLA-A*33 group comprised two alleles, A*3301 (4.3%) and A*3303 (43.7%). All 15 of the HLA-A*33 positive samples from the Tamil population of South India were found to be A*3303. One novel subtype of A*33, A*3306 was also observed in the North Indian sample. Conversely, only one subtype each of A*30, A*31 and A*33 was encountered in the Japanese population, of which A*3101 and A*3303 were the most frequent (58.5% and 39%, respectively, among the HLA-A*19 group of alleles). All other subtypes of A19 were not found in the Japanese in the present study. The study suggests a significant amount of genetic admixture in the North Indian gene pool from other racial groups, with profound oriental influence.

Alleles↗
PubMed2002

Common HLA-B8-DR3 haplotype in Northern India is different from that found in Europe.

The aim of this study was to determine whether a common diabetic haplotype, including human leukocyte antigen (HLA)-B8 and HLA-DR3, in Northern India is the same haplotype as the European HLA-B8-DR3 haplotype. DNA samples from Northern Indian subjects selected on the basis of HLA-B8 and HLA-DR3 were tested for microsatellite and single nucleotide polymorphism alleles throughout the major histocompatibility complex (MHC). It was found that the Indian samples represent a conserved haplotype in which all alleles were shared by Indian subjects with HLA-B8 and HLA-DR3, but were different to those that are characteristic of the European 8.1 ancestral haplotype. The Indian and European haplotypes share HLA-B*0801, HLA-DRB1*0301 and HLA-DQB1*02 but differ for subtypes of HLA-Cw*07 and HLA-DRB3 and all central MHC alleles tested. In contrast, Indian subjects selected on the basis of HLA-B58 ( 1-17) and HLA-DR3 shared the same alleles at other MHC loci as have been described in the common Chinese haplotype with HLA-B58/17 and HLA-DR3. A third haplotype, HLA-B50/21 and HLA-DR3, was also found to be highly conserved but shares little in common with the other two HLA-DR3-containing Indian haplotypes.

Diabetes Mellitus, Type 1↗
PubMed2002

Immunogenetics of autoimmune diseases in Asian Indians.

The HLA class II molecules play a critical role in the processing and presentation of specific peptides derived from autoantigens of pancreatic beta cells or gluten for T cell scrutiny in IDDM and CD. In the present study, extended DR3-positive haplotypes associated with autoimmunity in northern Indian patients have been reported. The haplotype A26-B8-DR3 was the most common autoimmunity-favoring haplotype encountered among these patients. This association is, indeed, unique to Indian autoimmune patients, as it replaces the otherwise most commonly associated Caucasian haplotype A1-B8-DR3 (AH8.1) in this population. Further, CD patients revealed 100% association with DQB1*0201 along with DQA*0501 (97%) either in cis or trans configuration.

Asian People↗
PubMed2002

Genetic diversity in the human major histocompatibility complex: lessons for vaccination approaches to HIV infection.

The major histocompatibility complex (MHC) harbours genes that have a primary function of regulating immune responsiveness. Our data on the distribution patterns of molecular subtypes of HLA class I and II extended haplotypes in India suggest that: (1) Asian Indians have extreme diversity in the MHC region, with several novel and unique alleles and disease-associated MHC haplotypes (e.g. the autoimmune-favouring A26-B8-DR3 haplotype); (2) there have been selective environmental and microbial pressures in India that directed either the generation of novel alleles through founder effect or the expansion of other alleles due to geophysical or socio-economic barriers, and (3) Asian Indians have a unique repertoire of peptide-presenting molecules to deal with pathogen-derived autoreactive antigens. This level of polymorphism concentrated within the MHC presents a formidable obstacle to the development of peptide-based vaccines, e.g. for AIDS. Further, studies conducted by us and others have provided a genetic basis for the possible predisposition and fast progression of HIV infections in the Indian population. Since there is selective predominance of different HLA alleles and haplotypes in different populations, a dedicated global screening effort is required to develop MHC-based vaccines against infectious diseases.

Journal Article↗
PubMed2002

Influence of HLA compatibility on renal graft survival using live unrelated & cadaver donors in India.

BACKGROUND & OBJECTIVES: Living unrelated donor (LURD) renal transplantation has shown a rising trend over the last 5 yr at our center following the passing of The Transplantation of Human Organs Act by the Government of India in 1994. In this paper, the results of LURD and cadaver (CAD) donor renal transplantation are compared. We have also looked into factors that have a bearing on graft survival such as the extent of HLA mismatch (MM), infections, acute rejections (AR), donor age and sex. METHODS: A total of 42 LURD and 25 CAD renal transplants performed between March 1994 and February 1999 has been included in the study. HLA typing, panel reactive antibody (PRA) screening and T and B cell cross match assay were performed by the complement dependent cytotoxicity (CDC) method for all patients. RESULTS: The graft survival rates were generally higher in the LURD category as compared to the CAD group and were significant at 6 month period (90 vs 56%, P = 0.002). A follow up of the patients up to 60 months revealed a matching effect since the 3, 4 allele MM group had better survival rates as compared to the 5, 6 MM group. Twenty six of the 67 recipients (39%) experienced episodes of acute rejection (AR). Patients with 3, 4 MM had fewer such episodes than those with 5, 6 allele MM (P < 0.05). Of the 32 deaths, 20 were those with a functional kidney, of which 15 were caused by severe infections. INTERPRETATION & CONCLUSION: Better HLA matching ensures fewer episodes of rejection and better long term graft survival in comparison to the poorly matched grafts. The graft survival for LURD recipients was appreciably higher than that of CAD recipients.

Adult↗
PubMed2002

Biodegradation of wastewater of Najafgarh drain, Delhi using autochthonous microbial consortia : a laboratory study.

There are seventeen drains, which discharge their untreated urban and industrial wastewaters into the Delhi segment of river Yamuna. The Najafgarh drain is the first and the largest drain, and it alone contributes 1667.84 mld i.e. 60% of the total wastewater discharge into the river Yamuna and as such add 81.36 tons of BOD load per day. As per the available data approximately 95% of the wastewater of this drain is biodegradable. In the present study, an attempt has been made to reduce the BOD load and COD levels of wastewater of Najafgarh drain using autochthonous microbial consortium. During this study the raw wastewater samples were treated for 6 h time interval with different concentration of consortium. It was observed that by increasing the existing microbial population in the wastewater sample by 150-200% there is a significant decrease in BOD and COD levels. Finally, BOD/COD ratios before and after biotreatment have been analyzed to assess the efficacy of the natural consortium.

Biodegradation, Environmental↗
PubMed2001

Long-term outcome of undifferentiated spondylarthropathy.

Undifferentiated spondylarthropathy is one of the common disease subsets in the group of so-called seronegative spondarthritides. It is not exactly known how often it differentiates into ankylosing spondylitis or other well-defined disease subsets over time. The present study was designed to find out the long-term outcome in this subset. Thirty-five patients diagnosed with undifferentiated spondylarthropathy between January 1987 and December 1988 were recruited. Twenty-two (63%) of them were available for detailed assessment 11 years after the original diagnosis. Their baseline characteristics did not differ from those of the original cohort of 35 patients and were as follows: male:female ratio 19:3, median age of onset 17 years (range 8-39), and median duration of disease 8 months (range 4-24). Clinical features were enthesitis (45%) and inflammatory pain in the back (100%), buttock (77%), hip (64%), shoulder (18%), knee (82%), ankle (77%), and hand and wrists (50%). There was no restriction in spinal movement. Family history was positive in two cases. Radiologically, the only finding was grade I sacroiliitis in 17 patients (77%). Human leukocyte antigen (HLA)-B27 was positive in all. Functionally, all were in class I. During follow-up, one patient developed psoriatic skin lesions after 9 years. Uveitis developed in four patients (18%). After a median follow-up of 11 years, 15 (68%) had ankylosing spondylitis, one developed psoriatic arthritis, four remained undifferentiated, and two had natural remission. Functionally, 19 patients (86%) were in class I and three (14%) were in class III. No patient had bamboo spine, but three underwent total hip replacement. Thus, a majority of patients (68%) with undifferentiated spondylarthropathy gradually developed ankylosing spondylitis of mild severity.

Adolescent↗