saba khan - Profile on Academia.edu (original) (raw)

Papers by saba khan

Experimental Dermatology, 2007

Abstract: Human tissue kallikreins are a family of 15 trypsin- or chymotrypsin-like secreted ser... more Abstract: Human tissue kallikreins are a family of 15 trypsin- or chymotrypsin-like secreted serine proteases (KLK1–KLK15). Many KLKs have been identified in normal stratum corneum (SC) and sweat, and are candidate desquamation-related proteases.We report quantification by enzyme-linked immunosorbent assay (ELISA) of KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14 in the SC and serum of atopic dermatitis (AD) patients by ELISA, and examine their variation with clinical phenotype, correlation with blood levels of eosinophils, lactate dehydrogenase (LDH) and immunoglobulin E. The overall SC serine protease activities were also measured.In the SC of AD, all KLKs, except KLK11, were significantly elevated. The elevation of chymotrypsin-like KLK7 was predominant, compared with trypsin-like KLKs. The SC overall plasmin- and furin-like activities were significantly elevated, while trypsin- and chymotrypsin-like activities did not differ significantly. In the serum of AD patients, KLK8 was significantly elevated and KLK5 and KLK11 were significantly decreased. However, their serum levels were not modified by corticosteroid topical agents. The alterations of KLK levels in the SC of AD were more pronounced than those in the serum. KLK7 in the serum was significantly correlated with eosinophil counts in the blood of AD patients, while KLK5, KLK8 and KLK11 were significantly correlated with LDH in the serum.In conclusion, we report abnormal kallikrein levels in the SC and the serum of AD patients. KLKs might be involved in skin manifestation and/or focal/systemic inflammatory reactions in AD. Our data may contribute to a better understanding of the pathogenesis of AD.

Tumor Biology, 2005

The human kallikrein gene 10 ( KLK10 ) is a member of the kallikrein gene family on chromosome 19... more The human kallikrein gene 10 ( KLK10 ) is a member of the kallikrein gene family on chromosome 19q13.4. This gene was identifi ed by its downregulation in breast cancer, and preliminary evidence suggests that it may act as a tumor suppressor. A computer-based analysis was performed on EST and SAGE clones from the Cancer Genome Anatomy Project and other databases. Experimental verifi cation of differential expression of KLK10 in cancer was performed by PCR using gene-specifi c primers. The mRNA and EST analysis allowed the construction of the longest transcript of the gene and characterization of a 5 extension of the reported mRNA. In addition, seven new splice variants of KLK10 were identifi ed. One of these variants, named KLK10 splice variant 3 (KLK10-SV3) which starts with a novel fi rst exon, was experimentally verifi ed. This variant is predicted to encode for the same protein as the 'classical' KLK10 mRNA, since the fi rst exon is untranslated. One variant mRNA partially

Tumor Biology, 2004

Kallikreins are a family of 15 serine proteases clustered together on the long arm of chromosome ... more Kallikreins are a family of 15 serine proteases clustered together on the long arm of chromosome 19. Recent reports have linked kallikreins to malignancy. The human kallikrein gene 6 (KLK6) is a newly characterized member of the human kallikrein gene family. Recent work has focused on the possible role of this gene and its protein product as a tumor marker and its involvement in diseases of the central nervous system. In this study, we performed extensive in silico analyses of KLK6 expression from different databases using various bioinformatic tools. These data enabled us to construct and verify the longest transcript for this kallikrein, to identify several polymorphisms among published sequences and to summarize the 21 single-nucleotide polymorphisms of the gene. Our expressed sequence tag (EST) analyses suggest the existence of seven new splice variants of the gene, in addition to the already reported ones. Most of these variants were identified in libraries from cancerous tissues. KLK6 orthologues were identified from three other species with approximately 86% overall homology with rat and mouse orthologues. We also utilized several databases to compare KLK6 gene expression in normal and cancerous tissues. The serial analysis of gene expression and EST expression profiles showed upregulation of the gene in female genital (ovarian and uterine) and gastrointestinal (gastric, colon, esophageal and pancreatic) cancers. Significant downregulation was observed in breast cancers and brain tumors, in relation to their normal counterparts.

Journal of Investigative Dermatology, 2006

Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region... more Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans.

Translational Research, 2011

Lymphocyte homeostasis in type 2 diabetes mellitus (T2DM) is associated with increased susceptibi... more Lymphocyte homeostasis in type 2 diabetes mellitus (T2DM) is associated with increased susceptibility to infections. Mitochondrial oxidative stress is implicated primarily in the immune pathophysiology of diabetes; however, the molecular underpinnings of lymphocyte mitochondrial dysfunction and ensuing downstream cellular effects are hitherto unreported. Both in early diagnosed patients and patients with late complications, we observed an inverse correlation between mitochondrial DNA content in lymphocytes and hemoglobin A1 (HbA1c) levels. This relation established for the first time might serve as a general, yet direct, predictor or indicator for mitochondrial dysfunction in T2DM. Compared with controls, nuclear DNA damage response was higher (P # 0.001) in diabetic subjects with increased accumulation of phospho-ataxia-telangiectasia (ATM), g-H2AX, along with active recruitment of repair proteins (Mre11, Rad50, and Nbs1). A higher frequency (.2%) of stable chromosomal anomalies with loss of telomere integrity was observed in cases with late complications. A significant decrease (P # 0.001) in enzyme activity of complex II, III, and IV of mitochondrial respiratory chain was evident in both diabetic groups in comparison with healthy controls. Activation in the cascade of nuclear factor kappa-beta (NF-kb)-mediated feed-forward proinflammatory cytokine response was noted among T2DM subjects. Increased oxidative stress, mitochondrial membrane depolarization, activation of caspase-3, and PARP observed in diabetic groups indicated bax triggered mitochondrial mediated cellular apoptosis. Our results provide the first insights of lymphocyte mitochondrial dysfunction that might be helpful in explaining the clinical significance of immunologic perturbation observed in type 2 diabetic conditions. Our data also indicate that maneuvering through the mitochondrial function might be a viable, indirect method to modulate lymphocyte homeostasis in T2DM. (Translational Research 2011;158:344-359) Abbreviations: 8-oxo-dG ¼ 8-oxo-2 0 -deoxyguanosine; ARP ¼ aldehyde reactive probe; ATM ¼ ataxia-telangiectasia; BMI ¼ body mass index; BrdU ¼ bromo-deoxy uridine; cb ¼ chromatid break; CMH2-DCFDA ¼ 5 0 , 6 0 -chloromethyl-2, 7-dichlorodihydro-fluorescein diacetate; CRP ¼ C-reactive protein; DCF ¼ 2 0 ,7 0 -dichlorofluorescein; del ¼ deletion; dic ¼ dicentric; ELISA ¼ enzyme-linked immunosorbent assay; FACS ¼ fluorescence-activated cell sorter; FITC ¼ fluorescein-isothiocyanate; FSC ¼ forward scatter; HbA1c ¼ glycated hemoglobin; GR ¼ glutathione reductase; g-H2AX ¼ gamma histone 2AX; IFN ¼ interferon; IL ¼ interleukin; JC-1 ¼ 5-5 0 -6-6 0 -tetrachloro-1-1 0 -3-3 0 -tetraethylbenzimidazol carbocyanine iodide; MRN ¼ Mre11, Rad50, and From the Research Wing,

Virus Research, 2010

Occult HBV infections (OHBI) are often associated with poor therapeutic response and increased ri... more Occult HBV infections (OHBI) are often associated with poor therapeutic response and increased risk of developing hepatocellular carcinoma. Despite a decade of research, OHBI still remains an intricate issue and much is yet to be defined about their possible immune implications. As HBV is known to infect peripheral blood lymphocytes, the present study aimed to explore the molecular mechanisms underlying DNA damage response triggered due to OHBI in host cells. The study was divided into three groups i.e. group A (OHBI patients n = 30, viral load ≤100 IU/mL); group B (chronic HBV patients, n = 30) and group C (controls, n = 30). Peripheral blood lymphocytes were isolated and DNA damage response, apoptosis and oxidative stress were the studied parameters. A significant increase in the phosphorylation of DNA damage response proteins (ATM, ATR, H2AX and p53) in OHBI in comparison to controls suggested that OHBI induces DNA damage in peripheral blood lymphocytes and elicit a PI3 kinase mediated cellular response. In addition, increased DNA fragmentation, circulating nucleosome levels and mitochondrial membrane depolarization observed in OHBI group indicated that this damage might lead to cellular demise and immune hypo-responsiveness. Moreover, OHBI was also observed to be strongly associated with oxidative stress as suggested by the augmented levels of DCF fluorescence and depleted GR activity. Collectively, these results provide the basic knowledge about the genotoxic effects of OHBI in peripheral blood lymphocytes. Such studies may possibly open up new avenues for identifying novel therapeutic targets for viral hepatitis.

Cell Biology and Toxicology, 2010

Implications of environmental toxins on the regulation of neutrophil function are being significa... more Implications of environmental toxins on the regulation of neutrophil function are being significantly appraised. Such effects can be varied and markedly different depending on the type and extent of chemical exposure, which results in direct damage to the immune system. Isocyanates with functional group (–NCO), are considered as highly reactive molecules with diverse industrial applications. However, patho-physiological implications resulting from their occupational and accidental exposures have not been well delineated. The present study was carried out to assess the immunotoxic response of isocyanates and their mode of action at a molecular level on cultured human neutrophils isolated from healthy human volunteers. Studies were conducted to evaluate both dose- and time-dependent (n = 3) response using N-succinimidyl N-methylcarbamate, a chemical entity that mimics the effects of methyl isocyanate in vitro. Measure of apoptosis through annexin-V-FITC/PI assay, active caspase-3, apoptotic DNA ladder assay and mitochondrial depolarization; induction of oxidative stress by CM-H2DCFDA and formation of 8′-hydroxy-2′-deoxyguanosine; and levels of antioxidant defense system enzyme glutathione reductase, multiplex cytometric bead array analysis to quantify the secreted cytokine levels (interleukin-8, interleukin-1β, interleukin-6, interleukin-10, interferon-γ, tumor necrosis factor, and interleukin-12p70) parameters were evaluated. Our results demonstrate that isocyanates induce neutrophil apoptosis via activation of mitochondrial-mediated pathway along with reactive oxygen species production; depletion in antioxidant defense states; and elevated pro-inflammatory cytokine response.

Cell Biology International, 2009

The toxic response of cultured human colon epithelial-FHC cells to methyl isocyanate was investig... more The toxic response of cultured human colon epithelial-FHC cells to methyl isocyanate was investigated with regard to genomic instability. Qualitative and quantitative assessments of the extent of phosphorylation of DNA damage signaling factors such as ATM, gH2AX and p53, was increased in treated cells compared to controls. At the same time, many treated cells were arrested at the G2/M phase of the cell cycle, and had an elevated apoptotic index and increased inflammatory cytokine levels. Cytogenetic analyses revealed varied chromosomal anomalies, with abnormal expression of pericentrin protein. Analysis through ISSR PCR demonstrated increased microsatellite instability. The results imply that isocyanates can cause genomic instability in colonocytes. Ó

International Journal of Toxicology, 2011

We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic po... more We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha leaf extracts (petroleum ether, benzene, chloroform, ethyl acetate, methanol, and water extracts) on 6 human cancer (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) and normal (IMR-90, HEK-293) cell lines. Of all the extracts tested, chloroform and ethyl acetate extracts of M piperita showed significant dose-and time-dependent anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative balance, upregulation of Bax gene, elevated expression of p53 and p21 in the treated cells, acquisition of senescence phenotype, while inducing pro-inflammatory cytokines response. Our results provide the first evidence of direct anticarcinogenic activity of Mentha leaf extracts. Further, bioassay-directed isolation of the active constituents might provide basis for mechanistic and translational studies for designing novel anticancer drugs to be used alone or as adjuvant for prevention of tumor progression and/or treatment of human malignancies.

Indian Journal of Clinical Biochemistry, 2011

The present study evaluated the plausible role of circulating biomarkers in immune pathogenesis o... more The present study evaluated the plausible role of circulating biomarkers in immune pathogenesis of chronic hepatitis considered a priority in clinical hepatology. Total viral load of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) patients was quantified and correlation studies were performed with circulating levels of Th1/Th2 cytokines; C reactive protein and circulating nucleosomes; glutathione reductase (GR) and superoxide dismutase. To our knowledge, the study is first among its kind that validates strong positive correlation of viral load with IL-4, IL-6, GR in HBV and IL-6, IL-10, GR in HCV infections. Although, multi-centric studies including large cohorts are required for translating our findings to clinical practice, however, role of these biomarkers with potential diagnostic or prognostic significance might be helpful in clinical assessment of high-risk individuals, thereby, designing interventional strategies, towards development of personalized medicare. The results of our study also offer valuable insights of immune signaling mediators engaged in development of hepatocellular carcinoma.

Journal of Allergy and Clinical Immunology, 2005

RATIONALE: Asthma care is still too often suboptimal and new strategies are needed to fill the ca... more RATIONALE: Asthma care is still too often suboptimal and new strategies are needed to fill the care gaps observed in asthma management. TEAM is a multipartnership and multidisciplinary disease management program developed to optimize asthma care. METHODS: We aimed at developing A) a data retrieval process from provincial «cartographies» and cohort/intervention studies to look at variations and magnitude of asthma-related morbidity, as well as care gaps between optimal and current care, B) analysis and review process of the data obtained and C) a series of peer-reviewed outcome research studies targeting high-risk populations and specific suboptimal interventions in asthma care. The domains addressed included: promotion of objective measurements of airway obstruction, health professionals and patient education, compliance to environmental control measures and medication use, development of tools to facilitate medical practice, pharmacists interventions, physician-patient communication skills assessment and multidisciplinary integrated care. RESULTS: This program was successful to generate 2 populational cartographies of asthma-related morbidity and a physician/patient cohort analysis, in addition to more than 15 outcome research intervention projects with an evaluative component. These new data should contribute to improve interventions in order to optimize asthma management and improve patients' quality of life. CONCLUSIONS: TEAM offers an innovative approach of population aimed at improving asthma care in developing innovative strategies to address care gaps. Its feasibility was demonstrated and such model of targeted analysis/intervention has the potential to help achieve optimal care of chronic diseases. Funding: Merck RATIONALE: Despite the widespread view that children have difficulty swallowing pills, limited data are available on this capability. METHODS: This observational cohort study examined the ability of children (6-11 years) to swallow a small oral tablet. Children who were healthy or had dermatologic and/or respiratory diseases were enrolled and asked if they thought they could swallow a tablet (yes/no). Subjects were assessed for their capability for swallowing a placebo tablet (a placebo match to Allegra ® 30 mg) using an ordinary plastic cup filled with water; for those who could not swallow the pill with an ordinary cup, a patented pill cup (Promotions Unlimited, Inc) was used. Ease of swallowing was determined on a 6-point scale. RESULTS: 124 children were enrolled, with an equal distribution across age groups. Overall, 113 (91%) subjects successfully swallowed a tablet either with an ordinary cup or using a pill cup. Fifty-seven subjects (46%) initially said that they could swallow a pill and all demonstrated proficiency in pill swallowing. Of the 67 children that answered that they could not swallow a pill at the start of the study, 47 subjects (70%) successfully learned how to swallow a pill with an ordinary cup. Of the remaining 20 children who were given instructions using a pill cup, a further 45% successfully learned how to swallow a tablet. Eleven subjects (9%) did not learn with either cup.

Clinical and Experimental Allergy, 2007

Background Perennial rhinitis is common and often results in substantial, potentially avoidable, ... more Background Perennial rhinitis is common and often results in substantial, potentially avoidable, impairment of quality of life. Quality of rhinitis care has been shown to be sub-optimal in general practice. Rigorous evaluation of educational interventions for healthcare professionals using randomized controlled trials is very uncommon.Objective To evaluate the effectiveness of standardized allergy training for healthcare professionals on patients' disease-specific quality of life.Methods Patients with clinician diagnosed perennial rhinitis and/or a prescription for relevant nasal medication were recruited from general practice. Following baseline measurement of quality of life using the validated rhino-conjunctivitis questionnaire (RQLQ), patients were centrally randomized to receive care from an allergy-trained primary healthcare professional or routine care. RQLQ was measured again at 13 months after randomization.Results Process measures revealed that the training was well received. 202 patients were included in the intention-to-treat analysis and 157 in the per-protocol analysis. There was a 0.23 greater mean improvement in quality-of-life scores in the intervention group when compared with controls (P=0.08) in the intention-to-treat analysis, this increasing to a 0.3 greater mean improvement if confined to a per-protocol analysis (P=0.05). The intention-to-treat analysis showed that 39/101 (39%) in the intervention group showed a clinically significant 0.5 improvement in RQLQ compared with 28/101 (28%) of controls (risk difference=11%, number needed to treat=9, P=0.1).Conclusions Standardized allergy education given to primary healthcare professionals leads to modest improvements in disease-specific quality of life in patients with perennial rhinitis.

Journal of Allergy and Clinical Immunology, 2007

Hayfever symptoms and medication use in UK teenagers

Journal of Allergy and Clinical Immunology, 2005

Monthly Notices of The Royal Astronomical Society, 2007

In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, desc... more In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, described within the Kerr geometric framework, transonicity has been examined by setting up the governing equations of the flow as a first-order autonomous dynamical system. The consequent linearized analysis of the critical points of the flow leads to a comprehensive mathematical prescription for classifying these points, showing that the only possibilities are saddle points and centre-type points for all ranges of values of the fixed flow parameters. The spin parameter of the black hole influences the multitransonic character of the flow, as well as some of its specific critical properties. The special case of a flow in the space-time of a non-rotating black hole, characterized by the Schwarzschild metric, has also been studied for comparison and the conclusions are compatible with what has been seen for the Kerr geometric case.

Monthly Notices of The Royal Astronomical Society, 2007

In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, desc... more In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, described within the Kerr geometric framework, transonicity has been examined by setting up the governing equations of the flow as a first-order autonomous dynamical system. The consequent linearised analysis of the critical points of the flow leads to a comprehensive mathematical prescription for classifying these points, showing that the only possibilities are saddle points and centre-type points for all ranges of values of the fixed flow parameters. The spin parameter of the black hole influences the multitransonic character of the flow, as well as some of its specific critical properties. The special case of a flow in the space-time of a non-rotating black hole, characterised by the Schwarzschild metric, has also been studied for comparison and the conclusions are compatible with what has been seen for the Kerr geometric case.

Although Indonesia was the first and worst hit of countries in the region, it was the last to beg... more Although Indonesia was the first and worst hit of countries in the region, it was the last to begin receiving relief aid. Two large aftershocks on Wednesday[clarification needed] caused many residents, traumatised by their experience, to flee from the coast. Looting of food was reported throughout this northmost province of Sumatra as aid has proved slow to arrive.

Experimental Dermatology, 2007

Abstract: Human tissue kallikreins are a family of 15 trypsin- or chymotrypsin-like secreted ser... more Abstract: Human tissue kallikreins are a family of 15 trypsin- or chymotrypsin-like secreted serine proteases (KLK1–KLK15). Many KLKs have been identified in normal stratum corneum (SC) and sweat, and are candidate desquamation-related proteases.We report quantification by enzyme-linked immunosorbent assay (ELISA) of KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14 in the SC and serum of atopic dermatitis (AD) patients by ELISA, and examine their variation with clinical phenotype, correlation with blood levels of eosinophils, lactate dehydrogenase (LDH) and immunoglobulin E. The overall SC serine protease activities were also measured.In the SC of AD, all KLKs, except KLK11, were significantly elevated. The elevation of chymotrypsin-like KLK7 was predominant, compared with trypsin-like KLKs. The SC overall plasmin- and furin-like activities were significantly elevated, while trypsin- and chymotrypsin-like activities did not differ significantly. In the serum of AD patients, KLK8 was significantly elevated and KLK5 and KLK11 were significantly decreased. However, their serum levels were not modified by corticosteroid topical agents. The alterations of KLK levels in the SC of AD were more pronounced than those in the serum. KLK7 in the serum was significantly correlated with eosinophil counts in the blood of AD patients, while KLK5, KLK8 and KLK11 were significantly correlated with LDH in the serum.In conclusion, we report abnormal kallikrein levels in the SC and the serum of AD patients. KLKs might be involved in skin manifestation and/or focal/systemic inflammatory reactions in AD. Our data may contribute to a better understanding of the pathogenesis of AD.

Tumor Biology, 2005

The human kallikrein gene 10 ( KLK10 ) is a member of the kallikrein gene family on chromosome 19... more The human kallikrein gene 10 ( KLK10 ) is a member of the kallikrein gene family on chromosome 19q13.4. This gene was identifi ed by its downregulation in breast cancer, and preliminary evidence suggests that it may act as a tumor suppressor. A computer-based analysis was performed on EST and SAGE clones from the Cancer Genome Anatomy Project and other databases. Experimental verifi cation of differential expression of KLK10 in cancer was performed by PCR using gene-specifi c primers. The mRNA and EST analysis allowed the construction of the longest transcript of the gene and characterization of a 5 extension of the reported mRNA. In addition, seven new splice variants of KLK10 were identifi ed. One of these variants, named KLK10 splice variant 3 (KLK10-SV3) which starts with a novel fi rst exon, was experimentally verifi ed. This variant is predicted to encode for the same protein as the 'classical' KLK10 mRNA, since the fi rst exon is untranslated. One variant mRNA partially

Tumor Biology, 2004

Kallikreins are a family of 15 serine proteases clustered together on the long arm of chromosome ... more Kallikreins are a family of 15 serine proteases clustered together on the long arm of chromosome 19. Recent reports have linked kallikreins to malignancy. The human kallikrein gene 6 (KLK6) is a newly characterized member of the human kallikrein gene family. Recent work has focused on the possible role of this gene and its protein product as a tumor marker and its involvement in diseases of the central nervous system. In this study, we performed extensive in silico analyses of KLK6 expression from different databases using various bioinformatic tools. These data enabled us to construct and verify the longest transcript for this kallikrein, to identify several polymorphisms among published sequences and to summarize the 21 single-nucleotide polymorphisms of the gene. Our expressed sequence tag (EST) analyses suggest the existence of seven new splice variants of the gene, in addition to the already reported ones. Most of these variants were identified in libraries from cancerous tissues. KLK6 orthologues were identified from three other species with approximately 86% overall homology with rat and mouse orthologues. We also utilized several databases to compare KLK6 gene expression in normal and cancerous tissues. The serial analysis of gene expression and EST expression profiles showed upregulation of the gene in female genital (ovarian and uterine) and gastrointestinal (gastric, colon, esophageal and pancreatic) cancers. Significant downregulation was observed in breast cancers and brain tumors, in relation to their normal counterparts.

Journal of Investigative Dermatology, 2006

Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region... more Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans.

Translational Research, 2011

Lymphocyte homeostasis in type 2 diabetes mellitus (T2DM) is associated with increased susceptibi... more Lymphocyte homeostasis in type 2 diabetes mellitus (T2DM) is associated with increased susceptibility to infections. Mitochondrial oxidative stress is implicated primarily in the immune pathophysiology of diabetes; however, the molecular underpinnings of lymphocyte mitochondrial dysfunction and ensuing downstream cellular effects are hitherto unreported. Both in early diagnosed patients and patients with late complications, we observed an inverse correlation between mitochondrial DNA content in lymphocytes and hemoglobin A1 (HbA1c) levels. This relation established for the first time might serve as a general, yet direct, predictor or indicator for mitochondrial dysfunction in T2DM. Compared with controls, nuclear DNA damage response was higher (P # 0.001) in diabetic subjects with increased accumulation of phospho-ataxia-telangiectasia (ATM), g-H2AX, along with active recruitment of repair proteins (Mre11, Rad50, and Nbs1). A higher frequency (.2%) of stable chromosomal anomalies with loss of telomere integrity was observed in cases with late complications. A significant decrease (P # 0.001) in enzyme activity of complex II, III, and IV of mitochondrial respiratory chain was evident in both diabetic groups in comparison with healthy controls. Activation in the cascade of nuclear factor kappa-beta (NF-kb)-mediated feed-forward proinflammatory cytokine response was noted among T2DM subjects. Increased oxidative stress, mitochondrial membrane depolarization, activation of caspase-3, and PARP observed in diabetic groups indicated bax triggered mitochondrial mediated cellular apoptosis. Our results provide the first insights of lymphocyte mitochondrial dysfunction that might be helpful in explaining the clinical significance of immunologic perturbation observed in type 2 diabetic conditions. Our data also indicate that maneuvering through the mitochondrial function might be a viable, indirect method to modulate lymphocyte homeostasis in T2DM. (Translational Research 2011;158:344-359) Abbreviations: 8-oxo-dG ¼ 8-oxo-2 0 -deoxyguanosine; ARP ¼ aldehyde reactive probe; ATM ¼ ataxia-telangiectasia; BMI ¼ body mass index; BrdU ¼ bromo-deoxy uridine; cb ¼ chromatid break; CMH2-DCFDA ¼ 5 0 , 6 0 -chloromethyl-2, 7-dichlorodihydro-fluorescein diacetate; CRP ¼ C-reactive protein; DCF ¼ 2 0 ,7 0 -dichlorofluorescein; del ¼ deletion; dic ¼ dicentric; ELISA ¼ enzyme-linked immunosorbent assay; FACS ¼ fluorescence-activated cell sorter; FITC ¼ fluorescein-isothiocyanate; FSC ¼ forward scatter; HbA1c ¼ glycated hemoglobin; GR ¼ glutathione reductase; g-H2AX ¼ gamma histone 2AX; IFN ¼ interferon; IL ¼ interleukin; JC-1 ¼ 5-5 0 -6-6 0 -tetrachloro-1-1 0 -3-3 0 -tetraethylbenzimidazol carbocyanine iodide; MRN ¼ Mre11, Rad50, and From the Research Wing,

Virus Research, 2010

Occult HBV infections (OHBI) are often associated with poor therapeutic response and increased ri... more Occult HBV infections (OHBI) are often associated with poor therapeutic response and increased risk of developing hepatocellular carcinoma. Despite a decade of research, OHBI still remains an intricate issue and much is yet to be defined about their possible immune implications. As HBV is known to infect peripheral blood lymphocytes, the present study aimed to explore the molecular mechanisms underlying DNA damage response triggered due to OHBI in host cells. The study was divided into three groups i.e. group A (OHBI patients n = 30, viral load ≤100 IU/mL); group B (chronic HBV patients, n = 30) and group C (controls, n = 30). Peripheral blood lymphocytes were isolated and DNA damage response, apoptosis and oxidative stress were the studied parameters. A significant increase in the phosphorylation of DNA damage response proteins (ATM, ATR, H2AX and p53) in OHBI in comparison to controls suggested that OHBI induces DNA damage in peripheral blood lymphocytes and elicit a PI3 kinase mediated cellular response. In addition, increased DNA fragmentation, circulating nucleosome levels and mitochondrial membrane depolarization observed in OHBI group indicated that this damage might lead to cellular demise and immune hypo-responsiveness. Moreover, OHBI was also observed to be strongly associated with oxidative stress as suggested by the augmented levels of DCF fluorescence and depleted GR activity. Collectively, these results provide the basic knowledge about the genotoxic effects of OHBI in peripheral blood lymphocytes. Such studies may possibly open up new avenues for identifying novel therapeutic targets for viral hepatitis.

Cell Biology and Toxicology, 2010

Implications of environmental toxins on the regulation of neutrophil function are being significa... more Implications of environmental toxins on the regulation of neutrophil function are being significantly appraised. Such effects can be varied and markedly different depending on the type and extent of chemical exposure, which results in direct damage to the immune system. Isocyanates with functional group (–NCO), are considered as highly reactive molecules with diverse industrial applications. However, patho-physiological implications resulting from their occupational and accidental exposures have not been well delineated. The present study was carried out to assess the immunotoxic response of isocyanates and their mode of action at a molecular level on cultured human neutrophils isolated from healthy human volunteers. Studies were conducted to evaluate both dose- and time-dependent (n = 3) response using N-succinimidyl N-methylcarbamate, a chemical entity that mimics the effects of methyl isocyanate in vitro. Measure of apoptosis through annexin-V-FITC/PI assay, active caspase-3, apoptotic DNA ladder assay and mitochondrial depolarization; induction of oxidative stress by CM-H2DCFDA and formation of 8′-hydroxy-2′-deoxyguanosine; and levels of antioxidant defense system enzyme glutathione reductase, multiplex cytometric bead array analysis to quantify the secreted cytokine levels (interleukin-8, interleukin-1β, interleukin-6, interleukin-10, interferon-γ, tumor necrosis factor, and interleukin-12p70) parameters were evaluated. Our results demonstrate that isocyanates induce neutrophil apoptosis via activation of mitochondrial-mediated pathway along with reactive oxygen species production; depletion in antioxidant defense states; and elevated pro-inflammatory cytokine response.

Cell Biology International, 2009

The toxic response of cultured human colon epithelial-FHC cells to methyl isocyanate was investig... more The toxic response of cultured human colon epithelial-FHC cells to methyl isocyanate was investigated with regard to genomic instability. Qualitative and quantitative assessments of the extent of phosphorylation of DNA damage signaling factors such as ATM, gH2AX and p53, was increased in treated cells compared to controls. At the same time, many treated cells were arrested at the G2/M phase of the cell cycle, and had an elevated apoptotic index and increased inflammatory cytokine levels. Cytogenetic analyses revealed varied chromosomal anomalies, with abnormal expression of pericentrin protein. Analysis through ISSR PCR demonstrated increased microsatellite instability. The results imply that isocyanates can cause genomic instability in colonocytes. Ó

International Journal of Toxicology, 2011

We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic po... more We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha leaf extracts (petroleum ether, benzene, chloroform, ethyl acetate, methanol, and water extracts) on 6 human cancer (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) and normal (IMR-90, HEK-293) cell lines. Of all the extracts tested, chloroform and ethyl acetate extracts of M piperita showed significant dose-and time-dependent anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative balance, upregulation of Bax gene, elevated expression of p53 and p21 in the treated cells, acquisition of senescence phenotype, while inducing pro-inflammatory cytokines response. Our results provide the first evidence of direct anticarcinogenic activity of Mentha leaf extracts. Further, bioassay-directed isolation of the active constituents might provide basis for mechanistic and translational studies for designing novel anticancer drugs to be used alone or as adjuvant for prevention of tumor progression and/or treatment of human malignancies.

Indian Journal of Clinical Biochemistry, 2011

The present study evaluated the plausible role of circulating biomarkers in immune pathogenesis o... more The present study evaluated the plausible role of circulating biomarkers in immune pathogenesis of chronic hepatitis considered a priority in clinical hepatology. Total viral load of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) patients was quantified and correlation studies were performed with circulating levels of Th1/Th2 cytokines; C reactive protein and circulating nucleosomes; glutathione reductase (GR) and superoxide dismutase. To our knowledge, the study is first among its kind that validates strong positive correlation of viral load with IL-4, IL-6, GR in HBV and IL-6, IL-10, GR in HCV infections. Although, multi-centric studies including large cohorts are required for translating our findings to clinical practice, however, role of these biomarkers with potential diagnostic or prognostic significance might be helpful in clinical assessment of high-risk individuals, thereby, designing interventional strategies, towards development of personalized medicare. The results of our study also offer valuable insights of immune signaling mediators engaged in development of hepatocellular carcinoma.

Journal of Allergy and Clinical Immunology, 2005

RATIONALE: Asthma care is still too often suboptimal and new strategies are needed to fill the ca... more RATIONALE: Asthma care is still too often suboptimal and new strategies are needed to fill the care gaps observed in asthma management. TEAM is a multipartnership and multidisciplinary disease management program developed to optimize asthma care. METHODS: We aimed at developing A) a data retrieval process from provincial «cartographies» and cohort/intervention studies to look at variations and magnitude of asthma-related morbidity, as well as care gaps between optimal and current care, B) analysis and review process of the data obtained and C) a series of peer-reviewed outcome research studies targeting high-risk populations and specific suboptimal interventions in asthma care. The domains addressed included: promotion of objective measurements of airway obstruction, health professionals and patient education, compliance to environmental control measures and medication use, development of tools to facilitate medical practice, pharmacists interventions, physician-patient communication skills assessment and multidisciplinary integrated care. RESULTS: This program was successful to generate 2 populational cartographies of asthma-related morbidity and a physician/patient cohort analysis, in addition to more than 15 outcome research intervention projects with an evaluative component. These new data should contribute to improve interventions in order to optimize asthma management and improve patients' quality of life. CONCLUSIONS: TEAM offers an innovative approach of population aimed at improving asthma care in developing innovative strategies to address care gaps. Its feasibility was demonstrated and such model of targeted analysis/intervention has the potential to help achieve optimal care of chronic diseases. Funding: Merck RATIONALE: Despite the widespread view that children have difficulty swallowing pills, limited data are available on this capability. METHODS: This observational cohort study examined the ability of children (6-11 years) to swallow a small oral tablet. Children who were healthy or had dermatologic and/or respiratory diseases were enrolled and asked if they thought they could swallow a tablet (yes/no). Subjects were assessed for their capability for swallowing a placebo tablet (a placebo match to Allegra ® 30 mg) using an ordinary plastic cup filled with water; for those who could not swallow the pill with an ordinary cup, a patented pill cup (Promotions Unlimited, Inc) was used. Ease of swallowing was determined on a 6-point scale. RESULTS: 124 children were enrolled, with an equal distribution across age groups. Overall, 113 (91%) subjects successfully swallowed a tablet either with an ordinary cup or using a pill cup. Fifty-seven subjects (46%) initially said that they could swallow a pill and all demonstrated proficiency in pill swallowing. Of the 67 children that answered that they could not swallow a pill at the start of the study, 47 subjects (70%) successfully learned how to swallow a pill with an ordinary cup. Of the remaining 20 children who were given instructions using a pill cup, a further 45% successfully learned how to swallow a tablet. Eleven subjects (9%) did not learn with either cup.

Clinical and Experimental Allergy, 2007

Background Perennial rhinitis is common and often results in substantial, potentially avoidable, ... more Background Perennial rhinitis is common and often results in substantial, potentially avoidable, impairment of quality of life. Quality of rhinitis care has been shown to be sub-optimal in general practice. Rigorous evaluation of educational interventions for healthcare professionals using randomized controlled trials is very uncommon.Objective To evaluate the effectiveness of standardized allergy training for healthcare professionals on patients' disease-specific quality of life.Methods Patients with clinician diagnosed perennial rhinitis and/or a prescription for relevant nasal medication were recruited from general practice. Following baseline measurement of quality of life using the validated rhino-conjunctivitis questionnaire (RQLQ), patients were centrally randomized to receive care from an allergy-trained primary healthcare professional or routine care. RQLQ was measured again at 13 months after randomization.Results Process measures revealed that the training was well received. 202 patients were included in the intention-to-treat analysis and 157 in the per-protocol analysis. There was a 0.23 greater mean improvement in quality-of-life scores in the intervention group when compared with controls (P=0.08) in the intention-to-treat analysis, this increasing to a 0.3 greater mean improvement if confined to a per-protocol analysis (P=0.05). The intention-to-treat analysis showed that 39/101 (39%) in the intervention group showed a clinically significant 0.5 improvement in RQLQ compared with 28/101 (28%) of controls (risk difference=11%, number needed to treat=9, P=0.1).Conclusions Standardized allergy education given to primary healthcare professionals leads to modest improvements in disease-specific quality of life in patients with perennial rhinitis.

Journal of Allergy and Clinical Immunology, 2007

Hayfever symptoms and medication use in UK teenagers

Journal of Allergy and Clinical Immunology, 2005

Monthly Notices of The Royal Astronomical Society, 2007

In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, desc... more In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, described within the Kerr geometric framework, transonicity has been examined by setting up the governing equations of the flow as a first-order autonomous dynamical system. The consequent linearized analysis of the critical points of the flow leads to a comprehensive mathematical prescription for classifying these points, showing that the only possibilities are saddle points and centre-type points for all ranges of values of the fixed flow parameters. The spin parameter of the black hole influences the multitransonic character of the flow, as well as some of its specific critical properties. The special case of a flow in the space-time of a non-rotating black hole, characterized by the Schwarzschild metric, has also been studied for comparison and the conclusions are compatible with what has been seen for the Kerr geometric case.

Monthly Notices of The Royal Astronomical Society, 2007

In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, desc... more In a stationary, general relativistic, axisymmetric, inviscid and rotational accretion flow, described within the Kerr geometric framework, transonicity has been examined by setting up the governing equations of the flow as a first-order autonomous dynamical system. The consequent linearised analysis of the critical points of the flow leads to a comprehensive mathematical prescription for classifying these points, showing that the only possibilities are saddle points and centre-type points for all ranges of values of the fixed flow parameters. The spin parameter of the black hole influences the multitransonic character of the flow, as well as some of its specific critical properties. The special case of a flow in the space-time of a non-rotating black hole, characterised by the Schwarzschild metric, has also been studied for comparison and the conclusions are compatible with what has been seen for the Kerr geometric case.

Although Indonesia was the first and worst hit of countries in the region, it was the last to beg... more Although Indonesia was the first and worst hit of countries in the region, it was the last to begin receiving relief aid. Two large aftershocks on Wednesday[clarification needed] caused many residents, traumatised by their experience, to flee from the coast. Looting of food was reported throughout this northmost province of Sumatra as aid has proved slow to arrive.