Search PubMed⌕ Search

Biomedical subjects

P Das

Publications and source records attributed to P Das.

At least 73 records · Page 4Linked to original sources
PubMed2000

Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site.

In situ immune infiltrates in lesional, perilesional, and nonlesional skin biopsies from patients with vitiligo were analyzed by immunohistochemistry and compared with immune infiltrates found in the skin of normal healthy donors and relevant disease controls. An increased influx of activated skin-homing T cells and macrophages were seen in the perilesional biopsies. The overall percentages of cutaneous leukocyte-associated antigen-positive (CLA+) T cells were similar to those found in normal healthy donors. This is compatible with the similar expression of E-selectin. Most strikingly, however, the CLA+ T cells in perilesional skin were mainly clustered in the vicinity of disappearing melanocytes, and 60% to 66% of these interacting T cells expressed perforin and granzyme-B. The perforin+/granzyme-B+ cells were not seen in locations different from that of disappearing melanocytes. Interestingly, the majority of the infiltrating T cells were HLA-DR/CD8+. Another hallmark of the present study is the focal expression of intercellular adhesion molecule (ICAM)-1 and HLA-DR in the epidermis at the site of interaction between the immune infiltrates and the disappearing melanocytes. The data presented in this study are consistent with a major role for skin-homing T cells in the death of melanocytes seen in vitiligo.

Adult↗
PubMed2000

The patient with a systolic murmur: severe aortic stenosis may be missed during cardiovascular examination.

Significant aortic stenosis is prevalent amongst elderly people. It may be subclinical, manifesting only as a murmur, but can still cause unexpected death with little warning after symptoms develop. Recent studies have highlighted the unreliability of the classical clinical signs of severe aortic stenosis, leading to concern that some patients may not be referred appropriately for echocardiography. Here, we review the evidence for the accuracy of each sign. We suggest that the assessment of the patient with a systolic murmur should be reappraised, and offer guidelines toward improving the recognition of aortic stenosis in the community.

Aged↗
PubMed2000

Clinical, radiographic, and genetic evaluation of a novel form of autosomal-dominant oligodontia.

A frameshift mutation recently identified within the paired domain of the transcription factor, PAX9, has been linked to a unique form of oligodontia in a single, multigenerational family (Stockton et al., 2000). We now describe the phenotypic and segregation analyses of this remarkable kindred, the initial approach taken to identify a candidate gene involved in this form of oligodontia, and the power of this single-family pedigree to generate significant linkage in a genome search. Of the 43 family members enrolled in this study, 21 individuals were affected with several congenitally missing permanent teeth. The pattern of inheritance of the oligodontia trait suggested the involvement of a single gene bearing a dominant mutation. To various degrees, affected members lacked permanent first, second, and third molars in all four quadrants. Several individuals with missing molars also lacked second premolars- most commonly, maxillary second premolars and mandibular central incisors. To the best of our knowledge, this pattern of non-syndromic, familial tooth agenesis has not been previously described in the literature. Since a missense mutation in the homeobox gene, MSX1, was previously linked to tooth agenesis in a single family lacking second premolars and third molars, we performed a mutational analysis of MSX1 by PCR. The absence of a mutation in exons 1 and 2 of MSX1 suggested that allelic mutations in the coding region of MSX1 are not associated with this phenotypically distinct form of oligodontia. Computer simulation of linkage analysis further proved that this pedigree alone was sufficient to generate a significant result for a total genome scan.

Adolescent↗
PubMed2000

Effects of shear stress on articular chondrocyte metabolism.

The articular cartilage of diarthrodial joints experiences a variety of stresses, strains and pressures that result from normal activities of daily living. In normal cartilage, the extracellular matrix exists as a highly organized composite of specialized macromolecules that distributes loads at the bony ends. The chondrocyte response to mechanical loading is recognized as an integral component in the maintenance of articular cartilage matrix homeostasis. With inappropriate mechanical loading of the joint, as occurs with traumatic injury, ligament instability, bony malalignment or excessive weight bearing, the cartilage exhibits manifestations characteristic of osteoarthritis. Breakdown of cartilage in osteoarthritis involves degradation of the extracellular matrix macromolecules and decreased expression of chondrocyte proteins necessary for normal joint function. Osteoarthritic cartilage often exhibits increased amounts of type I collagen and synthesis of proteoglycans characteristic of immature cartilage. The shift in cartilage phenotype in response to altered load yields a matrix that fails to support normal joint function. Mathematical modeling and experimental studies in animal models confirm an association between altered loading of diarthrotic joints and arthritic changes. Both types of studies implicate shear forces as a critical component in the destructive profile. The severity of cartilage destruction in response to altered loads appears linked to expression of biological factors influencing matrix integrity and cellular metabolism. Determining how shear stress alters chondrocyte metabolism is fundamental to understanding how to limit matrix destruction and stimulate cartilage repair and regeneration. At present, the precise biochemical and molecular mechanisms by which shear forces alter chondrocyte metabolism from a normal to a degenerative phenotype remain unclear. The results presented here address the hypothesis that articular chondrocyte metabolism is modulated by direct effects of shear forces that act on the cell through mechanotransduction processes. The purpose of this work is to develop critical knowledge regarding the basic mechanisms by which mechanical loading modulates cartilage metabolism in health and disease. This presentation will describe the effects of using fluid induced shear stress as a model system for stimulation of articular chondrocytes in vitro. The fluid induced shear stress was applied using a cone viscometer system to stimulate all the cells uniformly under conditions of minimal turbulence. The experiments were carried using high-density primary monolayer cultures of normal and osteoarthritic human and normal bovine articular chondrocytes. The analysis of the cellular response included quantification of cytokine release, matrix metalloproteinase expression and activation of intracellular signaling pathways. The data presented here show that articular chondrocytes exhibit a dose- and time-dependent response to shear stress that results in the release of soluble mediators and extracellular matrix macromolecules. The data suggest that the chondrocyte response to mechanical stimulation contributes to the maintenance of articular cartilage homeostasis in vivo.

Adult↗
PubMed2000

When is an aortic valve prosthesis too small? The need for dobutamine stress echocardiography.

We describe a patient who had undergone aortic valve replacement with a small prosthesis 10 years previously and who presented with exertional breathlessness. The resting transaortic pressure gradient was only 30 mmHg but increased to 165 mmHg on dobutamine stress. Conventional resting echocardiography may fail to demonstrate abnormal prosthetic aortic valve function; in the presence of symptoms, dobutamine stress echocardiography should be considered.

Adult↗
PubMed2000

Vitamin A mediated limb deformities in the common Indian toad, Bufo melanostictus (Schneider).

Several types of limb deformities were induced by vitamin A in B. melanostictus. These ranged from total suppression of all the limbs (ectromelia) to partial development of either the forelimb or the hindlimb or both (mesomelia) to reduction or absence of digits in either the forelimbs or hindlimbs or both and absence of long bones in either the forelimbs or hindlimbs or both (phocomelia) or duplication of the hindlimbs (polymelia). All the limb abnormalities were induced in the developing limbs of the tail amputated tadpoles of B. melanostictus following vitamin A treatment, which is all the more interesting. The results suggest that vitamin A induces the above mentioned abnormalities by either switching on or over-expressing or disrupting the limb-specific hox genes by yet unknown mechanisms.

Abnormalities, Drug-Induced↗
PubMed2000

HLA transgenic mice as models of human autoimmune diseases.

MHC class II alleles have been linked to several human autoimmune diseases such as rheumatoid arthritis (RA), Type I diabetes, and multiple sclerosis (MS). Although the mechanisms by which expression of certain MHC class II molecules predispose an individual to a particular autoimmune disease are not known, it is clear that increased susceptibility is associated with the polymorphic regions unique to these predisposing HLA alleles. These polymorphic differences may influence susceptibility by selecting potential autoreactive T cells during thymic education. Alternatively, nonsusceptible alleles may either delete or fail to select these potential autoimmune T cells, thus reducing the possibility of developing disease. In the periphery, the unique specificity of the HLA molecule derived from a susceptible allele may then recognize and present an autoantigenic peptide or foreign peptide that may cross-react with an autoantigen, activating these autoreactive T cells and leading to disease. To dissect these possibilities and to determine the exact role of particular HLA-DR or DQ molecules in disease susceptibility, we have generated several lines of HLA-DR and DQ transgenic mice. In this review, we present data summarizing the functions of these HLA class II molecules using well-established mouse models for autoimmune diseases.

Animals↗
PubMed1999

Hemizygosity for the COP9 signalosome subunit gene, SGN3, in the Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with an interstitial deletion of chromosome band 17p11.2. The critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA. Here we report the localization and partial characterization of the gene for subunit 3 of the COP9 signalosome, SGN3. SGN3 maps to the distal portion of the SMS critical interval, between SREBF1 and cCI17-638. We assessed the potential effect of haploinsufficiency of SGN3 in SMS patient lymphoblastoid cell lines through transfection studies and western analysis. Our results indicate that the COP9 signalosome assembles properly in these cells and appears to have normal expression and a kinase function intact. However, because the role of the COP9 signalosome in embryogenesis or differentiation is still uncertain, we cannot rule out the involvement of this gene in the Smith-Magenis syndrome.

Abnormalities, Multiple↗
PubMed1999

Intermolecular interactions of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase.

The regulatory subunit of phosphatidylinositol 3-kinase, p85, contains a number of well defined domains involved in protein-protein interactions, including an SH3 domain and two SH2 domains. In order to investigate in detail the nature of the interactions of these domains with each other and with other binding partners, a series of deletion and point mutants was constructed, and their binding characteristics and apparent molecular masses under native conditions were analyzed. The SH3 domain and the first proline-rich motif bound each other, and variants of p85 containing the SH3 and BH domains and the first proline-rich motif were dimeric. Analysis of the apparent molecular mass of the deletion mutants indicated that each of these domains contributed residues to the dimerization interface, and competition experiments revealed that there were intermolecular SH3 domain-proline-rich motif interactions and BH-BH domain interactions mediating dimerization of p85alpha both in vitro and in vivo. Binding of SH2 domain ligands did not affect the dimeric state of p85alpha. Recently, roles for the p85 subunit have been postulated that do not involve the catalytic subunit, and if p85 exists on its own we propose that it would be dimeric.

Amino Acid Sequence↗
PubMed1999

Integrated approach to prediction of cervical intra-epithelial neoplasia status through a case-control study.

A case-control study on cervical intra-epithelial neoplasia (CIN) was carried out on 398 subjects in the state of West Bengal, India. These samples were taken from mass screening programs organized by the authors, maintaining the uniformity of sampling to the extent possible. The cervical smears were tested by the Papanicolaou (PAP) method, following the Bethesda system for reporting of CIN status. Odds ratios and correlation coefficients among different variables, assumed to produce carcinoma of the cervix, show that 6 out of 11 variables, i.e., age, education, socio-economic status, duration of marriage, age at marriage and body surface, are associated with CIN. Multivariate analysis of logistic regression was carried out using BMDP-LR with dichotomized response variables considering CIN (0 and 1) in one group and CIN (2 and 3) in the other group. The outcome of the analysis indicated that age and educational level are 2 contributing factors for CIN. The percentage of correct classification in this analysis has improved to 74.5%, with a probability of 0.90. Polychotomous regression analysis was carried out using BMDP-PR in the next step. This analysis showed that parity was a contributing factor, in addition to age and educational level. These 3 factors provide a predictive model for identifying the high-risk group in a rational way. This approach would restrict screening to approximately 10% of the population. Subsequently, the model has been validated in a confirmatory trial among 85 new cases and was found to work satisfactorily.

Adult↗
PubMed1999

Induction of sister chromatid exchanges and chromosome aberrations in vivo in Etroplus suratensis (Bloch) following exposure to organophosphorus pesticides.

The genotoxic potential of methyl parathion and phosphamidon, two commercial formulations of organophosphorus pesticides, was evaluated through induction of sister chromatid exchanges (SCE) and chromosome aberrations in fish gill tissues. Fishes exposed to the medium containing 0.05, 0.1 and 0.2 ppm of methyl parathion or 0.5, 1.0, and 2.0 ppm of phosphamidon for a duration of 96 h revealed significant increase in the number of SCE and chromosome aberrations against control values. This demonstrates the feasibility of the fish in vivo system in detecting genotoxic potential of pollutants.

Animals↗
PubMed1999

The SH3 and BH domains of the p85alpha adapter subunit play a critical role in regulating class Ia phosphoinositide 3-kinase function.

We have investigated the role of the SH3 and BH domains in the function of the p85alpha adapter/regulatory subunit of PI 3-kinase. In these studies epitope-tagged adapter subunit constructs containing wild-type p85alpha, p85alpha lacking the SH3 domain (deltaSH3-p85alpha), or p85alpha lacking the Rac-GAP/BCR homology (BH) domain (deltaBH-p85alpha) were coexpressed with either the p110alpha or p110beta PI 3-kinase catalytic subunit in HEK293 cells. The deletion of either BH or SH3 domains had no effect on the intrinsic activity of the PI 3-kinase heterodimers. However, the ability of activated Rac to stimulate PI 3-kinase activity was only observed in heterodimers containing the p85alpha and deltaSH3-p85alpha, indicating that rac binding to the BH domain is responsible for rac-induced stimulation of class Ia PI 3-kinase. We also investigated the effect of SH3 and BH domain deletion on the ability of insulin to induce recruitment of these constructs into phosphotyrosine-containing signaling complexes. We find that p85alpha expressed alone is poorly recruited into such signaling complexes. However, when coexpressed with catalytic subunit, the p85alpha adapter subunit is recruited to an extent similar to that of endogenous p85alpha. Maximal insulin stimulation caused a similar level of recruitment of p85alpha, deltaSH3-p85alpha, and deltaBH-p85alpha to signaling complexes when these adapter subunits were coexpressed with catalytic subunit. However, there was a higher level of basal association of the deltaSH3-p85alpha and deltaBH-p85alpha with tyrosine-phosphorylated proteins, meaning that the insulin-induced fold increase in recruitment was lower for these forms of the adapter. These results indicate that the N-terminal domains of p85alpha play a critical role in the way the adapter subunit responds to growth factor stimulation.

Amino Acid Sequence↗
PubMed1999

Immunohistological analysis of in situ expression of mycobacterial antigens in skin lesions of leprosy patients across the histopathological spectrum. Association of Mycobacterial lipoarabinomannan (LAM) and Mycobacterium leprae phenolic glycolipid-I (PGL-I) with leprosy reactions.

The presence of mycobacterial antigens in leprosy skin lesions was studied by immunohistological methods using monoclonal antibodies (MAbs) to Mycobacterium leprae-specific phenolic glycolipid I (PGL-I) and to cross-reactive mycobacterial antigens of 36 kd, 65 kd, and lipoarabinomannan (LAM). The staining patterns with MAb to 36 kd and 65 kd were heterogeneous and were also seen in the lesions of other skin diseases. The in situ staining of PGL-I and LAM was seen only in leprosy. Both antigens were abundantly present in infiltrating macrophages in the lesions of untreated multibacillary (MB) patients, whereas only PGL-I was occasionally seen in scattered macrophages in untreated paucibacillary lesions. During treatment, clearance of PGL-I from granulomas in MB lesions occurred before that of LAM, although the former persisted in scattered macrophages in some treated patients. This persistence of PGL-I in the lesions paralleled high serum anti-PGL-I antibody titers but was not indicative for the presence of viable bacilli in the lesions. Interestingly, we also observed a differential expression pattern of PGL-I and LAM in the lesions of MB patients with reactions during the course of the disease as compared with those without reactions. In conclusion, the in situ expression pattern of PGL-I and LAM in MB patients may assist in early diagnosis of reactions versus relapse.

Antibodies, Bacterial↗
PubMed1999

An HLA-DRB1*0402 derived peptide (HV3 65-79) prevents collagen-induced arthritis in HLA-DQ8 transgenic mice.

On the basis of our studies with HLA class II transgenic mice, we had proposed that complementation of HLA-DQ and HLA-DR alleles may determine both disease susceptibility and severity in rheumatoid arthritis (RA). According to our model, certain HLA-DQ alleles, such as HLA-DQ8, predispose individuals to RA, while a self-peptide derived from the third hypervariable region (HV3 65-79) of HLA-DR alleles, such as DRB 1*0402, can protect from disease if presented by the DQ molecule. To test this hypothesis, we examined the immunomodulatory effects of the DRB1*0402 derived peptide (HV3 65-79) on collagen-induced arthritis (CIA) in HLA-DQ8 mice. Co-immunization of the DRB 1*0402 peptide significantly reduced the severity of arthritis (mean score = 1.5+/-0.6 vs 5.2+/-1.4 in controls), whereas multiple doses of the peptide reduced the incidence of disease (3.5% vs 35-60% in controls). Subsequent analysis revealed that the DRB1*0402 peptide mediated protection may be due to the generation of a subset of regulatory cells, which down-regulate collagen-specific pro-inflammatory responses. These results provide additional insights towards understanding the role of MHC class II molecules in RA predisposition.

Amino Acid Sequence↗