Biomedical subjects

S M Alam

Publications and source records attributed to S M Alam.

At least 37 records · Page 2Linked to original sources

PubMed1998

Posttranslational regulation of TCR Valpha allelic exclusion during T cell differentiation.

We have previously shown that phenotypic allelic exclusion of TCR alpha-chain is functional only in mature thymocytes. A significant proportion of immature thymocytes (TCRlow) express more than one cell surface alpha-chain, but mature thymocytes (TCRhigh) show phenotypic allelic exclusion and express only a single alpha-chain. We have analyzed thymocytes for both surface and intracellular alpha-chain expression and find that the majority of mature thymocytes express a second alpha-chain intracellularly. This result is predicted by a model in which the developmentally regulated allelic exclusion of the TCR alpha-chain is caused by competition between alpha-chains for the beta-chain rather than by models in which one alpha-chain is down-regulated or in which selection favors cells with only a single alpha-chain species. Changes in the relative amounts of alpha- and beta-chains available for pairing may therefore allow competition between the two alpha-chains for the beta-chain. Peripheral T cells also frequently express second alpha-chains in the cytoplasm (18-27%), despite a rather low frequency of dual alpha-chain expression on the cell surface (2-4%). The frequency of nonsurface expressed alpha-chains is reduced somewhat compared with thymocytes, indicating that an additional level of control of allelic exclusion operates during the maturation of peripheral T cells.

Alleles↗

PubMed1997

Partial-area method in bioequivalence assessment: naproxen.

Regulatory authorities require demonstration of bioequivalence through comparisons of different pharmacokinetic parameters, the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax), and the time to reach peak concentration (Tmax). The applicability and validity of regulatory requirements have been widely criticized on statistical and clinical relevance grounds. For most noncomplicated absorption models, the AUC correlates well with the extent of absorption. However, in nonlinear models of absorption, in mechanisms involving recycling of drugs, and for drugs with long half-life, the use of total AUC (from zero to infinity) can give erroneous and clinically irrelevant results since the area is mostly determined by elimination phase or by recycling. The calculation of total AUC also involves prolonged sampling, adding to the cost and risks associated with bioequivalence studies. The use of Cmax or Tmax as a measure of rate of absorption, to correlate with clinical relevance, is widely criticized on logical, technical, and statistical grounds. For drugs used on a multiple-dose basis, Cmax and Tmax evaluations become redundant since the average plateau concentration is not affected by these parameters. To resolve the drawbacks in the traditional methodology of bioequivalence evaluation, the use of partial areas in lieu of total AUC, Tmax, and Cmax is suggested. This study investigates the logic and robustness of the partial-area method in establishing bioequivalence. We conclude that the 5h AUC is a more relevant parameter to establish naproxen bioequivalence than AUCinf. We recommend against using symmetrical confidence intervals and report excellent agreement among several methods of calculating confidence intervals, probability values, and nonparametric tests. We suggest that a single-point short-term AUC is a better indicator of the bioequivalence of generic products than the total AUC, Cmax, and Tmax as required currently by the regulatory authorities.

Adult↗

PubMed1996

T-cell-receptor affinity and thymocyte positive selection.

Development of thymocytes involves two distinct outcomes resulting from superficially similar events. Recognition by thymocytes of major histocompatibility complex (MHC) proteins plus peptides leads to their rescue from apoptosis (positive selection), and recognition of antigenic peptide induces cell death (negative selection). Antigen analogues, and sometimes low concentrations of antigenic peptide, induce positive selection; such analogues are often antagonists of mature T-cell clones. Various models seek to explain how recognition of different peptide/MHC complexes leads to such different outcomes: quantitative models relate response to the affinity, avidity or kinetics of T-cell-antigen receptor (TCR) binding, whereas qualitative models require conformational or spatial changes in the TCR or associated molecules to modulate signal transduction. We have used surface plasmon resonance to measure the kinetics of TCR interactions with positively and negatively selecting ligands to distinguish between these models, and find that affinity correlates to the outcome of selection. A 'window' of affinity resulting in positive selection extends over a 1-log range starting threefold below the affinity for negative selection.

Amino Acid Sequence↗

PubMed1996

Dose dependent pharmacokinetics of naproxen in man.

The pharmacokinetics of one of the most widely used non-steroidal antiinflammatory drugs, naproxen, were studied in 28 healthy human volunteers at the two most commonly used dose levels, viz., 250 mg and 500 mg, in a cross-over design. The plasma levels of naproxen were analysed by a modified high-pressure liquid chromatography method. The plasma concentrations at higher doses were not proportional to dose, indicating a non-linearity in the pharmacokinetics at the dose levels studied; this finding is new since earlier studies had studied only higher doses and assumed that at lower doses the pharmacokinetics would be linear. There was, however, no significant difference in the elimination half-life (rate constant), time to reach peak concentration (Cmax), mean residence time (MRT), or area under first moment curve (AUMC). The clearance and distribution volume of naproxen were substantially increased at higher dose resulting in statistically lower proportional concentration and the total area under the curve (AUC). These observations are explained on the basis of a change in the plasma protein binding resulting in more free naproxen available for quicker clearance and wider penetration into tissues. These findings have several important clinical implications for the long-term use of naproxen as an antiarthritic drug. It is proposed that the clinical efficacy of naproxen can be increased and side-effects reduced by giving it in small divided doses instead of large doses.

Adult↗

PubMed1996

Enzymatic activities of some snake venoms from families Elapidae and Viperidae.

Alkaline phosphomonoesterase, phosphodiesterase, L-amino acid oxidase, hyaluronidase, 5'-nucleotidase, arginine ester hydrolase, phospholipase A2 and proteinase activities were determined in eight snake venoms, including three from sea snake, of families Elapidae and Viperidae from Pakistan. The species includes three sea snakes Hydrophis cyanocinctus, Enhydrina schsitosa, Microcephalophis gracilis gracilis and two land snakes Naja naja naja, Bungarus caeruleus of family Elapidae while three land snakes Vipera russelli russelli, Echis carinatus and Eristocophis macmahoni of family Viperidae. The venoms of family Elapidae are characterized by low levels to traces of proteinase, L-amino acid oxidase and arginine ester hydrolase activities with the exception of Naja naja naja and a moderate to high levels of phospholipase A2 activities. The venoms of family Viperidae, on the other hand, are characterized by the presence of moderate to high levels of 5'-nucleotidase, proteinase, phosphodiesterase and phosphomonoesterase activities.

Journal Article↗

PubMed1995

Allelic exclusion of mouse T cell receptor alpha chains occurs at the time of thymocyte TCR up-regulation.

We report a detailed analysis of TCR V alpha and V beta chain expression on immature versus mature thymocytes of normal, TCR beta-transgenic, and TCR alpha-hemizygous mice. Chain pairing between TCR V alpha and V beta chains is random on immature thymocytes, but individual chain pairs are selected in mature thymocytes. This indicates that V alpha-V beta chain pairing preferences are determined during thymic selection, and not as a result of structural constraints. Dual V alpha chain expression is found frequently on immature, but not mature thymocytes. It is not found in TCR alpha-hemizygous mice, showing that cell surface expression of dual alpha chains is caused by lack of allelic exclusion in immature thymocytes. Down-regulation of one of the alpha chains occurs concurrently with differentiation from TCRlo, CD69- to TCRhi, CD69+ phenotype, suggesting that it is associated with positive selection of the functional TCR.

Alleles↗

PubMed1995

Selection of TCR V alpha by MHC class II predicts superantigen reactivity.

Recognition of superantigens by T cells predominantly involves the TCR V beta region. The contribution of reactivity from the non-V beta portion of the TCR remains less clear. We have investigated the V alpha repertoire of T cells bearing one V beta element responding to different superantigen or polyclonal stimuli. The data indicate that the V alpha chain is not directly involved in superantigen recognition, since unrelated superantigens do not stimulate cells bearing different V alpha elements. Instead, analysis of V alpha elements used preferentially in the CD4+ or CD8+ cells, shows that the V alpha-regions predominating in the superantigen response are the same V alphas that are positively selected into the CD4+ lineage. Thus the ability of a V alpha-region to either aid or hinder the interaction with class II predicts its frequency in a superantigen-responding population of T cells.

Animals↗

PubMed1995

Effects of drugs against cytotoxic compoundsfrom marine animals iv-hepatotoxic activity ofsea-snake hydrophis cyanocinctus venom.

Hepatotoxic activity and pathogenesis of sea snake Hydrophis cyanocinctus venom have been studied in guinea pigs and albino rats by histopathological examination and determining total Ca(2+). Concentration in liver tissue. Efficacy of two Ca(2+). antagonist drugs, verapamil and diltiazem was also studied against the cytotoxic activity of this venom. Administration of both lethal and sublethal doses of Hydrophis cyancinctus crude venom induced increased cellularity within the portal area in liver accompanied by increased tissue Ca(2+) concentration. This elicit a close correlation between tissue necrosis and increased Ca(2+) content in tissues. Both verapamil and diltiazem administration after an injection of H. cyanocinctus venom showed significant decrease in Ca(2+) concentration and tissue necrosis. Increase in survival time was also noted in almost all animals receiving Ca(2+) - antagonist drugs. It is thus suggested that cytotoxic compounds present in this marine venom cause tissue and cellular necrosis by increasing Ca(2+) influx within the cells which in turn stimulates Ca(2+) -dependent processes resulting in both organ dysfunction and sometimes fatality in few cases. But both these effects could be inhibited by using antagonizing drugs which could reduce the pathological conditions induced by such compounds by blocking the cation influx and its dependent processes.

Animals↗

PubMed1993

Entamoeba histolytica cyst passers. Clinical profile and spontaneous eradication of infection.

The present study was carried out to examine whether Entamoeba histolytica cyst passers suffer from any parasite-related bowel symptoms and to assess the frequency of spontaneous eradication of this infection. The study was carried out in two parts. In part I, stool samples were collected at random from 3536 individuals living in rural communities around Delhi. E. histolytica was isolated by the culture technique in 345 (9.7%) subjects. There was no increase in the prevalence rate of bowel symptoms in the culture-positive compared to the culture-negative subjects. One hundred twenty-four (36%) of the culture-positive subjects agreed to take part in a longitudinal study; the subjects were left untreated and clinical assessment and stool examinations were carried out at three-month intervals. One hundred eighteen (95.2%) subjects had eradicated their parasite spontaneously at the end of one year; none developed any features of invasive amebiasis. Part II of the study was carried out on 625 patients attending our Gastroenterology Clinic. Positive cultures of E. histolytica were obtained from 99 (15.2%) patients. Again, there was no increase in the prevalence rate of bowel complaints in the culture-positive compared to the culture-negative subjects. Moreover, histological appearances of the rectal biopsy specimens were not significantly different between the two groups. Twenty-eight (28.2%) patients agreed to the longitudinal study and all eradicated the parasite spontaneously within five months; none developed any evidence of invasive amebiasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Altered lymphocyte populations in tumour invaded nodes of breast cancer patients.

Lymphocytes from matched pairs of tumour-invaded and tumour-free lymph nodes from 22 stage II breast cancer patients have been analysed for expression of phenotypic and activation markers by flow cytometry. Although the relative proportions of T and B lymphocytes were similar in the two nodes, significant differences in the distribution of T cell subsets were observed between nodes that were invaded and those that were not. The CD4/CD8 ratio was markedly depressed in tumour invaded nodes (P < 0.001). This was due to an increase in the number of CD8+ T cells (P < 0.001) and a decrease in the CD4+ T cell population (P = 0.008) in invaded nodes in comparison with tumour-free nodes. The percentage of CD8+ T cells expressing HLA DR (P = 0.023) and IL-2 receptors (Tac) (P = 0.029) was significantly higher in invaded nodes and, while CD4+ T cells expressing HLA DR (P = 0.036) were also in a higher proportion of Tac expressing CD4+ T cells failed to reach significance. Although invaded nodes in a few patients were found to have a higher percentage of IgG-expressing B cells, no significant differences were observed between the two groups of nodes. These results suggest that the presence of metastatic tumour cells in a lymph node is associated with specific alterations in the T cell population.

B-Lymphocytes↗

PubMed1993

Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose.

A randomised double-blind placebo-controlled trial of intravenous methylprednisolone versus oral methylprednisolone at equivalent high dose was carried out on 35 patients with an acute relapse of multiple sclerosis (MS). After baseline evaluation each was randomly allocated to oral treatment and intravenous placebo or intravenous treatment and oral placebo, receiving 500 mg of methylprednisolone for five consecutive days and with reassessment at days five and twenty-eight. There was no significant difference in response when disability or functional scores were compared in the two groups. Adverse effects were minor and equally distributed. In this study oral treatment with methylprednisolone was as effective as intravenous treatment in acute relapse of MS.

Administration, Oral↗

PubMed1993

Characterization of Reed-Sternberg cells with granulocyte specific monoclonal antibody.

Monoclonal antibody Leu M1 represents a highly specific marker to locate granulocyte antigen in Reed-Sternberg cells in Hodgkin's disease. Except the L&H variants of reed-sternberg cells in lymphocyte predominance variety in which antigens are probably sialylated. All the cases of non-Hodgkin's lymphoma were negative with this marker, because of absence of antigen. Therefore this specific marker characterizes granulocyte origin of reed-sternberg cells.

Antibodies, Monoclonal↗

PubMed1992

T cell receptor gamma/delta expression on lymphocyte populations of breast cancer patients.

The quantitative distribution and phenotype of gamma/delta lymphocytes in the peripheral blood (PBL), tumour draining lymph node (LNL) and tumour infiltrating lymphocytes (TIL) from breast carcinoma patients were determined by one- and two-colour flow cytometry. The TCR-gamma/delta + cells generally expressed the T cell lineage antigen CD3. The proportions of such cells were variable but generally small from all the three sources. Phenotypic analysis revealed that the CD8 marker was consistently and predominantly observed on gamma/delta + CD3+ cells in the tumour infiltrate, whereas CD4 expression, while generally low, was noted on a significant percentage (median 10%) of LNL gamma/delta + lymphocytes. In both PBL and LNL the predominant gamma/delta cell population was CD4-8-.

Antibodies, Monoclonal↗

PubMed1992

Flow cytometric analysis of tumour-draining lymph nodes in breast cancer patients.

The phenotype and activation status of lymphocytes from the peripheral blood and axillary lymph nodes of 40 patients with breast cancer were analysed using flow cytometry and compared with lymphocytes from the blood and lymph nodes of 7 control subjects. There was little difference in the overall proportions of T and B lymphocytes but there was a much larger population of B cells bearing surface IgG and a greater number of CD4+ helper T cells, particularly in the regional nodes, in the breast cancer patients. Many more T cells in the cancer patients were found to be carrying the HLA DR and Tac antigens. The axillary lymph nodes were the major site of B cells and CD4+ T cells whilst the primary tumour was the source of the CD8+ suppressor/cytotoxic T cells. Any immune response appeared to be largely loco-regional and may therefore destroyed by conventional surgery or radiotherapy.

Axilla↗

PubMed1992

Aneuploid subpopulations in tumour-invaded lymph nodes from breast cancer patients.

Fresh, paired primary tumours and lymph node metastases from breast cancer patients were compared by DNA flow cytometry. Although 65% of primary tumours were aneuploid, the detection of aneuploid peaks in corresponding nodal metastases was rare (only 6 cases out of 25) in single-parameter DNA analysis. Detection of aneuploid subpopulations in lymph nodes was greatly improved in dual-parameter DNA analysis using an anticytokeratin (CK) antibody which allowed ploidy determination on CK+ epithelial cells alone. Examination of 12 lymph nodes for CK+ cells revealed the presence of both diploid and aneuploid tumour cells in tumour invaded nodes. In patients with multiploid primary tumours, a subpopulation of the primary aneuploid cells was dominant in the nodal metastases. This suggests that aneuploidy is an integral property of metastatic cells and that within a primary tumour a subpopulation may have a higher metastatic potential.

Aneuploidy↗

PubMed1992

Oesophageal carcinoma in Karachi.

Between January, 1979 to August, 1990, 107 histologically proven cases of oesophageal carcinoma were seen. The ages of the patients ranged from 19-85 years (mean 55 +/- 14 years) with a male to female ratio of 1.2:1. Majority (70%) of the cases belonged to lower socioeconomic group and 56% were migrants from India. History of tobacco chewing or smoking was present in 78% cases. In 54%, the lesion was located in the middle third of the oesophagus, followed by lower third in 44%. Histology showed squamous cell carcinoma in 86% and adenocarcinoma in 10% cases. Of the 19 cases followed, 16 underwent surgery and 3 received chemotherapy. Two cases died within 7 months following surgery and in 6 carcinomas recurred. All cases receiving chemotherapy died within 8 months of treatment.

Adenocarcinoma↗

PubMed1991

Giardia lamblia in patients undergoing upper G.I. endoscopy.

To determine the frequency of giardiasis in patients undergoing upper G.I. endoscopy for dyspepsia and other upper G.I. disorders, duodenal aspirates were collected in 200 patients and simultaneous duodenal biopsies in 163 patients. Nine percent aspirates and 1.8% duodenal biopsies showed Giardia lamblia trophozoites. Giardia as a cause of dyspepsia should be considered in patients with negative endoscopy and in those who remain symptomatic inspite of adequate treatment for known upper G.I. disorders.

Adolescent↗

PubMed1991

Abnormal lipoprotein in uraemic patients treated conservatively and by maintenance haemodialysis.

Observations of serum lipids and lipoproteins in 35 uraemic patients treated conservatively (20 cases) and by maintenance haemodialysis (15 cases) are presented. Serum triglycerides levels of both groups (243.7 +/- 119.1 and 160.8 +/- 55.0 mg/dl) were significantly higher (p less than 0.001) and high density lipoprotein cholesterol (HDLC) levels (19.0 +/- 6.1 and 12.17 +/- 5.1 mg/dl) were significantly lower (p less than 0.001) in comparison to those in 20 controls. Agarose gel electrophoresis revealed a second, slow migrating pre-beta band in significantly higher percentage of uraemics (55% and 93.3%) as compared to controls (25%). Until the effects of uraemia and chronic haemodialysis on lipoprotein metabolism are better understood, caution should be exercised in the interpretation of HDLC levels in these patients.

Adolescent↗