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Biomedical subjects

S Sinha

Publications and source records attributed to S Sinha.

At least 235 records · Page 13Linked to original sources
PubMed1999

Implications for Src kinases in hematopoiesis: signal transduction therapeutics.

Signal transduction therapeutics is now the dominant theme of drug discovery, and its most immediate impact will be in cancer therapeutics. Blood cell proliferation, differentiation, and activation are controlled by cytokines, whose receptors contain tyrosine kinase catalytic domains or recruit cytosolic tyrosine kinases. Among the most important cytosolic protein tyrosine kinases are the Src and Jak families. Receptor or cytosolic protein tyrosine kinases activate a similar set of intracellular signaling molecules. In blood cells, excessive tyrosine kinase activity is associated with either cancer or autoreactive diseases. Therefore, tyrosine kinases and their substrates serve as excellent candidates for drug intervention. Herceptin has been approved for use in breast cancer. Other agents, such as SU101 and CGP 57418B, are well into phase I-III trials. Newer, more selective tyrosine kinase inhibitors are being evaluated for future use in the treatment of hematologic and solid tumors as well as a wide range of inflammatory or autoimmune diseases.

Animals↗
PubMed1999

Computing with distributed chaos.

We describe and discuss in detail some recent results by Sinha and Ditto [Phys. Rev. Lett. 81, 2156 (1998)] demonstrating the capacity of a lattice of threshold coupled chaotic maps to perform computations. Such systems are shown to emulate logic gates, encode numbers, and perform specific arithmetic operations, such as addition and multiplication, as well as yield more specialized operations such as the calculation of the least common multiplier of a sequence of numbers. Furthermore, we extend the scheme to multidimensional continuous time dynamics, in particular to a system relevant to chaotic lasers.

Journal Article↗
PubMed1999

Distribution of Husimi zeros in polygonal billiards.

The zeros of the Husimi function provide a minimal description of individual quantum eigenstates and their distribution is of considerable interest. We provide here a numerical study for pseudointegrable billiards which suggests that the zeros tend to diffuse over phase space in a manner reminiscent of chaotic systems but nevertheless contain a subtle signature of pseudointegrability. We also find that the zeros depend sensitively on the position and momentum uncertainties (Delta q and Delta p, respectively) with the classical correspondence best when Delta q = Delta p = square root of [Planck's constant/2]. Finally, short-range correlations seem to be well described by the Ginibre ensemble of complex matrices.

Journal Article↗
PubMed1999

Minimal model for complex dynamics in cellular processes.

Cellular functions are controlled and coordinated by the complex circuitry of biochemical pathways regulated by genetic and metabolic feedback processes. This paper aims to show, with the help of a minimal model of a regulated biochemical pathway, that the common nonlinearities and control structures present in biomolecular interactions are capable of eliciting a variety of functional dynamics, such as homeostasis, periodic, complex, and chaotic oscillations, including transients, that are observed in various cellular processes.

Biochemical Phenomena↗
PubMed1999

Specificity and function of immunogenic peptides from the 35-kilodalton protein of Mycobacterium leprae.

We identified a T-cell determinant of the 35-kDa antigen of Mycobacterium leprae which is discriminatory against cross-sensitization by its closely related homologue in Mycobacterium avium. From synthetic peptides covering the entire sequence, those with the highest affinity and permissive binding to purified HLA-DR molecules were evaluated for the stimulation of proliferation of peripheral blood mononuclear cells (PBMCs) from leprosy patients and healthy sensitized controls. Responses to the peptide pair 206-224, differing by four residues between M. leprae and M. avium, involved both species-specific and cross-reactive T cells. Lymph node cell proliferation in HLA-DRB1*01 transgenic mice was reciprocally species specific, but only the response to the M. leprae peptide in the context of DR1 was immunodominant. Of the cytokines in human PBMC cultures, gamma interferon production was negligible, while interleukin 10 (IL-10) responses in both patients and controls were more pronounced. IL-10 was most frequently induced by the shared 241-255 peptide, indicating that environmental cross-sensitization may skew the response toward a potentially pathogenic cytokine phenotype.

Animals↗
PubMed1999

Butachlor is cytotoxic and clastogenic and induces apoptosis in mammalian cells.

The ability of butachlor to induce cytotoxicity, clastogenicity and DNA damage was assessed using Chinese hamster ovary cells (CHO), Swiss mouse embryo fibroblasts (MEF) and human peripheral blood lymphocytes. A dose and time dependent loss of viability was evident upon treatment of CHO cells with butachlor. Cell killing to an extent of 50% was observed when cells were treated with 16.2 micrograms/ml of butachlor for 24 hr or with 11.5 micrograms/ml for 48 hr. The herbicide induced micronuclei significantly in cultured lymphocytes at 24 and 48 hr of treatment suggesting that it is clastogenic. To understand the mechanism of cell death caused by butachlor, its effect on DNA strand breaks was studied in MEF. A concomitant decrease in cell viability was observed with increase in DNA strand breaks. Agarose gel electrophoresis of DNA from herbicide treated CHO cells and cytochemical staining indicate the induction of apoptosis by butachlor.

Acetanilides↗
PubMed1999

Pulmonary infections after kidney transplantation.

OBJECTIVE: To retrospectively analyse the epidemiology, aetiology, temporal profile and outcome of lung infection following kidney transplantation. METHODS: Out of 142 consecutive renal transplant (RT) recipients who underwent live donor transplantation from June, 1990 to May, 1998, 43 (33%) had serious infection requiring hospitalisation of which 27 were pulmonary. All such pneumonia were included for retrospective analysis. All had a minimum follow up of six months (if alive) and were on triple drug immunosuppression. All had detailed and appropriate investigations for definitive diagnosis. RESULTS: The aetiological agents were Gram negative bacterial infection (2), Gram positive bacterial infection (1), nocardia (2), tuberculosis (10), aspergillosis (2), mixed bacterial and fungal infection (4), Pneumocystis (2) and unconfirmed (4). Four patients had pneumonia because of probable nosocomial exposure. Radiologically lobar/segmental pneumonia was observed in five, nodular lesion six, reticulonodular lesion eight, patchy consolidation five and pleural effusion three. Nodular pneumonias were due to aspergillosis or nocardiosis. Four patients developed secondary cavitation. Pulmonary infections were significantly associated with leucopenia (8/27) (p < 0.01) but not with renal dysfunction (creat > 2 mg%), diabetes, old age or additional immunosuppression (p > 0.05). There were 11 deaths. Mortality was related to failure to reach diagnosis (3) and delayed institution of therapy (6 patients). Pneumonia within first six months had a higher mortality (9/16) compared to late pneumonia (2/11). Immunomodulating virus (CMV 4, HEP B 2) was present in six patients of whom four succumbed. CONCLUSION: Pulmonary infection is a common and serious post-transplant infection requiring hospitalisation, is associated with high mortality. Patients with leucopenia are predisposed to these infections. Prophylaxis for Pneumocystis, Nocardia and tuberculosis needs strong consideration to reduce mortality of such infection. Nosocomial exposure risk needs careful consideration in outbreaks of opportunistic infection.

Adult↗
PubMed1998

Immunosuppressive effect of vestibulo-cerebellar lesion in rats.

Kainate lesion of the vestibulo cerebellum induces sympathetic hyperactivity, but the mechanism of immunosuppression observed as a result is not yet clarified. Here we report that vestibulo cerebellum lesioned (VCL) rats have depressed secretion of haematopoietic cytokines (bioimmunomodulator or BIM, a 12.7 kD peptide and thymosin FrV) in tissue cultures of bone marrow and thymus, respectively, compared with controls (P < 0.01). Peripheral blood leukocyte concentration, neutrophil myeloperoxydase response, T-SRBC rosette and antibody titre to sheep red blood cells (SRBC) are also significantly less, compared with control (P < 0.01). Injection of BIM (concentration 0.01 microg/g body weight) in VCL rats corrected the immunodeficiency. Partial restoration of immune competence is observed after injection of thymosin FrV (0.01 microg/g body weight) or after prolonged vestibular stimulation (18 rpm for 15 min/day for 21 days). The results indicate that the vestibular nodule (VN) through autonomic nerves (AN) can modulate the immune function of rats by regulating the secretion of cytokines from bone marrow and thymus.

Animals↗
PubMed1998

Fusion between retinal rod outer segment membranes and model membranes: a role for photoreceptor peripherin/rds.

Peripherin/rds plays an essential role in the maintenance of photoreceptor rod cell disk membrane structure. The purification of this protein to homogeneity [Boesze-Battaglia, K., et al. (1997) Biochemistry 36, 6835-6846] has allowed us to characterize the functional role of peripherin/rds in the maintenance of rod outer segment (ROS) membrane fusion processes. Utilizing a cell-free fusion assay system, we report that the fusion of R18-labeled ROS plasma membrane (R18-PM) with disk membranes or peripherin/rds-enriched large unilammellar vesicles (LUVs) is inhibited upon trypsinolysis of peripherin/rds. To understand this phenomenon, we tested the ability of a series of overlapping synthetic C-terminal peripherin/rds peptides to mediate model membrane fusion. Within the 63 amino acid long region of the C-terminus, we identified a minimal 15 residue long amino acid sequence (PP-5), which is necessary to promote membrane fusion. PP-5 was able to inhibit R18-PM disk membrane fusion and promoted ANTS/DPX contents mixing in a pure vesicle system. This peptide (PP-5) promoted calcium-induced vesicle aggregation of phosphatidylethanolamine:phosphatidylserine LUVs. FTIR analysis confirmed the structural prediction of this peptide as alpha-helical. When modeled as an alpha-helix, this peptide is amphiphilic with a hydrophobicity index of 0.75 and a hydrophobic moment of 0.59. PP-5 has substantial biochemical and functional homology with other well-characterized membrane fusion proteins. These results demonstrate the necessity for peripherin/rds in ROS membrane fusion, specifically the requirement for an intact C-terminal region of this protein.

Amino Acid Sequence↗
PubMed1998

The two activation domains of the CCAAT-binding factor CBF interact with the dTAFII110 component of the Drosophila TFIID complex.

The CCAAT-binding factor CBF is a heterotrimeric transcription factor that specifically binds to CCAAT sequences in many eukaryotic genes. Previous studies have shown that CBF contains two transcription activation domains: a glutamine-rich, serine-threonine-rich domain present in the CBF-B subunit and a glutamine-rich domain in the CBF-C subunit. In this study, by using a series of deletion mutations of CBF-B and CBF-C in transcription assay in vitro, we further delineated smaller segments in these domains that were sufficient to support transcriptional activation by CBF. To test whether transcription activation by CBF requires co-activators, we examined the interaction between CBF and dTAF110, a component of the Drosophila TFIID complex. Recent work has demonstrated that glutamine-rich domains of the Sp1 transcription factor interact with dTAF110 and that this interaction has an important role in mediating transcription activation. Here we first demonstrate in a direct interaction assay in vitro that CBF binds dTAF110. By using a yeast two-hybrid system we show that both of the transcription activation domains of CBF interact with dTAF110. A deletion analysis suggests that a segment of CBF-B needed for transcription activation is also involved in interaction with dTAF110. In CBF-C the C-terminal portion of the molecule seems to be needed for these two activities. Our results suggest that TAF110 might represent one of the co-activators that mediate transcriptional activation by CBF.

Animals↗
PubMed1998

Genetic alterations in brain tumors identified by RAPD analysis.

We report the utility of random amplified polymorphic DNA (RAPD) analysis for identifying subtle genomic alterations in meningiomas and gliomas by comparing the DNA band profile of tumor vis-à-vis its constitutional counterpart. Twenty out of the 29 decanucleotide GC-rich random primers utilized for the RAPD analysis of meningiomas revealed alteration(s) in the tumor genome. In gliomas, changes were detected by 16 of the 18 primers. While all the seven meningioma samples exhibited alterations in tumor DNA, changes were evident in 21 of the 24 glioma cases. These alterations in tumor DNA included the loss of a normal band, appearance of a new band and amplification of a pre-existing band. Many primers detected more than one alterations in a given tumor. Our approach, which covers the range from 0.4 to 2 kb, besides detecting a significant number of changes in a spectrum of brain tumors, complements existing DNA fingerprinting methods, such as microsatellite mapping (less than 0.4 kb) and Southern blotting (over 2 kb), for detecting genetic alterations in tumors.

Brain Neoplasms↗
PubMed1998

Metabolic drug interactions with selective serotonin reuptake inhibitor (SSRI) antidepressants.

The selective serotonin reuptake inhibitor (SSRI) antidepressants have become an important component of the therapeutic armamentarium in psychiatry and have attracted a great deal of public attention. Another interesting aspect of the SSRIs is their interaction with various isozymes of the cytochrome P450 (CYP) system which are responsible for metabolism of numerous drugs. This effect on the CYP isozymes has drawn attention to the importance of metabolic drug-drug interactions when dealing with drugs used to treat psychiatric disorders. Such interactions are of great relevance since psychiatry patients are frequently treated with multiple drugs and often these drugs undergo extensive biotransformation to metabolites which contribute to therapeutic and/or adverse effects. The present review deals with various aspects of metabolism mediated by CYP isozymes, particularly as they relate to pharmacokinetic interactions between the SSRIs and other drugs which are coadministered with them.

Animals↗
PubMed1998

Cellular and extracellular biology of the latent transforming growth factor-beta binding proteins.

The latent transforming growth factor-beta binding proteins (LTBP) are a recently identified family of widely expressed multidomain glycoproteins that range in size from 125 kDa to 240 kDa. Four LTBP genes have been described, and the homology of latent transforming growth factor-beta binding proteins molecules to the fibrillins has resulted in their inclusion in the so-called 'fibrillin superfamily'. They form intracellular covalent complexes with latent transforming growth factor-beta and target these growth factors to the extracellular matrix. This review describes their structure, summarizes current understanding of their dual roles as growth factor binding proteins and components of the extracellular matrix, and highlights their significance in tissue development and disease.

Amino Acid Sequence↗
PubMed1998

Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat.

Aromatase catalyzes the rate limiting step that converts androgens to estrogens. Postmenopausal women with hormone dependent breast cancer respond to first generation aromatase inhibitors such as aminoglutethimide with a marked suppression of circulating estradiol levels. In contrast, premenopausal women appear to be resistant to first generation aromatase inhibitors. The inability to block ovarian aromatase results from the low affinity of first generation inhibitors for the active site of the enzyme. Under these circumstances, the high substrate levels in the premenopausal ovary compete effectively with these inhibitors and do not allow binding of inhibitor to the active site of the enzyme. Second and third generation aromatase inhibitors with higher affinity for aromatase have now been developed and potentially could block ovarian aromatase. To test this possibility, we administered CGS 20267 (letrozole), a highly potent aromatase inhibitor, to cycling female rats. A dose dependent inhibition of uterine weight occurred with maximum effects produced by the 5 mg/kg/day dosage. During a period of 4 weeks, uterine weight was reduced to levels induced by ovariectomy. Ovarian tissue estradiol levels were inhibited by approximately 80%. As a reflection of inhibition of ovarian aromatase activity, the levels of androstenedione in the ovary increased by an order of magnitude. Both LH and FSH plasma levels increased but not to those observed after ovariectomy. The rise in gonadotropin levels induced a statistically significant but relatively small increase in ovarian weights. These results demonstrate the ability to persistently block ovarian aromatase activity in cycling rats with a potent aromatase inhibitor. This study provides a rationale for clinical trials of potent aromatase inhibitors in pre-menopausal women with breast cancer.

Animals↗
PubMed1998

A normal electrocardiogram precludes the need for left ventriculography in the assessment of coronary artery disease.

OBJECTIVE: To assess whether a normal electrocardiogram can identify good left ventricular function and obviate the need for routine left ventriculography in patients undergoing cardiac catheterization for suspected coronary artery disease. DESIGN: A prospective study of patients undergoing cardiac catheterisation. SETTING: A regional cardiac centre. PATIENTS: The electrocardiograms, coronary angiograms, and left ventriculograms of 391 consecutive patients undergoing investigations for suspected coronary artery disease were entered into the study. Patients with arrhythmias and cardiac pathologies other than coronary artery disease were excluded. MAIN OUTCOME MEASURES: The electrocardiogram was assessed using a 29 point QRS scoring system, and classified by two cardiologists and a trainee cardiologist as normal or abnormal. Left ventricular function was assessed by digital ventriculography. RESULTS: The sensitivity, specificity, and negative predictive value of a QRS score of 0 (normal QRS complexes) for discriminating good left ventricular function (ejection fraction > or = 50%) were 92.6%, 41.5%, and 97.2%, respectively. The figures for a normal electrocardiogram as assessed by a doctor were 96.3%, 40.4%, and 98.6% for cardiologist A; 96.3%, 37.4%, and 98.4% for cardiologist B; and 94.4%, 49.6%, and 98.2% for the cardiology trainee. CONCLUSIONS: If a cardiologist judges the ECG to be normal, left ventriculography is unnecessary and a formal QRS score does not improve reliability of this clinical judgment. Adopting this strategy would save 30-40,000 Pounds in consumables and 65-87 hours of catheter laboratory and staff time for a department catheterising 3000 patients with suspected coronary artery disease annually.

Adult↗