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Biomedical subjects

S Gupta

Publications and source records attributed to S Gupta.

At least 721 records · Page 40Linked to original sources
PubMed1997

Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa.

BACKGROUND: Malaria remains a major cause of mortality and morbidity in Africa. Many approaches to malaria control involve reducing the chances of infection but little is known of the relations between parasite exposure and the development of effective clinical immunity so the long-term effect of such approaches to control on the pattern and frequency of malaria cannot be predicted. METHODS: We have prospectively recorded paediatric admissions with severe malaria over three to five years from five discrete communities in The Gambia and Kenya. Demographic analysis of the communities exposed to disease risk allowed the estimation of age-specific rates for severe malaria. Within each community the exposure to Plasmodium falciparum infection was determined through repeated parasitological and serological surveys among children and infants. We used acute respiratory-tract infections (ARI) as a comparison. FINDINGS: 3556 malaria admissions were recorded for the five sites. Marked differences were observed in age, clinical spectrum and rates of severe malaria between the five sites. Paradoxically, the risks of severe disease in childhood were lowest among populations with the highest transmission intensities, and the highest disease risks were observed among populations exposed to low-to-moderate intensities of transmission. For severe malaria, for example, admission rates (per 1000 per year) for children up to their 10th birthday were estimated as 3.9, 25.8, 25.9, 16.7, and 18.0 in the five communities; the forces of infection estimated for those communities (new infections per infant per month) were 0.001, 0.034, 0.050, 0.093, and 0.176, respectively. Similar trends were noted for cerebral malaria and for severe malaria anaemia but not for ARI. Mean age of disease decreased with increasing transmission intensity. INTERPRETATION: We propose that a critical determinant of life-time disease risk is the ability to develop clinical immunity early in life during a period when other protective mechanisms may operate. In highly endemic areas measures which reduce parasite transmission, and thus immunity, may lead to a change in both the clinical spectrum of severe disease and the overall burden of severe malaria morbidity.

Anemia↗
PubMed1997

IFN-gamma potentiates atherosclerosis in ApoE knock-out mice.

The early colocalization of T cells and the potent immunostimulatory cytokine IFN-gamma to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-gamma in this process. First, the presence of CD4(+) and CD8(+) cells, which secrete lesional IFN-gamma, was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-gamma receptor (IFNgammaR) 0 mice to generate apoE 0/IFNgammaR 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-gamma promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-gamma signaling may lead to the formation of more lipid-poor and stable atheromata.

Animals↗
PubMed1997

Leukotriene C4 secretion from normal murine mast cells by a probenecid-sensitive and multidrug resistance-associated protein-independent mechanism.

P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are members of the superfamily of ATP-binding cassette transporter proteins. Because the ATP-dependent export system has been implicated in the release of leukotriene C4 (LTC4), we examined the roles of P-gp and MRP in the release of LTC4 from normal murine mast cells (MC-9). We have previously shown that MC-9 cells express P-gp at the level of protein and mRNA. In the present study, MRP expression in MC-9 cells was examined at the protein level by anti-MRP Ab, using flow cytometry and at the level of mRNA by PCR and Northern blot analyses. MC-9 cells were stimulated with calcium ionophore A23187 for 15 min in the presence or the absence of various concentrations of cyclosporin A (CsA) and its nonimmunosuppressive analogue CsA-1, which are known to inhibit P-gp efflux function, or in the presence or the absence of probenecid, an organic ion transport inhibitor that appears to inhibit MRP-mediated transport function. Culture supernatants were collected, and LTC4 was measured by ELISA assay. CsA and CsA-1 had no effect on LTC4 secretion from MC-9 cells, suggesting that P-gp is not involved in LTC4 release from MC-9 cells. In contrast, probenecid, in a concentration-dependent manner, inhibited LTC4 secretion from MC-9 cells without inhibiting its synthesis. However, MC-9 lacked MRP at both the protein and mRNA levels. These data suggest that LTC4 is secreted by normal mast cells by a probenecid-sensitive mechanism that is independent of MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

p67 transcription regulates translation in serum-starved and mitogen-activated KRC-7 cells.

The regulation of protein synthesis was studied in KRC-7 cells (rat hepatoma) grown in complete medium, during serum starvation, and mitogen activation. Upon serum starvation, the cells lost almost completely p67 mRNA, p67 protein, and protein synthesis activity. After phorbol 12-myristate 13-acetate addition, the same serum-starved cells regained p67 mRNA, p67 protein, and protein synthesis activity. Also, the extracts from the serum-starved cells phosphorylated the eukaryotic initiation factor-2 (eIF-2) alpha-subunit. This eIF-2 alpha-subunit phosphorylation was not observed when the extracts from either the cells grown in complete medium or mitogen-activated cells were used (Gupta, S., Wu, S., Chatterjee, N., Ilan, J., Ilan, J., Osterman, J. C., and Gupta, N. K. (1995) Gene Expr. 5, 113-122). We now report the following. 1) The eIF-2 kinase activity was the same in the cells grown in complete medium, after serum starvation, and subsequent mitogen stimulation. However, the eIF-2 kinase in the cells grown in complete medium and also after mitogen activation of the serum-starved cells cannot phosphorylate eIF-2 alpha-subunit as these cells contain p67. After removal of endogenous p67 by p67 antibodies, the extracts from all these cells similarly phosphorylated exogenously added eIF-2. 2) None of the cell extracts showed p67 deglycosylase activity. 3) The p67 mRNA was synthesized in serum-starved cells by expression of a p67 cDNA. The appearance of p67 mRNA in the serum-starved cells was accompanied by the appearance of p67 protein. Also, the rates of protein synthesis in the serum-starved cells were restored nearly to the level observed in the confluent cells. The expression of p67 cDNA also significantly increased protein synthesis rates in the cells grown in complete medium and in mitogen-activated cells. These results show that the loss of protein synthesis activity in serum-starved cells was due to loss of p67 mRNA. The expressed p67 mRNA was stable in serum-starved cells. These results, therefore, suggest that the loss of p67 mRNA in serum-starved cells is due to loss of p67 transcription. The p67 transcription regulates translation.

Aminopeptidases↗
PubMed1997

The relationship between schizophrenia and irritable bowel syndrome (IBS).

Irritable bowel syndrome (IBS) has been reported in 10-22% of adults. Amongst patients seeking medical attention for IBS 70-90% may have psychiatric co-morbidity, most commonly major depression. In contrast, few studies have looked at the prevalence of IBS in psychiatric patients. To our knowledge, there are no studies assessing the prevalence of IBS in patients with schizophrenia. Using a semistructured clinical interview to study the prevalence of IBS, we compared 47 patients with schizophrenia to an age-matched control group (n = 40) of patients who were seeking treatment in a primary care physicians office for other medical illnesses. IBS was diagnosed according to the criteria of Drossman et al. Nineteen percent (n = 9) of the patients with schizophrenia met criteria for IBS in contrast to 2.5% (n = 1) of the control group (p = 0.012). Schizophrenic patients seldom complain of gastrointestinal symptoms until specifically asked. Therefore, it may be important to inquire about gastrointestinal symptoms prior to initiating pharmacotherapy in order to differentiate side effects from a prior existing condition. Prospective studies should address the question whether remission of psychosis leads to improvement or resolution of IBS.

Adult↗
PubMed1997

Structure of active chromatin: isolation and characterization of transcriptionally active chromatin from rat liver.

Rat liver nuclei were isolated in low-ionic-strength buffer in the absence of bi- and multi-valent cations. Digestion of these nuclei by endogenous nuclease, micrococcal nuclease and DNase I revealed that a minor chromatin fraction was preferentially digested into poly- and oligo-nucleosomes. Southern blot hybridization with various active gene probes confirmed that these chromatin fragments represent coding and 5' upstream regions of transcriptionally active chromatin. Active chromatin fragments were released selectively into the medium, with inactive chromatin remaining inside the nuclei, under the above ionic conditions. The inclusion of bivalent cations during the digestion of nuclei reversed the solubility behaviour of active chromatin. Rearrangement and exchange of histone H1 between chromatin fragments was prevented by using low-salt conditions in all steps in the absence of bivalent cations. All histones, including H1, were present in stoichiometric amounts in this active chromatin fraction. Active nucleosomes showed a lower electrophoretic mobility than bulk nucleosomes in an acrylamide/agarose composite gel in the absence of Mg2+, but were selectively bound to the gel in the presence of this ion.

Animals↗
PubMed1997

A Ca2+-dependent autoregulation of lipopolysaccharide-induced IL-8 receptor expression in human polymorphonuclear neutrophils.

IL-8, a potent neutrophil chemotactic agent, is known to be a key mediator in several inflammatory diseases. We found that 10 ng/ml of serum-activated LPS (Escherichia coli) efficiently up-regulated IL-8R on the surface of neutrophils within 30 min of LPS stimulation by 115 to 120% through de novo protein synthesis. After 30 min of LPS stimulation, reduction of IL-8R level was initiated and the normal level was restored within 2 h of LPS interaction. EDTA or EGTA and bestatin separately inhibited the receptor down-regulation by 98%, indicating the involvement of metalloprotease(s), more specifically an aminopeptidase in the process. Induction and subsequent reduction of IL-8 binding in serum-activated LPS-stimulated cells have been demonstrated in autoradiography. Intracellular Ca2+ level in these stimulated neutrophils was increased and decreased with alteration of IL-8R level. Although IL-8 binding was drastically reduced, the total IL-8R level, as detected by anti-IL-8R Ab measured by 125I-labeled anti-rabbit IgG, remained almost unaltered, indicating that minimal proteolysis occurred in IL-8R. Anti-IL-8R Ab and IL-8 itself could prevent this down-regulation significantly, suggesting that the susceptible epitope(s) might be in the IL-8 binding domain of the receptor. Under Ca2+-depleted conditions, the proteolysis was inhibited, which was accelerated upon addition of 1 mM of CaCl2. The study demonstrates that LPS-induced up-regulation of IL-8R leads to amplified IL-8-mediated biologic responses of neutrophils that are restored to normal level by activation of a Ca2+-dependent aminopeptidase. This may be useful for understanding the regulation of LPS-mediated inflammatory responses of neutrophils during bacterial infection.

Aminopeptidases↗
PubMed1997

Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappaB and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways.

E-selectin expression by endothelium is crucial for leukocyte recruitment during inflammatory responses. Transcriptional regulation of the E-selectin promoter by tumor necrosis factor alpha (TNFalpha) requires multiple nuclear factor-kappaB (NF-kappaB) binding sites and a cAMP-responsive element/activating transcription factor-like binding site designated positive domain II (PDII). Here we characterize the role of the stress-activated family of mitogen-activated protein (MAP) kinases in induced expression of this adhesion molecule. By UV cross-linking and immunoprecipitation, we demonstrated that a heterodimer of transcription factors ATF-2 and c-JUN is constitutively bound to the PDII site. TNFalpha stimulation of endothelial cells induces transient phosphorylation of both ATF-2 and c-JUN and induces marked activation of the c-JUN N-terminal kinase (JNK1) and p38 but not extracellular signal-regulated kinase (ERK1). JNK and p38 are constitutively present in the nucleus, and DNA-bound c-JUN and ATF-2 are stably contacted by JNK and p38, respectively. MAP/ERK kinase kinase 1 (MEKK1), an upstream activator of MAP kinases, increases E-selectin promoter transcription and requires an intact PDII site for maximal induction. MEKK1 can also activate NF-kappaB -dependent gene expression. The effects of dominant interfering forms of the JNK/p38 signaling pathway demonstrate that activation of these kinases is critical for cytokine-induced E-selectin gene expression. Thus, TNFalpha activates two signaling pathways, NF-kappaB and JNK/p38, which are both required for maximal expression of E-selectin.

Activating Transcription Factor 2↗
PubMed1997

The Iowa Longitudinal Study of Recent Onset Psychosis: one-year follow-up of first episode patients.

The natural history of schizophrenia remains unclear. One strategy to further inform this area is to prospectively evaluate individuals early in the course of the disorder, both in terms of symptomatic and psychosocial/occupational functioning. Subjects were recruited into the study if they were in the midst of their first psychiatric hospitalization for a non-'organic' psychotic disorder. Subjects were extensively evaluated at index with semi-structured interviews including the Comprehensive Assessment of Symptoms and History (CASH), and followed at 6-month intervals. Data are presented on 35 subjects who were followed through 1 year. There was a significant improvement in overall symptomatology during index hospitalization, but this was accounted for primarily by improvement of positive symptoms, with negative symptoms remaining prominent. No further improvement was noted between discharge and 1-year follow-up in any of the symptom measures. Employment, interpersonal relationships, and sexual activity remained markedly impaired throughout the follow-up period. These data demonstrate that; (1) negative symptoms are prominent and stable early in the course of the disorder; (2) symptom severity at discharge from index hospitalization is predictive of symptom severity at 1 year; and (3) despite substantial overall symptomatic improvement during the first hospitalization, psychosocial and occupational functioning were found to be markedly impaired at 1-year follow-up.

Adult↗
PubMed1997

Induction and decline of hepatic cytochromes P4501A1 and 1A2 in rats exposed to hyperoxia are not paralleled by changes in glutathione S-transferase-alpha.

We investigated the effects of hyperoxia on the activities of hepatic ethoxyresorufin O-deethylase (EROD) (CYP1A1), methoxyresorufin O-demethylase (MROD) (CYP1A2), and glutathione transferase-alpha (GST-alpha), and the status of protein thiols (PSH) in male Sprague-Dawley rats. Twenty-four h of hyperoxia more than doubled EROD and MROD activities, which were increased 7.6- and 3.3-fold, respectively, after 48 h of hyperoxia. The increases in EROD and MROD activities were paralleled by enhanced CYP1A1/1A2 apoproteins contents, as detected by Western analysis. At 60 h of hyperoxia, by which time hyperoxic Sprague-Dawley rats display marked respiratory distress, pulmonary edema, and other markers of pulmonary dysfunction, the activities and levels of hepatic CYP1A1 and 1A2 had declined dramatically and returned to levels observed in air-breathing control animals. Hepatic activities of GST-alpha, as well as PSH status, were not altered significantly in the hyperoxic animals at any time point. The marked induction and subsequent decline of hepatic CYP1A1/1A2 activities in rats exposed to hyperoxia suggest that these enzymes may contribute to the mechanisms of injury and/or to adaptive responses to hyperoxic exposures in vivo.

Animals↗
PubMed1997

Argyrophilic nucleolar organizer regions: their value and correlation with clinical prognostic factors in breast carcinoma.

BACKGROUND AND OBJECTIVES: Argyrophilic nucleolar organizer regions (AgNORs) have been recently identified as a marker of proliferative index in various tumors. These were evaluated in 46 patients with primary breast carcinoma and were correlated with clinical prognostic parameters of breast cancer. Ten patients with benign breast tumors served as controls in the study. METHODS: AgNORs were stained in paraffin sections of the tissues using Ploton's silver technique. For each specimen, the number of AgNORs, within the nuclei of 100 tumor cells were calculated. The average number of AgNORs per nucleus was calculated and the results expressed as mean +/- S.D. RESULTS: AgNOR count was significantly higher in breast carcinoma (6.61 +/- 1.75) than in benign breast tumors (1.88 +/- 0.19). Further, the AgNOR count in breast carcinoma showed a statistically significant increase in correlation with the increase in the size of the tumor, stage of the cancer, number of metastatic lymph nodes, and tumor recurrence at various sites. However, the differences in AgNOR count at different lymph node levels and histologic grading were not statistically significant. CONCLUSIONS: These results indicate that breast tumors with a higher AgNOR count, even at the initial stage, have a poor prognosis and require aggressive treatment for better control of the disease. Further, it is suggested that the patients with a benign tumor and more than three AgNORs per nucleus need careful surveillance.

Adult↗
PubMed1997

Dexfenfluramine for weight gain secondary to psychotropics.

We describe the use of dexfenfluramine (Redux) in six patients with mood disorders (bipolar disorder = 3; major depression = 3) who developed significant weight gain as a result of their psychotropics. All patients were females with an age range of 27-58 years. The duration of the trial varied from 3 to 20 weeks, with the dexfenfluramine dosage being 15 mg twice daily. Weight loss ranged from 2 to 23 pounds. None of the patients had any evidence of primary pulmonary hypertension or serotonin syndrome, despite being on serotonergic agents such as fluoxetine, paroxetine, and sertraline.

Adult↗
PubMed1997

Chronic infection in the etiology of atherosclerosis--the case for Chlamydia pneumoniae.

Established cardiovascular risk factors do not fully explain the variations in the prevalence and severity of coronary heart disease. Recent evidence suggests that common chronic infections may contribute, either by direct or indirect mechanisms, to the etiology and/or progression of coronary atherosclerosis. Of the candidate infectious agents implicated, Chlamydia pneumoniae has emerged as the most likely pathogen to have a causal role. Evidence for this is based on seroepidemiologic, pathologic, and laboratory-based evidence, in addition to recent small-scale antibiotic intervention studies. Concerted efforts are now focused on the design of large prospective trials with antibiotics active against C. pneumoniae in the secondary prevention of coronary heart disease.

Animals↗
PubMed1997

Means to the goal of remembering: developmental changes in awareness of strategy use--performance relations.

We examined awareness of the causal relation between strategy use and recall performance among preschoolers, first graders, and third graders, and the relation of this awareness to children's study behavior and recall. In session 1, children were presented with two study-recall trials; the second trial included questions concerning the child's study behavior. During Session 2, children viewed videotapes in which a model's strategy use (labeling versus no labeling) and recall level (high versus low) were varied orthogonally. Children judged whether the model tried to remember, rated how hard the model tried to remember, and described how they knew. Children who gave mentalistic explanations for their study behaviors in Session 1 recalled more than those giving nonmentalistic explanations. In Session 2, age-related differences were observed in awareness of the relation between strategy use and performance level. Further, children who demonstrated understanding of strategy use-performance relations in Session 2 were more likely to give mentalistic explanations for their own study behaviors in Session 1. The results further delineate the metamemorial development that contributes to effective strategy utilization.

Attention↗
PubMed1997

Inhibition of carbamyl phosphate synthetase-I and glutamine synthetase by hepatotoxic doses of acetaminophen in mice.

The primary mechanisms proposed for acetaminophen-induced hepatic necrosis should deplete protein thiols, either by covalent binding and thioether formation or by oxidative reactions such as S-thiolations. However, in previous studies we did not detect significant losses of protein thiol contents in response to administration of hepatotoxic doses of acetaminophen in vivo. In the present study we employed derivatization with the thiol-specific agent monobromobimane and separation of proteins by SDS-PAGE to investigate the possible loss of specific protein thiols during the course of acetaminophen-induced hepatic necrosis. Fasted adult male mice were given acetaminophen, and protein thiol status was examined subsequently in subcellular fractions isolated by differential centrifugation. No decreases in protein thiol contents were indicated, with the exception of a marked decrease in the fluorescent intensity, but not of protein content, as indicated by staining with Coomassie blue, of a single band of approximately 130 kDa in the mitochondrial fractions of acetaminophen-treated mice. This protein was identified by isolation and N-terminal sequence analysis as carbamyl phosphate synthetase-I (CPS-I) (EC 6.3.4.16). Hepatic CPS-I activities were decreased in mice given hepatotoxic doses of acetaminophen. In addition, hepatic glutamine synthetase activities were lower, and plasma ammonia levels were elevated in mice given hepatotoxic doses of acetaminophen. The observed hyperammonemia may contribute to the adverse effects of toxic doses of acetaminophen, and elucidation of the specific mechanisms responsible for the hyperammonemia may prove to be useful clinically. However, the preferential depletion of protein thiol content of a mitochondrial protein by chemically reactive metabolites generated in the endoplasmic reticulum presents a challenging and potentially informative mechanistic question.

Acetaminophen↗
PubMed1997

Probenecid reverses multidrug resistance in multidrug resistance-associated protein-overexpressing HL60/AR and H69/AR cells but not in P-glycoprotein-overexpressing HL60/Tax and P388/ADR cells.

PURPOSE: To determine whether probenecid, an inhibitor of organic anion transport, is able to reverse multidrug resistance (MDR) through modulation of the drug transport function of MDR-associated protein (MRP) and P-glycoprotein (P-gP). METHODS: Two MRP-overexpressing cell lines (HL60/AR and H69/AR) and two P-gP-overexpressing cell lines (HL60/Tax and P388/ADR) were cultured with different concentrations of daunorubicin (DNR) or vincristine (VCR) in the presence or absence of various concentrations of probenecid (0.01-10 mM). Drug sensitivity was determined using an MTT assay. DNR accumulation and subcellular distribution were determined by flow cytometry and confocal microscopy respectively. VCR accumulation was determined by scintillation spectrometry. RESULTS: Probenecid, in a concentration-dependent manner, reversed resistance to DNR and VCR in HL60/AR and H69/AR tumor cell lines. This effect of probenecid on MDR was associated with an increased accumulation of DNR and VCR and correction of the altered subcellular distribution of DNR. The concentrations of probenecid that reversed MDR are clinically achievable in vivo. In contrast, probenecid did not reverse MDR in either HL60/Tax or P388/ADR tumor cell lines that overexpress P-gP. CONCLUSION: These results suggest that probenecid is an effective chemosensitizer of MRP-associated MDR tumor cells and is a potential candidate for clinical use to reverse MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗