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Biomedical subjects

S Gupta

Publications and source records attributed to S Gupta.

At least 487 records · Page 27Linked to original sources
PubMed1999

Paclitaxel shows cytotoxic activity in human hepatocellular carcinoma cell lines.

Paclitaxel stabilizes microtubules with inhibition of mitotic spindle formation and has been found effective in several solid cancers. To test whether paclitaxel could be cytotoxic in human HCC cell lines, we used established HuH-7 and HepG2 cell lines. Changes in cell number, DNA synthesis rates and cell viability were determined. We tested whether paclitaxel-treated cells underwent apoptosis, microtubular reorganization, and cell cycle restriction. Studies also examined whether chemosensitization with verapamil enhanced the antitumor activity of paclitaxel. The cell viability was impaired at greater than 0.01 microM paclitaxel concentrations (LD50, 0.8 microM), with flow cytometry indicating accumulation of cells in G2/M, and immunostaining showing polymerized microtubules with characteristic banding patterns. This G2/M restriction was further characterized by flow cytometry, which revealed cyclin A and cdc2 kinase accumulation in paclitaxel-treated cells. Exposure to paclitaxel decreased [3H]thymidine incorporation into DNA in cells at 24 h but this significantly increased at 72 h, most likely due to DNA repair mechanisms related to cell cycle restriction. The cell death was via both apoptotic and non-apoptotic mechanisms. Finally, co-administration of the chemosensitizer verapamil in doses as little as 1 microM increased the antitumor efficacy of paclitaxel by up to five-fold and changed the LD50 of paclitaxel to 0.1 microM. The findings indicate that paclitaxel is cytotoxic to cultured hepatocellular carcinoma cells. Clinical studies of paclitaxel in patients with hepatocellular carcinoma may help determine additional therapies.

Adolescent↗
PubMed1999

Position-specific gene expression in the liver lobule is directed by the microenvironment and not by the previous cell differentiation state.

Mechanisms directing position-specific liver gene regulation are incompletely understood. To establish whether this aspect of hepatic gene expression is an inveterate phenomenon, we used transplanted hepatocytes as reporters in dipeptidyl peptidase IV-deficient F344 rats. After integration in liver parenchyma, the position of transplanted cells was shifted from periportal to perivenous areas by targeted hepatic ablations with carbon tetrachloride. In controls, transplanted cells showed greater glucose-6-phosphatase and lesser glycogen content in periportal areas. This pattern was reversed when transplanted cells shifted from periportal to perivenous areas. Transplanted hepatocytes in perivenous areas exhibited inducible cytochrome P450 activity, which was deficient in periportal hepatocytes. Moreover, cytochrome P450 activity was rapidly extinguished in activated hepatocytes when these cells were transplanted into the nonpermissive liver of suckling rat pups. In cells isolated from the normal F344 rat liver, cytochrome P450 inducibility was originally greater in perivenous hepatocytes; however, periportal cells rapidly acquired this facility in culture conditions. These findings indicate that the liver microenvironment exerts supremacy over prior differentiation state of cells in directing position-specific gene expression. Therefore, persistence of specialized hepatocellular function will require interactions with regulatory signals and substrate availability, which bears upon further analysis of liver gene regulation, including in progenitor and/or stem cells.

Animals↗
PubMed1999

The effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens.

Cross-reactive antibodies produced by a mammalian host during infection by a particular microparasitic strain usually have the effect of reducing the probability of the host being infected by a different, but closely related, pathogen strain. Such cross-reactive immunological responses thereby induce between-strain competition within the pathogen population. However, in some cases such as dengue virus, evidence suggests that cross-reactive antibodies act to enhance rather than restrict the severity of a subsequent infection by another strain. This cooperative mechanism is thought to explain why pre-existing immunity to dengue virus is an important risk factor for the development of severe disease (i.e., dengue shock syndrome and dengue hemorrhagic fever). In this paper, we explore the effect of antibody-dependent enhancement on the transmission dynamics of multistrain pathogen populations. We show that enhancement frequently may generate complex and persistent cyclical or chaotic epidemic behavior. Furthermore, enhancement acts to permit the coexistence of all strains where in its absence only one or a subset would persist.

Animals↗
PubMed1999

Acquired immunity and postnatal clinical protection in childhood cerebral malaria.

By analysing data on the age distribution of cerebral malaria among sites of different transmission intensities, we conclude that the most plausible explanation for the epidemiological patterns seen is that (i) cerebral malaria is caused by a distinct set of Plasmodium falciparum antigenic types; (ii) these antigenic types or 'CM strains' are very common and induce strong strain-specific immunity; and (iii) the postnatal period of protection against cerebral malaria is much longer than the period of protection against other forms of severe disease. The alternative hypothesis that cerebral malaria may be caused by any 'strain' of P. falciparum is compatible with the data only if a single exposure is sufficient to protect against further episodes. This is not consistent with observations on the history of exposure of patients with cerebral malaria. Finally, it is clear that although the delayed peak in incidence of cerebral malaria (with age) can be generated by assuming that subsequent exposures carry a higher risk of disease, such an explanation is not compatible with the observation that severe disease rates are low among infants and young children in areas of high transmissibility.

Africa South of the Sahara↗
PubMed1999

Differentiation-specific regulation of transgene expression in a diploid epithelial cell line derived from the normal F344 rat liver.

To establish the differentiation potential of progenitor cells, non-parenchymal epithelial cells from the F344 rat liver (FNRL cells) were studied. These cells reacted with the OV-6 antibody marker of oval cells, but were negative for hepatocyte markers (albumin, transferrin, glycogen, glucose-6-phosphatase, H4 antigen), biliary markers (gamma glutamyl transpeptidase, cytokeratin-19), and alpha-fetoprotein, although exposure to sodium butyrate induced nascent albumin and alpha-fetoprotein mRNA transcription. When stably transduced, FNRL cells expressed a retroviral promotor-driven lacZ reporter in vitro, similar to transgene expression in hepatocyte-derived HepG2 cells. However, lacZ expression in FNRL cells was rapidly extinguished in intact animals, whereas the reporter remained active in HepG2 cells. Transplanted FNRL cells showed copious glucose-6-phosphatase expression; however, the cell differentiation programme remained incomplete, despite two-thirds partial hepatectomy, D-galactosamine treatment or bile duct ligation. Interestingly, lacZ expression resumed in cultures of FNRL cells explanted from recipients. Moreover, lacZ expression was down-regulated by gamma-interferon in FNRL cells, without affecting lacZ activity in HepG2 cells. The data indicate that although subpopulations of oval cells may not fully differentiate into mature hepatocytes, these cells might serve critical functions, such as glucose utilization, and help survival after liver injury. Also, introduced genes may be regulated in progenitor cells at multiple levels, including by interactions between regulatory sequences, differentiation-specific cellular factors, and extracellular signals; in vivo studies are thus especially important for analysing gene regulation in progenitor cells.

Animals↗
PubMed1999

Effects of increasing balloon pressure on mechanism and results of balloon angioplasty for treatment of restenosis after Palmaz-Schatz stent implantation: an angiographic and intravascular ultrasound study.

Repeat balloon angioplasty is a widely used therapeutic option for in-stent restenosis, but the optimal balloon inflation pressure has not yet been determined. We used angiography and intravascular ultrasound imaging to assess the mechanism and results of lumen enlargement at various inflation pressures. Thirteen consecutive patients with restenosis post-Palmaz-Schatz stent implantation were submitted to a four-step balloon angioplasty using increasing balloon pressure of 2, 4, 8, and >12 atm. As a global result, the lumen size was only 80% of that observed at stent implantation. Significant changes in angiographic minimal lumen diameter, minimal lumen cross-sectional area, and lumen volume were observed after each step except after the highest-pressure inflation. At low inflation pressure (<8 atm), the decrease in neointimal tissue and the stent over expansion explained the lumen enlargement, whereas after further high inflation pressure (>8 atm), only additional stent over expansion was observed. These results suggest that only moderate balloon inflation pressure (up to 12 atm) is needed for angioplasty of post-Palmaz-Schatz stent restenotic lesions.

Angioplasty, Balloon, Coronary↗
PubMed1999

Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium.

To establish the process by which transplanted cells integrate into the liver parenchyma, we used dipeptidyl peptidase IV-deficient F344 rats as hosts. On intrasplenic injection, transplanted hepatocytes immediately entered liver sinusoids, along with attenuation of portal vein radicles on angiography. However, a large fraction of transplanted cells (>70%) was rapidly cleared from portal spaces by phagocyte/macrophage responses. On the other hand, transplanted hepatocytes entering the hepatic sinusoids showed superior survival. These cells translocated from sinusoids into liver plates between 16 and 20 hours after transplantation, during which electron microscopy showed disruption of the sinusoidal endothelium. Interestingly, production of vascular endothelial growth factor was observed in hepatocytes before endothelial disruptions. Portal hypertension and angiographic changes resulting from cell transplantation resolved promptly. Integration of transplanted hepatocytes in the liver parenchyma required cell membrane regenesis, with hybrid gap junctions and bile canaliculi forming over 3 to 7 days after cell transplantation. We propose that strategies to deposit cells into distal hepatic sinusoids, to disrupt sinusoidal endothelium for facilitating cell entry into liver plates, and to accelerate cell integrations into liver parenchyma will advance applications of hepatocyte transplantation.

Animals↗
PubMed1999

Childhood iron deficiency anemia, maternal nutritional knowledge, and maternal feeding practices in a high-risk population.

BACKGROUND: Despite the proven success of national efforts such as the Special Supplementary Food Program for Women, Infants, and Children (WIC) to curb childhood iron deficiency anemia (IDA) in the United States, aggregate programmatic data may not accurately represent the experience of particularly high risk groups, such as the children of adolescent mothers of low socio-economic status. METHODS: This study evaluated the prevalence and severity of childhood anemia and associated risk factors, at one urban teen health center serving primarily low-income adolescent mothers and their children. A total of 175 pediatric WIC charts were reviewed to abstract hemoglobin status and other data. Additionally, 81 mothers were interviewed with regard to their nutritional knowledge and feeding practices; these findings were compared with the measured hemoglobin (Hgb) of their children. RESULTS: A total of 34.9% of children in the study population were found to be anemic (Hgb </= 11. 2). Low childhood Hgb status was significantly correlated with racial identification, child age, maternal perception of feeding difficulty, and the presence of concurrent pediatric medical illness. Report of extensive nutritional discussion with a physician was correlated with normal Hgb levels. No differences in nutritional knowledge or feeding practices were detected between mothers of children with low iron status. CONCLUSIONS: We conclude that the risk of iron deficiency, even among children receiving WIC services, may be underestimated in certain "nutritionally very high risk" populations. Further study of interventions for IDA in children of young, low-income mothers is recommended.

Adolescent↗
PubMed1999

Detection of subarachnoid and intravascular epidural catheter placement.

PURPOSE: To report the detection of subarachnoid and intravascular catheter placement using nerve stimulation through an epidural catheter. CLINICAL FEATURES: Electrical stimulation (1-10 mA) was applied through the catheter. A positive motor response (truncal or limb movement) indicated that the catheter was in the epidural space. Absence of a motor response indicated that it was not. A low milliamperage (<1 mA) with bilateral response indicated subarachnoid placement. Intravascular catheter placement was indicated by a positive response to the test, which remains at or returns to the baseline levels (i.e. prior to any local anesthetic injection), despite the administration of local anesthetics. In the first patient, the test confirmed subarachnoid catheter placement during attempts at continuous spinal anaesthesia even though CSF could not be aspirated. Bilateral motor response in the legs was observed at 0.2 mA. In the second patient, inadvertent subarachnoid placement was detected during attempted lumbar epidural block by observing bilateral motor response in the legs at 0.3 mA. In the third patient, intravascular placement was suspected and confirmed by failure to obliterate the motor response despite repeated local anesthetic injection. CONCLUSION: The new test provides objective information in managing epidural catheters when their position is uncertain.

Adult↗
PubMed1999

Congenital pouch colon in females.

From January 1995 to March 1998, congenital pouch colon (CPC) with anorectal agenesis was diagnosed in ten girls who were classified into four groups based on the length of normal colon proximal to the colonic pouch. Of six girls with little or no normal colon, one had a cloacal anomaly while five had a colovesical or colovestibular fistula along with a completely bifid uterus and cervix and a septate vagina. Initial surgery consisted of ligation of the fistula and subtotal pouch excision with tubularization of the remaining colon in four girls, ileostomy after excision of a gangrenous pouch in one, and window colostomy in another. None of the patients had a sacral abnormality or associated major malformation. Definitive surgery using the posterior sagittal approach consisted of a pull-through of the tubularized colon in three girls (including one in whom one-stage cloacal reconstruction was performed), the ileum in one, and the proximal colon in another. The four girls with a longer length of normal colon had an associated vestibular fistula. In these, a colostomy was constructed just proximal to the pouch with definitive surgery in two patients consisting of excision of the pouch and pull-through of the proximal colon. Definitive surgery was well tolerated in all seven patients. The embryogenesis of this condition and the related genitourinary tract abnormalities are discussed.

Abnormalities, Multiple↗
PubMed1999

Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

OBJECTIVES: To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. METHODS: Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. RESULTS: In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration-effect model, a tolerance term was needed to account for counterclockwise hysteresis. CONCLUSIONS: Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder.

Analysis of Variance↗
PubMed1999

Biliary changes in extrahepatic portal venous obstruction: compression by collaterals or ischemic?

BACKGROUND: The postulated mechanisms of biliary abnormalities in extrahepatic portal venous obstruction (EHPVO) are either extrinsic compression by collaterals or ischemic injury due to venous thrombosis. If the former hypothesis is correct, then biliary changes should revert to normal after portasystemic shunt surgery. METHODS: Five patients with EHPVO who underwent portasystemic shunt surgery were studied. One of these patients had obstructive jaundice due to portal cavernoma. Endoscopic retrograde cholangiography (ERC) was performed before as well as after the shunt surgery. Doppler ultrasound and splenoportovenography were obtained to confirm the diagnosis of EHPVO as well as shunt patency. RESULTS: All patients had biliary abnormalities on pre-shunt ERC. The post-shunt ERC showed partial reversal of biliary abnormalities in 3 patients, complete reversal in 1 patient, and no reversal in 1 patient. Smooth strictures opened after shunt surgery and proximal dilatation disappeared in most patients. The indentations and caliber irregularities disappeared after shunt surgery, whereas angulations and ectasias of biliary ducts persisted. CONCLUSION: Shunt surgery results in regression of some of the biliary abnormalities and relieves biliary obstruction, suggesting that mechanical compression by collaterals is the mechanism behind biliary abnormalities in EHPVO. However, some biliary changes persist after shunt surgery signifying fixed obstruction due to ischemia or fibrous scarring. Thus, the two theories are not mutually exclusive.

Adolescent↗
PubMed1999

Chronic infection in the aetiology of atherosclerosis--focus on Chlamydia pneumoniae.

An inflammatory basis to atherosclerosis is now accepted. It remains plausible (but unproven) that common infectious agents may contribute to the inflammatory signal, and hence the development (and/or progression of atherosclerosis and its clinical sequelae. Of the candidate microorganisms implicated, Chlamydia pneumoniae has emerged as the most likely pathogen to have a casual role. Evidence for this is based on sero-epidemiological, pathological and laboratory-based evidence, in addition to early animal models and small-scale antibiotic studies. A past decade of research has now culminated in prospective antibiotic intervention trials in coronary heart disease to be conducted. The results of these studies should help to finally determine whether infection with C. pneumoniae is a pathogenetic factor in atherosclerosis, and whether antibiotic therapy has a role in the secondary prevention of coronary heart disease.

Animals↗
PubMed1999

Identification of linear surface epitopes on the guinea pig sperm membrane protein PH-20.

The sperm plasma membrane protein PH-20 has previously been shown to be an effective immunogen for protection against fertilization in guinea pigs. To identify immunodominant regions on gpPH-20 that may be related to this contraceptive effect, we used several high-titer immune sera obtained from animals rendered infertile by gpPH-20 injections to screen a set of overlapping peptides that cover the entire 494-residue sequence. Multiple clusters of peptide sequences exhibited specific reactivity. Some of these sequences were then constructed as octameric synthetic peptides and tested for immunogenicity in female guinea pigs. Our results indicated two regions (res. 94-119 and res. 424-444) to be highly immunogenic and both are surface accessible when native gpPH-20 is in solution or anchored on sperm surface. Both anti-peptide antibodies are specific for gpPH-20 and one of them inhibited hyaluronidase activity partially. These monospecific antibodies should be useful probes for further molecular definition of gpPH-20 structure-function relationships.

Amino Acid Sequence↗