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Biomedical subjects

S Gupta

Publications and source records attributed to S Gupta.

At least 37 records · Page 2Linked to original sources
PubMed2001

A semiparametric deconvolution model to establish in vivo-in vitro correlation applied to OROS oxybutynin.

In vitro-in vivo correlation (IVIVC) models may be used to predict in vivo drug concentration-time profiles given in vitro release characteristics of a drug. This prediction is accomplished by incorporating in vitro release characteristics as an input function (A(vitro)) to a pharmacokinetics model. This simple approach often results in biased predictions of observed in vivo drug concentrations, and it can result in rejecting IVIVC. To solve this problem we propose a population IVIVC model that incorporates the in vitro information and allows one to quantify possibly changed in vivo release characteristic. The model assumes linear kinetics and describes the in vivo release as a sum of A(vitro) and a nonparametric function (A(d), a spline) representing the difference in release due to in vivo conditions. The function A(vitro) and its variability enter the model as a prior distribution. The function A(d) is estimated together with its intersubject variability. The number of parameters associated with A(d) defines the model: no parameters indicates perfect IVIVC, a large number of parameters indicates poor IVIVC. The number of parameters is determined using statistical model selection criteria. We demonstrate the approach to solve the IVIVC problem of an oral extended release oxybutynin form (OROS), administered in three pharmacokinetic studies. These studies present a particular challenging case; that is, the relative bioavailability for the OROS administration is >100% compared with that of the immediate-release form. The result of our modeling shows that the apparent lack of IVIVC can be overcome: in vivo concentration can be predicted (within or across data sets) based on in vitro release rate together with a simple form of systematic deviation from the in vitro release.

Biological Availability↗
PubMed2001

Correction of liver disease following transplantation of normal rat hepatocytes into Long-Evans Cinnamon rats modeling Wilson's disease.

To establish the efficacy of cell therapy in Wilson's disease, we used the Long-Evans Cinnamon (LEC) rat model with atp7b gene mutation and copper toxicosis. Several groups of LEC rats were established, including animals pretreated with retrorsine to exacerbate copper toxicosis and inhibit proliferation in native hepatocytes followed by partial hepatectomy to promote liver repopulation. Hepatocytes from normal, syngeneic LEA rats were transplanted intrasplenically. Animal survival, biliary copper excretion, and hepatic copper were determined. The magnitude of liver repopulation was demonstrated by measuring serum ceruloplasmin and hepatic atp7b mRNA. Long-term survival in LEC rats treated with retrorsine, partial hepatectomy, and cell transplantation was up to 90%, whereas fewer than 10% of animals pretreated with retrorsine, without cell therapy, survived, P < 0.001. Liver repopulation occurred gradually after cell transplantation, ranging from <25% at 6 weeks, 26 to 40% at 4 months, and 74 to 100% at 6 months or beyond. Liver repopulation restored biliary copper excretion capacity and lowered liver copper levels. Remarkably, liver histology was completely normal in LEC rats with extensive liver repopulation, compared with widespread megalocytosis, apoptosis, oval cell proliferation, and cholangiofibrosis in untreated animals. These data indicate that liver repopulation with functionally intact cells can reverse pathophysiological perturbations and cure Wilson's disease.

Adenosine Triphosphatases↗
PubMed2001

Gag-derived proteins of HIV-1 isolates from Indian patients: cloning, expression, and purification of p17 of B- and C-subtypes.

A simple and efficient method for expression in Escherichia coli and purification of matrix protein, p17, of human immunodeficiency virus type 1 (HIV-1) of both B- and C-subtypes is described. DNA sequences encoding p17 of B- and C-subtype were cloned from respective gag sequences. The gag sequences were obtained by PCR amplification using DNA extracted from peripheral blood lymphocytes of an HIV-1 infected patient from India. A T7-promoter-based expression system was optimized for expression of p17 in soluble form. p17 (B- and C-subtype) was purified to near homogeneity using conventional chromatographic techniques. Purification of p17 (C-subtype) is described for the first time with yield of 7.7 mg from a 1-liter culture. The yield of p17 (B-subtype) is 14.7 mg from a 1-liter culture, which is severalfold better than that reported earlier. N-terminal sequencing and CD spectra of the purified proteins, p17B and p17C, show that the proteins are properly processed and well-folded. The immunoreactivity of both types of p17 to sera from HIV-infected individuals is comparable.

Amino Acid Sequence↗
PubMed2001

Hepatocyte transplantation: new horizons and challenges.

Hepatocyte transplantation represents an alternative strategy for treating liver disease. Liver repopulation following acute liver failure could, potentially, eliminate the requirement for orthotopic liver transplantation. Similarly, the ability to repopulate the liver with disease-resistant hepatocytes offers new opportunities for correcting genetic disorders and treating patients with chronic liver disease. Recent advances concerning the fate of transplanted cells in the recipient liver, the efficacy of cell therapy in outstanding animal models of human disease. and the isolation of progenitor liver cells capable of differentiating into mature hepatocytes have renewed optimism in regard to treating people with hepatocyte transplantation. Recruitment of an increasing number of investigators to the field and the success of recent pilot studies indicate that hepatocyte transplantation will become routine clinical practice in the near future.

Animals↗
PubMed2001

Superficial temporal artery biopsy diagnostic for lung carcinoma.

PURPOSE: To report a unique finding of metastatic tumor cells in the lumen of a superficial temporal artery biopsy specimen in a patient with severe visual loss and optic neuropathy. METHODS: Case report. RESULTS: A 69-year-old man presented with anorexia, pancranial headaches, and acute unilateral visual loss. Ophthalmic examination showed a visual acuity of no light perception and an amaurotic pupil in the left eye. Fundus examination was normal. A superficial temporal artery biopsy, performed for presumed arteritic posterior ischemic optic neuropathy, demonstrated intraluminal cells with irregular nuclei and prominent nucleoli suggestive of metastatic malignancy. Further systemic evaluation uncovered a poorly differentiated adenocarcinoma of the lung with intravascular infiltration and multiple distant metastases. CONCLUSION: Extensive systemic intravascular tumor embolization may be associated with optic neuropathy.

Adenocarcinoma↗
PubMed2001

Paired human fibrosarcoma cell lines that possess or lack endogenous mutant N-ras alleles as experimental model for Ras signaling pathways.

We present here a human cell model for examination of mutant N-ras function. The HT1080 human fibrosarcoma cell line is pseudodiploid and contains a single endogenous mutant N-ras allele. MCH603c8 cells are a variant of HT1080 cells, in which the mutant allele has been deleted. The two cell lines differ dramatically in the constitutive levels of activation of downstream members of the Ras signaling pathways, and in biological features of transformation and tumorigenicity. Downregulation or activation of individual Ras-dependent pathways can be accomplished via transfection of dominant negatives or activated mutant cDNAs into HT1080 and MCH603c8 cells, respectively. The biochemical and biological consequences of expression of these mutant cDNAs can be assessed. There are dramatic effects on both the transformed and tumorigenic phenotype, depending on the cell line and mutant cDNA that is transfected.

Actins↗
PubMed2001

Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study.

BACKGROUND: Significant cardiac toxicity has been associated with some older antihistamines (eg, terfenadine and astemizole) when their plasma concentrations are increased. There is thus a need for a thorough assessment of the cardiac safety of newer antihistamine compounds. OBJECTIVE: This study was undertaken to assess the effects of coadministration of desloratadine or fexofenadine with azithromycin on pharmacokinetic parameters, tolerability, and electrocardiographic (ECG) findings. METHODS: Healthy volunteers aged 19 to 46 years participated in this randomized, placebo-controlled, parallel-group, third-party-blind, multiple-dose study. Subjects received desloratadine 5 mg once daily, fexofenadine 60 mg twice daily, or placebo for 7 days. An azithromycin loading dose (500 mg) followed by azithromycin 250 mg once daily for 4 days was administered concomitantly starting on day 3. Group 1 received desloratadine and azithromycin, group 2 received desloratadine and placebo, group 3 received placebo and azithromycin, group 4 received fexofenadine and azithromycin, and group 5 received fexofenadine and placebo. RESULTS: The results of the pharmacokinetic analysis revealed little change in mean maximum concentration (Cmax) and area under the concentration-time curve (AUC) values for desloratadine with concomitant administration of azithromycin: Cmax ratio, 115% (90% CI, 92-144); AUC, ratio 105% (90% CI, 82-134). The corresponding ratios for 3-hydroxydesloratadine were 115% (90% CI, 98-136) and 104% (90% CI, 88-122), respectively. A substantial increase was observed in mean Cmax and AUC values for fexofenadine when administered with azithromycin: Cmax, ratio, 169% (90% CI, 120-237); AUC ratio, 167% (90% CI, 122-229). Compared with the group receiving desloratadine and azithromycin, subjects receiving fexofenadine and azithromycin also displayed greater variability in pharmacokinetic parameters for the antihistamine. Mean Cmax and AUC values of azithromycin were slightly higher when administered with desloratadine (Cmax ratio, 131% [90% CI, 92-187]; AUC ratio, 112% [90% CI, 83-153]) but were lower when given in combination with fexofenadine (Cmax ratio, 87% [90% CI, 61-124]; AUC ratio, 88% [90% CI, 65-1201). The most common adverse event for all regimens was headache, reported in 20 (22%) subjects. All combinations of desloratadine or fexofenadine with and without azithromycin were well tolerated, and no statistically significant changes in PR, QT, or QT, interval, QRS complex, or ventricular rate were observed. CONCLUSIONS: Small increases (<15%) in mean pharmacokinetics of desloratadine were observed with coadministration of azithromycin. By contrast, peak fexofenadine concentrations were increased by 69% and the AUC was increased by 67% in the presence of the azalide antibiotic. Based on the reported adverse-events profile and the absence of changes in ECG parameters, the combination of desloratadine and azithromycin was well tolerated. This study suggests that desloratadine has a more favorable drug-interaction potential than does fexofenadine.

Adolescent↗
PubMed2001

A population-based eye survey of older adults in a rural district of Rajasthan: II. Outcomes of cataract surgery.

PURPOSE: To assess the outcomes of cataract surgery in rural northwest India. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 549 cataract-operated persons (723 operated eyes). METHODS: Cluster sampling was used in randomly selecting a cross-sectional sample of persons 50 years of age or older for visual acuity measurement, refraction, and slit-lamp and direct ophthalmoscope examination early in 1999. Those operated on for cataract were queried as to the date and place of surgery. The principal cause of reduced vision was identified for all examined eyes with presenting visual acuity worse than 6/18. MAIN OUTCOME MEASURES: Presenting and best-corrected visual acuity and cause of vision loss. RESULTS: Presenting visual acuity was less than 6/60 in the better eye in 33.7% of cataract-operated persons and greater than or equal to 6/18 in both eyes in 8.2%; 31.7% were bilaterally operated on. Of cataract-operated eyes, 44.1% initially had visual acuity less than 6/60 and 31.5% greater than or equal to 6/18; with best correction, the corresponding percentages were 14.0% and 61.5%. Intracapsular cataract extraction was used in 92% of cases, and 66% had been operated on in surgery camps. Surgical complications were common and a major cause of vision impairment. In multiple logistic regression modeling, female gender and residence in a rural area were associated negatively with both presenting and best-corrected visual acuity outcomes, and surgery conducted before 1990 was associated negatively with best-corrected visual acuity. Place of surgery and subject schooling were not associated with vision outcomes. CONCLUSIONS: Cataract surgery subjects in rural areas of India that are without adequately equipped facilities and skilled surgeons, and lack of availability of intraocular lenses, are not realizing the full sight-restoring potential of modern-day surgery. Emphasis on the quality of cataract surgery outcomes must be increased to keep pace with that being given to increasing surgical volume.

Aged↗
PubMed2001

A population-based eye survey of older adults in a rural district of Rajasthan: I. Central vision impairment, blindness, and cataract surgery.

PURPOSE: To assess the prevalence of central vision blindness and cataract surgery in older adults in rural northwest India. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 4284 examined persons 50 years of age or older. METHODS: A random selection of village-based clusters was used to identify a population sample in the predominantly rural Bharatpur district of Rajasthan. Eligible subjects in the 25 selected clusters were enumerated through a door-to-door household survey and invited to village sites for visual acuity testing and eye examination early in 1999. The principal cause of reduced central vision was identified for eyes that had visual acuity worse than 6/18. Independent replicate testing for quality assurance monitoring took place in participants with reduced vision and in a sample of those with normal vision in five of the study clusters. MAIN OUTCOME MEASURES: Presenting and best-corrected visual acuity and lens status. RESULTS: A total of 4728 eligible persons in 2821 households were enumerated, and 4284 (90.6%) were examined. The prevalence of presenting and best-corrected visual acuity worse than 6/60 in both eyes was 11.9% (95% confidence interval: 10.0%-13.9%) and 6.1% (95% CI: 4.7%-7.4%), respectively. Presenting blindness was associated with increasing age, female gender, lack of schooling, and rural residence. Cataract was the principal cause of blindness in one or both eyes in 67.5% of blind persons, with uncorrected aphakia and other refractive error affecting 18.4% in at least one eye. The prevalence of cataract surgery was 12.8% (95% CI: 11.6%-14.0%), with an estimated 65.7% of the cataract blind operated on; low surgical coverage was associated with lack of schooling. CONCLUSIONS: Blindness, particularly blindness because of cataract, continues to be a significant problem among the elderly living in remote areas of rural northwest India. Increased attention should be given to reaching women and the illiterate.

Age Factors↗
PubMed2001

Genotoxic effects after in vivo exposure of vegetable extracts containing heavy metals from the Dhapa area of Calcutta, India. I. Effects of cauliflower, spinach and radish.

Several reports have indicated that the sewage-fed vegetables of the Dhapa area, near the city of Calcutta, contain a very high amount of heavy metals. Currently 800 ha of land is being utilised throughout the year to cultivate more than eight types of vegetables, with a production of about 147 tonnes per day. A major population of Calcutta consumes these vegetables grown in the Dhapa area. Recently there has been huge pressure on the State Government to ban vegetables grown in the Dhapa area for human consumption. For this reason, we have studied the genotoxic effects of some of the most commonly used vegetable extracts from the Dhapa area after in vivo acute exposure in mice as measured by chromosomal aberrations (CA) and sister chromatid exchanges (SCE) to find out the minimum threshold dose to induce CA and SCE. Three different concentrations of the three most commonly used vegetable extracts (cauliflower, spinach, radish) were fed by gavage to mice for the study of CA and SCE. A significant increase in CA was observed only at the highest concentration of all the vegetable extract-treated groups when compared with the solvent control. A significant increase in SCE were observed in the middle and high doses of spinach and only the high dose of cauliflower and radish extract-treated series when compared with distilled water control. The lowest dose was equivalent to approximately 1 kg of vegetables consumed by a human (60 kg body weight) in a day. The middle and high doses of each vegetable extract were much higher than the normal amount of vegetables that a human can consume per day. So the minimum dose for inducing SCE and CA was much higher than the amount a human can consume in a day. Therefore this study indicates that these vegetables are safe for human consumption up to a certain limit, and attention should be given to reducing the heavy metal contents in the soil and sewage of the Dhapa area to thus reduce the heavy metal concentrations in the vegetables.

Animals↗
PubMed2001

Epidemiology of paediatric burns in Indore, India.

A retrospective study was carried out based on 110 paediatric burns (0-14 years) seen at the Burn unit, Choithram Hospital & Research Centre, Indore over a period of 7 years (1993-1999). Epidemiological data included age, sex, seasonal variation, place of burn and the cause and mode of burn. Hospitalised paediatric burns constituted 13.5% of total burn accidents. These children were categorised into three groups, the infants and toddlers (0-2 years), early childhood (>2-6 years) and late childhood (>6-14 years). In the first two groups scalding was the predominant cause of injury while in late childhood there were many more flame and electric burns. Males were mainly affected. Most of the burns (53.6%) occurred in the winter season between October and February. Ninety-five percent of accidents occurred at home. The overall mortality rate was 21.8%. An intense campaign to make people aware of the risk factors and their avoidance is required to reduce the number of burn accidents in children.

Accidents, Home↗
PubMed2001

Exploring the evolution of diversity in pathogen populations.

Pathogen biodiversity is an under-exploited source of inference regarding disease processes and the evolution of pathogens and pathogenesis. In addition, the structure of pathogen populations, especially for diverse organisms such as the meningococcus, has implications for public health interventions including vaccination and antibiotic use. The predominant paradigm for interpreting bacterial diversity has been the clonal population structure, which has been modified by the incorporation of the effects of horizontal genetic exchange. Multilocus models of variable antigens, which explore the effects of immune selection, provide alternative explanations for structured diversity in pathogen populations.

Antigenic Variation↗
PubMed2001

Genetic toxicology of a paradoxical human carcinogen, arsenic: a review.

Arsenic is widely distributed in nature in air, water and soil in the form of either metalloids or chemical compounds. It is used commercially, as pesticide, wood preservative, in the manufacture of glass, paper and semiconductors. Epidemiological and clinical studies indicate that arsenic is a paradoxical human carcinogen that does not easily induce cancer in animal models. It is one of the toxic compounds known in the environment. Intermittent incidents of arsenic contamination in ground water have been reported from several parts of the world. Arsenic containing drinking water has been associated with a variety of skin and internal organ cancers. The wide human exposure to this compound through drinking water throughout the world causes great concern for human health. In the present review, we have attempted to evaluate and update the mutagenic and genotoxic effects of arsenic and its compounds based on available literature.

Animals↗
PubMed2001

Gallbladder vasculitis associated with type-1 cryoglobulinemia.

A patient with type I cryoglobulinemia and monoclonal gammopathy of uncertain significance was found to have acute gallbladder vasculitis. The most prominent manifestation was upper abdominal pain in the setting of normal liver tests. An abdominal ultrasound demonstrated a thickened gallbladder wall, along with gallstones. HIDA scanning showed a nonfunctioning gallbladder with an edematous and thickened wall. There was characteristic leukocytoclastic vasculitis affecting the gallbladder. The patient recovered uneventfully subsequent to cholecystectomy. Gallbladder vasculitis should be considered in patients with unexplained upper abdominal pain and systemic vasculitis.

Abdominal Pain↗
PubMed2001

Single chain Fv: a ligand in receptor-mediated gene delivery.

We have used an anti-human polymeric immunoglobulin receptor (pIgR) single chain Fv (scFv) to deliver reporter genes to epithelial cells in vitro. The scFv was constructed from a monoclonal antibody directed against pIgR and a cysteine residue was added at the carboxyl end to facilitate its conjugation to polylysine (polyK) via the heterobifunctional cross-linker SPDP. ScFv-cys was expressed in Drosophila S2 cells and purified to homogeneity using conventional column chromatography. ScFv-polyK, and polyK as control, were condensed with a DNA expression plasmid containing the luciferase reporter gene driven by the CMV promoter into unimolecular (with respect to DNA) complexes under high salt conditions. Target cells were MDCK cells transfected with human pIgR and repeatedly sorted for high-level receptor expression, with untransfected MDCK cells as control. Receptor-bearing MDCK cells were readily transfected by scFv-cys containing, pIgR directed complexes, and expression could be blocked by addition of excess human secretory component (SC), the extracellular portion of pIgR. In contrast, MDCK cells that did not express pIgR were not transfected. Nontargeted complexes were not effective in transfecting MDCK cells with or without pIgR. Targeted complexes also transfected human tracheal epithelial cells in primary culture, corroborating the pIgR-mediated gene delivery. These data indicate that a scFv directed against human pIgR can direct foreign genes specifically into receptor-bearing cells in vitro. We have expressed and purified a ligand that is efficient and specific in pIgR-mediated gene delivery.

Animals↗
PubMed2001

Negative pressure pulmonary oedema after cryotherapy for tracheal obstruction.

We report a patient who suffered negative pressure pulmonary oedema because of tracheal obstruction after cryotherapy to granulation tissue in the trachea. The pathophysiology and clinical course of negative pressure pulmonary oedema is described. Though there are reports of negative pressure pulmonary oedema after airway obstruction, to our knowledge this is the first case reported after cryotherapy.

Aged↗