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Biomedical subjects

A Sharma

Publications and source records attributed to A Sharma.

At least 469 records · Page 26Linked to original sources
PubMed1997

Phase II study of flutamide as second line chemotherapy in patients with advanced pancreatic cancer.

Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma who had developed progressive disease following therapy with one 5-FU-based regimen. Fourteen patients were treated with flutamide, 250 mg orally three times per day. Therapy was generally well tolerated. No patients achieved objective tumor response. No patient had improvement in tumor-related symptoms as measured by improvement in pain intensity, analgesic requirement, performance status, or nutritional status. Median survival was 4.7 months. We conclude that flutamide is ineffective second line therapy for patients with advanced pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1997

Preclinical and clinical strategies for development of telomerase and telomere inhibitors.

BACKGROUND: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anti-cancer strategy. DESIGN: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.

Animals↗
PubMed1997

Liposome-mediated therapy of intracranial brain tumors in a rat model.

PURPOSE: Malignant brain tumors represent a serious therapeutic challenge, and survival often is low. We investigated the delivery of doxorubicin (DXR) to rat brain tumors in situ via liposomes, to test the hypothesis that intact liposomes undergo deposition in intracranial tumor through a compromised blood-tumor vasculature. Both therapeutic effect and intra-tumor drug carrier distribution were evaluated to identify variables in carrier-mediated delivery having impact on therapy. METHODS: The rat 9L gliosarcoma tumor was implanted orthotopically in Fischer 344 rats in the caudate-putamen region. The tumor-bearing rats were treated with DXR, either free or encapsulated in long-circulating, sterically-stabilized liposomes. Anti-tumor efficacy was assessed by survival time. In parallel, liposomes labeled with a fluorescent phospholipid analog were injected into tumor-bearing rats. At predetermined intervals, the brains were perfused with fixative, sectioned, and imaged with laser scanning confocal microscope (LSCM) to investigate the integrity of the tumor vascular bed and the intratumor deposition of liposomes. RESULTS: Free DXR given in 3 weekly iv injections was ineffective in increasing the life span of tumor-bearing rats at cumulative doses < or = 17 mg/kg, and at the highest dose (17 mg/kg) decreased survival slightly, compared to saline-treated controls. In contrast, DXR encapsulated in long-circulating liposomes mediated significant increases in life span at 17 mg/kg. Rats showed a 29% percent increase in median survival, respectively, compared to saline-control animals. The delay of treatment after tumor implantation was a major determinant of therapeutic effect. Fluorescent liposomes were deposited preferentially in tumor rather than normal brain, and were distributed non-uniformly, in close proximity to tumor blood vessels. CONCLUSIONS: Liposomes can be used to enhance delivery of drugs to brain tumors and increase therapeutic effect. The therapeutic effect may arise from release of drug from liposomes extravasated in discrete regions of the tumor vasculature and the extravascular space.

Animals↗
PubMed1997

Dietary chemoprevention of clastogenic effects of 3,4-benzo(a)pyrene by Emblica officinalis Gaertn. fruit extract.

Dietary supplementation with extract of fruit of Emblica officinalis Gaertn. (a rich source of vitamin C) to mice in vivo significantly reduced the cytotoxic effects of a known carcinogen, 3,4-benzo(a)pyrene. Age-matched Swiss albino mice were fed by gavaging the fruit extract daily for 28 days. From day 9, one dose of the carcinogen was given on alternate days up to a total of eight doses. On day 29, all mice were transferred to normal diet. Control sets received the extract alone, the carcinogen alone and olive oil alone. All mice were sacrificed at 12 weeks and 14 weeks after the end of the experiment. Chromosome preparations were made from bone marrow after the usual colchicine-hypotonic-fixative-air drying-Giemsa staining schedule. Cytogenetic end points screened were the frequencies of chromosomal aberrations and of damaged cells induced. The cytotoxic effects were significantly lower in the mice given the fruit extract with the carcinogen than in those given the carcinogen alone.

Animals↗
PubMed1997

MR evaluation of CSF fistulae.

PURPOSE: To evaluate the role of MR imaging in the localisation of cerebrospinal fluid (CSF) fistulae. MATERIAL AND METHODS: A total of 36 consecutive unselected patients with either clinically proven CSF leakage (n=26) or suspected CSF fistula (n=10) were prospectively evaluated by MR. All MR examinations included fast spin-echo T2-weighted images in the 3 orthogonal planes. Thin-section CT was performed following equivocal or negative MR examination. MR and CT findings were correlated with surgical results in 33 patients. RESULTS: CSF fistula was visualised as a dural-bone defect with hyperintense fluid signal continuous with that in the basal cisterns on T2-weighted images. MR was positive in 26 cases, in 24 of which the fistula was confirmed surgically. In 2 patients the CSF leakage was directly demonstrated on MR. MR sensitivity of 80% compared favourably with the reported 46-81% of CT cisternography (CTC). No significant difference in MR sensitivity in detecting CSF fistula was found between active and inactive leaks CONCLUSION: MR is recommended as the first investigation for detecting a CSF fistula owing to its efficacy and to its freedom from the potential complications encountered with CTC.

Adolescent↗
PubMed1997

Adolescent boys in Gujarat, India: their sexual behavior and their knowledge of acquired immunodeficiency syndrome and other sexually transmitted diseases.

We assessed the sexual behavior patterns of 368 unmarried, sexually active adolescent boys (294 rural, 74 urban) and their knowledge of sexually transmitted diseases (STDs) and correct use of condoms. The mean knowledge score for STDs was low and significantly associated with educational level (p < .0001). The mean awareness score for correct use of condoms was 0.42 on a scale of 10 and significantly associated with employment status and age at first coitus (p < .001). There was a negative correlation (-0.17) between literacy and knowledge of correct use of condoms. Selection of the first sexual partner, usually a prostitute, was influenced by employment status, age at first coitus, and literacy level. These data suggest that sexually active adolescent boys in Gujarat, India are inadequately prepared to protect themselves against STDs and, therefore, that it is imperative to impart to them some knowledge of safe sex.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Sequence variations in EBNA-1 may dictate restriction of tissue distribution of Epstein-Barr virus in normal and tumour cells.

In seropositive individuals Epstein-Barr virus (EBV) establishes a virus reservoir in peripheral blood lymphocytes (PBLs). Transmission from one individual to another occurs via saliva due to a lytic (virion productive) phase of infection in the oropharynx. EBNA-1 is responsible for maintaining viral episomes in the host cell and could, therefore, also affect the persistence of the virus in different cell lineages. Based on sequence analysis of EBNA-1 we now demonstrate that (i) in addition to the prototype EBNA-1 (identical to the B95.8 virus EBNA-1), EBV in normal individuals encompasses multiple EBNA-1 subtypes, both in PBLs and in oral secretions; (ii) although EBV with prototype EBNA-1 is the predominant virus in normal individuals, it is very rarely associated with either nasopharyngeal carcinoma (NPC) or Burkitt's lymphoma (BL); (iii) EBV with an EBNA-1 subtype (V-val) frequently associated with NPC is also selectively detected in oral secretions and not in PBLs; (iv) EBV with the EBNA-1 subtype V-pro is restricted to PBLs, while a mutated version of this subtype is present in BL, but not in NPC. These findings suggest that the variations in EBNA-1 may be relevant to the ability of EBV to persist in different cell types, and hence relevant to its oncogenic potential.

Amino Acid Sequence↗
PubMed1997

Design of a recognition system to predict movement during anesthesia.

The need for a reliable method of predicting movement during anesthesia has existed since the introduction of anesthesia. This paper proposes a recognition system, based on the autoregressive (AR) modeling and neural network analysis of the electroencephalograph (EEG) signals, to predict movement following surgical stimulation. The input to the neural network will be the AR parameters, the hemodynamic parameters blood pressure (BP) and heart rate (HR), and the anesthetic concentration in terms of the minimum alveolar concentration (MAC). The output will be the prediction of movement. Design of the system and results from the preliminary tests on dogs are presented in this paper. The experiments were carried out on 13 dogs at different levels of halothane. Movement prediction was tested by monitoring the response to tail clamping, which is considered to be a supramaximal stimulus in dogs. The EEG data obtained prior to tail clamping was processed using a tenth-order AR model and the parameters obtained were used as input to a three-layer perceptron feedforward neural network. Using only AR parameters the network was able to correctly classify subsequent movement in 85% of the cases as compared to 65% when only hemodynamic parameters were used as the input to the network. When both the measures were combined, the recognition rate rose to greater than 92%. When the anesthetic concentration was added as an input the network could be considerably simplified without sacrificing classification accuracy. This recognition system shows the feasibility of using the EEG signals for movement during anesthesia.

Anesthesiology↗
PubMed1997

Visual and auditory evoked responses in acute severe hepatitis.

Evoked responses have not been studied in patients with acute severe hepatitis (ASH) with or without hepatic encephalopathy. This prospective study was undertaken to find out diagnostic as well as prognostic value of visual evoked responses (VER), and brain stem auditory evoked responses (BAER) in patients with ASH with or without encephalopathy. Visual evoked responses and BAER were studied in 20 patients (14 males and six females) with ASH. The patients were diagnosed as having severe hepatitis if acute hepatitis was associated with raised serum bilirubin and serum transaminases, and if they had a prothrombin time index of < 50%. After a detailed neuropsychiatric examination of each patient, the study sample was divided into two groups of 10 patients: ASH without encephalopathy (ASH-WOE), and ASH with encephalopathy (fulminant hepatic failure, FHF). The median P100 latencies of FHF patients were significantly increased compared with controls and patients in the ASH-WOE group. Abnormal P100 latencies, exceeding 95th percentile values of the controls, were present in one patient in the ASH-WOE group and six patients in the FHF group. The median interpeak latencies I-III, III-V and I-V were significantly prolonged in the FHF group. Interpeak latencies III-V were also increased significantly in patients in the ASH-WOE group. While abnormal BAER were seen frequently in both groups, VER abnormalities were largely confined to patients in the FHF group. In the FHF group, six out of 10 patients survived and exhibited clinical improvement in the status of hepatic encephalopathy. Evoked responses were repeated after 2-3 weeks of recovery in these patients and VER abnormalities showed a tendency to normalize, thereby suggesting a prognostic implication. The incidence of abnormal VER in hepatic encephalopathy complicating ASH far exceeded that of abnormal BAER. Markedly prolonged P100 latencies in FHF patients indicate poor prognosis.

Acute Disease↗
PubMed1997

Granulocytic sarcoma of uterine cervix as presentation of acute myeloid leukemia: a case report and review of literature.

Localized extramedullary collection of leukemic cells is termed as granulocytic sarcoma. Incidences of 2-8% in acute myeloid leukemia have been reported in various autopsy studies. In female it usually involves ovary. Since most of such tumors are asymptomatic, they are detected only at autopsy. We report here a case who manifested as abnormal vaginal bleeding, large cervical mass, renal failure, and aspergillous fungaemia. The patient died before she could be treated. From the present report it would appear that granulocytic sarcoma at times may precede other manifestations of leukemia.

Adult↗
PubMed1997

Interactions between transvenous nonthoracotomy cardioverter defibrillator systems and permanent transvenous endocardial pacemakers.

Limited information is available regarding potential adverse interactions between transvenous nonthoracotomy cardioverter defibrillators and pacemakers. We describe our experience with 37 patients who have undergone successful implantation of both a transvenous defibrillator and pacemaker. The patients' mean age was 64 +/- 12.9 years. Thirty-three were male and four were female. The mean LVEF was 30.8% +/- 11.8%. The indications for pacemaker implantation included sick sinus syndrome in 13 patients, complete heart block in 15 patients, sinus bradycardia secondary to medications in 8 patients, and neurocardiogenic syncope in 1 patient. The indications for insertion of a defibrillator included medically refractory VT in 27 patients and sudden cardiac death in 10 patients. Twenty-three patients received an Endotak lead and 14 patients received a Transvene lead. Eighteen patients had a pacemaker prior to an ICD, 14 patients had an ICD prior to a pacemaker, and 4 patients had both devices placed simultaneously. Interaction was evaluated at implant of the second device and 1-3 days after both devices were placed. Detection of VF/VT was analyzed during asynchronous pacing (DOO/VOO) with maximum pacing output. In addition, in six patients, DFT was determined before and after pacemaker implantation. In 14 patients (38%), device interactions that could not always be optimally corrected were observed. In five patients, the pacemaker was reset to the "noise reversion" mode after high energy ICD discharge. Oversensing of atrial pacemaker stimuli resulted in inappropriate ICD firings in four patients. This was observed only with a specific device and could not be prevented by atrial lead repositioning in two of them, but required reprogramming of the pacemaker to the VVI mode. An increase in DFT was observed in five patients who had a pacemaker implanted after an ICD. Compared with previously published studies, a greater frequency of transvenous ICD and pacemaker interactions were observed. Considering that almost 50% of the patients already have a pacemaker at the time of ICD implant, the availability of defibrillators with dual chamber pacing capability will not eliminate the potential for this problem.

Aged↗
PubMed1997

The effects of buspirone on perceived exertion and time to fatigue in man.

Male subjects exercised at 80% maximal rate of O2 uptake (VO2,max) following oral administration of either placebo or the partial 5-HT1A agonist buspirone (45 mg), using a paired design. Ratings of perceived exertion were higher following buspirone and time to volitional fatigue (median and inter-quartile range) fell significantly by approximately a third from 26 min (24-30 min) on placebo to 16 min (11-19 min) following buspirone. Serum prolactin was significantly elevated following buspirone administration, indicating increased hypothalamic 5-HT1A receptor stimulation. There were no significant differences in blood lactate or serum glucose between the trials. This study supports the possible central modulation of exercise tolerance by serotonergic pathways, although a role for dopamine cannot be excluded.

Adult↗
PubMed1997

Biodegradation of glyceryl trinitrate by Penicillium corylophilum Dierckx.

Penicillium corylophilum Dierckx, isolated from a contaminated water wet, double-base propellant, was able to completely degrade glyceryl trinitrate (GTN) in a buffered medium (pH 7.0) containing glucose and ammonium nitrate. In the presence of 12 mg of initial fungal inoculum, GTN (48.5 to 61.6 mumol) was quantitatively transformed in a stepwise process to glyceryl dinitrate (GDN) and glyceryl mononitrate (GMN) within 48 h followed by a decrease in the GDN content with a concomitant increase in the GMN level. GDN was totally transformed to GMN within 168 h, and the complete degradation of GMN was achieved within 336 h. The presence of glucose and ammonium nitrate in the growth medium was essential for completion of the degradation of GTN and its metabolites. Complete degradation of GTN by a fungal culture has not been previously reported in the literature.

Biodegradation, Environmental↗
PubMed1997

Role of the carboxyl-terminal region of Porphyromonas gingivalis fimbrillin in binding to salivary proteins.

Porphyromonas gingivalis fimbriae are considered to play an important role in the adherence and colonization of the bacteria in the oral cavity. In this study, we generated and purified three carboxyl-terminal variants of recombinant fimbrillin (r-FimA 224-337, r-FimA 266-337, and r-FimA 287-337, corresponding to amino acid residues 224 to 337, 266 to 337, and 287 to 337, respectively, of the 43-kDa fimbrillin of P. gingivalis 2561). They were used as inhibitors of P. gingivalis cell binding to human salivary protein-coated hydroxyapatite (HAP) beads. All of the carboxyl-terminal region polypeptides inhibited binding in a dose-dependent manner; however, the inhibitory effect of r-FimA 287-337 was less than that of the other two polypeptides when HAP beads were coated with whole saliva or purified salivary proline-rich protein 1 (PRP1). Assays of binding of a synthetic peptide corresponding to amino acid residues 266 to 286 of P. gingivalis 2561 fimbrillin to salivary proteins showed that this peptide bound strongly to whole saliva or PRP1 but only weakly to statherin. These results suggest that the carboxyl-terminal region corresponding to amino acid residues 266 to 337 of P. gingivalis fimbrillin plays an important role in binding to salivary proteins and that the domain corresponding to amino acids 266 to 286 is likely a major binding site for PRP1s and the domain corresponding to amino acids 287 to 337 is likely a major binding site for statherin.

Adult↗
PubMed1997

Arginine-glycine-aspartic acid-specific binding by foot-and-mouth disease viruses to the purified integrin alpha(v)beta3 in vitro.

The integrin alpha(v)beta3 has been shown to act as the receptor for internalization of foot-and-mouth disease virus (FMDV) (A12), with attachment being through a highly conserved RGD motif located on the G-H loop of viral capsid protein VP1. In addition, however, we have recently shown that efficient infection of culture-grown cells by FMDV (O1BFS) requires binding to cell surface heparan sulfate. In this study, we have used a solid-phase receptor binding assay to characterize the binding by FMDV to purified alpha(v)beta3 in the absence of heparan sulfate and other cell surface components. In this assay, FMDV (O1BFS) successfully replicated authentic ligand binding by cellular alpha(v)beta3 in terms of its high affinity, dependence on divalent cations, and activation by manganese ions. Virus binding to this preparation of alpha(v)beta3 was exquisitely sensitive to competition by short RGD-containing peptides (50% inhibition at < 10(-8) M peptide), and this inhibition was highly sequence specific, with the equivalent RGE peptide being at least 10(4) fold less effective as a competitor. Representative viruses of the other six serotypes of FMDV bound to alpha(v)beta3 in a similar RGD-specific manner, although significant differences in sensitivity to RGD peptides suggest that the affinity of the different FMDV serotypes for alpha(v)beta3 is influenced, in part, by the variable amino acid residues in the VP1 G-H loop on either side of the RGD.

Aphthovirus↗
PubMed1997

Functional characterization of the transactivation properties of the PDX-1 homeodomain protein.

Pancreas formation is prevented in mice carrying a null mutation in the PDX-1 homeoprotein, demonstrating a key role for this factor in development. PDX-1 can also bind to and activate transcription from cis-acting regulatory sequences in the insulin and somatostatin genes, which are expressed in pancreatic islet beta and delta cells, respectively. In this study, we compared the functional properties of PDX-1 with those of the closely related Xenopus homeoprotein XIHbox8. Analysis of chimeras between PDX-1, XIHbox8, and the DNA-binding domain of the Saccharomyces cerevisiae transcription factor GAL4 revealed that their transactivation domain was contained within the N-terminal region (amino acids 1 to 79). Detailed mutagenesis of this region indicated that transactivation is mediated by three highly conserved sequences, spanning amino acids 13 to 22 (subdomain A), 32 to 38 (subdomain B), and 60 to 73 (subdomain C). These sequences were also required by PDX-1 to synergistically activate insulin enhancer-mediated transcription with another key insulin gene activator, the E2A-encoded basic helix-loop-helix E2-5 and E47 proteins. These results indicated that N-terminal sequences conserved between the mammalian PDX-1 and Xenopus XIHbox8 proteins are important in transcriptional activation. Stable expression of the PDX-1 deltaABC mutant in the insulin- and PDX-1-expressing betaTC3 cell line resulted in a threefold reduction in the rate of endogenous insulin gene transcription. Strikingly, the level of the endogenous PDX-1 protein was reduced to very low levels in these cells. These results suggest that PDX-1 is not absolutely essential for insulin gene expression in betaTC3 cells. We discuss the possible significance of these findings for insulin gene transcription in islet beta cells.

Amino Acid Sequence↗
PubMed1997

In vivo immunofluorescence to diagnose herpes simplex virus keratitis in mice.

BACKGROUND/AIMS: Herpes simplex virus keratitis (HSK) is the most common cause of corneal blindness in the Western world. Delay in the treatment of HSK can lead to a more significant corneal scar and topical steroid treatment in unsuspected active HSK can lead to corneal melting. Current culture techniques for herpes simplex virus (HSV) take several days and commercially available HSV laboratory based diagnostic techniques such as Herpchek vary in sensitivity. This study was conducted to assess the viability of a new, quicker, and simpler method to diagnose HSK. METHODS: Direct immunofluorescence was used in vivo in a masked study to diagnose HSK in mice using a standard slit lamp with cobalt blue illumination. Murine monoclonal fluorescently labelled antibody was applied to the cornea for 10 or 20 minutes and then washed off with phosphate buffered solution. Mice with HSK were stained with either fluorescently labelled monoclonal antibody against HSV or fluorescently labelled monoclonal antibody against cytomegalovirus. Mice with corneal abrasions of non-viral origin were given fluorescently labelled monoclonal antibody against HSV. RESULTS: Fluorescence was seen only in the mice with HSK given fluorescently labelled monoclonal antibody against HSV. This observation was confirmed upon microscopic immunofluorescent imaging of the corneal epithelial sheets. CONCLUSION: In vivo immunofluorescence may be useful in the clinical diagnosis of HSK.

Animals↗