Biomedical subjects
S Bhattacharya
Publications and source records attributed to S Bhattacharya.
Epirubicin-Lipiodol chemotherapy versus 131iodine-Lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma.
BACKGROUND: Arterially administered iodized oil (Lipiodol) is selectively retained by hepatocellular carcinomas (HCCs), and has been used as a vehicle for delivery of therapeutic agents to these tumors. This study compared the efficacy of Lipiodol-targeted epirubicin chemotherapy with Lipiodol-131I radiotherapy. METHODS: Ninety-five patients with unresectable HCC confined to the liver were administered either Lipiodol-epirubicin emulsion (n = 69; 61 cirrhotics; Okuda tumor Stage I, 14; II, 37; III, 18; epirubicin dose, 75 mg/m2) or Lipiodol-131I (131I) (n = 26; 18 cirrhotics; Okuda tumor Stage I, 6; II, 19; III, 1; dose 750-1050 MBq). The last 28 patients (17 epirubicin, 11 131I) were treated within a prospective randomized trial. Bolus drug or isotope was injected into the hepatic artery by transfemoral cannulation. Lipiodol and 131I uptake were gauged by 10th day computed tomography and 48-hour scintiscan. Treatments were repeated two-monthly when indicated. RESULTS: Tumor size at 2 months remained static or diminished partially in 21 of 38 epirubicin recipients (55%) and 15/22 131I recipients (68%). Actuarial survival at 6, 12, and 24 months was 40%, 25%, and 6% with epirubicin, and 58%, 25%, and 0% with 131I; 30-day mortality was 11% and 15%, respectively. Comparison with historic controls indicated survival benefit in Stages I and II. Similar findings were recorded in the 28 patients in the randomized trial. CONCLUSIONS: Patients with unresectable HCC receiving Lipiodol-epirubicin or Lipiodol-131I show good tumor localization, acceptable toxicity, and comparable survival benefit at 6 and 12 months with either modality.
Localization of human CREB-binding protein gene (CREBBP) to 16p13.2-p13.3 by fluorescence in situ hybridization.
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Surfactant lipids containing aromatic units produce vesicular membranes with high thermal stability.
Six new vesicle-forming, cationic surfactant lipids are synthesized. Four of them contain 'flat' aromatic units at different locations of hydrophobic segments. In order to estimate the influence of aromatic units in the lipid monomer two other surfactant lipids of related structure with n-butyloxy units in the places of aromatic groups were also prepared. Transmission electron microscopy confirmed the vesicular membrane formation from these newly synthesized lipids. DSC or temperature-dependent keto-enol tautomerism of benzoylacetanilide-doped vesicles reveal a remarkable increase in the thermal stability of the membranes formed from aromatic surfactant lipids in contradistinction to their counterparts that contain n-butyloxy units. The enhanced thermal stability originates presumably as a consequence of inter-monomer stacking.
cDNA sequence and gene locus of the human retinal phosphoinositide-specific phospholipase-C beta 4 (PLCB4).
Defects in the Drosophila norpA (no receptor potential A) gene encoding a phosphoinositide-specific phospholipase C (PLC) block invertebrate phototransduction and lead to retinal degeneration. The mammalian homolog, PLCB4, is expressed in rat brain, bovine cerebellum, and the bovine retina in several splice variants. To determine a possible role of PLCB4 gene defects in human disease, we isolated several overlapping cDNA clones from a human retina library. The composite cDNA sequence predicts a human PLC beta 4 polypeptide of 1022 amino acid residues (MW 117,000). This PLC beta 4 variant lacks a 165-amino-acid N-terminal domain characteristic for the rat brain isoforms, but has a distinct putative exon 1 unique for human and bovine retina isoforms. A PLC beta 4 monospecific antibody detected a major (130 kDa) and a minor (160 kDa) isoform in retina homogenates. Somatic cell hybrids and deletion panels were used to localize the PCLB4 gene to the short arm of chromosome 20. The gene was further sublocalized to 20p12 by fluorescence in situ hybridization.
Soluble ligands of the alpha v beta 3 integrin mediate enhanced tyrosine phosphorylation of multiple proteins in adherent bovine pulmonary artery endothelial cells.
Binding of substrate-bound extracellular matrix proteins to cell surface integrins results in a variety of cellular responses including adhesion, cytoskeletal reorganization, and gene expression. We have previously shown that addition of soluble SC5b-9, the complement-vitronectin complex, resulted in an RGD-dependent increase in lung venular hydraulic conductivity (Ishikawa, S., Tsukada, H., and Bhattacharya, J. (1993) J. Clin. Invest. 91, 103-109). To identify specific integrin(s) and signal transduction pathways that are responsive to soluble vitronectin-containing ligands, we exposed confluent bovine pulmonary artery cells to purified soluble human mono- or multimeric vitronectin, or SC5b-9, and determined the extent of endothelial cell protein tyrosine phosphorylation. Monomeric vitronectin (Vn) did not induce enhanced protein tyrosine phosphorylation. However, multimeric Vn and SC5b-9 elicited time- and concentration-dependent increases in tyrosine phosphorylation of numerous proteins. Antiserum against vitronectin, RGD peptides, and monoclonal and polyclonal antibodies against the alpha v beta 3 integrin blocked the vitronectin- or SC5b-9-induced enhanced accumulation of tyrosine phosphoproteins, while antibodies against beta 1 integrins and the alpha v beta 5 integrin did not. Clustering of the alpha v beta 3 integrin using monoclonal antibody LM609 caused a pattern of enhanced tyrosine phosphorylation similar to that caused by multimeric Vn and SC5b-9, suggesting that aggregation of alpha v beta 3 was critical for signaling. Among the proteins that underwent enhanced tyrosine phosphorylation in response to vitronectin were the cytoskeletal proteins paxillin, cortactin, and ezrin, as well as the SH2 domain-containing protein Shc, and p125FAK. We conclude that ligation of the alpha v beta 3 integrin by soluble ligands promotes enhanced phosphorylation of several proteins implicated in tyrosine kinase signaling and suggest that this pathway may be important in inflammatory states which are accompanied by accumulation of SC5b-9.
Flux-flow fingerprint of disorder: Melting versus tearing of a flux-line lattice.
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Evolutionary origins of apoB mRNA editing: catalysis by a cytidine deaminase that has acquired a novel RNA-binding motif at its active site.
The site-specific C to U editing of apolipoprotein B100 (apoB100) mRNA requires a 27 kDa protein (p27) with homology to cytidine deaminase. Here, we show that p27 is a zinc-containing deaminase, which operates catalytically like the E. coli enzyme that acts on monomeric substrate. In contrast with the bacterial enzyme that does not bind RNA, p27 interacts with its polymeric apoB mRNA substrate at AU sequences adjacent to the editing site. This interaction is necessary for editing. RNA binding is mediated through amino acid residues involved in zinc coordination, in proton shuttling, and in forming the alpha beta alpha structure that encompasses the active site. However, certain mutations that inactivate the enzyme do not affect RNA binding. Thus, RNA binding does not require a catalytically active site. The acquisition of polymeric substrate binding provides a route for the evolution of this editing enzyme from one that acts on monomeric substrates.
Flux flow noise and dynamical transitions in a flux line lattice.
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Ras membrane targeting is essential for glucose signaling but not for viability in yeast.
Ras proteins are small GTP binding proteins that serve as critical relays in a variety of signal transduction pathways in eukaryotic cells. Like most metazoan Ras proteins, yeast Ras is post-translationally modified by addition of a farnesyl and a palmitoyl moiety, and these modifications are required for targeting the protein to the cytoplasmic face of the plasma membrane and for biological activity of the protein. We have constructed mutants of the yeast (Saccharomyces cerevisiae) Ras that are farnesylated in vivo but are not palmitoylated. These mutant proteins are not localized to the plasma membrane but function in the cell as well as the wild-type protein. Such mutants are viable but fail to induce a transient increase in intracellular cAMP concentration in response to glucose addition, although this deficiency does not yield a marked growth phenotype. These results are consistent with the hypothesis that the essential role of the farnesyl moiety on yeast Ras is to enhance productive interaction between Ras and its essential downstream target, adenylyl cyclase, rather than to localize Ras to the plasma membrane.
The allosteric enhancer, PD 81,723, stabilizes human A1 adenosine receptor coupling to G proteins.
2-Amino-3-benzoylthiophenes such as PD 81,273 (PD) have been shown to increase agonist, but not antagonist, radioligand binding and to enhance functional effects of A1 adenosine receptor (A1AR) activation in tissues derived from rats and guinea-pigs. The mechanism by which PD produces this allosteric enhancement, and its effect on human A1ARs was not known. In this study, we demonstrate that PD modifies recombinant human A1AR binding and function in stably transfected CHO cells. In membranes, PD (20 microM) causes: (i) a 3-fold increase in the fraction of receptors found in a high affinity G-protein coupled conformation as assessed by the binding of [125I]N6-(3-iodo-4-aminobenzyladenosine) (125I-ABA), an A1AR agonist; (ii) a 2.44-fold increase in the potency of the agonist R-N6-phenylisopropyladenosine (R-PIA) to compete for binding with the antagonist radioligand, [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX); (iii) a 1.5-fold increase in the t1/2 of 125I-ABA to dissociate from A1AR; and (i.v.) a 2.2-fold increase in the concentration of guanosine-5'-3-O-(thio)triphosphate (GTP gamma S) required to half-maximally uncouple receptor-G-protein complexes. In intact CHO cells expressing A1AR, PD increases the potency of R-PIA to decrease forskolin-stimulated cAMP accumulation by 3.3-fold. We speculate that PD binds to A1AR at a site distinct from the agonist binding site and stabilizes agonist-R-G complexes.
Autosomal dominant macular dystrophy simulating North Carolina macular dystrophy.
OBJECTIVE: To characterize an autosomal dominant macular dystrophy with highly variable expression that does not fall clearly into a known disease entity. METHODS AND PATIENTS: Clinical, angiographic, and electrophysiologic data of five affected members in a family of Indian origin were evaluated. Molecular genetic analysis was undertaken to assess whether the gene responsible for the phenotype in this pedigree mapped to a region previously assigned to dominantly inherited macular dystrophies, including North Carolina macular dystrophy. RESULTS: The fundus appearance in the proband simulated stage 3 North Carolina macular dystrophy. Affected relatives had features in common with pattern dystrophy, fundus flavimaculatus with a dark choroid, and dominantly inherited drusen. Linkage to loci assigned to a number of retinal dystrophies principally affecting the posterior pole, including the North Carolina macular dystrophy locus, was excluded. CONCLUSION: The findings support the view that different genotypes are associated with similar phenotypes in autosomal dominant macular dystrophy.
Histopathological changes induced by chronic nonlethal levels of elsan, mercury, and ammonia in the small intestine of Channa punctatus (Bloch).
Histopathological changes in the intestine of Channa punctatus induced by chronic nonlethal levels of Elsan (211 ppb), mercury (16.7 ppb), and ammonia (15.64 ppm) were studied at 7-day intervals for 90 days and the data were presented only for days (7, 28, 63, and 90) when the most conspicuous changes were noted after treatment. In the earlier phases of Elsan treatment (7 and 28 days) overall destruction of the structure of villus and other layers was prominent. Histopathology of the intestine of C. punctatus, after 63-day Elsan exposure, could be described as collapsed villi with the tips merged with each other to give a flattened appearance. Ninety-day Elsan exposure demonstrated severe damage in the longitudinal muscle layer. After 7-day mercury treatment a high degree of necrosis was indicated by submucosal area, whereas 28-day mercury treatment revealed collapsed villi due to necrotic mucosal cells and goblet cells. Mercury treatment for 63 days caused disarray of all the layers, but some improvement of villus organization was noted in fish treated with mercury for 90 days. Seven-day exposure to ammonia deteriorated the normal structure of the villus, whereas in 28-day ammonia exposure, lesions were predominant in the submucosal layers. Sixty-three-day ammonia treatment demonstrated an effect similar to that produced by Elsan, associated with a more complete destruction of all the layers. Fishes under ammonia treatment for 90 days demonstrated extensive damage to the mucosal folds. The major changes in thickness of different layers of the intestine were also evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
Gonadotropin releasing hormone stimulation of cyclic 3',5'-AMP in the pituitary cell of a teleost (Channa punctatus, Bloch) requires extracellular calcium: its relationship to gonadotropin release.
Pituitary cells were prepared by enzymatic dispersion and incubated in vitro. To observe the effect of gonadotropin releasing hormone (GnRH) and Ca2+ on the murrel pituitary cyclic 3',5'-AMP (cAMP), cells were dispersed by 0.3% collagenase plus 0.05% trypsin in Earle's minimum essential medium without Ca2+ and a considerably high yield of viable cells were obtained. Addition of a murrel, Channa punctatus, GnRH (cGnRH, 10 micrograms/incubation) to pituitary cell incubation (6 x 10(4) cells/well) containing 4 mM theophylline, a phosphodiesterase (PDE) inhibitor, stimulated cAMP accumulation in the pituitary cell 2.4-fold and its release into the medium about 2-fold as compared to control. The extent of stimulation was greatly increased on addition of Ca2+ (2 mM/incubation) with cGnRH: accumulation 5.8-fold and release 3.7-fold, respectively, in comparison to control. A time-course study with cGnRH (20 micrograms/incubation) plus Ca2+ (2 mM/incubation) on pituitary cell cAMP accumulation showed that the peak of cAMP level was reached at 15 min and remained at the same level until 60 min in the presence of theophylline; this peak was drastically reduced (5-fold) at 30 min in the absence of theophylline, indicating rapid hydrolysis of cAMP by PDE. Ca(2+)-augmented cGnRH stimulatory effect on cAMP accumulation and release could be significantly (P < 0.01) inhibited by verapamil (3 microM/incubation), a specific calcium channel blocker, suggesting requirement of extracellular Ca2+ influx in this process. Calmodulin (CaM), a Ca2+ carrier protein, addition to cGnRH and Ca2+ incubation further augmented the increase of cellular accumulation of cAMP and its release by 39.5 and 45%, respectively, in comparison to cGnRH and Ca2+ (both were statistically significant, P < 0.01). CaM effect could be blocked by calmidazolium (1 microM/incubation), a specific inhibitor of CaM, indicating specificity of the stimulatory action of CaM. Addition of radioiodinated 125I-CaM, in the presence of Ca2+ or cGnRH plus Ca2+ resulted in the binding of 125I-CaM to pituitary cells and to the pellet of the lysed cells. 125I-CaM specifically binds to pituitary cell plasma membrane preparation and saturation of 125I-CaM binding occurred at 9 ng of 125I-CaM. To investigate whether cGnRH plus Ca(2+)-stimulation of pituitary cells cAMP is linked to gonadotropin (GtH) release, similar protocols were followed. It was found that GtH release was augmented to 7-fold by cGnRH plus Ca2+, which was inhibited by verapamil and stimulated by CaM in a similar manner as observed in the case of cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)
Blockade of the human platelet GPIIb/IIIa receptor by a murine monoclonal antibody Fab fragment (7E3): potent dose-dependent inhibition of platelet function.
The platelet glycoprotein (GP) IIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands; this binding is the final common pathway mediating platelet aggregation. The purpose of this study was to evaluate the safety and platelet inhibitory characteristics of the Fab fragment of the murine monoclonal anti-GPII/IIIa 7E3 antibody (m7E3 Fab) when administered intravenously as a single bolus dose, as a single and repeat bolus dose, and as a single bolus dose followed by continuous infusions of varying duration. Various dosage regimens of m7E3 Fab were studied in 74 patients with stable angina. Dosage regimens included single doses of m7E3 Fab from 0.1 to 0.3 mg/kg, a single dose of 0.20-0.30 mg/kg, and a repeat dose of 0.05 mg/kg, or a loading dose followed by a continuous infusion of m7E3 Fab for up to 36 hours. To assess the effect of m7E3 Fab on platelet function, quantitative blockade of GPIIb/IIIa receptors, inhibition of ex vivo platelet aggregation, and template bleeding time were measured in all patients. Dose-dependent inhibition of platelet function was evident in response to escalating bolus doses of m7E3 Fab, with maximum inhibition observed at 0.25-0.30 mg/kg body weight; at the 0.30 mg/kg dose, mean (+/- SE) GPIIb/IIIa receptor blockade was 81 +/- 3%, ex vivo platelet aggregation in response to 20 microM ADP was 14 +/- 6% of baseline, and the median bleeding time was > 20 minutes. Although platelet function gradually recovered following a single bolus injection, platelet inhibition could be sustained by continuous, low-dose infusion of the antibody. Platelet inhibition occurred within minutes, but m7E3 Fab that did not bind to platelets cleared rapidly from circulation. Sixteen percent of the m7E3 Fab-injected subjects exhibited low titer, human anti-murine antibody responses. No significant bleeding or allergic reactions were observed in any patients. One of the 74 patients developed transient thrombocytopenia soon after receiving m7E3 Fab. These studies establish that m7E3 Fab can be administered safely at doses that cause profound inhibition of platelet function.
A multitude of circular DNAs exist in the nucleus of Entamoeba histolytica.
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A prospective randomised study of the effects of prophylactic antibiotics on the incidence of bacteraemia following hysteroscopic surgery.
OBJECTIVE: To study the effect of prophylactic antibiotics on the incidence of bacteraemia following hysteroscopic surgery. DESIGN: Prospective randomized study. SETTING: Aberdeen Royal Infirmary. SUBJECTS: One hundred and sixteen women about to undergo either endometrial laser ablation (ELA) or transcervical resection of the endometrium (TCRE). INTERVENTION: Fifty-five women were randomised to receive 1.2 g of Augmentin (co-amoxiclav) i.v. at induction of anaesthesia. Sixty-one women received no antibiotic prophylaxis. Blood cultures were obtained at the end of the surgical procedure. RESULTS: Incidence of bacteraemia in the non-antibiotic group (16%) was significantly higher than that in the antibiotic group (2%) (95% confidence interval for difference from 5% to 25%). The majority of organisms were of dubious clinical significance and contamination could not be excluded in 7 cases out of 10. CONCLUSION: There is no convincing evidence that antibiotics are of value in this clinical setting.
Transventricular mitral valve dilator: an improved design concept.
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