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Biomedical subjects

A Mathur

Publications and source records attributed to A Mathur.

At least 55 records · Page 3Linked to original sources
PubMed2000

Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists.

The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1, 1'-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.

Administration, Oral↗
PubMed2000

Astrocytes express specific variants of CaM KII delta and gamma, but not alpha and beta, that determine their cellular localizations.

Multiple isoforms of type II Ca(2+)-calmodulin-dependent kinase (CaM KII) are composed of two major neuron-specific subunits, designated alpha and beta, and two less well-characterized subunits that are also expressed in non-neuronal tissues, designated delta and gamma. Regulated expression of these 4 gene products, and several variants produced by alternative splicing, shows temporal and regional specificity and influences intracellular targeting. We used immunoblotting and RT-PCR to analyze subunit and variant expression and distribution in cultured cerebellar astrocytes and neurons, and whole cerebellar cortex from rodent brain. The data indicate that: (i) astrocytes express a single splice variant of delta, namely delta(2); (ii) like neurons, astrocytes express two forms of CaM KII gamma; gamma(B) and gamma(A); (iii) these CaM KII variants are enriched in the supernate fraction in astrocytes, and the particulate fraction in neurons; (iv) unlike neurons, astrocytes do not express detectable levels of alpha or beta subunits or their respective splice variants. The results indicate that neurons and astrocytes express distinct CaM KII subunits and variants that localize to distinct subcellular compartments and, by inference, exert distinct cellular functions.

Animals↗
PubMed2000

An enzyme immunoassay for detection of Japanese encephalitis virus-induced chemotactic cytokine.

Japanese encephalitis virus (JEV) induces human peripheral blood monocytes to secrete a chemotactic cytokine [human macrophage-derived factor (hMDF)] which causes chemotaxis of neutrophils. The only known assay for hMDF cannot quantify its level in samples, so an enzyme immunoassay has been standardized for detection of hMDF and hMDF-specific antibodies in test samples. The reported enzyme linked immunosorbent assay (ELISA) was found to be sensitive (89%), specific (91%), accurate (92 2%) and reproducible and was able to detect a minimum concentration of 23 ng hMDF/ml in test samples. The chemotactic factor could be detected in JEV inoculated mouse sera and JEV infected culture fluids. Significant finding of the test was the detection of hMDF in sera of human cases of JE.

Animals↗
PubMed2000

Surgical myocardial revascularization without cardiopulmonary bypass.

BACKGROUND: Though coronary artery bypass grafting (CABG) without cardiopulmonary bypass is being performed with increasing frequency, in the absence of adequate angiographic follow-up, safety, reproducibility, and efficacy of the procedure remain doubtful. In this prospective study, we report the results obtained by 100% angiographic follow-up of 96 consecutive patients. METHODS: A total of 96 patients (age range 33 to 76 years) underwent CABG without cardiopulmonary bypass. Single vessel disease was present in 46 (47.9%) patients, double vessel disease in 31 (32.3%), and triple vessel disease in 19 (19.8%) patients. All patients were operated through a standard midsternotomy and an optimal combination of pharmacological and mechanical methods were used to restrict cardiac movements during anastomosis. All patients underwent coronary angiography before discharge from the hospital. RESULTS: A total of 160 grafts were placed (range 1 to 4 grafts per patient, average 1.7+/-0.3 grafts per patient). A single graft was placed in 46 patients, double grafts in 38, triple grafts in 10, and quadruple grafts in 2 patients. Various grafts included pedicled left internal mammary artery (LIMA) (n = 95), free LIMA (n = 1), right internal mammary artery (n = 14), radial artery (n = 24), right gastroepiploic artery (n = 5), and saphenous vein grafts (n = 21). Operative mortality was 1.0% (1 of 96). Two patients required reoperation for excessive bleeding. Mean hospital stay was 5.7+/-1.2 days. Overall angiographic patency was 95.0% with LIMA patency of 97.9% (93 of 95). One patient with block in midsegment of LIMA was reoperated using cardiopulmonary bypass. Follow-up ranged from 4 to 17 months (mean 8.2+/-3.1 months). Two patients (one with narrowed LIMA to left anterior descending artery anastomosis, and one with patent anastomosis) had residual angina. CONCLUSIONS: Coronary artery bypass grafting without cardiopulmonary bypass is a reproducible, effective, and safe option in selected group of patients. A conscientious approach in patient selection and route of operation is required.

Adult↗
PubMed2000

Evaluation of fluorescent dyes for the detection of mitochondrial membrane potential changes in cultured cardiomyocytes.

OBJECTIVE: Maintenance of the mitochondrial membrane potential (Deltapsim) is fundamental for the normal performance and survival of cells such as cardiomyocytes, that have a high energy requirement. Measurement of Deltapsim is therefore essential in order to develop an understanding of the molecular mechanisms controlling cardiomyocyte function. Here we have evaluated various potentiometric dyes for their ability to detect alterations of Deltapsim, using flow cytometry and confocal microscopy. METHODS: Primary cultures of cardiomyocytes from neonate rats were treated with mitochondrial uncouplers before or after loading with Rho123, DiOC(6)(3), CMXRos or JC-1, and then analysed by flow cytometry. Apoptotic cells were identified by light scatter and Annexin V staining. RESULTS: The four potentiometric dyes tested were able to discriminate between viable and apoptotic cells. However, only JC-1 was able to detect the collapse of Deltapsim induced by uncouplers of mitochondrial respiration. Confocal microscopic analysis confirmed that JC-1 stained mitochondria in a potential-dependent manner. In contrast, CMXRos stained cardiomyocytes irrespective of alterations in Deltapsim. CONCLUSIONS: We conclude that JC-1 is the optimal dye to use when measuring Deltapsim in cardiomyocytes.

Animals↗
PubMed2000

Antiviral effect of nitric oxide during Japanese encephalitis virus infection.

The ability of Japanese encephalitis virus (JEV) and JEV-induced macrophage derived neutrophil chemotactic factor (MDF) to produce nitric oxide (NO), and the possible antiviral effect of NO during JEV infection, was investigated. Splenic macrophages of JEV infected mice produced maximum NO in vivo at day 7 post infection, and in vitro at 24 h after JEV stimulation. MDF-induced NO production was dose dependent and maximal at 60 min after MDF treatment. The response was sensitive to anti-MDF antibody treatment and the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Pretreatment of mice with L-NMMA increased the mortality to 100% in JEV infected mice in vivo and inhibited NO production in vitro, while MDF stimulated macrophages inhibited virus replication with high levels of NO production. MDF treatment increased the survival rate of JEV infected mice. The findings thus demonstrate that MDF induces production of NO during JEV infection, which has an antiviral effect. This may be one of the important mechanisms of natural immunity in controlling the initial stages of JEV infection.

Animals↗
PubMed2000

Homograft mitral valve replacement: five years' results.

OBJECTIVE: Results of mitral valve replacement with a mitral homograft were evaluated at 5 years to assess the suitability of the procedure. METHODS: Thirty-seven patients (25 male subjects) aged 10 to 49 years (mean, 32 +/- 10 years) with rheumatic mitral valve disease underwent total (n = 35) or partial (n = 2) mitral valve replacement with a fresh antibiotic-preserved (n = 23) or cryopreserved (n = 14) mitral homograft. The predominant lesion was mitral stenosis (n = 30). RESULTS: There were 5 early deaths. Operative survivors were followed up for 1 to 60 months (mean, 26.6 +/- 12 months). Among these, 21 patients had severe mitral regurgitation during the follow-up period; 3 died and 8 underwent reoperation. The homograft failure rate was not affected by preoperative physiologic lesion (stenosis vs regurgitation, P =.4), type of homograft (antibiotic-preserved vs cryopreserved homograft, P =.9), papillary muscle pretreatment (yes vs no, P =.9), or addition of posterior collar annuloplasty (yes vs no, P =.2). Among the remaining patients, 5 had moderate mitral regurgitation, 4 had either trivial or mild mitral regurgitation, and 2 were lost to follow-up. Study of the explanted mitral homografts (n = 8) revealed that disruption of one of the donor papillary muscles was responsible for early failures (n = 2), whereas cuspal and chordal degeneration was responsible for late failures (n = 6). Microscopically, the explanted valve lacked any viable cellular elements, and there was no evidence of immunologic injury to the homografts. CONCLUSION: The mitral homograft did not fulfill our expectations as a suitable substitute for the diseased mitral valve.

Adolescent↗
PubMed2000

Vascular protection: A novel nonangiogenic cardiovascular role for vascular endothelial growth factor.

There is widespread interest in the use of the angiogenic cytokine, vascular endothelial growth factor (VEGF), for the treatment of cardiovascular disease. The main paradigm for VEGF cardiovascular therapy is the stimulation of "therapeutic angiogenesis" in ischemic myocardial and peripheral vascular limb disease. In this review, approaches to VEGF therapy based on the therapeutic angiogenesis model are critically assessed, and the alternative mechanism of vascular protection is advanced. Vascular protection is defined as the VEGF-induced enhancement of endothelial functions that mediate the inhibition of vascular smooth muscle cell proliferation, enhanced endothelial cell survival, suppression of thrombosis, and anti-inflammatory effects. VEGF-induced synthesis of NO and prostacyclin are both likely to be key mediators of VEGF-dependent vascular protection. Investigation into vascular protection should help us to gain insight into the underlying mechanisms of the cardiovascular actions of VEGF and should prove valuable in the development of novel therapeutic approaches based on local VEGF gene delivery.

Animals↗
PubMed2000

Diabetic autonomic neuropathy causing gall bladder dysfunction.

OBJECTIVE: The objective of the study was to study gall bladder volume in fasting and 45 minutes post-prandial, by real time ultrasound in healthy controls and diabetic patients with and without autonomic neuropathy and to compare them. METHOD: Age, Sex and body mass index (BMI) matched 50 healthy subjects and 10 patients with insulin dependent diabetes mellitus and 40 patients with noninsulin dependent diabetes mellitus were evaluated according to National diabetes Data Group of National Institute of Health (1979) criteria: 1. Fasting (overnight) venous plasma glucose concentration of > 140 mg/dl on two separate occasions. 2. Following ingestion of 75 gms of glucose, venous plasma glucose concentration of > 200 mg/dl at second hour and at one other occasion during two hour test. Autonomic neuropathy was assessed by the presence of symptoms like dysphagia, abdominal fullness, nausea, vomiting, diarrhea +/- nocturnal, faecal incontinence or constipation, dysuria, urinary incontinence, the gustatory sweating, impotence etc. and were confirmed by standing test for orthostatic hypotension, hand grip test, Valsalva test and deep breaths test. RESULT: The study showed that: 1. Patients of diabetes mellitus had statistically significant larger fasting gall bladder volumes and these values were highly significant amongst patients with autonomic neuropathy. 2. Patients of diabetes mellitus and statistically significant larger post fatty meal gall bladder volume and these values were highly significant in patients with autonomic neuropathy. CONCLUSIONS: We therefore conclude that impaired gall bladder contraction was found amongst patients of diabetes mellitus with autonomic neuropathy. The mechanism responsible for cholecystoparesis is attributed to vagal neuropathy. Incomplete gall bladder emptying leads to sequestration of cholesterol and nidus formation. Therefore gall bladder functions should be evaluated routinely in such patients and early intervention is recommended.

Adult↗
PubMed1999

Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis.

OBJECTIVE: To study the clinical correlates of lesions seen predominantly in the substantia nigra in some patients with Japanese encephalitis (JE). BACKGROUND: JE typically involves thalamus, brainstem, spinal cord, and cerebral cortex. Rarely, basal ganglia and cerebellum may be affected. Lesions are often widespread and discrete. Predominant involvement of substantia nigra in JE has not been previously reported. METHODS: Of 52 patients with JE seen in an endemic zone, five were selected on the basis of isolated lesions in the substantia nigra on MRI; all were subjected to detailed clinical and laboratory evaluation. RESULTS: Presenting symptoms were fever, alteration of consciousness, neck stiffness, and decreased body movements. Examination during acute illness revealed restricted eye movements, opsoclonus, upbeating nystagmus, and cogwheel rigidity. There was early and complete recovery of consciousness and eye signs. Parkinsonian features such as positive glabellar tap sign, masklike face, bradykinesia, tremors, and postural instability became apparent as these patients started walking. Reversible mutism was observed in three patients during the acute phase. Response to levodopa, amantadine, and trihexiphenedyl was partial. Three patients were followed for more than 1 year, during which time their parkinsonian features recovered completely. Substantial recovery was also observed in the two other patients 2 months after regaining consciousness. CONCLUSIONS: Some patients with Japanese encephalitis may have lesions predominantly in the substantia nigra. After recovery from acute encephalitic illness, they manifest clinically with typical parkinsonian features. Although several viruses are known to cause parkinsonism, this is the first demonstration of a virus producing lesions predominantly in the substantia nigra and causing parkinsonism.

Adolescent↗
PubMed1999

Protease and EGF1 domains of factor IXa play distinct roles in binding to factor VIIIa. Importance of helix 330 (helix 162 in chymotrypsin) of protease domain of factor IXa in its interaction with factor VIIIa.

Previous studies revealed that cleavage at Arg-318-Ser-319 in the protease domain autolysis loop of factor IXa results in its diminished binding to factor VIIIa. Now, we have investigated the importance of adjacent surface-exposed helix 330-338 (162-170 in chymotrypsin numbering) of IXa in its interaction with VIIIa. IXWT, eight point mutants mostly based on hemophilia B patients, and a replacement mutant (IXhelixVII in which helix 330-338 is replaced by that of factor VII) were expressed, purified, and characterized. Each mutant was activated normally by VIIa-tissue factor-Ca2+ or XIa-Ca2+. However, in both the presence and absence of phospholipid, interaction of each activated mutant with VIIIa was impaired. The role of IXa EGF1 domain in binding to VIIIa was also examined. Two mutants (IXQ50P and IXPCEGF1, in which EGF1 domain is replaced by that of protein C) were used. Strikingly, interactions of the activated EGF1 mutants with VIIIa were impaired only in the presence of phospholipid. We conclude that helix 330 in IXa provides a critical binding site for VIIIa and that the EGF1 domain in this context primarily serves to correctly position the protease domain above the phospholipid surface for optimal interaction with VIIIa.

Binding Sites↗
PubMed1999

Expression of a functional N-methyl-D-aspartate-type glutamate receptor by bone marrow megakaryocytes.

Better understanding of hemostasis will be possible by the identification of new lineage-specific stimuli that regulate platelet formation. We describe a novel functional megakaryocyte receptor that belongs to a family of ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype responsible for synaptic neurotransmission in the central nervous system (CNS). Northern blotting and reverse-transcriptase polymerase chain reaction (RT-PCR) studies identified expression of NMDAR1 and NMDAR2D type subunit mRNA in rat marrow, human megakaryocytes, and MEG-01 clonal megakaryoblastic cells. Immunohistochemistry and in vivo autoradiographic binding of the NMDA receptor-specific antagonist MK-801 confirmed that megakaryocytes expressed open channel-forming NMDA receptors in vivo. Western blots indicated that megakaryocyte NMDAR1 was either unglycosylated or only glycosylated to low levels, and of identical size to CNS-type NMDAR1 after deglycosylation with endoglycosidase F/peptide-N-glycosidase F. In functional studies, we demonstrated that NMDA receptor activity was necessary for phorbol myristate acetate (PMA)-induced differentiation of megakaryoblastic cells; NMDA receptor blockade by specific antagonists significantly inhibited PMA-mediated increases in cell size, CD41 expression, and adhesion of MEG-01 cells. These results provide evidence for a novel pathway by which megakaryocytopoiesis and platelet production may be regulated.

Animals↗
PubMed1999

Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death.

BACKGROUND: Genetic defects are being increasingly recognized in the etiology of primary cardiomyopathy (CM). Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step in the beta-oxidation spiral of fatty acid metabolism, the crucial pathway for cardiac energy production. METHODS AND RESULTS: We studied 37 patients with CM, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis, features suggestive of fatty acid oxidation disorders. Single-stranded conformational variance was used to screen genomic DNA. DNA sequencing and mutational analysis revealed 21 different mutations on the VLCAD gene in 18 patients. Of the mutations, 80% were associated with CM. Severe CM in infancy was recognized in most patients (67%) at presentation. Hepatic dysfunction was common (33%). RNA blot analysis and VLCAD enzyme assays showed a severe reduction in VLCAD mRNA in patients with frame-shift or splice-site mutations and absent or severe reduction in enzyme activity in all. CONCLUSIONS: Infantile CM is the most common clinical phenotype of VLCAD deficiency. Mutations in the human VLCAD gene are heterogeneous. Although mortality at presentation is high, both the metabolic disorder and cardiomyopathy are reversible.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1999

Does platelet glycoprotein IIb/IIIa receptor antibody improve in-hospital outcome of coronary stenting in high-risk thrombus containing lesions?

Coronary stenting in acute coronary syndromes probably increases the risk of acute stent thrombosis. Recently, use of platelet glycoprotein IIb/IIIa receptor antibody has been shown to improve percutaneous transluminal coronary angioplasty (PTCA) outcomes in high risk lesions. The purpose of this analysis was to determine safety and efficacy of platelet glycoprotein IIb/IIIa receptor antibody administration in patients receiving coronary stents in high-risk lesions. Between October 1995 and November 1996, 282 patients with acute ischemic syndromes received coronary stents at our center: 73 had thrombus containing lesions--40 presented with AMI and 33 with unstable angina and make up the study population. The mean age of these patients was 61+/-13 years, 56 were male, 35 had a history of myocardial infarctions (MI), 21 had prior coronary artery bypass graft (CABG), and 21 had prior PTCA. Coronary stenting was used for suboptimal result in 46 patients (63%), threatened closure in 25 patients (34%), and acute closure in 2 patients (3%). Platelet glycoprotein IIb/IIIa receptor antibody was administered during the procedure in 74% and after the procedure in 26%. A total of 115 stents were deployed (Gianturco-Roubin 80, Palmaz-Schatz 29, and Wallstent 6) in 24 LAD, 21 RCA, 15 LCX, and 13 saphenous vein graft (SVG) lesions. Procedural success was 100%. The mean diameter stenosis before and after intervention was 60%+/-31% and 4%+/-14%, respectively. In-hospital events included 1 Q-wave MI (1.4%), 13 non-Q-wave MI (18%), and 1 death (1.4%). There was no subacute stent thrombosis, emergency CABG, or repeat PTCA. Significant in-hospital bleeding complications were noted in seven (10%) patients, with five patients (6.8%) requiring blood transfusions. In this series of patients with acute ischemic syndromes associated with angiographic evidence of thrombus, combined use of platelet glycoprotein IIb/IIIa receptor antibody and stenting resulted in a very low incidence of subacute stent thrombosis and emergency target lesion revascularization. However, bleeding complications were higher than expected with conventional antiplatelet therapy following routine stenting.

Aged↗