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Biomedical subjects

B Singh

Publications and source records attributed to B Singh.

At least 505 records · Page 28Linked to original sources
PubMed1994

Pharmacologic and pharmacodynamic effects of the selective low Km cyclic AMP phosphodiesterase III inhibitors WIN 63291 and WIN 62582.

We describe the biochemical, pharmacologic, and in vivo pharmacodynamic profiles of two novel inhibitors of the cyclic GMP-inhibitable, low Km cyclic AMP phosphodiesterase (PDE) III; WIN 63291, a 6-quinolinyl analogue of the prototypic PDE III inhibitor milrinone and WIN 62582, an imidazopyridinone. Both WIN 62582 and WIN 63291 competitively inhibit PDE III from rat, dog, and human heart and from rat and canine aorta with IC50 values of 5-37 and 55-80 nM, respectively; the IC50 values for milrinone ranged from 300 to 520 nM. WIN 62582 and WIN 63291 are at least 1,000-fold selective for PDE III relative to inhibition of PDE isozymes I, II, IV, and V. We evaluated WIN 62582 and WIN 63291 in conscious rats and dogs after intravenous (i.v.) and oral (p.o.) administration. The dose of WIN 62582 required to reduce mean arterial blood pressure (MAP) by 20% (ED20) in rats was 1.8 mg/kg, with a pharmacodynamic duration of action of approximately 2 h. In comparison, the estimated i.v. ED20 for WIN 63291 in rats was 0.4 mg/kg, with a pharmacodynamic duration of action > 6 h. In conscious dogs, the i.v. doses of WIN 62582 and 63291 required to increase left ventricular (LV)dP/dtmax significantly were 0.1 and 0.01 mg/kg, respectively. In dogs, WIN 63291 0.1 mg/kg p.o. increased LVdP/dtmax by 86% in 30 min; LVdP/dtmax remained increased by 60% for at least 6 h. In comparison, WIN 62582, 0.3 mg/kg p.o., increased LVdP/dt by 56% in 30 min and remained increased by 40% at 6 h.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Changes in the composition and peroxidation of yeast membrane lipids during ethanol stress.

Lipid peroxidation in Saccharomyces cerevisiae cells increased with ethanol treatment of the cells. Such cells have decreased amount of total lipid, phospholipid and free sterols. Sterol:phospholipid ratio decreased slightly in the cells treated with 4% ethanol. However, this ratio significantly increased with further rise in ethanol concentration to 12%. Relative content of glycolipids (glycolipid to phospholipid ratio) increased in ethanol-treated yeast cells. Diphosphatidylglycerol content increased significantly and phosphatidylcholine to phosphatidylethanolamine ratio decreased in ethanol-treated cells. The amount of alpha-tocopherol decreased during ethanol stress. Catalase failed to counter the effect of ethanol. The results from the present study indicated that ethanol might be interfering with the antioxidant defence mechanisms of the yeast cells.

Catalase↗
PubMed1994

Prevalence of spatial disorientation in Indian Air Force aircrew.

The 1 Aero Medical Training Centre has surveyed aircrew of the Indian Air Force to determine the prevalence of Spatial Disorientation (SD), as related to aircraft stream, age, flying experience, geographical location and other operationally significant variables. The reported prevalence of SD is 75% among fighter aircrew, 64% in transport aircrew, and 55% in helicopter aircrew. Whereas the prevalence of SD does not appear to vary significantly with age and flying experience, it is higher in fully operational pilots and in pilots returning to flight duties after a ground tenure, as compared to ab-initio and type-converting pilots.

Adult↗
PubMed1994

An operational definition for spatial disorientation.

Spatial disorientation (SD) is a term which continues to have different meanings for different classes of people involved with aviation. The advent of new terms like "situational awareness" (SA), has only added to the plethora of existing definitions, leading to a difference of opinion among researchers worldwide. Lack of agreement regarding the semantics of SD among various aircraft accident investigators leads to different yardsticks in determining whether or not an accident is SD-related. These definitional differences do not allow for inter-Air Force comparisons of SD accident data, and a valuable opportunity to learn from the experience of others is lost. The authors examine the existing definitions, and propose a new practical operational definition of SD, for use in investigation and classification of aircraft accidents.

Aerospace Medicine↗
PubMed1994

Cyclic GMP potentiation by WIN 58237, a novel cyclic nucleotide phosphodiesterase inhibitor.

The objectives of this study were to determine the potency and selectivity of the structurally novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, WIN 58237 (1-cyclopentyl-3-methyl-6-(4- pyridyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one), and to determine if this compound possesses cyclic GMP (cGMP) PDE inhibitory activity in vitro and in vivo. WIN 58237 is a competitive inhibitor of cGMP PDE V from canine aorta, with a Ki value of 170 nM. It is a relatively less potent inhibitor of calmodulin-sensitive PDE I and cGMP-inhibitable cyclic AMP PDE III; but does inhibit cyclic AMP PDE IV with an IC50 value of approximately 300 nM. In vitro, WIN 58237 is a functional cGMP PDE inhibitor at submicromolar concentrations as evident by potentiation of both sodium nitroprusside- and atrial natriuretic factor-mediated vasorelaxation of contracted, endothelial-denuded rat aortic rings. Moreover, WIN 58237 possesses vasorelaxant activity in the presence of an intact endothelium or nitric oxide. Similar results are evident in vivo, as WIN 58237 (0.3-3.0 mg/kg i.v.) decreases mean arterial pressure in conscious spontaneously hypertensive rats with an associated increase in vascular (aortic) cGMP content in vivo. Both the decrease in mean arterial blood pressure and increase in aortic cGMP content are attenuated by the nitric oxide synthase inhibitor, N omega-nitro-l-arginine. However, WIN 58237 may possess an additional depressor mechanism of action. WIN 58237 restores vasorelaxation responsiveness to nitroglycerin in vitro and in vivo in models of vascular tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

Ultracytochemical study of multiple dose effect of monastral blue uptake by equine pulmonary intravascular macrophages (PIMs).

The pulmonary intravascular macrophages (PIMs) of the ponies possess all the characteristics of a fully differentiated resident macrophage, which forms adhesive plaques with the capillary-endothelial cells. In addition, it has a unique surface coat which does not conform to the concept of a carbohydrate rich membrane bound glycocalyx generally associated with macrophages. We studied the responses of these cells especially in the context of its globular surface coat to multiple doses of MB intravenously: 0.2 ml/kg body copper tracer substance. The ponies were treated with three doses of MB intravenously: 0.2 ml/kg body weight on day 0, 0.1 ml/kg at 48 h and a 0.05 ml/kg at 96 h after the first dose. The examination of lung tissue at the ultrastructural level revealed internalization of MB following complexing with the surface coat globules along the entire cell surface. The cell surface was extensively ruffled in the form of several lamellipods. The MB-globule complex was internalized mostly at the coated pits whereas concurrent internalization of nascent globules of the coat took place at the ruffled surface. In the former, the internalized material was seen in small, medium and large phagolysosomes which stained intensely for acid phosphatase, whereas in latter case enzyme activity was entirely absent in all the nascent globules carrying endosomes. Simultaneously there was hypertrophy of the Golgi complex, which showed intense staining for acid phosphatase. Relative to the Golgi response, acid phosphatase-positive tubular lysosomes in close association with extensive bundles of microtubules were conspicuous, thus adding to the battery of cell organelles of secretory pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1994

Evidence that halothane anaesthesia induces intracellular translocation of surface coat and Golgi response in equine pulmonary intravascular macrophages.

The pulmonary intravascular macrophages (PIMs) of horse contain a unique electron-dense globular surface-coat which is arranged in a linear fashion in conformity with the contours of the cell membrane. The coat is sensitive to heparin treatment and to the digestive effect of lipolytic lipase, suggesting that the coat is predominantly composed of lipoproteins. During the present study, ultrastructural features of PIMs were analysed after exposing horses to halothane inhalation which was chosen as the model agent of lipid-soluble anaesthetic. The surface-coat showed acute sensitivity to halothane by disappearing almost completely from the surface after 1-2 h of exposure. The cell membranes were thrown into extraordinary arrays of lamellipods, pseudopods and veils. Concurrently, the globular units of the coat were translocated into the endosomal-lysosomal system, most probably via receptor-mediated endocytosis. There was a high profile of the expanded Golgi apparatus especially the trans Golgi network (TGN) in close association with the centrioles and microtubules. Cytochemistry revealed an enrichment of the Golgi complex with acid phosphatase activity. On the other hand, halothane showed an inhibitory effect on the lysosomal acid phosphatase of the PIMs. It is proposed that the Golgi response occurred as an obligatory concomitant of internalization of the surface-coat and its subsequent passage through endosomal-lysosomal system. The acid phosphatase activity as a marker enzyme of the expanded Golgi is correlated with metabolic effects of the internalized coat which is unique to the pulmonary intravascular macrophages. Furthermore, the intense expression of acid phosphatase at the Golgi level of the PIMs may signify a component of secretory phenotype in order to produce vasoactive mediators at the onset of stressful stimuli triggered by the halothane anesthesia.

Acid Phosphatase↗
PubMed1994

Indian Air Force and world spatial disorientation accidents: a comparison.

Human error is known to be a major contributory factor in aviation accidents, with spatial disorientation (SD) a preeminent cause within this group. This paper presents incidence of SD-related accidents in some major Air Forces of the West, and compares it with Indian Air Force (IAF) data from 1970 to 1990. Incongruence between the Indian and Western (U.S. and British) data is discussed, and possible reasons for this are highlighted. The authors suggest a review of the existing working definition of spatial disorientation with particular reference to its usage by accident investigators.

Accidents, Aviation↗
PubMed1993

Characterization of murine T cell responses to peptides of the variable region of self T cell receptor beta-chains.

Immunization with peptides of the TCR may regulate cellular immune responses that are dominated by a particular TCR. However, no extensive study of the immunogenicity of peptides of different regions of the V beta chain of the TCR has been done. We have tested the immunogenicity of several V beta peptides in several strains of mice and characterized the cellular response to these peptides. We examined the ability of six strains of mice of H-2b, H-2d, or H-2k and of mouse lymphocyte stimulatory (Mls)-1a or Mls-1b haplotypes to respond to several peptides of the V beta 6 region and an NH2-terminal peptide of other V beta of the TCR. These include V beta 6 peptides 1-20, 32-48, 39-60, 48-75, 58-75, and V beta 3, V beta 8.1, and V beta 8.3 peptides 1-20. The various mouse strains respond to these peptides independently of deletion of V beta 6+ T cells from peripheral lymphocytes. All of the Mls deleting and nondeleting strains tested respond weakly to one peptide of V beta 6, V beta 6(39-60). Antibody titers were also demonstrated in BALB/c and DBA/2J to V beta 6(1-20), V beta 6(39-60) and V beta 6(48-75), but not to V beta 6(32-48). We demonstrated that T cells responding to V beta 6(32-48) produce IL-2 and IFN-gamma, consistent with the Th1 subset of T cells. None of the antipeptide antibodies recognized the intact V beta 6 TCR on the cell surface. In vitro antibody blocking studies with TCR peptides show that these peptides are presented by class II MHC to CD4+ T cells. We conclude that the T cell and B cell repertoires contain cells able to respond to peptides of self TCR and immunization with peptides induces CD4+ T cells and that these cells may have an immunoregulatory role.

Amino Acid Sequence↗
PubMed1993

Mammalian topoisomerase II inhibitory activity of 1-cyclopropyl-6,8- difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarb oxylic acid and related derivatives.

1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.

Animals↗
PubMed1993

Significant correlation between 14C-5-HT uptake by and 3H-paroxetine binding to platelets from healthy volunteers.

The lack of correlation between 5-HT uptake by platelets and the ability of platelet membrane to bind antidepressant drugs, particularly imipramine, has been reported. However, more recently it has been suggested that 3H-paroxetine could be a better drug with which to study the platelet 5-HT uptake mechanism in disease states. We have therefore compared the ability of platelet-rich plasma (PRP) from normal individuals to take up 5-HT with the ability of platelet membranes to bind paroxetine. A significant correlation was apparent between the Vmax of 14C-5-HT uptake by PRP and the Bmax of 3H-paroxetine binding to platelet membrane from 30 individuals (r = 0.6468, p = 0.0001). Furthermore, this correlation was highly significant in the 20 female (r = 0.7768, p = 0.00006) but not in the 10 male volunteers. There was also a significant association between Vmax and Bmax and the month of blood sampling but this did not totally account for the correlation between Vmax and Bmax. The simultaneous measurement of 5-HT uptake by PRP and paroxetine binding to platelet membranes from both depressed patients and matched controls should be carried out to confirm and extend these findings.

Adult↗
PubMed1993

Idiopathic long QT syndrome: asking the right question.

Infants and young children cannot describe symptoms of cardiogenic syncope accurately. If the attention in such cases is focused on the seizure activity that may follow, the patient will be treated inappropriately with anticonvulsants. We report such a presentation in 4 infants and young children (ages 6 to 48 months) with idiopathic long QT syndrome. All patients presented with recurrent seizures. All patients had a corrected QT interval (QTc) > or = 0.44 s and none had deafness. The diagnosis was suspected by careful history-taking which revealed episodes of loss of consciousness before convulsions in all patients. All patients were treated successfully with propranolol and remained free of symptoms during the follow-up period of 1-2 years. Screening the other family members revealed a prolonged QTc in 9 out of 16, and a history of 3 sudden and unexplained deaths in two families.

Child, Preschool↗
PubMed1993

Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice.

Insulin-dependent diabetes mellitus is an autoimmune disease that is characterized by the destruction of insulin-producing beta cells in the islet of Langerhans. We have recently reported that the induction of the disease in nonobese diabetic (NOD) mice can be prevented by a single injection of CFA. In this study, we have explored the cellular basis and the time course of the disease protection. Since CFA contains a mycobacterial cell wall that has adjuvant property, we investigated the protective role of mycobacteria in young NOD mice. Mice injected with Mycobacterium tuberculosis or Mycobacterium bovis (BCG vaccine) at 4 wk of age were also found to be protected from diabetes. We have found that complete protection from diabetes is only achieved by administration of CFA between 4 and 10 wk of age. Draining lymph node cells or spleen cells from CFA-treated NOD mice transfer the protection. Adoptive transfer of spleen cells from CFA-treated mice with spleen cells from acutely diabetic mice delayed the induction of disease into irradiated recipient mice. CFA-treated old NOD mice were also resistant to passive transfer of disease by spleen cells from acutely diabetic mice. Depletion of the Thy 1.2+ cells or CD4(+)-bearing T cells abrogated the protection. However, disease can be induced in the protected mice by cyclophosphamide treatment. We also found that thymocytes from NOD mice responded only weakly to mitogen Con A. CFA treatment, however, restored the ability of these cells to respond to Con A. Finally, our results suggest that T cells induced after CFA treatment of NOD mice prevent both the induction and effector phases of the disease.

Animals↗
PubMed1993

Factors influencing resumption of meiotic maturation and cumulus expansion of porcine oocyte-cumulus cell complexes in vitro.

The present study was undertaken to examine effects of various combinations of epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-beta 1), follicle-stimulating hormone (FSH), luteinizing hormone (LH), androstenedione (A4), and estradiol-17 beta (E2) on meiotic maturation and cumulus expansion in the pig using an in vitro model system. Oocyte-cumulus cell complexes (OCC) were cultured in the media containing the above-mentioned agents for 24 hr and were observed for germinal vesicle breakdown (GVBD), indicative of initiation of meiotic maturation, and for expansion of their cumulus cells. Treatment with EGF significantly increased (P < 0.05) incidence of GVBD, with maximal stimulation occurring at 1 ng/ml (55% vs. 12% in the control). Concentrations of EGF as low as 100 pg/ml significantly stimulated GVBD over control (37% vs. 12%). Addition of EGF (1 ng/ml) and FSH (1.5 micrograms/ml) together and LH (2 micrograms/ml) and FSH (1.5 micrograms/ml) together resulted in significantly higher (P < 0.01) GVBD levels than were observed in response to EGF, FSH, or LH alone. Addition of E2 (1 microgram/ml) had no effect by itself but significantly decreased the incidence of GVBD in the presence of FSH and of LH + FSH. Addition of A4 (1 microgram/ml) significantly reduced the percentage of oocytes undergoing GVBD when added alone or with FSH. Although both EGF and LH stimulated cumulus expansion, FSH was more effective in stimulating cumulus expansion than EGF or LH. TGF-beta 1 had no effect on GVBD or cumulus expansion.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstenedione↗