Search PubMed⌕ Search

Biomedical subjects

S Kaul

Publications and source records attributed to S Kaul.

At least 235 records · Page 13Linked to original sources
PubMed1995

A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection.

OBJECTIVES: To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. DESIGN: Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). PATIENTS: Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. RESULTS: As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. CONCLUSIONS: Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.

Administration, Oral↗
PubMed1995

Pattern of injuries in a hydro-electric project.

A study of work-related injuries at a hydro-electric project site (May 1991-April 1992) was undertaken to determine the incidence and pattern of the injuries out of a total number of 119 injuries in the year. A significant proportion of these were orthopaedic in nature and the commonest site of injury was limbs (both upper and lower limbs) like auto-amputations and head injuries. A large proportion of these accidents (24.37%) resulted in permanent disability likely to interfere in the normal activities or locomotion of those injured.

Accidents, Occupational↗
PubMed1995

CD80-transfected human breast and ovarian tumor cell lines: improved immunogenicity and induction of cytolytic CD8+ T lymphocytes.

Human tumor cell lines derived from breast and ovarian carcinomas have been found to be ineffective in stimulating the induction phase of an immune response such as T cell proliferation in allogeneic mixed tumor cell lymphocyte cultures. Since representative tumor cell lines are effectively lysed by activated T lymphocytes, the induction of an effector phase is not impaired. In order to reconstitute the potential to induce primary T cell activation, we transfected CD80 into a breast (KS) and an ovarian carcinoma (GG) cell line. CD80 expression in KS cells resulted in improved primary T cell activation, whereas it was ineffective in the case of GG cells. However, treatment of CD80-transfected GG cells with INF-gamma rendered them immunogenic, and resulted in T cell proliferation. Likewise, TNF-alpha and/or INF-gamma augmented T cell proliferation induced by CD80-transfected KS cells. Furthermore, T lymphocytes stimulated with cytokine-treated CD80+ KS cells gave rise to a long term proliferating CD8+ CTL line with class I MHC restricted cytolytic antitumor activity. These studies emphasize the requirement for costimulation in generating tumor-specific immunity, and demonstrate the efficacy of CD80 in generating CD8+ cytolytic T lymphocytes.

Antigens, CD↗
PubMed1995

Phase I study of etoposide phosphate (etopophos) as a 30-minute infusion on days 1, 3, and 5.

Etoposide phophate is a phosphate ester prodrug of etoposide designed to improve the pharmaceutical characteristics of the parent compound. A Phase I dose-escalating study of etoposide phosphate was conducted concurrently at two institutions to determine its toxicity, pharmacokinetics, and maximum tolerated dose. Etoposide phosphate was administered i.v. for 30 min on days 1, 3, and 5 every 21 days or on recovery from toxicity. Cohorts of at least three patients received etoposide phosphate at dose levels from 50 mg/m2 to 150 mg/m2 expressed as molar equivalents of etoposide. Blood and urine samples were obtained from all patients during the first cycle of treatment and the concentrations of etoposide phosphate and etoposide were measured. Thirty-nine patients with documented cancers received a total of 75 cycles of etoposide phosphate. The dose-limiting toxicity was myelosuppression which occurred at the 150-mg/m2 etoposide equivalent dose. Etoposide phosphate was rapidly and extensively converted to etoposide. No measurable etoposide phosphate was detectable in the plasma by 15-60 min after the end of the infusion. The mean half-life of etoposide at the different dose levels ranged from 5.5 to 9.3 h. The pharmacokinetics of etoposide, generated from etoposide phosphate, was linear over the dose range studied and was comparable to results reported in the literature for i.v. etoposide. In summary, i.v. etoposide phosphate is rapidly and extensively converted to etoposide. The maximum tolerated dose of etoposide phosphate when given on days 1, 3, and 5 is 150 mg/m2/day. The dose-limiting toxicity is myelosuppression. The maximum tolerated dose and adverse event profile are consistent with those of etoposide.

Adult↗
PubMed1994

The replication terminator protein of the gram-positive bacterium Bacillus subtilis functions as a polar contrahelicase in gram-negative Escherichia coli.

The replication terminator protein (RTP) of Bacillus subtilis is a dimer with a monomeric molecular mass of 14.5 kDa. The protein terminates DNA replication at a specific binding site. Although the protein has been crystallized and its crystal structure has been solved, the lack of an in vitro replication system in B. subtilis has been a serious impediment to the analysis of the mechanism of action of this protein. We have discovered that the protein is functional in the Gram-negative bacterium Escherichia coli in vivo and in vitro. RTP blocked replication forks initiated from a ColE1 replication origin at the cognate DNA-binding site (BS3) in a polar mode. The protein did not block rolling circle replication initiated from the pT181 origin in cell extracts of Staphylococcus aureus. RTP antagonized the helicase activity of DnaB but not that of helicase II of E. coli. Thus, RTP functioned as a polar contrahelicase blocking a helicase that participates in symmetric DNA replication but it did not impede rolling circle replication nor the action of a helicase involved in DNA repair.

Adenosine Triphosphatases↗
PubMed1994

Effect of retinol deficiency and curcumin or turmeric feeding on brain Na(+)-K+ adenosine triphosphatase activity.

The effect of retinol deficiency and curcumin and turmeric feeding on brain microsomal Na(+)-K(+)ATPase activity was investigated. The brain Na(+)-K(+)ATPase activity registered an increase of 148.5% as compared to the control group. Upon treating retinol deficient rats with curcumin or turmeric, the abnormally elevated activity showed a decrease of 36.9 and 47.1%, respectively, when compared to the retinol deficient group. An increase in Vmax by 67% and Km by 66% for ATP was observed in the retinol deficient group. Curcumin or turmeric fed retinol-deficient groups reduced the Vmax by 25 and 33%, while Km was reduced by 25 and 31%, respectively, compared to the retinol deficient group. Arrhenius plot of Na(+)-K(+) ATPase showed a typical bi-phasic pattern in all the groups. Cholesterol:Phospholipid ratio showed a decrease in the retinol-deficient group by 67.8%, which showed a marked increase in curcumin or turmeric treated groups. Detergents could increase the Na(+)-K(+) ATPase activity more in the control group than in the retinol deficient groups. Curcumin or turmeric improved the detergent action on the enzyme. Subsequent freezing and thawing over a period of 30 min decreased the enzyme activity by 22.8% in the retinol deficient group compared to 15.9% decrease in the control group. Curcumin or turmeric treated groups showed a decrease in the enzyme activity by 22.0 and 19.2%, respectively, when compared to the zero time in each group. In the presence of concanavalin-A (Con-A) there was only 52.4% stimulation in the enzyme activity in retinol deficient groups, compared to 108.0% in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Immunoscintigraphy of human mammary carcinoma xenografts using monoclonal antibodies 12H12 and BM-2 labeled with 99mTc and radioiodine.

For immunoscintigraphic localization of human breast cancer two monoclonal antibodies (mabs) 12H12 (immunoglobulin G1) and BM-2 (immunoglobulin G3) were developed. The mabs, directed against two different epitopes on the mucin glycoprotein TAG-12, showed reactivity with 96% of all primary mammary carcinomas. The antibodies were labeled with either 125I or 131I. In addition, 12H12 was directly labeled with 99mTc according to the method of Schwarz and Steinsträsser (A. Schwarz and A. Steinsträsser, J. Nucl. Med., 28:721, 1987). Biodistribution was measured in female nude mice bearing the human mammary carcinoma SF-15. Both radioiodinated mabs showed similar biodistribution with fast tumor uptake (8.5% injected dose/g at 6 h postinjection), which increased to 10-11% injected dose/g at 24 h and subsequently remained constant up to 120 h. 99mTc-Labeling of the mab 12H12 led to an enhanced tumor uptake of 10.5 and 14% injected dose/g at 6 and 24 h postinjection, respectively, and to significantly accelerated blood clearance of radioactivity. Similar results were obtained with a second mammary tumor (AR-1), while an endometrial tumor (EK-3) showed a 3-fold lower accumulation of radioactivity and no difference in uptake of radio-iodinated and 99mTc-labeled 12H12. Scintigraphic imaging of tumor-bearing nude mice with the 99mTc 12H12 at 24 h postinjection clearly demonstrated a diagnostic potential of the new mab for tumor localization and staging.

Animals↗
PubMed1994

Role of platelets and leukocytes in modulation of vascular tone.

Activated platelets and leukocytes release potent vasoactive factors that may modulate vascular tone. Activation of normal platelets produces dilatation of normal arteries. Vasodilatation is mediated by adenosine diphosphate (ADP), which releases endothelium-derived relaxing factor (EDRF) from endothelium. In atherosclerotic arteries, activation of platelets produces constriction and perhaps spasm. The constrictor response of atherosclerotic arteries is related in part to profound changes in vascular function: endothelial dysfunction with impaired endothelium-dependent vasodilator responses to ADP, and augmented vasoconstrictor responses to serotonin. In addition, hypercholesterolemia has a direct effect on platelets, resulting in impaired vasodilator responses. Thus, abnormal platelets and altered vascular function may both predispose to spasm of atherosclerotic arteries. Activation of leukocytes has little effect on resistance of large arteries in normal monkeys. In contrast, activation of leukocytes produces pronounced vasoconstriction in atherosclerotic monkeys. Possible mediators of vasoconstriction include prostaglandin E2, oxygen radicals, thromboxane, and a peptide (perhaps angiotensin II). In addition, leukocytes also alter vascular responses to platelets, in part by ADPase on the leukocyte membrane, which degrades ADP released by activated platelets. Leukocytes also release oxygen radicals, which may inactivate EDRF, thereby impairing ADP-mediated, endothelium-dependent vasodilator responses. Abnormal responses to platelets and leukocytes are largely reversed when atherosclerotic lesions regress in monkeys.

Animals↗
PubMed1994

Production of mouse monoclonal anti-idiotypic antibodies specific to epitopes of tumor-associated mucin TAG-12.

The tumor-associated mucin-glycoprotein TAG-12 is strongly expressed in approximately 96% of all breast cancer patients and nearly 68% of all ovarian cancers. The experimental results of this work indicated that humoral immune response against TAG-12 is possible. Immunization with anti-idiotypic monoclonal antibodies produces this response. In this experiment, anti-idiotypic monoclonal antibodies represent the internal image of a specific epitope on TAG-12. Monoclonal antibody (MAb) 12H12 was selected to produce anti-idiotypic antibodies (anti-Ids) because of its high reactivity with TAG-12. Syngeneic murine anti-Ids were developed by immunization of BALB/c mice with the 12H12-Fab-KLH conjugate. A competitive assay with purified TAG-12 was utilized to identify anti-Ids with mirror image function. Two MAbs with "internal image" specificity were selected, 5H8 and 5H2. Two New Zealand White rabbits were immunized with 5H8. Serum samples tested 6 weeks after the initial immunization showed comparable titers against TAG-12. The binding capacities of the rabbit sera to different human breast as well as nonbreast cancer cell lines demonstrated strong binding with TAG-12-positive breast cancer cell lines. Competitive inhibition assays demonstrate that Ab3 and purified TAG-12 totally inhibit the binding of 12H12 antibody to TAG-12-positive cells. No inhibition was detectable with unrelated MAbs or normal mouse immunoglobulin. Binding assays with polyclonal Ab3 serum and several human cancer cell lines showed reactivity to nearly every tested cell line. Soluble TAG-12 showed no inhibition, indicating that this binding is due to a different set of idiotypes. Anti-Id 5H8 elicited an immune response to TAG-12. Utilization of anti-Id as a vaccine against the breast cancer-associated tumor antigen TAG-12 was successfully demonstrated in a xenogeneic animal model.

Animals↗
PubMed1994

Pharmacokinetics of co-administered didanosine and stavudine in HIV-seropositive male patients.

The pharmacokinetics of single and co-administered didanosine and stavudine were evaluated in 10 HIV-seropositive subjects in an open, within subject design in which each subject received each of three treatments. Single doses of didanosine 100 mg were alternated randomly with single doses of stavudine 40 mg on days 1 and 2. Beginning on day 3, subjects received the same doses of both drugs simultaneously every 12 h for nine doses. Serial blood and urine samples were obtained on single dose days 1 and 2, first simultaneous dose day 3, and last simultaneous dose day 7. The average maximum plasma concentrations of didanosine and stavudine before and after simultaneous administration were 422 +/- 184 (s.d.) ng ml-1 and 603 +/- 160 (s.d.) ng ml-1, and 419 +/- 153 (s.d.) ng ml-1 and 726 +/- 188 (s.d.) ng ml-1, respectively. Didanosine and stavudine AUC values before and after simultaneous administration were 615 +/- 170 (s.d.) ng ml-1 h and 1246 +/- 230 (s.d.) ng ml-1 h, 637 +/- 155 (s.d.) ng ml-1 h and 1326 +/- 267 (s.d.) ng ml-1 h, respectively. No significant changes in maximum plasma concentration, AUC elimination half-life, or renal clearance of didanosine and stavudine were observed when the drugs were administered simultaneously. Co-administration of didanosine 100 mg and stavudine 40 mg is well tolerated and the drugs do not interact pharmacokinetically.

Adult↗
PubMed1994

Quantification of images obtained during myocardial contrast echocardiography.

This article describes currently used quantitative methods for analysis of data obtained during myocardial contrast echocardiography. The specific issues addressed are: obtaining time-intensity curves from the myocardium in order to derive transit rates of microbubbles through the myocardium; defining spatial distribution of flow within a myocardial segment; and color-coding algorithms used to define the extent and magnitude of hypoperfusion within a cross-section of the heart. These methods are being adopted by several companies dealing with acquisition and analysis of echocardiographic data and should become available soon for clinical use.

Algorithms↗
PubMed1994

Interaction of human platelets and leukocytes in modulation of vascular tone.

We tested the hypothesis that the vasodilator response to human platelets is modulated by polymorphonuclear leukocytes (PMNs). Responses to platelets activated with thrombin, as well as PMNs activated with N-formylmethionyl-leucyl-phenylalanine (FMLP), were examined in perfused rabbit carotid arteries in vitro. Activation of platelets produced marked dilatation, and activation of PMNs produced modest constriction in arteries preconstricted with phenylephrine. Vasodilator responses to platelets were greatly impaired during infusion of activated PMNs. Pretreatment of PMNs with superoxide dismutase (SOD) partially restored dilator responses to platelets. Because SOD only partially restored vasodilator responses to platelets, we tested the possibility that adenosine-diphosphatase (ADPase) activity of PMNs may degrade ADP released by platelets and thus reduce vasodilator responses. After incubation with PMNs, dilator responses to ADP, but not acetylcholine, were significantly impaired. These findings indicate that vasodilatation produced by activated human platelets is profoundly impaired by activated leukocytes. We conclude that two mechanisms may account for this effect: 1) endothelium-derived relaxing factor, released in response to platelet-derived ADP, is inactivated by superoxide anion generated by activated PMNs and 2) ADP is degraded by ADPase activity of PMNs. We speculate that platelet-leukocyte interaction may have important effects on vasomotor tone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Prevalence and pattern of major neurological disorders in rural Kashmir (India) in 1986.

In 1986 in the Kuthar Valley in the Anantnag District of south Kashmir (northwestern India), we studied the population to ascertain the prevalence and pattern of various neurological diseases. A house-to-house survey was done in a rural population of 63,645 (according to a World Health Organization protocol, 1981). 616 cases of major neurological disorders were detected, yielding a prevalence of ratio of 9.67/1,000 as of prevalence day November 1, 1986. The prevalence ratios for various common neurological disorders were: epilepsy 2.47/1,000; stroke 1.43/1,000; paralytic poliomyelitis 2.18/1,000; mental retardation 2.09/1,000; deaf mutism 1.63/1,000, and cerebral palsy 1.24/1,000. Persons with these conditions constituted 92% of all neurological cases. Patients with motor neuron disease, Alzheimer's dementia or multiple sclerosis were not found.

Adolescent↗
PubMed1994

The ex vivo transfer of the anti-HIV nucleoside compound d4T in the human placenta.

The purpose of this study was to determine the ex vivo maternal-fetal placental transfer of 2',3'-didehydro-3'-deoxythymidine (d4T) and to compare it to the perfusion characteristics of 3'-azido-2',3-dideoxythymidine (AZT). This study used the single cotyledon perfusion system and antipyrine to determine the clearance index of this thymidine-containing anti-human immunodeficiency virus (HIV) compound. The endogenous base thymidine and the inhibitor dipyridamole were used to determine if this anti-HIV compound crossed the placenta by simple diffusion. The clearance index of d4T was 0.24 +/- 0.07 at 1.0 micrograms/ml and 0.235 +/- 0.045 at 10.0 micrograms/ml. These data suggest that the clearance index of d4T is 77-81% of AZT. The presence of high concentrations of dipyridamole and endogenous thymidine did not alter the clearance of d4T. In studies in which both the maternal and fetal circulations were closed, the accumulation in the fetal circulation was linear when the maternal concentration was in the range of 1-100 micrograms/ml. These data suggest that d4T crosses the human placenta by simple diffusion, and has similar perfusion characteristics to that of AZT.

Diffusion↗
PubMed1994

Functional improvement precedes structural regression of atherosclerosis.

BACKGROUND: Vasoconstrictor responses to serotonin are augmented in monkeys with diet-induced atherosclerosis and improve after 18 months of normal diet. We tested the hypothesis that functional improvement may occur early during regression, before evidence of structural improvement. METHODS AND RESULTS: Responses of the iliac artery to serotonin were measured by quantitative angiography and a Doppler flow probe in several groups of monkeys: (1) normal monkeys, (2) monkeys fed an atherogenic diet for 2 years (atherosclerotic), and (3) monkeys fed an atherogenic diet for 2 years (preregression) followed by a normal diet for 4, 8, or 12 months (regression). In normal monkeys, serotonin produced minimal constriction of the iliac artery, and blood flow to the legs increased. In atherosclerotic monkeys, there was pronounced constriction of the iliac artery, and blood flow to the legs decreased markedly. After 4 months of regression diet, four of eight monkeys demonstrated marked reduction in hyperresponsiveness to serotonin angiographically, and by 8 months, six of eight monkeys had significant improvement. After regression, serotonin produced minimal changes in flow. There was no reduction in intimal area (ie, atherosclerotic lesion) in iliac arteries from regression monkeys compared with atherosclerotic monkeys, but there was a marked reduction in cholesteryl ester in arteries from regression monkeys. CONCLUSIONS: Abnormal vasoconstrictor responses to serotonin usually return to or toward normal within a few months during regression of atherosclerosis. Functional improvement occurs in conjunction with early resorption of lipid from the arterial wall and occurs before detectable changes in mass of the atherosclerotic lesion.

Animals↗
PubMed1994

Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction. New insights using myocardial contrast echocardiography.

BACKGROUND: Patency of the infarct-related artery (IRA) after acute myocardial infarction (AMI) may not reflect the magnitude of tissue perfusion. In animal models of AMI, myocardial cellular necrosis has been associated with extensive capillary damage. Because myocardial contrast echocardiography (MCE) can define the spatial distribution of microvascular perfusion, we hypothesized that it could be used in patients after recent AMI to distinguish myocardial regions that have an intact microvasculature and thus are viable from those without an intact microvasculature and thus are not viable. METHODS AND RESULTS: One hundred five patients with a recent AMI (range, 1 day to 4 weeks; median, 8 days) who were undergoing cardiac catheterization were included in the study. Two-dimensional echocardiography was performed at baseline and repeated 1 month later to assess regional function within the infarct zone (scores of 1 to 5 indicating normal to dyskinetic segments, respectively). MCE was performed in the cardiac catheterization laboratory to assess microvascular perfusion within the infarct bed. A contrast score index was derived by assigning scores to individual segments within the infarct zone (0, 0.5, and 1 denoting no, intermediate, and homogeneous contrast effect, respectively) and deriving the average score within the infarct bed. Revascularization was performed as clinically indicated. Although the baseline wall motion score and the contrast score index were similar in the 90 patients with a patent IRA and the 15 patients with an occluded IRA (median +/- 1 interquartile range, 3 +/- 1 versus 3.5 +/- 1; P = .41), wall motion score 1 month later was significantly better in those with open IRAs compared with those with closed IRAs (2 +/- 2 versus 3 +/- 2, P = .05). In the 90 patients with an open IRA, a strong correlation was noted between wall motion score 1 month later and the contrast score index (rho = -.64, P < .001). On multivariate analysis, the best correlate of the 1-month wall motion score was the contrast score index. CONCLUSIONS: In patients studied in the cardiac catheterization laboratory between 1 day and 4 weeks after AMI, an intact microvasculature as identified by MCE indicates myocardial regions that improve function 1 month later. This study demonstrates that microvascular patency is closely associated with myocardial cellular viability after AMI in humans.

Adult↗