Biomedical subjects
Publications and source records attributed to N Kumar.
Immunophenotyping of 28 gastrointestinal non-Hodgkin's lymphomas was done using specific antibodies. Twenty six of these were successfully classified using this technique.
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Identification of continuous epitopes in the target antigens of Plasmodium falciparum transmission-blocking antibodies is likely to facilitate the production of a subunit peptide vaccine. Two such epitopes shared among several sexual-stage antigens were identified with murine monoclonal antibodies. An epitope recognized by four monoclonal antibodies capable of blocking infectivity of gametocytes in the mosquitoes is shared among three antigens (230, 48/45 doublet, and 27 kDa). These antigens are synthesized at different times during the development and maturation of gametocytes, and the blocking epitope appears conserved among parasites from diverse geographical locations. Immune response against such a unique epitope (continuous, cross-reacting, and conserved) is likely to be boosted by natural infection. The 27-kDa protein is reported here as a target of malaria transmission-blocking monoclonal antibodies, and the cross-reacting epitope represents an attractive candidate for a transmission-blocking vaccine.
An antiserum against tubulin, NS20, has been previously shown to inhibit anterograde and retrograde axonal transport by 50% in vivo and in vitro. We report here that Protein A purified NS20 antibodies also attenuate sperm motility by 50% in demembranated sea urchin sperm. This inhibition is absorbed out by preincubating the NS20 antibodies with a biochemically purified porcine microtubule preparation, with recombinant Trypanosoma beta- (but not alpha-) tubulin and most specifically, with a 37 amino acid (a.a.) synthetic peptide corresponding to a domain near (but not including) the porcine beta-tubulin C terminus. Furthermore, addition of this beta-tubulin peptide alone is sufficient to attenuate motility by 50% in demembranated sperm, indicating that this critical 37a.a. NS20 antigen is a motor binding domain. Together, the results suggest that at least two phenotypically distinct forms of microtubule-based motility, axonal transport and flagellar beating, are homologous at the fundamental level of the microtubule domains (the beta-tubulin peptide and we suggest a distinct but similarly located alpha-tubulin domain) mediating the attachment of tubulin-associated motors.
Treatment of RIF-1 solid tumors with 5-fluorouracil (5-FU, 100 or 200 mg/kg, ip) caused substantial regression of the tumors, with regrowth initiated on Day 6 (100 mg/kg) or Day 9 (200 mg/kg). Blood perfusion in the tumor, estimated by uptake of 86Rb+, was significantly increased after treatment with 5-FU, while Rb+ uptake in normal tissues (skin, muscle) was unaffected. The increase in tumor perfusion during the first few days following treatment was significantly greater in animals treated with the higher dose of 5-FU. Perfusion-dependent 86Rb+ uptake returned to control levels by the 9th day after treatment with 100 mg/kg of 5-FU, but remained elevated on Days 9-12 after the higher dose. By the 1st day following treatment with 5-FU, in vivo 31P NMR spectra of treated tumors indicated significantly higher ratios of phosphocreatine to Pi, higher pH, and lower ratios of Pi to nucleoside triphosphates compared to untreated age-matched controls. These changes persisted for 9 days following the lower 5-FU dose and for at least 12 days following the higher dose. Treatment with 5-FU induces profound, dose-dependent changes in tumor bioenergetics, which may result, at least in part, from changes in tumor perfusion after cytoreduction.
To elucidate the value of conservative operation for aortic regurgitation, all consecutive patients operated on between July 1988 and July 1990 were reviewed. Of 251 patients with aortic regurgitation, 107 (42.6%) had nonprosthetic operation. The mean age was 23 years, and 90 patients (84.1%) were rheumatic. Two techniques were used: repair (annular and leaflet plasties, 69 cases) and cusp extension with glutaraldehyde-treated pericardium (25 bovine, 13 autologous). There were two hospital deaths (1.8%), both in the repair group, and no late deaths or embolic events. Only 5 patients (4.7%) were anticoagulated. In the repair group there were 12 reoperations, four (5.9%) due to aortic and eight to mitral dysfunction. In the cusp extension group there were two reoperations due to mitral dysfunction. Echocardiographic follow-up showed better results with cusp extension. In conclusion, conservative operation for aortic regurgitation is possible in a high percentage of young rheumatic patients and does not require anticoagulation. Cusp extension is more reliable than repair in terms of early results, although its long-term durability is not yet known.
Induction of heat shock-related stress proteins Pfhsp and Pfgrp, similar in sequence to hsp70 (heat shock protein) and grp78 (glucose-regulated protein), respectively, was studied in culture-derived parasite Plasmodium falciparum. Elevation in temperature from 26 degrees C to 37 degrees C and higher caused significant induction of Pfhsp with a moderate effect on the synthesis of Pfgrp also. Synthesis of Pfgrp, however, was not induced by partial glucose deprivation. On the contrary, lack of glucose in the medium resulted in cessation of protein synthesis in the parasites. Other known inducers of grp synthesis in mammalian cells, i.e., calcium ionophore A23187 and inhibitors of glycosylation (tunicamycin, 2-deoxy glucose) were also without any apparent effect on the synthesis of Pfgrp. Heat shock-induced responses were transient in nature: removal of stress caused repression of these responses. The effect of glucose deprivation was only partially reversible with better recovery if parasites were subjected to glucose starvation at 26 degrees C than at 37 degrees C. Northern blot analysis and in vitro translation of mRNA revealed a parallel increase in the levels of mRNA for Pfhsp upon heat shock. Immuno-gold electron microscopy with cultured parasites revealed nuclear location of Pfhsp and primarily cytoplasmic (probably endoplasmic reticulum) location of Pfgrp. These findings suggest that SDEL (carboxy terminal sequence of Pfgrp) might play a similar role in the cellular localization of Pfgrp as does the sequence KDEL in mammalian cells and HDEL in yeast.
Rats have very high endogenous levels of serum carboxylesterase (CAE) compared to primates. This difference accounts for the lower sensitivity of rats to toxic organophosphates, which interact with CAE instead of the more critical acetylcholinesterase. Pretreatment of rats with CAE inhibitors potentiates the effects of organophosphates. In this study, the effects of three putative CAE inhibitors, 2-(o-Cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP), bis-p-nitrophenyl-phosphate (BNPP), and tetraisopropyl pyrophosphoramide (Iso-OMPA), on the hydrolysis of several commercially available substrates were determined. Respective kinetic constants Km and Vmax were derived and effects of inhibitors compared using saturating amounts of substrate. Data presented here indicate significant differences in substrate affinity (Km), reactivity (Vmax), as well as effects of inhibitors. CBDP inhibits hydrolysis of specific naphthyl and paranitrophenyl esters at relatively low concentrations (1-10 microM). In contrast, significantly higher concentrations (mM) of BNPP and Iso-OMPA were required for inhibition of serum esterase activity. Of the inhibitors tested, Iso-OMPA in general exhibited the smallest inhibitory effect on ester hydrolysis. Although inhibition of hydrolysis of specific paranitrophenyl and naphthyl esters occurred in the presence of similar amounts of CBDP, the degree of inhibition differed significantly (50-75% vs. greater than 90%, respectively). These data suggest that there exists in rat serum, a pool of naphthyl ester esterase activity that is very sensitive ex vivo (greater than 90% inhibition) to CBDP and may be very useful in validating a rodent model for soman toxicity.
Embolization of parts of mechanical valves has been reported since the inception of prosthetic valve implantation. We report here two cases of embolization of one hemileaflet of a Duromedic bileaflet prosthesis in the mitral position due to a pivot fracture. Both presented with moderately severe mitral regurgitation and pulmonary edema and were successfully managed by replacement of the malfunctioning prostheses. The embolised disc was located in the left common iliac artery by abdominal ultrasound and removed by an inguinal, retroperitoneal approach with low morbidity. Both patients left hospital and are doing well to-date.
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A young adult presenting as subarachnoid haemorrhage, which was proved to be a thalamic haemorrhage on CT scan, with evidence of tuberculous arteritis, is reported.
The effect of a standard breakfast and a fatty breakfast on the pharmacokinetics and pharmacodynamics of a theophylline liquid preparation (160 mg-single dose) was examined in 6 healthy, non-smoking male volunteers. The plasma theophylline concentrations after both standard and fatty diet were found to be comparable at each point of time and pharmacokinetic parameters like Cmax, Tmax, T1/2a, T1/2 beta and AUC0-alpha, were also comparable. However, the time taken to attain the therapeutic plasma concentration was earlier and sustained along with the standard breakfast in comparison to that with fatty breakfast. Peak change in PEFR and pulse rate was also observed earlier with the standard diet than with fatty diet. The plasma theophylline concentrations produced after both diets were insufficient to produce any detectable change in subjective symptoms like tremor palpitation, heart burn, nausea, restlessness and tenseness. However, theophylline after fatty breakfast was better tolerated than that after a standard breakfast.
We report a patient with high jejunal stricture initially thought to be tubercular in origin. There was, however, no response to antitubercular treatment and enteroscopic biopsy revealed it to be an adenocarcinoma. This case illustrates the role of enteroscopy and biopsy in the definitive diagnosis of high small bowel strictures.
A forty year old female who presented with intra-abdominal lump in the left hypochondrium was clinically suspected to have a juxta splenic hydatid cyst. Histopathology and cytology of the specimen removed at surgery confirmed the diagnosis.
A method for the measurement of 7 alpha-methyl-19-nortestosterone (7MENT) in serum/plasma by radioimmunoassay (RIA) is described. The antiserum, raised against 7 alpha-methyl-19-nortestosterone-3-O-oxime-bovine serum albumin, had a low titer (final dilution = 1:4500) and low affinity (Ka = 1.17 x 10(9) l/mol) but showed little or no cross-reactivity with several of the steroids tested. The sensitivity of the RIA was 28.2 pg/ml and the mean recovery of added cold steroid was 86 to 100%. Intra- and inter-assay coefficients of variation ranged from 4.3 to 7.3% and 7.3 to 8.4%, respectively. This RIA was used to follow plasma 7MENT levels after a single i.v. injection of the steroid in rats and rabbits. The metabolic clearance rates (MCR) of 7MENT as determined from the plasma disappearance curve for rats and rabbits were 50 l/day and 336 l/day, respectively. The MCR of 7MENT in rats and rabbits lies in the same range as for testosterone. When compared to other nortestosterone derivatives such as norethisterone, 7MENT is metabolized relatively faster.
In the present studies, the regulatory role of adrenal hormones on the antitumor activity of recombinant human interleukin 1 alpha (IL-1 alpha) was investigated. Ketoconazole, a potent but transient inhibitor of adrenal steroid hormone biosynthesis, inhibited IL-1 alpha induced increases in plasma corticosterone. In s.c. RIF-1 tumors (C3H/HeJ mice) ketoconazole potentiated IL-1 alpha induced hemorrhagic necrosis (59Fe labeled RBC uptake) and prolonged intervals of low tumor perfusion (86Rb+ uptake) and attendant depletion of tumor high energy phosphate reserves as determined by in vivo 31P nuclear magnetic resonance spectroscopy. In normal muscle and skin the ketoconazole-IL-1 alpha combination had no effect on RBC content and little or no effect on tissue perfusion. Ketoconazole potentiation of IL-1 alpha induced tumor pathophysiologies was accompanied by time and ketoconazole dose dependent potentiation of RIF-1 tumor clonogenic cell killing. Although ketoconazole at 40 mg/kg and IL-1 alpha at 25 micrograms/kg alone each produced approximately 50% clonogenic cell kill, a combined treatment (IL-1 alpha 1 h after ketoconazole) resulted in surviving fractions of approximately 1.5%. In vitro, ketoconazole and IL-1 alpha induced only additive clonogenic cell kill in primary RIF-1 explant cultures. The effect of elevated plasma corticosterone levels, induced by ketamine-acepromazine anesthesia, on IL-1 alpha responsiveness was also studied in the RIF-1 tumor model. In C3H/HeJ mice, anesthesia increased plasma corticosterone levels within 30 min, abrogated the IL-1 alpha effect on tumor perfusion, and prevented depletion of tumor high energy phosphate metabolite reserves. Our results are consistent with the hypothesis that IL-1 alpha mediated adrenal hormone responses exert a profound negative feedback on IL-1 alpha antitumor activities. Our data also indicate that adrenal steroid hormone biosynthetic pathways could provide a focus for modulation strategies to increase the efficacy of cytokine based therapeutic interventions.
Qinghaosu, an anti-malaria drug, has been found to kill not only asexual blood stages but also the early stages of gametocytes of Plasmodium falciparum. The effect of qinghaosu in vitro depends on the concentration of the drug as well as on the initial parasitemia level (IC50 = 10-20 nM with 1% initial parasitemia). Resistance of P. falciparum to other anti-malaria drugs, e.g., chloroquine and pyrimethamine, did not affect susceptibility of its asexual and sexual stages to qinghaosu. Gametocytocidal effect of qinghaosu may play a role in the interruption of malaria transmission.