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Biomedical subjects

P Kumar

Publications and source records attributed to P Kumar.

At least 19 recordsLinked to original sources
PubMed1992

Detection of new metabolites of trifluridine (F3TdR) using 19F NMR spectroscopy.

The metabolism of 5-trifluoromethyl-2'-deoxyuridine (trifluridine, F3TdR) in male BALB/C mice has been studied by 19F NMR spectroscopy. Contrary to previous reports, a number of fluorinated metabolites were observed in urine, whole livers and blood samples taken from mice after i.p. injection of F3TdR. The present study describes the identification of two new metabolites in mouse urine using the 19F NMR technique. The NMR of crude urine showed the presence of F3TdR 5-trifluorothymine (F3T), the newly-identified metabolites, 5-trifluoromethyl-5,6-dihydrouracil (DHF3T) and 5-trifluoromethyl-5,6-dihydroxyracil (DOHF3T), and several new, as yet unidentified fluorinate metabolites. These two new metabolites were characterized by comparison to authentic compounds prepared synthetically from F3T.

Animals↗
PubMed1992

ABA-induced 'lipid melting' and its reversal by umbelliferone in the plasmalemma of guard cell protoplasts: a breakthrough in plant hormone-receptor binding and hormone action.

The dynamics of stomatal opening and closure had to date been ascribed largely to the K(+)-fluxes and cell wall elasticity. Using protoplasts of guard cells of Vicia faba as model system, we document convincing first hand evidence a that lipid phase alterations could regulate ABA-induced closure of stomates and its reversal by umbelliferone. Backed up by the presence of plasmalemma-located ABA-receptor in guard cells, a novel theory could be put forth explaining guard cell opening and closure mediated by hormone induced reconfiguration via a probable lipid-protein lattice modification. The phase reversal of the plasmalemma by umbelliferone is postulated to be through modified hormone receptor complex structure, which is yet to be substantiated.

Abscisic Acid↗
PubMed1992

Apoptosis and DNA fragmentation precede TNF-induced cytolysis in U937 cells.

The hypothesis that activation of apoptosis and DNA fragmentation is involved in TNF-mediated cytolysis of U937 tumor cells was investigated. Morphological, biochemical, and kinetic criteria established that TNF activates apoptosis as opposed to necrosis. Within 2-3 h of exposure to TNF, U937 underwent the morphological alterations characteristic of apoptosis. This was accompanied by cleavage of DNA into multiples of nucleosome size fragments. Both of these events occurred 1-2 h prior to cell death as defined by trypan blue exclusion or 51Cr release. DNA fragmentation was not a non-specific result of cell death since U937 cells lysed under hypotonic conditions did not release DNA fragments. The percentage of cells undergoing apoptosis depended on the concentration of TNF and was augmented by the addition of cycloheximide. A TNF-resistant variant derived from U937 did not undergo apoptosis in response to TNF, even in the presence of cycloheximide. Furthermore, TNF could still activate NFkB in this variant, suggesting that this pathway is not involved in TNF-mediated cytotoxicity. Two agents known to inhibit TNF-mediated cytotoxicity, ZnSO4 and 3-aminobenzamide, were shown to inhibit TNF-induced apoptosis. Taken altogether, these data support the hypothesis that activation of apoptosis is at least one essential step in the TNF lytic pathway in the U937 model system.

Benzamides↗
PubMed1992

SCM4, a gene that suppresses mutant cdc4 function in budding yeast.

The gene SCM4 encodes a protein which suppresses a temperature-sensitive allele of the cell division cycle gene CDC4 in Saccharomyces cerevisiae. SCM4 was cloned on a 1.8 kb BamHI fragment of yeast genomic DNA in the high copy-number vector pJDB207, which results in a 50- to 100-fold increase in the level of the 700 nucleotide SCM4 transcript in vivo. The SCM4 gene encodes a 20.2 kDa protein of 187 amino-acids with a clear tripartite domain structure in which a region rich in charged residues separates two domains of largely uncharged amino acids. Although the apparent allele specificity of cdc4 suppression suggests that the CDC4 and SCM4 proteins interact, disruption of SCM4 demonstrates that the gene product is not essential for mitosis or meiosis; however, it may be a member of a family of related, functionally redundant proteins.

Alleles↗
PubMed1992

Clinical studies in workers engaged in maintenance of watermark moulds in a paper mill.

Thirty subjects engaged in maintenance and repair of moulds used for producing watermarks on paper were studied, along with 27 control subjects from the same paper mill. The workers were simultaneously exposed to copper, chromium, zinc, xylol, and fumes of sulphuric acid in the course of their work. The study subjects were investigated for clinical, occupational, radiological haematological and psychological details. The aforementioned combined exposure was found to be responsible for a high prevalence of symptoms pertaining to the respiratory system and higher nervous functions. Breathlessness (26.7%), expectoration (10.0%) and emphysema (10.0%) were significantly higher among the exposed subjects. The exposed subjects also showed lowered visuomotor coordination and delayed reaction to light and sound stimuli.

Adult↗
PubMed1992

The value of intraoperative scans during CT-guided stereotactic procedures.

The accuracy stereotactic procedures performed during the pre-computed tomography (CT) era was confirmed by intraoperative X-ray pictures. With the availability of CT it is now possible to confirm the position of the probe-tip on an image of the target. For biopsy of small lesions in critical areas of the brain, permanent placement of radioactive seeds, or thalamotomy, it would be desirable to have confirmation of the site of the probe-tip prior to performing the main step of the procedure. Intraoperative CT was performed in 216 stereotactic procedures carried out on the scanner table including biopsies, aspiration of cysts, brachytherapy, aspiration of abscesses, thalamotomy, and evacuation of intracerebral hematoma. In 6 cases, inaccuracies were detected, which it was possible to correct so as to place the probe where desired.

Adolescent↗
PubMed1992

Selection of tumor cell variants for resistance to tumor necrosis factor also induces a form of pleiotropic drug resistance.

This study has addressed the question of whether there may be some common mechanism underlying the induction or expression of acquired cytokine and drug resistance in a tumor cell line. This study employed the tumor-necrosis-factor(TNF)-sensitive U937 tumor cell line as a model system to determine if selection of a tumor cell variant for cytokine resistance would also result in drug resistance and vice versa. Variants were selected by culturing in the presence of purified recombinant TNF or a mixed-lymphokine-containing supernatant derived from concanavalin-A-stimulated peripheral blood lymphocytes. The resulting variants were resistant not only to TNF, but also to certain chemotherapeutic drugs. The variants were most resistant to colchicine and the Vinca alkaloids, requiring drug concentrations 50- to 5000-fold higher to mediate levels of cytotoxicity comparable to that seen with the parental U937. The variants were moderately resistant to cycloheximide, actinomycin D, and mitomycin C. In contrast, these lines were relatively sensitive to doxorubicin or daunomycin. This phenomenon was not unique to U937 cells since we obtained a similar pattern of drug resistance by selecting TNF-resistant variants of the WEHI-164 tumor cell line. The cytokine-selected U937 variants were still lysed by NK cells, although they were somewhat less sensitive than the parental U937. Both variants were relatively resistant to lysis by activated macrophages, probably because of their TNF resistance. In an alternative selection procedure, U937 variants were derived by culturing in the presence of increasing concentrations of colchicine. The resulting variants were relatively resistant to TNF, providing further support for the existence of some common mechanism operating in induction or expression of acquired cytokine and drug resistance. The resistance mechanism apparently does not involve the P glycoprotein since the cytokine-selected U937 variants do not overexpress the mdr gene. This study has demonstrated that selection of TNF-resistant variants results in coexpression of a unique form of drug resistance that is characterized by resistance to microtubule-active drugs but not to the anthracycline antibiotics and is not associated with overexpression of the mdr gene.

Animals↗
PubMed1992

Human immunodeficiency virus type 2 envelope glycoprotein: differential CD4 interactions of soluble gp120 versus the assembled envelope complex.

Utilizing a recombinant vaccinia expression system, we investigated the biological properties and CD4 receptor interactions of the envelope glycoproteins of a noncytopathic human immunodeficiency virus type 2 strain, termed HIV-2/ST, and a highly cytopathic variant derived from it. The efficiency and host cell range of syncytium formation by the recombinant glycoproteins of both viruses were highly restricted compared to those of prototypic strains of HIV (HIV-2/ROD or HIV-1/IIIB). However, the glycoprotein of cytopathic but not wild-type ST generated numerous large syncytia in the human T-cell line Sup T1 from which it was derived. A single cell line (Molt 4 clone 8) was permissive to fusion by both wild-type and cytopathic ST envelopes, but only the glycoprotein of cytopathic ST could be inhibited with a soluble form of the viral receptor CD4 (sCD4). While these results indicated major differences in the envelope glycoprotein-CD4 receptor interactions of wild-type versus cytopathic ST, direct and competition binding assays utilizing soluble external glycoprotein (SU) and sCD4 surprisingly revealed equivalent low binding affinity for both viruses. From these experiments we conclude that relevant biological properties (e.g., CD4 binding, cytopathic potential, and sCD4 neutralization) of HIV viruses which differ in their pathogenic potential are reflected in the sCD4 interactions of the assembled native envelope complex (as on cell or virion surfaces) but not the soluble SU glycoprotein.

CD4 Antigens↗
PubMed1992

Testosterone sensitive dihydropyridine binding in the Harderian gland of the male hamster.

It is well known that in different tissues, dihydropyridines bind at nanomolar concentrations to a receptor and block voltage-operated Ca2+ channels. In studies reported here, Harderian gland tissue homogenates from intact male hamsters exhibited significant dihydropyridine binding (Bmax = 1700 fmoles/mg protein) of high affinity (Kd = 1.1 nM). Tissue homogenates from female animals exhibited a similar Kd value (1.35 nM) but receptor density per mg protein was significantly reduced (Bmax = 270 fmoles). Dihydropyridine binding of Harderian gland tissue homogenates from castrated males was reduced greater than 80% (Bmax = 225 fmoles/mg protein). Treatment of castrated males with subcutaneous testosterone pellets resulted in significant restoration of dihydropyridine binding activity (approximately 80%, Bmax = 1630 fmoles/mg protein) with a comparable binding constant (Kd = 1.50 nM) as observed for noncastrated, control animals. Addition of testosterone (ex vivo) to homogenates from castrated hamsters did not restore dihydropyridine binding to control levels. These data indicate: (a) the Harderian gland from male hamsters exhibits significant dihydropyridine binding; (b) ligand binding is abolished following castration; and (c) significant restoration of dihydropyridine binding occurs following in vivo testosterone treatment. The dependence of dihydropyridine binding restoration upon in vivo steroid hormone administration suggests probable involvement of the steroid at the transcriptional level although non-genomic mechanisms such as the binding of testosterone to a receptor resident in the plasma membrane and subsequent activation of Ca2+ channels can not be ruled out.

Animals↗
PubMed1992

The fast flush test measures the dynamic response of the entire blood pressure monitoring system.

The fast flush test (FT) is the only test that allows clinicians to determine in vivo the natural frequency (fn) and damping coefficient (zeta) of an invasive blood pressure monitoring system. The underlying assumption to the validity of the FT is that it activates the whole system including the distal catheter. We devised an in vitro model of a typical invasive blood pressure monitoring system to determine whether this assumption was true. The model consisted of a conventional transducer with a flush device attached to various lengths of connecting tubing (91.4, 182.9, and 274.3 cm) terminated by four different diameter catheters (5.1 cm 14 G, 16 G, 18 G, and 20 G). A microtipped transducer catheter was inserted into the distal catheter tubing system. A FT was performed and the fn and zeta were recorded from the conventional transducer and simultaneously from the microtipped transducer catheter. Similar studies were conducted using the ROSE damping device as well as with systems including 0.1 ml of air near the conventional transducer. These studies utilized 18- and 20-G catheters with each of the three lengths of connecting tubing. All measurements of fn and zeta at the proximal conventional transducer were identical to those measurements as recorded by the distal microtipped transducer catheter. We conclude that the FT activates the whole monitoring system and that fn and zeta are the same throughout the system including the distal catheter.

Blood Pressure Monitors↗
PubMed1992

Myocardial metabolism and adaptation during extreme hemodilution in humans after coronary revascularization.

OBJECTIVE: This study was designed to evaluate the oxygen transport adjustments and myocardial metabolic adaptation that occurs with different levels of hemodilution during normothermia after cardiopulmonary bypass. DESIGN: Prospective, nonrandomized study. SETTING: Operating room in a university hospital. PATIENTS: Eight patients with ejection fractions (> 40%) undergoing elective coronary artery bypass grafting. METHODS: Before the institution of cardiopulmonary bypass, blood was withdrawn from patients to a target hematocrit of 15%. After coronary artery bypass grafting, a catheter was inserted directly into the coronary sinus. After the patients were rewarmed to 37 degrees C, they were weaned from cardiopulmonary bypass. Hemodynamic indices were measured, as well as measurements of myocardial oxygen consumption (VO2) and myocardial metabolism (lactate extraction and coronary sinus hypoxanthine). Measurements were made at three different hematocrit values: 15%, 20%, and 25%. Hematocrit was increased by autologous blood transfusion. MEASUREMENTS AND MAIN RESULTS: The three levels of hemodilution (hematocrit: 17.4 +/- 3.4%; 23.0 +/- 3.7%; 27.8 +/- 4.8%) were significantly different from baseline (hematocrit 37 +/- 2.6%; p < .05). Oxygen delivery, which increased with autologous transfusion, exceeded 350 mL/min/m2 at each level of dilution. The myocardial VO2 increased significantly after autologous transfusion compared with the most dilute condition (7.0 +/- 3.7 mL/min at hematocrit 17.4% vs. 11.2 +/- 4.8 mL/min at hematocrit 23.0% and 12.4 +/- 4.0 mL/min at hematocrit 27.8%). This transfusion-induced increase was also true of myocardial oxygen extraction. Lactate extraction and hypoxanthine release were normal and unchanged at each level of hemodilution. Systemic oxygen extraction ratio increased with hemodilution and decreased with autologous transfusion. CONCLUSIONS: Hemodilution to a hematocrit of approximately 15% is tolerated in anesthetized humans after coronary artery bypass surgery. There was no evidence of myocardial ischemia, as demonstrated by absence of S-T depression on the electrocardiogram, lactate extraction, or hypoxanthine release. In selected patients, postoperative transfusion may be based on systemic physiologic end-points, such as oxygen extraction ratio, rather than set hematocrit values.

Blood Transfusion, Autologous↗