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Biomedical subjects

N Paul

Publications and source records attributed to N Paul.

At least 37 records · Page 2Linked to original sources
PubMed1997

Template directed incorporation of nucleotide mixtures using azole-nucleobase analogs.

DNA that encodes elements for degenerate replication events by use of artificial nucleobases offers a versatile approach to manipulating sequences for applications in biotechnology. We have designed a family of artificial nucleobases that are capable of assuming multiple hydrogen bonding orientations through internal bond rotations to provide a means for degenerate molecular recognition. Incorporation of these analogs into a single position of a PCR primer allowed for analysis of their template effects on DNA amplification catalyzed by Thermus aquaticus (Taq) DNA polymerase. All of the nucleobase surrogates have similar shapes but differ by structural alterations that influence their electronic character. These subtle distinctions were able to influence the Taq DNA polymerase dependent incorporation of the four natural deoxyribonucleotides and thus, significantly expand the molecular design possibilities for biochemically functional nucleic acid analogs.

Azoles↗
PubMed1996

Probing the conformation of the human T-lymphotropic virus I envelope protein complex with monoclonal antibodies.

We are investigating the binding of a series of monoclonal antibodies to native and detergent-treated human T-lymphotropic virus I (HTLV-I) envelope proteins to explore their conformation. A comparison of our data with previously published findings suggests that a central neutralization domain (aa 175-200) is folded such that only short stretches are exposed at the surface of the native envelope protein complex. However, the complete domain becomes accessible after treatment with mild non-ionic detergents, suggesting that envelope subunit interaction may partially obscure this domain. We further provide immunochemical evidence that a region containing a heptad repeat in the extracellular part of the transmembrane protein is folded towards the interior of the HTLV-I envelope complex.

Amino Acid Sequence↗
PubMed1996

The use of metoclopramide for the small bowel meal examination: pre-procedural versus peri-procedural oral administration.

Administration of oral metoclopramide reduces the transit time for barium to reach the caecum during a small bowel meal (SBM). Current practice is to administer the metoclopramide 5-10 min prior to the barium. We devised a prospective randomized, controlled trial to assess whether administration of metoclopramide 90 min prior to the barium would further reduce the transit time without adversely affecting the quality of the study. Although administration of oral metoclopramide significantly reduced the transit time when compared with a control population, there was no significant difference in transit time between the groups which received metoclopramide.

Antiemetics↗
PubMed1995

Cost utility analysis of maintenance treatment for recurrent depression.

This paper presents a cost-utility analysis of three maintenance treatments for recurrent depression: interpersonal therapy (IPT-M), imipramine drug therapy (Drug), and a combination of the two. We base our analysis on the results of the University of Pittsburgh's Controlled Clinical Trial of Maintenance Therapies for Recurrent Depression. We construct a Markovian state-transition model to incorporate clinical effectiveness into cost and quality-of-life impacts; we assign empirical values to the parameters of this model; and we then use Monte Carlo analysis to compare the relative cost effectiveness of the different maintenance treatments. For the patients who met the eligibility standards for the study, Drug maintenance treatment is cost-effective in the strongest sense of the term compared to either a placebo group or IPT-M: it both improves expected lifetime health (measured in quality-adjusted life years, or QALYs) and reduces direct medical costs. This is true even when relatively severe side effects of the drug are considered. Compared to the placebo group, IPT-M and the combination of IPT-M and Drug each improve expected lifetime health, although in neither case are expected direct medical costs reduced. Still, the cost of the resulting health improvements, under $5000/QALY, are very reasonable. A similar conclusion holds comparing Drug and IPT-M to IPT-M alone. All of the above conclusions are quite robust to sensitivity analyses.

Adult↗
PubMed1993

[Electron microscopic studies of the effect of x-rays and L-3,4-dihydroxyphenylalanine (L-Dopa)--alone and in combination-- on Harding-Passey melanoma cells in monolayer cell culture].

Monolayer cultures of Harding-Passey melanoma cells in exponential growth phase were exposed to 8 or 16 Gy by X-ray treatment. The 8 Gy treated cells revealed little ultrastructural changes, while the 16 Gy exposed cells showed increased damage as segregates, swollen mitochondria and vacuoles. Sole treatment with L-3,4-dihydroxyphenylalanine (2 x 10(-4) M L-Dopa) resulted in insignificant electronmicroscopically tangible cell alterations. Combined treatment--starting with 8 Gy irradiation followed by a six-day incubation in the presence of 2 x 10(-4) M L-Dopa--revealed more pronounced cell damage with final cell disintegration; the cytoplasm contained an increased number of vacuoles and segregates, a strongly decreased endoplasmic reticulum as well as swollen mitochondria and less pinocytosis vesicles; the cell surface showed less microvilli. Melanin containing organelles increased after the combination treatment. The growth inhibitory and cell destructive influence of L-Dopa on X-ray pretreated melanogenic melanoma cells was explained with the formation of cytotoxic oxidation products of L-Dopa.

Animals↗
PubMed1992

[Electron microscopic studies on the effects of irradiation and mitoxantrone hydrochloride (Novantrone), alone and in combination, on cells of Harding-Passey melanoma in monolayer culture].

2 Gy or 4 Gy irradiation of cultured Harding-Passey melanoma cells revealed electronmicroscopically none or little cell damage. 48 hour exposure of cultures to mitoxantrone concentrations of 1 x 10(-8) M or 3.3 x 10(-8) M also exhibited little cell damage. However, combination of these treatments--in comparison with single treatment--resulted in increased cell damage. The present paper describes the extent of Harding-Passey melanoma cell damage following a radiation exposure (2 or 4 Gy) or a mitoxantrone treatment (1 x 10(-8) M or 3 x 10(-8) M) for 48 hours alone or in combination.

Animals↗
PubMed1991

Acceleration of asynchronous enzyme transport in the rat exocrine pancreas following hormonal stimulation in vivo.

We have measured the rate of secretion in vitro of individual rat exocrine pancreatic enzymes and proenzymes from cells in pancreatic lobules of control animals and animals subjected to 24 h optimal hormonal prestimulation with cerulein, in vivo. With the controls secreted proteins were first detectable at 20 to 25 min of chase after a 5-min pulse label, and the amount of total secretion increased slowly thereafter. With stimulated lobules secretion was first detectable at 10 to 15 min postpulse. Comparison of the rates of secretion from control and experimental lobules showed that 24 h prestimulation in vivo resulted in a fivefold increase in the rate of secretion. Measurement of the rates of secretion of the individual enzymes and proenzymes showed that they were all increased to the same extent. In both situations the serine endoproteases, proelastase 2, chymotrypsinogen 1, and trypsinogen 1 and 2, were the most rapidly secreted proteins, while amylase, the procarboxypeptidases and prophospholipase A2 were amongst the slowest. The difference in the rates of secretion of proelastase 2 and prophospholipase A2, the two extremes, was three-fold before and after prestimulation, and their halftimes of secretion from the hormonally prestimulated lobules were 34 min and 190 min, respectively. Both electron microscopic autoradiography and immunocytochemistry showed that in the hormonally prestimulated cells the secreted proenzymes and enzymes followed the normal regulated exocytotic pathway and were transported between the Golgi apparatus and the apical plasma membrane in dense cored secretory granules.

Animals↗
PubMed1989

Interovarian relationship in the secretion of progesterone during the luteal phase of the capuchin monkey (Cebus apella).

In basal conditions, progesterone concentrations were similar in the ovarian veins of the ovary +CL (3211 +/- 526 ng/ml) and the ovary -CL (3165 +/- 554 ng/ml), but after blocking the blood flow between the ovary +CL and the uterus, the progesterone values in the vein draining the ovary -CL decreased to 1218 +/- 394 ng/ml (P less than 0.01). When [3H]progesterone was injected in the ovary +CL, the radioactivity appeared earlier and more concentrated in the vein draining the ovary -CL (30 sec, 0.53% of injected dose) than in the femoral vein (150 sec, 0.08% of injected dose). Removal of the ovary +CL was followed by a brief maintenance of peripheral progesterone within luteal-phase levels. The in-vitro progesterone production by a suspension of cells isolated from the corpus luteum was 47.5 +/- 12.8 ng/ml/2 h, whereas luteal-like cells isolated from the ovary -CL secreted 14.3 +/- 6.0 ng/ml/2 h (P less than 0.01) into the medium. We therefore suggest that the symmetrical and high secretion rate of progesterone by the ovaries of the capuchin monkey indicates a between-ovary communication system, and that the luteal-like tissue of the ovary -CL can produce relatively large amounts of progesterone.

Animals↗
PubMed1988

Augmentation by L-dopa of growth inhibition and melanin formation of X-irradiated Harding-Passey melanoma cells in culture.

Treatment of exponentially proliferating melanogenic Harding-Passey melanoma cells in monolayer culture (HPM-73 line) with a single dose of X-irradiation (up to 8 Gy) or continuously (for several weeks) with L-3,4-dihydroxyphenylalanine (L-Dopa) up to 5 X 10(-4) M resulted in a dose-dependent inhibition of cell proliferation, but not in death of all cells. Actually, 8 Gy-irradiated or L-Dopa (2 X 10(-4) M)-treated cultures finally reached the cell number and cell density of controls. However, a combination of a single dose of radiation (8 Gy) followed by L-Dopa (2 X 10(-4) M)-treatment resulted in destruction of all cells. Melanin formation was stimulated by L-dopa-treatment or X-irradiation, and was further elevated by the combined application of radiation and L-Dopa-exposure. Whether the effects of exogenously applied L-Dopa, an intermediary metabolite of melanin synthesis, are due to the conversion to growth-inhibitory metabolites (quinones, radicals, etc.) inside or outside the cell, was discussed. The latter might result from release (due to membrane damage or cell disintegration) of tyrosinase or/and melanosomes into the culture medium with the consequence of extracellular synthesis of potentially cytotoxic metabolites from medium substrates. Further, endocytosis of exogenous melanosomes and tyrosinase with potentially harmful effects is feasible. An application of such a combination therapy of melanoma to clinical medicine should be considered.

Animals↗
PubMed1987

Cytotoxic factors secreted by cells infected by human immunodeficiency virus type I.

Conditioned media from human immunodeficiency virus type I (HIV-1) infected cells were tested for cytotoxic cell-derived factors. The assay used a murine fibroblast cell line which is sensitive to the effects of tumor necrosis factors, but nonpermissive for HIV-1 replication. Cytotoxic activity was detected in cultures of peripheral blood mononuclear cells infected with HIV-1. However, no differences in activity were found in conditioned media from infected lymphoid or monocytoid cell lines compared to their uninfected counterparts. These data suggest that cytotoxic activities of this type are not mediators of cell killing resulting from HIV-1 infection. Thus, this cytotoxic activity is a direct or indirect result of virus replication or cytopathicity. One should consider a role for this cytotoxic factor, secreted by HIV-1 infected mononuclear cells, in various aspects of infection in vivo, such as AIDS encephalopathy or the systemic manifestations accompanying ARC.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Target cell DNA fragmentation is mediated by lymphotoxin and tumor necrosis factor.

Supernatant fluids containing lymphotoxin (LT) activity were examined for their ability to mediate the fragmentation of cellular DNA in target L929 cells in the manner observed in cytotoxic T lymphocyte mediated killing. These supernatants were able to mediate L929 target cell DNA fragmentation, requiring a time course of 48 hours. In an effort to determine whether or not LT was directly involved in mediating this activity, recombinant-derived human lymphotoxin was tested for its ability to bring about the same effect. Both recombinant-derived LT and recombinant-derived tumor necrosis factor (TNF), a factor produced by macrophages and having some activities in common with LT, were able to cause DNA fragmentation in L929 over the same time course. Electrophoretic analysis of DNA isolated from LT-treated L929 target cells revealed that it is fragmented into low molecular weight fragments in a pattern similar to that produced in DNA isolated from target cells after attack by cytotoxic T cell lethal hit.

Animals↗
PubMed1983

[Ultrastructural studies on the effect of roentgen rays and quinacrine (atebrin)--alone or in combination--on Ehrlich ascites tumor cells in monolayer culture].

Already two days after an X-ray irradiation with 8 Gy performed during the phase of exponential growth, the cells of an Ehrlich ascitic carcinoma in monolayer culture showed remarkable ultrastructural modifications, e.g. a markedly vacuolized endoplasmic reticulum, swollen mitochondria, increase of lysosome-like structures, and a decrease of microvilli in number and size. Ehrlich ascitic carcinoma cells submitted to an X-ray irradiation with 8 Gy and subsequently incubated with quinacrine (Atebrin) in a concentration of 4 x 10(-6) M, which alone had no significant effects on growth or ultrastructure, showed severe cellular lesions. The endoplasmic reticulum was still more vacuolized, the mitochondria were severely damaged, lysosome-like structures and residual bodies were increased, and the cellular surfaces had still less microvilli. Microtubules and microfilaments, however, seemed rather increased. The effects of quinacrine (Atebrin) on cells exposed to X-rays were discussed with respect to the known inhibiting action of this substance on DNA synthesis, especially with regard to DNA reparation. The modifications of the microtubule-microfilament system could be correlated to increased intracellular digestive processes involved in the catabolism of radiodamaged structures.

Animals↗
PubMed1981

[Action of x-rays and neuraminidase on pinocytotic activity and microtubule-microfilament system of Ehrlich ascites tumor cells in monolayer culture (author's transl)].

Monolayer cultures of Ehrlich ascites tumor cells in exponential growth phase were treated with X-rays and neuraminidase alone or in combination. A radiation dose of 2 Gy (200 rd) and higher effected a significant inhibition of DNA synthesis and cell proliferation. Neuraminidase treatment in addition to irradiation did not modify the growth-inhibitory irradiation effect. Cells pretreated for 0.5 to 1.0 hours with neuraminidase (in Earle's salt solution) and cultured thereafter (4h) in serum-containing growth medium exhibited an enhanced development of the microtubule-microfilament-system. Morphometric analysis of microtubules on electronmicroscopic sections revealed a nearly 4-fold increased number in neuraminidase treated cells while the average length of microtubules was similar to controls. Pinocytosis as measured by the ultrastructural uptake of ferritin appeared to be increased following neuraminidase treatment. A connection between neuraminic acid containing components (glycoproteins or glycolipids?) of the cell membrane or cell surface, on the one hand, and the cytoskeleton and the endocytotic process of these tumor cells, on the other hand, is suggested.

Animals↗
PubMed1981

Effect of 1-aminoadamantanes on adenine nucleotide and serotonin storage in blood platelets.

The platelet release reaction, the liberation of adenine nucleotides and serotonin (5-HT) from osmiophilic dense granules, can be induced in human platelets by C-alkyl-derivatives of the antiviral and anti-Parkinson drug 1-aminoadamantane (D 1). The release-inducing activity is enhanced with increasing chain length and with the number of C-alkylsubstituents, respectively. The parent compound, D 1, liberates only 5-HT. Analyses of LDH activity in the incubation medium of the platelets and electron micrographs of platelets treated with 1-aminoadamantanes support the assumption that ATP, ADP, and 5-HT are released from the organelles by an exocytosis-like process rather than by destruction of the plasma and organelle membranes. The number of osmiophilic dense granules in platelets isolated from human and rabbit blood is decreased by the action of the drugs. This is in contrast to other subcellular structures where no morphological changes can be observed. The ADP-stimulated platelet aggregation is inhibited by preincubation with 1-aminoadamantanes. The inhibitory activity of the drugs on platelet aggregation parallels the effects observed after induction of the release reaction: the inhibition of platelet aggregation is enhanced with increasing C-alkylation. Hence, the inhibition of ADP-induced platelet aggregation can be used to screen for the releasing activity of 1-aminoadamantanes which have, as far as tested, similar effects on 5-HT storage in blood platelets and in the CNS. The time-, temperature, and concentration-dependent 5-HT uptake by platelets (K = 0.75 micro M; V max = 0.22 nmoles/min X 10 9 cells) is noncompetitively inhibited by the drugs with K1-values varying from 10 to 100 micro M depending on the degree of C-alkylation.

Adenosine Diphosphate↗
PubMed1978

[Influence of serum content of the culture medium upon growth and microtubule-microfilament system of Ehrlich ascites tumor cells in monolayer culture (author's transl)].

Withdrawal of serum from the medium of monolayer cultures of the Ehrlich ascites tumor within their phase of exponential growth resulted in a nearly complete inhibition of growth during a 25-hour incubation, but cells were not dying off. In the course of this serum-free incubation no significant alteration of the cellular glycolytic rate was seen. Addition of serum to cultures which previously had been incubated without serum led to a resumption of cell proliferation. The microtubule-microfilament system of cells cultivated without serum as compared to cells cultured in presence of serum was significantly reduced concerning the number and length of microtubules as well as the diffuse, bunchy or reticular arrangement of the microfilaments. The lesser development of the microtubule-microfilament system corresponds well to the reduced pinocytosis activity (ascertained by former studies) which is caused by a lack of serum. The present experiments altogether give support to the concept that serum factors as exogenous stimuli are necessary not only for cell growth but also for the probably closely interrelated development of the microtubule-microfilament system needed e.g. for the organization of cell surface structures and activities.

Animals↗