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Biomedical subjects

J Adams

Publications and source records attributed to J Adams.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N omega-amino-L-arginine.

BACKGROUND: Interleukin-1-alpha (IL-1) is a cytokine with potentially therapeutic immunoproliferative and tumoricidal activities. Preliminary clinical studies suggest that use of IL-1 may be restricted by dose-limiting hypotension. PURPOSE: The purpose of this study was to investigate the role of nitric oxide (NO.) as a possible mediator of this hypotension. METHODS: Cytokine-treated rat aortic smooth muscle cells were assayed for nitrite production, a stable breakdown product of nitric oxide. Nitric oxide synthase from smooth muscle cells was partially characterized in cytosol preparations using a novel Fe(2+)-myoglobin method to test for nitric oxide production. To determine the role of NO. on the immunorestorative and antineoplastic activity of IL-1, N omega-amino-L-arginine (NAA) or N omega-monomethyl-L-arginine (NMA), inhibitors of nitric oxide synthase, were added to either cultures of IL-1-dependent T cells or A375 melanoma cells exposed to IL-1. To investigate the effects of NAA in vivo, pentobarbital anesthetized dogs, which were made hypotensive by administration of IL-1, received a single intravenous bolus dose of NAA. The effects of NAA were then reversed by the administration of L-arginine. RESULTS: Our results show that cultured IL-1-activated rat aortic smooth muscle cells synthesize nitric oxide, a potent vasodilator. Induction of nitric oxide synthase is augmented by interferon-gamma and blocked by IL-1 receptor antagonist and by inhibitors of RNA or protein synthesis. Nitric oxide synthesis by IL-1-activated smooth muscle cells is inhibited by NAA, NMA, and N omega-nitro-L-arginine (NNA) with ED50 (i.e., effective dose for 50% inhibition) values of 20, 60, and 1000 microM, respectively; this rank order of inhibition is characteristic of an agonist-unregulated, inducible isoform of nitric oxide synthase. In smooth muscle cells, inhibition of NO. synthesis by NAA is reversed by excess L-arginine. Consistent with the induction of unregulated NO. synthesis in vascular smooth muscle in vivo, administration of IL-1 (50 micrograms/kg) to dogs caused a 33.5% decrease in systemic vascular resistance and a 28% decrease in blood pressure within 3 hours. Subsequent administration of NAA (20 mg/kg) rapidly and completely reversed the hypotension and increased systemic vascular resistance; these effects of NAA were reversed by L-arginine. Neither the immunoproliferative nor the tumoricidal activity of IL-1 was diminished by NAA. CONCLUSIONS: Our results indicate that (a) vascular smooth muscle is a likely source as well as a target of IL-1-induced NO. synthesis, causing vasodilatation and hypotension, (b) nitric oxide synthase inhibitors can fully reverse this hypotension, and (c) the therapeutically useful properties of IL-1 are not diminished by nitric oxide synthase inhibitors. IMPLICATIONS: Administration of inhibitors of nitric oxide synthase can reverse the pathological cardiovascular effects of IL-1 at concentrations that do not interfere with the potentially useful immunoproliferative or tumoricidal effects of this cytokine. In the context of the current clinical trials of IL-1, this finding would represent a very significant advantage.

Amino Acid Oxidoreductases↗
PubMed1992

The population biology and evolutionary significance of Ty elements in Saccharomyces cerevisiae.

The basic structure and properties of Ty elements are considered with special reference to their role as agents of evolutionary change. Ty elements may generate genetic variation for fitness by their action as mutagens, as well as by providing regions of portable homology for recombination. The mutational spectra generated by Ty1 transposition events may, due to their target specificity and gene regulatory capabilities, possess a higher frequency of adaptively favorable mutations than spectra resulting from other types of mutational processes. Laboratory strains contain between 25-35 elements, and in both these and industrial strains the insertions appear quite stable. In contrast, a wide variation in Ty number is seen in wild isolates, with a lower average number/genome. Factors which may determine Ty copy number in populations include transposition rates (dependent on Ty copy number and mating type), and stabilization of Ty elements in the genome as well as selection for and against Ty insertions in the genome. Although the average effect of Ty transpositions are deleterious, populations initiated with a single clone containing a single Ty element steadily accumulated Ty elements over 1,000 generations. Direct evidence that Ty transposition events can be selectively favored is provided by experiments in which populations containing large amounts of variability for Ty1 copy number were maintained for approximately 100 generations in a homogeneous environment. At their termination, the frequency of clones containing 0 Ty elements had decreased to approximately 0.0, and the populations had became dominated by a small number of clones containing > 0 Ty elements. No such reduction in variability was observed in populations maintained in a structured environment, though changes in Ty number were observed. The implications of genetic (mating type and ploidy) changes and environmental fluctuations for the long-term persistence of Ty elements within the S. cerevisiae species group are discussed.

Biological Evolution↗
PubMed1992

Adaptation and major chromosomal changes in populations of Saccharomyces cerevisiae.

Thirteen independent populations of Saccharomyces cerevisiae (nine haploid and four diploid) were maintained in continuous culture for up to approximately 1000 generations, with growth limited by the concentration of organic phosphates in medium buffered at pH 6. Analysis of clones isolated from these populations showed that a number (17) of large-scale chromosomal-length variants and rearrangements were present in the populations at their termination. Nine of the 16 yeast chromosomes were involved in such changes. Few of the changes could be explained by copy-number increases in the structural loci for acid phosphatase. Several considerations concerning the nature and frequency of the chromosome-length variants observed lead us to conclude that they are selectively advantageous.

Acid Phosphatase↗
PubMed1992

Genetic changes accompanying increased fitness in evolving populations of Escherichia coli.

Two populations of Escherichia coli, each initiated with a single clone containing a derivative of the plasmid pBR322, were maintained for long periods in glucose-limited continuous culture. In both populations, after an extensive number of generations had elapsed, clones were isolated in which the transposon Tn3 from the plasmid had integrated into the bacterial chromosome. In both cases examined, the transpositions were shown to increase relative fitness approximately 6-7%, in the environment in which the populations were maintained. The loci of integration were mapped to approximately 13.2 min (population 1) and approximately 32.8 min (population 2).

Biological Evolution↗
PubMed1992

Fitness effects of Ty transposition in Saccharomyces cerevisiae.

It has been suggested that the primary evolutionary role of transposable elements is negative and parasitic. Alternatively, the target specificity and gene regulatory capabilities of many transposable elements raise the possibility that transposable element-induced mutations are more likely to be adaptively favorable than other types of mutations. Populations of Saccharomyces cerevisiae containing large amounts of variation for Ty1 genomic insertions were constructed, and the effects of Ty1 copy number on two components of fitness, yield and growth rate were determined. Although mean stationary phase density decreased with increased Ty1 copy number, the variance and range increased. The distributions of stationary phase densities indicate that many Ty1 insertions have negative effects on fitness, but also that some may have positive effects. To test directly for adaptively favorable Ty1 insertions, populations containing large amounts of variability for Ty1 copy number were grown in continuous culture. After 98-112 generations the frequency of clones containing zero Ty1 elements had decreased to approximately 0.0, and specific Ty1-containing clone families had predominated. Considering that most of the genetic variation in the populations was due to Ty1 transposition, and that Ty1 insertions had, on average, a negative effect on fitness, we conclude that Ty1 transposition events were directly responsible for the production of adaptive mutations in the clones that predominated in the populations.

Blotting, Southern↗
PubMed1992

Electrophysiological effect of the maze procedure on canine sinoatrial node function.

The maze procedure is an operation that has had great initial success in curing atrial fibrillation. This procedure includes several right atrial incisions that may interrupt the integrity of the sinoatrial node or its arterial supply. To assess the effect of the maze procedure on sinus node function (SNF), the following studies were performed: sinus node recovery times (SNRT), corrected SNRT (CSNRT), CSNRT under autonomic blockade maximal heart rate and intrinsic heart rates. Thirty-four dogs underwent a right thoracotomy with cardiopulmonary bypass (CPB). The dogs were divided into three groups. Group 1 (n = 9), the sham group, underwent CPB without any incisions. Group 2 (n = 8) underwent CPB and one of the right atrial incisions. Group 3 (n = 18) underwent CPB and all three of the right atrial incisions. SNF was determined before and after the procedure. Groups 1 and 2 had no significant difference in measured SNF acutely after the procedure. In Group 3 the mean SNRT increased from 552 msec to 1,984 msec (P = 0.005). Sinus node dysfunction was corroborated by all studies. In the chronic studies, a trend toward recovery of SNF was observed. The maze procedure results in significant acute sinus node dysfunction. This dysfunction may resolve spontaneously over the ensuing months. Modifications of the maze procedure that avoid the sinus node or its blood supply area may reduce procedure related sinus node dysfunction.

Animals↗
PubMed1992

Difficulties in localization and treatment of insulinomas in type 1 multiple endocrine adenomatosis (MEA).

A 15 year old girl with a family history of type 1 multiple endocrine adenomatosis presented with reversible neurological disturbances, hypoglycaemia and hyperinsulinaemia. Initial radiology was normal, but portal venous sampling suggested an insulinoma in the tail of the pancreas which was removed with conservation of the spleen. Hypoglycaemia persisted despite high doses of diazoxide and intravenous dextrose. A second laparotomy revealed a pancreatic endocrine tumour and sub-total pancreatectomy was performed. Histology revealed islet cell microadenomatosis. Hypoglycaemia persisted despite treatment with somatostatin analogues and 40% intravenous dextrose was required to maintain normoglycaemia. A possible lesion near the splenic hilum on computed tomographic scan was reported as a splenunculus although further peripheral, hepatic and portal venous sampling suggested hepatic or systemic lesions. A positron emission scan and selective visceral angiography suggested a lesion in the left upper quadrant. Acute lactic acidosis, rhabdomyolysis and renal failure supervened. Post mortem revealed the putative 'splenunculus' to be a residual insulinoma, whilst the splenic vein was thrombosed, accounting in part for discrepant venous sampling data. Hyperinsulinaemia in type 1 multiple endocrine adenomatosis may require more aggressive surgical and hormonal intervention than when dealing with solitary insulinomas. Insulinomas may mimic developmental abnormalities on computed tomographic scanning.

Adolescent↗
PubMed1992

Relation between hospital experience and in-hospital mortality for patients with AIDS-related Pneumocystis carinii pneumonia: experience from 3,126 cases in New York City in 1987.

There is marked debate about whether outcomes of care, particularly mortality, vary as a function of hospital and physician experience with a disease. This issue is especially important with respect to AIDS because greater than 200,000 individuals have now been diagnosed with this disease. We analyzed discharge data for 3,126 persons with AIDS who had Pneumocystis carinii pneumonia and who were treated at one of 73 New York City hospitals in 1987. In-hospital mortality was 25%. Factors associated with higher chances of short-term death were older age, being black, not having private health insurance, and being severely ill. A logistic regression model indicated that after controlling for differences in patient and hospital characteristics, the chances of death decreased when care was given at hospitals with higher caseloads of patients with Pneumocystis carinii pneumonia. Our findings suggest that hospital experience may decrease mortality in this subset of patients with human immunodeficiency virus disease, although it is unknown whether this is due to differences in quality of care.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Morphologic and physiologic effects of artificial tear formulations on corneal epithelial derived cells.

The biological effects of four commercially available artificial tear formulations were evaluated using sensitive in vitro techniques. Two of the formulations contained ingredients implicated in cell damage; the other two products were not chemically preserved, and their components have not been reported to damage corneal tissue. We assayed the effects of these formulations on viability, morphology, and physiology in corneal cell (SIRC) cultures. Their effect on the hydration of excised rabbit corneas was also determined. In all formulations, cell viability declined with time relative to control cells, but the time course varied significantly. Viability remained at 100% for 6 h in an unpreserved carboxymethylcellulose-based product (CMC-U), and decreased to 50% after greater than 16 hours. Viability decreased to 50% in 3 h for the other unpreserved, polyvinyl alcohol-based product (PVA-U), and in 1 h for a hydroxypropylmethylcellulose formulation (HPMC-P) that contains edetate disodium (EDTA). Cells in a preserved formulation (PVA-P), using polyvinyl alcohol as the polymer and containing EDTA and benzalkonium chloride (BAK), failed to survive even 15 min of treatment. Overall, cells treated with the unpreserved products were nearly indistinguishable from those in the control solution with respect to morphology, electrophysiology, and corneal hydration. Also, the relative ranking from least to most deleterious (control less than CMC-U less than PVA-U less than HPMC-P less than PVA-P) was consistent across several measures. Of the preserved formulations, HPMC-P, which contains the chelating agent EDTA as an additive, was less damaging than was PVA-P, which contains two chemicals, EDTA and BAK, that reportedly damage cells.

Animals↗
PubMed1991

Characterization of the binding site for nevirapine (BI-RG-587), a nonnucleoside inhibitor of human immunodeficiency virus type-1 reverse transcriptase.

Nevirapine (BI-RG-587) is a potent and specific non-nucleoside inhibitor of human immunodeficiency virus type-1 reverse transcriptase. The compound is non-competitive with respect to template, primer, and nucleoside triphosphates indicating that BI-RG-587 does not act directly at the catalytic site. The binding site for this inhibitor was investigated by employing an azido photoaffinity analogue, BI-RJ-70, to covalently label the enzyme. The resulting photoadduct was subjected to enzymatic digestion by trypsin and endoproteinase lys-C and a single, highly labeled peptide was identified as residues 174-199. Sequencing of this peptide identified Tyr-181 and Tyr-188 as labeled residues.

Affinity Labels↗
PubMed1991

Role of nitric oxide in lysis of tumor cells by cytokine-activated endothelial cells.

The purpose of these studies was to determine whether nitric oxide produced by cytokine-activated murine lung vascular endothelial cells plays a role in their lytic destruction of M-5076 reticulum cell sarcoma. Vascular endothelial cells harvested from perfused lungs of mice were adapted to grow in culture. Cloned lines ascertained to be of endothelial origin were incubated in vitro with interferon gamma and tumor necrosis factor. Lysis of radiolabeled tumor cells and accumulation of nitrite in the culture medium were determined at several time points. The concentration of nitrite in the culture medium directly correlated with endothelial cell-mediated tumor cell lysis. Endothelial cells cultured in L-arginine-free medium did not produce significant tumor cell lysis nor accumulation of nitrite in the medium. Both tumor cell lysis and nitrite accumulation were observed when the deficient medium was reconstituted with L-arginine, suggesting that endothelial cell-mediated tumor lysis was dependent on L-arginine, a precursor of nitric oxide. Moreover, specific inhibition of nitric oxide synthesis by NG-methyl-L-arginine resulted in complete inhibition of endothelial cell-mediated lysis of the M-5076 reticulum cell sarcoma. Similarly, treatment of cytokine-activated endothelial cells with dexamethasone inhibited both target cell lysis and production of nitrite. Collectively, these results suggest that nitric oxide plays a major role in the lysis of tumor cells mediated by cytokine-activated endothelial cells.

Animals↗
PubMed1991

A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site.

A novel dipyridodiazepinone, 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]- [1,4]diazepin-6-one (BI-RG-587), is a selective noncompetitive inhibitor of HIV-1 reverse transcriptase (RT-1). An azido photoaffinity analogue of BI-RG-587 was synthesized and found to irreversibly inhibit the enzyme upon UV irradiation. BI-RG-587 and close structural analogues competitively protected RT-1 from inactivation by the photoaffinity label. A thiobenzimidazolone (TIBO) derivative, a nonnucleoside inhibitor of RT-1, also protected the enzyme from photoinactivation, which suggests a common binding site for these compounds. Substrates dGTP, template-primer, and tRNA afforded no protection from enzyme inactivation. A tritiated photoaffinity probe was found to stoichiometrically and selectively label p66 such that 1 mol of probe inactivates 1 mol of RT-1.

Affinity Labels↗
PubMed1991

A catalytic antibody uses a multistep kinetic sequence.

Antibody NPN43C9 catalyses the hydrolysis of a p-nitrophenyl ester and p-nitroanilide. Kinetic investigations show that hydrolysis of the ester involves at least two steps whose relative importance changes with pH. We propose that the reaction proceeds via formation of an acyl intermediate that deacylates through attack by hydroxide. The rate-limiting step changes from product release at high pH to hydroxide ion-mediated hydrolysis at low pH. This multistep pathway shares similarities with that used by serine proteases.

Antibodies↗
PubMed1991

Plasmid macro-evolution: selection of deletions during adaptation in a nutrient-limited environment.

Under conditions where plasmid-carriage is deleterious to the cell, evolutionary changes may be expected which result in an attenuation of the deleterious effect of the plasmid. During long-term growth in glucose-limited continuous culture, initiated with a single clone of Escherichia coli containing a derivative of the plasmid pBR322, a structural change arose in the plasmid and predominated in the plasmid-containing sector of the population. This variant possessed a 2.25 kb deletion encompassing the tetracycline resistance operon as well as a region of about 1.5 kb upstream from this operon. Competition experiments involving strains carrying the plasmid with the spontaneous deletion, and strains carrying plasmids with artificially constructed deletions, revealed that deletion of this region of the plasmid, involving loss of tetracycline resistance, resulted in an increment in fitness of between 10 and 20%. From the magnitude of the growth advantage, we conclude that the attenuation of the deleterious effect of the plasmid was mainly due to a reduction in the plasmid mediated interference in the metabolism of the cell caused by a deletion of the tetracycline resistance gene.

Adaptation, Physiological↗
PubMed1991

Screening for vertebral osteoporosis using individual risk factors. The Multicentre Vertebral Fracture Study Group.

Osteoporosis is a major cause of ill health in postmenopausal women. Several risk factors for osteoporosis have been identified, and they have been widely recommended as a means of identifying subgroups of postmenopausal women who might benefit from prophylaxis and therapy. Evidence to support this use of risk factors is currently lacking, however. We have constructed and evaluated a profile of putative risk factors as a means of identifying women attending general practitioners who have sustained vertebral fractures. The overall prevalence of vertebral fractures in the 1012 women (mean age 64.4 years) studied was 7.8%. Women who had sustained vertebral fractures in this population were significantly (p less than 0.05) older and shorter than those without fractures. They reported a significantly (p less than 0.05) earlier menopause, lower parity and a greater prevalence of hyperthyroidism. However, the best screening instrument devised was not sufficiently predictive to warrant widespread use.

Aged↗