Biomedical subjects
R Horton
Publications and source records attributed to R Horton.
v-Src enhances phosphorylation at Ser-282 of the Rous sarcoma virus integrase.
The Rous sarcoma virus (RSV) integrase (IN) and the beta polypeptide (beta) of the reverse transcriptase are posttranslationally modified by phosphorylation on Ser at amino acid position 282 of IN. When IN was immunoprecipitated from RSV (Prague A strain) virions, approximately 30 to 40% of the IN molecules were phosphorylated. When IN was immunoprecipitated from a v-src deletion mutant (delta Mst-A) of RSV or from avian myeloblastosis virus (AMV), the percentage of IN molecules that were phosphorylated was significantly reduced. This reduction in phosphorylation of IN between virions was verified by [35S]Met-[35S]Cys or 32P labeling of IN, followed by immunoprecipitation analysis using antisera directed to the amino or carboxyl terminus of IN. In delta Mst-A or AMV, a nonphosphorylated, slightly truncated (at the carboxyl terminus) polypeptide was the major species of IN. The enhanced phosphorylation of IN does not appear to be a general function of transformed cells, since enhanced phosphorylation was not detected in AMV derived from viremic chickens or from a v-src deletion mutant of RSV propagated in a chemically transformed quail cell line, QT6. From these data, we conclude that v-Src is necessary for efficient phosphorylation of IN and beta.
Benign prostatic hyperplasia: new insights.
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Altered regulation of renin secretion by insulinlike growth factors and angiotensin II in diabetic rats.
The etiology of the low renin state in DM is not clear. To assess the role of certain growth and regulatory factors in this process, we studied the effects of insulin, IGF-I, and IGF-II on the renin-angiotensin system in normal and 8-wk STZ-induced diabetic rats. Renin secretion was studied both in static incubations and by perifusion of rat renal cortical slices. In diabetic rats, both plasma renin activity (0.65 +/- 1.6 vs. 4.0 +/- 1.2 ng ANG I.ml-1.h-1) and tissue renin concentrations (27 +/- 5 vs. 51 +/- 8 ng ANG I.mg tissue-1.h-1) were reduced. Insulin (0.1-1.0 mu/ml) and IGF-I (10(-9) to 4 x 10(-9) M) stimulated renin secretion in normal tissue (control, 95 +/- 3%; insulin [0.5 mu/ml], 134 +/- 7%; IGF-I [4 x 10(-9) M], 149 +/- 7%). IGF-I stimulated renin secretion in perifusions as early as 30 min, whereas IGF-II had no effect. However, in diabetic renal tissue, neither insulin (0.1-1.0 mu/ml) nor IGF-I (10(-9) to 4 x 10(-9) M) had an effect on renin. This lack of effect was overcome by adding up to 100-fold higher concentrations of these growth factors. ANG II (10(-10) M-10(-8) M) had an exaggerated inhibitory effect on renin secretion in diabetic tissue. This study suggests that the low renin state in DM may be explained by the enhanced inhibitory effect of ANG II and the resistance to the secretogogue actions of insulin and IGF-I.
Nurses' perceptions of infection control issues in two small district general hospitals.
The need for quality assurance is given considerable emphasis in the Strategy for Nursing (1). Quality assurance is arguably inseparable from effective infection control, the practice of which is dependent on an adequate knowledge of microbiology. Yet research suggests that infection control in hospitals could be significantly improved (2) and that much of the problem is due to inadequate knowledge of microbiology on the part of both tutors and nurses (3). This paper presents the results of a study aimed at eliciting both the value placed on, and the general awareness of, infection control by tutors and nurses in two small general hospitals in two health districts. Technical knowledge was not tested (except indirectly). The overall findings suggest that nurses rely almost exclusively on the knowledge gained through training to inform their infection control practice. This, together with the research quoted above, suggests that if infection control in hospitals is to be improved, nurse education must place a much greater emphasis on microbiology than is currently the case.
Molecular cloning, characterization and expression of cDNA for rabbit brain tissue factor.
Tissue factor (TF) is a membrane anchored glycoprotein that initiates blood coagulation by forming a complex with circulating factor VII or VIIa. TF has been identified in atherosclerotic plaques and may possibly trigger thrombosis after spontaneous plaque rupture as seen in acute myocardial infarction or angioplasty. We have previously developed an atherosclerotic rabbit model for study of the acute and chronic outcomes following angioplasty. As a first step in developing inhibitors of TF, we have isolated and characterized a rabbit cDNA coding for the mature TF. The sequence comparison of rabbit TF cDNA with those of human and mouse TFs show considerable similarity at both the nucleotide and amino acid levels. The TF cDNA when expressed in E. coli demonstrates a procoagulant activity comparable to that of native rabbit brain TF. The TF activity can be blocked by a polyclonal antibody against rabbit TF.
Influence of age and endocrine factors on the volume of benign prostatic hyperplasia.
To determine whether endocrine factors influence the volume of benign prostatic hyperplasia (BPH), 23 hormonal factors were measured in the serum of 64 men ages 42 to 71 years with low volume prostatic cancer and these levels were correlated with the volume of benign hyperplastic tissue in their radical prostatectomy specimens. With age there was a significant increase in the volume of BPH. Also with age there was a significant decrease in the serum levels of free testosterone, androstenedione, dehydroepiandronsterone (DHA), dehydroepiandronsterone sulphate (DHA-S), delta 5-androstenediol, and 17-hydroxypregnenolone, and a significant increase in sex hormone-binding globulin (SHBG), LH, and FSH. When BPH volume and hormone levels were corrected for age, BPH volume correlated positively with free testosterone, estradiol, and estriol. These data indicate that with age patients with larger volumes of BPH have higher serum androgen and estrogen levels suggesting that serum androgen and estrogen levels may be factors in the persistent stimulation of BPH with age. If so, therapeutic attempts at lowering plasma testosterone levels, reducing estrogen levels, or blocking androgenic stimulation through other mechanisms may interfere with the progression of BPH with age. Conversely, the fact that androgen production declines gradually with age may explain the observation that only 20 to 30% of men who live to age 80 require surgical treatment for urinary obstruction from BPH.
Phosphorylation of the avian retrovirus integration protein and proteolytic processing of its carboxyl terminus.
The integration protein (IN) of the Prague A strain of Rous sarcoma virus (RSV) was analyzed by high-resolution sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Three polypeptides of similar proportions and molecular mass (32 kDa) were immunoprecipitated by an antiserum directed against the first 10 amino acids of the amino terminus of IN. However, the faster-migrating nonphosphorylated polypeptide was not immunoprecipitated by two different polyclonal antisera directed against the last 11 amino acids of the carboxyl terminus of IN. These results suggest that the faster-migrating species was proteolytically processed at its carboxyl terminus. RSV IN is phosphorylated on an S residue located five amino acids from its carboxyl terminus. Two different missense mutations at this S residue resulted in the isolation of slow-growing viable mutants whose phenotypes were stable. Each mutation at residue 282 eliminated both major phosphorylated-Ser-containing tryptic peptides observed with wild-type IN. An S----F mutation resulted in the conversion of all IN polypeptides to one species that was not precipitable by carboxyl-terminal antisera, suggesting that this amino acid transition promoted proteolysis at the carboxyl terminus. An S----D mutation resulted in the recovery of one major (greater than 95%) slower-migrating polypeptide that was immunoprecipitated by carboxyl-terminal antisera, suggesting that this negatively charged D residue (similar to phosphorylated Ser) inhibited proteolysis. Modification of the S residue at amino acid 262 to R had no apparent effect on the proteolytic processing or phosphorylation of IN.
Neuroendocrine challenge studies in puerperal psychoses. Dexamethasone suppression and TRH stimulation.
Subjects admitted to hospital with post-partum psychoses were compared with matched normal post-partum controls using two neuroendocrine challenge tests: dexamethasone suppression of cortisol and TRH stimulation of TSH. Post-dexamethasone cortisol levels were significantly elevated. There were less-clear hints of blunting of TSH response. In the small samples there was no obvious association of abnormalities with any particular diagnoses within the range of mania, psychotic depression and schizoaffective disorders.
The significance of autocorrelation in fetal monitoring.
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Effects of renin inhibition in systemic hypertension.
The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet, plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for greater than or equal to 6 hours (11.9 +/- 4 to 1.0 +/- 0.6 ng angiotensin I/ml/hour, p less than 0.05). Mean arterial blood pressure declined gradually (108 +/- 5 to 84 +/- 4 mm Hg, p = 0.02), as did plasma aldosterone concentration (14.4 +/- 3.8 to 4.4 +/- 0.8 ng/dl, p = 0.03), whereas plasma immunoreactive active renin concentration increased progressively (35 +/- 14 to 160 +/- 60 pg/ml, p greater than 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F1 alpha) decreased slightly, but not significantly (42 +/- 10 to 33 +/- 11 ng/g creatinine, p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system, without significantly altering urinary prostacyclin excretion, in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.
Effect of dopamine on renal blood flow, prostaglandins, renin and electrolyte excretion in normal and hypertensive humans.
A low dose of dopamine (1 microgram/min/kg) infused for 3 h, which is without systemic hemodynamic effects in normal subjects, increased the renal blood flow and renal production of prostacyclin (PGI2). This action was blocked by metoclopramide as well as by either of two cyclooxygenase (CO) blockers, but effects were not altered by administration of the alpha 1 blocker prazosin. Much of the effect of dopamine (DA) is apparently via the DA1 receptor, since fenoldopam (0.1 microgram/min/kg) reproduced these actions. However, although fenoldopam increased glomerular filtration rate and urinary Na+, CO blockers were without effect. In contrast neither DA or fenoldopam infusions changed either renal blood flow or PGI2 in a group of patients with essential hypertension. Renin secretion was shown to be increased via DA1 receptor activation both in humans and rat renal tissue. The DA2 receptor may also play a role since domperidone can reduce renal blood flow.
Pharmacokinetics of intravenous amoxycillin and potassium clavulanate in seriously ill children.
The pharmacokinetics of amoxycillin and potassium clavulanate were studied in 15 sick children after a 30 min iv infusion of 50 mg/kg amoxycillin and 5 mg/kg clavulanic acid as the potassium salt. Levels of both compounds in plasma were assayed microbiologically. Mean peak concentrations at the end of the infusion were 121.0 mg/l of amoxycillin and 12.0 mg/l of clavulanate, falling to a mean of 15.8 and 1.92 mg/l respectively after 2 h. Mean beta phase T 1/2 was 0.88 h for amoxycillin and 0.79 h for clavulanate. The elimination half-life of clavulanate in some individuals was much shorter because of higher plasma clearance. The data suggest that the treatment of some infections due to beta-lactamase producing organisms in such severely ill children may require more frequent iv administration of amoxycillin and potassium clavulanate, than in less severely affected children.
Tumor necrosis factor and interleukin-1 may regulate renin secretion.
Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) are not only immunoregulatory polypeptides, but may have endocrine functions. We have studied the direct effects of recombinant and purified TNF and IL-1 on renin secretion using both static incubations and perifusions of rat renal cortical slices. Ultrapure human IL-1 (hIL-1) at concentrations as low as 5 U/ml (3 X 10(-12) M) significantly stimulated renin secretion (control, 98 +/- 4%; hIL-1, 153 +/- 13%; P less than 0.01). TNF similarly induced renin release [control, 97 +/- 6%; TNF (10 U/ml), 151 +/- 13%; P less than 0.005]. TNF and recombinant human IL-1 beta (rhIL-i beta) also blocked the inhibitory actions of angiotensin-II (AII) on renin release [control, 100 +/- 3%; AII (2 X 10(-7) M), 80 +/- 5%; AII plus TNF (20 U/ml), 102 +/- 7%; AII plus rhIL beta (10 U/ml), 106 +/- 6%; both P less than 0.02 vs. AII]. A cyclooxygenase (CO) blocker, meclofenamate (M), which does not significantly alter basal renin release, attenuated the TNF- and rhIL-1 beta-induced renin secretion [TNF (20 U/ml), 132 +/- 11%; TNF plus M (5 X 10(-5) M), 100 +/- 3% (P less than 0.01); rhIL-1 beta (10 U/ml), 135 +/- 9%; rhIL-1 beta plus M, 105 +/- 10% (P less than 0.05)]. The stimulatory effects of TNF and IL-1 on renin were reversible. These results suggest that IL-1 and TNF are renin secretagogues and can also block the inhibitory actions of AII on renin. Since the effect of TNF and IL-1 on renin can be blocked by a (CO) inhibitor, the studies indicate a role of prostaglandins in their action. Therefore, locally produced TNF and IL-1 may play an important paracrine role in regulation of the renin-angiotensin system.
Simultaneous measurement of two major prostacyclin metabolites in urine.
We describe a combined HPLC-RIA technique to measure both major metabolites of prostacyclin (PGI2): 6-keto PGF1 alpha and 2,3-dinor-6 keto PGF1 alpha. The measurement of the former, which originates from renal blood vessels, and the latter, from systemic vessels and the liver, may provide a better overall evaluation of production than measurement of one metabolite. An aliquot of acidified urine with added 3H-labeled metabolites is adsorbed and then eluted from a C18 Bond-Elut column. The sample is then passed through an HPLC system by use of an isocratic solvent combination that separates the two metabolites from known prostaglandins. The purified metabolites are then quantified by RIA. Using a logit-log10 transform, one can measure between 12 and 250 pg of either metabolite, with high accuracy and precision (CVs of 12% for a low concentration and 7% for a high concentration). Reference values for apparently healthy subjects were, respectively, 107 (SD 45) and 171 (SD 69) ng/g creatinine for 6-keto PGF1 alpha and the dinor metabolite in men (n = 18) and 45 (SD 22) and 141 (SD 28) ng/g creatinine, respectively, in women (n = 15). Indomethacin in standard doses reduced both metabolite values by 50%. Intravenous administration of angiotensin II (5 ng/kg of body wt per minute) did not alter excretion rates, but equipressor doses of norepinephrine (0.1 microgram/kg per minute) increased the production of both metabolites (6-keto greater than dinor).
Medical student selection.
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