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Biomedical subjects

T O Morgan

Publications and source records attributed to T O Morgan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Prospective use of free prostate-specific antigen to avoid repeat prostate biopsies in men with elevated total prostate-specific antigen.

OBJECTIVES: We prospectively evaluated whether free PSA improves the specificity of PSA and can be useful as a clinical guide to avoid repeat prostate biopsies in patients with persistent PSA elevations, normal digital rectal examinations, and previous negative prostate biopsies. METHODS: Sixty-seven men with persistent PSA elevations (median 9.5, range 4.1-24.8 ng/mL), normal digital rectal examinations and two or more prior sextant biopsies (mean 2.8) had serum collected for measurement of total and free PSA. All patients were rebiopsied to determine the receiver operating characteristics of total PSA versus percent free PSA for prostate cancer detection. RESULTS: The study biopsy identified 11 prostate cancer cases. The median percent free PSA was significantly higher at 18.0% among men without prostate cancer compared to 6.7% in men with prostate cancer (P < 0.00005). When sensitivity was plotted against 1-specificity, the area under the receiver operating characteristic curve for percent free PSA was 0.93, compared to 0.69 for free PSA density, 0.66 for PSA density, and 0.51 for PSA. In patients with elevated total PSA levels, normal digital rectal examinations and two prior negative sets of sextant prostate biopsies, a cutoff of 10% free PSA would maintain sensitivity at 91% with a corresponding specificity of 86%. CONCLUSIONS: Selective measurement of percent free PSA can significantly improve the specificity of prostate cancer screening with PSA. A low percent free PSA (< 10%) appears to be a powerful predictor of prostate cancer even after two negative prostate biopsies.

Biopsy↗
PubMed1996

Prospective use of free PSA to avoid repeat prostate biopsies in men with elevated total PSA.

BACKGROUND: Prostate-specific antigen (PSA) is a most valuable tool for the early detection of prostate cancer; however, it has a high false-positive rate as presently used in prostate cancer screening programs. Patients with persistent PSA elevations, normal digital rectal examinations, and multiple negative biopsies present a clinical dilemma. We prospectively evaluated whether free PSA improves the specificity of PSA and can be useful as a clinical guide to avoid repeat prostate biopsies in a group of such patients. METHODS: Sixty-seven men with persistent PSA elevations (mean 9.6 ng/mL; range 4.1-24.8 ng/mL), normal digital rectal examinations, and two or more prior sextant biopsies (mean 2.8), had serum collected for measurement of total and free PSA. All patients were rebiopsied to determine the receiver-operating characteristics (ROC) of total PSA vs. percent free PSA for prostate cancer detection. RESULTS: This study by biopsy identified 11 new prostate cancer cases. The median percent free PSA was significantly higher at 18.1% among men without prostate cancer, compared to 6.4% in men with prostate cancer (P < 0.00005). When sensitivity was plotted against I-specificity, the area under the receiver-operating curve (ROC) for percent free PSA was 0.95, compared to 0.75 for free PSA density, 0.59 for PSA density, and 0.54 for PSA. In patients with elevated total PSA levels, normal digital rectal examinations, and two prior sets of negative sextant prostate biopsies, a cutoff of 10% free PSA would maintain sensitivity at 91% with a corresponding specificity of 86%. CONCLUSIONS: Selective measurement of percent free PSA in cases of uncertain diagnosis can significantly improve the specificity of prostate cancer detection compared to total PSA alone. A low percent free PSA (< 10%) appears to be a significant predictor of prostate cancer even after two or more negative prostate biopsies.

Aged↗
PubMed1995

Amniotic fluid composition and fetal and placental growth rates in genetically hypertensive and normotensive rats.

Reduced birth weight has been observed in offspring of the spontaneously hypertensive rat (SHR) and in human hypertension. To determine which uterine factors might contribute to this fetal underdevelopment, fetal and placental growth rates and the volume and composition of amniotic fluid were measured in SHR and normotensive control Wistar Kyoto (WKY) rats during the final trimester of intra-uterine development. SHR and WKY fetuses were collected on Days 15-22 of pregnancy, and fetal and placental weight and amniotic fluid volume were recorded. The sodium and potassium concentrations of amniotic fluid were also measured. Placental weight was significantly lower in SHR than in WKY between Days 15 and 20 of gestation, but significantly higher on Days 21 and 22. Fetal weight was significantly lower in SHR between Days 17 and 22. These differences were reduced or abolished when fetal and placental weights were corrected for differences in maternal weight between strains. Amniotic fluid volume was significantly lower in SHR between Days 15 and 18, but significantly higher at Days 20, 21 and 22. Amniotic fluid sodium concentration was relatively constant over the period of observation and not different between strains. SHR amniotic fluid potassium concentration was significantly lower than that of WKY near term. Thus, the altered fetal and placental weight of SHR may be due to the overall reduced growth rate of this strain. However, the rate of fluid and electrolyte resorption close to term is markedly different between strains. The mechanism for this altered fluid and electrolyte handling by the SHR feto-placental unit remains to be determined.

Amniotic Fluid↗
PubMed1995

Effects of endothelin-1 on the contractility of cardiomyocytes from the spontaneously hypertensive rat.

1. Disturbances in cardiovascular responsiveness to endogenous endothelin-1 (ET-1) may play a significant role in the pathogenesis of essential hypertension. In this study the inotropic responses of cardiomyocytes derived from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) strains to ET-1 (10(-11)-10(-8) mol/L) were characterized. Isotonic contraction cycles of ventricular cardiomyocytes isolated from age-matched (11 week) WKY and SHR rats were recorded using a rapid digital imaging technique and evaluated by computation of a range of normalized parameters. 2. The maximum effect of ET-1, eliciting a 60-70% increase in myocyte shortening after 3 min, was observed at 10(-9) mol/L in both strains, and was associated with elevations in the rate of shortening and lengthening, abbreviated latency, contractile cycle prolongation and delayed time to peak shortening. 3. No evidence for a significant strain dependent difference in the relative responsiveness to ET-1 was detected. This finding indicates that altered sensitivity to ET-1 is unlikely to be a major factor underlying the development of hypertension in this model. 4. The distinct nature of the alterations in contractile parameters produced by ET-1 compared with angiotensin II (AII) suggests that the prevailing cellular mechanisms of action of these peptides are different and that ET-1 is not a paracrine or autocrine inotropic intermediate for AII.

Angiotensin II↗
PubMed1995

Effect of dose on trough peak ratio of antihypertensive drugs in elderly hypertensive males.

1. The study was undertaken in male patients aged 61-73 years with essential hypertension. 2. The patients had previously had their blood pressure controlled with the drug studied. 3. A randomized crossover study compared the effect of different drug doses on peak (3 h) and trough (24 h) blood pressure compared to placebo. 4. All drug doses used lowered blood pressure at peak response and the responses with different doses of angiotensin converting enzyme inhibitors were similar. The peak response to felodipine had some dose dependency. 5. Trough blood pressure was not different from placebo with enalapril, 5 and 10 mg, perindopril, 2 mg, felodipine, 2.5 mg but was different with enalapril, 20 and 40 mg, perindopril, 4 and 8 mg and felodipine, 5 and 10 mg. 6. Trough peak ratio was dose dependent, with the greatest dependency seen with enalapril which has the shortest half-life. 7. When low doses of enalapril (5 or 10 mg), perindopril (2 mg) or felodipine ER (2.5 mg) are used it is important to check blood pressure prior to the next dose to ensure that control is achieved and maintained.

Aged↗
PubMed1995

Vascular endothelial growth factor: tissue distribution and size of multiple mRNA splice forms in SHR and WKY.

1. We have determined the optimal polymerase chain reaction (PCR) conditions for the amplification and detection of mRNA for a new vascular growth factor-vascular endothelial growth factor (VEGF)-and determined its size and tissue distribution in genetically normotensive and hypertensive rats. 2. Multiple VEGF mRNA subtypes were obtained which were 625, 520 and 480 base pairs in length. 3. All three species of VEGF mRNA were found in heart, kidney, aorta, adrenal and brainstem and the size and tissue distribution of VEGF mRNA subtypes were not different between spontaneously hypertensive rats (SHR) of the Okamoto strain and normotensive Wistar-Kyoto (WKY) controls. 4. Thus multiple forms of VEGF mRNA can be readily detected by PCR in a variety of tissues. While these preliminary results suggest no difference in size and tissue distribution between SHR and WKY, sequencing and quantitative studies will be required to confirm this.

Animals↗
PubMed1995

Altered uterine environment in the spontaneously hypertensive rat.

1. In order to determine the role of the uterine environment in the development of hypertension in the spontaneously hypertensive rat (SHR) we examined the patterns of fetal and placental growth and the composition of amniotic fluid of SHR and normotensive Wistar-Kyoto (WKY) rats during the final trimester of pregnancy. 2. SHR and WKY embryos and amniotic fluid were collected at days 15 and 20 of pregnancy, and fetal and placental weight and amniotic fluid volume were recorded. The sodium and potassium concentration of amniotic fluid was also measured. 3. Fetal and placental weights were significantly lower in SHR compared to WKY at 15 and 20 days of gestation. Amniotic fluid volume was significantly lower in SHR at 15 days, but significantly higher at 20 days. Amniotic fluid sodium concentration was significantly lower in SHR at 15 days but not different at 20 days when compared to WKY. Potassium concentration was lower in SHR at both ages. 4. Thus the reduced placental weight early in the gestational period of the SHR may play a role in its underdevelopment in utero and hence its reduced birthweight. The SHR foetus is also bathed in a hypokalaemic amniotic fluid of increased volume. How this might influence fetal development and later blood pressure is unclear. Also whether these changes are of maternal or fetal origin remain to be determined.

Amniotic Fluid↗
PubMed1995

Brief treatment of SHR with an ace inhibitor fails to cause long-term normotension but markedly increases mortality.

1. We examined the effect of three doses (0.03, 0.3 and 3 mg/kg per day) of the angiotensin converting enzyme (ACE) inhibitor, perindopril, on the long-term blood pressure of spontaneously hypertensive rats (SHR) of the Okamoto strain after treatment during the developmental stage of hypertension development. 2. While the 0.03 mg/kg per day dose, given between the ages of 4-10 weeks of age, failed to lower blood pressure, the two higher doses resulted in normotension over this treatment period as did the highest dose given between the ages of 4-20 weeks of age. 3. Only the 0.3 mg/kg per day dose resulted in a moderate (17%) long-term fall in blood pressure upon cessation of treatment when compared to untreated SHR controls. The highest dose, given over the 4-20 week period resulted in a significant rebound hypertension above the blood pressure level of untreated, control SHR. 4. The 3 mg/kg per day dose, whether given over the 4-10 or 4-20 week treatment period, resulted in 100% mortality in these groups by 52 weeks of age. There were no deaths in the groups receiving the two lower doses. 5. We conclude that treatment of SHR with perindopril during the developmental phase of hypertension development results in only a modest fall in long-term blood pressure upon cessation of treatment and that the relationship between the dose of this ACE inhibitor and long-term blood pressure is not linear. The 100% mortality in the two groups receiving the highest dose of perindopril may be due to either a toxic action of this drug or vascular rupture due to insufficient hypertrophy for the rapid rise in blood pressure upon cessation of treatment.

Aging↗
PubMed1994

Platelet-activating factor and WEB-2086 directly modulate rat cardiomyocyte contractility.

In various isolated cardiac tissue preparations the phospholipid mediator platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine) may elicit a positive, negative or no inotropic response. In the multicellular preparation it is difficult to differentiate and characterize the direct actions of PAF on the myocardium from the effects due to the release of secondary mediators from non-myocyte cell types. Thus in the present study the inotropic effects of PAF (10(-11), 10(-9), 10(-7) M) and a specific PAF receptor antagonist, WEB-2086, PAF receptor antagonist. WEB-2086, on the contractility of enzymatically isolated adult rat cardiomyocytes have been investigated. PAF (10(-7) M) reduced maximum cell shortening by 23% compared to the initial level, delayed excitation contraction coupling, abbreviated the contraction cycle and reduced the maximum rate of cell lengthening during relaxation. Lower concentrations of PAF elicited smaller negative inotropic responses. There was no evidence of a positive inotropic effect of PAF at any concentration tested or at any time after the onset of treatment. Co-treatment with WEB-2086 (10(-5) M) prevented the negative inotropic response to PAF. WEB-2086 alone increased maximum shortening by 16% compared to initial performance, extended the contraction cycle and increased the maximum rates of shortening and lengthening. WEB-2086 had no effect on excitation contraction coupling latency. The selective alteration of contraction parameters induced by PAF and WEB-2086 indicates that, in addition to antagonizing the negative inotropic action of exogenous PAF, WEB-2086 alone enhances contractility. These results demonstrate that PAF has a direct, receptor-mediated negative inotropic effect on adult contractility. These results demonstrate that PAF has a direct, receptor-mediated negative inotropic effect on adult cardiomyocytes.

Animals↗
PubMed1994

A new restriction fragment length polymorphism in the first intron of the spontaneously hypertensive rat renin gene.

1. Amplification of the entire first intron of the renin gene of spontaneously hypertensive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley rats (SD) followed by Bgl II digestion uncovered a new deletion (approximately 50 bp) which exists upstream of the SHR renin gene first intron tandem repeat element. 2. The SHR tandem repeat element was 600 bp shorter than that in the WKY while the WKY tandem repeat element was 280 bp shorter than that in the SD. 3. Since elements regulating gene expression are known to exist in the first intron of other genes, this new restriction fragment length polymorphism (RFLP) might play a role in the reported overexpression of the SHR renin gene independent of changes in the length of the tandem repeat element.

Animals↗
PubMed1994

Effects of atrial natriuretic factor on cyclic nucleotides in rabbit proximal tubule.

Atrial natriuretic factor induces renal sodium excretion by several mechanisms, including inhibition of angiotensin II-stimulated sodium reabsorption in the proximal tubule. In most tissues, the action of atrial natriuretic factor involves generation of the intracellular second messenger, cyclic GMP, but in the proximal tubule the presence of this signal transduction pathway has remained controversial. We used intrarenal arterial infusion of iron oxide followed by enzymatic dispersion and magnetic separation to obtain suspensions of rabbit kidney cortex enriched with either glomeruli or proximal tubules. When suspensions enriched with proximal tubules or preparations of microdissected proximal tubules were incubated with atrial natriuretic factor (1 mumol/L), cyclic GMP concentrations increased significantly. Addition of angiotensin II (1 mumol/L) together with atrial natriuretic factor had no significant effect on the stimulation of cyclic GMP accumulation observed with atrial natriuretic factor alone. Neither atrial natriuretic factor nor angiotensin II altered intracellular concentrations of cyclic AMP in tubule-enriched suspensions or microdissected tubules. We conclude that cyclic GMP acts as a second messenger for atrial natriuretic factor in rabbit proximal tubule. However, we found no evidence to support the view that alterations in intracellular cyclic AMP levels are involved in the proximal tubular actions of angiotensin II and have not been able to demonstrate that interactions between cyclic AMP and cyclic GMP underlie the antagonistic effect of atrial natriuretic factor on angiotensin II-stimulated proximal sodium transport.

Angiotensin II↗
PubMed1994

Sodium depletion, renal denervation, beta adrenergic blockage and renin secretion and synthesis.

The role of the macula densa in the control of renin synthesis during sodium depletion was studied in Balb/c mice which had their left kidney made hydronephrotic 6 weeks earlier. The role of the nervous system was studied by giving the mice propranolol or by denervation of the left kidney. There was no net secretion of renin from the left hydronephrotic kidney on control or low sodium diet. All plasma renin came from the right kidney. Sodium depletion caused similar rises in renin content of the normal and hydronephrotic kidney. These rises were accompanied by increases in mRNA for renin in both kidneys. Denervation of the left hydronephrotic kidney caused a fall in renal renin content. However, sodium depletion caused a significant rise in both renin mRNA and renal renin in the control and denervated hydronephrotic kidney. Propranolol decreased the renin content of normal and hydronephrotic kidneys. Sodium depletion caused a rise in mRNA and renal renin in both kidneys although the absolute final amount was less than in the control animals. Sodium depletion stimulates renin synthesis in a normal kidney and a kidney without a macula densa. This response is not affected by the nervous supply to the kidney. In the hydronephrotic mouse subjected to sodium depletion the synthesis and secretion of renin appear to be disassociated.

Adrenergic beta-Antagonists↗
PubMed1993

Accurate determination of the size of the first intron deletion in the renin gene of SHR from an Australian colony.

1. It has been reported that the first intron of the renin gene of the spontaneously hypertensive rat (SHR) is shorter than that of the Wistar-Kyoto (WKY) rat, suggesting a role for this difference in the development of hypertension. 2. The genealogy of some Australian SHR colonies has raised doubts about its similarity to the Japanese, American and European colonies. 3. The polymerase chain reaction (PCR) technique has been used with primers identical to the flanking region of the first intron of the renin gene to determine its length in SHR, WKY and Sprague-Dawley (SD) from an Australian colony. 4. The size of the first intron of the renin gene in SHR, WKY and SD was found to be approximately 3870, 4550 and 5000 base pairs, respectively, results which agree with those previously published. 5. It was concluded that the first intron deletion, and its size, has been conserved in an Australian SHR colony.

Animals↗
PubMed1993

Altered blood pressure, renal tubular function and levels of circulating inhibitors of Na-K-ATPase in mature SHR exposed to low salt diet in the perinatal period.

1. It has been shown previously that low salt diet, confined to the perinatal period only, reduces blood pressure (BP) and sodium retention in spontaneously hypertensive rat (SHR) offspring at maturity when compared with those given high salt diet. 2. In this study it is shown that such high salt diets are associated with an increased level of circulating Na-K-ATPase inhibitor (CINK) activity. 3. Animals given perinatal high salt diet have a significantly greater tubular reabsorptive capacity when compared with those given low salt diet. 4. The finding of a high level of circulating Na-K-ATPase inhibitory material in the face of increased renal tubular capacity and blood pressure suggests that while this inhibitory material may play a role in the elevated blood pressure of animals given high salt diet, it cannot cause the elevated rate of fluid reabsorption.

Animals↗
PubMed1992

Antihypertensive efficacy and safety of perindopril in mild-to-moderate essential hypertension: results of a double-blind multicenter study versus atenolol.

A 3-month double-blind multicenter trial compared the efficacy and safety of perindopril, a new angiotensin-converting enzyme (ACE) inhibitor, with atenolol in mild-to-moderate essential hypertension. A total of 190 patients, 49 of whom were diabetic, entered the perindopril-atenolol comparison. Of these, 163 had been previously treated and had a 4-week run-in period on placebo; 27 had previously been untreated and received placebo for 2 weeks. At entry, all patients who had a supine diastolic blood pressure (DBP) of 95-115 mm Hg were randomized to receive perindopril 2 mg or atenolol 25 mg, once daily. Patients were assessed at 2 weekly intervals for the first month and then monthly for 2 more months. If supine DBP was greater than 90 mm Hg, treatment was increased by stepwise doubling of dose up to 8 mg perindopril or 100 mg atenolol once daily, and later by the addition of hydrochlorothiazide 25 mg, (indapamide 2.5 mg in diabetic patients) once daily. The two groups were homogeneous prior to treatment except for supine and erect heart rate, which were higher in the perindopril group than in the atenolol group (p less than 0.05). Mean supine DBP was 101.1 +/- 0.6 mm Hg in the perindopril group (n = 94) and 99.9 +/- 0.6 mm Hg in the atenolol group (n = 96). After 3 months' active treatment, 74% of patients in the perindopril group achieved a supine DBP of less than or equal to 90 mm Hg and 73% of patients in the atenolol group achieved the same goal. Monotherapy controlled supine DBP in 67% of the perindopril group and 63% of the atenolol group. The decrease in supine DBP was not significantly different between the two groups (-12.9 +/- 0.9 versus -14.7 +/- 0.9 mm Hg) but the decrease in erect DBP was lower in the perindopril group (-10.3 +/- 0.9 versus - 13.4 +/- 1.0 mm Hg, p less than 0.02). Heart rate was reduced in the atenolol group (p less than 0.001). Sixteen patients withdrew from the study; nine were attributed to adverse events, two in the perindopril group and seven, including one death, in the atenolol group. Cough was spontaneously reported by 13% patients of the perindopril group and 1% patients of the atenolol group. In 5% of the perindopril cases this was mild and associated with upper respiratory tract infection. The nature and incidence of other symptoms were similar with both drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1992

Preferred salt levels and salt taste acuity in human subjects after ingestion of untasted salt.

We have examined whether salt loading alters the salt preference or salt taste acuity of nine human subjects on continuous low salt diet. Subjects were randomly assigned to either untasted salt tablets (120 mmol/day) or placebo over a 2-week period at the end of which salt preference and salt recognition thresholds were measured. Subjects then received the alternate substance for another 2 weeks and the measurements were repeated. While urinary Na+ and Cl- were significantly increased while on salt tablets, urinary volume, K+, urea and creatinine concentrations, blood pressure, body weight, salivary and plasma electrolyte concentrations were unchanged. Plasma renin and aldosterone levels were reduced while on salt tablets but not significantly. Salt tablets caused a significant increase in sodium recognition threshold but a significant decrease in salt addition to unsalted tomato juice and in ideal salt level assessed by presalted (150 mmol/l) tomato juice. Thus, an increase in untasted dietary salt may reduce salt preference in human subjects, a finding opposite to that with an increased, tasted salt intake over a similar period.

Adult↗
PubMed1992

Comparison and interaction of low dose felodipine and enalapril in the treatment of essential hypertension in elderly subjects.

The antihypertensive effect and tolerance of the combined low doses of felodipine and enalapril (5 + 5 mg daily) were compared with those of either drug at a higher dose level (10 mg daily). Our double-blind, three-way crossover study (balanced Latin square design) involved 36 elderly subjects (mean age 67 +/- 6 years) with essential hypertension. After a 4-week placebo run-in phase the subjects were randomized to the active treatment periods, starting with 5 mg felodipine plus 5 mg enalapril, 5 mg felodipine, or 5 mg enalapril daily for the first 4 weeks. The doses in the felodipine and enalapril periods were then doubled for another 2 weeks. All medication was given once daily in the morning, and blood pressure was measured 24 h after a previous dose. The supine blood pressure for subjects given placebo was 178/101 mm Hg. After 6 weeks' treatment systolic and diastolic supine blood pressures were significantly lower with 5 mg felodipine plus 5 mg enalapril (154/85 mg Hg) than with 10 mg felodipine (159/88 mm Hg) or with 10 mg enalapril (162/91 mm Hg), and the diastolic blood pressure was significantly lower with felodipine than with enalapril. At the end of the felodipine plus enalapril, felodipine, and enalapril treatment periods, 75, 69, and 56% of the subjects, respectively, had a supine diastolic blood pressure 90 mm Hg or less. The combination was tolerated better than either monotherapy. The most commonly reported adverse event was swollen ankles, which occurred in one, nine, and five subjects during felodipine plus enalapril, felodipine, and enalapril treatment, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗