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Biomedical subjects

G H Williams

Publications and source records attributed to G H Williams.

At least 55 records · Page 3Linked to original sources
PubMed1999

Melatonin rhythm observed throughout a three-cycle bright-light stimulus designed to reset the human circadian pacemaker.

Exposure to light and darkness can rapidly induce phase shifts of the human circadian pacemaker. A type 0 phase response curve (PRC) to light that has been reported for humans was based on circadian phase data collected from constant routines performed before and after a three-cycle light stimulus, but resetting data observed throughout the entire resetting protocol have not been previously reported. Pineal melatonin secretion is governed by the hypothalamic circadian pacemaker via a well-defined neural pathway and is reportedly less subject to the masking effects of sleep and activity than body temperature. The authors reasoned that observation of the melatonin rhythm throughout the three-cycle light resetting trials could provide daily phase-resetting information, allowing a dynamic view of the resetting response of the circadian pacemaker to light. Subjects (n = 12) living in otherwise dim light (approximately 10-15 lux) were exposed to a noncritical stimulus of three cycles of bright light (approximately 9500 lux for 5 h per day) timed to phase advance or phase delay the human circadian pacemaker; control subjects (n = 11) were scheduled to the same protocols but exposed to three 5-h darkness cycles instead of light. Subjects underwent initial and final constant routine phase assessments; hourly melatonin samples and body temperature data were collected throughout the protocol. Average daily phase shifts of 1 to 3 h were observed in 11 of 12 subjects receiving the bright light, supporting predictions obtained using Kronauer's phase-amplitude model of the resetting response of the human circadian pacemaker. The melatonin rhythm in the 12th subject progressively attenuated in amplitude throughout the resetting trial, becoming undetectable for >32 hours preceding an abrupt reappearance of the rhythm at a shifted phase with a recovered amplitude. The data from control subjects who remained in dim lighting and darkness delayed on average -0.2 h per day, consistent with the daily delay expected due to the longer than 24-h intrinsic period of the human circadian pacemaker. Both temperature and melatonin rhythms shifted by equivalent amounts in both bright light-treated and control subjects (R = 0.968; p<0.0001; n = 23). Observation of the melatonin rhythm throughout a three-cycle resetting trial has provided a dynamic view of the daily phase-resetting response of the human circadian pacemaker. Taken together with the observation of strong type 0 resetting in humans in response to the same three-cycle stimulus applied at a critical phase, these data confirm the importance of considering both phase and amplitude when describing the resetting of the human circadian pacemaker by light.

Adolescent↗
PubMed1999

The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

Adult↗
PubMed1999

Relationship between insulin resistance and nonmodulating hypertension: linkage of metabolic abnormalities and cardiovascular risk.

Insulin resistance is a feature common to patients with diabetes and to some with hypertension. It is assumed that this feature confers the increased metabolic risk in hypertension. However, the state of the renin-angiotensin system might contribute to cardiovascular risk, although there is no clear mechanistic explanation. Our recent observation that insulin levels are increased in a specific subset of patients with normal/high-renin hypertension, the nonmodulators, provided the background for the current hypothesis: to ascertain whether abnormalities in lipid and carbohydrate metabolism are observed in the same patients in whom alterations in sodium transport, sodium homeostasis, and the renin-aniotensin system response have been identified. Exploration of a family history of cardiovascular risk was a secondary goal. Insulin sensitivity (assessed by a 75-g oral glucose load), lipid levels, and two defects in the renin-angiotensin system were assessed in 62 hypertensive and 14 normotensive subjects placed on a high (210 mmol/l) and a low (10 mmol/l) sodium intake for 2 weeks, to classify them as low-renin, nonmodulator, or modulating hypertensive subjects. Only in nonmodulators were the following cardiovascular risk factors significantly increased: fasting insulin (P < 0.01); increment in post-glucose load insulin (P < 0.01); total, LDL, and VLDL cholesterol and triglyceride levels (P < 0.05); and erythrocyte Na+/Li+ countertransport activity (P < 0.001). Both nonmodulators and low-renin hypertensive subjects had a significantly (P < 0.01) increased frequency of a family history of hypertension by questionnaire compared with subjects with intact modulation. However, only nonmodulators had a significantly (P < 0.02) higher frequency of a family history of myocardial infarction. Thus, there is a clustering of metabolic abnormalities in a discrete subset of the essential hypertensive population with a specific dysregulation of the renin-angiotensin system--nonmodulation. The absence of this cluster in low-renin hypertensive subjects may explain their relatively diminished cardiovascular risk. Its presence in nonmodulators likely contributes to the increased cardiovascular risk observed in normal/high-renin hypertension.

Adult↗
PubMed1999

The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type II diabetes mellitus.

We have recently reported a combination of renal features that suggests independent angiotensin-mediated control of the renal circulation in the majority of hypertensive patients with type II diabetes. To ascertain whether other tissue elements of the renin-angiotensin-aldosterone system (RAAS) also were activated, we examined the adrenal response to angiotensin II (AngII) infusion on a low salt diet. We assessed also the renin response to the upright position in patients on a low salt diet and renin suppression in patients on a high salt diet. We compared responses in 42 hypertensive patients with type II diabetes (53.1 +/- 1.4 years, mean +/- SEM), 25 healthy controls (52.6 +/- 4.4 years); and 137 essential hypertensives without diabetes (43.3 +/- 1.2 years). A low renin state, defined as a plasma renin activity (PRA) <2.5 ng angiotensin I (AI)/mL/h after 5 to 7 days on a 10-mmol Na diet and 2 h of upright posture, was found in 21% of the essential hypertensives, but in only 14% of patients with type II diabetes. On this diet, PRA increased from 2.7 +/- 0.4 supine to 10.1 +/- 1.3 ng AI/mL/h upon standing in healthy subjects. In patients with type II diabetes, PRA was 3.6 +/- 0.4 and increased to 9.1 +/- 1.0 ng AI/mL/h. On a high salt (200 mmol) diet, healthy subjects showed the expected PRA suppression (0.3 +/- 0.1), but in patients with type II diabetes the PRA was less suppressed (1.2 +/- 0.3 ng AI/mL/h; P = .003). Thus, in most hypertensive patients with type II diabetes the RAAS shows normal activation, but is poorly suppressible. AngII infused intravenously to assess adrenal responsiveness in patients on a low salt diet caused an essentially identical increase in aldosterone concentration in patients with type II diabetes (21.1 +/- 1.7 to 44.0 +/- 5.9 ng/dL) and in essential hypertension (20.6 +/- 1.4 to 43.7 +/- 2.8 ng/ dL). The frequency of nonmodulation assessed as a blunted adrenal response to AngII infusion was identical in type II diabetes (47%) and in essential hypertension (46%) after exclusion of the low renin patients. Thus, at the level of one tissue renin system, the adrenal glomerulosa, responses were unaltered in patients with type II diabetes. The relative unresponsiveness of the renal blood supply to infused AngII in type II diabetes in association with an enhanced renal vasodilator response to angiotensin converting enzyme inhibition probably reflects local, intrarenal actions secondary to the diabetic state. The infrequency of a low renin state, and the inappropriately high renin levels on a high salt intake, provide a rational basis for pharmacologic interruption of the renin system to treat patients with type II diabetes.

Adult↗
PubMed1999

Minichromosome maintenance proteins as biological markers of dysplasia and malignancy.

Dysplasia, an intermediate stage in the progression from normal tissue to neoplasia, is defined morphologically by a loss of normal orientation between epithelial cells, with changes in cellular and nuclear shape and size. However, little is known about the functional properties of dysplastic cells, including their replicative state, largely due to a lack of available biological markers. We have used novel antibodies against minichromosome maintenance (MCM) proteins to examine the proliferative status of a range of histological lesions and to characterize dysplastic cells in functional terms. Immunoperoxidase staining was used to localize the MCM proteins, components of the prereplicative complex that is essential for initiating eukaryotic DNA replication. These proteins are down-regulated in cells undergoing differentiation or quiescence and, thus, serve as specific markers for proliferating cells. In normal and some reactive tissues, MCM expression was present only in restricted proliferative compartments, consistent with our published findings in the uterine cervix. In dysplastic and malignant tissues, in contrast, MCM proteins were expressed in the majority of cells, extending to surface layers of dysplastic stratified epithelia. In carcinomas, the frequency of expression of MCM proteins showed an inverse correlation with the degree of tumor differentiation. Thus, we suggest that dysplastic cells may be characterized in functional terms as remaining in cell cycle, due to deregulation of normal controls over cell proliferation. Antibodies against MCM proteins have potential clinical applications, for example, in the assessment of tumor prognosis in histological sections and the identification of proliferating cells in clinical samples using biochemical or cytological assays.

Biomarkers, Tumor↗
PubMed1998

Cdc6 protein causes premature entry into S phase in a mammalian cell-free system.

We exploit an improved mammalian cell-free DNA replication system to analyse quiescence and Cdc6 function. Quiescent 3T3 nuclei cannot initiate replication in S phase cytosol from HeLa or 3T3 cells. Following release from quiescence, nuclei become competent to initiate semiconservative DNA replication in S phase cytosol, but not in G0 phase cytosol. Immunoblots show that quiescent cells lack Cdc6 and that minichromosome maintenance (MCM) proteins are not associated with chromatin. Competence of G1 phase nuclei to replicate in vitro coincides with maximum Cdc6 accumulation and MCM protein binding to chromatin in vivo. Addition of recombinant Cdc6 to permeabilized, but not intact, G1 nuclei causes up to 82% of the nuclei to initiate and accelerates G1 progression, making nuclei competent to replicate prematurely.

3T3 Cells↗
PubMed1998

Improved cervical smear assessment using antibodies against proteins that regulate DNA replication.

Carcinoma of the cervix is one of the most common malignancies. Papanicolaou (Pap) smear tests have reduced mortality by up to 70%. Nevertheless their interpretation is notoriously difficult with high false-negative rates and frequently fatal consequences. We have addressed this problem by using affinity-purified antibodies against human proteins that regulate DNA replication, namely Cdc6 and Mcm5. These antibodies were applied to sections and smears of normal and diseased uterine cervix by using immunoperoxidase or immunofluorescence to detect abnormal precursor malignant cells. Antibodies against Cdc6 and Mcm5 stain abnormal cells in cervical smears and sections with remarkably high specificity and sensitivity. Proliferation markers Ki-67 and proliferating cell nuclear antigen are much less effective. The majority of abnormal precursor malignant cells are stained in both low-grade and high-grade squamous intraepithelial lesions. Immunostaining of cervical smears can be combined with the conventional Pap stain so that all the morphological information from the conventional method is conserved. Thus antibodies against proteins that regulate DNA replication can reduce the high false-negative rate of the Pap smear test and may facilitate mass automated screening.

Antibodies↗
PubMed1998

Late feedback effects of hypothalamic-pituitary-adrenal axis hormones in healthy subjects.

We tested the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis hormones exert prolonged negative feedback on corticotropin (ACTH) secretion. Ten healthy subjects underwent a standard protocol 4 x and each time received i.v., under double blind conditions and in random order, corticotropin-releasing hormone (CRH) 1 microgram/kg, co-syntropin (ACTH1-24) 0.25 mg, cortisol (hydrocortisone) 15 mg, or placebo. Subjects had a venipuncture for cortisol and ACTH levels at 0900h on Day 1, then had i.v. insertion and cortisol and ACTH levels measured at 1600 and 1855h. The test substance was given at 1900h and cortisol and ACTH levels were monitored until 2300h, when the i.v.'s were discontinued. Subjects then had venipunctures for cortisol and ACTH levels at 0900 and 1600h on Day 2 and 3. Hormones had the expected acute effects. Hormones did not differ from placebo in effects on cortisol levels measured over Days 2 and 3. There were significant differences between test substances in effects on afternoon ACTH levels on Days 2 and 3, with ACTH levels increasing significantly less from baseline to Day 2 and 3 after CRH administration than after placebo, and tending to increase less from baseline to Day 3 after ACTH administration than after placebo. Examination of Day 2 and 3 morning ACTH levels showed a significant interaction between the test substances and time (Day 2 vs. 3), and interpretation of this interaction is not straightforward. We conclude that CRH and possibly ACTH exert late inhibitory effects on ACTH secretion measured in the afternoon of the 2 days following hormone administration.

Adrenocorticotropic Hormone↗
PubMed1998

Assessing patient wellness: new perspectives on quality of life and compliance.

Hypertension remains a major contemporary health problem in the United States despite being one of the most prevalent chronic diseases for which treatment is readily available. In spite of increased public awareness, active preventative campaigns, and notable progress in antihypertensive pharmacologic therapies, many patients remain untreated or inadequately treated. The reasons for this relative management failure are complex and multifactorial, and include the effects that pharmacologic agents have on quality of life. A patient's overall level of well-being and perception of functional capacity may be more sensitive to the pharmacologic effects of antihypertensive agents than previously recognized. Compliance, frequently related to a patient's sense of deterioration in quality of life secondary to medical treatment, may well be the ultimate determinate of success with any antihypertensive regimen. Therefore, it is essential that clinicians implement pharmacologic therapy that balances biophysiologic needs with quality-of-life considerations to achieve the most successful and viable patient outcomes.

Antihypertensive Agents↗
PubMed1998

Dissociation of vascular and adrenal responsiveness to angiotensin II following calcium channel blockade.

Calcium channel blockers as a class reduce both vascular resistance and systemic blood pressure. However, it is not known if different classes of calcium channel blockers have similar effects on the renin-angiotensin-aldosterone system. We investigated vascular and adrenal responses to endogenous and exogenous angiotensin II in normotensive subjects before and after receiving isradipine or diltiazem. Subjects achieved low salt balance before study and underwent an angiotensin II infusion and upright posture study. After re-achieving salt balance the subjects received either isradipine (n=10), or diltiazem (n=7) for three days before repeating the study. Both agents lowered blood pressure and significantly shifted the dose response relationship of angiotensin II and mean blood pressure (P<0.01). In contrast, aldosterone secretion in response to upright posture and angiotensin II infusion was significantly reduced (P<0.01) by isradipine but not by diltiazem. The in vitro effects of both agents on aldosterone secretion from bovine adrenal glomerulosa cells paralleled the in vivo observations showing that angiotensin II-stimulated aldosterone secretion was markedly blunted by isradipine and minimally by diltiazem. These results suggest a tissue specificity for the effects of different classes of calcium channel blockers. Dihydropyridine calcium channel blockers may exert their antihypertensive effect by blocking both vascular and adrenal responses to angiotensin II.

Adrenal Glands↗
PubMed1998

Impact of dietary Na+ on glycyrrhetinic acid-like factors (kidney 11beta-(HSD2)-GALFs) in human essential hypertension.

Our previous studies have shown that human urine contains glycyrrhetinic acid-like factors (GALFs) that possess inhibitory activity against kidney 11beta-hydroxysteroid dehydrogenase isoform 2 (HSD2). The present studies were undertaken to determine the impact of dietary Na+ intake on the levels of kidney 11beta(HSD2)-GALFs. The excretion of kidney 11beta(HSD2)-GALFs in 24-hour urine samples of 30 unmedicated subjects (10 normotensive and 10 high/normal-renin and 10 low-renin essential hypertensive subjects) on both 200- and 10-mmol Na+ diets was studied. No differences in the urinary levels of kidney 11beta(HSD2)-GALFs were observed among the three groups on the high-Na+ diet. However, with a low-Na+ diet, the levels of kidney 11beta(HSD2)-GALFs were significantly increased in hypertensive subjects but not in normal subjects. Levels increased from 8.3+/-1.4 to 17.3+/-2.9 and 6.7+/-1.3 to 10.6+/-1.4 carbenoxolone sodium units/d in high/normal-renin (P=.01) and low-renin hypertensive subjects (P=.07), respectively; normal subjects changed from 8.0+/-1.9 to 10.6+/-2.4. The levels of kidney 11beta(HSD2)-GALFs were significantly higher in the high/normal-renin hypertensive subjects than in either the control normotensive subjects or the low-renin hypertensive subjects when challenged with the low-Na+ diet (P<.05 by Wilcoxon rank-sum test). The greater response of the high/normal-renin essential hypertensive subjects indicated that they may utilize kidney 11beta(HSD2)-GALFs when challenged with a low-Na+ diet, whereas the low-renin essential hypertensive subjects do not.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Increased urinary free cortisol: a potential intermediate phenotype of essential hypertension.

We evaluated urinary cortisol excretion as a potential intermediate phenotype of essential hypertension in 153 white patients with essential hypertension and 18 normotensive white control subjects. Analyses were controlled for dietary sodium and gender to adjust for potential confounding effects of these variables on cortisol excretion. Urinary cortisol excretion measured on both high- and low-salt diets was significantly related to hypertension by repeated measures ANCOVA (P=.02). Additional determinants of urinary free cortisol included dietary sodium intake and gender; cortisol excretion was significantly higher in men (P=.0006) and during a high-sodium diet (P=.0001). Maximum likelihood analysis showed urinary cortisol to have a bimodal distribution on both 200-mmol (P<.01) and 10-mmol (P<.002) sodium diets in hypertensive subjects. On the low-salt diet, the mean urinary cortisol in normotensive subjects (108.7+/-44.7 nmol/d) was similar to the mean of hypertensive subjects in the low mode (127.2+/-43.0 nmol/d). The high mode comprised 31.2% of the hypertensive population and had a mean urinary cortisol of 224.3+/-93.8 nmol/d. Subjects with the highest urinary free cortisol showed the least sensitivity of blood pressure to dietary sodium loading (P<.05). These data suggest that there is an association between salt-resistant hypertension and high urine cortisol levels. This association may have a genetic basis.

Adult↗
PubMed1998

Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1.

Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P<10(-7)) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6. 7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7+/-4.6 versus 16. 1+/-3.3 and 16.3+/-3.7 ng/mL, respectively; P<0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1.

Adult↗
PubMed1998

Use of calcium channel blockers in hypertension.

During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These agents also probably create a compliance problem for hypertensive patients because of the need for multiple daily doses and their unpleasant side effects, e.g., ankle edema, palpitations, and flushing. Therefore, they are not useful or indicated for the treatment of hypertensive patients. No data have suggested that long-acting dihydropyridines or nondihydropyridine calcium channel blockers share the same fate. Indeed, several lines of evidence suggest the opposite: they have a cardioprotective effect. However, definitive information will require the completion of several long-term trials, including ALLHAT, CONVINCE, HOT, INSIGHT and NORDIL. Finally, it is important to reflect on the lessons learned from the controversy associated with the potential risks of calcium channel blockers. First, disagreements are common when one uses case-controlled studies and are reflective of the poor precision of the methods used. What is statistically relevant in one study may not hold true for another and may have no clinical relevance, particularly if the relative risk is less than 2. Investigators need to temper their enthusiasm to reflect this reality. Second, at the cutting edge of science there is probably relatively little agreement about what is correct among equally competent scientists. All have bias in their positions and should both recognize and admit so to themselves and their colleagues. Inferring that those who disagree have an unstated secondary agenda that will bring personal financial rewards or government accolades is inappropriate and counterproductive. Third, the randomized clinical trial, despite all its imperfections, is still the best tool to establish common ground on controversial issues. Finally, what may seem best from the public health perspective may not be in the best interest of the individual patient--a possibility that physicians have to constantly consider. For example, no public health benefit occurs if patients remain hypertensive because they fail to take their medications, no matter what the medication.

Antihypertensive Agents↗
PubMed1997

Funding for patient-oriented research. Critical strain on a fundamental linchpin.

CONTEXT: Interest in clinical investigative careers has declined over the past 2 decades. While several factors are likely involved in this decline, one is the perceived difficulty in obtaining support for investigator-initiated clinical research projects. OBJECTIVE: To analyze the priority scores and funding rates of patient-oriented research (POR) compared with laboratory-oriented research (LOR) when grant applications to the National Institutes of Health (NIH) are reviewed by study sections of the NIH Division of Research Grants. DESIGN: Research grant applications submitted to NIH were classified by the applicant as involving human subjects or not (LOR). Those classified as involving human subjects were divided into clinical (POR) and nonclinical research. The association of priority score and POR or LOR status was evaluated using chi2 statistical techniques. SETTING AND PARTICIPANTS: Twelve thousand investigator-initiated grant applications (RO1s) in 2 of the 1994 NIH review cycles. MAIN OUTCOME MEASURES: Grant application priority scores and funding rates. RESULTS: On the basis of the following 3 criteria, POR applications fare less well than LOR applications: (1) POR status and ranking in the total application pool; (2) percentage of POR vs LOR applications in the top 20th percentile; and (3) funding rates of POR applications. Furthermore, the fate of a POR application depended on which study section reviewed the application. Those applications that were reviewed in study sections that primarily reviewed POR applications fared equivalently to LOR applications; in contrast, POR applications reviewed in study sections that primarily reviewed LOR applications encountered a less favorable fate. CONCLUSIONS: These objective data provide strong support to the clinical research community's concern that investigator-initiated POR applications are not reviewed equitably at the NIH. By restructuring the review process, fairness is likely to be restored. Without restructuring, the POR component of the medical research community may be critically damaged.

Clinical Trials as Topic↗
PubMed1997

Cortisol feedback effects on plasma corticotropin levels in healthy subjects.

An abnormality of rapid cortisol feedback on activity of the hypothalamic-pituitary-adrenal axis has been reported in depression. However, there is controversy regarding the existence of rapid cortisol feedback on corticotropin (ACTH) secretion in humans. We investigated the effects of cortisol on ACTH levels in healthy subjects using a placebo-controlled, double blind, random assignment, cross-over design. Ten medication-free volunteers with no psychiatric history and no active medical problems underwent a standard protocol on two occasions separated by at least 2 weeks. Each time, subjects were admitted to a General Clinical Research Center and had infusion of 15 mg cortisol (hydrocortisone sodium succinate) over 120 min or placebo. Serum levels of cortisol and plasma ACTH levels were determined at baseline and over the 4 h after the start of the infusion. Over the two GCRC admissions subjects received both cortisol and placebo infusions, and the order of the two infusions was randomized. Compared to placebo, cortisol infusion produced a significant decrease in plasma ACTH levels beginning within 60 min from the start of the infusion. We conclude that cortisol infusion produces early inhibition of ACTH secretion in normal humans.

Adrenocorticotropic Hormone↗
PubMed1997

Autonomy of the renin system in type II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE inhibition.

Recognition that non-insulin-dependent diabetes mellitus (NIDDM) is a leading cause of end-stage renal disease (ESRD), and a focus of recent therapeutic and genetic studies on the renin system have rekindled interest in mechanisms by which angiotensin converting enzyme (ACE) inhibitors influence the diabetic kidney. We evaluated the renal hemodynamic status of 19 hypertensive patients with NIDDM under controlled sodium balance, low (10 mmol/day for 5 to 7 days) or high (200 mmol/day for 5 to 7 days). The renal plasma flow (RPF) response to ACE inhibition and to angiotensin II (Ang II) infusion was measured as para-aminohippurate (PAH) clearance before and during enalapril administration (10 mg b.i.d. for 3 days). Our premise was that if renal vasodilation induced by ACEI involves kinins, prostaglandins, and/or nitric oxide, vasoconstrictor responses to Ang II would be blunted. Conversely, if the dominant ACE inhibitor action were a reduction in Ang II formation, the consequence would be up-regulation and an enhanced vasoconstrictor response to exogenous Ang II. RPF in NIDDM on a high-salt diet was lower than in age-matched controls (477 +/- 25 vs. 551 +/- 25 ml/min/1.73 m2; P = 0.02). Enalapril increased RPF in NIDDM to 511 +/- 29 ml/min/1.73 m2 (P < 0.05) and enhanced renal vasoconstrictor responses to Ang II infusion, from -68 +/- 9 to -106 +/- 18 ml/min/1.73 m2 (P = 0.03). Baseline plasma renin activity (PRA) and plasma aldosterone significantly exceeded matched normotensive controls (1.1 +/- 0.5 vs. 0.3 +/- 0.1 ng AI/ml/hr and 10 +/- 0.9 vs. 4.1 +/- 0.5 ng/dl, P < 0.01, respectively). Conversely all measures in studies on a low-salt diet were normal. Our findings indicate that: (1) NIDDM with hypertension is associated with reduced RPF when dietary salt intake is high, (2) reduced Ang II formation is the dominant mechanism of ACEI-induced renal vasodilation in hypertensives with NIDDM; and (3) the sustained renal hemodynamic responses to ACE inhibition despite high-salt balance, and the increased PRA suggest an autonomous renin-angiotensin system suppressed subnormally by a high salt diet in patients with NIDDM despite greater volume expansion.

Adult↗