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G H Williams

Publications and source records attributed to G H Williams.

At least 19 recordsLinked to original sources
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

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

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↗
PubMed1997

Sodium balance modulates thirst in normal man.

Several lines of evidence suggest that angiotensin II (AII) plays an important physiologic role in the control of thirst in laboratory animals but a conflicting one in humans. Sodium (Na+) balance plays a key role in the control of the renin-angiotensin system, but studies assessing the effect of sodium balance on thirst perception in humans are limited at best. To address this question, we studied the relationship between thirst perception and plasma osmolality during 5% saline infusion (.08 ml/kg/min x 120 min) in 5 healthy volunteers while in metabolic balance on both a 10 mEq. sodium (LS) and 200 mEq. sodium (HS) diet with and without infusion of AII (5 ng/kg/min). Thirst perception was quantified using a linear visual analogue scale. The relationship between serum Na+ (a measure of osmolality) and thirst perception was analyzed using linear regression. The mean x-intercept ([Na+] mEq/l) which represents the osmotic threshold to thirst was 138.2 +/- 0.5 in LS vs 140.7 +/- 0.8 in HS, p < 0.05. We conclude that the osmotic threshold for thirst is lower in LS (high endogenous AII) vs HS (low endogenous AII). There was no evidence for substantial extracellular volume change in HS vs LS with no significant differences in weight, hematocrit or total serum protein. Acute AII infusion did not result in changes in slope or x-intercept, but the pressor response to exogenous AII may have inhibited its dipsogenic effect (as has been shown in animal studies). These data suggest a physiologic role of sodium balance (possibly mediated via endogenous AII) in the control of thirst in normal humans.

Aldosterone↗
PubMed1997

Genetic approach to diagnostic and therapeutic decisions in human hypertension.

In the most exciting genetic advances in the diagnosis of essential hypertension, genes responsible for three distinct forms of low-renin hypertension have been identified. Two of these forms are dominant: glucocorticoid remediable hypertension (a new gene created by the fusion of the 11 beta-hydroxylase and aldosterone synthase genes) and Liddle's syndrome (a defect in the epithelial sodium channel). One of the forms is recessive: the syndrome of apparent mineralocorticoid excess (a defect in renal 11 beta-hydroxysteroid dehydrogenase). The role of more than 20 other genes in causing hypertension has been assessed with variable findings. The most convincing evidence supports a role for the angiotensinogen gene, where linkage has been documented and an association with an intermediate phenotype of hypertension (nonmodulation) has been reported.

Angiotensinogen↗
PubMed1997

Age, gender, and non-modulation. A sexual dimorphism in essential hypertension.

The angiotensinogen gene is one of the very few related by linkage analysis to human hypertension, but the linkage has been consistently shown only among males. Moreover, polymorphisms in this gene predict an abnormal renal responsiveness to angiotensin II, a feature of non-modulation, but again, only among males. To pursue these related bridges between genetics and physiology, we evaluated the effects of sex on a second feature of non-modulation, the aldosterone response to infused angiotensin II during low sodium balance. We tested the resultant hypothesis-that non-modulation would be less frequent in women-by conducting identical protocols on 225 hypertensive inpatients (70 women, 155 men). Non-modulation was strikingly less frequent among women (26%; 95% confidence interval, 16% to 37%) than men (49%; 95% confidence interval, 40% to 57% (P = .001). We tested the hypothesis that sex steroids play a role by comparing young, premenopausal women (< 35 years) with women who were perimenopausal (45 to 55 years) and postmenopausal (> 55 years). Among the youngest women, the frequency of non-modulation was only 7%, significantly less than in young men (41%, P = .02). A steady increase in non-modulation frequency accompanied advancing age in women, reaching 47% in those older than 55 years, equal to the fraction of men affected. Age influenced non-modulation frequency in men far less. We conclude that a striking sex difference underlies the non-modulation phenotype and that female sex hormones may confer protection against a genotypic predisposition in women. This "override" of genotype, manifest by a very low frequency of non-modulation in young women, may participate in their known protection against cardiovascular disease.

Adolescent↗
PubMed1997

Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism.

Unlike other forms of primary aldosteronism, recent prospective studies have paradoxically revealed that glucocorticoid-remediable aldosteronism (GRA) is usually characterized by normal potassium (K+) levels. To evaluate this paradox we studied 10 GRA subjects and 14 healthy controls in two protocols: 1) the renal K+ excretory response to acute oral administration of 50 mmol K+ chloride and to fludrocortisone, 0.2 mg p.o. q12 h x 4 doses; and 2) the aldosterone response to administration of 50 mmol K+ chloride. The K+ excretion rate (KER) in GRA subjects (n = 6) at baseline (45.6 +/- 8.3 microEq/min), after K+ (134 +/- 34.2 microEq/min), and after fludrocortisone (100 +/- 35.0 microEq/min) was not significantly different than that seen in the control (n = 8) subjects (54.9 +/- 19.0, 154 +/- 35.5, 112 +/- 45.8 microEq/min, respectively). Thus the renal kaliuretic response to K+ ingestion and exogenous mineralocorticoid is normal in GRA. Serum aldosterone increased from 5.0 +/- 3.8 at baseline to a maximum of 13.1 +/- 6.6 ng/dL 60 min after K+ ingestion in control subjects (n = 7), but failed to increase in GRA subjects (n = 14), going from 8.7 +/- 3.8 (baseline) to 8.8 +/- 5.4 ng/dL at 60 min (P = 0.004 vs. control). The blunted aldosterone response to K+ in GRA in association with the sharp diurnal decline in aldosterone in this ACTH-regulated syndrome probably results in a milder degree of hyperaldosteronism compared with other forms of primary aldosteronism, thereby producing volume expansion with minimal renal K+ wasting.

Adult↗
PubMed1997

Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum.

PURPOSE: Although Angiotensin II (Ang II) is a major modulator of regional blood flow in the extracavernosal segments of the vascular bed, its role in erectile function is unknown. The corpus cavernosum penis is a modified vascular tissue that contains endothelial and smooth muscle cells. In other segments of the vascular bed, these cell types produce Ang II. Therefore, we explored the presence and function of an Ang II producing paracrine system in the corpus cavernosum. METHODS: The angiotensin content of the human corpus cavernosum was measured by radioimmunoassay. The distribution pattern of Ang II containing cells within the corpus cavernosum was assessed by an immunohistochemical technique, and the rate of its secretion was determined by superfusion. The effects of Ang II and its antagonist, losartan, on intracavernosal pressure were determined under in vivo conditions, in anesthetized dogs. RESULTS: Human corpus cavernosum contained 1178 +/- 223 (SEM) fmol Ang II, 528 +/- 171 fmol Ang I, 475 +/- 67 fmol des-asp-Ang I, and 1897 +/- 371 fmol des-asp-Ang II/gm. tissue (n = 4). Ang II was found mainly in endothelial cells lining blood vessels and smooth muscle bundles within the corpus cavernosum. Superfused cavernosal tissue secreted immuno-reactive Ang II (Ang II(ir)) at a rate of 57 +/- 36.5 fmol Ang II(ir)/gm. tissue/minute (n = 10). The amount of Ang II released per gram of tissue in an hour was 3-fold greater than the Ang II content/gm. tissue, suggesting a local production of Ang II. Papaverine and prostaglandin E1 suppressed Ang II secretion significantly (p <0.001, p = 0.013). The responsiveness to inhibition was a function of the initial rate of Ang II secretion. Tissue samples with a high rate of secretion were less responsive to the inhibitors than tissue that secreted small amounts of Ang II (n = 6). In anesthetized dogs, intra-cavernosal injection of Ang II terminated spontaneous erections, while losartan increased the intracavernosal pressure in a dose dependent manner up to the mean arterial pressure (n = 4). CONCLUSIONS: The corpus cavernosum produces and secretes physiologically relevant amounts of Ang II. The rate of Ang II secretion can be modulated by pharmacologic agents that regulate cytosolic calcium levels and are used clinically to treat erectile dysfunction. Intracavernosal injection of Ang II causes contraction of cavernosal smooth muscle and terminates spontaneous erection in anesthetized dog, while administration of an Ang II receptor antagonist results in smooth muscle relaxation and thus erection.

Alprostadil↗
PubMed1997

Screening for postpartum depression. An antepartum questionnaire.

OBJECTIVE: To develop and evaluate a questionnaire used antepartum to screen for postpartum depression. STUDY DESIGN: Demographic and clinical data, based on previously identified variables, were obtained from 106 second-trimester gravidas (sample I) by interview, self-administered questionnaire and medical record review. The Beck Depression Inventory (BDI) was administered at 1, 6 and 12 weeks postpartum (PP). Statistical analysis, including stepwise linear regression with maximum r-squared improvement, identified a subset of the 24 most predictive variables. This antepartum questionnaire (APQ) was validated retrospectively in the original sample and prospectively in a second group of 99 women (sample II). RESULTS: In both sample populations the APQ had acceptable sensitivity (80-82%) and specificity (78-82%). The incidence of postpartum depressive symptoms (PPDS) rose from 10% to 17% by six weeks without an appreciable decline at 12 weeks (15%). The percentage of women showing more than mild depressive symptoms increased with PP time from 30% at 1 week to 47% at 12. CONCLUSION: The APQ is now available for screening and evaluating early therapeutic intervention in PPDS.

Adolescent↗
PubMed1996

Learning disability in children with postmeningitic cochlear implants.

OBJECTIVE: To determine the effects of learning disability on measures of auditory perception, receptive language development, and sequential organization in children with postmeningitic cochlear implants. DESIGN: Retrospective study. Follow-up ranged from 12 months to 7 years. SETTING: Tertiary care center. PATIENTS: Ten pediatric patients with cochlear implants, 5 with documented learning disability. MAIN OUTCOME MEASURE: Pediatric cochlear implant test battery performance. RESULTS: Children with learning disability showed slower progress, more inconsistencies, and lower test scores than their partners without learning disability. CONCLUSION: Learning disability is not a contraindication to cochlear implantation, but preoperative counseling must be available to families and support personnel about preoperative achievements and expectation for these children.

Child↗
PubMed1996

Analysis of the RET proto-oncogene in sporadic parathyroid adenomas.

Missense germline mutations of the RET proto-oncogene have recently been identified in the hereditary cancer syndromes MEN2A, MEN2B, and FMTC, all characterized by medullary carcinoma, but also including phaeochromocytoma in MEN2A and MEN2B and parathyroid disease in MEN2A. In addition, somatic RET proto-oncogene mutations have been identified in a subset of sporadic medullary carcinomas and phaeochromocytomas. This study investigated the possibility that RET plays a role in sporadic parathyroid neoplasia. Firstly, normal and neoplastic parathyroid tissues were screened for expression of the RET proto-oncogene, using an RT-PCR approach on autopsy material. Secondly, 20 archival parathyroid adenomas were screened for somatic mutations in the transmembrane region of RET, the region associated with germline mutations in MEN2A and hence parathyroid disease, using a PCR-solid phase direct sequencing approach. RET expression was identified in all the parathyroid tissues analysed. However, no mutations were identified in any of the 20 adenomas, suggesting either that other mechanisms of RET activation occur, such as translocation, or that RET plays a more minor role in the growth control of the parathyroid cells than in C cells or phaeochromocytes.

Adenoma↗
PubMed1996

RET activation in adult and childhood papillary thyroid carcinoma using a reverse transcriptase-n-polymerase chain reaction approach on archival-nested material.

Activation of the RET tyrosine kinase domain occurs in a proportion of thyroid papillary carcinomas. Three chromosomal rearrangements have been described, of which PTC1 is the commonest. Wide differences (2.5-25%) in frequency of PTC1 in different populations have been reported; it is not clear whether these are due to environmental factors, racial differences or technical reasons. We have developed a simple and rapid reverse transcriptase nested polymerase chain reaction (RT-nPCR) method enabling the detection of gene expression from single 5 microns sections of formalin-fixed paraffin wax-embedded archival material. We have applied this approach to detect expression of the RET tyrosine kinase domain, allowing identification of RET activation resulting from any rearrangement, whether characterised or not, or from overexpression. A retrospective study was performed on 22 adult and 21 childhood papillary carcinomas. Thirteen of 22 (59%) adult and 10 of 21 (48%) childhood carcinomas showed evidence of RET activation, demonstrating a major role for the RET oncogene in UK thyroid papillary carcinogenesis. This study also shows a similar frequency of RET activation in both children and adults. The use of a technique that allows reliable amplification of RNA from archival material, using primers chosen in different exons so that amplified products are readily distinguished from genomic DNA, will allow correlation of translocations and chromosomal rearrangements with a variety of specific tumour types.

Actins↗