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Biomedical subjects

G H Williams

Publications and source records attributed to G H Williams.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1996

Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity.

OBJECTIVE: Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235 --> threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II. METHODS: Hypertensive (n = 34, all off medication) and normotensive (n = 57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration. RESULTS: After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P = 0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P = 0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response. CONCLUSIONS: Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.

Adolescent↗
PubMed1996

Hypertension, dyslipidemia, and insulin resistance: links in a chain or spokes on a wheel?

Rather than a link in a causal chain leading to hypertension, insulin resistance and resultant hyperinsulinemia may be 'spokes on a wheel', with central or visceral obesity as the postulated hub of the wheel. Hypertension, hypertriglyceridemia and high density lipoprotein cholesterol are depicted as other spokes. Newly identified metabolic pathways in adipose tissue or the modulating effects of various predisposing genes may lead to variable expression of various components of the multiple metabolic syndrome in individuals with a predisposition to the collection of visceral fat.

Adipose Tissue↗
PubMed1996

Elevated lymphocyte cytosolic calcium in a subgroup of essential hypertensive subjects.

Abnormalities of intracellular calcium homeostasis and sodium-proton exchange have been implicated in the pathophysiology of essential hypertension. To further define the nature of cytosolic calcium abnormalities and whether they relate to increased sodium-proton exchange in hypertension, we have studied peripheral lymphocytes from normotensive and hypertensive subjects. Lymphocyte cytosolic calcium was significantly increased (P < .01) in hypertensive compared with normotensive subjects while consuming a high salt diet. Using maximum likelihood analysis, we found that cytosolic calcium levels in our study population were not normally distributed and observed three modes (P < .02). The means of the first mode and the two upper modes were separated (+/-2 SD) at a cytosolic calcium level of 120 nmol/L. We conducted further analysis in the subgroups with cytosolic calcium levels > 120 nmol/L or < 120 nmol/L. The majority of the normotensive subjects (86%) and half of the hypertensive subjects (52%) had levels < 120 nmol/L. Clinical characteristics of the two subgroups did not differ. Subjects with levels < 120 nmol/L had a rise in cytosolic calcium when changed to a low salt diet; those with levels > 120 nmol/L did not show a change in cytosolic calcium but their blood pressure fell significantly with salt restriction. Hypertensive subjects also had increased sodium-proton exchange activity compared with normotensive subjects when both groups were studied in a high salt balance. A positive correlation between sodium-proton exchange and cytosolic calcium was observed in subjects with levels < 120 nmol/L. There was insufficient power to draw conclusions on this relationship in subjects with levels > 120 nmol/L. Thus, many hypertensive subjects have increased cytosolic calcium, but this abnormality is not associated with sodium-proton exchange activity in all individuals. The salt-induced change in cytosolic calcium in subjects with levels < 120 nmol/L and its link to sodium-proton exchange suggest regulation by factors involved in salt-volume homeostasis. Individuals with cytosolic calcium > 120 nmol/L, most of whom were hypertensive, may have abnormalities in this regulation, contributing to hypertension.

Adult↗
PubMed1996

Effect of progesterone on aldosterone secretion in rats.

In both human and animal studies high progesterone states are associated with elevated aldosterone production but variable changes in PRA. These experiments were designed to test the hypothesis that progesterone has an effect similar to a low sodium diet on the glomerulosa cell: increasing aldosterone synthase messenger RNA activity and aldosterone production. Ovariectomized (OVX) rats were injected with progesterone (1 mg/100 g) or vehicle (SHAM) for 5 days. In a separate study, intact rats were placed on a low (0.02%) or high (1.6%) sodium diet for 5 days. On the day of death, rats were decapitated and blood collected for serum hormone determinations. Isolated adrenal glomerulosa cells were incubated +/- 10 nM angiotensin II (A II), after which aldosterone and corticosterone were measured. Early (conversion of cholesterol to pregnenolone) and late (conversion of corticosterone to aldosterone) aldosterone pathway activity was assessed in parallel incubates by adding cyanoketone and excess corticosterone with subsequent measurement of pregnenolone and aldosterone. In vivo, progesterone administration, like dietary sodium restriction, caused a significant increase in PRA (p < or = 0.043) and plasma aldosterone (p < or = 0.009), with no change in plasma corticosterone. Additionally, both treatments caused a significant increase in baseline (P < or = 0.01) and A II-stimulated (p < or = 0.027) aldosterone secretion in vitro. This increased responsiveness was secondary to activation of late pathway activity (p < or = 0.022) as determined by both an increased conversion of corticosterone to aldosterone and by an increase in messenger RNA levels of the late pathway enzyme aldosterone synthase. Thus, chronic progesterone administration apparently does not directly influence aldosterone secretion, but rather acts indirectly to increase aldosterone by mechanisms similar to sodium restriction.

Aldosterone↗
PubMed1995

Identification of tumour-specific translocations in archival material.

A reverse transcriptase nested polymerase reaction (RT-nPCR) method has been developed to detect the presence of a tumour-specific translocation in archival formalin-fixed, paraffin-embedded tissue. This technique can be applied to the large numbers of tumours in pathology departments' archives, allowing correlation of translocations with morphological diagnosis, response to therapy, and survival.

Base Sequence↗
PubMed1995

Metabolic derangements in nonmodulating hypertension.

A positive association exists between insulin resistance, dyslipidemia, and hypertension, specifically salt-sensitive hypertension. A subgroup of salt-sensitive normal and high renin hypertensives called nonmodulators (NM) manifest an inability to modulate the adrenal and renal blood flow responses to a change in dietary sodium. Therefore, we tested the hypothesis that the NM subgroup would be insulin resistant and dyslipidemic when compared with normal and high renin hypertensives, in whom modulation is intact (M). Forty-six nondiabetic hypertensive individuals were evaluated and their modulation status defined by either renal or adrenal criteria. Fasting blood was drawn for measurement of several metabolic factors. Since the NM group had a greater body mass index (BMI) it was subdivided into a "lean" subgroup that matched the BMI of the M group. The fasting insulin levels in both the total NM and lean NM groups was significantly higher than in the M group (P = .013 and .04, respectively). There were no differences in age, blood pressure, or plasma/serum levels of glucose, triglycerides, total cholesterol, or potassium. NM had elevated fasting insulin levels compared to M, compatible with an insulin resistant state, but this insulin resistance are dissociable in the hypertensive population.

Blood Glucose↗
PubMed1995

Comparison of protein phosphorylation patterns produced in adrenal cells by activation of cAMP-dependent protein kinase and Ca-dependent protein kinase.

Bovine adrenal fasciculata cells, exposed to either ACTH or AII, synthesize glucocorticoids at an enhanced rate. It is generally accepted that the signaling pathways triggered by these two peptides are not identical. ACTH presumably acts via a cAMP-dependent protein kinase (PKA) and AII, via a calcium-dependent protein kinase. We have found that either peptide hormone stimulates synthesis of a mitochondrial phosphoprotein pp37, leading to accumulation of its proteolytically processed products pp30 and pp29. On the basis of a number of criteria, this 37 kDa protein is the bovine homolog of the 37 kDa protein that we have characterized in rodent steroidogenic tissue (Epstein L. F. and Orme-Johnson N. R.: J. Biol. Chem 266 (1991) 19,739-19,745). Further, bovine pp37 is phosphorylated when PKA or protein kinase C (PKC) is activated directly by (Bu)2 cAMP or PMA, respectively. These studies indicate that either pp37 is a common substrate for PKA and PKC in these cells or there is a common downstream kinase, which is activated by exposure to either ACTH or AII. Rat adrenal glomerulosa cells, exposed to either ACTH or AII, show an enhanced rate of mineralocorticoid synthesis. As for bovine fasciculata cells, it is thought that the signaling pathway triggered by ACTH differs from that triggered by AII. As we found for bovine fasciculata, pp37 is phosphorylated when the rat cells are exposed to either peptide hormone. However, in contrast to the finding for bovine fasciculata, while exposure of the rat glomerulosa cells to (Bu)2cAMP does cause the synthesis of pp37, exposure of the cells to PMA does not. Taken together, these findings provide further evidence that the subcellular signaling events, triggered by the action of AII on bovine adrenal fasciculata and rat adrenal glomerulosa cells, differ. Further, the fact, that pp37 is phosphorylated only when the rate of steroidogenesis is enhanced, reaffirms its potential involvement in the signaling pathway that causes stimulation of steroid hormone biosynthesis.

Adrenal Glands↗