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Biomedical subjects

R G Dluhy

Publications and source records attributed to R G Dluhy.

At least 37 records · Page 2Linked to original sources
PubMed1994

Glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant form of human hypertension. In GRA in which aldosterone secretion is positively and solely regulated by ACTH, glucocorticoid administration relieves this mineralocorticoid excess syndrome. Recent studies demonstrate that GRA is caused by a gene duplication fusing regulatory sequences of the steroid 11 beta-hydroxylase gene to the coding sequences of the aldosterone synthase gene. This gene mutation, which results in ectopic expression of aldosterone synthase activity in the zona fasciculata, provides the basis for a simple, direct genetic test for GRA from a small sample of peripheral blood.

Aldosterone↗
PubMed1993

Diagnosis and treatment of psychogenic erectile dysfunction in a urological setting: outcomes of 18 consecutive patients.

The diagnostic criteria and treatment outcomes of 18 consecutive patients with psychogenic erectile dysfunction were examined. Average patient age was 38 years, and all patients had either awakening penile or masturbatory rigidity. Each patient was studied with home monitoring (ART-1000) on 2 consecutive nights. The average number of maximum erectile episodes, the event during which the maximum rigidity was maintained for at least 5 minutes, was 1.6. The maximum sleep erectile episodes averaged 11.2 minutes during which penile rigidity averaged 572 gm. The main predictor for remission of erectile dysfunction in this study was whether the dysfunction was primary or secondary. Of 14 patients with secondary psychogenic erectile dysfunction, that is history of being able to achieve and maintain penile rigidity sufficient for at least 5 minutes of vaginal intercourse, 10 (71%) experienced remission. Three patients noticed spontaneous remission during the initial evaluation and another 3 experienced remission within 3 months of completion of the evaluation and reassurance that they had normal erectile capacity. Two patients had remission while considering penile vascular surgery and in 2 normal erectile function returned during injection therapy. Only 2 of 3 patients referred for sex therapy actually received it (Freudian theory), and neither noticed improvement in erectile function. One patient received yohimbine without benefit. None of the patients elected treatment with the vacuum constriction device. All 4 patients with primary psychogenic erectile dysfunction, that is never able to achieve and/or maintain penile rigidity sufficient to achieve vaginal intercourse, failed to respond to physician reassurance and time. Of 2 patients who received sex therapy (1 Freudian and 1 behavioral) without improvement in erectile function 1 has entered the pharmacological erection program and has achieved vaginal penetration, and the other is considering the pharmacological erection program. The remaining 2 patients have deferred all therapy. Based on this experience, we currently reassure patients with secondary psychogenic erectile dysfunction that they have erectile capacity for sustained vaginal intercourse and schedule a followup visit in 3 months. Additional individualized therapy (pharmacological erection program, vacuum constriction device, sensate focus/psychodynamic specific therapy or penile prosthesis) is offered as needed and requested. Patients with primary psychogenic erectile dysfunction are initially offered the pharmacological erection program or the vacuum constriction device and sex sensate focus/psychodynamic specific therapy. The penile prosthesis is considered for treatment failures.

Adult↗
PubMed1992

Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype.

OBJECTIVE: To define the clinical spectrum of glucocorticoid-remediable aldosteronism (GRA) in a large kindred. DESIGN: Screening all at-risk relatives of a proband for GRA using a specific biochemical phenotype and collecting of medical histories of kindred members from five generations. SETTING: Outpatient General Clinical Research Centers and patients' homes. MEASUREMENTS: Screening was done while patients were on a self-selected diet and included blood pressure determinations; serum potassium and plasma renin activity and aldosterone measurements; and 24-hour urinary tetrahydroaldosterone, 18-oxotetrahydrocortisol, and 18-hydroxycortisol measurements. RESULTS: Diagnosis of GRA was established on the basis of a previously described specific biochemical abnormality, overproduction of the cortisol C-18 oxidation products (18-oxotetrahydrocortisol and 18-hydroxycortisol) in urine and their ratio relative to tetrahydroaldosterone. Glucocorticoid-remediable aldosteronism was diagnosed in 11 additional patients spanning three generations; this group included the youngest patient (3 months old) ever diagnosed with GRA. Complete penetrance of the biochemical abnormality is likely, with 11 of 18 at-risk patients displaying the phenotype. All patients with GRA had elevated blood pressure. Affected adult patients had been diagnosed as hypertensive before reaching 21 years of age (n = 7 mean, 16.1 +/- 3.4 years). All affected patients were normokalemic (4.3 +/- 0.3 mmol/L). CONCLUSION: Hypertension is a characteristic feature of GRA. Elevated blood pressure in this kindred developed at an early age and often was severe. Because a normal potassium level does not exclude the diagnosis of GRA, the disorder may be underdiagnosed. The value of a specific cortisol C-18 oxidation phenotype in the diagnosis of GRA has been confirmed.

Adolescent↗
PubMed1992

A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension.

Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.

Base Sequence↗
PubMed1992

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Alleles↗
PubMed1992

Non-modulation as an intermediate phenotype in essential hypertension.

Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1989

Premature menopause: monoclonal antibody defined T lymphocyte abnormalities and antiovarian antibodies.

The presence of other organ-specific autoimmune disorders in some patients with premature menopause has supported the concept of an autoimmune etiology. The authors analyzed the peripheral blood of 23 women with the diagnosis of premature menopause to detect the presence of monoclonal antibody-defined T-lymphocyte abnormalities and/or antiovarian antibodies. All subjects were less than 40 years of age with the duration of menopause ranging from less than 1 year to 11 years at the time of study. Thirty-five percent of the subjects had an elevated percentage of Ia+ (Dr-activated) T cells using monoclonal antibody L243. The percent T4 (helper) T8 (suppressor/cytotoxic) T cells and T4/T8 ratio were normal in the study group. Four subjects (approximately 17%) had elevated percentages of the age-related 3G5+ T cell subset. Two of the subjects with increased 3G5+ T cells also exhibited increased Ia+ T cells. Antiovarian steroid cell antibodies and antiadrenal cortical antibodies were present in approximately 9% of subjects. Anti-islet cell antibodies were not present. Thyroid antimicrosomal antibodies were present in 17% of subjects. Study subjects exhibited immunologic abnormalities that the authors hypothesize may play a role in the development of premature menopause in a larger percentage of patients than was previously suspected.

Adolescent↗
PubMed1989

Prolonged converting enzyme inhibition in non-modulating hypertension.

Patients with normal- or high-renin non-modulating essential hypertension fail to shift their adrenal sensitivity on a low sodium diet in response to an infusion of angiotensin II (Ang II). In a prior study, 72 hours of converting enzyme inhibition (CEI) partially corrected this subnormal aldosterone response to Ang II in patients with non-modulating hypertension. Since it was uncertain whether the failure to restore normal adrenal responsiveness reflected a continued abnormality or an insufficient duration of CEI, the present study was performed wherein subjects were studied before CEI and then 72 hours and 6 weeks after CEI. Adrenal and renovascular responses were assessed in 13 subjects with normal- or high-renin hypertension in response to an infusion of Ang II (0.3, 1.0, and 3.0 ng/kg/min) in balance on a 10 meq Na+/100 meq K+ diet. Eight of 13 had a normal plasma aldosterone increment above control levels (greater than or equal to 15 ng/dl) and were classified as modulators; the remaining subjects (five of 13) were classified as non-modulators. Enalapril was then administered for 72 hours and 6 weeks, and the assessment of the Ang II dose-response relations was repeated. In the modulators, there was no change compared with levels before CEI in the aldosterone dose-response curve or threshold sensitivity to infused Ang II at either 3 days or 6 weeks after CEI administration. In the non-modulators, CEI for 72 hours partially restored aldosterone responsiveness, but more prolonged CEI for 6 weeks completely corrected the defect, restoring aldosterone responsiveness on a sodium-restricted diet to that seen in modulators and in normotensive control subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldosterone↗
PubMed1989

Evidence for heritability of non-modulating essential hypertension.

We have previously described a subset of subjects with essential hypertension who fail to appropriately modulate renal vascular and adrenal reactivity with changes in dietary sodium and in response to infused angiotensin II (Ang II). In this paper, we studied these responses in 13 unselected hypertensive subjects in whom the family history of hypertension had been carefully detailed. Nine of these 13 subjects had a positive family history (FH+) for hypertension and had significantly smaller decrements in renal blood flow with Ang II infusion than the four subjects who had a negative family history (FH-) (-84 +/- 16 ml/min/1.73 m2 for FH+ vs. -149 ml/min/1.73 m2 for FH-, p = 0.024). These FH+ subjects also showed smaller increases in renal blood flow with increases in dietary sodium than FH- subjects (7 +/- 10 ml/min/1.73 m2 vs. 72 +/- 24 ml/min/1.73 m2, respectively; p = 0.014). When classified as modulators or non-modulators by previously established criteria, all seven non-modulators were FH+, and seven of nine FH+ subjects were non-modulators. This association between non-modulation and family history of hypertension is significant (p = 0.021). To further clarify the association between non-modulation and family history of hypertension, we have studied the renal blood flow response to Ang II in 31 hypertensive siblings from 14 sibships. Twenty-five of these 31 subjects (81%) behaved as non-modulators (p = 0.008 compared with expected value in an unselected hypertensive population). Additionally, strong concordance of non-modulation between sibling pairs was observed (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1989

Reversible alteration of red cell lithium-sodium countertransport in patients with thyroid disease.

Thyroid hormones may alter red blood cell (RBC) sodium content and transport. The functional importance of lithium-sodium (Li-Na) countertransport in regulating sodium (Na) transport in vascular smooth muscle and kidney by Na-H countertransport and the potential effect of thyroid hormone on these processes led us to study Li-Na countertransport and other sodium transporters in RBCs of patients with thyroid dysfunction. Patients with untreated hypothyroidism (10) and hyperthyroidism (10) were studied, along with normal subjects (10). The mean value for Li-Na countertransport was significantly higher in the hypothyroid group [0.46 +/- 0.08 (+/- SE) mmol/L cell.h; P less than 0.05] and lower in the hyperthyroid group (0.15 +/- 0.04 mmol/L cell.h; P less than 0.05) compared to that in the normal subjects (0.25 +/- 0.03 mmol/L cell.h). When all groups were combined, significant negative correlations were found between Li-Na countertransport and serum T4 (r = -0.48; P less than 0.01), free T4 index (r = -0.42; P less than 0.05), and serum T3 (r = -0.38; P less than 0.05). Li-Na countertransport was positively correlated with serum triglyceride (r = 0.57; P less than 0.01), but not with serum cholesterol levels (r = 0.28; P = NS). The values became normal in subsets of the hypothyroid (n = 5) and hyperthyroid groups (n = 5) during treatment. We found a bidirectional effect of thyroid status on RBC Li-Na countertransport, which was reversible when serum thyroid hormone levels became normal. Changes in Li-Na countertransport, a pathway of Na-H exchange, may influence renal sodium handling and vascular tone in patients with thyroid disease and contribute to abnormalities such as hypertension that occur in patients with hypothyroidism.

Biological Transport↗
PubMed1989

Adrenocorticotropin stimulation of aldosterone: prolonged continuous versus pulsatile infusion.

Continuous iv administration of ACTH leads to a sustained stimulation of cortisol but a transient stimulation of aldosterone followed by a decline to prestimulation levels by 72 h. Since CRH and ACTH are released in a pulsatile pattern in man, this study sought to investigate whether pulsatile administration of alpha-cosyntropin-(1-24) would lead to the maintenance of aldosterone stimulation over time. Eight normal male subjects on a 10-meq sodium, 100-meq potassium diet received both a continuous and a pulsatile (0.33 U ACTH/pulse over 15 min, pulsed every 2 h) infusion of cosyntropin (4 U/24 h) for 48 h (n = 4) or 72 h (n = 4). Aldosterone and cortisol were sampled every 6 h, and PRA and angiotensin-II every 24 h. Continuous infusion led to a stimulation of aldosterone followed by a progressive decline to preinfusion levels by 72 h [preinfusion 29 +/- 5 ng/dL (810 +/- 139 pmol/L); 72 h, 38 +/- 10 ng/dL (1054 +/- 277 pmol/L); P = 0.40]. Pulsatile infusion led to a stimulation of aldosterone which was maintained up to 72 h [preinfusion 33 +/- 7 ng/dL (915 +/- 194 pmol/L); 72 h, 85 +/- 13 ng/dL (2358 +/- 361 pmol/L); P less than 0.05]. Regression analysis of aldosterone (y) over time (x) from the peak level at 18 h for the continuous infusion showed a significant negative relation (r = 0.63; P = 0.001), indicating a progressive decline in aldosterone. However, for the pulsatile infusion, there was no relation (r = 0.02; P = 0.85), indicating maintenance of aldosterone levels. There were no significant differences in sodium, potassium, PRA, angiotensin-II, or cortisol between infusions to explain these differences in aldosterone levels. Therefore, pulsatile infusion of cosyntropin maintains aldosterone secretion over time.

Adrenocorticotropic Hormone↗
PubMed1988

Heritable abnormalities of the renin-angiotensin-aldosterone system in essential hypertension.

A subset of essential hypertensives sensitive to salt and having normal or high renin levels are termed nonmodulators. These subjects fail to modulate their renal blood flow and aldosterone responsiveness when dietary sodium is changed. We have found that a positive family history of hypertension in a first degree relative is exceedingly common in nonmodulators, suggesting that nonmodulation may be inherited. We have therefore begun a study in hypertensive sibships (two sibs in a family with essential hypertension under the age of 60 years), assessing the basal renal blood flow [p = aminohippurate (PAH) clearance] and the response of renal blood flow to infused angiotensin II (AII) (3 ng/kg/min) on a 200-mEq sodium intake. Nonmodulators fail to reduce their renal blood flow by at least 120 ml/min/1.73 m2 below control. We found that basal PAH clearance was significantly lower in nonmodulating versus modulating hypertensives on a high salt diet. Nonmodulation and basal PAH clearance were also found to significantly aggregate in families, and this was independent of sodium intake. Thus, these studies support the hypothesis that nonmodulation of renal blood flow in response to sodium loading is a heritable trait.

Adult↗