Biomedical subjects

H Raff

Publications and source records attributed to H Raff.

At least 37 records · Page 2Linked to original sources

PubMed1998

Late-night salivary cortisol as a screening test for Cushing's syndrome.

The clinical features of Cushing's syndrome (such as obesity, hypertension, and diabetes) are commonly encountered in clinical practice. Patients with Cushing's syndrome have been identified by an abnormal low-dose dexamethasone suppression test, elevated urine free cortisol (UFC), an absence of diurnal rhythm of plasma cortisol, or an elevated late-night plasma cortisol. Because the concentration of cortisol in the saliva is in equilibrium with the free (active) cortisol in the plasma, measurement of salivary cortisol in the evening (nadir) and morning (peak) may be a simple and convenient screening test for Cushing's syndrome. The purpose of this study was to evaluate the usefulness of the measurement of late-night and morning salivary cortisol in the diagnosis of Cushing's syndrome. We studied 73 normal subjects and 78 patients referred for the diagnosis of Cushing's syndrome. Salivary cortisol was measured at 2300 h and 0700 h using a simple, commercially-available saliva collection device and a modification of a standard cortisol RIA. In addition, 24-h UFC was measured within 1 month of saliva sampling. Patients with proven Cushing's syndrome (N = 39) had significantly elevated 2300-h salivary cortisol (24.0 +/- 4.5 nmol/L), as compared with normal subjects (1.2 +/- 0.1 nmol/L) or with patients referred with the clinical features of hypercortisolism in whom the diagnosis was excluded or not firmly established (1.6 +/- 0.2 nmol/L; N = 39). Three of 39 patients with proven Cushing's had 2300-h salivary cortisol less than the calculated upper limit of the reference range (3.6 nmol/L), yielding a sensitivity of 92%; one of these 3 patients had intermittent hypercortisolism, and one had an abnormal diurnal rhythm (salivary cortisol 0700-h to 2300-h ratio <2). An elevated 2300-h salivary cortisol and/or an elevated UFC identified all 39 patients with proven Cushing's syndrome (100% sensitivity). Salivary cortisol measured at 0700 h demonstrated significant overlap between groups, even though it was significantly elevated in patients with proven Cushing's syndrome (23.0 +/- 4.2 nmol/L), as compared with normal subjects (14.5 +/- 0.8 nmol/L) or with patients in whom Cushing's was excluded or not firmly established (15.3 +/- 1.5 nmol/L). Late-night salivary cortisol measurement is a simple and reliable screening test for spontaneous Cushing's syndrome. In addition, late-night salivary cortisol measurements may simplify the evaluation of suspected intermittent hypercortisolism, and they may facilitate the screening of large high-risk populations (e.g. patients with diabetes mellitus).

Adult↗

PubMed1997

Corticosterone inhibition of osmotically stimulated vasopressin from hypothalamic-neurohypophysial explants.

Glucocorticoids inhibit and glucocorticoid deficiency increases vasopressin (AVP) release in vivo. To determine whether the effect of glucocorticoids is hypothalamic and mediated via a glucocorticoid receptor, explants of the hypothalamic-neurohypophysial system were used to measure AVP release during agonist and antagonist exposure. Explants from adult rats, which contained AVP neurons of the supraoptic nucleus with axonal projections terminating in the neural lobe but excluded the paraventricular nucleus, were perifused with an osmotic stimulus (increase of 5 mosmol/h over 6 h) in the absence or presence of corticosterone (100 micrograms/dl) or with corticosterone (100 micrograms/dl) in the absence or presence of the glucocorticoid antagonist RU-486 (10 microM). AVP release was not increased during osmotic stimulation in the presence of corticosterone (Cort) and was 20-30% lower than osmotically stimulated release observed in the absence of Cort. RU-486 reversed the inhibitory effect of corticosterone on AVP release. No changes in AVP mRNA content were detected. These results suggest that Cort inhibits osmotically stimulated AVP release by a direct effect within the hypothalamus and/or neurohypophysis. This effect is mediated by the glucocorticoid receptor through either genomic or nongenomic mechanisms.

Animals↗

PubMed1997

Adrenergic, respiratory, and cardiovascular effects of core cooling in humans.

The adrenergic, respiratory, and cardiovascular responses to isolated core cooling were assessed in awake human subjects. Mild core hypothermia was induced by intravenous infusion of 30 or 40 ml/kg of cold saline (4 degrees C) on 2 separate days. A warm intravenous infusion (30 ml/kg, 37 degrees C) was given on a third day as a control treatment. Mean norepinephrine concentration increased 400% and total body oxygen consumption increased 30% when core temperature decreased 0.7 degrees C. Mean norepinephrine concentration increased 700% and total body oxygen consumption increased 112% when core temperature decreased 1.3 degrees C. Core cooling was associated with peripheral vasoconstriction and increased mean arterial blood pressure, whereas heart rate was unchanged. Plasma epinephrine and cortisol concentrations were unchanged during core cooling. There were no changes in any measured parameter with the warm infusion. These findings suggest that mild hypothermia induced by isolated core cooling is associated with an adrenergic response characterized by peripheral sympathetic nervous system activation without a significant adrenocortical or adrenomedullary response. The respiratory and cardiovascular responses to core cooling are characterized by a shivering-induced increase in metabolic rate, norepinephrine-mediated peripheral vasoconstriction, and increased arterial blood pressure.

Adolescent↗

PubMed1997

Effect of exposure to hypoxia from birth on aldosterone in rabbits: role of unesterified fatty acids.

Hypoxia and fluid and electrolyte disturbances are serious risks to normal postnatal development. Because a decrease in inspired O2 (hypoxic hypoxia) inhibits aldosterone synthesis in the adult and aldosterone controls water and electrolyte balance, we studied adrenocortical function in rabbits exposed to normobaric normoxia or hypoxic hypoxia (fraction of inspired O2 0.09) from birth. At 21 days of age, rabbits were anesthetized, the adrenals were rapidly removed, and the adrenal capsules containing mostly zona glomerulosa cells were separated. Cells were dispersed with collagenase and studied in vitro. Hypoxia in vivo resulted in a 73% decrease in basal aldosterone release and a 86% decrease in adenosine 3',5'-cyclic monophosphate-stimulated aldosterone release in vitro. We hypothesized that increased unesterified fatty acids could be partly responsible for inhibition of aldosterone synthesis. Total serum unesterified fatty acids in hypoxic kits were significantly increased (298 +/- 14 micromol/l) compared with normoxic kits (184 +/- 31 micromol/l). When cells from hypoxic rabbits were washed with fatty acid-free albumin and studied under conditions devoid of fatty acids, aldosterone production was partially restored. Corticosterone production was not affected by washing. Washing had no effect on aldosterone synthesis by cells from normoxic rats. Finally, exposing washed zona glomerulosa cells to oleic acid (10-50 microM) inhibited aldosteronogenesis. We conclude that exposure to hypoxia from birth attenuates aldosterone production in part due to an increase in levels of unesterified fatty acid levels.

Aging↗

PubMed1997

Liddle's syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred.

Liddle's syndrome is an autosomal dominant form of hypertension that resembles primary hyperaldosteronism, is characterized by the early onset of hypertension with hypokalemia and suppression of both PRA and aldosterone, and is caused by mutations in the carboxyl-terminus of the beta- or gamma-subunits of the renal epithelial sodium channel. We describe a kindred (K176) whose distinguishing clinical features were mild hypertension and decreased aldosterone secretion. The index case was a 16-yr-old girl with intermittent mild hypertension and hypokalemia and subnormal PRA, aldosterone, 18-hydroxy-corticosterone, and deoxycortisol levels, but normal cortisol/cortisone metabolite ratio and cortisol half-life. A frameshift mutation in the carboxyl-terminus of the beta-subunit of the epithelial sodium channel was identified in the index case, establishing the diagnosis of Liddle's syndrome. Sixteen at-risk relatives of the index case were tested. Seven new subjects were heterozygous for the mutation found in the index case, and two deceased obligate carriers were identified. All genetically affected adult subjects had a history of mild hypertension, and four had a history of hypokalemia. Basal and postcosyntropin plasma aldosterone and urinary aldosterone levels were significantly suppressed in those positive for the mutation. The family demonstrates variability in the severity of hypertension and hypokalemia in this disease, raising the possibility that this disease may be underdiagnosed among patients with essential hypertension.

Adolescent↗

PubMed1997

Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

High dose dexamethasone suppression testing has been widely employed in the differentiation between pituitary ACTH-dependent hypercortisolism [Cushing's disease (CD)] and the ectopic ACTH syndrome. We hypothesized that the high dose dexamethasone suppression test as it is performed in practice does not improve the ability to differentiate between these two types of ACTH-dependent Cushing's syndrome. Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing's syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing's syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates. Of the 112 patients with ACTH-dependent Cushing's syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing's syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 microg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing's syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing's syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0-99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541-0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9. Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing's syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20-33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.

ACTH Syndrome, Ectopic↗

PubMed1997

Intraoperative adrenocorticotropin levels during transsphenoidal surgery for Cushing's disease do not predict cure.

Recently, intraoperative rapid immunochemiluminometric assay (ICMA) ACTH measurements have been used to evaluate the completeness of resection of ectopic ACTH-secreting tumors. This study evaluates whether this method can be applied to patients undergoing transsphenoidal surgery (TSS) for Cushing's disease to predict complete pituitary tumor resection. Eighteen patients with Cushing's disease undergoing TSS had plasma ACTH concentrations measured by a standard ICMA every 10 min for 1 h immediately after pituitary tumor removal. Patients were evaluated postoperatively for cure by standard criteria. ACTH levels were evaluated for percentage decrease from baseline at each time point. Patients who were cured (n = 11) had statistically greater decreases in ACTH levels (mean decrease 54%) than patients who were not (n = 7; 26% mean decrease, P < 0.04). By Receiver-Operator Characteristic (ROC) analysis, a reduction of at least 40% best predicted which patients were cured and which were not cured. This level of reduction was observed in 82% of cured patients, and a reduction of less than 40% was observed in 71% of those not cured. The analysis misclassified 4 of the 18 patients, resulting in a diagnostic accuracy of 78%. Although the mean maximal decrease in ACTH concentrations after tumor removal was significantly different between cured and not cured patients with Cushing's disease, it was less dramatic than results in the previous ectopic ACTH study. This may relate to incomplete suppression and/or surgical manipulation of normal pituitary corticotrophs in patients with pituitary disease. In summary, in contrast to the ectopic ACTH syndrome, decline of plasma ACTH during TSS does not accurately predict complete tumor resection.

Adrenocorticotropic Hormone↗

PubMed1996

Aldosterone release from adrenal cells is inhibited by reduced oxygen levels in vitro during maturation in rabbits.

Hypoxia in vivo leads to a decrease in aldosterone not completely explained by extrinsic controllers of adrenal function including adrenocorticotrophic hormone, renin-angiotensin II, and K+. The dissociation of renin and aldosterone during acute hypoxia in vivo may be explained by the finding that aldosterone synthesis in adrenal cells is reversibly and specifically inhibited by decreases in O2 levels within the physiological range. The present study investigated whether the direct effect of acute decreases in O2 levels on aldosteronogenic pathway is altered during maturation. Adrenal cells (whole adrenals) were prepared from fetal (27 days gestation), neonatal (1 day), and infant (10 days) New Zealand White rabbits, and capsular cells were prepared from young (21 days) and adult (3 months) rabbits. All cells were dispersed with collagenase. Basal and cAMP-stimulated aldosterone production were assessed under two different levels of O2 (pO2 = 20.0 kPa or pO2 = 8.7 kPa). Decreased O2 levels significantly inhibited cAMP-stimulated aldosterone production in cells obtained from rabbits of all ages by 60 +/- 5% cAMP-stimulated aldosterone production was significantly lower in cells obtained from neonates and premature animals under both normoxic and reduced O2 conditions as compared with animals > or = 10 days old. Corticosterone production by cells obtained from adults and 21-day-old rabbits was unaffected by reduced O2 conditions suggesting a specific effect on the aldosterone pathway. The data demonstrate that the O2 sensitivity of the aldosterone pathway is present throughout development.

Adrenal Glands↗

PubMed1996

Vasopressin responses to corticotropin-releasing factor and hypertonicity after truncal vagotomy in dogs.

Infusion of corticotropin-releasing factor (CRF) augments the plasma vasopressin response to infusion of hypertonic saline in conscious dogs. Furthermore, afferent vagal nerve input from the abdomen is involved in the control of vasopressin release and may be altered by CRF. The purpose of the present study was to characterize the effect of CRF on the vasopressin response to hypertonic saline and to determine if it is mediated by afferent input carried from the abdominal vagus. Conscious male dogs (n = 5) underwent infusion of isotonic saline (vehicle), CRF (10 or 20 ng.kg-1.min-1), hypertonic saline (0.2 mmol.kg-1.min-1), or the combination of CRF and hypertonic saline. Hypertonic saline increased plasma sodium from 147 +/- 1 to 153 +/- 1 meq/1 and plasma vasopressin from 2.5 +/- 0.1 to 5.8 +/- 0.4 pg/ml. CRF infusion alone had no effect on plasma vasopressin. The addition of 10 or 20 ng.kg-1.min-1 CRF augmented the vasopressin response to hypertonic saline to 7.7 +/- 1.7 and 6.9 +/- 0.3 pg/ml, respectively. Truncal vagotomy did not attenuate the vasopressin response to hypertonic saline with or without CRF infusion. We conclude that CRF augments the vasopressin response to hypertonic saline and that this effect is not mediated via afferents from the abdominal vagus.

Animals↗

PubMed1996

Hypoxia in vivo inhibits aldosterone synthesis and aldosterone synthase mRNA in rats.

Hypoxia leads to a decrease in aldosterone that cannot be entirely explained by extrinsic controllers of adrenal function. We have shown that acute hypoxia attenuates aldosterone synthesis via a direct inhibition of the function of the aldosterone enzyme pathway. The mechanism of the sustained decrease in aldosterone during chronic hypoxia is unknown. The present study evaluated the hypothesis that chronic hypoxia leads to a decrease in the expression of the steroidogenic enzyme P-450c11AS unique to the aldosterone pathway. Rats were exposed to 3 days of normoxia, moderate hypoxia (12% O2), or severe hypoxia (10% O2). Adrenal glands were removed and prepared for biochemical analysis of steroidogenesis in vitro (dispersed capsular cells) and for measurement of steady-state enzyme mRNA levels by reverse-transcription competitive polymerase-chain reaction (RT-cPCR) and by in situ hybridization histochemistry (ISHH). Moderate hypoxia had no effect on steroidogenesis. Adrenal cells from rats exposed to severe hypoxia demonstrated a decreased conversion of corticosterone to aldosterone (late pathway catalyzed by P-450c11AS) without a change in the other mitochondrial cytochrome P-450 enzyme activities. Adrenal cells from rats exposed to hypoxia also demonstrated a three- to fourfold decrease in P-450c11AS mRNA without a change in the other mitochondrial cytochrome P-450 enzymes mRNAs, as determined by either RT-cPCR or ISHH. We conclude that relatively short-term chronic hypoxia in rats leads to a decrease in aldosteronogenesis by decreasing the expression of the gene for the late-pathway enzyme unique to the aldosterone pathway (P-450c11AS).

Aldosterone↗

PubMed1995

Differentiation of the expression of aldosterone synthase and 11 beta-hydroxylase mRNA in the rat adrenal cortex by reverse transcriptase-polymerase chain reaction.

The adrenocortical enzymes of the steroidogenic late pathway in the rat are aldosterone synthase (P450aldo), which catalyzes the production of aldosterone, and 11 beta-hydroxylase (P45011 beta), which catalyzes the production of corticosterone throughout the cortex. These two enzymes are highly homologous and are encoded by the genes CYP11B2 and CYP11B1, respectively. The purpose of the present study is to describe the development of two sets of primers and the reverse transcription-polymerase chain reaction (RT-PCR) conditions that are capable of discriminating between rat P450aldo and P45011 beta mRNAs. The P450aldo primer set did not amplify full length cDNA P45011 beta plasmid and the P45011 beta primer set did not amplify full length cDNA P450aldo plasmid indicating minimal crosstalk. The fidelity of the PCR primers and method was further established by sequencing the PCR products and demonstration of virtual identity with the published sequences of P450aldo and P45011 beta. RT-PCR of mRNA from adrenal capsules (zona glomerulosa) and subcapsules (zona reticularis/fasciculata) from rats demonstrated no effect of sodium diet on the expression of P45011 beta mRNA but an approximately 8-fold greater expresison in P450aldo mRNA on low vs high sodium intake. Similar results were found when single hemicapsules were subjected to RT-PCR, demonstrating the sensitivity of the method. We conclude that the two sets of PCR primers and the RT-PCR method described are capable of evaluating the expression of the highly homologous mRNAs for P450aldo and P45011 beta with great precision and sensitivity.

Adrenal Cortex↗

PubMed1995

Elevated follicular fluid angiotensin II and pregnancy outcome.

OBJECTIVE: To assess whether a relationship exists between follicular fluid (FF) angiotensin II (AII) concentration and pregnancy outcome or earlier fecundity parameters and whether correlations exist among FF AII concentrations and P, E2, T, androstenedione (A), or various ratios of these. DESIGN: Retrospective study in which hormone concentrations in FF samples were measured. SETTING: In vitro fertilization clinic-Assisted Reproductive Technology Program, Rush Medical Center. PATIENTS: Twenty-six female patients underwent ovarian stimulation for IVF. INTERVENTION: Leuprolide acetate was combined with hMG and FSH for ovarian stimulation. MAIN OUTCOME MEASURE: Follicular fluid aspirates were collected and oocytes were recovered 34 to 36 hours after hCG injection. The patients proceeded to undergo IVF and ET. Follicular fluid hormones were measured using standard RIA. Angiotensin II and steroid hormone concentrations in FF were compared for pregnant versus nonpregnant women using the Student's t-test and rank-sum test. Pearson multiple-correlation analysis was performed to calculate correlation coefficients among AII concentrations and steroid concentrations in FF aspirates. RESULTS: Mean FF concentration of AII was significantly lower in samples from women showing clinical pregnancies (112.2 +/- 13.9 pg/mL [107.3 +/- 13.3 pmol/L]) compared with samples from women who did not achieve pregnancy (217.1 +/- 23.8 pg/mL [207.5 +/- 22.7 pmol/L]) (mean +/- SE). A negative correlation was observed between FF concentrations of AII and P. Correlations of AII with E2, T, A, or with ratios of these did not show significance. CONCLUSION: These data suggest that high AII concentration at time of oocyte recovery may indicate poor pregnancy outcome in women undergoing ovarian stimulation for IVF. These data corroborate previous results in animal models showing that AII predisposes follicles to undergo atresia-like conditions.

Adult↗

PubMed1995

Case report: renal phosphate wasting, syndrome of inappropriate antidiuretic hormone, and ectopic corticotropin production in small cell carcinoma.

Renal phosphate wasting related to a tumor (oncogenous osteomalacia) is a rare disorder usually associated with benign mesenchymal tumors. In this article, the authors describe a man with renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone associated with small cell carcinoma. Chemotherapy markedly reduced tumor burden and was associated with normalization of renal phosphate handling and serum sodium. With recurrence, renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone developed again, with the additional complication of hypercortisolism secondary to ectopic corticotropin production. The authors report the rare occurrence of renal phosphate wasting with small cell carcinoma (5 previously reported cases) and the unique co-existence of this paraneoplastic syndrome with the syndrome of inappropriate antidiuretic hormone and ectopic corticotropin production.

Adrenocorticotropic Hormone↗

PubMed1995

The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia. A randomized clinical trial.

BACKGROUND: Unintended hypothermia occurs frequently during surgery and may have adverse effects on the cardiovascular system. Although the mechanisms responsible for the cardiovascular manifestations of hypothermia are unclear, it is possible that they are sympathetically mediated. In this prospective study, relationships between body temperature, the neuroendocrine response, and hemodynamic changes in the perioperative period were examined. METHODS: Seventy-four elderly patients, undergoing abdominal, thoracic, or lower extremity vascular surgical procedures, were randomly assigned to either "routine care" (n = 37) or "forced-air warming" (n = 37) groups. Throughout the intraoperative and early postoperative periods, the routine care group received standard thermal care, and the forced-air warming group received forced-air skin-surface warming. Core temperature, forearm minus fingertip skin-surface temperature gradient, and plasma concentrations of epinephrine, norepinephrine, and cortisol were measured throughout the perioperative period, and the two groups were compared. In addition, heart rate and arterial blood pressure were compared between groups. RESULTS: The routine care and forced-air warming groups did not differ with regard to age, sex, type of surgical procedures, anesthetic techniques, or postoperative analgesia. Mean core temperature was lower in the routine care group on admission to the postanesthetic care unit (routine care, 35.3 +/- 0.1 degree C; forced-air warming, 36.7 +/- 0.1 degree C; P = 0.0001) and remained lower during the early postoperative period. Forearm minus fingertip skin-surface temperature gradient (an index of peripheral vasoconstriction) was greater in the routine care group in the early postoperative period. The mean norepinephrine concentration (pcg/ml) was greater in the routine care group immediately after surgery (480 +/- 70 vs. 330 +/- 30, P = 0.02) and at 60 min (530 +/- 50 vs. 340 +/- 30, P = 0.002) and 180 min (500 +/- 80 vs. 320 +/- 30, P = 0.004) postoperatively. Mean epinephrine concentrations were not significantly different between groups. Mean cortisol concentrations were increased in both groups during the early postoperative period (P < 0.01), but the differences between groups were not significant. Systolic, mean, and diastolic arterial blood pressures were significantly higher in the routine care group. CONCLUSIONS: Compared with patients in the forced-air warming group, patients receiving routine thermal care had lower core temperatures, a greater degree of peripheral vasoconstriction, higher norepinephrine concentrations, and higher arterial blood pressures in the early postoperative period. These findings suggest a possible mechanism for hypothermia-related cardiovascular morbidity in the perioperative period.

Aged↗

PubMed1995

Catecholamine and cortisol responses to lower extremity revascularization: correlation with outcome variables. Perioperative Ischemia Randomized Anesthesia Trial Study Group.

OBJECTIVE: To determine whether catecholamine and cortisol secretory responses to surgery contribute to postoperative complications. DESIGN: Prospective, randomized, case series. SETTING: A university hospital operating suite and surgical intensive care unit. PATIENTS: Sixty patients undergoing lower extremity vascular surgery. INTERVENTIONS: Patients were randomized to receive either epidural anesthesia/epidural opiate analgesia (regional anesthesia) or general anesthesia/intravenous patient-controlled analgesia (general anesthesia). MEASUREMENTS AND MAIN RESULTS: Anesthesia was managed according to a prospectively designed protocol. Hemodynamic parameters and plasma catecholamine concentrations were determined at specific intraoperative and postoperative time points. Intraoperative and postoperative urine samples were collected and analyzed for free cortisol concentrations. Outcomes evaluated were cardiac (nonfatal myocardial infarction and cardiac death) and surgical (graft occlusion). Mean arterial pressure during emergence from anesthesia and in the early postoperative period correlated positively with plasma norepinephrine concentration (p < .01). In addition, plasma catecholamine concentrations were higher in patients with postoperative hypertension. Plasma norepinephrine concentrations at the time of emergence from anesthesia and postoperatively were also higher in patients requiring repeat surgery for graft revision, thrombectomy, or amputation (p < .05). Multivariate analysis indicated that the norepinephrine concentration at the time of emergence, but not type of anesthesia, correlated with reoperation for graft occlusion, suggesting that the previously reported beneficial effect of regional anesthesia may be due to modulation of the stress response. Myocardial infarction or cardiac death occurred in three patients. These patients had markedly increased catecholamine concentrations. CONCLUSIONS: The catecholamine response to lower extremity vascular surgery contributes to the development of postoperative hypertension and may also be important in the development of thrombotic complications.

Adult↗

PubMed1995

O2 dependence of pregnenolone and aldosterone synthesis in mitochondria from bovine zona glomerulosa cells.

Hypoxia in vivo results in a decrease in aldosterone not accounted for by extra-adrenal controllers. We have demonstrated that aldosteronogenesis but not cortisol synthesis in the whole cell is O2 sensitive. In the intact glomerulosa cell, this sensitivity is located in the late pathway step catalyzed by conversion of corticosterone to aldosterone (P-450aldo), whereas the early pathway catalyzed by conversion of cholesterol to pregnenolone (P-450scc) is not inhibited until PO2 is very low. Because P-450aldo and P-450scc are mitochondrial enzymes that depend on the same NADPH-specific electron transport proteins, we hypothesized that O2 sensitivity would be independent of energy production and expressed in isolated mitochondria. We measured the conversion of exogenous 25(OH)-cholesterol to pregnenolone and of exogenous corticosterone to aldosterone in the presence of cyanoketone in mitochondria isolated from bovine zona glomerulosa cells and exposed to an experimental gas (1-100% O2) vs. a room air control. Pregnenolone production was not affected until PO2 was < 35 Torr and decreased to almost nil when PO2 was < 30 Torr. In contrast, aldosterone production increased under hyperoxia and decreased under moderate decreases in O2. The conversion of corticosterone to aldosterone was maintained at approximately 50% of control, even when PO2 was < 20 Torr. The sensitivity of the aldosterone pathway to changes in O2 within the physiological range appears to reside in the mitochondrial late pathway (i.e., P-450aldo) and is not significantly influenced by cytosolic regulators of steroidogenesis or by limitation of reducing equivalents.

Aldosterone↗

PubMed1995

Intraoperative measurement of adrenocorticotropin (ACTH) during removal of ACTH-secreting bronchial carcinoid tumors.

The optimal treatment for ectopic ACTH syndrome is the complete removal of the tumor secreting ACTH. These tumors are often occult, with their location suggested but not proven with imaging techniques. The intraoperative measurement of ACTH by immunoradiometric assay in five patients with the occult ectopic ACTH syndrome during removal of suspicious intrapulmonary lesions is reported. A significant ACTH gradient was detected in the pulmonary veins of the affected lobes in two patients. ACTH had decreased significantly in all five patients by 10 and 15 min after tumor removal. All five patients had histologically proven ACTH-secreting bronchial carcinoid tumors, suppressed plasma ACTH by 24 h after tumor removal, and subsequent secondary adrenal insufficiency indicating successful surgical therapy (five of five true-positive). In one patient, previous surgery was not curative and did not result in a decrease in intraoperative measurement of ACTH (one of one true-negative). It was demonstrated that a rapid ACTH immunochemiluminescence assay with a 15-min incubation time has sufficient sensitivity and precision to detect decreases in ACTH described above. These results demonstrate that complete removal of ACTH-secreting bronchial carcinoid tumors can be detected intraoperatively by a decrease in arterial ACTH by 15 min. The modification of the ACTH immunochemiluminescence assay to 15 min incubation allows the documentation of a successful tumor removal in the operating room. It may also be used to locate the tumor intraoperatively by selective pulmonary vein sampling. This protocol may be applicable to the intraoperative measurement of ACTH during pituitary microadenomectomy for Cushing's disease.

Adrenocorticotropic Hormone↗

PubMed1994

Adherence of group B streptococci to cultured epithelial cells: roles of environmental factors and bacterial surface components.

Group B streptococci (GBS) are the major cause of neonatal pneumonia, sepsis, and meningitis. Steps considered to be important in the pathogenesis of this infection include colonization of the rectum and vagina of the mother, aspiration of GBS into the fetal lung during or just prior to delivery, and invasion of GBS into pulmonary epithelial cells. We have previously demonstrated that GBS can invade pulmonary epithelial cells both in vivo and in vitro. Adherence of GBS to epithelial cells may play an important role in colonization of the rectum and vagina and constitute a first step in invasion of pulmonary epithelial cells. Because GBS can both adhere to and invade epithelial cells, we have developed two assays for GBS adherence which measure cell surface and not intracellular bacteria. Using these assays, we were able to demonstrate specific adherence of GBS to pulmonary epithelial cells. Adherence levels were similar at 4 and 37 degrees C and for log- and stationary-phase bacteria. Physiologic conditions vary considerably between the rectum, vagina, and lung, and a range of conditions was therefore tested. Adherence was enhanced in hypotonic solutions, while magnesium and calcium had no effect on adherence at physiologic concentrations. In comparison with adherence at neutral pH, adherence was increased 6- to 20-fold at pH 4, which is the normal vaginal pH. Neither capsular polysaccharide nor lipoteichoic acid was important for adherence in these assays. Treatment of GBS with trypsin decreased their adherence by more than 75%, indicating that surface proteins play an important role.

Bacterial Adhesion↗