Observations of apparent C-type particles in baboon (Papio cynocephalus) placentas.

Ultrastructural investigations have revealed the presence of apparent endogenously derived C-type particles in the placental villi of each of 13 baboons studied. Both budding and mature forms were observed in the syncytiotrophoblast of these animals at various stages of pregnancy.

Studies of the control of plasma aldosterone concentration in normal man. II. Effect of dietary potassium and acute potassium infusion.

The responses of plasma aldosterone, cortisol, and corticosterone to an infusion of 75 mEq of potassium chloride over 120 min were studied in 10 normal subjects. Five subjects were fed a 10 mEq and five a 200 mEq sodium diet, while all subjects ingested 40 mEq and 200 mEq potassium sequentially. Two potassium infusions were performed in each subject when in balance on a fixed sodium intake and low and then high potassium diets. Regardless of dietary intake, increases of serum potassium of 0.5-1.5 mEq/liter above preinfusion levels were usually associated with significant increments in plasma aldosterone concentration. Our data agree with previous evidence that the potassium ion stimulates the adrenal cortex directly to secrete aldosterone. Peripheral renin activity did not increase after the potassium infusion. Plasma cortisol and corticosterone levels generally followed the expected diurnal decline during the infusion, implying that ACTH secretion did not increase. The plasma aldosterone response to incremental changes in serum potassium was linear on each of the four diets. The slopes of these linear relationships increased significantly when the potassium intake was increased from 40 to 200 mEq. No increase in slope occurred on either potassium intake when dietary sodium was restricted from 200 to 10 mEq. Thus, identical increases in serum potassium were associated with greater increments in plasma aldosterone above preinfusion levels on either sodium intake when the 200 mEq potassium diet was compared with the 40 mEq potassium intake.

Insulin, prostaglandins, and the pathogenesis of hypertension.

Hypertension is associated with hyperinsulinemia in the presence or absence of obesity or glucose intolerance. Physiological concentrations of insulin decrease the catecholamine-induced production of prostaglandin I2 (PGI2; prostacyclin) and PGE2, two potent vasodilators, in adipose tissue, one of the largest organs in the body. This finding suggests that hyperinsulinemia increases peripheral vascular resistance and blood pressure by inhibiting the stimulatory effect of adrenergic agonists (and perhaps other agonists) on the production of PGI2 and PGE2 in adipose tissue (and perhaps other tissues). This concept is supported by evidence that PGI2 and PGE2 modulate vascular reactivity in states of health and disease. For example, during insulin deficiency, i.e., in diabetic ketoacidosis, PGI2 and PGE2 production by adipose tissue are increased, and peripheral vascular resistance and blood pressure are decreased. This hypothesis is also supported by evidence that blood flow through rat and human adipose tissue is decreased in obesity and that insulin decreases the blood flow through adipose tissue in nonobese rats. Thus, insulin may regulate PGI2 and PGE2 production by adipose tissue (and possibly other tissues) through a wide range of concentrations with important physiological and clinical consequences.

Omega-3 fatty acids in diabetes mellitus. Gift from the sea?

The potential role of omega-3 fatty acids in the prevention of atherosclerotic disease in the nondiabetic population currently engenders interest, enthusiasm, and controversy. Some apparently beneficial effects of omega-3 fatty acids on platelet function, eicosanoid formation, plasma triglyceride levels, and blood pressure have been described in patients with diabetes mellitus. However, enthusiasm for the use of omega-3 fatty acids in diabetes has been dampened by reports of potentially deleterious effects of these agents, including increased plasma glucose, glycosylated hemoglobin, plasma total cholesterol and LDL cholesterol, and serum apolipoprotein B levels. These adverse effects have been achieved with large, perhaps excessive, doses of omega-3 fatty acids, in the range of 4-10 g/day. The magnitude of these adverse effects has been small (typically 10-36%). It cannot be assumed that the effects of omega-3 fatty acids are the same in patients with diabetes mellitus as in nondiabetic subjects or patients with primary hyperlipidemia. First, the biosynthesis and composition of fatty acids is abnormal in diabetic animals and possibly in diabetic patients. Second, many potential mechanisms implicated in the pathogenesis of atherosclerosis are present in diabetic but not necessarily in nondiabetic subjects. Third, the mechanisms of many of the risk factors in diabetic patients differ from the mechanisms of these abnormalities in nondiabetic subjects, reflecting the effects of insulin deficiency, hyperglycemia, and their sequelae. Finally, because diabetes is a heterogeneous group of diseases, the effects of omega-3 fatty acids must be addressed separately for patients with insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, and possibly other forms of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin production by isolated adipocytes.

Isolated rat adipocytes produce prostacyclin (PGI2) in relatively large quantities during norepinephrine (NE)-induced lipolysis. The endogenous NE-induced production rate of PGI2, calculated from the NE-induced production rate of PGI2 observed in our studies (2.2 ng/10(6) cells/2 h) and from the number of fat cells in the normal organism, is 1.46 ng/kg/min for rats, 4.46 ng/kg/min for men, and 11.86 ng/kg/min for women. These rates are comparable to the exogenous PGI2 infusion rate that alters platelet aggregation and blood pressure in rats and humans. Exogenous PGI2 failed to modify the rate of NE-induced lipolysis. Inhibition of endogenous PGI2 production by indomethacin had no effect on the rate of NE-induced lipolysis when either a maximal or submaximal lipolytic concentration of NE was used. PGI2 [rather than prostaglandin (PG) E2] may be the substance that accounts for the functional vasodilatation that accompanies hormone-induced lipolysis. PGI2 is produced in large quantities than PGE2 during NE-induced lipolysis and is a more potent vasodilator than PGE2. Its instability can account for the inability of previous investigators to detect a vasodilator substance in the venous effluent of adipose tissue. The production of PGI2 by adipocytes may be an important modulator of the regulation of vascular tone and platelet aggregation by catecholamines in the vascular bed of adipose tissue and perhaps other tissues. PGI2 produced by adipocytes, by virtue of its ability to cause vasodilatation and inhibit platelet aggregation, may contribute to the maintenance of luminal patency in the vascular bed of adipose tissue and possibly other tissue as well.

Cooperation of adipocytes and endothelial cells required for catecholamine stimulation of PGI2 production by rat adipose tissue.

Disturbances of prostaglandin I2 (PGI2, prostacyclin) production by adipose tissue contribute to the pathogenesis of diabetic ketoacidosis and may contribute to the pathogenesis of hypertension and vascular disease. We studied the cellular basis of PGI2 production in adipose tissue, measured as release of 6-keto-PGF1 alpha in response to epinephrine. Adipocytes did not produce PGI2 when nonfat cells were removed by repeated washing. The nonadipocyte cellular constituents of adipose tissue (nonfat cells) did not produce PGI2 in the absence of adipocytes. Both adipocytes and nonfat cells were required for PGI2 production in response to epinephrine. Adipocytes pretreated with 0.2 mM aspirin to inhibit PGH synthase nevertheless promoted PGI2 production when mixed with nonfat cells. Nonfat cells preincubated with aspirin did not produce PGI2 when mixed with adipocytes. The nonfat cells converted arachidonic acid to PGI2 but adipocytes did not. Epinephrine stimulated lipolysis and PGI2 production in a dose-dependent parallel manner, but the responses were distinct above 10(-6) M. Characterization of the nonfat cells by fractionation on a Percoll density gradient followed by measurement of angiotensin-converting enzyme activity and 6-keto-PGF1 alpha production indicated that the nonfat cells were predominantly vascular endothelial cells. We conclude that catecholamine-stimulated PGI2 production in adipose tissue results from the cooperation of adipocytes and vascular endothelial cells. The adipocytes provide arachidonic acid, which is converted to PGI2 by the vascular endothelial cells. Because adipose tissue is located near blood vessels throughout the body, adipocytes may be an important source of arachidonic acid for vascular endothelial cells in various circumstances in health and disease. Our findings raise the possibility that adipocytes may, under some circumstances, release arachidonic acid into the systemic circulation where it is used by vascular endothelial cells throughout the body to produce PGI2 and other eicosanoids.

Coordinate control of lipolysis by prostaglandin E2 and prostacyclin in rat adipose tissue.

PGE2 is a potent antilipolytic agent produced by adipose tissue, but its role as a physiological regulator of triglyceride lipolysis is controversial because inhibitors of prostaglandin synthesis have not enhanced hormone-stimulated lipolysis in adipose tissue consistently. Adipose tissue also produces PGI2, but this eicosanoid has not had a demonstrated effect on lipolysis under physiological conditions previously. We investigated both PGE2 and PGI2 production and their effects on lipolysis in rat adipose tissue. We found that 1) EPI-stimulated PGE2 production (like PGI2 production) requires the cooperation of adipocytes and endothelial cells, 2) adipose tissue produces PGE2 and PGI2 at comparable rates, 3) indomethacin inhibits EPI-induced PGE2 and PGI2 production and has no effect on EPI-stimulated lipolysis when added to a mixture of adipocytes and endothelial cells or to intact epididymal fat pads, 4) PGI2 is a potent lipolytic agent when added to isolated adipocytes in the absence of endothelial cells under physiological conditions, 5) the magnitudes and the ED50s of the antilipolytic effect of PGE2 and the lipolytic effect of PGI2 in isolated adipocytes in the absence of endothelial cells are comparable, 6) PGI2 antagonizes the antilipolytic effect of PGE2 in isolated adipocytes in the absence of endothelial cells in a dosage-related manner, and 7) the antilipolytic effect of added PGE2 in isolated adipocytes is greater in the absence of endothelial cells than in their presence, suggesting that endogenous eicosanoid production reduces the effectiveness of added PGE2. These studies demonstrate that catecholamine-induced lipolysis is under the coordinate control of PGE2, a potent antilipolytic agent, and PGI2, a potent lipolytic agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma level of 13,14-dihydro-15-keto-PGE2 in patients with diabetic ketoacidosis and in normal fasting subjects.

Plasma levels of 13,14-dihydro-15-keto-PGE2, a stable derivative of PGE2, are elevated in rats with diabetic ketoacidosis (DKA) and decrease in response to insulin therapy. In patients with insulin-dependent diabetes mellitus type I (IDDM) the plasma levels of this derivative also rise in response to insulin withdrawal and then fall in response to insulin replacement. We wished to determine whether the level of this substance is elevated acutely when patients present with DKA and to determine whether the levels fall during treatment. We also wished to identify the origin of the circulating 13,14-dihydro-15-keto-PGE2 in patients with DKA and in normal fasting subjects. We measured the plasma level of 13,14-dihydro-15-keto-PGE2 in five patients with DKA and in six normal subjects during a 24-h fast. In the patients with DKA before treatment, the plasma 13,14-dihydro-15-keto-PGE2 level was threefold above normal. During therapy, the 13,14-dihydro-15-keto-PGE2 level fell toward normal. There was a significant direct correlation between the plasma free fatty acid (FFA) level and the plasma 13,14-dihydro-15-keto-PGE2 level before and during treatment. In addition, the inverse correlation between the plasma free-insulin level and the plasma 13,14-dihydro-15-keto-PGE2 level approached significance (P = .06). In contrast, in the normal fasting subjects the plasma FFA level rose to values comparable to those observed in the patients with DKA, but there was no significant increase in the plasma 13,14-dihydro-15-keto-PGE2 level.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin and pathogenesis of hemodynamic abnormalities of diabetic ketoacidosis in rats.

The pathogenesis of the hemodynamic abnormalities of diabetic ketoacidosis (DKA) is not well understood. Previous studies suggest that prostacyclin (PGI2) production by adipose tissue is increased in DKA. We investigated the role of PGI2 in the pathogenesis of the reduced vascular resistance in DKA. Rats with streptozocin-induced DKA were anesthetized with pentobarbital sodium, and flow was measured with an electromagnetic probe on the infradiaphragmatic aorta. The plasma level of 6-keto-PGF1 alpha (stable derivative of PGI2) was higher (mean +/- SE 0.91 +/- 0.05 ng/ml) and vascular resistance lower (4.9 +/- 0.2 mmHg.ml-1.min-1.100 g-1 [resistance units, RU]) in 67 rats with DKA than in 21 normal rats (0.34 +/- 0.03 ng/ml, P less than .01, and 9.0 +/- 0.7 RU, P less than .01, respectively). Inhibition of cyclooxygenase activity with either indomethacin or meclofenamic acid reduced the plasma 6-keto-PGF1 alpha level but failed to raise vascular resistance. Infusions of PGI2 in rats with DKA demonstrated that the vasculature was responsive to PGI2. Inhibition of cyclooxygenase activity not only reduced PGI2 production but also suppressed renin release. When the effects of the renin-angiotensin system were excluded by bilateral nephrectomy, indomethacin caused a significant increase (P less than .05) in vascular resistance. Thus, the failure of cyclooxygenase inhibitors to raise vascular resistance in DKA was a result of concurrent suppression of vasodilator (PGI2) and vasoconstrictor (renin-angiotensin system) mechanisms that are activated in DKA. Insulin administration increased vascular resistance (P less than .01) and decreased the level of plasma 6-keto-PGF1 alpha (P less than .01). Combined administration of PGI2 and insulin did not alter vascular resistance, suggesting that the increase in vascular resistance with insulin was predominantly due to the reduction of circulating PGI2. Thus, vascular resistance is decreased in DKA primarily as a result of the vasodilator effects of PGI2 produced by adipose tissue. The activation of the renin-angiotensin system represents a partial compensation. The increase in PGI2 production may contribute to the hypotension and mortality of DKA.

Treatment of severe lactic acidosis with dichloroacetate.

Four patients with severe lactic acidosis associated with septic shock were treated with sodium dichloroacetate (DCA) (50 mg/kg body wt), an activator of pyruvate dehydrogenase. All patients were in a group with an expected mortality rate of 90-100%, based on previous studies. In one patient, treatment with DCA was associated with a decrease in blood lactate levels from 11.2 mM before treatment to 0.8 mM 16 h later. Markedly elevated blood pyruvate and alanine levels also decreased to normal. After treatment, the arterial blood pH rose to 7.53, and vasopressor agents were no longer needed to support blood pressure. Some degree of biochemical improvement was also noted in the other cases in whom the blood lactate levels before treatment were 15, 17, and 31 mM. However, all three patients eventually died of refractory acidosis.

Nesidioblastosis associated with insulin-mediated hypoglycemia in an adult.

Nesidioblastosis, the process of differentiation of pancreatic islets from ductular epithelium, is a well-described cause of insulin-mediated hypoglycemia in neonates and infants, but not in adults. A 58-yr-old woman with characteristic clinical features of fasting hypoglycemia had inappropriately elevated plasma immunoreactive insulin levels during symptomatic episodes of fasting hypoglycemia. Angiography, palpation at laparotomy, and resection of the distal three-quarters of the pancreas provided no evidence of a tumor. Pathologic examination of the resected pancreas revealed the findings of nesidioblastosis, i.e., budding of islets from the wall of ductules, and also increased number and size of islets and abnormal shape and location of islets. An entire spectrum of islet cell abnormalities including nesidioblastosis can cause insulin-mediated hypoglycemia in adults, as it does in neonates and infants.

Effects of a small quantity of omega-3 fatty acids on cardiovascular risk factors in NIDDM. A randomized, prospective, double-blind, controlled study.

OBJECTIVE: To study the effects of a low dose of omega-3 fatty acids on platelet function and other cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: We performed a randomized, prospective, double-blind, controlled study of a low dose of omega-3 fatty acids (2.5 g/day) in 20 ambulatory subjects with NIDDM. Subjects ingested five 1-g fish oil capsules each containing 0.5 g omega-3 fatty acids or five 1-g safflower oil capsules per day for 6 weeks followed by a 6-week washout period. RESULTS: Nine subjects completed the study in each group. Both groups exhibited moderate control of glucose levels; modest elevations in baseline total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels; and normal blood pressure values. In the fish oil group, plasma omega-3 fatty acid levels increased significantly. Fish oil significantly reduced the slope of the dose-response curves for collagen-induced platelet aggregation to one-third the value observed with safflower oil. No difference was observed in collagen-induced production of thromboxane A2 (TXA2, measured as the stable derivative TXB2), or in adenosine-5'-diphosphate- (ADP) induced platelet aggregation or TXA2 generation. Patients with high initial collagen-induced platelet TXA2 production showed a significantly larger drop after fish oil than safflower oil. Fish oil significantly reduced TG levels by 44 mg/dl and decreased upright systolic blood pressure (sBP) by 8 mmHg compared with safflower oil. Fish oil caused a significant but small increase in HbA1c (0.56%) and total cholesterol (20 mg/dl) but had no effect on fasting glucose, high-density lipoprotein cholesterol, or LDL-cholesterol levels. CONCLUSIONS: Small doses of fish oil inhibit platelet aggregation and TXA2 production, reduce upright sBP and TG levels, and have only a small effect on glucose and cholesterol levels in patients with moderately controlled NIDDM. Small quantities of omega-3 fatty acids or dietary fish are safe and potentially beneficial in NIDDM patients.

Stimulation of prostacyclin production in isolated rat adipocytes by angiotensin II, vasopressin, and bradykinin: evidence for two separate mechanisms of prostaglandin synthesis.

We compared the effects of three vasoactive peptides (angiotensin II, vasopressin, and bradykinin) and norepinephrine on the production of prostaglandin I2 [prostacyclin (PGI2)] and PGE2 by isolated rat adipocytes. Angiotensin II, vasopressin, and bradykinin stimulated PGI2 production but had minimal or no effect on PGE2 production or triglyceride lipolysis in isolated rat adipocytes, while norepinephrine stimulated PGI2 production, PGE2 production, and triglyceride lipolysis. The arachidonic acid that serves as substrate for PGI2 production in adipocytes in response to the vasoactive peptides appears to be derived from the cellular phospholipids rather than the triglycerides in these triglyceride-laden cells. The adipocyte contains two separate mechanisms for PG production: 1) a catecholamine-stimulated mechanism for the production of PGI2 and PGE2 that is activated concomitantly with triglyceride lipolysis, and 2) a mechanism activated by vasoactive peptides for the stimulation of PGI2 production independent of triglyceride lipolysis and PGE2 production. These mechanisms may have distinct functions.

Prostacyclin production by isolated rat adipocytes: evidence for cyclic adenosine 3',5'-monophosphate-dependent and independent mechanisms and for a selective effect of insulin.

The rat adipocyte contains two separate mechanisms for prostaglandin (PG) production. Norepinephrine stimulates prostacyclin (PGI2) and PGE2 production and triglyceride lipolysis in isolated rat adipocytes. In contrast, the vasoactive peptides angiotensin II, vasopressin, and bradykinin stimulate PGI2 production, but not PGE2 production or triglyceride lipolysis, in these cells. In this study, we characterized the two separate mechanisms of PG production with respect to the time course, the role of cAMP, the identity of the adrenergic receptor, and the effects of insulin and glucocorticoids. Angiotensin II stimulated PGI2 production rapidly (at 5 min) and independently of cAMP. beta-Adrenergic stimulation with isoproterenol produced a rapid 11-fold increase in the cAMP concentration and stimulated PGI2 production more slowly (at 120 min). The phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (0.2 and 0.5 mM) and the adenylate cyclase activator forskolin (10 microM) also stimulated cAMP production rapidly and PGI2 production more slowly. 1-Methyl-3-isobutylxanthine (5.0 mM) further stimulated cAMP levels, but prevented the increase in PGI2 production and blunted the increase in glycerol release seen at lower concentrations. beta-Adrenergic blockade with propranolol or timolol completely inhibited the norepinephrine- or isoproterenol-stimulated production of PGI2 and triglyceride lipolysis, respectively. Insulin selectively inhibited isoproterenol-stimulated PGI2 production and triglyceride lipolysis at physiological concentrations, but had no effect on angiotensin II-stimulated PGI2 production. In contrast, dexamethasone inhibited PGI2 production induced by both isoproterenol and angiotensin II. We conclude that: angiotensin II stimulates PGI2 production rapidly and independently of cAMP, but isoproterenol stimulates PGI2 production more slowly, an effect that is cAMP dependent; insulin inhibits the cAMP-dependent beta-adrenergic stimulation of PGI2 production (and triglyceride lipolysis), but not the cAMP-independent angiotensin II-induced stimulation of PGI2 production (this suggests that the former effect is mediated by a decrease in cAMP levels in the adipocyte); and dexamethasone inhibits both mechanisms of PGI2 production. Both mechanisms of PGI2 production by rat adipocytes are exquisitely sensitive to hormonal regulation.

Congenital goiter and the development of metastatic follicular carcinoma with evidence for a leak of nonhormonal iodide: clinical, pathological, kinetic, and biochemical studies and a review of the literature.

We report a large kindred of patients with congenital goiter, followed for 15 yr, in which two siblings (one male and one female) developed metastatic follicular thyroid carcinoma. These two patients were evaluated by iodine kinetic analysis. None of the classical defects of T4 biosynthesis was present in either patient. Rather, both patients had extremely rapid rates of iodine turnover, with elevated 131I uptake and excessive spillage of iodide in the urine. Serum iodoalbumin was present, probably as a nonspecific result of glandular hyperplasia. Iodine kinetic analysis after the ingestion of potassium perchlorate and methimazole was compatible with a leak of nonhormonal iodide from the thyroid. It is not possible to determine whether this iodide leak is the primary pathogenetic defect or is secondary to another unidentified abnormality. The unprecedented development of metastatic thyroid cancer in patients with congenital goiter occurred, in both instances years after subtotal thyroidectomy without thyroid hormone replacement therapy, suggesting a role for TSH in the genesis of human thyroid cancer. On the basis of our study of these patients and a review of the literature, we conclude that TSH is likely to be a factor in the induction of human follicular thyroid carcinoma.

Increased insulin-like growth factor II production and consequent suppression of growth hormone secretion: a dual mechanism for tumor-induced hypoglycemia.

We investigated the pathophysiology of fasting hypoglycemia associated with large tumors of mesenchymal origin. We studied two patients with symptomatic fasting hypoglycemia (plasma glucose, 1.92 and 2.03 mmol/L) and a large mesenchymal neoplasm. Before therapy, the plasma insulin-like growth factor II (IGF-II) level measured by RIA was elevated (1879 and 1084 micrograms/L; normal range, 358-854 micrograms/L), the serum GH response to hypoglycemia was impaired, and the plasma IGF-I level was low in both patients. After treatment of the tumor, all of these abnormalities resolved in both patients. Northern blot analysis of tumor RNA revealed extremely high levels of IGF-II mRNA (greater than 100-fold higher than those in normal adult liver). Tumor fragments released IGF-II into tissue culture medium (2.1 and 7.2 micrograms IGF-II/g tissue.24 h). These findings indicate that secretion of IGF-II into the circulation by the tumor was the likely source of the elevated plasma IGF-II levels. We suggest that the primary event in tumor-induced hypoglycemia is overproduction of IGF-II by the tumor, which gives rise to hypoglycemia by a dual mechanism: increased glucose utilization mediated by the insulin-like actions of IGF-II and inhibition of GH secretion.

Effect of carbohydrate supplementation on reproductive hormones during fasting in men.

We previously demonstrated that during a 10-day fast in mildly obese men, urinary gonadotropin excretion significantly increased, and serum testosterone concentrations significantly decreased. The mechanisms by which these changes occur are unknown. We postulated that the mechanism of the gonadotropinuria might involve decreased proximal renal tubular reabsorption of gonadotropins during fasting and might be related to renal tubular reabsorption of ketones during fasting, a process that is enhanced by carbohydrate (CHO) administration. We studied the effects of CHO supplementation on ketosis, ketonuria, and reproductive hormone secretion and excretion in 14 mildly obese men, 24-54 yr old, who were 14-69% above ideal body weight. Group I (n = 6) received no CHO supplementation, group II (n = 4) received 15 g CHO, and group III (n = 4) received 45 g CHO daily during the 10-day fast (F). During the control (C) and refeeding (R) periods, all subjects received a 1500-cal diet. Daily 24-h urine collections were made for the measurement of total ketones (millimolar concentrations) and LH and FSH (expressed as international units of the Second International Reference Preparation of human menopausal gonadotropin). Values (mean +/- SE) for 3 representative days (control day 3, fasting day 8, and refeeding day 3) for all subjects are shown below: (table; see text) We also studied the effects of CHO supplementation on serum levels of pituitary gonadotropins, LH and FSH responses to exogenous LHRH stimulation, biological activity of LH, and circulating total and free testosterone levels. Neither dose of CHO prevented the decline in total and free testosterone levels. Serum LH concentrations, as measured by both the RIA and in vitro bioassay did not change significantly with fasting. Serum FSH concentrations in daily samples did not change significantly. The previously reported decline in the FSH response to LHRH stimulation with fasting was not prevented by CHO. We conclude that CHO supplementation prevents the gonadotropinuria of fasting in men. The effect appears to occur in the kidney. The mechanisms may be related to that by which CHO promotes the renal tubular reabsorption of ketones. The reduced serum testosterone level cannot be explained by a lack of biologically active LH. It appears that fasting has a direct effect on the testis, possibly by reducing its responsiveness to gonadotropic stimulation or by inhibiting steroidogenesis.

Glucocorticoid therapy.

1. There is a poor relationship between the circulating half-life a glucocorticoid and either its potency or its duration of action. Many actions of a glucocorticoid have unequal durations. The duration of action varies with the dose. 2. The presence of biological activity as a glucocorticoid depends on the presence of a hydroxyl group at carbon number 11. Cortisone and prednisone, which are 11-keto compounds, must be converted to 11-beta-hydroxyl compounds to be effective. This reaction may be impaired in the presence of liver disease. 3. Iatrogenic Cushing's syndrome differs from spontaneous Cushing's syndrome in several respects, possibly because in the former ACTH is suppressed but in Cushing's syndrome associated with bilateral adrenal hyperplasia ACTH levels are elevated...

Invasive external otitis. Report of 21 cases and review of the literature.

We report 21 cases of invasive external otitis and review 130 cases from the English literature. Invasive external otitis is the term that most appropriately describes the locally invasive Pseudomonas infections that begins in the external ear canal, breaches the epithelial barrier and results in signs of local subcutaneous tissue invasion. Nineteen patients were diabetic. FIfteen of these 19 had preexistent, long-standing diabetes (average 15.8 years) and 10 had microvascular disease. Studies of the skin of the temporal bone in two patients provided evidence of diabetic microangiopathy of the dermal capillaries. Pseudomonas aeruginosa was isolated from the involved area in all cases. All patients without neurologic deficits survived, compared with six of nine with deficits of the central nervous system. All 13 patients in whom initial therapy was successful received a combination of an aminoglycoside and a semisynthetic penicillin, whereas all six episodes of recurrent disease occurred when only one antibiotic was used. The overall mortality was 15 percent (three of 20 in whom the long-term outcome is known). We propose that diabetic microangiopathy of the skin of the temporal bone results in poor local perfusion and creates an environment well suited for invasion by Pseudomonas aeruginosa. There is a good correlation between the extent of disease clinically and prognosis. Effective treatment requires early diagnosis and combination therapy with an aminoglycoside and a semisynthetic penicillin.

Plasma eicosanoid levels in rats with nonketotic diabetes mellitus: effect of severity.

Nonketotic diabetes mellitus (DM) is associated with increased platelet production of thromboxane (TX) A2 and decreased endothelial production of prostacyclin (prostaglandin [PG]I2), but measurements of stable derivatives of these substances in the circulation have yielded discordant results. We studied the relationship between the severity of nonketotic DM and the plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha, and TXB2 (stable derivatives of PGE2, PGI2, and TXA2, respectively) in rats, using three commonly employed doses of streptozotocin (40, 50, and 60 mg/kg body weight) to induce nonketotic DM of varying severity. Small differences in the severity of DM were associated with considerable differences in the plasma levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1 alpha but not TXB2. Each eicosanoid responded differently to variations in the severity of DM. The plasma 13,14-dihydro-15-keto-PGE2 level was significantly lower than normal in the rats given 40 mg/kg streptozotocin, was unchanged from normal in the rats given 50 mg/kg and was significantly higher than normal in the rats given 60 mg/kg. The plasma 6-keto-PGF1 alpha level was significantly increased in rats given 40 mg/kg and 60 mg/kg, but was unchanged in those given 50 mg/kg. The plasma TXB2 level was not significantly different from normal in any one of the three groups of rats with nonketotic DM. The effect of severity on the plasma levels of the PGE2 and PGI2 derivatives is unexplained, but may reflect the origin of these derivatives from diverse organs and tissues, and the differing effects of abnormal metabolic factors (eg, fatty acids, glucose, insulin, pH) on the synthesis of these derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)