Elevated leg systolic pressures and arterial calcification in diabetic occlusive vascular disease.

Systolic occlusion leg and brachial pressures were determined using a Doppler ultrasonic method in 24 diabetic subjects with either past or evolving gangrene due to arterial occlusive disease of the lower extremities. The leg-brachial ratios were correlated with x-ray determined leg vascular calcification. Ratios above 1.10 were invariably associated with heavy continuous calcification of the tibial vessels; lesser degrees of arterial calcification had normal or depressed leg-brachial ratios. Medial calcification might be causally related to the abnormally elevated leg systolic pressures not infrequently noted in diabetic patients. Based on the observed occurrence of reamputation in association with normal or elevated leg-brachial ratios, it appears that a Doppler pressure index above 0.90 is not a reliable indicator of adequate blood flow in severe diabetic occlusive arterial disease.

Acquired partial corticosterone methyl oxidase type II defect in diabetes mellitus. Case of hyperreninemic hypoaldosteronism.

The aim of this study was to investigate the pathogenesis of hypoaldosteronism in diabetes. Endogenous elevation of plasma renin activity and exogenous corticotropin were used to study steroidogenesis. Observations were made over 12 yr on the evolution and treatment of hyperkalemia in a diabetic subject. In 1977, potassium, baseline cortisol, aldosterone, and renin activity were normal; renin activity increased normally with posture; and cortisol responded normally to ACTH infusion. Nine yr later, persistent hyperkalemia was documented. Upright renin activity was elevated to 5.26 ng.L-1.s-1, with concomitant elevation of 18-hydroxycorticosterone (18-OHB) and a low-normal aldosterone level. One hour after administration of 0.25 mg i.m. cosyntropin, cortisol increased normally, aldosterone increased from 220 to 360 pM, and 18-OHB increased from 3700 to 4800 pM. During treatment with fludrocortisone, fludrocortisone with furosemide, and furosemide alone, improvement of hyperkalemia was noted. Endogenous hyperreninemia and basal elevations of 18-OHB, accompanied by limited aldosterone responsiveness to renin and ACTH, suggest the presence of a partial corticosterone methyl oxidase type II defect. Evolution of hyperkalemia between 1977 and 1986 suggests this defect was acquired.

Alendronate administration and skeletal response during chronic alcohol intake in the adolescent male rat.

Alendronate is an aminobisphosphonate that inhibits bone resorption in osteoporotic humans and rats but does not induce osteomalacia. Several bisphosphonates, including alendronate, also have direct positive actions on osteoblasts, bone formation, and mineralization. We studied the effects of alendronate on skeletal development in adolescent male rats during chronic alcohol intake. Four groups of age- and weight-matched male Sprague-Dawley rats (35 days of age) were fed the Lieber-DeCarli diet containing 36% of calories as EtOH (E), the EtOH diet plus 60 mg/kg alendronate (EA) every other day intraperitoneally (ip), an isocaloric diet (I), or the isocaloric diet plus 60 mg/kg alendronate (IA) every other day ip. Body weight, femur length, serum levels of osteocalcin (OC), insulin-like growth factor 1 (IGF-1), testosterone, and luteinizing hormone (LH); femur distal metaphyseal and middiaphyseal bone mineral density (BMD) and tibial metaphyseal gene expression for alpha-1-type I collagen (Col I), OC, and bone alkaline phosphatase (AP); and femur strength by four-point bending to failure were measured after 28 days of feeding and alendronate injections. Serum alcohol levels at death were 156 +/- 13 mg/dl (E) and 203 +/- 40 mg/dl (EA). Alendronate given to alcohol-fed rats increased metaphyseal BMD by more than 3-fold over rats fed alcohol alone. Alendronate given to isocaloric pair-fed rats increased metaphyseal BMD by more than 2.5-fold over rats fed the isocaloric diet alone. Cortical BMD was reduced by alcohol but was increased by alendronate. Alcohol consumption reduced serum IGF-1 levels, and alendronate increased IGF-1 levels in alcohol-fed rats. Serum OC, testosterone, and LH were unaffected by alcohol and alendronate. Quantitative dot blot hybridization using rat complementary DNA (cDNA) probes and normalization against 18S subunit ribosomal RNA (rRNA) levels revealed no changes in tibial metaphyseal gene expression for type I collagen, osteocalcin, or alkaline phosphatase. Alcohol significantly reduced the biomechanical properties of the femurs that were partially compensated by alendronate. Chronic alcohol consumption uncouples formation from ongoing resorption, and resorption is inhibited by alendronate. However, alendronate's positive effects on osteoblast-mediated mineralization during chronic alcohol consumption point to the potential use of bisphosphonates in the treatment of decreased bone formation secondary to alcohol-induced diminished osteoblast function.

Rat spleen lymphocytes contain an immunoactive and bioactive luteinizing hormone-releasing hormone.

An interaction between the immune and endocrine systems has been long known. This association is further strengthened by the finding that splenic lymphocytes have the capacity to produce molecules similar to if not the same as classical hormones, including several members of the opiate family, PRL, GH, and neuropeptide Y. Because of such findings and because of information from other laboratories suggesting that LHRH might have direct effects upon the immune system, we hypothesized that immune cells themselves might contain LHRH. Lymphocytes were purified from spleens of intact adult male Sprague-Dawley rats and the cells were lysed with sodium hydroxide. The concentration of immunoreactive LHRH was 403 +/- 184 pg/20 X 10(6) lymphocytes. Increasing amounts of lymphocyte lysate displaced [125-I]LHRH from LHRH antibody in a manner parallel to that produced by synthetic hypothalamic LHRH, suggesting immunologic similarity between lymphocyte and hypothalamic LHRH. Lymphocyte LHRH-like immunoactivity coeluted from Nova-Pak C18 columns with synthetic hypothalamic LHRH. When lymphocyte lysates were applied to rat anterior pituitary cells in monolayer culture, significant stimulation of LHRH secretion was seen, from 2,144 +/- 54 pg LH/ml.4 h to 15,364 +/- 587 pg LH/ml.4 h (P less than 0.001), a finding verified in five additional experiments. In other studies, this LH response evoked by lymphocyte lysates was found to be dose dependent and could be significantly inhibited by an LHRH-antagonist. Furthermore, when lymphocyte lysate and identically treated synthetic LHRH were HPLC fractionated, there was coelution of lysate and hypothalamic LHRH bioactivity. The lysate itself contained no substantial LH immunoreactivity. Thus, lymphocytes from spleens of adult male rats contain an immunoactive and bioactive LHRH, a finding further strengthening an association between the endocrine and immune systems.

The effect of "binge" ethanol exposure on growth hormone and prolactin gene expression and secretion.

The effects of ethanol (EtOH) on GH and PRL have been previously explored, and a dicotomy in results noted. While serum GH levels appear to fall after EtOH exposure, PRL levels rise. We have attempted to expand these studies by examining the impact of acute or "binge" EtOH in vivo on GH and PRL synthesis and secretion. At 0.5, 1.5, and 3.0 h after one dose of ip EtOH, serum GH levels fell significantly compared with those seen in saline-injected controls. This correlated with a fall in GH mRNA levels, but no change in pituitary GH content. Conversely, serum PRL levels rose significantly, while the mRNA for PRL decreased by approximately 20%. There was no change in pituitary PRL content. Interestingly, the mRNA for pit-1 (GHF-1), a transcription factor important to both GH and PRL gene expression, was unchanged at any time point. Despite the fall in GH and PRL mRNA levels, the pituitary cAMP content was markedly elevated at 0.5 h, with no change at any other time point. In summary, acute EtOH exposure in vivo appears to dampen both GH and PRL synthesis, while serum levels behave dissimilarily. Possible explanations for these findings are discussed.

Basilar artery aneurysm simulating pheochromocytoma.

Stimulation of sympathetic vasomotor centers by lesions in the posterior fossa has been described in humans and animals. We describe a patient with a pheochromocytoma-like syndrome and a basilar artery aneurysm. Repair of the aneurysm was followed by disappearance of hypertensive episodes. Posterior fossa lesions must be considered in patients with hypertensive crises when diagnostic procedures do not indicate an adrenal or extra-adrenal pheochromocytoma.

Graded sucrose/carbohydrate diets in overtly hypertriglyceridemic diabetic patients.

Overtly hypertriglyceridemic patients with non-insulin-dependent diabetes mellitus were given a control diet containing 120 g of sucrose and 50 percent carbohydrate, and later randomly assigned to receive isocaloric high- (220 g), intermediate- (120 g), or low- (less than 3 g) sucrose/carbohydrate diets for four weeks. The low-sucrose diet group demonstrated a modest but significant decrease in mean fasting serum glucose level in the first week only, although this change was no different from the other two dietary groups and was not sustained. All groups had little change in late postprandial serum glucose levels from control values, and no significant alterations in 24-hour glycosuria. The high-sucrose diet group demonstrated a significant increase in fasting serum triglyceride levels by the second week of the study, whereas the intermediate- and low-sucrose diet groups showed a decrease in mean fasting triglyceride levels. In contrast, the low-sucrose diet group's late postprandial serum triglyceride levels increased by the fourth week, whereas levels fell in the high-sucrose diet group. Mean fasting serum cholesterol concentrations decreased from control values in the high-sucrose diet group. Thus, although very high sucrose and carbohydrate consumption is clearly deleterious to fasting tryglyceride levels in non-insulin-dependent diabetes mellitus with preexisting hypertriglyceridemia, it appears that low dietary sucrose and carbohydrate proportions do not further improve preprandial glycemia and glycosuria and may adversely affect late postprandial serum triglyceride concentration. This study suggests that isocaloric sucrose and carbohydrate restriction below usual daily levels (120 g per day) offers no consistent benefit in glycemia or lipid control in overt type II diabetes.

In-vivo effect of ethanol on release of LH-releasing hormone and LH in rats.

The effect of exposure to ethanol on hypothalamic LH-releasing hormone (LHRH) release in vivo was investigated in rats both acutely (i.p. injection) and after 3 days of administration, utilizing a permanent gastric cannula. In both designs, the animals were castrated before being given ethanol and, in both experiments, ethanol successfully lowered the post-castration LH rise compared with control castrated animals. In both the acutely and chronically treated groups, basal LHRH release was not impaired, despite the documented decrease in LH levels. Finally, stimulated LHRH release was investigated with depolarizing concentrations of potassium and, again, no change was noted between the hypothalamic release of this decapeptide in the ethanol-exposed compared with the ethanol-naive animals. Thus, ethanol failed to inhibit basal or stimulated LHRH secretion in the acutely and chronically treated animal. This lack of effect on LHRH occurred despite a concomitant lowering of serum concentrations of LH.

Anaesthesia with alphaxalone plus alphadolone acetate decreases serum concentrations of LH in castrated rats.

Alphaxalone is considered the anaesthetic of choice in neuroendocrine reproductive studies in female rats, since it appears to have little, if any, effect on release of gonadotrophin-releasing hormone. There has been less study of the effects of this anaesthetic on the male reproductive neuroendocrine axis, however. Accordingly, the time-dependent effects of alphaxalone, as well as of urethane and ketamine, on the increased levels of LH in castrated rats were determined. Each anaesthetic was administered i.p. and each depressed LH levels significantly compared with those in castrated unanaesthetized rats killed by decapitation (controls). The effect of the anaesthetics was noted 15 min after administration and persisted at 30 and 60 min in animals anaesthetized with alphaxalone and urethane. Only in ketamine-anaesthetized animals did serum concentrations of LH finally rise to concentrations not significantly different from those in control rats. Thus alphaxalone, though useful in female neuroendocrine studies, is as profoundly disruptive as other anaesthetics on the male rat hypothalamic-pituitary reproductive unit.

Testosterone receptor blockade restores cellular immunity in male mice after burn injury.

Males are known to have increased risk for septic complications after traumatic injury, which appears to be mediated by the inhibitory effects of testosterone on immune function. The role of testosterone in immunity after burn injury, however, remains unclear. Herein, we examined the effects of a testosterone receptor antagonist, flutamide, on delayed type hypersensitivity response (DTH), splenocyte proliferation, interleukin (IL)-2 secretion, and IL-2 receptor (IL-2R) expression in male BALB/c mice subjected to a 15% total body surface area burn or sham injury. Burn- or sham-injured mice were given flutamide s.c. at 30 min and 24 h after injury. At 48 h, burn injury caused a 48% (P<0.001) decrease in DTH response; however, mice that received flutamide treatment did not demonstrate significant suppression of DTH. Likewise, splenocyte proliferation and IL-2 production were depressed in burned animals in comparison with sham-injured controls, and flutamide treatment resulted in a partial restoration of these responses. In vitro studies indicated that splenocytes from sham- and burn-injured mice were equally sensitive to the suppressive effects of 5alpha-dihydrotestosterone in regard to proliferation and IL-2 production. Further evaluation revealed a decrease in IL-2R expression on splenocytes from burned mice and a partial restoration of this expression with flutamide treatment. Thus blocking testosterone receptor activation improves the cellular immunity in thermally injured mice, possibly through restoration of IL-2 production and IL-2R expression. It remains to be determined whether the effects of testosterone in this injury model are direct or indirect.

Effect of chronic ethanol on reproductive and growth hormones in the peripubertal male rat.

Ethanol (EtOH) has previously been shown to have profound effects on various endocrine systems. The present study further investigates the action of EtOH on testosterone and on the GH-IGF-I axis. Since these hormones are particularly important in male rats progressing through puberty, we examined the effect of 10 days of EtOH treatment at three different ages (35, 50 and 65 days old) as male rats progressed through puberty into adulthood. After 10 days of feeding a 6% EtOH liquid diet, serum testosterone levels were markedly decreased in all three ages (P < 0.02 at 35 days, P < 0.01 at 50 days and P < 0.03 at 65 days). IGF-I was assessed and was differentially affected at each age. At 35 days IGF-I levels were suppressed by EtOH (P < 0.0002), at 50 days no change was apparent, and at 65 days levels were significantly higher in EtOH-treated (P < 0.01) compared with liquid-fed controls. The levels of IGF-I in the EtOH-treated animals paralleled pituitary GH mRNA levels with a significant fall in the expression of GH mRNA levels noted at 35 days (P < 0.04), no change at 50 days and a significant rise observed at 65 days (P < 0.03). At the hypothalamic level, GH-releasing hormone (GRF) mRNA was significantly reduced in the two younger EtOH-treated age groups compared with controls (P < 0.04 at 35 days; P < 0.02 at 50 days). At 65 days of age, EtOH did not alter GRF mRNA levels. No EtOH-induced changes were seen in GRF content at any age. These observations indicate definite age-related alterations in hormonal gene expression and circulating serum hormone levels and emphasize the importance of studying these critical peripubertal ages after chronic EtOH exposure.

Ethanol, growth hormone and testosterone in peripubertal rats.

The deleterious effects of ethanol on the hypothalamic pituitary growth hormone axis in adult male humans and animals have been well documented. It is also well established that ethanol has toxic effects on testicular function in adult humans and animals. Much less is known, however, about the effects of ethanol on the growth hormone (GH) axis and testicular function in adolescence. Recent studies have established that adolescent problem drinking is a widespread and growing threat to the health of young people in the United States. In the present study, therefore, we investigated if acute ethanol exposure in peripubertal male Sprague-Dawley rats altered normal pituitary and testicular function. Serum levels of GH and testosterone were measured at 1.5, 3, 6, and 24 h after a single i.p. injection of either saline or 3 g/kg body weight ethanol. Histologic analysis as well as serum testosterone levels allowed us to assign animals to either early puberty (35-day-old animals), mid-puberty (41-day-old animals), or young adult (51- and 66-day-old animals) status. Ethanol produced significant decrements in serum testosterone in the 51- and 66-day-old animals, with a trend toward suppression in the 41-day-old group. Furthermore acute ethanol administration significantly decreased serum GH (P < 0.0001 by 3 way ANOVA) demonstrating a significant effect of ethanol on serum GH in all age groups and at all time points studied when compared with saline injected controls (P < 0.01 by Turkey's studentized range test). Despite this significant fall in peripheral GH levels, there was no decrease in either GH mRNA or growth hormone-releasing factor (GRF) mRNA levels nor in hypothalamic concentration of GRF peptide. We conclude that, as in adult animals, acute exposure to ethanol causes a prolonged and severe decrement in serum GH which is possibly mediated at the level of secretion. In addition, there is attenuation in testosterone secretion. These data are all the more important since GH and testosterone play critical roles in organ maturation during this stage of development.

Simultaneous primary hyperparathyroidism and nodular thyroid disease.

Of 351 patients treated for primary hyperparathyroidism from 1966 to 1981, 70 (20%) had grossly evident nodular thyroid disease at the time of subtotal parathyroidectomy. These patients have been reviewed to determine if prior radiation exposure may play a role in their coexistence and if combined subtotal parathyroidectomy and thyroidectomy are safe and efficacious. Thirty-three of the 70 patients (47%) had received prior radiation therapy for benign conditions of the head and neck. Nine of 15 patients with nonmedullary thyroid carcinoma had received previous irradiation. In addition to subtotal parathyroidectomy, 28 patients underwent total thyroidectomy, 14 underwent bilateral subtotal thyroidectomy, and 28 underwent unilateral lobectomy. There were no deaths and no permanent recurrent laryngeal nerve injury from combined subtotal parathyroidectomy and thyroidectomy. Two patients in whom parathyroid tissue was not autotransplanted required calcium and vitamin D supplementation. This study shows that (1) primary hyperparathyroidism and nodular thyroid disease occur simultaneously with sufficient frequency to warrant careful preoperative and intraoperative evaluation of both glands, (2) radiation probably does play a role in the pathogenesis of coexistent primary hyperparathyroidism and nodular thyroid disease, and (3) in experienced hands combined subtotal parathyroidectomy and thyroidectomy can be safely performed.

Follicular cell predominance in the cytologic examination of dominant thyroid nodules indicates a sixty percent incidence of neoplasia.

The interpretation of aspiration cytologic smears that contain a predominance of follicular components often presents a dilemma to the clinician who is treating a patient who has a dominant thyroid nodule, especially when thyroid-stimulating hormone suppression does not produce any significant involution of the dominant nodule. We reviewed a consecutive series of 555 fine-needle aspiration cytologic examinations of dominant thyroid nodules. All specimens that contained colloid or follicular cells mixed with lymphocytes or Hürthle cells were excluded from this review. Additionally, nine aspirates contained degenerated follicular cells with insufficient material for cytologic diagnosis. The remaining 76 specimens contained a predominance of follicular cells: 27 specimens were interpreted as containing "normal" follicular cells, and the remaining 49 specimens were read as "atypical" follicular cells. Histopathologic examination of the resected specimens indicated a 60% incidence of neoplasia (30% carcinoma, 30% adenoma) in which the aspiration cytologic study was interpreted as "normal" follicular cells. On the other hand, a 63% incidence of neoplasia (27% carcinoma, 36% adenoma) occurred in which the cytologic study was read as "atypical." In conclusion, aspirates showing a predominance of follicular cells, whether "normal" or "atypical" indicate a 60% incidence of neoplasia in dominant thyroid nodules that do not decrease significantly in size with thyroid-stimulating hormone suppression.

The endocrine system: alcohol alters critical hormonal balance.

Alcohol's effects on the hormonal (i.e., endocrine) system have widespread consequences for virtually the entire body. Alcohol-related hormonal disturbances can result in cardiovascular abnormalities and reproductive deficits in both males and females. Other endocrine problems stemming from excess alcohol consumption include immune dysfunction and bone disease. Researchers are exploring ways of using hormonal mechanisms to help treat alcoholics as well as to identify people predisposed to alcoholism.

Alcohol's effects on male reproduction.

The male reproductive system consists of the hypothalamus, the anterior pituitary gland, and the testes. Alcohol can interfere with the function of each of these components, thereby causing impotence, infertility, and reduced male secondary sexual characteristics. In the testes, alcohol can adversely affect the Leydig cells, which produce and secrete the hormone testosterone. Studies found that heavy alcohol consumption results in reduced testosterone levels in the blood. Alcohol also impairs the function of the testicular Sertoli cells that play an important role in sperm maturation. In the pituitary gland, alcohol can decrease the production, release, and/or activity of two hormones with critical reproductive functions, luteinizing hormone and follicle-stimulating hormone. Finally, alcohol can interfere with hormone production in the hypothalamus.

Consequences of alcohol use in diabetics.

The hormone insulin, which is produced in the pancreas, is an important regulator of blood sugar levels. In people with diabetes, the pancreas does not produce sufficient insulin (type 1 diabetes) or the body does not respond appropriately to the insulin (type 2 diabetes). Alcohol consumption by diabetics can worsen blood sugar control in those patients. For example, long-term alcohol use in well-nourished diabetics can result in excessive blood sugar levels. Conversely, long-term alcohol ingestion in diabetics who are not adequately nourished can lead to dangerously low blood sugar levels. Heavy drinking, particularly in diabetics, also can cause the accumulation of certain acids in the blood that may result in severe health consequences. Finally, alcohol consumption can worsen diabetes-related medical complications, such as disturbances in fat metabolism, nerve damage, and eye disease.

Adult nesidioblastosis. An unusual cause of fasting hypoglycemia.

Laidlaw coined the term nesidioblastosis in 1938 to characterize the neodifferentiation of the islet cells of Langerhans from pancreatic duct epithelium. It is well recognized in the pediatric population as a frequent cause of persistent neonatal hypoglycemia. However, its occurrence in adults is presumed to be rare and, therefore, it is not appreciated as a cause of hyperinsulinism. Three women, aged 29, 42, and 63, with adult onset hyperinsulinism secondary to nesidioblastosis are reported. All three patients required near-total pancreatectomy. The preoperative findings were consistent with hyperinsulinemic hypoglycemia as with insulinomas. Results of pancreatic imaging studies were normal in two patients and one patient had a pancreatic examination by computerized tomography and magnetic resonance imaging, with false-positive results. Two of the three patients had previously undergone a 50 per cent distal pancreatectomy in which the resected specimens were interpreted as normal in one patient and consistent with nesidioblastosis in the second. Both patients subsequently developed recurrent symptomatic hyperinsulinemic hypoglycemia that persisted despite dosage adjustments in diazoxide therapy. The oldest patient underwent a 95 per cent pancreatectomy at the initial surgical exploration because an insulinoma could not be identified. The other patients underwent a completion 95 per cent pancreatectomy. In both, histochemical examination of each specimen disclosed nesidioblastosis, characterized by clusters of islet cells interspersed throughout the exocrine tissue.

In vivo effects of acute EtOH on rat alpha and beta luteinizing hormone gene expression.

The suppressive effects of ethanol (EtOH) on the male rodent reproductive axis, especially on serum luteinizing hormone (LH) levels, are well known. In this study we examined, in coordinate fashion, the effects of EtOH on LH secretion and on steady-state levels of the mRNA for the two genes that direct LH synthesis, namely alpha- and beta-LH. A single intraperitoneal (IP) injection of EtOH given to castrated male rats produced a statistically significant fall in serum LH levels at 1.5 (p less than 0.05) and 3 hours (p less than 0.01) after injection compared to saline-injected controls. This effect had dissipated by 24 and 72 hours after treatment. Intrapituitary LH content was significantly increased in EtOH-compared to saline-treated animals 1.5 hours after injection (p less than 0.05) at the same time there was a significant decrease in serum LH. Steady-state levels of beta-LH mRNA were significantly diminished in EtOH-treated animals at 1.5 (p less than 0.05) and 3 hours (p less than 0.001) after injection, but returned to control levels thereafter. Since the half-life of beta-LH mRNA is greater than 8 hours, this fall is most likely due to decreased beta-LH mRNA stability and may also involve decreased beta-LH gene transcription. alpha mRNA levels were unchanged at all time points investigated. These findings were verified in four repetitions of this experiment. These data suggest that the EtOH-induced fall in serum LH is due to impaired secretion of LH and to decreased LH synthesis as indicated by diminished steady-state levels of beta-LH subunit mRNA, secondary mainly to altered mRNA stability.

Failure of in vitro ethanol to inhibit LHRH release from the hypothalamus.

The reproductive alterations induced by ethanol (ETOH) in the male rodent have been intensively investigated. Although gonadal effects are well characterized, the impact of ETOH on the hypothalamic peptide luteinizing hormone-releasing hormone (LHRH) has been less well defined. The releasability of hypothalamic LHRH in the presence of ETOH has not been directly studied. We report here that ETOH in concentrations of 50 mg% to 400 mg% failed to inhibit LHRH release in vitro.