Acute effects of oral and intravenous ethanol on rat hepatic enzyme activities.

1. Oral administration of ethanol (3 ml) of 95% in 12 ml total volume over a two day period) significantly decrease plasma glucose and insulin levels and the activities of two key gluconeogenic enzymes, pyruvate carboxylase (pyruvate: CO2 ligase (ADP), EC 6.4.1.1) and fructose diphosphatase, (D-Fru-1,6-P2 1-phosphohydrolase, EC 3.1.3.11), and one glycolytic enzyme, fructose-1,6-P2 aldolase (Fru-1,6-P2 D-glyceraldehyde-3-P lyase, EC 4.1.2.13). In each instance, the administration of 2400 mug daily of oral folate in conjuction with the ethanol prevented these alterations in carbohydrate metabolism. 2. Intravenous injection of ethanol produced a rapid decrease (within 10--15 min) in the activities of hepatic phosphofructokinase, (ATP:D-fructose-6-phosphate 6-phosphotransferase, EC 2.7.1.11), pyruvate kinase, (ATP:pyruvate phosphotransferase, EC 2.7.1.40), fructose diphosphatase and fructose-1,6-P2 aldolase. 3. Intravenous ethanol significantly increased hepatic cyclic AMP concentration approximately 60% within 10 min, while oral ethanol did not alter hepatic cyclic AMP concentrations. 4. These data confirm the known antagonism ethanol and folate and suggest that oral folate might offer a protective effect against hypoglycemia in rats receiving ethanol.

Postmenopausal estrogen therapy, 1995.

Estrogen therapy offers women important benefits, including the potential prolongation of life by prevention of coronary heart disease (CHD) and osteoporotic fractures, and improvement of life by prevention of menopausal symptoms. Not all women can accept the potential side effects and risks, however, which include uterine bleeding, cystic mastitis, fluid retention, and increased risk of uterine cancer and breast cancer. Thus, the benefits and risks must be patiently weighed for each individual, and the alternatives of no treatment or other treatment should be clear. We review here the pertinent information that now makes these decisions quite sound.

Serum angiotensin-converting enzyme activity. Its use in the evaluation and management of hypercalcemia associated with sarcoidosis.

Serum angiotensin-converting enzyme (SACE) was measured in 14 patients (eight women and six men) with sarcoidosis and hypercalcemia. Thirteen patients were treated with prednisone, and 12 achieved normal or nearly normal serum calcium values. Two patients had coexistent hyperparathyroidism. Seven of eight patients with serial SACE measurements exhibited parallel falls in SACE and serum calcium levels. Eleven patients were successfully treated with alternate-day prednisone regimens. The data suggest that serial SACE measurements are useful in the evaluation and management of sarcoidosis with hypercalcemia. In patients with sarcoidosis, the reduction of SACE levels during glucocorticoid treatment may be due to a suppression of granuloma formation. Concomitant falls in serum calcium level suggest an important role of the granuloma or its cellular precursors in vitamin D metabolism.

Abnormal sella turcica. A tumor board review of the clinical significance.

Sixty of 146 patients with intracranial neoplasms or arterial aneurysms had roentgenographic abnormalities of the sella turcica. These abnormalities were most commonly due to chromophobe adenoma, craniopharygioma, and acromegaly, but ten of them were caused by lesions arising distant to the sella. There were also three cases of empty sella syndrome. Headache, visual disturbance, and sexual dysfunction were the most frequent presenting complaints, with visual field abnormality being most common. Pituitary dysfunction was manifested most frequently by alterations in growth hormone level and gonadotrophin secretion and less frequently by hypothyroidism and adrenocortical insufficiency. When the abnormal sella was associated with evidence of symptomatic intracranial disease, endocrine dysfunction, or visual field compromise as evidence of an anatomically aggressive intracranial neoplasm, specialized neuroroentgenographic localizing procedures were usually positive, and treatment for most of the causative lesions was highly effective.

An analysis of diabetic pregnancies at Mayo Clinic, 1950-79.

We reviewed the records of pregnant diabetic women attended at Mayo Clinic during the years 1950-79 and matched each nonaborted diabetic pregnancy with two control pregnancies. Abortions occurred in 49 of 277 diabetic pregnancies (17.7%). The relative risk of other adverse outcomes of pregnancy (+/- 95% confidence interval) in comparison with controls was as follows: perinatal mortality, 7.0 (3.6-13.8); major congenital birth defects, 6.3 (2.8-14.2); and respiratory distress, 9.0 (4.5-17.9). Diabetic ketoacidosis resulted in fetal death in 5 of 18 cases. Patients with mean fasting blood glucose levels of less than or equal to 140 mg/dl had a perinatal mortality of 81 per 1000 births and an incidence of respiratory distress and congenital birth defects of 18.9% and 9.9%, respectively. Patients with mean blood glucose levels greater than 140 mg/dl had corresponding rates of 306 per 1000, 20.4%, and 11.2%, respectively. Hydramnios occurred almost exclusively in diabetic women, and its presence was associated with a twofold increase in the frequency of perinatal death. Analysis of diabetic pregnancy outcome by decade showed no appreciable decrease in the occurrence of perinatal mortality, congenital birth defects, or respiratory distress over the 30-yr period.

Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial.

Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems. We conducted a 1-year prospective, randomized, double-blind trial in 143 postmenopausal osteoporotic women (mean +/- SD age, 68.4+/-5.0 years) with at least one prevalent vertebral fractures and low bone mineral density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase (-14.9%, -8.87%), serum osteocalcin (-20.7%, -17.0%), and urinary C-telopeptide fragment of type I collagen/creatinine (-24.9%, -30.8%), markers of bone turnover; for serum total cholesterol (-7.0% for RLX60) and low density lipoprotein cholesterol (LDL) (-11.4% for RLX60) and for the LDL/HDL cholesterol ratio (-13.2%, -8.3%). BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (for RLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff, there was a dose-related reduction (p = 0.047). We conclude that raloxifene therapy is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy.

Hyperphosphatemic tumoral calcinosis: effects of phosphate depletion on vitamin D metabolism, and of acute hypocalcemia on parathyroid hormone secretion and action.

In hyperphosphatemic tumoral calcinosis, plasma 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are inappropriately elevated, suggesting an abnormality in vitamin D metabolism. To define this abnormality further, we measured vitamin D metabolites in two patients and four controls before and after phosphate depletion. The patients showed elevated plasma levels of 1,25(OH)2D in the basal state. Phosphate depletion reduced serum phosphate in patients from a mean of 6.1 to 2.6 mg/dl; this was accompanied by a rise in plasma 25-hydroxyvitamin D from 33.6 to 41.9 ng/dl, and in 1,25(OH)2D from 67.7 to 93.2 pg/ml. The absolute rise in 1,25(OH)2D was similar to that of controls. EDTA infusion produced a normal increase of serum immunoreactive PTH levels and urinary cAMP excretion. In this form of tumoral calcinosis, 1,25(OH)2D levels are elevated despite hyperphosphatemia, normal immunoreactive PTH, and normal serum calcium concentrations, suggesting an abnormality in the regulation of 1,25(OH)2D synthesis or metabolism, or alternatively, another undefined stimulus for 1,25(OH)2D synthesis. These patients appear to have concurrent abnormalities of renal tubular phosphate transport and vitamin D metabolism.

Phosphorus excretion in tumoral calcinosis: response to parathyroid hormone and acetazolamide.

The cause of hyperphosphatemia in patients with tumoral calcinosis never been explained. We studied two related patients who had tumoral calcinosis and hyperphosphatemia and two normal controls to determine their renal tubular response to parathyroid hormone (PTH) and acetazolamide (ACZ). During baseline periods, the patients had abnormally low fractional excretion of phosphorus (FEP) despite their hyperphosphatemia. Values for patients were 0.114 and 0.128; for controls, values were 0.193 and 0.165. PTH caused an increase in FEP and urinary cAMP in both patients and controls. ACZ also increased FEP in both groups, and the effects of PTH and ACZ were additive, suggesting that patients with tumoral calcinosis have normal sensitivities to PTH and normal responses to ACZ. Levels of vitamin D metabolites in the patients were normal. We conclude that patients with tumoral calcinosis have a reduced ability to excrete phosphorus. This defect does not seem to be due to impaired PTH secretion, an abnormal phosphaturic response to this hormone, or a disturbance of vitamin D metabolism.

Improvement in jejunal enzyme adaptation in obese adult-onset diabetic patients following a 30-day fast.

The adaptive responses of gastrointestinal enzymes, glucose tolerance, and plasma insulin to diet, folic acid, and insulin of five obese adult-onset diabetic patients were studied before and after a 30-day fast. Their data were compared to the adaptive responses of gastrointestinal enzymes to diet, folic acid, and insulin of 15 normal male volunteer subjects, ages 18 to 24. Each group during each testing period received a carbohydrate diet (50% calories as carbohydrate consisting of 1/2 glucose and 1/2 fructose) and a noncarbohydrate diet (70% of calories as corn oil and 30% as sodium caseinate) each without and with folic acid (5 mg three times per day). The effect of insulin was studied only on the carbohydrate diet plus folic acid. Our data demonstrate that obese adult-onset diabetic patients have an impaired adaptive response of jejunal carbohydrate-metabolizing enzyme activities (hexokinase, pyruvate kinase, fructose-1-6-diphosphate aldolase, fructosediphosphatase) to dietary carbohydrate, oral folic acid, and insulin when compared to normal subjects and nondiabetic obese patients. Following a 30-day fast, the obese diabetic patients showed an improvement in glucose tolerance, hyperinsulinemia, and the adaptive response of the jejunal carbohydrate-metabolizing enzyme activities to dietary carbohydrate, folic acid, and insulin. The greatest improvement in the adaptive response of the jejunal enzyme activities occurred on the carbohydrate diet.

Epidemiology and clinical features of osteoporosis in young individuals.

Due to the lack of epidemiologic data on osteoporosis in the young, we identified all 22 Olmsted County, MN, residents aged 20-44 years when first diagnosed with established osteoporosis in 1976-1990. The overall age- and sex-adjusted incidence rate was 4.1 per 100,000 person-years (95% CI 2.4-5.9) with a female to male ratio of age-adjusted rates of 1.2:1. The majority represented secondary osteoporosis (12 steroid-induced, 3 postmenopausal, 2 delayed puberty, 2 anticonvulsant-induced, 2 gastrointestinal disease, 2 alcoholism, 1 anorexia nervosa, and 7 other etiologies; some individuals had more than one factor present) but two had idiopathic osteoporosis (incidence 0.4 per 100,000 person-years, 95% CI 0-0.9). To further characterize the patients with idiopathic osteoporosis, we also reviewed the entire Mayo Clinic experience with such patients from 1976 to 1990, regardless of residency. A total of 56 patients (30 female/26 male) were identified with a median age at diagnosis of 34 years. Only 8% were hypercalciuric at presentation. There was a preponderance of cancellous bone fractures (vertebral 81%, rib 37%, wrist 13%), although 13% did have hip fractures. Transiliac bone biopsies were available in 18 patients. As compared to age- and sex-matched controls, the osteoporotic subjects had a significant reduction in trabecular bone volume, cortical thickness, and mean wall thickness, the latter suggesting an abnormality in osteoblast function in these individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined testing of anterior pituitary gland with insulin, thyrotropin-releasing hormone, and luteinizing hormone-releasing hormone.

Provocative tests of hypothalamic-pituitary function were performed in 20 healthy subjects to learn whether the simultaneous testing by three agents--insulin, thyrotropin-releasing hormone, and luteinizing hormone-releasing hormone--was feasible. The responses to simultaneous testing on one day did not differ significantly from those to testing on three separate days. The time and expense of pituitary-hypothalamic testing can thus be much reduced with no impairment of reliability and with no increased risk to the patient.

Relative value of transdermal and oral estrogen therapy in various clinical situations.

OBJECTIVE: In this study, we reviewed the comparative effectiveness of transdermal and oral estrogen therapy in various groups of women. DESIGN: On the basis of published data and personal clinical experience, we compiled recommendations for use of the various modes of estrogen replacement therapy. MATERIAL AND METHODS: The use of injectable estrogen or implantable estrogen pellets can no longer be recommended because of their expense, inconvenience, and unphysiologic pattern of serum estrogen response. The two main estrogen preparations currently used in the United States--orally administered conjugated estrogens and transdermally administered estradiol--undergo different metabolism, and these processes are reflected in differing levels of circulating hormones and hepatic by-products, including blood clotting factors, binding proteins, renin substrate, and apolipoproteins, and in varied composition of the bile. RESULTS: At least theoretically, transdermal estrogen therapy might be more beneficial than oral estrogen therapy for women who smoke cigarettes or who have migraine headaches, hypertriglyceridemia, hepatobiliary disorders, fibrocystic breast disease, or a history of thromboembolism. In contrast, women with hypercholesterolemia might respond better to oral than to transdermal estrogen therapy. CONCLUSION: Additional properly designed clinical studies are necessary before these recommendations for estrogen replacement therapy can be validated or refuted.

The predictive value of serum angiotensin-converting enzyme activity in the differential diagnosis of hypercalcemia.

Serum angiotensin-converting enzyme (SACE) activity is usually elevated in sarcoidosis, and this raises the possibility that SACE may be a useful diagnostic tool in distinguishing sarcoidosis from other hypercalcemic disorders. We therefore measured SACE in a large number of patients with various granulomatous, metabolic, and hypercalcemic disorders to determine its predictive value. We found elevated SACE activity in 4 of 35 surgically proven cases of primary hyperparathyroidism and in 3 of 13 patients with oncogenic hypercalcemia. In six patients with sarcoidosis and hypercalcemia, SACE activity was elevated; corticosteroid therapy lowered both the serum calcium and SACE levels to normal. We conclude that SACE activity is not a specific test for the differential diagnosis of hypercalcemia but that it remains useful as a chemical marker of successful treatment of sarcoidosis.

Estrogen replacement therapy: current recommendations.

Estrogen replacement therapy is effective for the prevention and treatment of postmenopausal osteoporosis and should be offered to all women at high risk for osteoporosis. Such therapy is particularly beneficial for prevention of spinal compression fractures; in addition, it alleviates menopausal symptoms (hot flushes, genitourinary symptoms, and changes in mood). In each patient, these benefits must be weighted against the potential risks of endometrial hyperplasia and carcinoma, breast tenderness, hypertension, vascular headaches, and the inconvenience of menstrual bleeding if the uterus is intact. The risk of endometrial cancer associated with estrogen replacement therapy can be considerably reduced by the addition of a progestin, and other side effects can be diminished or eliminated by use of the new transdermal estrogen preparations. Thus, estrogen replacement therapy should be considered in all women who have experienced natural or surgically induced menopause, and it is advisable in women who have osteoporosis or an increased risk for this disorder and no contra-indications to its use. Estrogen replacement therapy should be instituted as soon after menopause as possible and seems to be well tolerated until at least 75 years of age.

Outpatient percutaneous biopsy of the iliac crest: methods, morbidity, and patient acceptance.

Bone histology and histomorphometry have become important in the diagnosis and management of metabolic bone disease, but the invasive nature of the biopsy procedure has limited its use. We describe an outpatient technique for obtaining one or more transiliac bone biopsy specimens. Thirty-eight women with osteoporosis, each of whom had sustained one or more spinal compression fractures, underwent two separate bone biopsies during which two 7.5-mm transiliac cores of bone were removed. No morbidity (such as infection or hemorrhage) was encountered. Subjective responses to the level of pain were surveyed by questionnaire. At the time of biopsy, 46% of the study subjects experienced no or only mild discomfort, and 24% judged their pain to be severe. At 16 hours after biopsy, 64% had no or mild pain and 8% experienced severe pain. At 7 days after biopsy, 79% experienced no or mild pain but 9% judged their pain to be severe. In four patients, temporary ambulatory disability occurred but resolved spontaneously in 7 to 10 days. We conclude that the described outpatient bone biopsy procedure is safe, efficient, and generally acceptable to patients.

Influence of phlebotomy treatment on abnormal hypothalamic-pituitary function in genetic hemochromatosis.

To test the hypothesis that deficiencies in hypothalamic-pituitary function in genetic hemochromatosis result from cellular injury by iron deposits, we conducted provocative tests in 11 men with genetic hemochromatosis before and after iron depletion by serial phlebotomy and in 10 control subjects. We gave combination intravenous injections of insulin (0.15 U/kg), luteinizing hormone releasing hormone (LHRH, 100 micrograms), and thyrotropin releasing hormone (400 micrograms) and then measured plasma glucose, growth hormone, corticosteroids, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone at 30-minute intervals for 90 minutes. Phlebotomy caused a substantial decrease in median values for serum ferritin, deferoxamine-chelatable iron, and hepatic iron concentration. Before phlebotomy, stimulation by hypoglycemia and thyrotropin releasing hormone caused significantly less secretion of growth hormone (P = 0.004) and prolactin (P = 0.03) in patients than in control subjects. No significant improvement was noted, however, in growth hormone or prolactin secretion after phlebotomy. Of the 11 patients, 7 had secondary hypogonadism, and phlebotomy did not improve the serum testosterone, follicle-stimulating hormone, luteinizing hormone, or responses to LHRH in any case. Chlorpromazine injections failed to elevate serum prolactin in all patients, and administration of levodopa caused a partial reduction in serum prolactin; thus, the hypothalamus may be an important locus of endocrine malfunction in these patients. We conclude that abnormal hypothalamic-pituitary function in genetic hemochromatosis is not substantially improved by iron-depletion therapy.

Ovarian leiomyoma with hilus cell hyperplasia that caused virilization.

A 68-year-old woman had noted gradual virilization and depression for 3 years. Examination revealed a 10-cm right pelvic mass. Plasma testosterone was substantially elevated (1,082 ng/dl), but urinary ketosteroid and ketogenic steroid excretion was normal. Laparotomy revealed a 10-cm mass that replaced the right ovary and weighed 210 g. Histologic analysis revealed a leiomyoma and proliferation of hilus cells in the periphery of the mass. The plasma testosterone decreased postoperatively to 45 ng/dl. We believe that this is the first report of an ovarian leiomyoma associated with hilus cell hyperplasia that caused virilization.

Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women.

Raloxifene hydrochloride (HCl) is a selective estrogen receptor modulator with estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on reproductive tissues. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established. This paper presents an early safety assessment of raloxifene effects on cognition and mood in postmenopausal women participating in a randomized, double-blind osteoporosis treatment trial. Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day). The Memory Assessment Clinics (MAC) battery and Walter Reed Performance Assessment Battery (PAB) were used to assess multiple and independent aspects of cognitive function, while mood was assessed with the Geriatric Depression Scale (GDS). After 12 months of treatment, there were no significant differences between the raloxifene groups and placebo on performance in either the MAC battery or the PAB. The only significant difference observed was a slight increase in performance favoring the raloxifene 120 mg/day group in an assessment of verbal memory on the MAC battery after 1 month of treatment. Scores on the GDS and the self-reported incidence of mood-related events were not different between treatment groups at any of the assessment periods. These data do not suggest that raloxifene impairs cognition or affects mood in postmenopausal women treated for 1 year. Studies to further assess the safety and potential efficacy of raloxifene with respect to cognitive function are ongoing.

The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis.

Osteoporosis can affect almost everyone in the population, and although clinical outcome of fracture is manifested in late life, the disease process begins in the early postmenopausal years in women. The pharmacologic agents currently available for osteoporosis prevention and treatment act by inhibiting bone resorption, and include estrogen or hormone replacement therapy (estrogen with progestin), bisphosphonates, salmon calcitonin nasal spray, and selective estrogen receptor modulators (SERMs). Raloxifene is a benzothiophene SERM that has estrogen against effects in bone and on serum lipid metabolism and estrogen antagonist effects on breast and uterine tissue. This article summarizes the effects of these antiresorptive agents, as measured by changes in bone mineral density, biochemical markers of bone turnover, and incident fractures in postmenopausal osteoporosis.

Acute cerebral dysfunction in diabetic ketoacidosis: survivial followed by panhypopituitarism.

We report a unique case of a 15-yr-old diabetic patient who survived ketoacidosis complicated by acute severe encephalopathy, hypopituitarism, and optic atropy. We reviewed our 25-yr experience with fatal diabetic ketoacidosis; three additional cases resembled the "cerebral edema" syndrome. We observed that (1) cerebral edema is not often documented in this syndrome, (2) the cause of the acute neuronal disturbance in these patients may be hypoxic, with cerebral edema a secondary development, and (3) development of encephalopathy was probably unrelated to overvigorour correction of acidosis and hyperglycemia in our cases.