The effects of adiponectin and leptin on changes in bone mineral density.

UNLABELLED: We tested the hypothesis that low leptin and high adiponectin levels are associated with higher rates of bone mineral density (BMD) loss among 3,075 men and women, aged 70-79, from the Health Aging and Body Composition Study. Results suggest that adiponectin, but not leptin, is a risk factor for bone loss in women. INTRODUCTION: Adiponectin and leptin are hormones secreted by adipose cells that may impact BMD. Few studies have evaluated the longitudinal association of leptin and adiponectin levels with rates of BMD change. METHODS: Hip and whole-body areal BMD (aBMD) were measured five times using dual-energy X-ray absorptiometry over 10 years (average follow-up time, 7.95 ± 1.92 years). Trabecular lumbar spine volumetric BMD (vBMD) was measured using quantitative computed topography at baseline and year 6 in the Pittsburgh cohort only. Random slope and intercept models were used to account for within person correlation as a result of repeated measures of hip and whole-body aBMD. Linear regression was used to model changes in spine trabecular vBMD. RESULTS: Among women, the annualized rate of hip aBMD loss in the highest tertile of adiponectin was -0.67% (95% CI -0.77, -0.58) compared to [-0.43% (95% CI -0.51, -0.35)] in the lowest tertile (p trend = 0.019) after adjusting for age, race, BMI, diabetes, baseline hip aBMD, and weight change. In men, hip aBMD loss was greatest in the high adiponectin group (tertile 3), however this association was not significant (p trend = 0.148). After adjusting for weight change in women, the association between higher leptin and lower hip aBMD loss was attenuated and no longer significant (p trend = 0.134). Leptin and adiponectin levels were not associated with whole-body aBMD or trabecular lumbar spine vBMD loss. CONCLUSIONS: Adiponectin was associated with increased hip aBMD loss in women only, supporting evidence that adiponectin may have an important role in bone health.

The association of serum 25-hydroxyvitamin D with indicators of bone quality in men of Caucasian and African ancestry.

UNLABELLED: We examined the association of serum 25-hydroxyvitamin D [25(OH)D] with indices of bone quality in older men. Positive associations for 25(OH)D and bone mineral density, content, cortical thickness, and axial and polar strength strain indices were observed among Caucasians; however, among men of African descent findings were either null or negative. INTRODUCTION: There are limited data on serum 25(OH)D and bone measures in men of African ancestry. To better understand racial differences in vitamin D status and bone health, a cross-sectional study among 446 Caucasian men in the US and 496 men of African ancestry in Tobago (age ≥ 65 years) was conducted. METHODS: Serum 25(OH)D (liquid chromatography and tandem mass spectrometry) was measured, and peripheral quantitative computed tomography scans were administered. Bone measures estimated included trabecular and cortical volumetric bone mineral density (vBMD), bone mineral content (BMC), bone geometry (cross-sectional area and cortical thickness), and polar and axial strength strain indices (SSIp and SSIx). RESULTS: Men of African ancestry had higher 25(OH)D than Caucasians (34.7 vs. 27.6 ng/ml, p < 0.01). Among Caucasians, 25(OH)D was positively (p trend < 0.05) associated with cortical vBMD, total BMC, cortical thickness, SSIp, and SSIx at the distal radius after adjustment for potential confounders. Similar patterns were observed at the distal tibia. In contrast, in men of African ancestry, there was an inverse association (p trend < 0.05) between 25(OH)D and the cross-sectional area, and SSIx. Race modified (p for interaction < 0.05) the association between 25(OH)D and total BMC, cross-sectional area, SSIp, SSIx, and trabecular vBMD of the radius. In men of African ancestry, there was evidence of a threshold effect (at approximately 18 ng/ml) for 25(OH)D on tibial total BMC and cortical thickness. CONCLUSIONS: More studies are needed to better comprehend these race differences for 25(OH)D and bone density, geometry, and indices of bone strength.

Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy.

All would agree that hypercalcemia occurs among patients with humoral hypercalcemia of malignancy (HHM) as a result of osteoclastic bone resorption. Some studies suggest that enhanced renal calcium reabsorption, which plays an important pathophysiological role in the hypercalcemia occurring in primary hyperparathyroidism, is also important pathophysiologically in HHM. Other studies have not agreed. In large part, these differences result from the inability to accurately assess creatinine and calcium clearance in critically ill subjects with HHM. To circumvent these issues, we have developed steady state 48-h PTH-related protein (PTHrP) infusion and 8-h hypercalcemic calcium clamp protocols. These techniques allow assessment of the effects of steady state PTHrP and calcium infusions in normal healthy volunteers in a setting in which renal function is stable and measurable and in which the filtered load of calcium can be matched in PTHrP- and calcium-infused subjects. Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subjects receiving PTHrP, as expected, displayed mild hypercalcemia (10.2 mg/dL), suppression of endogenous PTH-(1--84), and phosphaturia. Subjects receiving the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hypercalcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp group was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the PTHrP-infused subjects was approximately 50% lower (between 2.5--3.7%), and no different from that in the normal controls, which ranged from 1.5--3.0%. These studies demonstrate that PTHrP is able to stimulate renal calcium reabsorption in healthy volunteers. These studies suggest that PTHrP-induced renal calcium reabsorption, in concert with the well established acceleration of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.

Therapeutic controversies in primary hyperparathyroidism.

There is little debate about the primacy of surgery in the management of classical PHPT. Rather, the question has been what to do about the many patients with nonclassical disease. A 1990 NIH consensus conference (55) clearly recommended surgery for patients with significant adverse effects of PHPT, for patients with complicating coexistent illnesses, for younger patients, and for those in whom consistent long-term follow-up could not be assured. It allowed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up would outweigh the burden of surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms and their reversibility, the evidence of "asymptomatic" but harmful effects reversible by surgery, and the accumulating evidence for surgical reduction of increased long-term mortality risk substantially strengthen the argument for surgery in such patients. For these reasons, parathyroidectomy should generally be recommended for patients with a secure diagnosis of PHPT, even in the absence of classical symptoms.

Metabolic effects of oral contraceptives in women with polycystic ovary syndrome.

Insulin resistance and dyslipidemia have been described in women with polycystic ovary syndrome (PCOS), a disorder characterized by hyperandrogenism and oligomenorrhea. Although oral contraceptives (OC) are often instituted to regulate menses and suppress HA in women with PCOS, their use has been postulated to cause a deterioration in insulin sensitivity and to adversely affect circulating lipids. To investigate these effects, 9 women with PCOS and 10 age- and weight-matched control women were studied before and during the third month of therapy with a low-dose norethindrone-containing triphasic combination OC using the hyperglycemic clamp technique. At baseline, the PCOS group had higher androgen, triglyceride, and glycosylated hemoglobin concentrations, with a greater insulin response to oral glucose and a lower insulin sensitivity index (ISI) than controls. During OC therapy, a reduction in ISI was observed in both groups, whereas an increase in triglycerides was observed only in controls, removing any observed difference between the two groups in ISI or lipids. In women with PCOS, an increase in insulin concentrations during hyperglycemia accounted for the decline in ISI (P = 0.026), whereas in control women the decrease in ISI was attributable to a decrease in glucose disposal (P = 0.004). In conclusion, PCOS is characterized by insulin resistance in the untreated state. Short-term therapy with a triphasic OC results in a further decline in ISI in women with PCOS, without inducing additional adverse effects on lipids. A more pronounced decline in ISI together with an elevation in triglyceride levels occurs in normal women with OCs. The mechanisms leading to this decrease in ISI are different for each group.

Comparison of the minimal model and the hyperglycemic clamp for measuring insulin sensitivity and acute insulin response to glucose.

Glucose clamp techniques are established methods for assessment of insulin sensitivity and secretion. The minimal model technique (MMT) has been proposed as an alternative approach to the hyperinsulinemic-euglycemic clamp technique for determination of an insulin sensitivity index (ISI), but has not been directly compared with the hyperglycemic clamp for measurement of ISI or insulin secretion. To address this issue, the present study was undertaken to compare determinations of ISI and the acute insulin response to glucose (AIRg) obtained using the MMT with similar measures obtained from a hyperglycemic clamp. Measures for ISI and AIRg obtained from MMT analysis of a tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIGT) were compared with similar measures obtained from a 3-hour hyperglycemic clamp performed at a plasma glucose level of 10 mmol/L (180 mg/dL). Paired comparisons were performed in 14 women with normal glucose tolerance. Significant positive correlation coefficients were obtained for both ISI (r = .88, P < .001) and AIRg (r = .75, P < .005) between the MMT and clamp studies. We conclude that indices for ISI and AIRg obtained with the MMT are highly correlated with those obtained using the hyperglycemic clamp. The MMT is a valid alternative to the hyperglycemic clamp for assessing insulin sensitivity and AIRg.

Developmental expression and anatomical localization of endothelin-1 messenger ribonucleic acid and immunoreactivity in the rat placenta: a northern analysis and immunohistochemistry study.

Endothelin-1 (ET-1) immunoreactivity and messenger ribonucleic acid (mRNA) have previously been identified in the mammalian placenta. In the present study we examined the developmental expression of ET-1 mRNA and the localization of ET-1 mRNA and immunoreactivity within the rat placenta. Placental tissues were removed from primiparous Sprague-Dawley rats on gestational days 14, 18, and 21 and processed for blot hybridization of ET-1 mRNA and immunohistochemistry of ET-1 immunoreactive peptide. Placental tissue contained a 2.3 kb size ET-1 mRNA transcript. Placental ET-1 mRNA abundance increased approximately five-fold from day 14 to 21 of gestation (p = 0.02). To localize ET-1 mRNA within the rat placenta, day 18 placentas were dissected into the basal and labyrinth layers and processed separately for blot hybridization of ET-1 mRNA. ET-1 mRNA localized to the labyrinth zone. This was confirmed by immunohistochemical staining of day 18, 20, and 21 placental tissues with an antiserum specific to ET-1. The presence of ET-1 immunoreactivity and the stage-specific increase in ET-1 mRNA in the rat placenta suggest that ET-1 may exert paracrine effects on the placenta or uterus of the pregnant rat.

Expression of the endothelin-1 and oxytocin genes in the hypothalamus of the pregnant rat.

Endothelin (ET)-1, a neuropeptide and possible neuromodulator, has been found in the hypothalamic supraoptic and paraventricular nuclei (SON and PVN) of the rat in the distribution of oxytocin (OT) neurons. Within the hypothalamus of the pregnant rat, we investigated the developmental expression of the ET-1 gene and the possibility of coordinate expression of the ET-1 and OT genes. Blots containing hypothalamic mRNAs from 4-, 14-, 18-, and 21-day-old pregnant rats were hybridized to a 32P-labeled probe specific to the rat ET-1 gene. Hypothalamic tissue contained an ET-1 transcript of approximately 2.3 kb size. ET-1 mRNA abundance increased significantly in the SON and PVN from early to late gestation (P = 0.005 and 0.05, respectively). Blots containing hypothalamic mRNA were rehybridized to a 32P-labeled probe specific to exon C of the rat OT gene. OT gene expression increased significantly within both the hypothalamic SON (p = 0.0009) and PVN (P = 0.003) as gestation advanced. The sizes of the hypothalamic ET-1 and OT transcript sizes remained unchanged throughout gestation. Hypothalamic ET-1 and OT transcripts display stage-specific increases during gestation. ET-1 may be a neuroendocrine regulator of pregnancy-related events in the rat, and may act alone or in concert with OT.

Primary hyperparathyroidism and parathyroid hormone-related protein.

Hypercalcemia is most commonly associated with primary hyperparathyroidism and malignancy due to parathyroid hormone-related protein (PTHrP). Primary hyperparathyroidism is characterized by excessive secretion of parathyroid hormone in association with hypercalcemia. The modern presentation of primary hyperparathyroidism is as an asymptomatic disorder. Diagnostic tools such as bone mineral densitometry, bone histomorphometry, and the measurement of markers of bone turnover, as well as other clinical assessments, have all led to the development of guidelines to help direct decisions for parathyroid surgery or for medical management. Hypercalcemia of malignancy is often distinguishable from primary hyperparathyroidism by the presence of an obvious tumor. Primary hyperparathyroidism is excluded by the immunoradiometric assay for parathyroid hormone, which is suppressed. A number of clinical characteristics of hypercalcemia of malignancy can be explained on the basis of the tumor product, PTHrP, which directly causes hypercalcemia in many cases. Assays for PTHrP show elevated levels in patients in whom hypercalcemia is associated with the classic syndrome. Recent recognition that PTHrP is found ubiquitously in virtually all normal tissues and that it is possibly involved in a number of normal physiologic processes, apart from its pathologic role, provides an exciting basis for future research.

Endothelin-1 gene expression in human pheochromocytoma.

We examined expression of human endothelin-1 (ET-1) in adrenal tissues removed from five patients with pheochromocytomas and two patients with aldosterone-producing adenomas. The pheochromocytomas contained a 2.3 kilobase ET-1 transcript, which was not found int he aldosteronomas. Constitutive expression of ET-1 varied in magnitude among the pheochromocytomas but was generally at a low level. Immunohistochemical staining of the pheochromocytomas with an antiserum to human ET-1 showed the presence of immunoreactive ET-1 as well. The presence of ET-1 messenger ribonucleic acid and ET-1 immunoreactivity in human pheochromocytomas suggests a possible paracrine role for this peptide in human chromaffin cells.

The Leyla retractor: use in acoustic neuroma and neurotologic surgery.

The Leyla retractor is a self-retaining retractor used in the translabyrinthine removal of acoustic neuroma and middle fossa surgery. It is used to maintain constant, even pressure on a decompressed sigmoid sinus and cerebellum in translabyrinthine surgery and the temporal lobe in middle fossa surgery. The Leyla retractor provides excellent exposure and greater freedom and dexterity for the neurotologist.

Progressive necrotizing external otitis: treatment with ticarcillin and tobramycin.

The history of necrotizing external otitis, its diagnosis and management are reviewed. A case history is presented of a patient who was diagnosed as having progressive necrotizing external otitis with facial paralysis. In spite of standard medical treatment and aggressive surgical management, the disease process continued with progressive involvement of Cranial nerves IX and X. The Pseudomonas aeruginosa bacteria developed an increased minimal inhibitory concentration (MIC) to carbenicillin and gentamicin by requiring near toxic blood levels to be effective. Investigational ticarcillin (alpha-carboxy-3-thienylmethylpenicillin) and tobramycin were used successfully in resolving the infection.