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Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.

The testicular dysgenesis syndrome (TDS) hypothesis proposes that maldevelopment of the testis, irrespective of cause, leads to malfunction of the somatic (Leydig, Sertoli) cells and consequent downstream TDS disorders. Studies in rats exposed in utero to di(n-butyl) phthalate (DBP) have strongly supported the TDS concept, but so far no direct evidence has been produced that links dysgenesis per se to somatic cell dysfunction, in particular to androgen production/action during the 'masculinization programming window' (MPW; e15.5-e18.5). Normal reproductive tract development and anogenital distance (AGD) are programmed within the MPW, and TDS disorders arise because of deficiencies in this programming. However, DBP-induced focal testicular dysgenesis (Leydig cell aggregation, ectopic Sertoli cells, malformed seminiferous cords) is not evident until after the MPW. Therefore, we used AGD as a read-out of androgen exposure in the MPW, and investigated if this measure was related to objectively quantified dysgenesis (Leydig cell aggregation) at e21.5 in male fetuses exposed to vehicle, DBP (500 or 750 mg/kg/day) or the synthetic glucocorticoid dexamethasone (Dex; alone or plus DBP-500) from e15.5-e18.5 (MPW), e13.5-e20.5 or e19.5-e20.5 (late window). Dysgenesis was found only in animals exposed to DBP during the MPW, and was negatively correlated (R² = -0.5) with AGD at e21.5 and at postnatal day 8, irrespective of treatment period. Dysgenesis was also negatively correlated (R² = -0.5) with intratesticular testosterone (ITT) at e21.5, but only when treatments in short windows (MPW, late window) were excluded; the same was true for correlation between AGD and ITT. We conclude that AGD, reflecting Leydig cell function solely within the MPW, is strongly related to focal dysgenesis. Our results point to this occurring because of a common early mechanism, targeted by DBP that determines both dysgenesis and early (during the MPW) fetal Leydig cell dysfunction. The findings provide strong validation of the TDS hypothesis.

Numerous epidemiological studies have shown that exposure to an adverse environment in early life is associated with a substantially increased risk of later disease; a phenomenon termed 'early life programming'. There is increasing evidence that these effects may not be limited to the first, directly exposed generation but may also be transmissible to subsequent generations through non-genomic mechanisms. There are a number of mechanisms which may underpin the intergenerational transmission of the programmed phenotype, including persistence of the abnormal environment across generations, programmed effects on maternal physiology and the transmission of epigenetic information through the germline. In this review we discuss the evidence for these mechanisms in human and animal studies and the potential importance of this field for child health.

Exposure to an adverse early life environment is associated with increased cardio-metabolic disease risk, a phenomenon termed "programming." The effects of this are not limited to the exposed first (F1) generation but can be transmissible to a second generation (F2) through male and female lines. Using a three generation animal model of programming by initial prenatal glucocorticoid overexposure we have identified effects on fetal and placental weight in both the F1 and F2 offspring. However, the expression of candidate imprinted genes in the fetus and placenta differed between the F1 and F2, with marked parent-of-origin effects in F2. Since DNA methylation at imprinted genes is maintained at fertilization, they are potential templates for the transmission of programming effects across generations. Although we detected alterations in DNA methylation at differentially methylated regions (DMRs) of the key prenatal growth factor Igf2 in F1 and F2 fetal liver, the changes in DNA methylation at these DMRs do not appear to underlie the transmission of effects on Igf2 expression through sperm. Thus, multigenerational programming effects on birth weight and disease risk is associated with different processes in F1 and F2. These findings have implications for the pathogenesis and future attempts to stratify therapies for the "developmental component" of cardiometabolic disease.

Introduction: Fertility, sperm counts, and testis weights are reduced in men whose mothers smoked in pregnancy. Animal studies suggest this could be due to impaired androgen action. Anogenital distance (AGD) provides a readout of fetal androgen exposure and is reduced by in utero exposure to harmful chemicals in rodents. This study assessed whether maternal cigarette smoking disturbs AGD in the second trimester human fetus., Materials and Methods: Morphological indices, including AGD, and circulating cotinine concentrations were measured in 83 electively terminated, normally progressing, second-trimester fetuses between 11 and 20 wk gestation., Results: A gender difference in AGD (1.4-fold longer in males) was already apparent at 11-13 wk, rising to 2.00-fold longer in males at 17-20 wk gestation. In males, AGD and AGD normalized against ponderal index (a measure of fetal leanness) were significantly increased by maternal smoking (1.19- and 1.31-fold, respectively). The difference between smoke-exposed and nonexposed male AGD was greatest at 11-13 wk (1.25-fold) but had declined to 1.01-fold by 17-20 wk gestation. AGD in females was not affected by maternal cigarette smoking., Conclusions: Androgen programming of masculinization occurs before 11-13 wk gestation in the human because AGD is already significantly longer in male fetuses by that stage. AGD reaches the 2-fold difference reported for the neonate by 17-20 wk gestation. Significantly longer AGD in smoke-exposed males was surprising and may indicate increased androgen exposure in the early programming window. Convergence of AGD by late second trimester suggests, however, that by birth, male AGD may be shorter in smoke-exposed individuals.

Objectives: Post-traumatic hypopituitarism is well described amongst adult traumatic brain injury (TBI) survivors. We aimed to determine the prevalence and clinical significance of pituitary dysfunction after head injury in childhood., Design: Retrospective exploratory study., Patients: 33 survivors of accidental head injury (27 boys). Mean (range) age at study was 13·4 years (5·4-21·7 years) and median (range) interval since injury 4·3 years (1·4-7·8 years). Functional outcome at study: 15 good recovery, 16 moderate disability, two severe disability., Measurements: Early morning urine osmolality and basal hormone evaluation were followed by the gonadotrophin releasing hormone (GnRH) and insulin tolerance (n = 25) or glucagon tests (if previous seizures, n = 8). Subjects were not primed. Head injury details were extracted from patient records., Results: No subject had short stature (mean height SD score +0·50, range -1·57 to +3·00). Suboptimal GH responses (<5 μg/l) occurred in six peri-pubertal boys (one with slow growth on follow-up) and one postpubertal adolescent (peak GH 3·2 μg/l). Median peak cortisol responses to insulin tolerance or glucagon tests were 538 and 562 nm. Nine of twenty-five and two of eight subjects had suboptimal responses, respectively, two with high basal cortisol levels. None required routine glucocorticoid replacement. In three, steroid cover was recommended for moderate/severe illness or injury. One boy was prolactin deficient. Other basal endocrine results and GnRH-stimulated LH and FSH were appropriate for age, sex and pubertal stage. Abnormal endocrine findings were unrelated to the severity or other characteristics of TBI or functional outcome., Conclusions: No clinically significant endocrinopathy was identified amongst survivors of accidental childhood TBI, although minor pituitary hormone abnormalities were observed., (© 2010 Blackwell Publishing Ltd.)

The prevalence of obesity among pregnant women is increasing. In addition to the short-term complications of obesity during pregnancy in both mother and child, it is now recognised that maternal obesity has long-term adverse outcomes for the health of her offspring in later life. Evidence from both animal and human studies indicates that maternal obesity increases the risk for the offspring in developing obesity and altering body composition in child- and adulthood and, additionally, it also has an impact on the offspring's cardiometabolic health with dysregulation of metabolism including glucose/insulin homoeostasis, and development of hypertension and vascular dysfunction. Potential mechanisms include effects on the development and function of adipose tissue, pancreas, muscle, liver, the vasculature and the brain. Further studies are required to elucidate the mechanisms underpinning the programming of disease risk in the offspring as a consequence of maternal obesity. The ultimate aim is to identify potential targets, which may be amenable to prevention or early intervention in order to improve the health of this and future generations.

We have shown previously that deficient androgen action within a masculinization programming window (MPW; e15.5-e18.5 in rats) is important in the origin of male reproductive disorders and in programming male reproductive organ size, but that androgen action postnatally may be important to achieve this size. To further investigate importance of the MPW, we used two rat models, in which foetal androgen production or action was impaired during the MPW by exposing in utero to either di(n-butyl) phthalate (DBP) or to flutamide. Reduced anogenital distance (AGD) was used as a monitor of androgen production/action during the MPW. Offspring were evaluated in early puberty (Pnd25) to establish if reproductive organ size was altered. The testes, penis, ventral prostate (VP) and seminal vesicles (SV) were weighed and penis length measured. Both DBP and flutamide exposure in the MPW significantly reduced penis, VP and SV size along with AGD at Pnd25; AGD and organ size were highly correlated. In DBP-, but not flutamide-, exposed animals, testis weight was also reduced and correlated with AGD. Intratesticular testosterone was also measured in control and DBP-exposed males during (e17.5) or after (e21.5) the MPW and related to AGD at e21.5. To evaluate the importance of postnatal androgen action in reproductive organ growth, the effect of combinations of prenatal and postnatal maternal treatments on AGD and penis size at Pnd25 was evaluated. In prenatally DBP-exposed animals, further postnatal exposure to either DBP or flutamide significantly reduced AGD and penis size in comparison with prenatal DBP exposure alone. In comparison, rats exposed postnatally to testosterone propionate after prenatal vehicle-exposure showed considerable increase in these parameters vs. controls. In conclusion, we show that the size of all male reproductive organs is programmed by androgen exposure in the MPW, but that growth towards this size is dependent on androgen action postnatally.

The association between low birth weight and cardiovascular disease is amplified by the development of obesity. We explored the effects of postnatal high-fat (HF) feeding in dexamethasone (Dex)-programmed rats, in which prenatal glucocorticoid overexposure is associated with reduced birth weight and adult glucose intolerance. Male Wistar rats exposed to Dex or vehicle (Veh) during the last week of gestation were weaned onto HF or control diets for 6 months. Dex-exposed animals were of lower birth weight and showed catch-up growth by 7 wk. There were no differences in obesity or hyperinsulinaemia between Dex-HF and Veh-HF animals. However, Dex-HF animals had increased hepatic triglyceride content compared with Veh-HF animals. mRNA transcript profiles in adipose tissue revealed depot-specific changes in the expression of genes involved in fatty acid esterification and triglyceride synthesis and storage with prenatal Dex exposure. Thus, antenatal glucocorticoid overexposure in rats does not confer increased sensitivity to HF diet-induced obesity, but increases susceptibility to fatty liver. This may be due to depot-specific-programmed alterations in fat metabolism in adipose tissue.

Epidemiological studies have shown that the environment experienced in early life can 'programme' susceptibility to later disease. Furthermore, there is increasing evidence that these effects can be transmissible to subsequent generations through non-genomic mechanisms, with profound implications for human populations. Several mechanisms can underpin the intergenerational transmission of the programmed phenotype, including persistence of the abnormal environment across generations, maternal effects and the transmission of epigenetic information through the germline. In this review, we discuss the evidence for these mechanisms in human and animal studies and the potential importance of this field for human health., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Objective: To report a case that substantiates the presence of hypoglycemia at the time of death of a young man with type 1 diabetes, who was found unresponsive in his undisturbed bed in the morning., Methods: We describe a 23-year-old man with a history of type 1 diabetes treated with an insulin pump, who had recurrent severe hypoglycemia. In an effort to understand these episodes better and attempt to eliminate them, a retrospective (non-real-time) continuous subcutaneous glucose monitoring system (CGMS) was attached to the patient. He was found dead in his undisturbed bed 20 hours later. The insulin pump and CGMS were both downloaded for postmortem study., Results: Postmortem download of the data in the CGMS demonstrated glucose levels below 30 mg/dL around the time of his death, with only a minimal counter-regulatory response. This finding corresponded to a postmortem vitreous humor glucose of 25 mg/dL. An autopsy showed no major anatomic abnormalities that could have contributed to his death., Conclusion: To our knowledge, this is the first documentation of hypoglycemia at the time of death in a patient with the "dead-in-bed" syndrome. This report should raise the awareness of physicians to the potentially lethal effects of hypoglycemia and provide justification for efforts directed at avoiding nocturnal hypoglycemia.

Stars with initial masses such that 10M[symbol: see text] or= 140M[symbol: see text] (if such exist) develop oxygen cores with masses, M(core), that exceed 50M[symbol: see text], where high temperatures are reached at relatively low densities. Conversion of energetic, pressure-supporting photons into electron-positron pairs occurs before oxygen ignition and leads to a violent contraction which triggers a nuclear explosion that unbinds the star in a pair-instability supernova. Transitional objects with 100M[symbol: see text] < M(initial) < 140M[symbol: see text] may end up as iron-core-collapse supernovae following violent mass ejections, perhaps as a result of brief episodes of pair instability, and may already have been identified. Here we report observations of supernova SN 2007bi, a luminous, slowly evolving object located within a dwarf galaxy. We estimate the exploding core mass to be M(core) approximately 100M[symbol: see text], in which case theory unambiguously predicts a pair-instability supernova. We show that >3M[symbol: see text] of radioactive (56)Ni was synthesized during the explosion and that our observations are well fitted by models of pair-instability supernovae. This indicates that nearby dwarf galaxies probably host extremely massive stars, above the apparent Galactic stellar mass limit, which perhaps result from processes similar to those that created the first stars in the Universe.

Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg . d dibutyl phthalate (DBP), 0.1 mg/kg . d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg . d DBP and exacerbated the effects of 100 mg/kg . d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.

Background: To address the need of caring for the growing number of patients with diabetes, East Carolina University implemented a 1-year fellowship in diabetes. Most of the region has been designated as Health Professional Shortage Areas., Description: The objective of the fellowship is to educate primary care physicians to serve as regional specialists in diabetes. The program is administered by physicians, educators, and representatives of the university's affiliated teaching hospital. The curriculum includes clinical, didactic, and experiential learning strategies in outpatient and inpatient settings. Adult and pediatric endocrinologists, obstetricians, and generalists mentor and evaluate the fellows., Evaluation: This innovative training program has improved the availability of high-quality diabetes care for underserved patients in the region. Mean glycemic control in fellows' patients improved and other clinical endpoints were also met., Conclusions: A 1-year diabetes fellowship is a replicable solution to address the need for diabetes care specialists.

Objective: To address the likelihood of thyroid malignancy for each cytologic interpretation, highly cellular and benign vs. follicular carcinoma, with particular attention to the indeterminate cytologic result, follicular neoplasm., Study Design: We retrospectively reviewed thyroid nodule cytologic and histologic interpretations from 1994 to 2002 in a tertiary medical center setting. Patients were referred for evaluation of thyroid nodules found incidentally or on physical examination., Results: A total of 886 thyroid nodules were aspirated in 802 patients (500 benign, 195 indeterminate, 129 inadequate, 62 malignant). Of 195 indeterminate lesions, 180 were classified as follicular neoplasm or "cannot rule out/possible" follicular neoplasm, with 144 of these ultimately removed and with malignant histologic findings in 28. Any mention of follicular neoplasm in the cytology report conferred a 19.4% risk of malignancy in patients who went on to surgery (including an unexpected 18.2% rate of malignancy in the subcategory in which a possible follicular neoplasm was a secondary listing in an otherwise-benign cytologic differential diagnosis)., Conclusion: There was no difference in the likelihood of histologic malignancy between the cytologic subcategories of "definite "follicular neoplasm and "cannot rule out/possible" follicular neoplasm. We recommend that cytologic reports on fine needle aspiration of thyroid nodules with a diagnosis of follicular neoplasm reflect this fact.

Fetal androgen action is an important determinant of Sertoli cell (SC) number at birth. Androgens "program" reproductive tract development in rats between embryonic d (e) 15.5 and e17.5 ("male programming window"), and this is reflected for life by anogenital distance (AGD). We investigated if androgen regulation of SC number/proliferation was also programmed by androgens in this window. Pregnant rats were treated in various fetal time windows with vehicle (control) or 500 mg/kg.d di(n-butyl) phthalate (DBP), which suppresses fetal intratesticular testosterone (ITT). ITT and SC number/proliferation index were determined at e17.5 or e21.5; AGD was also determined at e21.5. In controls, SC number increased 11-fold and ITT by 10-fold from e17.5-e21.5. In animals exposed daily to DBP from e13.5, SC number was reduced by approximately 50% at e21.5, but increased 6-fold, as did ITT, from e17.5-e21.5; DBP had no effect on ITT at e15.5, reduced ITT by 50% at e17.5, and by more than 75% at e19.5-21.5. DBP exposure just in the male programming window did not alter SC number at e17.5 or 21.5 but reduced AGD. DBP treatment beyond e19.5 caused major reductions in SC number/proliferation index and ITT at e21.5. Only DBP treatments that included the male programming window led to reduced AGD at e21.5, but SC number was clearly not programmed in this window. Nevertheless, testis weight correlated highly (P<0.001) with AGD at e21.5, and postnatal d 25 and 90 in animals exposed in utero to vehicle or DBP (e13.5-e21.5). Thus, AGD may predict adult testis size but probably not through a direct relationship with SC number.

Compelling epidemiological evidence suggests that exposure to an adverse intrauterine environment, manifested by low-birth weight, is associated with cardiometabolic and behavioural disorders in adulthood. These observations have led to the concept of 'fetal programming'. The molecular mechanisms that underlie this relationship remain unclear, but are being extensively investigated using a number of experimental models. One major hypothesis for early life physiological programming implicates fetal overexposure to stress (glucocorticoid) hormones. Several animal studies have shown that prenatal glucocorticoid excess, either from endogenous overproduction with maternal stress or through exogenous administration to the mother or fetus, reduces birth weight and causes lifelong hypertension, hyperglycaemia and behavioural abnormality in the offspring. Intriguingly, these effects are transmitted across generations without further exposure to glucocorticoids, which suggests an epigenetic mechanism. These animal observations could have huge implications if extrapolated to humans, where glucocorticoids have extensive therapeutic use in obstetric and neonatal practice.

Objective: To describe a rare case of acute myocardial infarction in a patient with neurofibromatosis 1 and pheochromocytoma and to review the literature on the coexistence of these 2 diseases, the causes of myocardial injury in patients with pheochromocytoma, and the utility of genetic testing and pheochromocytoma screening for those patients and their families., Methods: We present a case report, including the detailed clinical, laboratory, and radiographic data, results of adrenal mass pathology, and results of coronary angiography. We also survey other relevant reports available in the literature., Results: A 43-year-old woman with a history of long-standing hypertension, neurofibromatosis 1, headaches, sweating, and palpitations presented to the hospital with chest pain and shortness of breath. She was found to have an acute myocardial infarction and pulmonary edema, as well as a right adrenal mass. A pheochromocytoma was suspected, and phenoxybenzamine was added to her treatment regimen. Cardiac catheterization showed nonobstructive coronary disease. The levels of plasma catecholamine metabolites were extremely high. The patient underwent uncomplicated laparoscopic right adrenalectomy 2 weeks after this admission. Surgical pathology confirmed the diagnosis of pheochromocytoma., Conclusion: Adrenergic crisis attributable to pheochromocytoma can result in acute myocardial infarction even in the absence of obstructive coronary disease. Inclusion of pheochromocytoma in the differential diagnosis of hypertension in patients with neurofibromatosis is very important and helps avoid mistakes in the management of such patients.

Papillary thyroid carcinoma (PTC) commonly metastasizes to cervical lymph nodes. Distant metastases are unusual with the lungs most frequently involved. Well-differentiated thyroid carcinoma very rarely presents with metastases to the spleen. This is the case of a 25-year-old man with a history of PTC (1.4 cm primary; no capsular invasion and negative lymph node metastases). One year after initial surgery, recurrent disease was found in multiple neck nodes by central neck dissection. Whole body scan (WBS) following a therapeutic ablation dose of 150 mCi I(131) revealed mediastinal metastases. Computerized axial tomography (CT) of the chest one year later showed no gross mediastinal or pulmonary disease. However, multiple large splenic lesions were incidentally noted. Evaluation by ultrasound (US) showed lesions to be solid echogenic masses without remarkable Doppler characteristics to suggest vascular tumors. US-guided percutaneous fine-needle aspiration biopsy (FNAB) of one lesion was nondiagnostic. After withdrawal from Levothyroxine, serum TSH was >100 mU/L with a thyroglobulin of 9.4 ng/mL and negative anti-thyroglobulin antibodies. Diagnostic WBS revealed faint splenic uptake but was otherwise unremarkable. Following treatment with 192 mCi I(131), WBS demonstrated increased activity in the mediastinum as well as in the spleen suggesting mediastinal and splenic metastases. Contrast CT of the abdomen showed multiple low-attenuated heterogeneously enhancing splenic masses, normal liver and no intra-abdominal lymphadenopathy. The largest mass (4.5 x 3.5 cm) was exophytic and in close proximity to the splenic capsule. Despite the serum thyroglobulin of only 9.4 ng/mL, the finding of I(131) accumulation within solid splenic masses led to a preoperative diagnosis of thyroid carcinoma metastases. To establish the diagnosis and to remove the risk for splenic rupture, a laparoscopic splenectomy was performed. Histopathologic analysis showed large littoral cell angiomas (LCA). False-positive radioiodine scintigraphy in the setting of PTC involving a vertebral hemangioma has been reported. To our knowledge, this is the first case that describes multiple angiomas mimicking metastatic thyroid carcinoma to the spleen. In one-third of all cases reported, LCA co-exists with various visceral organ cancers or malignant lymphoma. This is the first report of an association between LCA and thyroid carcinoma.

Altered peripheral glucocorticoid metabolism may be important in the pathogenesis of obesity in humans and animal models. Genetically obese Zucker rats, Lep/ob mice, and obese humans exhibit increased regeneration of active glucocorticoids selectively in adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) and increased glucocorticoid clearance by hepatic A-ring reductases. We have examined whether dietary obesity in rats induces the same changes in glucocorticoid metabolism. Male Wistar rats were weaned onto high-fat (HF; 45% kcal from fat) or control (10% fat) diets. After 3 wk, HF rats showed no differences in weight but were glucose intolerant, had lower 11beta-HSD-1 activity in liver (3.8 +/- 0.2 vs. 4.9 +/- 0.2 pmol product/min.mg protein; P <0.01), sc fat (0.03 +/- 0.01 vs. 0.09 +/- 0.01 pmol product/min.mg protein; P <0.01), and omental fat (0.02 +/- 0.001 vs. 0.03 +/- 0.003 pmol/ product/min.mg protein; P <0.05) and higher hepatic 5beta-reductase activity (0.26 +/- 0.05 vs. 0.10 +/- 0.007 pmol product/min.mg protein; P <0.05). After 20 wk, HF rats were obese, hyperglycemic, and hyperinsulinemic, but differences in 11beta-HSD-1 and 5beta-reductase activities were no longer apparent. Mature male rats given HF diets for 24 or 72 h showed increased hepatic 5beta-reductase activity and a trend for decreased sc adipose 11beta-HSD-1 activity. Dietary obesity is not accompanied by the changes in 11beta-HSD-1 and 5beta-reductase expression and activity observed in genetically obese rodents. Acute exposure to HF diet alters glucocorticoid metabolism, predicting lower hepatic and adipose intracellular glucocorticoid concentrations, which may be a key mechanism protecting against the metabolic complications of obesity.

Epidemiological studies linking low birth weight and subsequent cardiometabolic disease have given rise to the hypothesis that events in fetal life permanently program subsequent cardiovascular risk. The effects of fetal programming may not be limited to the first-generation offspring. We have explored intergenerational effects in the dexamethasone-programmed rat, a model in which fetal exposure to excess glucocorticoid results in low birth weight with subsequent adult hyperinsulinemia and hyperglycemia underpinned by increased activity of the key hepatic gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found that the male offspring of female rats that had been exposed prenatally to dexamethasone, but were not manipulated in their own pregnancy, also had reduced birth weight (5.66 +/- 0.06 vs. 6.12 +/- 0.06 g, P < 0.001), glucose intolerance, and elevated hepatic PEPCK activity (5.7 +/- 0.6 vs. 3.3 +/- 0.2 nmol.min(-1).mg protein(-1), P < 0.001). These effects resolved in a third generation. Similar intergenerational programming was observed in offspring of male rats exposed prenatally to dexamethasone mated with control females. The persistence of such programming effects through several generations, transmitted by either maternal or paternal lines, indicates the potential importance of epigenetic factors in the intergenerational inheritance of the "programming phenotype" and provides a basis for the inherited association between low birth weight and cardiovascular risk factors.

One hundred sixty-four (164) healthy, young Caucasian women enrolled as midshipmen at the United States Naval Academy with no known disease or bone injury were followed for 3.6 years. Change in bone mineral density (BMD) of the hip, lumbar spine and distal tibia, and total body bone mineral content (TBMC) was measured by dual energy X-ray absorptiometry (DXA). Bone mineral density and TBMC of these women were measured within 2 months (60 +/- 4 days) of entering the Academy and annually. Over the study period, hip BMD increased 2.26% (P < 0.001), lumbar spine BMD increased 3.27% (P < 0.001) and distal tibia BMD increased 5.2% (P < 0.001). Total body bone mineral content showed a 5.25% (P < 0.001) increase during the study period. In this group of young women, gain in BMD and TBMC continued until age 22. These results suggest that bone mass may accrue in certain groups of women beyond age 22. The significance of this increase in bone mass during early adulthood on risk for osteoporotic fractures in later life and its impact on exercise-related bone injuries are unknown and warrant further examination.

Objective: To compare the clinical and biochemical features, bone densitometry data, and results of diagnostic imaging to localize parathyroid tumors in patients with radiation-associated hyperparathyroidism (R-HPT) and patients with HPT who had no history of radiation exposure (NR-HPT)., Methods: We performed a retrospective analysis of 34 patients with HPT who underwent evaluation and subsequent neck exploration between 1990 and 1995. We recorded and compared the symptoms, biochemical findings, bone densitometry data, results of diagnostic imaging, and pathologic findings in R-HPT and NR-HPT groups., Results: The R-HPT group (8 men and 4 women)generally was older than the NR-HPT group (14 men and 8 women), but the age difference was not statistically significant. Patients in the R-HPT group had received radiotherapy (6.9 to 21.7 Gy) between 2 and 9 years of age for various diagnoses. Eight patients (67%) in the R-HPT group and 13 (59%) in the NR-HPT group had no symptoms of HPT. The rest of the patients in both groups had nonspecific symptoms, such as fatigue and dyspepsia. Four patients (18%) in the NR-HPT group had nephrolithiasis, and 3 (14%) had skeletal manifestations at initial assessment. Serum calcium, phosphorus, and parathyroid hormone levels and 24-hour urine calcium excretion were similar in both groups. Mean lumbar spine bone mineral density was lower in women in the R-HPT group than in those in the NR-HPT group, but the prevalence of osteoporosis did not differ significantly in the two study groups. Sestamibi scintigraphy accurately localized adenomas in both groups equally well (sensitivity >90%). In the R-HPT group, 11 patients had a single parathyroid adenoma and 1 had hyperplasia of all four parathyroid glands. In the NR-HPT group, 21 patients had a single parathyroid adenoma and 1 had parathyroid hyperplasia. In nine patients in the R-HPT group, ultrasonography showed thyroid nodules >1 cm. Pathologic examination of surgical specimens in the R-HPT group confirmed thyroid carcinoma in 11 patients ( 10 papillary and 1 follicular can-cer); no patient in the NR-HPT group had thyroid cancer. Six weeks after thyroidectomy, patients with thyroid can-cer received 1311 (mean dose, 145 mCi), five of whom needed additional 1311 treatments., Conclusion: Patients with a history of childhood neck irradiation who have HPT have a high likelihood of coexisting thyroid cancer. This observation may justify surgical exploration rather than vigilant follow-up in asymptomatic patients with primary HPT and coexisting thyroid nodules who have a history of radiation exposure.

We report four white adolescents aged 13 to 15 years (three females, one male) from the south and west region of England who presented with type 2 diabetes mellitus associated with significant obesity (body mass index more than +3SDS) in the past two years. Although these are the first reported obese, white cases from the UK to present with diabetes, we believe this clinical scenario will become more prevalent given the epidemic of childhood obesity in this country.

The nature of dark matter remains mysterious, with luminous material accounting for at most approximately 25 per cent of the baryons in the Universe. We accordingly undertook a survey looking for the microlensing of stars in the Large Magellanic Cloud (LMC) to determine the fraction of Galactic dark matter contained in massive compact halo objects (MACHOs). The presence of the dark matter would be revealed by gravitational lensing of the light from an LMC star as the foreground dark matter moves across the line of sight. The duration of the lensing event is the key observable parameter, but gives non-unique solutions when attempting to estimate the mass, distance and transverse velocity of the lens. The survey results to date indicate that between 8 and 50 per cent of the baryonic mass of the Galactic halo is in the form of MACHOs (ref. 3), but removing the degeneracy by identifying a lensing object would tighten the constraints on the mass in MACHOs. Here we report a direct image of a microlens, revealing it to be a nearby low-mass star in the disk of the Milky Way. This is consistent with the expected frequency of nearby stars acting as lenses, and demonstrates a direct determination of a lens mass from a microlensing event. Complete solutions such as this for halo microlensing events will probe directly the nature of the MACHOs.

Aims: To investigate pancreatic function in children attending an obesity clinic., Methods: Thirty six children (of which 34 were white) with severe obesity of prepubertal onset (body mass index more than +2 SDS) were reviewed clinically and dysmorphologically, with assessment of pancreatic function., Results: Eight had dysmorphic features and 13 had learning difficulties. Four of 17 prepubertal children had hyperinsulinaemia and seven had hyperproinsulinaemia. All 19 pubertal children had hyperinsulinaemia, 14 had hyperproinsulinaemia, and one had type II diabetes., Conclusions: Metabolic abnormalities predictive of type II diabetes occur in severely obese white children.

Eighty-six healthy, young Caucasian 18-year-old men with no known disease or bone injury were recruited to this study at the United States Naval Academy. Change in bone mineral density (BMD) of the hip, lumbar spine, and distal tibia, and total body bone mineral content (TBMC) was measured by dual-energy X-ray absorptiometry (DXA). BMD and TBMC of these men were measured within 2 months (67 +/- 3 days) of entering the Academy, and, at the end of their first, second, and fourth years. Hip BMD was unchanged during the study period (p > 0.05). Lumbar spine BMD increased 3% (p < 0.001) and distal tibia BMD increased 5% (p < 0.001). TBMC showed a 7.5% increase over the study period. In this group of young men, gain in BMD and TBMC is greatest to age 21 years, with minimal further increase after age 21. The significance of this rise in bone mass during early adulthood on risk for osteoporotic fractures in later life or its impact on exercise-related bone injuries is unknown and warrants further examination.

Aim: To assess the changes in services for children with diabetes in the south west of England between two region-wide audits performed in 1994 and 1998., Methods: Questionnaires were sent to consultant paediatricians, specialist diabetes nurses, dietitians, and Local Diabetes Service Advisory Groups. Information was gathered on consultant and nursing caseload, clinic structure, dietetic and psychological services, glycated haemoglobin use, and screening services., Results: In 1994 there were 21 consultant paediatricians caring for children with diabetes, only seven of whom fulfilled the British Paediatric Association definition of a specialist. By 1998 there were 14, 12 of whom fulfilled this definition. In 1994 a significant number of children were being seen in general paediatric clinics; by 1998 all centres stated that children were being seen in designated diabetes clinics. Between the two audits, despite a decrease in the average caseload of specialist diabetes nurses, nursing services in many centres remained deficient, as did dietetic and psychology services. Glycated haemoglobin use increased from 16 of 21 consultants to all consultants. In 1998 there was still patchy paediatric representation on Local Diabetes Service Advisory Groups., Conclusions: The 1994 audit was followed by a change in clinical practice, in contrast to continuing deficiencies in resources, despite the availability of national recommendations and the widespread distribution of the audit report to those in a position of influence.

Usual causes of intolerance to thyroxine sodium include coronary artery disease, advanced age, untreated adrenal insufficiency, and severe hypothyroidism. We describe 4 patients with iron deficiency anemia and primary hypothyroidism. After treatment with thyroxine sodium, these patients developed palpitations and feelings of restlessness, which necessitated discontinuation of the thyroid hormone. After the anemia was treated with ferrous sulfate for 4 to 7 weeks, they were able to tolerate thyroxine sodium therapy. Iron deficiency anemia coexisting with primary hypothyroidism results in a hyperadrenergic state. In such patients, we postulate that thyroid hormone administration causes palpitations, nervousness, and feelings of restlessness. Correction of any existing pronounced anemia in hypothyroid patients who are intolerant to thyroxine sodium therapy may result in tolerance to this agent.

Growth hormone hypersecretion is extremely rare in childhood. We report a girl with neurofibromatosis type 1, an extensive optic nerve glioma and growth hormone hypersecretion. She was treated with chemotherapy to prevent further extension of her sight-threatening tumour. Three years after chemotherapy her growth hormone hypersecretion has resolved although she has gone on to develop precocious puberty., (Copyright 2001 S. Karger AG, Basel)

Objective: To assess the efficacy of alendronate therapy on bone mineral density (BMD) at the lumbar spine and hip in men with osteoporosis., Methods: Medical records of male patients with osteoporosis, who had undergone follow-up in the Endocrinology Clinic at the National Naval Medical Center, were reviewed, and nine patients treated with alendronate for at least 1 year were identified. Patients were excluded from analysis if they had evidence of osteomalacia or if baseline and follow-up BMD results on the same dual-energy x-ray absorptiometry (DEXA) densitometer, at least 10 months apart, were not available. DEXA BMD results at the lumbar spine and hip, before and after at least 10 months of alendronate treatment, were analyzed for significant differences. Patients were also receiving calcium supplementation (1,000 to 1,500 mg/day), and all but one patient received vitamin D (400 to 800 U/day)., Results: Lumbar spine BMD increased by 6.4 +/- 1.8% per year with alendronate treatment (P = 0.008). A mean absolute gain of 0.052 +/- 0.010 g/cm 2 (P = 0.005) in lumbar spine BMD was noted for the entire study group (N = 9), after a mean duration of treatment of 14 +/- 1 months. The mean lumbar spine BMD Z score improved by 0.40 +/- 0.09 (P = 0.002) with alendronate therapy. The femoral neck BMD also increased by 4.5 +/- 1.4% per year with alendronate treatment (P = 0.013). The mean absolute gain in femoral neck BMD was 0.028 +/- 0.009 g/cm 2 (P = 0.013) for the study group (N = 9) after 14 +/- 1 months of therapy. The mean femoral neck BMD Z score improved 0.30 +/- 0.08 (P = 0.005) with treatment. BMD gains at the greater trochanter of 3.2 +/- 1.5% per year (P = 0.067) and at Ward's triangle of 9.1 +/- 4.2% per year (P = 0.061) were not statistically significant. Two patients discontinued alendronate treatment after 1 year because of epigastric or retrosternal pain., Conclusion: Oral alendronate treatment, given in combination with calcium supplementation and physiologic doses of vitamin D, resulted in significant improvements in lumbar spine and femoral neck BMD after a 14-month period in this small group of men with osteoporosis. Although controlled, prospective trials involving larger numbers of male patients with fracture incidence data are needed before definitive conclusions can be made, alendronate treatment seems to be effective in improving BMD in men with osteoporosis, similar to its efficacy in women.

Objective: To assess the clinical utility of bone mineral density (BMD) of Ward's triangle by dual-energy absorptiometry (DEXA) as an indicator of osteoporosis in comparison with quantitative computed tomography (QCT) of the lumbar spine and DEXA of the lumbar spine and hip sites (trochanter and femoral neck)., Methods: We conducted a retrospective study of all patients (28 men and 17 women) with decreased BMD by QCT (T-score less than -1.0) who had DEXA BMD performed at the lumbar spine and hip between October 1993 and January 1995 in our Endocrine Clinic., Results: Osteoporosis based on the World Health Organization criteria (T-score less than -2.5) was defined by QCT lumbar spine BMD in 78% of the study subjects and by DEXA of Ward's triangle in 53%, of the femoral neck in 22%, of the trochanter in 7%, and of the lumbar spine in 2%. In the men, the only DEXA BMD measurement that was sensitive for detecting osteoporosis was Ward's triangle. Of the 24 men with osteoporosis by QCT BMD, 14 were defined as having osteoporosis by DEXA exclusively at Ward's triangle. The DEXA lumbar spine BMD measurement was actually above the mean for young normal control subjects in 8 of the 24 men with osteoporosis by QCT BMD. In the 11 women with osteoporosis by QCT BMD, the DEXA BMD at Ward's triangle and the femoral neck were equally sensitive in detecting osteoporosis, whereas the DEXA lumbar spine and trochanter BMD measurements were insensitive., Conclusion: DEXA BMD of Ward's triangle is a sensitive indicator of osteoporosis, particularly in men, and should be used to identify patients at increased risk for osteoporosis-related fractures.

Objective: To characterize a disorder of episodes of flushing and increased levels of 5-hydroxyindoleacetic acid (5-HIAA) in men with secondary hypogonadism who respond to testosterone therapy., Material and Methods: We present detailed case reports of three male patients who had flushing, secondary hypogonadism, and increased urinary 5-HIAA levels and describe their clinical and laboratory features before and after treatment with testosterone. In addition, six male patients with hypogonadism (three with primary and three with secondary hypogonadism) without flushing were assessed., Results: The three patients with flushing and secondary hypogonadism (serum total testosterone 5.45 +/- 0.63 nmol/L, free testosterone 89.3 +/- 7.0 pmol/L, follicle-stimulating hormone 3.85 +/- 0.58 IU/L, and luteinizing hormone 4.41 +/- 0.98 IU/L) had increased urinary 5-HIAA levels (98.5 +/- 12.2 micromol/24 h) but normal blood serotonin levels (9.66 +/- 1.58 micromol/L). During a pentagastrin-calcium stimulation test, serum calcitonin and blood serotonin values were normal in patients with secondary hypogonadism and flushing. Detailed investigation showed no evidence of a carcinoid tumor. Urinary 5-HIAA levels became normal (16.6 +/- 1.73 micromol/24 h) after treatment with testosterone. When testosterone therapy was discontinued in two patients, flushing and increased urinary 5-HIAA levels recurred. Furthermore, flushing and the elevated urinary 5-HIAA values resolved when testosterone treatment was reinitiated. The six patients with hypogonadism without flushing had normal urinary 5-HIAA levels (14.9 +/- 3.31 micromol/24 h)., Conclusion: Male patients with flushing and increased urinary 5-HIAA levels should undergo assessment for hypogonadism after screening for carcinoid tumor. If hypogonadism is diagnosed, resolution of flushing and normalization of 5-HIAA may be achieved with testosterone treatment. We suggest that pseudocarcinoid syndrome associated with hypogonadism be the descriptive label used for this combination of clinical features.

It is estimated that there are up to 14 to 15 million diabetics in the United States and that many are unaware of their condition. Millions of women will become pregnant each year, although many will take oral contraceptives to prevent pregnancy. Thousands of patients are prescribed chronic doses of glucocorticoid medications every year. Many of these patients can be expected to seek some degree of dental care. The dentist must have a basic understanding of the physiologic changes associated with each of these endocrinological conditions to provide safe and appropriate dental care.

Objective: To evaluate the effects of nicotinic acid on serum thyroid hormone levels in the absence of systemic illness or hepatic dysfunction., Design: We determined the effect of treatment with nicotinic acid on serum thyroid hormone levels in one female and four male patients (mean age, 44.4 years) with hyperlipidemia., Material and Methods: In the five study patients, we measured serum lipids in conjunction with serum thyroxine (T4), triiodothyronine (T3) resin uptake, T3, free T4, thyroid-stimulating hormone (TSH), and thyroxine-binding globulin before, during, and after treatment with nicotinic acid., Results: Serum lipid levels responded appropriately to nicotinic acid treatment. Thyroid function studies done a mean of 1.3 years (range, 0.5 to 3.5) after initiation of nicotinic acid therapy (mean daily dose, 2.6 +/- 0.7 g) revealed significant decreases in serum levels of total T4 (21%), free T4 index (16%), T3 (13%), and thyroxine-binding globulin (23%) (P < 0.02), whereas no significant changes were noted in free T4, T3 resin uptake, and TSH levels. During the course of treatment, the patients, who were carefully questioned, had no symptoms of hypothyroidism. Hypothyroidism was further excluded in three patients who had a normal serum TSH response to administration of thyrotropin-releasing hormone. In two patients, measurements of thyroid function returned to pretreatment levels after discontinuation of nicotinic acid therapy. No patient had significant abnormalities in liver-associated enzymes or evidence of systemic illness during the course of treatment., Conclusion: These results suggest that nicotinic acid decreases serum thyroid hormone concentrations while maintaining a euthyroid state. This effect may be mediated through reduction in thyroxine-binding globulin, but other mechanisms may also be involved.

This study was undertaken to investigate whether the normal dog heart would switch to lactate as the preferred substrate when the arterial lactate level was raised. Sodium L-Lactate (pH adjusted to 7.0) was infused intravenously in sufficient quantity to raise the arterial lactate levels to those found in moderate to severe exercise (over 4.5 mmol . litre-1). The dogs were studied under chloralose anaesthesia breathing spontaneously. Blood samples were obtained from a branch of the femoral artery and the coronary sinus, and analysed for lactate, glucose, fatty free acids (FFA) and oxygen content. The ratio of lactate consumption to oxygen consumption was used to express the amount of lactate oxidised as a percentage of total substrate. This ratio was found to be a function of arterial lactate and reached a maximum at an arterial lactate concentration of 4.5 mmol . litre-1; this was uninfluenced by raised arterial glucose or FFA--the myocardium preferred lactate to glucose or FFA. A direct measurement of lactate oxidised as a percentage of total fuel was obtained in experiments with L-Lactate-[14C(U)], these showed that when the arterial lactate concentration was above 4.5 mmol . litre-1, even in the presence of high glucose or FFA, 87% of the total substrate oxidised was lactate. These results show that when the normal dog heart is presented with a choice of substrates, lactate is the preferred substrate for energy production.

We measured glucose metabolism in five dogs before and 3 weeks after cardiac denervation; after this time myocardial norepinephrine is depleted. The discharge by the myocardium, of 14CO2 from infused 14C-D-glucose (U), decreased following denervation (P = 0.05). The ratio of 14CO2 to total CO2 production, which measured the proportion of glucose to total substrate oxidized, also decreased following denervation (P = 0.05). The inhibition of glucose oxidation by denervation was not due to an increase in arterial lactate concentration. There was an associated increase in myocardial content of fructose-6-phosphate in an additional seven dogs (P < 0.01). We postulate that myocardial tissue norepinephrine is one of the controllers of the activity of phosphofructokinase.

The metabolic and haemodynamic effects of adrenaline were investigated in 6 intact anaesthetized dogs, which were subjected to an infusion of adrenaline. The dose given was similar to the endogenous production rate of adrenaline in experimental myocardial infarction. Adrenaline infusion (0.8, 1.17 ot 1.05 micrograms . kg-1 . min-1) over two hours led to a variable rise in blood level of this amine, regardless of the rate of infusion. Dogs with high blood adrenaline (over 3.5 ng . ml-1) exhibited haemodynamic deterioration, i.e. a rise in peripheral vascular resistance together with a fall in cardiac output and external cardiac work. Dogs with low blood adrenaline showed little change in peripheral vascular resistance, a rise in cardiac output and external cardiac work. The myocardial consumption of each of the substrates lactate, pyruvate, glucose and FFA was measured, and its equivalent oxygen consumption expressed as a percentage of the total myocardial oxygen consumption. No relationship was found between myocardial utilisation of individual substrates and the type of haemodynamic response. Thus in intact dogs exposed to adrenaline excess, similar to that found in acute myocardial infarction, the different types of haemodynamic response cannot be attributed to the type of substrate utilization by the myocardium, but to different rates of clearance of adrenaline. Low clearance rates lead to high blood adrenaline levels and an unfavourable response of the cardiovascular system.

Substrate extraction is the disappearance of a substance from arterial blood into the myocardium, substrate utilization being the combustion of that substrate. The terms used for extraction and utilization are defined. There are many problems of accurately measuring glucose and free fatty acid oxidation. Lactate is the preferred substrate of the normal, blood-perfused heart. If the substrate oxidized affects the myocardial oxygen consumption, this could be of considerable importance under conditions of limited oxygen supply. At present there is conflicting evidence. It may be beneficial to switch the heart from one substrate to another, e.g., from fat to carbohydrate fuels. The conditions of ischaemia and hypoxaemia are not the same, and future investigations should be made under carefully controlled conditions.

Experiments were carried out to further investigate the possibility that dopamine may have a functional role in the heart. Measurement of the activity of the enzyme tyrosine hydroxylase showed that this enzyme was present both in control hearts and in tissue with total sympathetic denervation. Furthermore, radioligand binding studies showed that there are high-affinity binding sites for dopamine in both control and denervated hearts. Our results support the view that there is dopamine in the heart which is not associated with noradrenergic nerves.