bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Ectopic or Abnormal Membrane Hormone Receptors Frequently Present in Adrenal Cushing’s Syndrome?1
Authors: Mircescu Hortensia , Jilwan Jose , N′Diaye Nina , Bourdeau Isabelle , Tremblay Johanne , Hamet Pavel , Lacroix André
Published: January 2014

Twenty consecutive patients with adrenal Cushing’s syndrome were studied with an in vivo protocol to determine the prevalence and diversity of the presence of ectopic or abnormal hormone receptors in their adrenal tissues. All six patients with bilateral ACTH-independent macronodular adrenal hyperplasia were found to have one or two abnormal adrenal receptors, including those for gastric inhibitory polypeptide, vasopressin (V1-vasopressin),β -adrenergic agonists, LH/human CG, or serotonin 5-HT4. The presence of abnormal hormone receptors was found to be less frequently present in unilateral adenomas or carcinomas (3 of 14). The identification of abnormal adrenal hormone receptors can allow new pharmacological therapies of hypercortisolism. We suggest that the clinical screening for the presence of abnormal hormone receptors should be conducted in patients with adrenal Cushing’s syndrome and, more particularly, in those with ACTH-independent macronodular adrenal hyperplasia, in the hope of offering medical therapy as an alternative to bilateral adrenalectomy.
Insights from a Successful Case of Intrahepatic Islet Transplantation into a Type 1 Diabetic Patient
Authors: Davalli Alberto M. , Maffi Paola , Socci Carlo , Sanvito Francesca , Freschi Massimo , Bertuzzi Federico , Falqui Luca , Di Carlo Valerio , Pozza Guido , Secchi Antonio
Published: January 2014

We report a case of long-term (>4 yr) successful intrahepatic islet transplantation into a type 1 diabetic patient chronically immunosuppressed for a prior kidney graft. The exogenous insulin requirement decreased progressively after transplantation, and insulin treatment was withdrawn at 6 months. Glycosylated hemoglobin levels were in the normal range at 1 and 2 yr (5.3%) and increased slightly above the upper normal limit at 3 and 4 yr (6.3% and 6.4%). Fasting C peptide levels remained stable during the entire follow-up, but the proinsulin to insulin ratios increased dramatically at yr 3. Glycemic levels after an oral glucose tolerance test showed a diabetic profile at 1 yr, a normal profile at 2 yr, and an impaired glucose tolerance profile at 3 yr. Intravenous glucose tolerance test-induced first phase insulin release, present at 1 and 2 yr, disappeared at 3 yr. Diabetes-related autoantibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase-like protein antibodies) were undetectable before transplantation and remained so during the entire follow-up. The patient died of myocardial infarction 50 months after transplantation while she was still in good metabolic control (glycosylated hemoglobin, <6.8%) in the absence of exogenous insulin administration. The autoptic liver showed well granulated islets, richly vascularized and without evidence of lympho-mononuclear cell infiltration. The morphometrically extrapolated intrahepaticβ -cell mass was 99.9 mg. In conclusion, this successful islet graft showed a bell-shaped clinical effect, maximal at 2 yr after transplantation, followed by a slow progressive decline. The absence of allo- and autoreactivities against the transplanted islets points to a nonimmune-mediated β-cell loss as the cause of graft functional deterioration.
Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche1
Authors: Ibáñez Lourdes , Valls Carme , Potau Neus , Marcos Maria Victoria , de Zegher Francis
Published: January 2014

Precocious pubarche in girls is often preceded by low weight at birth and followed by hirsutism, ovarian hyperandrogenism, and oligomenorrhea in adolescence, the latter usually being accompanied by dyslipidemia and hyperinsulinism, which are, in turn, two major risk factors for cardiovascular disease in later life. We hypothesized that insulin resistance may be a key pathogenetic factor in this sequence.

We tested the hypothesis by assessing the effects of an insulin-sensitizing agent, metformin, given at a daily dose of 1275 mg for 6 months to 10 nonobese adolescent girls (mean age, 16.8 yr; body mass index, 21.9 kg/m2; birth weight, 2.7 kg) with hirsutism, ovarian hyperandrogenism (diagnosis by GnRH agonist test), oligomenorrhea, dyslipidemia, and hyperinsulinemia after precocious pubarche. Before the metformin trial, longitudinal studies in these girls had shown that hyperinsulinism was present at prepubertal diagnosis of precocious pubarche, and that it increased markedly in late puberty or early postmenarche.

Metformin treatment was well tolerated and was accompanied by a marked drop in hirsutism score, insulin response to oral glucose tolerance test, free androgen index, and baseline testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate levels (all P < 0.01). During metformin treatment, the LH and 17-hydroxyprogesterone hyperresponses to GnRH agonist were attenuated (P < 0.01); serum triglyceride, total cholesterol, and low density lipoprotein cholesterol levels decreased; and high density lipoprotein cholesterol rose. All girls reported regular menses within 4 months. Withdrawal of metformin treatment was followed, within 3 months, by a consistent reversal toward pretreatment conditions.

In conclusion, metformin treatment reduced hyperinsulinemia, hirsutism, and hyperandrogenism; attenuated the LH and 17hydroxyprogesterone hyperresponses to GnRH agonist; improved the atherogenic lipid profile; and restored eumenorrhea in nonobese adolescent girls with a history of precocious pubarche. These observations corroborate the idea that insulin resistance may indeed be a prime factor underpinning the sequence from reduced fetal growth, through precocious pubarche, to adolescent endocrinopathies that are reminiscent of so-called polycystic ovary syndrome.
Male Infertility Caused by a de Novo Partial Deletion of the DAZ Cluster on the Y Chromosome1
Authors: Moro Enrico , Ferlin Alberto , Yen Pauline Hsiao , Franchi Paolo Guanciali , Palka Giandomenico , Foresta Carlo
Published: January 2014

Deletions in distal Yq interval 6 represent the cause of 10–15% of idiopathic severe male infertility and map to a region defined AZFc (azoospermia factor c). The testis-specific gene DAZ is considered a major AZFc candidate, and its deletion has been associated with a severe disruption in spermatogenesis. However, DAZ is actually a multicopy gene family consisting of seven clustered copies spanning about 1 megabase. Only deletions removing the entire DAZ gene cluster together with other genes have been reported in infertile males. Because no case of spermatogenic failure has been traced to intragenic deletions, point mutations, or even deletions not involving all the DAZ copies, the definitive proof for a requirement of DAZ for spermatogenesis is still debatable. Here we report the first case of a partial deletion of the DAZ cluster removing all but one of the copies. This deletion is present in a patient affected with severe oligozoospermia who had a testicular phenotype characterized by a great quantitative reduction of germ cells (severe hypospermatogenesis). The absence of this deletion in the fertile brother of the patient suggests that this de novo mutation indeed caused the spermatogenic failure.
Impact of Antiandrogen Treatment on the Fatty Acid Profile of Neutral Lipids in Human Meibomian Gland Secretions1
Authors: Sullivan Benjamin D. , Evans James E. , Krenzer Kathleen L. , Reza Dana M. , Sullivan David A.
Published: January 2014

The purpose of this study was to determine whether the use of antiandrogen medications is associated with significant alterations in the fatty acid (FA) profiles of neutral lipids in human meibomian gland secretions. Meibomian gland secretions were obtained from both eyes of patients receiving antiandrogen therapy and from age-related controls. Samples were processed for high-performance liquid chromatography/mass spectrometry and an evaluation of the mass/charge ratios of neutral lipid FA. Our results demonstrate that antiandrogen therapy is associated with significant and consistent alterations in the mass/charge ratios of neutral lipid fractions of meibomian gland secretions. Patients taking antiandrogen medications had significant changes in the occurrence of numerous diglyceride, triglyceride, and wax/cholesterol ester FA products, compared with age-matched controls. Statistical analyses of data within groups demonstrated very high correlation coefficients, and cross-correlation analyses revealed characteristic shifts in FA patterns between groups. Our findings show that antiandrogen use is paralleled by significant changes in the FA profiles of neutral lipid fractions in meibomian gland secretions.
Octreotide May Act as A Radioprotective Agent in Acromegaly
Authors: Landolt Alex M. , Haller Dieter , Lomax Nicoletta , Scheib Stefan , Schubiger Othmar , Siegfried Jean , Wellis Georgios
Published: January 2014

Clinical experience shows that an increasing number of patients undergoing radiation treatment for recurring acromegaly or acromegaly persisting after surgery are treated with octreotide. We, therefore, performed a follow-up study of patients undergoing stereotactic radiosurgery (Gamma Knife) to determine whether this medication has an influence on the ultimate result of radiation therapy in either a positive or negative sense. It has been suggested that the combination of radiation with antisecretory drugs may increase the effectiveness of radiation. A follow-up study of 31 patients suffering from recurrent acromegaly and acromegaly persisting after surgery, and who had been treated with stereotactic radiosurgery, showed that patients treated with octreotide at the time of radiation application simultaneously reached a normal level of growth hormone and insulin-like growth factor-I only after a significantly longer interval than patients who did not receive the drug. The two groups of patients did not demonstrate significant differences in the main clinical findings (age, sex, target volume, radiation dose, baseline growth hormone, and baseline insulin-like growth factor-I).
Mannheim Classification of Nongenomically Initiated (Rapid) Steroid Action(s)
Authors: Falkenstein Elisabeth , Norman Anthony W. , Wehling Martin
Published: January 2014

There is increasing evidence for rapid effects of steroids that are incompatible with the classical model of genomic steroid action. To address the diversity of mechanisms for rapid steroid signaling described over the past years, a classification of rapid steroid effects has been proposed to promote the discussion and understanding of nongenomic steroid action.
Papillary Thyroid Carcinoma Associated with Papillary Renal Neoplasia: Genetic Linkage Analysis of a Distinct Heritable Tumor Syndrome*
Authors: Malchoff Carl D. , Sarfarazi Mansoor , Tendler Beatriz , Forouhar Faripour , Whalen Giles , Joshi Vijay , Arnold Andrew , Malchoff Diana M.
Published: January 2014

Papillary thyroid carcinoma usually is sporadic, but may occur in a familial form. The complete clinical and pathological phenotype of familial papillary thyroid carcinoma (fPTC) has not been determined, and the susceptibility gene(s) is unknown. We investigated the clinical and pathological characteristics of an unusually large three- generation fPTC kindred to characterize more fully the clinical phenotype. We performed linkage analysis to determine the chromosomal location of a fPTC susceptibility gene. In addition to the known association of fPTC with nodular thyroid disease, we observed the otherwise rare entity of papillary renal neoplasia (PRN) in two kindred members, one affected with PTC and the other an obligate carrier. The multifocality of PRN in one subject adds weight to the likelihood of a true genetic predisposition to PRN. Both genetic linkage and sequence analysis excluded MET, the protooncogene of isolated familial PRN, as the cause of the fPTC/PRN phenotype. A genome-wide screening and an investigation of specific candidate genes demonstrated that the fPTC/PRN phenotype was linked to 1q21. A maximum three-point log of likelihood ratio score of 3.58 was observed for markers D1S2343 and D1S2345 and for markers D1S2343 and D1S305. Critical recombination events limited the region of linkage to approximately 20 cM. A distinct inherited tumor syndrome has been characterized as the familial association of papillary thyroid cancer, nodular thyroid disease, and papillary renal neoplasia. The predisposing gene in a large kindred with this syndrome has been mapped to 1q21.
Quantitative Insulin Sensitivity Check Index: A Simple, Accurate Method for Assessing Insulin Sensitivity In Humans
Authors: Katz Arie , Nambi Sridhar S. , Mather Kieren , Baron Alain D. , Follmann Dean A. , Sullivan Gail , Quon Michael J.
Published: January 2014

Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The “gold standard” glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 non-obese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SIClamp) and minimal model analysis (SIMM) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I0) and glucose (G0)] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I0) + log(G0)]) that has substantially better correlation with SIClamp (r = 0.78) than the correlation we observed between SIMM and SIClamp. Moreover, we observed a comparable overall correlation between QUICKI and SIClamp in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
Risk for Diabetes Mellitus in Middle-Aged Caucasian Male Participants of the PROCAM Study: Implications for the Definition of Impaired Fasting Glucose by the American Diabetes Association
Authors: von Eckardstein Arnold , Schulte Helmut , Assmann Gerd
Published: January 2014

The criteria of the American Diabetes Association and the WHO for the diagnosis of diabetes mellitus are controversially discussed. In a prospective population study, we evaluated the data of 3737 men, aged 36–60 yr, without diabetes mellitus and with fasting serum glucose levels less than 7 mmol/L at entry into the study who had at least 1 repeat examination during a follow-up of 4–10 yr. During a mean follow-up of 6.3 yr, 200 men developed diabetes mellitus. They differed significantly from 3537 men by body mass index, fasting serum levels of glucose, high density lipoprotein cholesterol, and family history positive for diabetes mellitus. Receiver operating curve analysis revealed that a glucose level of 5.72 mmol/L was the best discriminatory cut-off. Upon global risk estimation by multiple logistic function (MLF) analysis, 69.6% of all diabetes mellitus incidences occurred in the highest quintile as defined by the MLF algorithm. The relative risk of a men in this quintile was 8.7 compared to that in the residual population. The performance of risk assessment by MLF as estimated by the area under the receiver operator characteristic curve was similar to fasting glucose levels.

Global risk estimation by multiple risk factors does not improve the prediction of diabetes mellitus by fasting glucose in middle-aged men. The lower discriminatory cut-off of 5.72 mmol/L glucose may help to reduce the previously reported discordance between impaired fasting glucose (American Diabetes Association) and impaired glucose tolerance (WHO) in diagnosis of the prediabetic state.
Postpartum Thyroid Dysfunction in Pregnant Thyroid Peroxidase Antibody-Positive Women Living in an Area with Mild to Moderate Iodine Deficiency: Is Iodine Supplementation Safe?
Authors: Nøhr Susanne B. , Jørgensen Annemette , Pedersen Klaus M. , Laurberg Peter
Published: January 2014

In moderately iodine-deficient, pregnant, thyroid peroxidase antibody (TPO-Ab)-positive women the role of iodine supplementation in the development of postpartum thyroid dysfunction (PPTD) was studied in a placebo-controlled, randomized, double blind trial. Screening for TPO-Ab was performed in early pregnancy in a population of healthy pregnant Danish women with no previous diagnosed thyroid disease (prevalence, 117 of 1284; 9.1%). The participants were randomized, stratified according to TPO-Ab level, to three groups. All participants received a daily vitamin and mineral tablet with 150 μg iodine or no iodine. The +/+ group received iodine during pregnancy and the postpartum period, the +/− group received iodine during pregnancy only, and the −/− group received no iodine supplementation. A total of 66 TPO-Ab positive women were followed, and in the postpartum period sera were collected at 8-week interval for biochemical evaluation of thyroid function and antibody level. Compliance was evaluated by 24-h urinary iodine measurements.

PPTD developed in 55% of the participants. In 67% of the cases abnormal TSH was accompanied by abnormalities in thyroid hormones, whereas 33% had abnormal serum TSH only. There was no statistically significant difference in the frequency of PPTD in the three groups:+ /+ group, 59% (95% confidence interval, 36−79%); +/− group, 60% (36−81%); and −/− group, 46% (26–67%). There were also no differences in the severity of the PPTD, as evaluated by duration and grade of deviation of TSH and thyroid hormones from normality. The occurrence, severity, and type of PPTD predominantly depended on the TPO-Ab level: TPO-Ab below 200 U/L at screening, 35% developed PPTD; TPO-Ab of 200–900 U/L, 54%; and TPO-Ab above 900 U/L, 75% developed PPTD. Women with low levels of antibodies predominantly remained euthyroid or had hyperthyroidism only, whereas women with high antibody levels had hyperthyroidism followed by hypothyroidism or hypothyroidism only. We conclude that iodine supplementation (150 μg) during pregnancy and the postpartum period to TPO-Ab-positive women living in an area with mild to moderate iodine deficiency did not induce or worsen PPTD. The study confirmed that screening for TPO-Ab in early pregnancy can predict women at high risk for development of PPTD.
Diminished Melatonin Secretion in the Elderly Caused by Insufficient Environmental Illumination1
Authors: Mishima K. , Okawa M. , Shimizu T. , Hishikawa Y.
Published: January 2014

The pineal hormone melatonin has some circadian regulatory effects and is assumed to have a close relation with sleep initiation and maintenance. Many previous reports have described age-related decreases in melatonin levels, especially in elderly insomniacs (EIs), which may act as causal or exacerbating factors in sleep disturbances in the elderly. Ten elderly residents with psychophysiological insomnia (mean age, 74.2 yr), 10 healthy residents of the same home [elderly control (EC) group; mean age, 72.7 yr], and 10 healthy young control subjects (mean age, 20.9 yr) living at home participated in this study. The elderly persons, especially the EIs, were exposed to significantly less environmental light and simultaneously suffered from significantly diminished nocturnal melatonin secretion. Supplementary exposure to 4 h (1000 to 1200 h, 1400 to 1600 h) of midday bright light in the EI group significantly increased melatonin secretion to levels similar to those in the young control group without circadian phase-shifting. There was a tendency for the magnitude of the increase in nocturnal melatonin secretion stimulated by bright light to parallel amelioration of sleep disturbances in these subjects. The present findings suggest that we need to pay attention to elderly individuals who suffer under conditions of poor environmental light resulting in disorganized circadian rhythms, including the sleep-wake cycle.
Association between Serum Leptin Concentrations and Bone Mineral Density, and Biochemical Markers of Bone Turnover in Adult Men
Authors: Sato Mayumi , Takeda Noriyuki , Sarui Hiroshi , Takami Rieko , Takami Kazuhisa , Hayashi Makoto , Sasaki Akihiko , Kawachi Shinnichi , Yoshino Koji , Yasuda Keigo
Published: January 2014

Leptin, the product of the ob gene, has been shown to inhibit bone formation in mice. We addressed whether leptin has any role in the regulation of bone mineral density (BMD) in humans. Subjects were 221 adult men with a mean (±sd) age and body mass index of 52.1 ± 8.7 yr and 23.6 ± 2.8 kg/m2. Serum leptin, carboxyterminal propeptide of type 1 procollagen (PICP; a marker of bone formation), and cross-linked carboxyterminal teleopeptide of type 1 collagen (a marker of bone resorption) were measured by RIA. BMD was assessed by single photon absorptiometry, and total fat mass was determined by bioimpedance analysis. BMD was inversely associated with serum leptin concentrations and total fat mass after adjustment for body weight. PICP, but not cross-linked carboxyterminal teleopeptide of type 1 collagen, was inversely correlated with serum leptin. These results may suggest that an increase in serum leptin reduces bone formation and decreases BMD in adult men. Leptin may be a regulator of BMD in humans.
The Utility of Plasma CRH as a Predictor of Preterm Delivery
Authors: Inder Warrick J. , Prickett Timothy C. R. , Ellis M. Jane , Hull Louise , Reid Rosemary , Benny Peter S. , Livesey John H. , Donald Richard A.
Published: January 2014

It has been suggested that CRH is a placental clock that controls the duration of pregnancy and that the timing of the rise in CRH may permit prediction of the onset of labor. We have performed a prospective longitudinal study, in 297 women, to examine the utility of a single second-trimester plasma CRH measurement to predict preterm delivery. Venous blood samples were taken at 4-weekly intervals, beginning at 16–20 wk gestation, until delivery for CRH and its binding protein. A time point at which a single plasma CRH test might give optimal data to predict preterm delivery was determined. Thirty-one subjects delivered prematurely (10.4%). Sampling for plasma CRH at 26 wk gestation seemed the optimal time point to maximize sensitivity and specificity of the test. The mean (± sd) plasma CRH in women at this gestation who eventually delivered after spontaneous labor within 1 wk of their due date (39–41 wk, n = 127) was 34.7 ± 27.0 pm. A plasma CRH of more than 90 pm at 26 wk gestation had a sensitivity of 45% and a specificity of 94% for prediction of preterm delivery. The positive predictive value was 46.7%. Calculation of free CRH did not improve these figures. In conclusion, a single measurement of plasma CRH, toward the end of the second trimester, may identify a group at risk for preterm delivery, but over 50% of such deliveries will be unpredicted. These data do not support the routine clinical use of plasma CRH as a predictor of preterm labor.
Effect of Exogenous Cholecystokinin (CCK)-8 on Food Intake and Plasma CCK, Leptin, and Insulin Concentrations in Older and Young Adults: Evidence for Increased CCK Activity as a Cause of the Anorexia of Aging
Authors: MacIntosh Caroline G. , Morley John E. , Wishart Judith , Morris Howard , Jansen Jan B. M. J. , Horowitz Michael , Chapman Ian M.
Published: January 2014

Healthy aging is associated with reductions in appetite and food intake—the so-called anorexia of aging, which may predispose to protein-energy malnutrition. One possible cause of the anorexia of aging is an increased satiating effect of cholecystokinin (CCK). To investigate the impact of aging on the satiating effects of CCK, 12 young and 12 older healthy subjects received 25-min iv infusions of saline (control) and CCK-8, 1 ng/kg per min or 3 ng/k per min, on 3 separate days before a test meal. Older subjects ate less than young subjects, and food intake was suppressed 21.6% by CCK-8, compared with the control day (P < 0.05). The suppression of energy intake by CCK-8 in older subjects was twice that in young subjects (32 ± 6% vs. 16 ± 6% sem, P < 0.05) and was related to plasma CCK-8 concentrations, which were higher at baseline (P < 0.05) and increased more during CCK-8 infusions in older than young subjects (P < 0.01). The extent of suppression of food intake per given rise in plasma CCK-8 concentrations did not differ between the two age groups (P = 0.35). Endogenous CCK concentrations were higher at baseline in older subjects (P < 0.001) and decreased during the CCK-8 but not control infusions (P < 0.01), suggesting that CCK suppresses its own release. Plasma leptin concentrations were not affected by CCK infusion, whereas postprandial insulin concentrations were lowered and the peak postprandial glucose concentration was delayed but not affected by CCK-8 infusion. Because older people retain their sensitivity to the satiating effects of exogenous CCK and plasma endogenous CCK concentrations are higher in older people, increased CCK activity may contribute to the anorexia of aging.
Associations of Serum Osteoprotegerin Levels with Diabetes, Stroke, Bone Density, Fractures, and Mortality in Elderly Women1
Authors: Browner Warren S. , Lui Li-Yung , Cummings Steven R.
Published: January 2014

Osteoprotegerin (OPG) and its ligand are cytokines that regulate osteoclastogenesis and that may be involved in the regulation of vascular calcification. We examined whether serum OPG levels were associated with stroke, mortality, and cardiovascular risk factors, including diabetes, as well as with bone mineral density and fractures in a sample of 490 participants in a prospective cohort of white women, at least 65 yr of age. We found that OPG levels, assayed blinded from serum obtained at baseline, were about 30% greater in women with diabetes (mean ± sd, 0.30 ± 0.17 ng/mL) than in those without diabetes (0.23 ± 0.10 ng/mL; P= 0.0001). OPG levels were associated with all-cause mortality[ age-adjusted odds ratio, 1.4/sd (0.11 ng/mL) increase in serum OPG level; 95% confidence interval, 1.2–1.8] and cardiovascular mortality (odds ratio, 1.4; 95% confidence interval, 1.1–1.8); these effects were not confounded by diabetes. OPG levels were not associated with baseline bone mineral density or with subsequent strokes or fractures. The association of serum OPG levels with diabetes and with cardiovascular mortality raises the possibility that OPG may be a cause of or a marker for vascular calcification.
Interleukin (IL)-1β Regulation of IL-1β and IL-1 Receptor Antagonist Expression in Cultured Human Endometrial Stromal Cells1
Authors: Huang Hong-Yuan , Wen Yan , Kruessel Jan S. , Raga Francisco , Soong Yung-Kuei , Polan Mary Lake
Published: January 2014

The interleukin (IL)-1 system is a major regulator of local cellular interactions during embryonic implantation. Because IL-1β and IL receptor antagonist (IL-1ra) are both expressed in human endometrium, we hypothesized that an appropriate ratio of IL-1β to IL-1ra might favor the process of embryo implantation. Therefore, we investigated IL-1 regulation of the quantitative ratio of IL-1β/IL-1ra messenger RNA (mRNA) expression in human endometrial stromal cells using quantitative competitive PCR, as well as intracellular protein expression after stromal cell solubilization. Confluent stromal cell cultures were stimulated with human IL-1β (0–1000 IU/mL) for 24 h. After 24 h, total RNA was extracted, reverse transcribed, and coamplified by PCR with a defined amount of internal standard. The quantitative ratio was determined by the density of target to the internal standard. After culture with IL-1β for 24 and 48 h, stromal cells were solubilized, and the intracellular protein levels of IL-1β and IL-1ra were measured by enzyme-linked immunosorbent assay. The IL-1β and IL-1ra mRNA were both up-regulated, and IL-1R tI mRNA was down-regulated, by IL-1β in a dose-dependent manner. The quantitative ratio of IL-1β to IL-1ra mRNA was constant with the presence of increasing concentrations of IL-1β (1–1000 IU/mL). IL-1β and IL-1ra protein was not detected in conditioned media of cultures before addition of IL-1β. IL-1β and IL-1ra protein levels increased with increasing amounts of IL-1β after solubilization of stromal cells. The IL-1β was detectable after 12 h of culture, in comparison with IL-1ra, which was detectable after 24 h of IL-1β stimulation. These results suggest that IL-1 may play a crucial role in embryo-maternal interaction by regulating stromal cell expression of IL-1β and IL-1ra, resulting in an appropriate ratio during the process of embryonic implantation.
Insulin Sensitivity Regulates Autonomic Control of Heart Rate Variation Independent of Body Weight in Normal Subjects1
Authors: Bergholm R. , Westerbacka J. , Vehkavaara S. , Seppälä-Lindroos A. , Goto T. , Yki-Järvinen H.
Published: January 2014

It is unclear whether insulin sensitivity independent of body weight regulates control of heart rate variation (HRV) by the autonomic nervous system.

Insulin action on whole-body glucose uptake (M-value) and heart rate variability were measured in 21 normal men. The subjects were divided into 2 groups [normally insulin sensitive (IS, 8.0 ± 0.4 mg/kg·min) and less insulin sensitive (IR, 5.1 ± 0.3 mg/kg·min)] based on their median M-value (6.2 mg/kg·min). Spectral power analysis of heart rate variability was performed in the basal state and every 30 min during the insulin infusion.

The IS and IR groups were comparable, with respect to age (27 ± 2 vs. 26 ± 2 yr), body mass index (22 ± 1 vs. 23 ± 1 kg/m2), body fat (13± 1 vs. 13 ± 1%), systolic (121 ± 16 vs. 117 ± 14 mm Hg) and diastolic (74 ± 11 vs. 73 ± 11 mm Hg) blood pressures, and fasting plasma glucose (5.4 ± 0.1 vs. 5.5 ± 0.1 mmol/L) concentrations. Fasting plasma insulin was significantly higher in the IR (30 ± 4 pmol/L) than in the IS (17 ± 3 pmol/L, P < 0.05) group. In the IS group, insulin significantly increased the normalized low-frequency (LFn) component, a measure of predominantly sympathetic nervous system activity, from 36 ± 5 to 48 ± 4 normalized units (nu; 0 vs. 30–120 min, P < 0.001); whereas the normalized high-frequency (HFn) component, a measure of vagal control of HRV, decreased from 66 ± 9 to 48 ± 5 nu (P< 0.001). No changes were observed in either the normalized LF component [35 ± 5 vs. 36 ± 2 nu, not significant (NS)] or the normalized HF component (52 ± 6 vs. 51 ± 4 nu, NS) in the IR group. The ratio LF/HF, a measure of sympathovagal balance, increased significantly in the IS group (0.92 ± 0.04 vs. 1.01 ± 0.04, P < 0.01) but remained unchanged in the IR group (0.91 ± 0.04 vs. 0.92 ± 0.03, NS). Heart rate and systolic and diastolic blood pressures remained unchanged during the insulin infusion in both groups.

We conclude that insulin acutely shifts sympathovagal control of HRV toward sympathetic dominance in insulin-sensitive, but not in resistant, subjects. These data suggest that sympathetic overactivity is not a consequence of hyperinsulinemia.
Effect of Various Doses of Recombinant Human Thyrotropin on the Thyroid Radioactive Iodine Uptake and Serum Levels of Thyroid Hormones and Thyroglobulin in Normal Subjects
Authors: Torres Mira S. T. , Ramirez Luis , Simkin Peter H. , Braverman Lewis E. , Emerson Charles H.
Published: January 2014

Recombinant human TSH (rhTSH), usually given as 0.9-mg doses im on 2 successive days, increases serum thyroglobulin (Tg) and radioactive iodine uptake (RAIU) in residual thyroid tissue in patients with thyroid cancer. We previously reported that a single, relatively low dose of rhTSH (0.1 mg im) is a potent stimulator of T4, T3, and Tg secretion in normal subjects. The present study describes the effects of higher doses of rhTSH on thyroid hormone and Tg secretion. Six normal subjects for each dose group, having no evidence of thyroid disease, received either 0.3 or 0.9 mg rhTSH by im injection. Serum TSH, T4, T3, and Tg concentrations were measured at 2, 4, and 8 h and 1, 2, 3, 4, and 7 days after rhTSH administration. The peak serum TSH concentrations were 82 ± 18 and 277 ± 89 mU/L, respectively, for the 0.3- and 0.9-mg doses of rhTSH. Serum T4, T3, and Tg concentrations increased significantly in subjects receiving 0.3 and 0.9 mg rhTSH, with significant increases in T4 and T3 being observed before significant increases in serum Tg. Peak concentrations of serum T4, T3, and Tg, after 0.3 mg rhTSH administration, were 100 ± 19, 131 ± 14, and 1035 ± 724% above individual baselines, respectively. Similarly, peak concentrations of serum T4, T3, and Tg, after 0.9 mg rhTSH administration, were 102 ± 16, 134 ± 7, and 1890 ± 768% above individual baselines, respectively. These data, compared with previously reported data for the responses to 0.1 mg rhTSH, indicated that 0.1, 0.3, and 0.9 mg rhTSH had similar quantitative stimulatory effects on thyroid hormone and Tg secretion, except that the T4 response was greater in groups receiving 0.3 and 0.9 mg rhTSH than in the group receiving 0.1 mg rhTSH. We also studied the effect of rhTSH on the thyroid RAIU in the group that received 0.9 mg rhTSH. The 6- and 24-h RAIU values were significantly higher after rhTSH (pre-rhTSH, 6-h value = 12.5 ± 1.8%; 24 h value = 23 ± 2.7%; post-rhTSH, 6 h value = 27 ± 4.8%; 24-h value = 41 ± 4.2%). The stimulating effects of 0.9 mg rhTSH on the 6- and 24-h RAIUs were similar. rhTSH is a potent stimulator of T4, T3, and Tg secretion and the RAIU in normal subjects. Single doses greater than 0.1–0.3 mg do not seem to further enhance thyroid hormone or Tg secretion.
Parathyroid Hormone-Related Protein-(1–36) Stimulates Renal Tubular Calcium Reabsorption in Normal Human Volunteers: Implications for the Pathogenesis of Humoral Hypercalcemia of Malignancy1
Authors: Syed Mushtaq A. , Horwitz Mara J. , Tedesco Mary Beth , Garcia-Ocaña Adolfo , Wisniewski Stephen R. , Stewart Andrew F.
Published: January 2014

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.
Antagonists of Growth Hormone-Releasing Hormone and Somatostatin Analog RC-160 Inhibit the Growth of the OV-1063 Human Epithelial Ovarian Cancer Cell Line Xenografted into Nude Mice1
Authors: Chatzistamou Ioulia , Schally Andrew V. , Varga Jozsef L. , Groot Kate , Armatis Patricia , Busto Rebeca , Halmos Gabor
Published: January 2014

The effects of antagonists of GHRH and the somatostatin analog RC-160 on the growth of OV-1063 human epithelial ovarian cancer cells xenografted into nude mice were investigated. Treatment with 20μ g/day of the GHRH antagonist JV-1-36 or MZ-5-156 and 60 μg/day of the somatostatin analog RC-160 for 25 days decreased tumor volume by 70.9% (P < 0.01), 58.3% (P< 0.05), and 60.6% (P < 0.01), respectively, vs. the control value. The levels of GH in serum were decreased in all of the treated groups, but only RC-160 significantly reduced serum insulin-like growth factor I (IGF-I). The levels of messenger ribonucleic acid (mRNA) for IGF-I and -II and for their receptors in OV-1063 tumors were investigated by multiplex RT-PCR. No expression of mRNA for IGF-I was detected, but treatment with JV-1-136 caused a 51.8% decrease (P < 0.05) in the level of mRNA for IGF-II in tumors. Exposure of OV-1063 cells cultured in vitro to GHRH, IGF-I, or IGF-II significantly (P < 0.05) stimulated cell growth, but 10−5 mol/L JV-1-36 nearly completely inhibited (P < 0.001) OV-1063 cell proliferation. OV-1063 tumors expressed mRNA for GHRH receptors and showed the presence of binding sites for GHRH. Our results indicate that antagonistic analogs of GHRH and the somatostatin analog RC-160 inhibit the growth of epithelial ovarian cancers. The effects of RC-160 seem to be exerted more on the pituitary GH-hepatic IGF-I axis, whereas GHRH antagonists appear to reduce IGF-II production and interfere with the autocrine regulatory pathway. The antitumorigenic action of GHRH antagonists appears to be mediated by GHRH receptors found in OV-1063 tumors.
Familial Corticosteroid-Binding Globulin Deficiency Due to a Novel Null Mutation: Association with Fatigue and Relative Hypotension
Authors: Torpy David J. , Bachmann Anthony W. , Grice Jeffrey E. , Fitzgerald Stephen P. , Phillips Patrick J. , Whitworth Judith A. , Jackson Richard V.
Published: January 2014

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue −12 of the procorticosteroid-binding globulin molecule (c.121G→A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 ± 1.3 μg/ml (reference range, 30–52 μg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 μg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue. Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 ± 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 ± 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 ± 2.5 in 18 adults with the mutation vs. 4.2 ± 1.5 in 23 healthy controls (P < 0.0001). Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.
Expression of Leptin (Ob) and Leptin Receptor (Ob-R) in Human Fibroblasts: Regulation of Leptin Secretion by Insulin
Authors: Glasow A. , Kiess W. , Anderegg U. , Berthold A. , Bottner A. , Kratzsch J.
Published: January 2014

Leptin, a hormone of the cytokine family, is mainly synthesized by white adipocytes. As fibroblasts and adipocytes share a common stem cell origin, we hypothesized that connective tissue may be another candidate for leptin synthesis. We demonstrated leptin receptors, inclusive of all isoforms, on cultured fibroblasts (n = 13) by RT-PCR and immunohistochemistry. In contrast to its receptor, basal leptin mRNA expression and protein secretion were found in 8 of 13 cultures, reaching 1.4 ng/350,000 cells·24 h. Incubation with physiological insulin concentrations (1 nmol/liter) increased leptin secretion in fibroblast culture supernatants to 152% of basal levels. A maximal stimulation of the basal level up to 192% was found with 10 nmol/liter insulin after 24 h. Actinomycin D and cycloheximide abolished this effect, providing evidence that active RNA and protein synthesis are involved in insulin’s action. Completing these in vitro results, we could show protein expression for leptin and leptin receptors in fibroblasts by immunostaining of human skin biopsies in situ. In conclusion, we provide evidence of leptin synthesis and secretion by human fibroblasts that are regulated by insulin. Leptin produced by fibroblasts may thus exert important local autocrine and paracrine actions and contribute to the total plasma pool. Hence it might in part account for variations in body mass index-dependent reference ranges of leptin as well as disruptions in the relationship between fat content and leptin.
Significant Population Variation in Adult Male Height Associated with the Y Chromosome and the Aromatase Gene
Authors: Ellis Justine A. , Stebbing Margaret , Harrap Stephen B.
Published: January 2014

The determination of human adult height is dependent on both environmental and genetic factors. Rare causes of abnormal stature have been identified, including mutations in the gene encoding aromatase (CYP19) and regions on the Y chromosome. However, the possible role of these loci in the genetic control of normal adult height is unknown. We have performed an association study using common biallelic polymorphisms within CYP19 and the Y chromosome to determine whether these loci are associated with variation in height in 413 adult males and 335 females drawn at random from a large population sample. An association between CYP19 and height was found (difference, 2.0 cm; 95% confidence interval, 0.16–3.8; P = 0.003), but this was more evident in men (difference, 2.3 cm; 95% confidence interval, 0.38–4.4; P = 0.05) than women (difference, 0.2 cm; 95% confidence interval, −2.1 to 1.6; P = 0.94). An association was also found with the Y chromosome (P = 0.009; difference of 1.9 cm; 95% confidence interval, 0.5–3.4). Additionally, when men were grouped according to haplotypes of the CYP19 and Y chromosome polymorphisms, a difference of 4.2 cm (95% confidence interval, 0.67–7.3) was detected (P = 0.004). These results suggest that in men, genetic variation in CYP19 and on the Y chromosome are involved in determining normal adult height, and that these loci may interact in an additive fashion.
Troglitazone, an Insulin-Sensitizing Thiazolidinedione, Represses Combined Stimulation by LH and Insulin of de Novo Androgen Biosynthesis by Thecal Cells in Vitro
Authors: Veldhuis Johannes D. , Zhang George , Garmey James C.
Published: January 2014

Polycystic ovarian syndrome (anovulatory hyperandrogenism) is marked by adolescent onset of systemic hyperinsulinism, oligoovulation, hirsutism, excessive LH and androgen secretion, and variable reduction in fertility. Insulin and LH are believed to act in concert to promote ovarian androgen hypersecretion in this disorder. Administration of troglitazone, an insulin-sensitizing agent and putative PPARγ agonist, can decrease hyperinsulinism, suppress T production, and ameliorate oligoovulation in some women with this endocrinopathy. The present study tests the hypothesis that troglitazone directly inhibits de novo androgen biosynthesis stimulated jointly by LH and insulin in primary cultures of (porcine) thecal cells. We show that troglitazone dose-dependently antagonizes LH/insulin’s combined stimulation of androstenedione and T production by thecal cells in vitro. Consistent steroidogenic inhibition of 80–95% was achieved at drug concentrations of 3–6.8 μm (P < 0.001). Exposure of thecal cells to the thiazolidinedione derivative also blocked bihormonally stimulated accumulation of CYP17 (cytochrome P450 17 α-hydroxylase/C17–20 lyase) gene expression, as reflected by decreased accumulation of cognate heterogeneous nuclear RNA and mRNA (by 30–65%; P < 0.05). Moreover, troglitazone suppressed LH/insulin-induced phosphorylation of the 52-kDa immunoprecipitated CYP17 enzyme by 88% (P < 0.001). A putative natural agonist of PPARγ nuclear transcription, 15-deoxy-δ-12,14-prostaglandin J2, also inhibited LH/insulin-driven androstenedione biosynthesis and CYP17 gene expression in thecal cells. In conclusion, a synthetic thiazolidinedione (troglitazone) and a natural ligand of PPARγ (15-deoxy-δ-12,14-prostaglandin J2) effectively impede the concerted stimulation by LH and insulin of in vitro thecal cell androgen production, CYP17 gene expression, and CYP17 protein phosphorylation. This ensemble of inhibitory actions on LH/insulin-stimulated steroidogenesis offers a plausible mechanistic basis for at least part of the observed clinical efficacy of troglitazone in mitigating androgen excess in women with polycystic ovarian syndrome.