bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased Prorenin Processing Develops before Autonomic Dysfunction in Type 1 Diabetes1
Authors: Hoeldtke Robert D. , Bryner Kimberly D. , Komanduri Padma , Christie Ian , Ganser Gary , Hobbs Gerald R. 
Published: January 2014

It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598–1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2–22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied.
PRA in the diabetic patients at the time of the second and third evaluations was 1.71 ± 0.24 ng angiotensin I/mL·h and 1.67± 0.24 ng angiotensin I/mL·h, respectively, significantly lower (P &lt; 0.05) than that of the control subjects in whom PRA was 2.96 ± 0.38 ng angiotensin I/mL·h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 ± 0.03, 0.235± 0.05, and 0.227 ± 0.05, respectively, significantly lower (P &lt; 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 ± 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04–0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P &lt; .001) correlation with the renin to prorenin ratio. High frequency (0.15–0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P &lt; 0.01).
We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.
Tissue Iodine Content and Serum-Mediated 125I Uptake-Blocking Activity in Breast Cancer*
Authors: Kilbane M. T. , Ajjan R. A. , Weetman A. P. , Dwyer R. , McDermott E. W. M. , O’Higgins N. J. , Smyth P. P. A. 
Published: January 2014

Abstract
In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I− symporter (NIS), whereas in the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2 of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total tissue iodine levels of 80.9 ± 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher than those in 19 breast cancers taken from either the tumor (18.2 ± 4.6 ng I/mg) or morphologically normal tissue taken from within the tumor-bearing breast (31.8 ± 4.9 ng I/mg; P&lt; 0.05 in each case). Inhibition of 125I uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49 (16.3%) benign breast disease, and 27 of 86 (31.4%) Graves’ patients, but in only 1 of 33 (3.0%) age-matched female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly associated with thyroid peroxidase antibody positivity (P &lt; 0.05) in sera from breast cancer patients, but not in those with benign breast disease, once again suggesting an association between thyroid autoimmunity and breast carcinoma.
Glucose Metabolism Rather Than Insulin Is a Main Determinant of Leptin Secretion in Humans
Authors: Wellhoener Peter , Fruehwald-Schultes Bernd , Kern Werner , Dantz Dorle , Kerner Wolfgang , Born Jan , Fehm Horst L. , Peters Achim 
Published: January 2014

AbstractCirculating plasma insulin and glucose levels are thought to be major regulators of leptin secretion. There is evidence from in vitro and animal experiments that glucose metabolism rather than insulin alone is a main determinant of leptin expression. Here, we tested the hypothesis that in humans also leptin secretion is primarily regulated by glucose uptake and only secondarily by plasma insulin and glucose. In 30 lean and healthy men we induced 4 experimental conditions by using the blood glucose clamp technique. A total of 60 hypoglycemic and euglycemic clamps, lasting 6 h each, were performed. During these clamps insulin was infused at either high (15.0 mU/min·kg) or low (1.5 mU/min·kg) rates, resulting in low-insulin-hypo, high-insulin-hypo, low-insulin-eu, and high-insulin-eu conditions. Serum leptin increased from 0–360 min by 20.5 ± 4.1% in the low-insulin-hypo, 33.6 ± 7.6% in the high-insulin-hypo, 39.6 ± 6.0% in the low-insulin-eu, and 60.4 ± 7.6% in the high-insulin-eu condition. Multiple regression analysis revealed a significant effect of circulating insulin (low vs. high insulin; P = 0.001) and blood glucose (hypoglycemia vs. euglycemia; P = 0.001) on the rise of serum leptin. However, when the total amount of dextrose infused during the clamp (grams of dextrose per kg BW) was included into the regression model, this variable was significantly related to the changes in serum leptin (P = 0.001), whereas circulating insulin and glucose had no additional effect. These findings in humans support previous in vitro data that leptin secretion is mainly related to glucose metabolism.
Expression of Leptin Receptor in Human Endometrium and Fluctuation during the Menstrual Cycle
Authors: Kitawaki Jo , Koshiba Hisato , Ishihara Hiroaki , Kusuki Izumi , Tsukamoto Katsumi , Honjo Hideo 
Published: January 2014

Abstract
Leptin is secreted by adipocytes and regulates appetite through interaction with hypothalamic leptin receptors (OB-R). Accumulated evidence shows that leptin is involved in the stimulation of reproductive functions and that local expression of leptin and OB-R in the ovary, oocyte, embryo, and placenta plays a role in early development. To investigate the role of leptin in implantation, we examined the expression of OB-R and leptin in the human endometrium. Northern and Western blot analyses and RT-PCR showed that the long form of OB-R (OB-RL) messenger ribonucleic acid (mRNA) and protein were expressed. In contrast, leptin mRNA or protein was not detected. All of the splice variants of OB-R (OB-RT) and OB-RL transcripts were expressed in 90% and 84% of the cases, respectively. OB-R mRNA expression peaked in the early secretory phase. Decidual tissue of early gestation also expressed OB-RT and OB-RL. Their incidence and abundance were comparable among endometria with benign uterine diseases and disease-free endometria and were not related to a body mass index within the normal range. The present results indicate that OB-R, but not leptin, is expressed in the human endometrium.
The Plasma Levels of Dehydroepiandrosterone Sulfate Are Decreased in Patients with Chronic Heart Failure in Proportion to the Severity*
Authors: Moriyama Yasushi , Yasue Hirofumi , Yoshimura Michihiro , Mizuno Yuji , Nishiyama Koichi , Tsunoda Ryusuke , Kawano Hiroaki , Kugiyama Kiyotaka , Ogawa Hisao , Saito Yoshihiko , Nakao Kazuwa 
Published: January 2014

AbstractDehydroepiandrosterone sulfate (DHEAS) is the major secretory steroid of the human adrenal glands. The secretion of DHEAS decreases with aging. The incidence of heart failure also rises in the elderly population. We measured the plasma levels of DHEAS and cortisol in 49 patients with chronic heart failure (CHF) and 32 age-matched controls and assessed its relation to plasma levels of A-type natriuretic peptide and B-type natriuretic peptide, biochemical markers of heart failure. Plasma levels of DHEAS were significantly lower in patients with CHF than in controls, whereas there was no significant difference in plasma levels of cortisol between the two groups. In stepwise regression analysis, the plasma level of DHEAS was significantly and independently correlated with age (β = −0.451; P &lt; 0.0001) and the plasma level of B-type natriuretic peptide (β = −0.338; P &lt; 0.001), and the plasma cortisol/DHEAS ratio was significantly and independently correlated with the plasma levels of A-type natriuretic peptide (β = 0.598; P &lt; 0.0001) and thiobarbituric acid-reactive substances (a marker of oxidative stress;β = 0.252; P &lt; 0. 01) and age (β = 0.171; P &lt; 0.05). These results indicate that the plasma levels of DHEAS are decreased in patients with CHF in proportion to its severity and that oxidative stress is associated with decreased levels of DHEAS in patients with CHF.
Cytokine Gene Polymorphisms in Autoimmune Thyroid Disease
Authors: Hunt P. J. , Marshall S. E. , Weetman A. P. , Bell J. I. , Wass J. A. H. , Welsh K. I. 
Published: January 2014

AbstractSusceptibility to the autoimmune thyroid diseases, Graves’ disease (GD) and autoimmune hypothyroidism (AIH), depends on a complex interaction between environmental and genetic factors. The human leukocyte antigen and cytotoxic T lymphocyte-associated-4 regions appear to influence susceptibility to disease, but the effect is not major, and the other genes remain unknown. Cytokines are crucial in the regulation of immune and inflammatory responses and therefore are potential candidate genes for autoimmune thyroid disease. In a case-control study, using a unified method of genotyping, we have examined 15 polymorphisms in 9 cytokine genes in 215 patients with autoimmune thyroid disease (GD, 138; AIH, 77) and 101 normal controls.Polymorphisms in the genes for interleukin-1α (IL-1α), IL-1β, IL-1 receptor antagonist, IL-1 receptor 1, IL-4, IL-4 receptor, IL-6, IL-10, and transforming growth factor-β were investigated. Genotyping was performed using the PCR and sequence-specific primers. Analysis showed a reduced frequency of the variant t allele in the IL-4 promoter polymorphism (position −590) in patients with GD and in the entire patient group (GD and AIH) compared with the control group [corrected P (Pc) = 0.00004 and Pc &lt; 0.00001 for GD and all patients, respectively]. This was reflected in a reduction in the heterozygote genotype in the patient groups compared to the controls [c/t heterozygotes GD, 12%; Pc = 0.06, odds ratio, 0.4 (95% confidence interval, 0.2–0.7); all patients, 11%; Pc = 0.008; odds ratio, 0.4 (95% confidence interval, 0.2–0.7); control subjects, 23%]. There were no significant differences between the study groups for the other polymorphisms examined, and subgroup analysis revealed no association with clinical parameters of disease.These results suggest that an IL-4 variant or a closely linked gene has a modest protective effect against the development of autoimmune thyroid disease, particularly GD. This variation in the IL-4 gene may provide further clues to the pathogenesis of autoimmune thyroid disease and other organ-specific autoimmune diseases. Furthermore, these results suggest that subtle variation in immunoregulatory genes may be associated with autoimmune disease states.
Sex-Determining Gene(s) on Distal 9p: Clinical and Molecular Studies in Six Cases*
Authors: Muroya Koji , Okuyama Torayuki , Goishi Keiji , Ogiso Yoshifumi , Fukuda Shin , Kameyama Junji , Sato Hirokazu , Suzuki Yoshimi , Terasaki Hiroshi , Gomyo Hiroki , Wakui Keiko , Fukushima Yoshimitsu , Ogata Tsutomu 
Published: January 2014

Abstract
We report on clinical and molecular findings in five karyotypic males (cases 1–5) and one karyotypic female (case 6) with distal 9p monosomy. Cases 1–3 and 6 had female external genitalia, case 4 showed ambiguous external genitalia, and case 5 exhibited male external genitalia with left cryptorchidism and right intrascrotal testis. Gonadal explorations at gonadectomy in cases 3 and 4 revealed that case 3 had left streak gonad and right agonadism, and case 4 had bilateral hypoplastic testes. Endocrine studies in cases 1–4 and 6 showed that cases 1, 3, and 6 had definite primary hypogonadism, with basal FSH levels of 54, 39, and 41 IU/L, respectively, whereas case 2 with severe malnutrition was unremarkable for the baseline values, and case 4 had fairly good testicular function. Fluorescence in situ hybridization and microsatellite analyses demonstrated that all cases had hemizygosity of the 9p sex-determining region distal to D9S1779, with loss of the candidate sex-determining genes DMRT1 and DMRT2 from the abnormal chromosome 9. Sequence analysis in cases 1–4 and 6 showed that they had normal sequences of each exon of DMRT1 and the DM domain of DMRT2 on the normal chromosome 9, and that cases 1–4 had normal SRY sequence.
The results provide further support for the presence of a sex-determining gene(s) on distal 9p and favor the possibility of DMRT1 and/or DMRT2 being the sex-determining gene(s). Furthermore, as hemizygosity of the 9p sex-determining region was associated with a wide spectrum of gonadogenesis from agonadism to testis formation in karyotypic males and with primary hypogonadism regardless of karyotypic sex, it is inferred that haploinsufficiency of the 9p sex-determining gene(s) primarily hinders the formation of indifferent gonad, leading to various degrees of defective testis formation in karyotypic males and impaired ovary formation in karyotypic females.
Stimulatory Effect of Adrenocorticotropin on Cortisol, Aldosterone, and Dehydroepiandrosterone Secretion in Normal Humans: Dose-Response Study*
Authors: Arvat Emanuela , Di Vito Lidia , Lanfranco Fabio , Maccario Mauro , Baffoni Claudia , Rossetto Ruth , Aimaretti Gianluca , Camanni Franco , Ghigo Ezio 
Published: January 2014

Abstract
The short ACTH test is widely used in clinical practice for the diagnosis of adrenal insufficiency. It is classically performed administering 250.0 μg ACTH(1–24) although 1.0 μg ACTH dose has been reported having maximal stimulatory effect on cortisol levels in normal subjects. We aimed to define the maximal and the minimal stimulatory ACTH dose on cortisol, aldosterone, and dehydroepiandrosterone (DHEA) in humans. To this goal, in 12 normal volunteers (6 males and 6 females; age, 22–34 yr; body mass index 20–25 kg/m2; body surface 1.6–1.9 m2), we studied the dose-response effect of eight ACTH doses (0.01, 0.03, 0.06, 0.125, 0.5, 1.0, 25.0, and 250.0 μg) on cortisol, aldosterone, and DHEA levels. Each ACTH dose administered at 0 min was followed by a second ACTH dose of 250.0 μg at +60 min. The cortisol Δ areas under response curve (ΔAUCs) after all ACTH doses, apart from 0.01 μg, were significantly higher (P &lt; 0.02) than that after placebo, showing a clear dose-response relationship (P&lt; 0.001). The doses of 0.03 and 1.0 μg ACTH were the minimal and maximal effective doses, respectively. The cortisol response to 250.0μ g ACTH was not modified by pretreatment with 0.01, 0.03, and 0.06μ g ACTH doses, whereas it was progressively reduced by increasing the dose of ACTH pretreatment (P &lt; 0.001). The aldosteroneΔ AUCs to all but 0.01 μg ACTH doses were significantly higher (P &lt; 0.02) than that after placebo, showing a clear dose-response relationship (P &lt; 0.001). The dose of 0.03 μg was the minimal effective stimulating dose, whereas 25.0 μg showed the same aldosterone-releasing effect of 250.0 μg. The aldosterone response to 250.0 μg ACTH, preceeded by placebo, was not modified by pretreatment with 0.01 and 0.03 μg ACTH doses, whereas it was reduced by increasing the dose of ACTH pretreatment (P &lt; 0.05–0.02). The DHEA ΔAUCs to all ACTH doses were significantly higher (P &lt; 0.01) than that after placebo, showing a clear dose-response relationship (P&lt; 0.001). The doses of 0.01 and 1.0 μg ACTH were the minimal and maximal effective dose, respectively. The DHEA response to 250.0 μg ACTH was not modified by pretreatment with 0.01, 0.03, 0.06, and 0.125μ g ACTH doses, whereas it was progressively reduced by pretreatment with 0.5, 1.0, and 25.0 μg ACTH doses (P &lt; 0.01). In conclusion, these results show that an extremely low ACTH dose is needed to stimulate adrenal steroids and, among them, DHEA seems the most sensitive to corticotropin stimulation.
Ovarian Response to Follicle-Stimulating Hormone (FSH) Stimulation Depends on the FSH Receptor Genotype*
Authors: Mayorga Maritza Perez , Gromoll Jörg , Behre Hermann M. , Gassner Claudia , Nieschlag Eberhard , Simoni Manuela 
Published: January 2014

Abstract
Because the ovarian response to FSH stimulation in assisted reproduction is variable, ranging from hyporesponse to hyperresponse, with the possible complication of ovarian hyperstimulation, it would be of great benefit to predict the response of the patients to FSH. To date, no clear-cut predictors of ovarian responsiveness to FSH have been identified. In this study, we investigated the role of two distinct FSH receptor (FSHR) variants, Thr307/Asn680 and Ala307/Ser680, in the response to FSH in women undergoing controlled ovarian stimulation.
The FSHR polymorphism at position 680 was analyzed by restriction-fragment-length polymorphism in 161 ovulatory women below the age of 40 yr. With reference to the couple, infertility has been diagnosed as being attributable to male causes (76%), tubal factor (11%), or both (13%). The distribution was 29% for the Asn/Asn, 45% for the Asn/Ser, and 26% for the Ser/Ser FSHR variant. Peak estradiol levels, number of preovulatory follicles, and number of retrieved oocytes were similar in the 3 groups. However, basal FSH levels were significantly different among the 3 groups (6.4 ± 0.4 IU/L, 7.9 ± 0.3 IU/L, and 8.3 ± 0.6 IU/L for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P &lt; 0.01). The number of FSH ampoules required for successful stimulation was significantly different among the 3 groups (31.8 ± 2.4, 40.7 ± 2.3, and 46.8 ± 5.0 for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P &lt; 0.05). According to multiple linear regression analysis, the number of ampoules needed could be predicted from a linear combination of both the type of polymorphism and basal FSH levels (P &lt; 0.001).
These clinical findings demonstrate that the ovarian response to FSH stimulation depends on the FSHR genotype.
Increased Final Height in Precocious Puberty after Long-Term Treatment with LHRH Agonists: The National Institutes of Health Experience
Authors: Klein Karen Oerter , Barnes Kevin M. , Jones Janet V. , Feuillan Penelope P. , Cutler Jr. Gordon B. 
Published: January 2014

We report 98 children who have reached final adult height in a long-term trial of LHRH agonist treatment. These children were 5.3± 2.1 yr old at the start of treatment and were treated with either deslorelin (4 μg/kg·d sc) or histrelin (4–10 μg/kg·d) for an average of 6.1 ± 2.5 yr. Final height averaged 159.8 ± 7.6 cm in the 80 girls, which was significantly greater than pretreatment predicted height (149.3 ± 9.6 cm) but still significantly less than midparental height (MPH) (163.7 ± 5.6). Final height averaged 171.1 ± 8.7 cm in the 18 boys, which was significantly greater than pretreatment predicted height (156.1 ± 14.2 cm) but still significantly less than MPH (178.3 ± 5.2 cm). However, the average adult height of the 54 children who had less than a 2-yr delay in the onset of treatment was not significantly different from their MPH, and 21 children exceeded MPH.
Final height sd score correlated positively with duration of treatment (P &lt; 0.01), midparental height (P &lt; 0.001), predicted height at the start of treatment (P &lt; 0.001), and growth velocity during the last year of treatment (P &lt; 0.001) and correlated inversely with delay in the onset of treatment (P &lt; 0.001), age at the start of treatment (P &lt; 0.001), bone age at the start of treatment (P &lt; 0.001), bone age at the end of treatment (P &lt; 0.001), breast stage at the start of treatment (P = 0.02), and bone age minus chronological age at the start of treatment (P = 0.001).
We conclude that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 yr for girls or 9 yr for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronological and bone age at the onset of treatment all lead to greater final height. All children with onset of pubertal symptoms before age 8 in girls and age 9 in boys should be evaluated for possible treatment. Treatment is appropriate in children with rapidly progressing puberty, accelerated bone maturation, and compromise of adult height prediction, regardless of bone age or chronological age at time of evaluation. However, once treatment is considered appropriate, it should be initiated quickly, because longer delays lead to shorter final height. In addition, the longer the treatment is continued, the greater is the final height outcome.
Pretreatment with Recombinant Human TSH Changes the Regional Distribution of Radioiodine on Thyroid Scintigrams of Nodular Goiters
Authors: Nieuwlaat Willy-Anne , Hermus Ad R. , Sivro-Prndelj Ferida , Corstens Frans H. , Huysmans Dyde A. 
Published: January 2014

In a recent study, we demonstrated that pretreatment with a single, low dose of recombinant human TSH (rhTSH) doubles 24-h thyroid radioactive iodine uptake in patients with nodular goiter. The purpose of the present study was to investigate whether rhTSH pretreatment induces changes in the regional distribution of radioiodine as visualized on thyroid scintigrams in these patients.
Anterior planar thyroid 123I scintigrams were obtained in 26 patients with a nodular goiter (23 women and 3 men; age, 62 ± 9 yr, mean ± sd; thyroid weight, 165 ± 72 g) 24 h after administration of a diagnostic dose of radioiodine. All patients were studied twice: first, without rhTSH pretreatment (baseline study), and second, after an im injection of 0.01 mg (n = 10) or 0.03 mg rhTSH (n = 16), given 24 h before radioiodine administration (rhTSH study). For quantification of regional differences in radioiodine uptake, a region of interest method was used.
Upon visual inspection, baseline scintigrams showed a heterogeneous uptake of radioiodine. In general, rhTSH scintigrams also showed heterogeneous radioiodine uptake. In some patients, the distribution of radioiodine in the rhTSH scintigram was considerably more homogeneous than in the baseline scintigram. In a few patients, originally“ cold” areas had changed into “hot” ones, whereas originally hot areas had changed into cold ones. Quantification of regional radioiodine uptake showed that pretreatment with rhTSH caused a larger increase in radioiodine uptake in relatively cold areas and a smaller increase in radioiodine uptake in relatively hot areas, compared with the increase in radioiodine uptake in the entire thyroid. In patients with a baseline serum TSH level of 0.5 mU/liter or lower, the increase in radioiodine uptake in relatively cold areas was significantly larger than in patients with a baseline serum TSH level higher than 0.5 mU/liter.
In conclusion, a single, low dose of rhTSH not only doubled 24-h radioactive iodine uptake but also caused a more homogeneous distribution of radioiodine within the thyroid gland in patients with a nodular goiter by stimulating radioiodine uptake in relatively cold areas more than in relatively hot areas. This was most marked in patients with a low baseline serum TSH level. Our data suggest that pretreatment with rhTSH may improve the efficacy of radioiodine treatment for volume reduction of nodular goiters, especially in patients with a low baseline serum TSH level.