bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma adiponectin and serum advanced glycated end-products increase and plasma lipid concentrations decrease with increasing duration of type 2 diabetes
Authors: Gottsater A , Szelag B , Kangro M , Wroblewski M , Sundkvist G
Published: January 2005

OBJECTIVE: To prospectively follow the concentrations of plasma adiponectin (p-adiponectin) and serum advanced glycation end-products (s-AGE) in relation to plasma lipids and retinopathy over 3 years in type 2 diabetic patients. DESIGN AND METHODS: P-adiponectin, s-AGE, plasma lipids and diabetic retinopathy were prospectively evaluated in 61 type 2 diabetic patients at baseline and at follow up 3 years later. RESULTS: Mean p-adiponectin (from 8.84+/-5.14 to 11.05+/-6.16 microg/ml; P=0.006) and s-AGE (from 637+/-242 to 781+/-173 ng/ml; P<0.0001) concentrations had increased at follow up. In addition, HbA1c (7.7+/-1.7 to 7.4+/-1.4%; P=0.0045) and fasting C-peptide (1.00+/-0.38 to 0.81+/-0.35 nM; P=0.019) had decreased and all lipid variables had significantly improved at follow up. P-adiponectin correlated inversely with fasting C-peptide (r(s)=-0.273; P=0.045) and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio (r(s)=-0.362; P=0.011), and directly with plasma HDL cholesterol (r(s)=0.381; P=0.005) at follow up. Analysis of variance with adiponectin and s-AGE as dependent variables and fasting C-peptide, plasma HDL and plasma LDL cholesterol as covariates demonstrated that the increase in s-AGE was independent (P=0.001) and the increase in p-adiponectin dependent on covariate changes (P=0.862). There was a slight correlation between s-AGE at baseline versus the degree of retinopathy at follow up (r(s)=0.281; P=0.0499). CONCLUSION: Both p-adiponectin and s-AGE increased during the 3 years. The increase in p-adiponectin was explained by improvements in insulin sensitivity and dyslipidaemia, whereas the increase in s-AGE was independent of changes in metabolic covariates. s-AGE increase when the duration of type 2 diabetes increases.
PAX8 and peroxisome proliferator-activated receptor gamma 1 gene expression status in benign and malignant thyroid tissues
Authors: Lacroix L , Mian C , Barrier T , Talbot M , Caillou B , Schlumberger M , Bidart JM
Published: January 2005

OBJECTIVE: Genetic alterations involving the thyroid transcription factor PAX8 and the peroxisome proliferator-activated receptor gamma 1 (PPARgamma1) genes have been described in thyroid neoplasms. We investigated in a series of thyroid samples, including 14 normal, 13 hyperfunctioning tissues, 26 follicular adenomas, 21 follicular and 41 papillary carcinomas, both the frequency of the PAX8-PPARgamma1 rearrangement and the expression of the PAX8 and PPARgamma transcripts. METHODS: Using RT-PCR followed by sequencing PCR products, PAX8-PPARgamma1 translocation was not detected in benign tissues nor in papillary carcinomas and was detected in 4 (19%) of 21 follicular carcinomas and in one (4%) of 26 follicular adenomas. RESULTS: Specific real-time quantitative RT-PCR (Q RT-PCR) methods detected high levels of PPARgamma transcripts in follicular carcinomas presenting the rearrangement. Interestingly, the level of PPARgamma transcripts was significantly decreased in papillary carcinomas in comparison with those found in benign adenomas and follicular carcinomas. Finally, PAX8 gene expression was decreased in both papillary and follicular thyroid carcinomas, and in these tumors to the same extent in the presence or absence of the rearrangement. These alterations in both PPARgamma and PAX8 gene expression may explain the poorly differentiated histotype of follicular carcinomas harboring the translocation.Immunohistochemistry showed that nuclear PPARgamma staining was weak in normal tissues, adenomas, papillary carcinomas and in some follicular carcinomas, and strong in the follicular carcinomas positive for the PAX8-PPARgamma1 translocation, but also in some follicular tumors in which no translocation could be evidenced. CONCLUSION: These observations confirm that the PAX8-PPARgamma1 translocation characterizes a subset of thyroid follicular carcinomas but is not a specific marker of carcinoma and that its frequency is lower than that initially reported. Finally, immunohistochemistry is not a reliable method for the specific detection of the translocation, that can be specifically evidenced by Q RT-PCR.
Neonatal stimulation of the thyroid gland with iodine or suppression during adolescence with triiodothyronine changes the prevalence of autoimmune thyroiditis in BB rats
Authors: Hartoft-Nielsen ML , Rasmussen AK , Kaas A , Feldt-Rasmussen U , Buschard K
Published: January 2005

OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.
RGS 2 expression is regulated by TSH and inhibits TSH receptor signaling
Authors: Eszlinger M , Holzapfel HP , Voigt C , Arkenau C , Paschke R
Published: January 2005

OBJECTIVE: A new family of guanosine triphosphatase-activating proteins known as regulators of G protein signaling (RGS) has been found to regulate the desensitization of several G protein-coupled ligand-induced processes. The expression of nine RGS mRNAs was found in human thyroid tissue (RGS 2, 3, 5, 6, 9, 10, 12, 14 and 16). At present, little is known as to whether any of the RGS proteins play a role in TSH signaling. DESIGN AND METHODS: To explore the involvement of RGS proteins in the regulation of TSH receptor (TSHR) signal transduction, mRNA expression levels of the RGS proteins were analyzed after TSH stimulation of human thyroid primary cultures by real-time RT-PCR. Furthermore, the effects of RGS 2 expression on TSHR signaling (cAMP-, inositol-3-phosphate accumulation, TSHR cell surface expression) were studied in COS-7 cells. RESULTS: Only RGS 2 mRNA was found to be regulated by TSH in thyroid primary cultures. Co-expression of RGS 2 and TSHR in COS-7 cells reduced the TSHR signaling via inositol-3-phosphate but not via cAMP after stimulation with TSH. CONCLUSION: TSH-dependent RGS 2 mRNA expression and the suppression of TSH-G(q)alpha signaling by the overexpression of RGS 2 imply that RGS 2 is involved in TSHR-induced G(q) signal transduction.
Immunohistochemical detection of GHRH and its receptor splice variant 1 in primary human breast cancers
Authors: Chatzistamou I , Schally AV , Kiaris H , Politi E , Varga J , Kanellis G , Kalofoutis A , Pafiti A , Koutselini H
Published: January 2005

OBJECTIVE: GHRH is secreted by the hypothalamus and, upon binding to specific GHRH receptors in the pituitary, stimulates growth hormone (GH) production and release from the pituitary. In addition to this neuroendocrine action, accumulated evidence implies additional roles for GHRH in carcinogenesis in non-pituitary tissues. In vitro and in vivo studies have shown that splice variant 1 (SV1) of the GHRH receptor, which is widely expressed in non-pituitary tissues and cancers, can mediate the proliferative effects of GHRH. The aim of the present study was to investigate the operation of an autocrine stimulatory loop between GHRH and SV1 in primary breast tumors. DESIGN: Fifty-three primary breast tumors were evaluated for GHRH and SV1 expression. METHODS: Expression of GHRH and SV1 was assessed by immunohistochemistry using anti-GHRH SV95 and anti-SV1 2317/5 polyclonal antibodies. RESULTS: About 40% of the specimens tested express GHRH and/or SV1 (approx. 25% each), while in 35% of these positive specimens co-expression of these antigens was detected (P<0.01). Furthermore, a correlation of GHRH, but not SV1, expression was detected in lobular compared with ductal carcinomas. CONCLUSIONS: These results constitute the first demonstration for the expression of GHRH and SV1 in primary breast cancers, and provide evidence for the operation of an autocrine stimulatory loop between GHRH and SV1 in primary cancers. Our findings indicate that GHRH analogs could have diagnostic and therapeutic applications for the management of breast cancer.
Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties
Authors: Grossmann C , Scholz T , Rochel M , Bumke-Vogt C , Oelkers W , Pfeiffer AF , Diederich S , Bahr V
Published: January 2005

BACKGROUND: Glucocorticoids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy. However, the data describing gluco- and mineralo-corticoid (MC) properties of widely applied synthetic GCs are often based on diverse clinical observations and on a variety of in vitro tests under various conditions, which makes a quantitative comparison questionable. METHOD: We compared MC and GC properties of different steroids, often used in clinical practice, in the same in vitro test system (luciferase transactivation assay in CV-1 cells transfected with either hMR or hGRalpha expression vectors) complemented by a system to test the steroid binding affinities at the hMR (protein expression in T7-coupled rabbit reticulocyte lysate). RESULTS AND CONCLUSIONS: While the potency of a GC is increased by an 11-hydroxy group, both its potency and its selectivity are increased by the Delta1-dehydro-configuration and a hydrophobic residue in position 16 (16-methylene, 16alpha-methyl or 16beta-methyl group). Almost ideal GCs in terms of missing MC effects, as defined by our in vitro assay, are therefore prednylidene, budesonide, beclomethasone and betamethasone.The MC potency of a steroid is increased by a 9alpha- or a 6alpha-fluoro substituent. A hydrophilic substituent in position 16 (like 16-hydroxylation in triamcinolone) decreases both MC and GC properties. As no substituent that leads to an isolated reduction of GC activity could be characterized in our experiments, 9alpha-fluorocortisol, the most frequently used steroid for MC substitution, seems to be the best choice of available steroids for this purpose.
Effects of androgen substitution on lipid profile in the adult and aging hypogonadal male
Authors: Schleich F , Legros JJ
Published: January 2005

The decrease in serum bioavailable testosterone may be responsible for the catabolic sequelae noticed in the aging man (decrease in libido, decrease in muscle mass, osteoporosis and increase in adiposity). After a brief review of androgen and lipid metabolism as well as their modifications with aging, we discuss current knowledge of the effects of androgen substitution on the lipid profile in hypogonadal men. The results of studies concerning the effect of androgen substitution therapy on lipids are conflicting but might be favorable. The small decrease in high-density lipoprotein cholesterol observed when administering standard dosages of testosterone is accompanied by a significant decrease in total cholesterol (CT) and low-density lipoprotein cholesterol. A counterbalancing of these effects plausibly accounts for the absence of increase cardiovascular risk. The currently available preparations are oral, injectable or transdermal formulations of natural testosterone. The development of new androgen preparations that are more potent, metabolically stable and tissue-specific will improve therapeutic benefits and reduce side effects.
Transsexuals and competitive sports
Authors: Gooren LJ , Bunck MC
Published: January 2005

Men generally have an inherent performance advantage over women due to their average greater height and muscle mass and power, as the result of correspondingly different exposures to androgens. Therefore, it is considered fair that in sports men and women compete in separate categories. The question now emerging is whether reassigned transsexuals can compete in fairness with others of their new sex. The pertinent question is how far the previous effects of testosterone in male-to-female transsexuals (M-F) are reversible upon androgen deprivation so that M-F have no advantage over women, and, vice versa, what the effects are of androgen exposure in female-to-male transsexuals (F-M) on variables relevant to competition in sports. Before puberty, boys and girls do not differ in height, muscle and bone mass. Recent information shows convincingly that actual levels of circulating testosterone determine largely muscle mass and strength, though with considerable interindividual diversity. This study analyzed the effects of androgen deprivation in 19 M-F and of androgen administration to 17 F-M on muscle mass, hemoglobin (Hb) and insulin-like growth factor-1 (IGF-1). Before cross-sex hormone administration, there was a considerable overlap in muscle mass between M-F and F-M. In both M-F and F-M, height was a strong predictor of muscle mass. Androgen deprivation of M-F decreased muscle mass, increasing the overlap with untreated F-M, but mean muscle mass remained significantly higher in M-F than in F-M. Androgen administration to F-M increased muscle mass without inducing an advantage over nontreated M-F. The conclusion is that androgen deprivation in M-F increases the overlap in muscle mass with women but does not reverse it, statistically. The question of whether reassigned M-F can fairly compete with women depends on what degree of arbitrariness one wishes to accept, keeping in mind, for instance, that similar blood testosterone levels in men have profoundly different biologic effects on muscle properties, rendering competition in sports intrinsically a matter of how nature endows individuals for this competition.
Intravenous administration of ghrelin stimulates growth hormone secretion in vagotomized patients as well as normal subjects
Authors: Takeno R , Okimura Y , Iguchi G , Kishimoto M , Kudo T , Takahashi K , Takahashi Y , Kaji H , Ohno M , Ikuta H , Kuroda Y , Obara T , Hosoda H , Kangawa K , Chihara K
Published: January 2005

OBJECTIVE: Ghrelin is a potent peptide stimulating GH secretion. Besides its direct action on the pituitary, ghrelin has been reported to stimulate GH release via the vagal afferent nerve in rats. To examine the involvement of vagal nerve in ghrelin-induced GH secretion in humans, GH responses to ghrelin were compared between vagotomized patients with gastrectomy and normal subjects. METHODS: Ghrelin (0.2 microg/kg) or GHRH (1 microg/kg) was administered intravenously in vagotomized patients and normal subjects on separate days, and plasma GH responses to the stimuli were examined. RESULTS: Ghrelin caused a significant plasma GH rise in both vagotomized patients and normal subjects. Peak GH levels in vagotomized patients (37.5+/-16.9 ng/ml) were not different from those in normal subjects (29.9+/-23.1 ng/ml). The areas under the curve of GH response to ghrelin did not differ between the two groups. GHRH also increased GH levels, and peak GH levels and areas under the curve after GHRH stimulation were also comparable between vagotomized patients and normal subjects. CONCLUSIONS: In the present study, the involvement of the afferent vagal nerve in ghrelin-induced GH secretion was not confirmed in humans.
Circulating and cerebrospinal fluid ghrelin and leptin: potential role in altered body weight in Huntington's disease
Authors: Popovic V , Svetel M , Djurovic M , Petrovic S , Doknic M , Pekic S , Miljic D , Milic N , Glodic J , Dieguez C , Casanueva FF , Kostic V
Published: January 2005

OBJECTIVE: In addition to neurological impairment, weight loss is a prominent characteristic of Huntington's disease (HD). Neuropathologically, the disease affects the caudate nucleus and the cerebral cortex, and also the hypothalamus. The recently discovered orexigenic hormone of gastric origin, ghrelin and the adipocyte hormone leptin, are two peripherally produced hormones exerting opposite effects on specific populations of hypothalamic neurons that play a key role in regulating energy intake and energy output. The aim of this study was to investigate the possible involvement of cerebrospinal fluid (CSF) and circulating ghrelin and leptin in the regulation of energy balance in patients with HD. METHODS: Twenty healthy normal-weight subjects undergoing orthopedic surgery, and fifteen patients with genetically verified HD, were enrolled in this study. The unified Huntington's disease rating scale (UHDRS) was used to assess clinical course of the disease. Blood samples for hormonal measurements were obtained by venipuncture and in-parallel CSF samples for leptin/ghrelin determination were obtained by lumbar puncture. RESULTS: Patients with HD had increased concentrations of ghrelin in plasma compared with healthy subjects (4523.7+/-563.9 vs 2781.1+/-306.2 pg/ml, P<0.01). On the other hand, patients with HD had decreased concentrations of leptin in plasma compared with healthy subjects (4.8+/-1.6 vs 10.9+/-2.4 ng/ml, P<0.01). The concentrations of CSF ghrelin and CSF leptin were equivalent to values in healthy subjects. No correlation was found between disease duration--and other clinical features of HD--and plasma or CSF leptin/ghrelin levels. In patients with HD, baseline levels of GH, IGF-I, insulin and glucose did not differ from those in healthy subjects. CONCLUSION: High circulating ghrelin and low leptin levels in patients with HD suggest a state of negative energy balance. Early nutritional support of patients with HD is advocated since patients with HD and higher body mass index at presentation have slower progression of the disease.
Serum thyrotropin-receptor autoantibodies levels after I therapy in Graves' patients: effect of pretreatment with methimazole evaluated by a prospective, randomized study
Authors: Andrade VA , Gross JL , Maia AL
Published: January 2005

OBJECTIVE: Radioiodine therapy (131I) in hyperthyroid Graves' disease is generally followed by a transitory increase in levels of thyrotropin receptors antibodies (TRAb). Immunosuppressive effects of antithyroid drugs are still a matter of debate. In this study we evaluated the effect of methimazole pretreatment on the TRAb boost induced by 131I. DESIGN: A randomized, prospective clinical trial. METHODS: 61 patients were randomly assigned to receive 131I alone (32 patients) or 131I plus pretreatment with methimazole (30 mg/day; 29 patients). Serum TRAb levels were measured on the day of 131I dosing (D0), and at 1, 3, 6 and 12 months after 131I administration. RESULTS: The mean serum TRAb levels decreased significantly from baseline to D0 in patients treated with methimazole (80.8 vs 48.8 U/l; P<0.05). After 131I treatment, TRAb levels increased at 3 months (48.8 to 60 U/l; 19%) and they were still elevated at 6 months compared with D0 values (99.9 U/l; 105%). Thereafter, TRAb levels decreased to baseline values (47.8 U/l) at 12 months. In hyperthyroid patients, TRAb levels increased significantly from D0 to 1 month (45.0 to 78 U/l; 73%) reaching their highest levels at 3 months (225 U/l; 400%). After this, we observed a progressive decrease to the baseline levels at 12 months (40.0 U/l). The course of TRAb levels after 131I treatment was significantly different between the two groups (P<0.05). Multiple regression analysis identified serum TRAb levels on D0 as independent predictors of TRAb increment after 131I therapy (r2=0.34; P=0.001). A higher increment in serum TRAb levels was associated with hypothyroidism after 1 year of follow-up. CONCLUSION: Methimazole pretreatment attenuates the 131I-induced rise in serum TRAb levels. The effects of methimazole could be attributed to a direct immunomodulatory action or may be due to its effects on the control of hyperthyroidism, which is a known cause of immune dysregulation.
Increased serum soluble leptin receptor levels in children and adolescents with type 1 diabetes mellitus
Authors: Kratzsch J , Deimel A , Galler A , Kapellen T , Klinghammer A , Kiess W
Published: January 2005

OBJECTIVE: We investigated whether or not serum levels of the soluble leptin receptor (sOB-R) and leptin are related to anthropometric and metabolic changes during pubertal development of children and adolescents with type 1 diabetes mellitus. DESIGN AND METHODS: Blood levels of sOB-R, leptin and HbA1C, as well as body-mass index (BMI), diabetes duration and daily insulin doses, were determined in 212 (97 girls; 115 boys) children with type 1 diabetes mellitus and compared with the sOB-R serum levels in 526 healthy children and adolescents. RESULTS: OB-R serum levels and parallel values of the molar ratio between sOB-R and leptin were significantly higher in children with diabetes than in normal children (P<0.05) in almost all investigated Tanner stages. Furthermore, in the entire group of patients, we demonstrated statistically significant correlations (P<0.02) between sOB-R and the duration of diabetes (r=0.30), HbA1c levels (r=0.32) and the insulin dose (r=0.18). Multiple-regression analysis revealed that HbA1c (12.4%), height (7.9%) and duration of diabetes (8.7%) contributed to 29% variance of sOB-R in diabetic children. CONCLUSIONS: Our data suggest that poor glycemic control in diabetes may lead to increased serum levels of sOB-R. This regulation of sOB-R appears to be independent of leptin, but may have an impact on leptin action. The consequently developing molar excess of sOB-R related to leptin could reduce leptin sensitivity and may, therefore, influence leptin-related anthropometric and metabolic abnormalities.
Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis
Authors: Boelen A , Kwakkel J , Platvoet-ter Schiphorst M , Mentrup B , Baur A , Koehrle J , Wiersinga WM
Published: January 2005

OBJECTIVE: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), as shown by studies with IL-6-/- and IL-12-/- mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity. DESIGN: By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18-/-, IFNgammaR-/- and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI. RESULTS: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P<0.05, ANOVA) in WT mice, but not in IL-18-/- mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24 h similarly in IL-18-/-, and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was significantly lower in IL-18-/- mice than in WT, while IL-12 mRNA expression was similar. IFNgammaR-/- mice had higher basal D1 activity in the pituitary than WT mice (P<0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgammaR-/- mice and WT mice, and the decrease in serum T3 and T4 levels and hepatic D1 mRNA was also similar. CONCLUSIONS: The relative decrease in serum T3 and T4 and liver D1 mRNA in response to LPS is similar in IL-18-/-, IFNgammaR-/- and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18-/- mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgammaR-/- mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illness.
Dose-response of estrogen on bone versus the uterus in ovariectomized mice
Authors: Modder UI , Riggs BL , Spelsberg TC , Fraser DG , Atkinson EJ , Arnold R , Khosla S
Published: January 2005

BACKGROUND: Estrogen is known to have important effects on both reproductive and non-reproductive tissues. Moreover, there is increasing interest in developing compounds that may have selective effects on bone versus reproductive tissues. METHODS: Since mouse models are often used in these studies, we administrated increasing doses of estradiol (E2) (0 to 500 microg/kg/day) by slow release pellets to ovariectomized 6-month-old C57BL/6 mice and assessed skeletal and uterine responses following 2 months of treatment. RESULTS: The mice lost bone at multiple sites following ovariectomy (OVX); however, while the lowest E2 dose of 5 microg/kg/day completely prevented loss of cancellous bone (at the lumbar spine and tibial metaphysis), it had no stimulatory effects on the uterus. Higher doses of E2 resulted in further increases in bone mineral density, with eventual stimulation of the uterus at a dose of 40 microg/kg/day. By contrast, when 3-month-old C57BL/6 mice were administered the same doses of E2 and studied after 1 month, the 5 microg/kg/day dose resulted in uterine hypertropy, but was not able to prevent loss of cancellous bone. CONCLUSIONS: Thus these results (i) provide data on the dose-response for the effects of E2 on mouse bone and (ii) indicate that the relative effects of E2 on bone versus the uterus are highly dependent on the particular experimental conditions used. This issue needs to be considered in evaluating agents with potential 'selective' effects on bone versus reproductive tissues.
Mono-allelic expression of the IGF-I receptor does not affect IGF responses in human fibroblasts
Authors: Hammer E , Kutsche K , Haag F , Ullrich K , Sudbrak R , Willig RP , Braulke T , Kubler B
Published: January 2005

OBJECTIVE: It has been suggested that mono-allelic deletion of the IGF-I receptor gene is causally related to severe intrauterine and postnatal growth deficiency whereas no IGF-I resistance was observed in the patients' fibroblasts. The expression and regulation of the growth-modulating IGF binding proteins (IGFBPs) have been investigated in serum and fibroblasts of a short girl with mono-allelic loss of the distal long arm of chromosome 15 (15q26.1-qter). PATIENT AND METHODS: The mono-allelic loss of the IGF-I receptor (IGF1R) gene was confirmed in a child with prenatal and severe postnatal growth retardation by fluorescence in situ hybridization, and was evaluated on the protein level in fibroblasts of the patient by FACS analysis and IGF cross-linkage. Additionally, expression of IGFBPs and cell-mediated degradation of IGFBP-3 were examined in the patient's fibroblasts. RESULTS: Levels of GH, IGF-I, and IGFBP-3 were above the 95th percentile in the serum of the 3-year-old girl with a mono-allelic deletion of the IGF1R gene, suggesting IGF-I resistance. In the patient's fibroblasts the IGF-I receptor concentration was half that in control cells. Whereas the pattern of secreted IGFBPs in response to IGFs was not altered, the abundance of secreted IGFBPs was higher in the patient's cells than in controls. Moreover, fibroblast-mediated degradation of 125I-labeled IGFBP-3 appears to be reduced in the patient's fibroblasts. The higher abundance of IGFBPs in the patient's fibroblasts might be responsible for the lack of IGF-I-stimulated [alpha-1-14C]methylaminoisobutyric acid transport. CONCLUSION: Our results suggest that the expression and regulation of IGFBPs in tissues from patients with mono-allelic deletion of the IGF-I receptor gene may lead to IGF sequestration and contribute to IGF-I resistance and growth retardation.
The glucagonoma syndrome and necrolytic migratory erythema: a clinical review
Authors: van Beek AP , de Haas ER , van Vloten WA , Lips CJ , Roijers JF , Canninga-van Dijk MR
Published: January 2005

The glucagonoma syndrome is a rare disease in which a typical skin disorder, necrolytic migratory erythema, is often one of the first presenting symptoms. Weight loss and diabetes mellitus are two other prevalent characteristics of this syndrome. Necrolytic migratory erythema belongs to the recently recognized family of deficiency dermatoses of which zinc deficiency, necrolytic acral erythema and pellagra are also members. It is typically characterized on skin biopsies by necrolysis of the upper epidermis with vacuolated keratinocytes. In persistent hyperglucagonemia, excessive stimulation of basic metabolic pathways results in diabetes mellitus at the expense of tissue glycogen stores, and muscle and fat mass. Multiple (essential) nutrient and vitamin B deficiencies develop, which contribute to the dermatosis. In addition, glucagonomas may produce various other products, like pancreatic polypeptide, that add to the catabolic effects of glucagon.
Follow-up and management of differentiated thyroid carcinoma: a European perspective in clinical practice
Authors: Schlumberger M , Pacini F , Wiersinga WM , Toft A , Smit JW , Sanchez Franco F , Lind P , Limbert E , Jarzab B , Jamar F , Duntas L , Cohen O , Berg G
Published: January 2005

As differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We have proposed, in a previous issue of this Journal, an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. We report here the case of a paradigmatic patient with papillary thyroid carcinoma, with the goal of illustrating the benefits of applying this algorithm in routine clinical practice. We also offer expanded and additional comments on various issues in the management of DTC.
Impaired health-related quality of life in Graves' disease. A prospective study
Authors: Elberling TV , Rasmussen AK , Feldt-Rasmussen U , Hording M , Perrild H , Waldemar G
Published: January 2005

OBJECTIVE: In the acute, thyrotoxic phase, patients with Graves' disease often have both thyrotoxic and neuropsychiatric symptoms. The purpose of this prospective study was to examine health-related quality of life (HRQOL) in newly diagnosed and untreated Graves' patients and the effect of antithyroid medical treatment on HRQOL. In addition, we examined the potential influence of thyroid hormones and psychiatric symptoms on the impairment of HRQOL in the thyrotoxic phase. METHODS: A total of 30 consecutively referred patients with newly diagnosed and untreated Graves' disease and 34 age-, sex- and education-matched healthy volunteers were included in the study. HRQOL was assessed with the Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36) before treatment, after reaching euthyroidism and 1 year after initiation of treatment. RESULTS: In the thyrotoxic phase of Graves' disease, HRQOL was significantly impaired, in physical, mental and social dimensions. After reaching euthyroidism, the patients reported much fewer limitations on the subscales of SF-36. One year after initiation of treatment, all SF-36 scores had normalized. However, in some patients, HRQOL continues to be impaired even 1 year after initiation of treatment, as reviewed by the individual analysis. The reduced HRQOL in the acute phase of Graves' disease was correlated to depressive and anxiety symptoms, but thyroid-associated orbitopathy also influenced HLQOL. CONCLUSIONS: Impaired HRQOL is common in the acute phase of Graves' disease. A significant proportion of the patients demonstrated persistent HRQOL impairment 1 year after initiation of treatment. Improvement of HRQOL in these patients remains a challenge for the clinician.
Low triiodothyronine (T3) state: a predictor of outcome in respiratory failure? Results of a clinical pilot study
Authors: Scoscia E , Baglioni S , Eslami A , Iervasi G , Monti S , Todisco T
Published: January 2005

BACKGROUND AND AIM: Various low triiodothyronine (T3) states have been described in severe nonthyroidal diseases and associated with a poor prognosis in cardiovascular disease patients. We assessed thyroid function in patients with severe respiratory failure from pulmonary disorders, and needing invasive or noninvasive mechanical ventilation, in order to evaluate the prognostic value of nonthyroidal illness syndrome. METHODS: We studied 32 consecutive patients with acute or acute-on-chronic respiratory failure. Measured variables upon admission included APACHE II score, the ratio of the partial pressure of oxygen in arterial blood to the fraction of oxygen in inspired gas (PaO(2)/FiO(2)), and plasma levels of free T3 (fT3) and free thyroxine (fT4), and TSH levels. Thyroid function was further evaluated at discharge. RESULTS: Plasma levels of fT3 were below normal in 17 patients (53%). Plasma fT3 was correlated with PaO(2)/FiO(2) (P<0.001), and with APACHE II score (P=0.003). In four patients (12.5%) who died, fT3 levels were significantly lower (P=0.002) than in patients who survived. In univariate logistic regression analysis, fT3 was the only factor significantly associated with an increased risk of death (odds ratio, 64.23; 95% confidence interval, 1.78-2316.86, P=0.023). Normalization of thyroid function was observed at discharge with a significant correlation between the percent increase in both fT3 and PaO(2)/FiO(2) (P=0.015). P values were calculated using Spearman's Correlation Coefficient. CONCLUSION: Our preliminary data suggest that the low T3 state is a predictor of outcome in pulmonary patients with respiratory failure.
Blockade of endogenous growth hormone-releasing hormone receptors dissociates nocturnal growth hormone secretion and slow-wave sleep
Authors: Jessup SK , Malow BA , Symons KV , Barkan AL
Published: January 2005

OBJECTIVES: A temporal association between non-rapid eye movement (NREM) sleep stages 3 and 4 and nocturnal augmentation of GH release was found long ago, yet the precise mechanism for this association has not been identified. It has been shown, however that pulsatile GHRH administration increases both slow-wave sleep (SWS) and GH. Based on these data, a role for GHRH as an inducer of SWS was proposed. To test this hypothesis, we have performed the corollary experiment whereby the action of endogenous GHRH has been antagonized. DESIGN: Healthy men (20-33 years old) had an infusion of GHRH antagonist ((N-Ac-Tyr(1), D-Arg(2)) GHRH-29 (NH(2))) or saline for a 12-h period, between 2100 and 0900 h. An i.v. bolus of GHRH was given at 0700 h and GH samples were drawn from 0700 to 0900 h to document the efficacy of GH suppression by the GHRH antagonist. METHODS: A limited montage sleep study was recorded from 2300 to 0700 h during each admission. Plasma GH concentrations were analyzed by the use of a sensitive chemiluminometric assay. RESULTS: Effectiveness of the GHRH antagonist was validated in all subjects by demonstrating 93+/-1.8% (P=0.012) suppression of GH response to a GHRH bolus. Polysomnography demonstrated that the percentage of SWS was not different when saline and GHRH antagonist nights were compared (P=0.607); other quantifiable sleep parameters were also unchanged. CONCLUSIONS: We conclude that endogenous GHRH is indispensable for the nocturnal augmentation of GH secretion, but that it is unlikely to participate in the genesis of SWS.
Circulating levels of active ghrelin is associated with abdominal adiposity, hyperinsulinemia and insulin resistance in patients with type 2 diabetes mellitus
Authors: Katsuki A , Urakawa H , Gabazza EC , Murashima S , Nakatani K , Togashi K , Yano Y , Adachi Y , Sumida Y
Published: January 2005

OBJECTIVE: To investigate the relationship between the circulating level of active ghrelin and abdominal adiposity, serum levels of insulin or insulin resistance in patients with type 2 diabetes mellitus. DESIGN: We measured the plasma levels of the active form of ghrelin in 18 obese and 18 nonobese patients with type 2 diabetes mellitus using a radioimmunoassay (RIA) kit. Body fat accumulation was measured by computed tomography (CT) and insulin resistance by the glucose infusion rate (GIR) during an euglycemic hyperinsulinemic clamp study. RESULTS: Plasma levels of ghrelin in obese patients with type 2 diabetes mellitus were significantly decreased compared with nonobese patients. There were significant correlations between the plasma levels of ghrelin and BMI (r=-0.505, P<0.01), visceral (r=-0.444, P<0.01), subcutaneous (r=-0.506, P<0.01) and total (r=-0.534, P<0.01) fat area, serum levels of insulin (r=-0.513, P<0.01) or GIR (r=0.478, P<0.01) in type 2 diabetic patients. The plasma level of ghrelin was significantly associated with serum levels of insulin (F=8.468, P<0.05) or GIR (F=8.522, P<0.05) after adjustment for BMI in patients with type 2 diabetes mellitus. CONCLUSIONS: Decreased plasma levels of active ghrelin are significantly associated with abdominal adiposity, hyperinsulinemia and insulin resistance in type 2 diabetic patients. Hyperinsulinemia associated with insulin resistance may suppress plasma levels of active ghrelin in patients with type 2 diabetes mellitus.
Greater use of insulin by southern European compared with Anglo-Celt patients with type 2 diabetes: the Fremantle Diabetes Study
Authors: Clifford RM , Davis WA , Cull CA , Bruce DG , Batty KT , Davis TM
Published: January 2005

OBJECTIVE: To investigate the relationship between blood glucose-lowering therapy, glycaemia and ethnicity in urban Australians with type 2 diabetes. DESIGN: Prospective observational community-based study of diabetes care, control and complications. METHODS: We analysed cross-sectional data from 1057 patients, 238 from a southern European (SE) migrant background and 819 Anglo-Celts (AC). Follow-up data were available for 539 patients (113 SE, 426 AC) who had annual reviews over 4 years. RESULTS: The SE patients were of similar age to the AC patients but had longer diabetes duration, were less fluent in English and had less formal education. After adjustment for diabetes duration, glycosylated haemoglobin and glutamic acid decarboxylase antibody positivity in a logistic regression model, insulin use at study entry was approximately twice as frequent amongst SE as AC patients (odds ratio (95% confidence interval); 1.90 (1.20-3.02)). In the prospective arm, progression to insulin increased in both groups, from 18.0% at baseline to 22.1% at 4 years in SE and from 7.1% to 14.4% in AC patients. beta-cell function (%B) and insulin sensitivity (%S) using the homoeostasis model assessment in a subset of diet-treated patients at baseline showed that SE ethnicity was associated with lower %B and greater %S than in the AC group. CONCLUSIONS: SE patients with early non-antibody-mediated beta-cell failure progress to insulin requirement within the first 4-5 years of type 2 diabetes. This could reflect either a longer period of undiagnosed diabetes or a more rapid loss of beta-cell function after diagnosis.
Thyrotropin-producing pituitary adenoma associated with Graves' disease
Authors: Koriyama N , Nakazaki M , Hashiguchi H , Aso K , Ikeda Y , Kimura T , Eto H , Hirano H , Nakano S , Tei C
Published: January 2005

OBJECTIVES: The examination of potential associations between Graves' disease and thyrotropin-producing pituitary adenoma (TSHoma) after treatment using octreotide, and of the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma). DESIGN AND METHODS: A specimen of resected TSHoma tissue from our case was immunohistochemically examined for expression of somatostatin receptor 2A (SSTR2A) and PPAR gamma. Specimens of thyroid tissue from two cases with Hashimoto's thyroiditis were immunohistochemically examined for expression of SSTR2A. RESULTS: Expression of SSTR2A and PPAR gamma was identified in TSHoma cells. SSTR2A was also expressed in lymphocytes that had infiltrated thyroid tissue in Hashimoto's thyroiditis. In previous reports, three of four patients with TSHoma displayed Graves' disease after tumor resection, and TSH is also known to play a major role in regulating immunomodulatory gene expression in thyrocytes. CONCLUSIONS: Both the immunomodulatory effects of octreotide on intrathyroidal lymphocytes and rapid reductions in TSH may contribute to the onset of Graves' disease. Patients with TSHoma-associated autoimmune thyroiditis should undergo careful follow-up for development of Graves' disease after treatment. Both octreotide and the PPAR gamma receptor-activating ligands, thiazolidinediones, may be effective for patients with TSHoma.
Involvement of the gp130 cytokine transducer in MtT/S pituitary somatotroph tumour development in an autocrine-paracrine model
Authors: Graciarena M , Carbia-Nagashima A , Onofri C , Perez-Castro C , Giacomini D , Renner U , Stalla GK , Arzt E
Published: January 2005

OBJECTIVE: gp130 cytokines are placed as auto-paracrine regulators of pituitary function, since they, as well as their receptors, have been shown to be expressed in and to act in normal and tumoral anterior pituitary cells. The objective of this work was to study their involvement in a model that shows the interaction between different cellular types that participate in a tumorigenic process. DESIGN: The dependence of a pituitary somatotrophic cell line (MtT/S) on a gp130 cytokine-producing folliculostellate (FS) cell line (TtT/GF) for tumorigenesis in vivo has been described. In order to study the participation of gp130 cytokines in the auto-paracrine stimulation of MtT/S growth, we generated MtT/S gp130 sense (gp130-S) and gp130 antisense (gp130-AS) clones stably transfected with pcDNA3/gp130 sense and pcDNA3/gp130 antisense vectors respectively. METHODS AND RESULTS: Functional characterization studies revealed that gp130-AS clones have an inhibited gp130 signalling, and proliferation studies showed that they have an impaired response to gp130 cytokines but respond normally to other independent stimuli. When injected into nude mice, MtT/S clones respond differently depending on cell number; at high concentrations MtT/S clones alone generated tumours equivalent in size to tumours derived from MtT/S plus TtT/GF cells. At low concentrations, MtT/S sense and control clones generated tumours of smaller size than tumours derived from these same clones plus TtT/GF cells, showing a dependence on FS cells. In both cases MtT/S gp130-AS clones had impaired tumour development. Furthermore, vessel density was significantly lower in tumours derived from gp130-AS plus TtT/GF cells. CONCLUSIONS: This study underlines the importance of gp130 cytokines in proliferation and establishes its role in auto-paracrine pituitary growth regulation.
Identification of a novel mutation in the arginine vasopressin-neurophysin II gene affecting the sixth intrachain disulfide bridge of the neurophysin II moiety
Authors: Baglioni S , Corona G , Maggi M , Serio M , Peri A
Published: January 2005

OBJECTIVE: Most mutations of the arginine vasopressin-neurophysin II (AVP-NPII) gene cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). Such mutations are predicted to alter the three-dimensional structure of the prohormone, which accumulates in the cell body, ultimately leading to neuronal degeneration and hormonal deficit. In this study we describe the case of a 26-year-old female reporting a long-lasting history of polyuria/polydipsia. The father of the patient was affected by diabetes insipidus and was under desmopressin treatment until the time of his death. Nevertheless, the patient had never been subjected to endocrine evaluation. DESIGN AND METHODS: Clinical and genetic studies were performed. An 8-h fluid deprivation test plus desmopressin challenge and a 5% saline solution test were performed, in order to confirm the diagnosis. DNA was extracted from peripheral blood lymphocytes and subjected to direct sequencing of the entire coding region of the AVP-NPII gene. RESULTS AND CONCLUSIONS: Clinical assessment of the patient confirmed the diagnosis of neurohypophyseal diabetes insipidus. Desmopressin treatment was started, which effectively reversed the polyuria/ polydipsia syndrome. Genetic analysis revealed a novel mutation (1665T>A) in exon 2 of the AVP-NPII gene, disrupting one of the disulfide bonds present in the NPII moiety which play a fundamental role in determining the proper folding of the molecule. In summary, in the present study we have described a novel mutation of the AVP-NPII gene, which is consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI.
Tumor necrosis factor-alpha (TNF-alpha) promotes cell survival during spermatogenesis, and this effect can be blocked by infliximab, a TNF-alpha antagonist
Authors: Suominen JS , Wang Y , Kaipia A , Toppari J
Published: January 2005

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) has been shown to inhibit germ cell death in human seminiferous epithelium. In the present study, we wanted to explore the effects of TNF-alpha in the rat seminiferous epithelium and to study molecular mechanisms of germ cell apoptosis. Furthermore, the effects of infliximab were studied. Infliximab is a TNF-alpha antagonist used in autoimmune disorders, such as rheumatoid arthritis and Crohn's disease. METHODS: Rat seminiferous tubule segments were cultured in the presence and absence of TNF-alpha, infliximab and SN50, a NF-kappa B inhibitor. TUNEL-staining and cleaved caspase-3 immunohistochemistry combined with squash preparations of rat seminiferous tubule segments were used to evaluate the number of apoptotic cells. Western blot analyses were performed on cultured seminiferous tubule segments for Bcl-2 family proteins (Bax, Bad, Bcl-w, Bcl-xL) and fas ligand. RESULTS: TNF-alpha promotes cell survival in the rat seminiferous epithelium, and this prosurvival effect can be blocked by infliximab, a TNF-alpha antagonist. Bcl-xL was found to be upregulated in mitochondrial membranes by TNF-alpha, and this upregulation was inhibited by infliximab. Inhibition of NF-kappa B translocation to the nucleus prevented the prosurvival effect of TNF-alpha on seminiferous epithelium. CONCLUSIONS: The present study demonstrates that TNF-alpha promotes cell survival in the rat seminiferous epithelium, and this effect can be blocked by infliximab. This is the first study to show the effects of infliximab in the testis. The prosurvival effect of TNF-alpha might be at least partly mediated by modulating the expression and subcellular localization of Bcl-2 family proteins.