bluuebunny/crossref_metadata_2025 huggingface dataset:
Pituitary size in patients with Laron syndrome (primary GH insensitivity)
Authors: Kornreich L , Horev G , Schwarz M , Karmazyn B , Laron Z
Published: January 2005

OBJECTIVE: The purpose of the present study was to investigate whether lifelong secretion of high levels of GH, characteristic of Laron syndrome, leads to an increase in the size of the pituitary gland. METHODS: Eleven patients (six females, five males) with Laron syndrome underwent magnetic resonance imaging of the pituitary region with a system operating at 0.5 T. There were nine adults aged 36-68 Years and two children, a 4-Year-old boy and a 9-Year-old girl. The latter patient had been treated with IGF-I (150-180 mg/kg per day) since the age of 3 Years; all the other patients were untreated. The height of the adenohypophysis was measured on the sagittal images and compared with reference values for age and sex. RESULTS: The height of the adenohypophysis was within the normal range for age and gender in all patients, except for one male, who had a small gland. No congenital anomalies of the pituitary-hypothalamic region were detected. CONCLUSION: Despite the lifelong high levels of GH, no pituitary hypertrophy was detected. The anatomy of the pituitary-hypothalamic region in Laron syndrome is normal.
Decreased plasma adiponectin concentrations in nondiabetic women with elevated homeostasis model assessment ratios
Authors: Matsubara M , Katayose S , Maruoka S
Published: January 2005

OBJECTIVE: Whether the adipocyte-derived protein adiponectin is associated with insulin resistance independently of the effects of adiposity and the diabetic state is an important question. We explored, in a cross-sectional study of 486 Japanese nondiabetic women, the relationship between the calculated insulin resistance (homeostasis model assessment ratio (HOMA-R)) and adiponectin levels determined using a validated sandwich ELISA. DESIGN AND METHODS: All participants were stratified into tertiles for HOMA-R (approximately <1.5, 1.5< or = approximately <3.0, 3.0< or = approximately ) and the differences across tertiles of continuous variables were tested with ANOVA. Two-way ANOVA was used to determine possible relationships for plasma adiponectin between tertiles of HOMA-R and several stratified parameters. Multiple regression analyses were performed with HOMA-R or fasting serum insulin as dependent variable, and diastolic blood pressure (BP), body mass index (BMI), serum triglyceride (TG), leptin and adiponectin as independent determinants. RESULTS: Mean plasma adiponectin in the high HOMA-R group decreased compared with that in the low HOMA-R group both before (mean+/-s.e.m. 6.2+/-0.6 vs 9.2+/-0.3 microg/ml, P<0.001) and after adjustment for body fat mass (BFM) as kg or percent (0.31+/-0.04 vs 0.69+/-0.03, 0.18+/-0.02 vs 0.34+/-0.01, both P<0.001). HOMA-R was inversely associated with adiponectin levels both before (r=-0.37, P<0.001) and after adjustment for BFM (r=-0.49, -0.46, both P<0.001). After covariate adjustment for age, diastolic BP, BMI and serum TG, HOMA-R retained a significant correlation with adiponectin/BFM (kg). Both adiponectin and leptin were the significant determinants of HOMA-R or fasting insulin in multiple regression models. CONCLUSIONS: Adiponectin was inversely associated with insulin resistance in nondiabetic subjects, independently from age, BP, adiposity and serum lipids. Because adiponectin is thought to have an anti-atherogenic action, the presence of hypoadiponectinemia may predispose subjects to atherosclerosis, and may progress the atherogenesis in insulin resistance.
The extracellular portion of the insulin receptor beta-subunit regulates the cellular trafficking of the insulin-insulin receptor complex. Studies on Chinese hamster ovary cells carrying the Cys 860-->Ser insulin receptor mutation
Authors: Benzi L , Cecchetti P , Ciccarone AM , Novelli S , Paoli A , Bertacca A , Maffei M , Maggi D , Andraghetti G , Del Prato S , Cordera R
Published: January 2005

OBJECTIVE: Chinese hamster ovary (CHO) cells transfected with human engineered insulin receptor (IR) cDNA to mutate Cys 860 to Ser (CHO-IR(C860S)) showed a defective insulin internalization without affecting insulin binding and IR autophosphorylation. Moreover, this mutation reduces insulin receptor substrate (IRS)-1 tyrosine phosphorylation and insulin-induced metabolic and mitogenic effects. Altogether, these observations support a role of the extracellular domain of IR beta-subunit in insulin and receptor intracellular targeting as well as in insulin signaling. DESIGN AND METHODS: This study assesses in more details the effect of IR(C860S) mutation on the trafficking of the insulin-IR complex. In particular, IR internalization, phosphorylation, dissociation and recycling, as well as insulin degradation and retroendocytosis have been investigated in CHO cells overexpressing either wild type (CHO-IR(WT)) or mutated IRs. RESULTS: the C860S mutation significantly decreases IR internalization both insulin stimulated and constitutive. In spite of a similar dissociation of internalized insulin-IR complex, recycling of internalized IR was significantly faster (half life (t(1/2)): 21 min vs 40 min, P<0.001) and more extensive (P<0.01) for IR(C860S) than for IR(WT). On the other hand, insulin degradation and retroendocytosis were superimposable in both cell lines. As expected, insulin-induced phosphorylation was similar in both IRs, however dephosphorylation was much more rapid and was greater (P<0.01) in CHO-IR(WT) as compared with CHO-IR(C860S) cells. CONCLUSIONS: Transmembrane and intracellular domain of IR seem to be determinants for IR internalization. Now we report that Cys 860 in the IR beta-subunit ectodomain may be of relevance in ensuring a proper internalization and intracellular trafficking of the insulin-IR complex.
Type-1 response in peripheral CD4+ and CD8+ T cells from patients with Hashimoto's thyroiditis
Authors: Mazziotti G , Sorvillo F , Naclerio C , Farzati A , Cioffi M , Perna R , Valentini G , Farzati B , Amato G , Carella C
Published: January 2005

OBJECTIVE: In this study we performed single-cell analysis of the intracellular cytokine expression in peripheral CD4+ and CD8+ lymphocytes from patients with Hashimoto's thyroiditis (HT) to investigate the type-1 response separately for the two lymphocyte sub-populations. DESIGN AND METHODS: Twenty-nine patients affected by HT and 20 healthy subjects, matched for sex and age, were enrolled. After the analysis of the lymphocyte sub-populations, the intracellular content of interferon-gamma (IFN-gamma) in phorbolmyristate acetate (PMA)-stimulated CD4+ and CD8+ lymphocytes was assayed. Moreover, the CD4+ lymphocytes were also evaluated for the intracellular expression of IL-4. RESULTS: No significant differences in CD3+, CD4+ and CD8+ lymphocytes were found between HT patients and control subjects. However, the HT patients showed higher numbers of CD4+ IFN-gamma+, CD4+ IL-4+ and CD8+ IFN-gamma+ (t-test, P< or =0.001) cells than the control subjects. Analysing the intracellular expression of IFN-gamma and IL-4 in relation to thyroid function, we found that the euthyroid patients (18 cases) showed more expression of IL-4 in CD4+ lymphocytes than the control subjects, without any significant modification of IFN-gamma expression in CD4+ and CD8+ lymphocytes. However, the hypothyroid patients (11 cases) showed an increase of IFN-gamma expression in both CD4+ and CD8+ lymphocytes with respect to the control subjects and the euthyroid patients. Moreover, the expression of IL-4 in CD4+ cells from hypothyroid patients was significantly lower than that seen in the euthyroid cases and comparable to that found in the control subjects. CONCLUSIONS: Our study has demonstrated that the peripheral CD4+ and CD8+ T lymphocytes from the HT patients show a type-1 activation strictly correlated to the occurrence of hypothyroidism. Further studies will be needed to clarify the exact role of peripheral lymphocytes in HT and whether they could provide a reliable marker of thyroid immune involvement.
Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis
Authors: Duntas LH , Mantzou E , Koutras DA
Published: January 2005

OBJECTIVE: Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and the autoimmune process. Therefore, we performed a randomised, placebo-controlled prospective study to investigate the effects of Se treatment on patients with autoimmune thyroiditis (AIT). DESIGN AND METHODS: Sixty five patients aged 22-61 years (median age 48 years) with AIT were recruited into two groups. Group I (Gr I) (n=34) was treated with selenomethionine (Seme) 200 microg, plus L-thyroxine (LT(4)) to maintain TSH levels between 0.3-2.0 mU/l, whereas group II (Gr II) (n=31) received LT(4) plus placebo over a period of 6 months. Moreover, the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h, 4 h, 6 h and 24 h after oral administration of a 200 microg tablet of Seme. Finally, Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels. RESULTS: In the pharmacokinetics study, basal serum concentration of Se (75+/-6 microg/l) was within the reference range (70-125 microg/l), it promptly increased at 2 h, peaked at 4 h (147+/-17 microg/l; P<0.0001) and it was abundant in serum at 24 h. In Gr I, antibodies against thyroid peroxidase (anti-TPO) levels showed an overall decrease of 46% at 3 months (from 1875+/-1039 U/l to 1013+/-382 U/l; P<0.0001) and of 55.5% at 6 months. In Gr II the overall decrease of anti-TPO amounted to 21% at 3 months and to 27% at 6 months (from 1758+/-917 U/l to 1284+/-410 U/l; P<0.005). There were no significant changes of antibodies against thyroglobulin levels between the groups. At the end of this study Se levels were found to be statistically significantly increased in Gr I (n = 9/34) compared with Gr II (n=11/31) (97+/-8.4 vs 79+/-8; P<0.01) but no correlation with thyroid hormone was found. CONCLUSIONS: Seme is proven to be rapidly absorbed by the gastrointestinal tract. It appears to be useful as adjunctive therapy with LT(4) in the treatment of AIT. The exact mechanism(s) is not very well determined, it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress.
Recurrence of hyperparathyroidism; a long-term follow-up after surgery for primary hyperparathyroidism
Authors: Hedback G , Oden A
Published: January 2005

OBJECTIVE: In general it is thought that recurrence of primary hyperparathyroidism is a rare event. To our knowledge, however, only one large patient series has been reported with a mean of more than 7 years of follow-up. The aim of the present study was to determine the long-term recurrence rate in 785 out of 886 patients operated on for primary hyperparathyroidism and followed-up for a mean of 10.03 years after surgery. DESIGN: Medical records were scrutinised. The patients who were still alive answered a questionnaire and had laboratory tests. METHODS: Follow-up data concerning the state of health, medical treatment, other diagnoses, renal function, and serum calcium and creatinine levels were found in the medical records of 203 patients, and were registered at the start of investigation of 582 patients. Intact parathyroid hormone values were determined in 252 patients. Recurrence rate and 95% confidence interval (C.I.) were calculated. RESULTS: Recurrence rate of hyperparathyroidism with constant or intermittent hypercalcaemia (n=39) was 4.97% (95% C.I.=3.45-6.74%) during a mean of 10 years of follow-up. Nine out of 39 had elevated serum creatinine levels. Recurrence rate of hyperparathyroidism with normal serum creatinine levels, including patients with normocalcaemia, intermittent hypercalcaemia, and constant hypercalcaemia was estimated to be 7-8% during a mean of 10 years of follow-up. CONCLUSIONS: Recurrence rate was determined with reasonable precision in this large patient series, and recurrence of hyperparathyroidism cannot be considered to be extremely rare, but it may occur more than 20 years after treatment in both single and multiple gland disease.
The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients
Authors: Socin HV , Chanson P , Delemer B , Tabarin A , Rohmer V , Mockel J , Stevenaert A , Beckers A
Published: January 2005

OBJECTIVE: Our aim was to report the recent changes in diagnosis and management of TSH-secreting pituitary adenomas. METHODS: We retrieved 43 consecutive patients with TSH-secreting pituitary tumors (23 male and 20 female) among 4400 pituitary adenomas followed between 1976 and 2001 in six Belgian and French centers. RESULTS: TSH was elevated in 18/43 and alpha subunit in 13/32 patients. In patients with intact thyroid (n=30), mean free tri-iodothyronine was 13.1 pmol/l (range 3.5-23) and mean free thyroxine was 38.4 pmol/l (range 10.2-62.7). Hyperprolactinemia and acromegaly were associated in 9/43 and 8/43 cases. The number of associated hypersecretions was higher in macroadenomas than in microadenomas (Chi square = 11.2, P<0.01). Two women had sporadic multiple endocrine neoplasia type 1-associated syndrome. The proportion of microadenomas versus macroadenomas was 1/11 (period 1974-1986) and 8/32 (period 1987-2001). Bilateral petrosal sinus sampling, (111)In-pentreotide scintigraphy and ((11)C)-l-methionine positron emission tomography scan confirmed diagnosis in four questionable microadenomas. Macroadenomas with extrasellar extension (31 cases) had a tendency to be medially located. Medical treatment with somatostatin analogs was initiated as first-line treatment in 26 patients. TSH levels were reduced by more than 50% in 23/26 cases. A tumoral shrinkage of more than 20% was observed in 5/13 cases. Surgery was performed in 36 patients. After 1 year, 21 of them (58.3%) met the criteria of surgical favorable outcome. Pituitary radiotherapy (n=8) and somatostatin analogs allowed normalization in cases not cured by surgery. CONCLUSION: Ultrasensitive methods for TSH measurement led to an earlier recognition of TSH-secreting pituitary tumors. In this series, we observed that TSH-secreting pituitary tumors are today more frequently found at the stage of microadenomas, medially located, without associated hypersecretions and needing new exploration methods as compared with older series. This changing spectrum in the presentation of TSH-secreting pituitary tumors and the excellent response to somatostatin analogs has been accompanied by an improvement in the prognosis of the disease.
Raloxifene lowers IGF-I levels in acromegalic women
Authors: Attanasio R , Barausse M , Cozzi R
Published: January 2005

BACKGROUND: IGF-I suppression in acromegaly obtained by tamoxifen, a selective estrogen receptor modulator (SERM), prompted us to evaluate the effects of the administration of a newer SERM, raloxifene (RAL), devoid of estrogenic activity at uterine level, on GH/IGF-I levels in patients with this disease. PATIENTS: Thirteen post-menopausal acromegalic women (aged 55-84 years) with active acromegaly entered a prospective open pilot study of RAL treatment at 60 mg/day. Nine of the patients, who were resistant to somatostatin analog and dopamine agonist treatment, were not undertaking therapy; the other four, who were partially sensitive to medical treatment, maintained treatment at the maximally effective dosages throughout the study. RESULTS: IGF-I levels fell significantly from 444 (median, interquartile 393-590) microg/l to 300 (216-608) microg/l (P=0.0192) after 1 month of RAL administration and this fall remained stable up to the final evaluation at 5+/-1 months from the start of RAL treatment (260 (187-410) microg/l). An IGF-I decrease greater than 30% of basal values was observed in 10 patients (mainly in patients with IGF-I levels lower than 600 microg/l) and normal values were reached in seven (54%). GH levels did not change (basal 6 (4.1-8) microg/l, final 5.5 (3.2-7.4) microg/l). The clinical picture improved in patients sensitive to RAL. RAL withdrawal was followed by the return of IGF-I levels to pretreatment values within 8 weeks in all patients. CONCLUSIONS: RAL decreases IGF-I levels in most acromegalic women with mild or intermediate disease (i.e. with values lower than 600 microg/l) and normalizes it in many. A prospective randomized study in patients resistant or partially sensitive to other medical treatments is warranted.
Sleep disturbances in patients with Addison's disease
Authors: Lovas K , Husebye ES , Holsten F , Bjorvatn B
Published: January 2005

OBJECTIVE: The standard replacement therapy in Addison's disease does not restore normal nocturnal levels of the hormones of the hypothalamic-pituitary-adrenal axis. The aim of the study was to describe the prevalence and characteristics of sleep disturbances in patients with Addison's disease. METHODS: Sixty patients completed a self-administered sleep questionnaire and the Epworth Sleepiness Scale (ESS) questionnaire. Activity-based monitoring (actigraph recordings) and sleep diaries were obtained from eight patients. RESULTS: Thirty-four percent reported weekly sleep disturbances (difficulties falling asleep in 13%; repeated awakenings in 14%; early morning awakenings in 20%). The sleep need was 8.21 h (s.d. 1.34; range 6-14 h), and sleep onset latency was 29 min (s.d. 29, range 2-150 min). Forty percent of the patients were tired during daily activities more than once a week, but the scores of the ESS were 6.0 (s.d. 3.5), which is not higher than normal. The actigraph recordings showed higher sleep efficiency than the subjective recordings. CONCLUSION: We did not identify specific sleep disturbances which were characteristic for patients with Addison's disease. Patients with Addison's disease have increased daytime fatigue, but no more daytime sleepiness than normal.
A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy
Authors: Pohlenz J , Ahrens W , Hiort O
Published: January 2005

OBJECTIVE: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine. CASE REPORT: A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found. METHODS AND RESULTS: Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsalpha) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsalpha protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsalpha protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism. CONCLUSION: In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.
Regulation of nuclear receptor and cofactor expression in breast cancer cell lines
Authors: Vienonen A , Miettinen S , Manninen T , Altucci L , Wilhelm E , Ylikomi T
Published: January 2005

OBJECTIVE: The aim of this study was to compare the expression profile of nuclear receptors (NRs) and cofactors in different breast cancer cell lines as well as their regulation by estradiol, insulin and progestin R5020. METHODS: Expression of NRs and cofactors were determined from MCF-7, T-47D and ZR-75-1 breast cancer cell lines. Multiprobe ribonuclease protection assay and real-time RT-PCR were used to quantitate mRNA levels of steroid receptors, vitamin D receptors (VDR) and retinoic acid receptors (RAR) and cofactors: amplified in breast cancer-1, cyclic AMP response element binding protein (CBP), p300/CBP-associated factor, p300, nuclear receptor corepressor and silencing mediator of repressed transcription. RESULTS: Basal expression levels of NRs and cofactors varied depending on the cell line. Cell line-specific regulation of androgen receptor, estrogen receptor-alpha (ERalpha), RARalpha, RARgamma and VDR expression was observed after estradiol treatment. Likewise, differences in the regulation of ERalpha, RARalpha and VDR expression after R5020 treatment were observed. We did not observe significant regulation of cofactor expression after estradiol, insulin or progestin treatment in any cell line analyzed. CONCLUSIONS: The results showed that not only is the expression profile of the NRs and cofactors cell line specific but also the regulation of NR expression. Thus the determinants of the ligand action (receptor and cofactor expression) varied considerably among different cell clones of the breast cancer cells. This suggested a gradient of NR-ligand sensitivities in the hormone-dependent breast cancers, which produces an additional challenge in developing novel ligands for hormone replacement therapy and breast cancer treatment.
Intracellular depletion of insulin: a comparative study with palmitate, oleate and elaidate in INS-1 cells
Authors: Bollheimer LC , Kemptner DM , Kagerbauer SM , Kestler TM , Wrede CE , Buettner R
Published: January 2005

OBJECTIVE: Free fatty acids (FFAs) deplete the intracellular insulin stores of pancreatic beta-cells. It has been suggested that this results from a lipotoxic dysregulation of both insulin secretion and insulin synthesis. In the present study, this hypothesis was tested within a 12-h time-course by directly relating the FFA-induced loss of intracellular insulin to corresponding parameters of insulin secretion and de novo biosynthesis. Palmitate, cis-monoenic oleate and the trans-monoenic elaidate were employed as model FFAs to elucidate potentially different effects due to chain length and configuration. METHODS: INS-1 cells were incubated for 1, 4 or 12 h with 11.2 mmol/l glucose with 200 micromol/l palmitate, oleate or elaidate and compared with non-FFA-exposed controls with respect to content and secretion of immunoreactive insulin (IRI). Biosynthesis of insulin was monitored by pulse-labeling experiments and by Northern blot analysis. RESULTS: IRI content dropped by 50-60% after a short-term exposure with all FFAs employed (P< or =0.001). It tended to recover after 12 h of treatment with oleate and elaidate but not with palmitate. FFA treatment increased insulin secretion by 25% (P< or =0.05) which could not account quantitatively for the intracellular loss. FFA-induced changes in insulin biosynthesis did not correlate clearly with the FFA-induced intracellular loss. CONCLUSIONS: The FFA-induced loss of IRI is an acute effect independent of the FFA employed. It cannot be sufficiently explained by FFA-induced perturbances of IRI secretion and biosynthesis. We therefore postulate an additional FFA-triggered mechanism, e.g. intracellular IRI degradation.
Multi-center study on the characteristics and treatment strategies of patients with Graves' orbitopathy: the first European Group on Graves' Orbitopathy experience
Authors: Prummel MF , Bakker A , Wiersinga WM , Baldeschi L , Mourits MP , Kendall-Taylor P , Perros P , Neoh C , Dickinson AJ , Lazarus JH , Lane CM , Heufelder AE , Kahaly GJ , Pitz S , Orgiazzi J , Hullo A , Pinchera A , Marcocci C , Sartini MS , Rocchi R , Nardi M , Krassas GE , Halkias A
Published: January 2005

To improve management of patients with Graves' orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves' Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves' orbitopathy patients. This form was used in this first multi-center study. AIM: To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. METHODS: Newly referred patients with Graves' orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. RESULTS: One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis > or =21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P<0.02). There were no important differences among the eight centers regarding the severity and the activity of their patients. CONCLUSIONS: In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible.
Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas
Authors: Puxeddu E , Moretti S , Giannico A , Martinelli M , Marino C , Avenia N , Cristofani R , Farabi R , Reboldi G , Ribacchi R , Pontecorvi A , Santeusanio F
Published: January 2005

OBJECTIVE: RET proto-oncogene rearrangements (ret/PTCs) represent the most common genetic alterations found in papillary thyroid carcinomas (PTCs). Correlation of ret/PTC expression with clinical outcome is controversial. The aim of the present study was to analyze the frequency of RET rearrangements in adult PTCs, and to investigate if ret/PTCs influence biological behavior and clinical features of the cancers. DESIGN: Ret/PTC rearrangements were looked for in tIssue samples of 48 PTCs collected at our institution. Data about clinical and pathological features of the tumors were also reviewed. Three separate association analyses were carried out on the cohort evaluating the effects of, respectively, ret/PTC positivity, preferential RET tyrosine kinase domain (RET-TK) expression, and ret/PTC plus RET-TK positivity, on age, sex, tumor size, staging, number of neoplastic foci, and histological subtype. METHODS: The genetic study was conducted with the RT-PCR-Southern blot technique. Standard Student's t-test and Fisher exact test were applied for the association analyses. RESULTS: The molecular genetic study demonstrated the positivity of ret/PTC1 and ret/PTC3 in 13 of 48 tumors (27.1%), and an exclusive or preferential RET-TK expression in 17 cases (35.4%). None of the three genetico-clinical analyses showed any significant association between ret/PTC expression and the clinical and pathological features of the cancers. CONCLUSIONS: These data indicate that RET rearrangements may not play any distinctive role in driving histotype development and cancer progression in these neoplasms. Moreover, they weaken the possibility of using ret/PTC as a prognostic marker for papillary thyroid carcinomas.
Treatment of GH-deficient children with two different GH doses: effect on final height and cost-benefit implications
Authors: Radetti G , Buzi F , Paganini C , Pilotta A , Felappi B
Published: January 2005

OBJECTIVE: Treatment of GH-deficient (GHD) children with higher doses of recombinant human GH (rhGH) than conventional ones has been reported to result in higher growth velocity and increased final height. These findings, however, were observed by comparing large but heterogeneous groups of children. We wanted to verify whether the same results could be obtained in two groups of appropriately well-matched children with isolated GHD treated with high vs conventional doses of rhGH. METHODS: Out of two cohorts of GHD children, cohort A (on a weekly rhGH dose of 0.3 mg/kg body weight) and cohort B (on a weekly rhGH dose of 0.15 mg/kg body weight), we selected two groups, each including 13 patients, who before treatment were matched for age, sex and height standard deviation score (SDS). They were followed up until final height. RESULTS: Final height SDS was significantly higher in group A (-0.45+/-0.36 (s.d.) vs -1.07+/-0.7; P=0.008), as well as height gain SDS (1.81+/-0.58 vs 1.23+/-0.62; P=0.002). The difference between final height SDS and target height SDS was positive only in group A and significantly higher in group A than in group B (0.33+/-0.51 vs -0.46+/-0.7; P=0.01). Glucose tolerance was always normal in the group treated with higher doses. CONCLUSION: The final height of children treated with higher doses of rhGH is increased, also in relation to their genetic target. The economical burden of this choice of treatment, however, has to be taken into account when evaluating the results.
Effect of cyclical intermittent etidronate therapy on circulating osteoprotegerin levels in patients with rheumatoid arthritis
Authors: Valleala H , Mandelin J , Laasonen L , Koivula MK , Risteli J , Konttinen YT
Published: January 2005

OBJECTIVE: To evaluate the role of serum osteoprotegerin (OPG) as a biochemical marker for disease activity assessment and drug monitoring in patients with rheumatoid arthritis (RA) treated with cyclical etidronate. DESIGN: Forty patients (35 women and 5 men) with RA of <5 years duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with anti-rheumatic therapy or anti-rheumatic therapy alone (without etidronate) in a 2-year, open-label protocol. METHODS: Radiographs of hands and feet and serum samples for the determination of OPG, amino terminal propeptide (PINP), cross-linked C-telopeptide (ICTP) and amino terminal telopeptid of type I collagen were obtained at baseline and at 24 months. RESULTS: Etidronate treatment had no effect on circulating OPG levels, although the significant decline in PINP and ICTP (P=0.001 and P=0.04 respectively) reflected the efficacy of the anti-resorptive therapy. At baseline and at study termination, serum OPG correlated significantly with age (r=0.45; P=0.003 and r=0.56; P=0.0002 respectively). OPG was not related to biochemical markers of bone metabolism, indices of disease activity or radiographic disease progression. At baseline, the mean serum OPG was higher in patients receiving 5-10 mg/day prednisone (82.8+/-4.0 pg/ml, n=16) compared with those receiving <5 mg/day or with no prednisone (69.7+/-4.7 pg/ml, n=23) (P=0.05). CONCLUSIONS: Our results suggested that serum OPG measurement, perhaps because of the complexity of the regulation of the OPG, may be difficult to utilize in the evaluation of anti-resorptive therapy. Moreover, low dose corticosteroid-associated osteoporosis is probably not mediated by inhibition of OPG.
Sex steroids and body composition in men with cystic fibrosis
Authors: Leifke E , Friemert M , Heilmann M , Puvogel N , Smaczny C , von zur Muhlen A , Brabant G
Published: January 2005

OBJECTIVE: Delayed sexual maturation and low body weight is common in cystic fibrosis (CF). Concomitant data on sex hormones and concomitant body composition are lacking in men with CF. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: Serum levels of testosterone, 17beta-oestradiol (E(2)), 25-hydroxyvitamin D (25(OH)D), sex hormone-binding globulin (SHBG) and LH were measured by RIA and total and regional lean body mass (LBM), fat body mass (FBM), bone mineral content and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry, in men with CF (n=40; age 24.7+/-5.4 years) and age-matched healthy controls (n=28; age 25.7+/-3.7). Only men without acute disease exacerbation or systemic glucocorticoid treatment were included. RESULTS: Mean levels of hormonal serum parameters differed significantly between healthy controls (testosterone=20.2+/-5.5 nmol/l; E(2)=95.0+/-20.2 pmol/l; 25(OH)D=62.8+/-28.3 nmol/l) and patients (testosterone=15.9+/-4.1 nmol/l; E(2)=60.7+/-19.4 pmol/l; 25(OH)D=39.5+/-17.8 nmol/l; P<0.001) while no difference was found for SHBG or LH. Eleven (for E(2), 19 of 40, for 25(OH)D, 20 of 40) out of 40 patients had serum testosterone levels 2 s.d. below the mean of normal. Men with CF showed a relative shift from FBM to LBM and a different body fat distribution compared with healthy controls (P<0.01). Testosterone was not correlated with weight, total or regional LBM or FBM, but significantly with BMD (r=0.32; P<0.05) independently from body height and 25(OH)D levels. E(2) was correlated with regional and total FBM (r=0.48; P<0.05). In a multiple regression analysis of the joint effect of testosterone and body components on E(2), a testosterone-independent effect was found for FBM. CONCLUSIONS: CF patients with stable disease have moderately reduced serum testosterone levels. This might already imply detrimental effects on bone. The change in LBM of patients appears to have no direct association with sex hormone levels while low FBM might cause reduced net conversion of serum testosterone to E(2) with possible effects on FBM distribution.
Serum concentrations of activin and follistatin are elevated and run in parallel in patients with septicemia
Authors: Michel U , Ebert S , Phillips D , Nau R
Published: January 2005

OBJECTIVE: Activin is a growth and differentiation factor of many cell types, and has recently been implicated in inflammatory processes. Clinical data linking activin and its binding protein, follistatin (FS), are lacking. We measured serum levels of activin and FS in patients diagnosed with septicemia. PATIENTS AND MEASUREMENTS: Eight male and seven female patients of different ages, various forms of septicemia and different clinical outcome were investigated and compared with age- and sex-matched healthy controls. Serum concentrations of FS, activin, C-reactive protein (CRP) and blood leukocyte counts were determined during septicemia. RESULTS: The median of the maximum activin concentrations of septicemic patients was 3.9-fold higher than in age- and sex-matched healthy control subjects (P<0.01); the median of the maximum FS concentrations was 2.6-fold higher (P<0.01). The highest increase of activin in septicemic patients was approximately 15.8-fold, whereas FS increased by up to 13.2-fold above normal. FS, activin and CRP serum levels generally paralleled each other, but were not correlated with leukocyte counts or clinical outcome. CONCLUSIONS: Circulatory concentrations of activin and FS are elevated in patients diagnosed with septicemia, consistent with potential roles in the systemic inflammatory response.
Autoantibodies to steroidogenic enzymes in patients with premature ovarian failure with and without Addison's disease
Authors: Dal Pra C , Chen S , Furmaniak J , Smith BR , Pedini B , Moscon A , Zanchetta R , Betterle C
Published: January 2005

DESIGN: Adrenal cortex autoantibodies (ACA), steroid-producing cell autoantibodies (StCA) and autoantibodies (Abs) to steroidogenic enzymes in three groups of patients with premature ovarian failure (POF), 15 with autoimmune Addison's disease (AD), 26 with non-adrenal autoimmune diseases and 31 with isolated POF, have been assessed. METHODS: ACA and StCA were measured using an immunofluorescence technique. Abs to 21-hydroxylase (21-OH), to 17alpha-hydroxylase (17alpha-OH) and to cytochrome P450 side-chain cleavage (P450scc) were measured using an immunoprecipitation assay. RESULTS: Seventy-three percent of patients with POF and AD were positive for StCA, 93% for 17alpha-OH and/or P450scc Abs, 93% for ACA and 100% for 21-OH Abs. Among patients with POF and non-adrenal autoimmune diseases, 8% were positive for StCA, 12% for 17alpha-OH and/or P450scc Abs, and 8% and 12% for ACA and 21-OH Abs respectively. StCA, 17alpha-OH and/or P450scc Abs were all found in 10% of patients with isolated POF, and 13% had ACA and 21-OH Abs. All StCA-, 17alpha-OH- and/or P450scc Abs-positive patients were also positive for ACA and 21-OH Abs. Two patients with isolated POF who were ACA and 21-OH Ab positive developed AD 3 and 5 Years after the onset of POF. CONCLUSION: This study has shown that, when POF is associated with AD, StCA, 17alpha-OH and/or P450scc Abs are present in the majority of patients, while in the other two groups these Abs are detectable in a much lower proportion of patients. Measurement of ACA/21-OH Abs in some patients with POF may be important in identifying patients at risk of developing overt AD.
Progesterone effects during sequential hormone replacement therapy
Authors: Andreen L , Bixo M , Nyberg S , Sundstrom-Poromaa I , Backstrom T
Published: January 2005

OBJECTIVE: The aim was to investigate the effect on mood and the physical symptoms of two dosages of natural progesterone and a placebo in postmenopausal women with and without a history of premenstrual syndrome (PMS). DESIGN: A randomized, placebo-controlled, double-blind, crossover study was performed. METHOD: Postmenopausal women (n=36) with climacteric symptoms were recruited. They received 2 mg estradiol continuously during three 28-day cycles. Vaginal progesterone suppositories with 800 mg/day, 400 mg/day, or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale were kept. RESULTS: Women without a history of PMS showed cyclicity in both negative mood and physical symptoms while on 400 mg/day progesterone but not on the higher dose or the placebo. Women without a history of PMS had more physical symptoms on progesterone treatment compared with placebo. Women with prior PMS reported no progesterone-induced symptom cyclicity. CONCLUSION: In women without prior PMS natural progesterone caused negative mood effects similar to those induced by synthetic progestogens.
Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women
Authors: Cetani F , Pardi E , Borsari S , Vignali E , Dipollina G , Braga V , Adami S , Pinchera A , Marcocci C
Published: January 2005

OBJECTIVE: Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. DESIGN: The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). METHODS: A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. RESULTS: The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. CONCLUSIONS: Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.
Serum insulin-like growth factor binding protein-2 levels as an indicator of functional ability in elderly men
Authors: van den Beld AW , Blum WF , Pols HA , Grobbee DE , Lamberts SW
Published: January 2005

BACKGROUND: In a cross-sectional study in 403 healthy, independently living elderly men (mean age 78 years), we determined which are the main physiological determinants of functional ability in the elderly, and which components of the somatotropic system contribute to the maintenance of functional ability. METHODS: Functional ability was assessed by the number of problems in activities of daily living and by a measure of physical performance. Other physical characteristics included leg extensor strength, bone mineral density of total body and proximal femur, and body composition, including lean mass and fat mass. Serum insulin-like growth factor (IGF)-I and its binding proteins (IGFBP) -1, -2 and -3 concentrations were all measured by RIA. RESULTS: Muscle strength was related to a lower degree of disability. Further, it was positively related to physical performance and bone mineral density (all P<0.001). Fat mass influenced activities of daily living and physical performance negatively and bone mineral density positively (all P<0.001). Serum concentrations of IGF-I and IGFBP-3 were not related to any of the physical characteristics. High serum IGFBP-2 concentrations were related to a higher degree of disability (P<0.001), a lower physical performance (P=0.006), muscle strength (P=0.002), bone mineral density of proximal femur (P=0.007), lean mass and fat mass (both P<0.001). Serum insulin and IGFBP-1 concentrations were independently, positively related to lean mass (P=0.003) and fat mass (P<0.001). CONCLUSIONS: In independently living elderly men, functional ability appears to be determined by muscle strength (positive) and fat mass (negative). Low serum IGFBP-2 concentrations are a powerful indicator for overall good physical functional status, probably inversely reflecting the integrated sum of nutrition and the biological effects of growth hormone, IGF-I and insulin.
Acute hyperglycemia and activation of the beta-adrenergic system exhibit synergistic inhibitory actions on growth hormone (GH) releasing hormone-induced GH release
Authors: Park C , Yang I , Woo J , Kim S , Kim J , Kim Y , Park S
Published: January 2005

OBJECTIVE: Acute hyperglycemia stimulates somatostatin (SRIH) release by the hypothalamus which, in turn, suppresses growth hormone (GH) secretion from the anterior pituitary gland. Although it has been suggested that the cholinergic pathway mediates glucose-induced SRIH release, other regulatory systems have not been examined. Therefore, we investigated whether blocking or activating the beta-adrenergic pathway alters glucose-mediated inhibition of GH release. DESIGN AND METHODS: One set of experiments was performed with a beta-adrenergic antagonist, propranolol, and the other set with a beta-adrenergic agonist, isoproterenol. Each set of experiments was performed in ten healthy subjects and consisted of four tests. Test 1, a 100 microg GHRH bolus i.v. at 0 min; test 2, 100 g glucose orally at -30 min, followed by a 100 microg GHRH bolus at 0 min; test 3, after a 100 microg GHRH bolus i.v. at 0 min, a continuous infusion of propranolol (0.2 mg/kg) or isoproterenol (0.012 microg/kg) was administered between 0 and 120 min; test 4, after a 100 g glucose oral load at -30 min, and a 100 microg GHRH bolus i.v. at 0 min, a continuous infusion of propranolol (0.2 mg/kg) or isoproterenol (0.012 microg/kg) was administered between 0 and 120 min. Blood was drawn every 10 min from -30 min to 120 min to measure GH and glucose concentrations. RESULTS: Pretreatment with glucose significantly suppressed GHRH-induced GH secretion. Propranolol infusion significantly increased the GHRH-induced GH secretion, but it did not block glucose-induced suppression of GH secretion. Isoproterenol infusion alone significantly suppressed GHRH-induced GH secretion and augmented the inhibitory action of glucose on GH release. CONCLUSION: This study demonstrates that glucose-induced suppression of GHRH-stimulated GH release is independent of beta-adrenergic tone. Since previous data supports a role for SRIH in both glucose and beta-adrenergic suppression of GH release, the current results suggest that subsets of SRIH neurons are differentially responsive to these external cues. Therefore, a combined glucose and isoproterenol test may provide a useful assessment of hypothalamic somatostatinergic activity.
Comparison of the impact of the I27L polymorphism of the hepatocyte nuclear factor-1alpha on estimated and measured beta cell indices
Authors: Chiu KC , Chuang LM , Chu A , Yoon C , Wang M
Published: January 2005

OBJECTIVE: We investigated the impact of the I27L polymorphism of the hepatocyte nuclear factor-1alpha gene on measured and estimated beta cell indices. We also examined the conservation of this amino acid among different species. DESIGN AND METHODS: Estimated first and second phase insulin responses (1stPH(S) and 2ndPH(S)) were estimated from oral glucose tolerance tests in 78 glucose tolerant subjects. Among these subjects, first and second phase insulin responses (1stIR and 2ndIR) were measured in 60 subjects. The I27L genotypes were determined from genomic DNA. We also reviewed the published peptide sequence data on this polymorphism. RESULTS: The estimated beta cell indices correlated well with the measured indices. Although the impact of this polymorphism was noted in the measured indices (P<0.01 for 1stIR and P=0.04 for 2ndIR) from 60 subjects, the differences in the estimated indices were only noted in the extended sample set with 78 subjects (P=0.05 for 1stPH(S) and P=0.04 for 2ndPH(S)). This polymorphism occurs in the dimerization domain, which is completely conserved within human, rat, mouse and hamster. This amino acid is also conserved in chicken and zebrafish, but not in the frog. This conservation suggests a possible biological importance of this amino acid. CONCLUSIONS: By increasing the sample size, we demonstrated the role of the I27L polymorphism in the pathogenesis of type 2 diabetes by using estimated beta cell indices. The conservation among species suggests a possible biological importance of this amino acid. Analysis of the published data confirms a modest role of this polymorphism in type 2 diabetes.