bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium-iodide symporter (NIS) gene expression in lymph-node metastases of papillary thyroid carcinomas
Authors: Arturi F , Russo D , Giuffrida D , Schlumberger M , Filetti S
Published: January 2005

OBJECTIVE: To investigate the molecular mechanisms underlying the influence of alteration of iodine trapping on the prognosis of metastatic papillary thyroid carcinomas, focusing on the expression of the Na+/I(-) symporter (NIS). DESIGN: We evaluated the expression of the NIS gene in a series of 11 enlarged neck lymph-node metastases of papillary thyroid carcinomas, including four patients in whom an enlarged lymph node represented the first sign of the tumoral disease. Nine lymph nodes, either reactive or metastatic for non-thyroid tumors, were also investigated. METHODS: Expression of the NIS gene was evaluated by RT-PCR in material obtained by fine-needle aspiration biopsy. RESULTS: The NIS gene was expressed in eight (73%) of 11 differentiated thyroid cancer metastatic lymph nodes examined. Five of these metastatic lymph nodes were positive at the post-treatment total-body iodine-131 scan; in the other three, the total-body scan showed no uptake in the metastatic tissues, indicating an alteration downstream to the NIS mRNA synthesis causing the loss of iodide uptake. As expected, when the NIS mRNA expression was absent, total-body (131)I scan showed no uptake in the metastatic lymph nodes. CONCLUSIONS: Our study demonstrates that NIS gene expression may be absent in metastatic differentiated thyroid carcinomas and that different mechanisms, other than loss of NIS transcription, may also be involved in the loss of iodide uptake in metastatic thyroid cells. Study of NIS gene expression in the metastatic lymph nodes, therefore, may provide useful information in the management of patients with thyroid carcinoma.
Age- and gender-dependent urinary iodine concentrations in an area-covering population sample from the Bernese region in Switzerland
Authors: Als C , Keller A , Minder C , Haldimann M , Gerber H
Published: January 2005

OBJECTIVE: Before a scheduled increase of salt iodide content up to 20 p.p.m. in Switzerland, urinary iodine concentration (UIC, microg/l) of a randomly selected, area-covering, age-stratified population subgroup was sampled in spring 1997. In contrast to former published studies on UIC, we minimized biases by age, gender, rural/urban, socio-economic and cultural influences. METHODS: We contacted 750 households in the Bernese region using random telephone numbers. Per household, one proband selected by play dice collected a spot urine sample. We defined seven age categories: infants, children, adolescents, adults I-III and seniors, aged 0-5, 6-12, 13-20, 21-35, 36-50, 51-65 and >65 years respectively. Randomized UIC data were compared with WHO criteria of iodine deficiency (ID) and previous non-randomized, age-dependent Swiss UIC data. To recruit a perfect random group of volunteers proved difficult, as study participation of adolescent and male populations was somewhat lower than that of elder and female (P<0.005) populations respectively. Study participation of inhabitants of rural and suburban regions was comparable (P=0.139). Out of 413 obtained urine spots, 412 (55%) were analyzed statistically (58% women, 42% men, P<0.005). RESULTS: Ninety per cent of all UIC values ranged between 25 and 200 microg/l. Median UIC showed mild ID (94 microg/l). UIC varied significantly between age categories (P=0. 0006). Women had lower UIC than men (P=0.014). Infants had no ID. Women in child-bearing age (13-35 years), adults II, adults III and seniors had mild ID. Compared with recommended supplies of 150 and 200 microg I/day in children and male adolescents respectively, we consider their UIC (110 and 144 microg/l) as at least borderline deficient. Absolute UIC was lowest in seniors. Probands from rural/suburban households had similar UICs. Our UIC data were comparable to published ones. CONCLUSIONS: Despite long-term national efforts with iodized salt (15 p.p.m. in 1997), mild ID still prevailed in Bern in spring 1997, with rare extreme UIC values. Mild ID with women in child-bearing age (and probably also with children and male adolescents) was a serious concern, as goiter growth with puberty or pregnancy might be the consequence. Mild ID in adults and seniors might be due to restricted NaCl intake. Results of our randomly selected subgroup from a 650 000 population show that age- and gender-dependency are important when comparing our collected data with published UIC data. This fact must be considered with non-randomly selected population subgroups.
Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT)
Authors: Bjoro T , Holmen J , Kruger O , Midthjell K , Hunstad K , Schreiner T , Sandnes L , Brochmann H
Published: January 2005

OBJECTIVE: To examine the prevalence of thyroid disease and dysfunction including thyroid autoimmunity in Norway. MATERIALS AND METHODS: All inhabitants 20 years and older (94009) in Nord-Trondelag were invited to participate in a health survey with a questionnaire and blood samples. RESULTS: The prevalence of former diagnosed hyperthyroidism was 2.5% in females and 0.6% in males, hypothyroidism 4.8% and 0.9%, and goitre 2.9% and 0.4% respectively. In both sexes the prevalence increased with age. In individuals without a history of thyroid disease the median, 2.5 and 97.5 percentiles for TSH (mU/l) were 1.80 and 0.49-5.70 for females and 1. 50 and 0.56-4.60 for males. The TSH values increased with age. When excluding individuals with positive thyroid peroxidase antibodies (TPOAb) (>200U/ml), the 97.5 percentiles dropped to 3.60 mU/l and 3. 40 mU/l respectively. The prevalence of pathological TSH values in females and males were TSH >/=10mU/l 0.90% and 0.37%; TSH 4.1-9. 9mU/l 5.1% and 3.7%; and TSH</=0.05mU/l 0.45% and 0.20% respectively. The prevalence of positive TPOAb (>200U/ml) was 13.9% in females and 2.8% in males. In females the lowest percentage (7.9%) of positive TPOAb was seen with TSH 0.2-1.9mU/l and increased both with lower and higher levels of TSH. The percentage of males with positive TPOAb was lower than in females in all TSH groups except for those with TSH>10mU/l (85% TPOAb positive). CONCLUSIONS: In spite of a high prevalence of recognised thyroid disease in the population a considerable number of inhabitants have undiagnosed thyroid dysfunction and also positive TPOAb.
No acute response of leptin to an oral fat load in obese patients and during circadian rhythm in healthy controls
Authors: Guerci B , Hadjadj S , Quilliot D , Ziegler O , Drouin P
Published: January 2005

This study was done to elucidate the relationship between postprandial leptin and obesity, and the possible influence of the circadian rhythm on the dynamic leptin response to an oral fat load (OFLT). In experiment 1, we measured the leptin and insulin responses to an oral fat load in 16 non-diabetic obese subjects and in 16 healthy controls, matched for age and gender. In experiment 2, we measured the leptin and insulin responses to an OFLT according to the time of fat load ingestion: 0700 h (diurnal (D) test) or 2200 h (nocturnal (N) test) in nine normal-weight healthy males. Baseline leptin concentration was correlated with the body mass index, body fat mass and percentage of body fat mass in both experiments. The leptin concentrations were higher in women than in men (P<0.001). In experiment 1, the leptin concentrations were higher in obese subjects than in controls, but did not change over time in either group. The plasma insulin concentrations at baseline and during the postprandial state, as well as the area under the curve (AUC) of insulin, were higher in obese subjects than in controls (P<0.05-0. 0001). There was no correlation between postprandial insulin responses and postprandial leptin responses in either obese or control groups. In experiment 2, leptin (D vs N, 2.9+/-1.4 vs 2. 9+/-1.0 ng/ml) and insulin (D vs N, 41+/-18 vs 25+/-9 pmol/l) concentrations were similar at the beginning of the D and N tests after a 10 h fast. The leptin concentrations did not change after D or N tests and were not statistically different for D and N tests. Our results indicate that the leptin concentration in healthy controls and in obese patients is not acutely influenced by a high fat load.
Anthropometric, computed tomography and fat cell data in an obese population: relationship with insulin, leptin, tumor necrosis factor-alpha, sex hormone-binding globulin and sex hormones
Authors: Garaulet M , Perex-Llamas F , Fuente T , Zamora S , Tebar FJ
Published: January 2005

OBJECTIVE: To correlate anthropometric, computed tomography and fat cell data from abdominal regions with the levels of serum insulin, C-peptide, leptin, tumor necrosis factor-alpha (TNF-alpha), testosterone, 17beta-estradiol, androstenedione, dehydroepiandrosterone sulphate (DHEA-S) and sex hormone-binding globulin (SHBG). DESIGN AND METHODS: The sample consisted of 84 obese patients (29 men, 22 premenopausal women and 33 postmenopausal women) who had undergone abdominal surgery. Weight, height, percentage of body fat by skinfolds, waist, hip and thigh circumferences, sagittal and coronal diameters, visceral and subcutaneous area, serum hormones and fat cell data were studied. RESULTS AND CONCLUSIONS: Premenopausal women showed the lowest values in most abdominal distribution parameters, although, depending on the waist circumference criteria at the umbilicus level perimeter (W1) or midway between lower rib margin and iliac crest perimeter (W2), the population was classified differently, as gynoid or android. Although there were no differences in fat cell size between genders, gynoid women had smaller and more numerous fat cells than the android type. Perivisceral fat cell size was significantly smaller than subcutaneous fat cell size. In women, central obesity was significantly correlated with an increase in serum insulin, leptin, TNF-alpha, testosterone and androstenedione levels, and a decrease in 17beta-estradiol and DHEA-S, while in men significant correlations were positive with insulin and negative with testosterone and androstenedione. Fat cell size was positively correlated with serum levels of leptin, insulin, DHEA-S, androstenedione and inversely correlated with SHBG. These data indicate that hormones seem to interact not only with body fat distribution but also with fat cell size. This interaction differs between genders and between the different abdominal adipose tissue regions.
Bone mass and body composition of adult women with congenital virilizing 21-hydroxylase deficiency after glucocorticoid treatment since infancy
Authors: Hagenfeldt K , Martin Ritzen E , Ringertz H , Helleday J , Carlstrom K
Published: January 2005

AIM: To study bone mass, body composition and androgenic/anabolic activity in adult women with virilizing congenital adrenal hyperplasia (CAH) treated with glucocorticoids since infancy and to relate this to the postmenarcheal glucocorticoid impact. PATIENTS AND METHODS: Thirteen adult women with virilizing CAH treated with gluco- and mineralocorticoids but otherwise medicine-free were investigated with respect to bone mineral content, body composition by dual energy X-ray absorptiometry and endocrine status. In addition an index of accumulated postmenarcheal exogenous glucocorticoid impact was calculated. Seven of the patients had regular menstrual periods, and six were oligomenorrheic but responded with withdrawal bleedings on cyclic progestagens. The data for the patients were compared with those of age-matched healthy reference subjects. RESULTS: In spite of their shorter stature, CAH patients were significantly heavier and had a significantly higher body mass index and fat/lean body mass ratio than the controls. Their bone mineral area density (BMD) was significantly lower than that of the controls. Serum concentrations of androgens were subnormal in all except two of the patients. Strong negative associations were found between BMD and the calculated index of accumulated postmenarcheal glucocorticoid dose but not between BMD and circulating androgen levels. CONCLUSION: The results indicate that glucocorticoids were administered in excess in most of the patients, resulting in subnormal levels of adrenocortical androgens, increased body fat and bone demineralization. Increased catabolic activity due to hypercortisolism rather than decreased androgenic/anabolic steroids is probably the major cause of the subnormal BMD in the treated CAH patients.
Influence of physical mobility and season on 25-hydroxyvitamin D-parathyroid hormone interaction and bone remodelling in the elderly
Authors: Theiler R , Stahelin HB , Kranzlin M , Somorjai G , Singer-Lindpaintner L , Conzelmann M , Geusens P , Bischoff HA
Published: January 2005

OBJECTIVE: To investigate influences of physical mobility and season on 25-hydroxyvitamin D-intact parathyroid hormone (iPTH) interaction in the elderly. DESIGN: We examined 188 frail institutionalized elderly at the expected nadir of their serum vitamin D concentrations (winter). This group was compared with 309 healthy ambulatory elderly at the expected time of maximum vitamin D repletion (summer), to accentuate the influences of season and physical activity. METHODS: Serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, iPTH and urinary deoxypyridinoline (DPD) were measured. RESULTS: Vitamin D metabolites were significantly lower in the institutionalized elderly (P<0.0001), with an 82.5% prevalence of vitamin D deficiency (25-hydroxyvitamin D <12ng/ml) in institutionalized elderly in wintertime and 15.5% in ambulatory elderly in summertime. Overall, median iPTH did not differ between groups. However, median iPTH secretion in the presence of low vitamin D serum concentrations (5-30ng/ml) was greater in ambulatory elderly. This could be explained by lower mobility status being correlated with greater serum calcium concentrations (r=0.24, P=0.02 in women; r=0.35, P=0. 001 in men) and greater urinary excretion of DPD (r=0.41, P=0.0001 in women; r=0.42, P=0.0002 in men), independent of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and iPTH. CONCLUSIONS: These data support the hypothesis that immobility, even in the presence of vitamin D deficiency, acts as an overriding influence on bone metabolism by promoting bone resorption (measured as urinary DPD) and increasing serum calcium independent of iPTH. Therefore mobility status may substantially affect 25-hydroxyvitamin D threshold values and the degree to which patients benefit from vitamin supplementation.
In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study
Authors: Pontiroli AE , Monti LD , Costa S , Sandoli PE , Pizzini A , Solerte SB , Mantovani E , Piatti PM
Published: January 2005

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.
Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells
Authors: Canning MO , Grotenhuis K , de Wit HJ , Drexhage HA
Published: January 2005

BACKGROUND: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development. AIM: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (10 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development. RESULTS: The continuous presence of DHEA (10 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity). The continuous presence of DEX at a concentration of 10 M in the monocyte/DC cultures resulted in the generation of plastic-adherent macrophage-like cells in place of typical immature DC, with increased CD14 expression, but decreased expression of the typical DC markers CD1a, CD40 and CD80. These cells were strongly reactive to acid phosphatase, but equally capable of stimulating T cell proliferation as immature DC. The production of IL-12 by these macrophage-like cells was virtually shut down, whereas the production of IL-10 was significantly higher than that of control immature DC. CONCLUSION: The continuous presence of a high level of GC during the generation of immature DC from monocytes can modulate this development away from DC towards a macrophage-like cell. The combination of a low CD80 expression and a shutdown of IL-12 production suggests the possibility of DEX-generated cells initiating a Th2-biased response. These effects by DEX on DC development contrast with those by DHEA, which resulted in a more typical DC although possessing a phenotype possibly indicating a more mature state of the cell.
mRNA expression of type I and type II receptors for activin, transforming growth factor-beta, and bone morphogenetic protein in the murine erythroleukemic cell line, F5-5.fl
Authors: Machida H , Ogawa K , Funaba M , Mizutani T , Tsujimoto M
Published: January 2005

OBJECTIVE: Intracellular signaling of activin and transforming growth factor-beta (TGF-beta) is thought to be mediated by the same molecules (Smad2/3 and Smad4). Although differentiation of murine erythroleukemia F5-5.fl cells is induced by activin, it is not induced by TGF-beta, suggesting that at some point TGF-beta signaling is defective. The aim of this study was to investigate the unresponsiveness of F5-5.fl cells to TGF-beta. DESIGN: mRNA expression of ligands, receptors, and signal mediators for the TGF-beta family was examined in F5-5.fl cells using RT-PCR. RESULTS: Activin induced erythrodifferentiation of F5-5.fl cells in a dose-dependent manner. Neither TGF-beta1 nor bone morphogenetic protein (BMP)-4 affected the differentiation of F5-5.fl cells in the presence or absence of activin. Although mRNAs of TGF-betas (TGF-beta1, TGF-beta2 and TGF-beta3) were detected, those of inhibin/activin (alpha-, betaA- and betaB-subunits) and BMPs (BMP-2, BMP-4 and BMP-7) could not be detected in the cells, suggesting that neither activins nor BMPs are produced in F5-5.fl cells. The expression of both type I (ALK-4/ActRIB) and type II (ActRII) receptors for activin was detected in F5-5.fl cells. In contrast, while the expression of type I receptor for TGF-beta (ALK-5/TbetaRI) was detected, that of type II receptor (TbetaRII) was not. The mRNA of all Smads examined was detected in F5-5.fl cells. CONCLUSIONS: A defect in the type II receptor might cause unresponsiveness to TGF-beta in F5-5.fl cells. An erythrodifferentiation assay using F5-5.fl cells would be useful for measuring net activin activity because it would not be necessary to consider endogenous activins and BMPs.
Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function
Authors: Perfetti R , Merkel P
Published: January 2005

Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a pro-satiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases beta-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.
Positive effect of radiotherapy and surgery on hormonally active pulmonary metastases of primary parathyroid carcinoma
Authors: Rasmuson T , Kristoffersson A , Boquist L
Published: January 2005

Objective

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. Surgery is the primary treatment in recurrent or metastatic disease. Radiotherapy has been used as an adjuvant to control subclinical local disease but is otherwise considered ineffective.

Design

We report on a patient with parathyroid carcinoma with hypercalcaemia and pulmonary metastases, treated with pamidronate and radiotherapy and later with surgery.

Methods

The treatment was evaluated using serial analysis of serum parathyroid hormone (PTH) and calcium, clinical evaluation and chest radiographs.

Results

Intravenous pamidronate alone had limited effect on hypercalcaemia. Following irradiation of the pulmonary lesions (34 Gy in ten fractions), serum levels of calcium and PTH decreased and pamidronate could be discontinued. The patient's general condition improved parallel to a radiological response. At clinical relapse 18 months following radiotherapy, the pulmonary metastases were resected and serum PTH was normalised.

Conclusions

The results indicate that parathyroid carcinoma can be radiosensitive. Thus radiotherapy may be an alternative to palliate symptoms of hypercalcaemia in patients not suited for surgery.
Advantages of combined technetium-99m-sestamibi scintigraphy and high-resolution ultrasonography in parathyroid localization: comparative study in 91 patients with primary hyperparathyroidism
Authors: Lumachi F , Zucchetta P , Marzola M C , Boccagni P , Angelini F , Bui F , D'Amico D F , Favia G
Published: January 2005

Objective

To evaluate the usefulness of the combination of Tc-sestamibi/Tc-pertechnetate subtraction scintigraphy (SS) and high-resolution neck ultrasonography (US) in patients with primary hyperparathyroidism (pHPT) undergoing parathyroidectomy.

Design and Methods

Ninety-one patients with proved pHPT were studied, excluding patients with persistent or recurrent disease. There were 65 (71.4%) women and 26 (28.6%) men, with a median age of 59 years (range 18-78 years). All patients underwent both SS and US prior to surgery, and the results were compared with operative and histological findings. The intraoperative quick-parathyroid hormone assay was available for 52 (57.1%) patients. When multiglandular disease was found, both SS and US were considered truly positive only when at least two enlarged parathyroid (PT) glands had been localized.

Results

Eighty-three (91.2%) solitary PT adenomas and three (3.3%) carcinomas were found. Moreover, two (2.2%) patients had a double adenoma and three (3.3%) patients had diffuse PT hyperplasia. The overall sensitivity of combined SS+US was 94.5% (86.8% and 80.4% for SS and US respectively). There was a significant (P<0.05, Student's t-test) difference in size between the PT glands correctly identified and undetected by SS, whereas the site of the removed PT tumors significantly (P<0.05, Fisher exact test) influenced only the US sensitivity.

Conclusions

When the preoperative localization of the PT glands is chosen, the combination of SS and US represents a reliable noninvasive localization technique and should be considered for use in each patient with pHPT undergoing surgery.
Markers of tumor invasion are major predictive factors for the long-term outcome of corticotroph microadenomas treated by transsphenoidal adenomectomy
Authors: Vallette-Kasic S , Dufour H , Mugnier M , Trouillas J , Valdes-Socin H , Caron P , Morange S , Girard N , Grisoli F , Jaquet P , Brue T
Published: January 2005

Objective

To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension.

Design

Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences). Pre-, per- and postoperative parameters were analyzed as predictors of the long-term outcome.

Methods

Baseline hormone assessments were performed preoperatively, 8 days after surgery and every 6-12 months thereafter. Pituitary magnetic resonance imaging (MRI) allowed analysis of possible tumor extension to adjacent structures. Apparent completeness of the surgical removal was determined, and fragments labeled either 'tumor' or 'surrounding pituitary tissue' were submitted to serial sectioning.

Results

Immediate control of hypercortisolism was achieved in 43/53 patients (81%). However, later recurrences were observed in five patients (9%). Preoperative MRI showed tumor extension into adjacent structures with good specificity (91%) for prediction of surgical failure. Evidence of local invasion at surgery was also significantly predictive of the long-term outcome. A corticotroph adenoma was found at histological examination in 96% of the patients, and 26% had irregular limits, a feature significantly correlated with a poor outcome. Immediate postoperative plasma cortisol did not allow discrimination between long-term remissions and recurrences.

Conclusion

Surgical failure was best predicted by signs of tumor 'invasiveness' at MRI, confirmed by peroperative examination and histology.
Effects of growth hormone replacement therapy on levels of cortisol and cortisol-binding globulin in hypopituitary adults
Authors: Tschop M , Lahner H , Feldmeier H , Grasberger H , Morrison K M , Janssen O E , Attanasio A F , Strasburger C J
Published: January 2005

Objective

To determine if human growth hormone (hGH) replacement therapy alters pharmacokinetics of hydrocortisone (CS) substitution in hypopituitary adults.

Design

To this aim, we analysed serum and salivary CS profiles 270 min after oral CS administration at baseline and 6 and 12 months after initiation of hGH replacement therapy.

Methods

Serum IGF-I, cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG) and sex hormone-binding hormone (SHBG) were measured using commercially available radioimmunoassays. In-house immunofluorometric assays were employed for measurements of CS and hGH.

Results

hGH replacement did not change total serum CS bioavailability (area under the serum cortisol profile curve). Interference of orally administered CS with salivary measurement of free CS (fCS) caused significant bias. Therefore, fCS levels were calculated from their total CS and cortisol-binding globulin (CBG) levels. CBG decreased by approximately 30% after both 6 and 12 months of hGH replacement therapy (n=20, P<0.01). A significant negative correlation between deltaCBG (CBG6months-CBGbaseline) and deltaIGF-I (IGF-I6months-IGF-Ibaseline) was observed (P=0.04). The calculated values of free CS tended to increase with physiological hGH replacement, but this effect was marginal and did not reach statistical significance. In contrast to the CBG concentrations, plasma levels of sex hormone-binding globulin and thyroxine-binding globulin were essentially stable.

Conclusion

Given that no clinically relevant alterations in pharmacokinetics of CS were evoked by initiation of hGH replacement in hypopituitary adults, we conclude that CS substitution does not require dose adjustment after initiation of hGH replacement.
A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome
Authors: Matsuo T , Okamoto S , Izumi Y , Hosokawa A , Takegawa T , Fukui H , Tun Z , Honda K , Matoba R , Tatsumi K , Amino N
Published: January 2005

Objective

Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. In this study we describe monozygotic twins with Kallmann syndrome due to the same mutation in the KAL1 gene.

Design

We studied male monozygotic twins with Kallmann syndrome.

Methods

We analyzed the KAL1 gene using the PCR-direct sequencing method. The twins' mother was examined for the identified mutation.

Results

We identified a 14 bp deletion from codon 419 in exon 9 (Pro419del14) in both KAL1 genes of the twins. This was a novel mutation in the KAL1 gene and was responsible for Kallmann syndrome. As Pro419del14 was not detected in the mother of the twins, Pro419del14 was a germline mutation originating from them. These monozygotic twins showed different LH and FSH responses to LH-RH stimulation and different phenotypes such as complications, physiques and psychiatric characters.

Conclusions

We report an identical KAL1 gene mutation in the monozygotic twins with Kallmann syndrome. As these monozygotic twins showed different phenotypes in some respects, we suggest that factors other than mutations in the KAL1gene affect the symptomatic features of Kallmann syndrome.
Follistatin (FS) in human cerebrospinal fluid and regulation of FS expression in a mouse model of meningitis
Authors: Michel U , Ebert S , Schneider O , Shintani Y , Bunkowski S , Smirnov A , Stringaris A , Gerber J , Bruck W , Nau R
Published: January 2005

Objective

Follistatin (FS) is the specific binding protein of activin and expression of both factors is regulated by inflammatory agents. Therefore, FS concentrations were determined in cerebrospinal fluid (CSF) of patients with bacterial and viral meningitis or multiple sclerosis (MS), as well as in the CSF of patients without meningial inflammation or autoimmune diseases. Furthermore, a mouse pneumococcal meningitis model was used to localise the cellular sources of FS in brains of normal and meningitic mice.

Methods

FS concentrations in CSF were determined by ELISA; FS in mice was localised by in situ hybridisation and immunohistochemistry.

Results

FS concentrations were > or =0.4 microg/l in 22 of 66 CSF samples of meningitis patients versus 2 of 27 CSF samples from patients with multiple sclerosis (P<0.05) and 2 of 41 CSF specimen from patients without neuroinflammatory diseases (P<0.01). In the CSF of patients with meningitis, the concentration of FS was correlated with total protein (P<0.005) and lactate concentrations (P<0.05), but not with leukocyte counts, interval between onset of disease and CSF analysis, or clinical outcome. The CSF-to-serum ratios of FS and albumin also correlated significantly (P<0.0005). In some patients with meningitis the CSF-to-serum ratios suggested that the elevated FS in CSF did not originate from serum alone. FS was localised in mice brains to neurones of the hippocampus, dentate gyrus, neocortex, and to the choroid plexus. Analyses of brains and other organs from uninfected and infected animals sacrificed 6-36 h after infection did not reveal any obvious differences in the distribution and intensity of FS mRNA and protein expression.

Conclusions

The concentration of FS in humans is elevated during meningitis. In some patients the increase is caused by a release of FS from brain into CSF. Data from the mouse meningitis model suggest that increased CSF concentrations of FS in meningitis appear not to be accompanied by an elevated number of cells containing FS mRNA or protein in the brain.
Cyclin D and cyclin E expression in normal and adenomatous pituitary
Authors: Jordan S , Lidhar K , Korbonits M , Lowe DG , Grossman AB
Published: January 2005

OBJECTIVES: Cyclins play an important role in the regulation of cell progression through the cell cycle. Over-expression of the cyclins has been shown in many different tumour types. Pituitary adenomas are a common form of endocrine neoplasia in the human, but have been little studied in terms of the expression of the principal cyclins regulating checkpoint exit, cyclin D1 and cyclin E. METHODS: We therefore investigated the expression of cyclin D1 and cyclin E in a range of benign and metastatic pituitary tumours. We studied a total of 95 pituitaries, including normal pituitary (n=20), Cushing's disease (n=19), somatotroph tumours (n=19), non-functioning adenomas (n=18), prolactinomas (n=7), aggressive tumours (n=9) and pituitary carcinoma (n=3). All tumours and normal tissue were immunostained for cyclin D1 and cyclin E using a standard technique, and were then subjected to blinded analysis by a single observer and the extent of staining quantified on the basis of 500 cell counts per tissue. The distribution of positive staining between different tissues was analysed by non-parametric test procedures. RESULTS: There was no cytoplasmic staining for cyclin D1 in any tissue. Nuclear staining was generally sparse, but was statistically more frequent in non-functioning and aggressive tumours compared with other tumour types or normal pituitary. Cyclin E was also sparsely expressed, but was specifically increased in corticotroph tumours from patients with Cushing's disease. CONCLUSIONS: We report cyclin D1 over-expression in aggressive and non-functioning pituitary tumours, and that cyclin E expression is more frequently seen in Cushing's disease. The high level of cyclin E expression in Cushing's disease may relate to the low level of p27 protein expression previously reported in corticotroph tumours.
Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats
Authors: Seoane LM , Tovar S , Baldelli R , Arvat E , Ghigo E , Casanueva FF , Dieguez C
Published: January 2005

Ghrelin is a growth hormone-releasing acylated peptide from stomach. The purified peptide consist of 28 amino acids in which the serine 3 residue is n-octanoylated. Ghrelin has been reported to increase in vitro GH secretion as well as in vivo plasma GH levels in pentobarbital anaesthetized rats. The aim of this work was to characterize the stimulatory effect of Ghrelin on in vivo GH secretion in freely-moving rats. Furthermore, we compare the effect of Ghrelin with GHRH. In addition to vehicle, we administered different doses of Ghrelin (3 nmol/Kg, 12 nmol/Kg and 60 nmol/Kg); GHRH (3 nmol/Kg and 12 nmol/kg). Plasma GH levels were measured in blood samples taken at 5, 10, 15, 20, 30 and 45 min after their administration as an i.v. bolus at 0 min. Administration of Ghrelin led to an increase in plasma GH levels at all time-points tested (5, 10, 15, 20 and 30 min, P<0.01; and 45 min, P<0.05) in comparison to control untreated rats. A maximal stimulatory effect on plasma GH was observed following administration of 12 nmol/Kg of Ghrelin, the effect being similar to the one obtained with 60 nmol/Kg in terms of both AUC and mean peak GH levels. At the dose of 3 nmol/Kg GHRH and Ghrelin exhibited a similar stimulatory effect in term of both, AUC and mean peak GH levels. However following administration of a dose of 12 nmol/Kg, the effect of Ghrelin was much greater than the same dose of GHRH in terms of both AUC and mean peak GH levels. In summary, this study provides the first evidences that Ghrelin exert a marked stimulatory effect in plasma GH levels in freely-moving rats and provides further evidences that Ghrelin may play an important role in the physiological control of GH secretion.
Ghrelin-induced growth hormone secretion in humans
Authors: Peino R , Baldelli R , Rodriguez-Garcia J , Rodriguez-Segade S , Kojima M , Kangawa K , Arvat E , Ghigo E , Dieguez C , Casanueva F F
Published: January 2005

Ghrelin is a novel growth hormone (GH) releaser acylated peptide that has recently been purified from stomach, and which potently binds to the GH secretagogue receptor. Ghrelin releases GH in vitro and in vivo in animal models, however its actions, potency and specificity in humans are unknown. In the present study, 12 healthy subjects were studied: 6 underwent four tests with ghrelin administered i.v. at the dose of 0 (placebo), 0.25, 0.5 and 1 microg/kg which corresponds to 0, 18, 37 and 75 microg total dose. A further 6 volunteers underwent two tests on different days with ghrelin at the dose of 3.3 or 6.6 microg/kg which corresponds to 250 microg and 500 microg total dose. Ghrelin-mediated GH secretion showed a dose-response curve, in which 1 microg/kg was the minimally effective dose in some individuals, but not as a group. On the contrary, the total doses of 250 microg and 500 microg elicited a powerful GH secretion, with a mean peak of 69.8+/-9.2 microg/l and 90.9+/-16.9 microg/l respectively, and areas under the curve of 4435+/-608 and 6125+/-1008 microg/l per 120 min respectively. All of them statistically significant vs placebo and vs the 1 microg/kg dose. Ghrelin administration also elicited a relevant dose-response mediated prolactin secretion suggesting no specificity of its actions. No relevant side effects were observed with ghrelin apart from a hyperhydrosis episode in two individuals tested with the higher ghrelin doses. In conclusion, ghrelin is a potent releaser of GH in normal individuals, with a dose-response pattern of operation. No saturating dose was observed.
Somatostatin receptors and the potential use of Sandostatin to interfere with vascular remodelling
Authors: Bruns C , Shi V , Hoyer D , Schuurman H , Weckbecker G
Published: January 2005

Graft vessel disease (GVD) is a major cause of graft loss after the first year following transplantation. GVD is a complex, multifunctional process that involves immunological as well as non-immunological events such as ischaemia/reperfusion injury. An important target cell to interfere with the development of GVD is the smooth muscle cell (SMC). Somatostatin (SRIF) analogues have been shown previously to inhibit the proliferation of SMC in vitro and in vivo. We provide evidence that Sandostatin, an octapeptide SRIF analogue that is known to have anti-proliferative properties on SMC proliferation, inhibits vascular remodelling in a rat angioplasty model. Furthermore, in two allotransplantation models, Sandostatin effectively interferes with the development of signs of chronic rejection/GVD. The role of the different SRIF receptor subtypes in chronic graft rejection is currently under investigation.
The somatostatin immunoregulatory circuit present at sites of chronic inflammation
Authors: Weinstock JV , Elliott D
Published: January 2005

Somatostatin is part of an immunoregulatory circuit that helps limit interferon-gamma (IFNgamma) production at sites of chronic inflammation. In murine schistosomiasis. parasite eggs induce focal, chronic granulomatous inflammation in the liver and intestines. These granulomas produce somatostatin 1-14 and express somatostatin receptor subtype number 2 (SSTR2), which is the exclusive somatostatin receptor present in this inflammation. Granuloma and splenic macrophages as well as macrophage cell lines make somatostatin. There appears to be no other inflammatory cell source of the peptide. Various inflammatory mediators induce this expression, whereas substance P inhibits somatostatin production. Somatostatin can suppress IFN-gamma secretion from T cells via interaction with the SSTR2 receptor expressed on these cells. Other cells within the granuloma also display SSTR2. The effect of somatostatin on these other cell types remains unknown. The thymus of normal mice has a complete somatostatin regulatory circuit. The thymic epithelial and dendritic cells make somatostatin. Like the granulomas of murine schistosomiasis, the thymus expresses only SSTR2. Somatostatin likely has an important role in thymic T cell education and selection.
Plasma thyrotropin bioactivity in Down's syndrome children with subclinical hypothyroidism
Authors: Konings CH , van Trotsenburg AS , Ris-Stalpers C , Vulsma T , Wiedijk BM , de Vijlder JJ
Published: January 2005

OBJECTIVE: Subclinical hypothyroidism occurs in a number of children with Down's syndrome (DS). The reason for the mildly elevated plasma thyrotropin (TSH) concentrations is not known. The present study investigated whether decreased TSH bioactivity plays a role in this phenomenon. DESIGN: A retrospective study of plasma specimens from DS children with mildly elevated plasma TSH concentrations and thyroid hormone levels within the reference range, using a TSH receptor-adenylate cyclase mediated bioassay. METHODS: Strain JP26 Chinese hamster ovary (CHO) cells, stable transfected with the human TSH receptor, were incubated with unfractionated plasma (1/10 diluted in hypotonic incubation medium) of 10 DS children with subclinical hypothyroidism and nine euthyroid children with insulin-dependent diabetes mellitus as controls. cAMP released in the incubation medium was measured by RIA. Mock-transfected CHO cells were used to correct for non-specific CHO response. WHO Second International Reference Preparation of human TSH was dissolved and diluted in pooled normal human plasma and simultaneously bioassayed to match patient and control results. RESULTS: Plasma TSH levels were slightly increased in DS (mean +/- S.D., 6.5+/-1.3 mU/l, reference range 0.4-4.0 mU/l). Plasma TSH levels for controls (1.3+/-0.4 mU/l) were within the reference range. Plasma thyroid hormone levels in patients and controls were normal, plasma TSH binding inhibitory immunoglobulin and thyroid peroxidase antibodies were negative. cAMP levels (corrected for non-specific CHO response) in DS patients (18.4+/-3.9 pmol/well) and in controls (14.3+/-1.3 pmol/well) did not significantly differ from cAMP levels generated by patient-TSH equivalent TSH standards (16.3+/-0.9 pmol/well). CONCLUSIONS: The present results demonstrate normal TSH bioactivity in plasma of DS children, indicating that subclinical hypothyroidism in these patients is of primary (thyroidal) origin.
Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH
Authors: Lippi F , Capezzone M , Angelini F , Taddei D , Molinaro E , Pinchera A , Pacini F
Published: January 2005

OBJECTIVE: This study tested the hypothesis that administration of human recombinant thyroid-stimulating hormone (rhTSH: Thyrogen, thyrotropin alpha) could promote iodine-131 ((131)I) uptake in the therapy for metastatic or locally invasive differentiated thyroid cancer (DTC), obviating L-thyroxine suppressive therapy (L-T4) withdrawal and hypothyroidism in patients with advanced disease. METHODS: Twelve totally (or almost completely) thyroidectomized adults, nine of whom had received earlier therapy after L-T4 withdrawal, underwent (131)I treatment while euthyroid on L-T4, after rhTSH administration. Nine underwent diagnostic whole-body scanning (WBS) after two consecutive daily i.m. injections (0.9 mg) of rhTSH. They then received an identical second course of rhTSH to promote therapeutic (131)I uptake. Post-therapy WBS was performed one week later. Three patients received only rhTSH (131)I therapy. RESULTS: Administration of rhTSH promoted (131)I uptake in all patients, as demonstrated by post-therapy WBS. Administration of rhTSH also promoted a significant increase in serum thyroglobulin (Tg) concentrations. According to the most recent measurements, 3-12 months after therapy, serum Tg levels fell in four, and stabilized in two out of eleven patients. Upon additional rhTSH-WBS 8 months post-study, a reduction in one metastatic site was noted in one patient. The rhTSH was well tolerated, with mild, transient fever and/or nausea occurring in only a minority of patients. Individuals with bone metastases experienced degrees of peritumoral pain and swelling that were similar (though more short-lived) to those seen in the same or other patients after L-T4 withdrawal. CONCLUSIONS: Administration of rhTSH is a safe, successful tool for inducing (131)I uptake in local and metastatic DTC lesions, and avoids L-T4 withdrawal, preserving metabolic homeostasis and preventing the debilitating effects of hypothyroidism.
A new and accurate prediction model for growth response to growth hormone treatment in children with growth hormone deficiency
Authors: Schonau E , Westermann F , Rauch F , Stabrey A , Wassmer G , Keller E , Bramswig J , Blum WF
Published: January 2005

OBJECTIVE: To identify parameters which predict individual growth response to recombinant human GH (rhGH) therapy and to combine these parameters in a prediction model. DESIGN: Fifty-eight prepubertal patients with GH deficiency (17 females) participated in this prospective multicenter trial with 1 year of follow-up. METHODS: Auxological measurements, parameters of GH status and markers of bone metabolism were measured at baseline and at 1, 3 and 6 months after the start of rhGH treatment. Correlations with height velocity during the first 12 months of treatment (HV+12) were calculated. Prediction models were derived by multiple regression analysis. RESULTS: The model which best predicted HV+12 combined the following parameters: pretreatment bone age retardation as a fraction of chronological age, pretreatment serum levels of IGF-I, urinary levels of deoxypyridinoline (a marker of bone resorption) after 1 month of treatment and height velocity after 3 months of treatment. This model explained 89% of the variation in HV+12 with a standard deviation of the residuals of 0.93 cm/year. Defining successful rhGH therapy as a doubling of pretreatment height velocity, the model had a specificity of 90% and a sensitivity of 100% in predicting therapeutic success. CONCLUSIONS: This model is an accurate and practicable tool to predict growth response in GH-deficient children. It may help to optimize rhGH therapy by individual dose adjustment and contribute to improved overall outcomes.