bluuebunny/crossref_metadata_2025 huggingface dataset:
Nociceptin Stimulates Thyrotropin Secretion in Rats
Authors: Mitsuma Terunori , Hirooka Yoshifumi , Mori Yuichi , Kayama Masato , Adachi Koshin , Rhue Nebi , Ping Jing , Ikai Rumiko , Nakayashiki Atsuko , Nogimori Tsuyoshi
Published: April 2003

Effects of nociceptin on thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) secretion in rats were studied. Nociceptin (150 μg/kg) was injected intravenously and rats were serially decapitated after the injection. The effects of nociceptin on TRH release from the hypothalamus and TSH release from the anterior pituitary in vitro were also investigated. TRH and thyroid hormones were measured by individual radioimmunoassays. TSH was determined by enzyme immunoassay. TRH contents in the hypothalamus decreased significantly after nociceptin injection, whereas plasma TRH concentrations showed no changes. Plasma TSH concentrations increased significantly in a dose-related manner. The TRH release from the hypothalamus was enhanced significantly in a dose-related manner with the addition of nociceptin. The TSH release from the anterior pituitary in vitro was not affected by the addition of nociceptin. The plasma thyroxine and 3,3′,5-triiodothyronine levels did not change significantly after nociceptin administration. The inactivation of TRH by plasma or hypothalamus in vitro after nociceptin injection did not differ from that of controls. The findings suggest that nociceptin acts on the hypothalamus to stimulate TRH and TSH secretion.
Prognosis of Children with Malignant Pheochromocytoma
Authors: Coutant R. , Pein F. , Adamsbaum C. , Oberlin O. , Dubousset J. , Guinebretière J.M. , Teinturier C. , Bougnères P.F.
Published: April 2003

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, 131I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 ± 9% (mean ± SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.
Should We Treat Children with Idiopathic Short Stature?
Authors: Kelnar C.J.H. , Albertsson-Wikland K. , Hintz R.L. , Ranke M.B. , Rosenfeld R.G.
Published: April 2003

The use of growth hormone (GH) to treat short children who are clearly GH-deficient is now well accepted. However, GH treatment of short children who have no currently recognizable abnormalities in their GH-insulin-like growth factor I axis remains controversial. Whether such children with so-called idiopathic short stature (ISS) should be treated with GH was the subject of an international workshop held in St.-Paul-de-Vence, France, in April 1999. This article summarizes the issues discussed at the workshop, including the definition of ISS, ethical and health-economic aspects of treatment, results from clinical trials and surveillance studies, and the use of prediction models in aiding treatment decisions.
Endocrine Characteristics of Human Breast Epithelial Cells, MCF-10F
Authors: Singhal H. , Guo L. , Bradlow H.L. , Mittelman A. , Tiwari R.K.
Published: April 2003

MCF-10F is a spontaneously immortalized nontransformed human breast epithelial cell line which does not grow in soft agar or form tumors in nude mice. Though the presence of estrogen receptors has not been found in these cells, they can metabolize estradiol very efficiently. The present study describes the endocrine characteristics of this cell line with respect to growth response to estradiol and its metabolites, estradiol metabolism and aromatase activity. MCF-10F cells were growth stimulated by 16α-hydroxyestrone and estriol, whereas, estradiol and other estradiol metabolites did not affect cell proliferation. The constitutive level of 16α-hydroxyestrone, a metabolite of estradiol biotransformation that has been associated with enhanced carcinogenesis in several animal, cell and tissue culture models, was a hundredfold higher in the non-transformed MCF-10F cells than in the transformed MCF-7 cells. Treatment with the carcinogen, dimethylbenz(a)anthracene (DMBA), however, did not upregulate 16α-hydroxylation as was observed in transformed MCF-7 cells. MCF-10F cells also had no detectable aromatase activity though the level of 17-oxidation was unusually high as compared with MCF-7 cells. Our results using the non-transformed MCF-10F cells as a model system suggests that the presence of high level of 16α-hydroxyestrone, a metabolite previously shown to be associated with malignant phenotype, may not be sufficient for breast cancer transformation.
Secretion of Noncomplexed ‘Big’ (10–18 kD) Forms of Insulin-Like Growth Factor-II by 12 Soft Tissue Sarcoma Cell Lines
Authors: Elmlinger Martin W. , Rauschnabel Uta , Koscielniak Ewa , Weber Karin , Ranke Michael B.
Published: April 2003

The paraneoplastic production of pro-insulin-like growth factor-II (IGF-II) forms causes tumour hypoglycaemias and presumably also has an effect on tumour cell growth. We investigated the molecular weights of IGF-II forms and their ability to form complexes with IGF binding proteins (IGFBPs) in conditioned culture media (CM) from 12 paediatric soft tissue sarcoma (STS) cell lines and from two healthy fibroblast lines. Untreated CM were separated by size exclusion chromatography using biocompatible HPLC. Subsequently, IGF-II, IGFBP-2 and IGFBP-3 were determined in the HPLC fractions by specific RIAs. In the CM, IGF-II concentrations between 0.5 and 8.6 ng/106 cells were measured but no IGF-I was detectable. Parallel to this investigation, a high IGF-II mRNA level averaging 44.4 ± 29.7% was measured by semi-quantitative RT-PCR. The STS cell lines secreted a higher proportion of big-IGF-II forms reaching 10–18 kD (10–33% of the total IGF-II secreted) compared to the healthy fibroblasts (2.5–5%). At the same time, the proportion of IGF-II bound with IGFBP in complexes of 35– 70 kD and 150 kD was reduced by up to 85% in CM from tumour cells. The tumour cell lines apparently secrete a different spectrum of IGF-II forms than healthy fibroblasts. The reduced ability to form complexes with IGFBP and the higher molecular weight of the IGF-II forms produced by the tumour cells indicate that these forms could in fact be the known tumour-associated pro-IGF-II forms. Due to these characteristics, the big-IGF-II forms probably have an altered biological effect on the tumour cells when compared to IGF-II.
Intellectual and Physical Performance and Morbidity in Relation to Height in a Cohort of 18-Year-Old Swedish Conscripts
Authors: Tuvemo Torsten , Jonsson Björn , Persson Ingemar
Published: April 2003

To test whether short stature in young men without malformations or chronic childhood diseases is associated with intellectual and physical performance and morbidity, a large cohort of apparently healthy 18-year-old Swedish men was analysed. The original cohort consisted of all men born in 1976 and conscripted in 1994 (n = 38,900). After exclusion due to growth-affecting disorders or missing data, 32,887 subjects were available for analysis. Short conscripts (height below or equal to –2 SD scores) demonstrated increased overall morbidity compared with taller conscripts (above –2 SD scores). Specifically, short conscripts had more psychiatric and musculoskeletal diagnoses and were more often considered psychologically unsuitable for military service. Mean intellectual performance increased continuously with height; the mean ‘standard nine’ score was 4.22 for the short men and 5.17 for the rest (p < 0.001). Short conscripts scored less well than taller conscripts in assessment of psychological functioning during mental stress, and were evaluated as less suitable for leadership positions. Maximal working capacity per kilogramme body weight correlated negatively with height (p < 0.001). In conclusion, short stature was associated with increased morbidity and psychological problems and with lower mean intellectual performance. To what extent this association is direct or indirect needs further evaluation.
Alternative Splicing of Exon 17 and a Missense Mutation in Exon 20 of the Insulin Receptor Gene in Two Brothers with a Novel Syndrome of Insulin Resistance (Congenital Fiber-Type Disproportion Myopathy)
Authors: Vorwerk Peter , Christoffersen Claus T. , Müller Jørn , Vestergaard Henrik , Pedersen Oluf , De Meyts Pierre
Published: April 2003

The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the –1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing either of the two mutated receptors lacked basal or stimulated IR β-subunit autophosphorylation. A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype.
Activating Mutation of GSα in McCune-Albright Syndrome Causes Skin Pigmentation by Tyrosinase Gene Activation on Affected Melanocytes
Authors: Kim Il-Soo , Kim Eun Ryoung , Nam Hye Jung , Chin Mi Ok , Moon Young Ho , Oh Myung Ryurl , Yeo Un Cheol , Song Seng Mi , Kim Jung Sim , Uhm Mee Ryung , Beck Nam Seon , Jin Dong Kyu
Published: April 2003

McCune-Albright syndrome (MAS) is a sporadic disease characterized by café-au-lait spots, polyostotic fibrous dysplasia and hyperfunctional endocrinopathies. To elucidate the mechanism of skin pigmentation, melanocytes, keratinocytes and fibroblasts were primary cultured from the café-au-lait spot of a MAS patient. Then, mutational analysis and morphologic evaluation were performed. Also, cAMP level and tyrosinase gene expression in cultured cells were determined. Only Gsα mutation was found in affected melanocytes and the cAMP level in affected melanocytes was higher than that of normal melanocytes. The mRNA expression of tyrosinase gene was increased in the affected melanocytes. This study suggests that skin pigmentation of MAS results from activating mutation of Gsα in melanocytes and the mechanism involves the c-AMP-mediated tyrosinase gene activation.
Lipoprotein(a) Levels in Formerly Small-for-Gestational-Age Children
Authors: Pulzer F. , Haase U. , Kratzsch J. , Richter V. , Rassoul F. , Kiess W. , Keller E.
Published: April 2003

Lipoprotein(a) (Lp(a)) is an independent and inherited risk factor for coronary artery disease. Concentrations of Lp(a) have been widely described in adolescents, but little is known about its concentration in children born small for gestational age (SGA). To assess the influence of intrauterine growth on Lp(a) levels we examined 50 children born SGA and 21 children born adequate for gestational age (AGA). Lp(a) blood levels (mean ± SD) of the SGA children differed significantly (p < 0.05) from AGA children (22.3 ± 22.1 vs. 10.9 ± 7.6 mg/dl). 14 out of 50 adolescents of the SGA group but 1 out of 21 of the AGA group had elevated Lp(a) (>30 mg/dl) concentrations (p < 0.05). These children also had higher triglyceride (1.0 ± 0.6 mmol/l vs. 0.74 ± 0.38 mmol/l) levels (p < 0.05) compared to children with Lp(a) levels <30 mg/dl. Adolescents with Lp(a) levels >30 mg/dl showed a significant inverse relation between Lp(a) levels and gestational age (r = –0.68, p < 0.005). We hypothesize that impairment of fetal growth might influence serum Lp(a) levels in later life.
Pubertal Growth of the Short Normal Girl
Authors: Mulligan J. , Bailey B.J.R. , Voss L.D. , Betts P.R.
Published: April 2003

Objectives: To determine the timing, magnitude and duration of the pubertal spurt for short normal and average height girls, to compare these with Tanner’s standard and to investigate predictors of pubertal growth. Methods: The growth of 46 short normal and 55 control girls, identified at school entry, was monitored throughout puberty. Height and weight were measured at 6-month intervals from which body mass index (BMI) was derived. Annual velocities were calculated and used to estimate the age and magnitude of peak height velocity (PHV). Age of menarche was recorded to the nearest month. Parents provided information on the child’s medical and social history. Results: The mean age at PHV, the magnitude of PHV and age at menarche were similar for both groups and close to Tanner’s 50th centile values. Pre-pubertal BMI predicted age at menarche for short and control girls, accounting for 17% of the variance. There was a tendency for early maturing girls of average stature to have greater PHV. However, this relationship was not observed in short girls, nor did any other variable, genetic or environmental, predict the timing or magnitude of their pubertal spurt. Conclusions: Delayed puberty in short normal girls is unlikely and their growth during puberty is comparable to girls of average height. The pubertal variables measured remain close to Tanner’s original standards for both groups, suggesting the lack of a secular trend towards earlier puberty in girls. The onset of menstruation is influenced by pre-pubertal BMI. However, the clinician should be aware that short normal girls have normal pubertal growth and that no genetic or environmental variable can predict the timing or magnitude of their growth spurt.
Leptin Levels in Menopause: Effect of Estrogen Replacement Therapy
Authors: Cento Rosa Maria , Proto Caterina , Spada Rosario Sebastiano , Napolitano Valerio , Ciampelli Mario , Cucinelli Francesco , Lanzone Antonio
Published: April 2003

To evaluate the effect of menopause and estrogen replacement therapy on leptin levels, 17 white postmenopausal women were recruited for the study. After an overnight fasting, blood samples were collected for LH, FSH, estradiol, testosterone, androstenedione, DHEA sulfate, insulin and leptin assays. Body mass index (BMI) and the waist-to-hip ratio were also evaluated. Patients were reanalyzed after a 12-week administration of transdermal estrogen patches delivering 50 μg 17β-estradiol. The results were compared to those obtained from a group of 11 female volunteers in reproductive age, in whom basal blood was sampled during the early follicular phase of their cycle. Patients were divided into lean and obese according to their BMI. Obese postmenopausal women showed lower leptin levels when compared to premenopausal counterparts (25.1 ± 5.9 vs. 37 ± 11.3; p < 0.05), whereas no significant differences were found between the lean groups (14.5 ± 3.8 vs. 14.4 ± 4.9). Estrogen administration did not significantly change serum leptin concentrations in hypoestrogenized women (obese: 25.1 ± 5.9 vs. 28.6 ± 9.2; lean: 14.4 ± 4.9 vs. 17.6 ± 7.2). A positive linear correlation was found between leptin plasma levels and BMI only in obese patients (r = 0.58; p < 0.01) both before and after estrogen treatment. Menopause is characterized by a decreased expression of the obese gene, even if estrogens do not seem to represent a main causal factor.
Relation of Leptin and Tumor Necrosis Factor α to Body Weight Changes in Patients with Pulmonary Tuberculosis
Authors: Çakır Bekir , Yönem Arif , Güler Serdar , Odabaşı Ersin , Demirbaş Berrin , Gürsoy Gül , Aral Yalçın
Published: April 2003

In this study we investigated whether leptin and TNFα levels change with improvement in body weight with antituberculotic therapy in active tuberculosis patients. 30 patients (8 females and 22 males) with active pulmonary tuberculosis formed the patient group, and 25 sex- and age-matched healthy subjects (8 females and 17 males) served as the control group. Body weight, body mass index (BMI) and serum leptin and plasma TNFα levels are measured before and in the sixth month of therapy in all patients. Before the initiation of therapy, BMI of the patients was significantly lower than BMI of the controls (20.2 ± 1.6 vs. 25.2 ± 2.7 kg/m2, respectively; p < 0.05). After treatment, BMI of the patients increased significantly to 21.4 ± 1.9 kg/m2 (p < 0.05), but was still lower than that of the controls (p < 0.05). Pretreatment serum leptin (4.5 ± 0.9 vs. 2.1 ± 0.2 ng/ml, respectively; p < 0.05) and plasma TNFα (27.9 ± 3.4 vs. 23.9 ± 3.0 pg/ml, respectively; p < 0.05) levels of the patients were significantly higher than those of the controls. After treatment, serum leptin levels increased to 6.7 ± 2.2 ng/ml, but this rise was not statistically significant (p > 0.05). Treatment did not result in any significant change in TNFα levels, either. Δ leptin was highly related to Δ BMI in patients with tuberculosis (r = 0.68, p = 0.02). In the pretreatment period, there was a significant correlation between leptin and TNFα levels in the whole patient group (r = 0.78, p < 0.001), and in female (r = 0.74, p < 0.001) and male patients separately (r = 0.74, p = 0.035). In conclusion, leptin and TNFα may be responsible for the weight loss in pulmonary tuberculosis patients, but their levels do not change with improvement in body weight with antituberculotic treatment.
Tamoxifen Inhibits Lipoprotein Activity: In vivo and in vitro Studies
Authors: Hozumi Yasuo , Kawano Mikihiko , Hakamata Yoji , Miyata Michio , Jordan V. Craig
Published: April 2003

Tamoxifen, a nonsteroidal antiestrogenic antitumor agent, has weak estrogen-like effects on lipid metabolism, however, the mechanism remains unknown. We previously reported that tamoxifen decreases the activity of lipoprotein lipase (LPL), a key enzyme in triglyceride metabolism, in patients with breast cancer. This study evaluated the effect of tamoxifen on LPL activity in vitro and in vivo. In experiment 1, total cholesterol, triglyceride, adipose tissue weight, and LPL activity of post-heparin plasma were measured in ovariectomized female rats with and without tamoxifen treatment. In experiment 2, purified very-low-density lipoprotein (VLDL) and purified LPL were incubated with and without tamoxifen or estrogen, and the triglycerides in VLDL were measured using an enzymatic method. In experiment 1, total cholesterol and adipose tissue weight decreased significantly in tamoxifen-treated rats (p < 0.001 and p < 0.01, respectively). Triglyceride measurements were not significantly different between the two groups, however, the LPL activity was lower in tamoxifen-treated rats (p < 0.005). In experiment 2, triglycerides in VLDL were significantly higher after VLDL and LPL were incubated with tamoxifen and estrogen (p < 0.005). We concluded that tamoxifen inhibits the hydrolytic activity of LPL in vivo and in vitro. This mechanism may explain the elevated serum triglyceride levels in some patients treated with tamoxifen.
Mutational Analysis in Lebanese Patients with Congenital Adrenal Hyperplasia due to a Deficit in 21-Hydroxylase
Authors: Delague Valérie , Souraty Noëlle , Khallouf Eliane , Tardy Véronique , Chouery Eliane , Halaby Georges , Loiselet Jacques , Morel Yves , Mégarbané André
Published: April 2003

Molecular defects in the gene encoding steroid 21-hydroxylase (CYP21) result in impairment of adrenal steroid synthesis in patients affected with autosomal-recessive congenital adrenal hyperplasias (CAH). In this study, we report on the molecular screening of six point mutations, large deletions, gene conversion events and duplications in 25 unrelated Lebanese families affected by CAH due to steroid 21-hydroxylase. The methods used (PCR-digestion and southern blot) allowed the detection of 96% of the disease chromosomes. In classical forms, the most frequent mutation was the splice site mutation in intron 2 accounting for 39% of the disease alleles. Gene conversion events accounted for 14% of the alleles, but no large deletions were found. In nonclassical forms, the V281L mutation in exon 7 represent 86% of the tested alleles. Genotype-phenotype correlations were as expected: Δ8nt, Q318X and gene conversion correspond to SW forms, whereas the intron 2 splice site mutation may give either SW or SV forms; the V281L mutation was responsible for nonclassical forms. The spectrum of mutations underlines the genetic diversity of the Lebanese population. No correlation could be drawn out between mutations and some specific religious communities, except for the Δ8nt mutation, which is present only in the Christian Maronite group. Molecular study of the CYP21 gene might constitute a good support for clinicians, especially in consanguineous families, for whom we could provide genetic counselling.
Activating and Inactivating Hormone Receptor Mutations
Authors: Huhtaniemi Ilpo
Published: April 2003

The unravelling of gene structures of hormones, their receptors and the various components of their signal transduction apparatus has enabled diagnosis of the aetiology of hormone resistance at the molecular level. Inactivating mutations can be found in hormone receptor genes or those encoding components of the post-receptor signal transduction cascade. Another category of receptor mutation is that causing constitutive receptor activation, which results in ligand-independent, inappropriate or supraphysiological hormone action and in some cases malignant growth. The purpose of this contribution is to review the different types of inactivation and activation mechanisms that are induced by receptor mutations, using some of the best characterised mutations as examples. In addition, the currently known mutations of hormone receptors are briefly summarised.
Growth Hormone – Hormone Replacement for the Somatopause?
Authors: Savine Richard , Sönksen Peter
Published: April 2003

Twenty-four-hour growth hormone (GH) secretion reaches a peak at around puberty and by the age of 21 has begun to decrease. Thereafter the fall in GH secretion is progressive such that by the age of 60 most adults have total 24-hour secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland. Patterns of GH secretion are similar to those in younger people but GH pulses are markedly reduced in amplitude. Sleep and exercise remain the major stimuli for GH secretion. The fall in GH secretion seen with ageing coincides with changes in body composition and lipid metabolism that are similar to those seen in adults with GH deficiency. In elderly subjects, although GH secretion is markedly reduced, remaining GH secretion correlates closely with body composition (particularly with lean body mass and inversely with central abdominal fat). Pioneering studies carried out by Rudman showed that GH administration to elderly subjects with low insulin-like growth factor-I levels resulted in reversal of many of the changes associated with GH deficiency, namely an increase in lean body mass and bone mineral density and a reduction in body fat and plasma cholesterol. These changes were remarkably similar to those shown a year earlier in adults with GH deficiency given GH replacement. Subsequent studies of GH replacement in elderly adults have confirmed Rudman’s initial observations but have been dominated by side effects which have led to a high number of dropouts. It is now clear that the elderly are very sensitive to GH and the doses used need to be very low, increased very slowly and tailored to the individual needs of each patient. Using this more cautious approach, recent studies have been very positive. A series of papers from Blackman’s group, presented at the US endocrine meeting in San Diego in 1999, investigated the effects of GH with or without testosterone supplements (in men) and oestrogen supplements (in women). Their results showed positive effects of GH on lean body mass, central fat, low-density lipoprotein cholesterol and aerobic capacity. In many instances there was a positive interaction between GH and hormone replacement with testosterone and oestrogen, but it appeared that GH showed the most potent anabolic effects. Clearly more studies are needed before GH replacement for the elderly becomes established. Safety issues will require close scrutiny, but the data available so far are sufficiently positive to undertake large multicentre, placebo-controlled trials, particularly looking at endpoints associated with prevention of frailty and loss of independence.
The Somatopause:To Treat or Not to Treat?
Authors: Lamberts S.W.J.
Published: April 2003

There is much evidence that some aspects of ageing are similar to those observed in selective hormone deficiencies during adulthood. Replacement therapy in hypogonadism and/or growth hormone (GH) deficiency in adulthood is very successful in reversing the related clinical symptomatology. However, preliminary studies of GH treatment in the normal elderly have been largely disappointing: an increase in muscle mass is only accompanied by improved muscle strength if exercise is also increased during this period. No real benefit of GH therapy, additional to that of exercise, has been reported. Epidemiological studies indicate a relationship between high-normal insulin-like growth factor-I levels and cancer development. No definitive answers can presently be given regarding the safety of long-term GH therapy in otherwise healthy individuals during the somatopause.
Growth Hormone Therapy in Achondroplasia
Authors: Seino Yoshiki , Yamanaka Yoshitaka , Shinohara Mayu , Ikegami Saeko , Koike Mio , Miyazawa Mari , Inoue Masaru , Moriwake Tadashi , Tanaka Hiroyuki
Published: April 2003

Achondroplasia is one of the most common causes of severe rhizomelic dwarfism. We have previously reported the growth-promoting effect of growth hormone (GH) in this disorder. In this expanded clinical study, dose dependency and the long-term effect of GH were also investigated. Prepubertal children with achondroplasia (82 males and 63 females) were randomly divided into 2 groups. Patients were treated with 0.5 IU/kg per week or 1.0 IU/kg per week subcutaneous recombinant human GH. Of 75 patients, the mutational analysis of fibroblast growth factor receptor-3 revealed that G1138A was detected in 70 and G1138C was found in 2. GH increased growth rate and height z score in a dose-dependent manner. GH also increased serum insulin-like growth factor (IGF)-I, IGF-binding protein-3 and osteocalcin. No adverse effects were observed in either group. We conclude that GH therapy is a useful method for improvement of severe growth retardation of achondroplasia.
Hypophosphataemic Rickets
Authors: Saggese Giuseppe , Baroncelli Giampiero I.
Published: April 2003

X-Linked hypophosphataemic rickets (XLH) is frequently associated with short stature even when conventional treatment (1,25-dihydroxyvitamin D3 or 1α-hydroxyvitamin D3 plus inorganic phosphate salts) is administered for a long time. The pathogenesis of growth retardation is probably multifactorial. Affected patients usually show normal growth hormone (GH) secretion. In some poorly growing XLH patients, long-term GH treatment associated with conventional therapy improves linear growth. GH treatment also increases phosphate retention but this effect is transient.
Estrogen Receptors and the Activity of Nitric Oxide Synthase in the Artery of Female Rats Receiving Hormone Replacement Therapy
Authors: Wu Saizhu , Ruan Yunjun , Zhu Xiaohu , Lai Wenyan
Published: April 2003

Objective: To observe the expression of estrogen receptor and the activity of NOS in the arteries of female rats receiving estrogen replacement therapy. Methods: Seventy-two female rats were randomly divided into four groups: group A: sham-ovariectomy; group B: ovariectomy; group C: ovariectomy with estrogen replacement therapy (benzoate estradiol, 5 μg i.m. once in 2 days); group D: ovariectomy with estrogen and progesterone replacement therapy (benzoate estradiol, 5 μg i.m. once in 2 days and progesterone, 1 mg i.m. once in 2 days). The rats were killed after 2 months. The receptor-binding assay was adopted to measure the estrogen receptors in the arteries of the rats, and the activity of NOS in the arteries was assessed by the hemoglobin reductase method. Results: The ER number and NOS activity in the arteries of the ovariectomized group are less than those in sham-ovariectomy group (p < 0.05). The ER number and NOS activity in the arteries of groups C and D are larger and higher than those in the ovariectomized group (p < 0.05). No significant differences in the ER number and NOS activity were observed between groups C and D. Conclusion: The ER number and NOS activity in the rat artery significantly decrease after ovariectomy, while hormone replacement therapy can significantly increase the artery NOS activity and retain the ER number in the artery of the ovariectomized rats to normal level. The result may contribute to explaining the beneficial effect of estrogen in the prevention of coronary artery diseases in postmenopausal women.
Effects of Octreotide Infusion, Surgery and Estrogen on Suppression of Height Increase and 20K Growth Hormone Ratio in a Girl with Gigantism due to a Growth Hormone-Secreting Macroadenoma
Authors: Minagawa Masanori , Yasuda Toshiyuki , Someya Tomohiro , Kohno Yoichi , Saeki Naokatsu , Hashimoto Yoshihide
Published: April 2003

We treated an extremely tall 13-year-old girl with a growth hormone (GH)-secreting macroadenoma and GH levels of 120–495 ng/ml with a combination of preoperative octreotide infusion, surgery and postoperative octreotide infusion plus estrogen, which resulted in reduced tumor size prior to surgery, reduced GH levels and completely suppressed growth after surgery. 20K GH is produced by alternative splicing of 22K GH mRNA and the ratio of 20K GH to 22K GH is within a small range in the normal population and high in a GH-secreting tumor. The 20K/22K GH ratio in this patient was persistently elevated during each phase of the treatment and may serve as a sensitive index of tumor-derived GH secretion.
Human Sex Differentiation: From Transcription Factors to Gender
Authors: Migeon Claude J. , Wisniewski Amy B.
Published: April 2003

Over the past decade, knowledge of the genetic control of human sex differentiation has greately expanded our understanding of the developmental processes needed to form a male or female. The purpose of this review is to discuss how transcription factors are relevant to such processes. Additionally, an attempt is made to relate current knowledge of these factors with gender development of subjects with intersex conditions. Finally, we discuss how information about the genetic control of sex differentiation may contribute to decisions about medical treatment of individuals with conditions of abnormal sex differentiation.
Evidence for de novo Cholesterol Synthesis by Term Human Fetal Amnion and Chorion: A Comparative Study Using the Reverse-Isotope Dilution Technique
Authors: Loganath A. , Peh K.L. , Wong Y.C. , Ng S.C.
Published: April 2003

The cholesterol biosynthetic activity was assessed using [2-14C]-acetate as substrate in the homogenates of amnion and chorion obtained from women (n = 6, age 26–39 years) after spontaneous labour at term (37–40 weeks of gestation) having uncomplicated pregnancies. Reverse-isotope dilution analysis gave positive identification of [14C]-cholesterol acetate in all incubations of viable tissues. This metabolite was not evident in heat-denatured homogenates which served as controls. The extent of enzymic conversion for amnion at 2.6 × 10–3 to 0.19% was persistently higher than that of the chorion at 1.7 × 10–3 to 9.0 × 10–3%. The results indicate that human term fetal membranes possess the full complement of enzymes to catalyze the transformation of acetate to cholesterol. This study provides evidence that fetal membranes possess the capacity for de novo cholesterol biosynthesis, the sterol being essential for steroidogenesis as well as in embryo viability during pregnancy.
Growth Hormone Normalises Height, Prediction of Final Height and Hand Length in Children with Prader-Willi Syndrome after 4 Years of Therapy
Authors: Eiholzer Urs , l’Allemand Dagmar
Published: April 2003

Background: Based on the reported favourable effects of growth hormone (GH) treatment on growth and body composition in Prader-Labhart-Willi syndrome, we studied age dependency and the long-term effects on growth dynamics to elucidate the assumed hypothalamic GH deficiency. Methods: We examined 23 children treated with hGH (24 U/m2/week) during a median of 4 (range 1.5–5.5) years; group 1: 10 young underweight (age 0.3–4.1 years), group 2: 8 prepubertal overweight (age 3.7–9.5 years) and group 3: 5 pubertal overweight children (age 9.0–14.6 years). Results: After 4 years of therapy, height gain amounted to 1.8 SD; height (0.0 SD) and hand length (–0.2 SD) were normalised in the 2 prepubertal groups; in children above 6 years, height prediction approached parental target height. Weight for height rose in group 1 (to 0.64 SD) and decreased in group 2 (to 0.71 SD) to normal levels. Bone maturation of the pubertal children was too advanced to show a clear growth response to GH (height gain 0.42 SD). Even in this group, weight for height was reduced, but remained supernormal. Conclusion: Under exogenous GH, growth and body proportions are normalised in prepubertal children. With early institution of treatment, final height prediction reaches the parental target height range after 3 years. Such a growth-promoting effect of exogenous GH has so far only been described in children with GH deficiency.
Energy Expenditure, Energy Intake and Prevalence of Obesity after Therapy for Acute Lymphoblastic Leukemia during Childhood
Authors: Mayer Eleonore I. E. , Reuter Marianne , Dopfer Roland E. , Ranke Michael B.
Published: April 2003

Objectives: To investigate the prevalence and potential risk factors of obesity after therapy for childhood acute lymphoblastic leukemia (ALL). Study Design: 39 ALL patients (age 10.7–20.5 years) who were in first remission for 3.4–14.6 years after standardized treatment with chemotherapy plus cranial irradiation (n = 25) or with chemotherapy alone (n = 14) were examined. After fasting overnight, the following parameters were investigated: body mass index (BMI) of patients and their parents; patients’ BMI before ALL therapy; serum free thyroxin, growth hormone-dependent factors, estradiol, testosterone, cortisol, leptin and c-peptide; fat-free mass (bioelectrical impedance); resting metabolic rate (RMR, indirect calorimetry); caloric intake (24-hour recall); and physical activity (questionnaire). RMR data were applied to the fat-free mass and compared with 83 controls. Results: The prevalence of obesity (criterion: BMI > 2 SDS) was significantly (p < 0.05) higher after ALL therapy (38%; irradiated patients 48%, non-irradiated patients 21%) than before therapy (3%). Compared to non-irradiated patients, irradiated patients had significantly lower RMRs (–1.07 ± 0.24 vs. –0.32 ± 0.21 SDS; p < 0.05), reduced physical activity levels (1.41 ± 0.03 vs. 1.52 ± 0.03; p < 0.05), and lower concentrations of insulin-like growth factor-binding protein-3 (–0.65 ± 0.17 vs. 0.25 ± 0.33 SDS; p < 0.05) and of free thyroxin (1.17 ± 0.06 vs. 1.38 ± 0.08 ng/dl; p < 0.05). Caloric intake was adequate. Conclusions: After ALL during childhood, patients face a higher risk of obesity. In the cranially irradiated patients, the likely causes are low physical activity, RMRs and hormonal insufficiency.
Body Composition Abnormalities in Children with Prader-Willi Syndrome and Long-Term Effects of Growth Hormone Therapy
Authors: Eiholzer Urs , l’Allemand Dagmar , van der Sluis Inge , Steinert Hans , Gasser Theo , Ellis Kenneth
Published: April 2003

Obesity and hypothalamic GH deficiency contribute in different ways to the disturbances of body composition in Prader-Willi syndrome (PWS); while both increase the fat compartment, the reduction of lean tissue mass has been attributed mainly to GH deficiency. Therefore, body composition measured by dual-energy X-ray absorptiometry was prospectively studied in 12 overweight children with PWS and weight for height (WfH) SDS >0 before and during 3.5 years of treatment with hGH (0.037 mg/kg/day) on average. In the long term, there is a net reduction of body fat from 3.1 to 1.2 SD, with a minimum at the end of the second year of treatment. WfH SDS correctly reflects body fat mass and its changes. The initial deficit of lean mass (–1.6 SD) is counteracted by GH only during the first year of therapy (increase to –1.25 SD). But in the long term, GH therapy does not further compensate for this deficit, when lean mass is corrected for its growth-related increase. In conclusion, exogenous GH changes the phenotype of children with PWS: fat mass becomes normal, but, at least in the setting studied, GH is not sufficient to normalize lean tissue mass.
Effects of Discontinuation of Growth Hormone Treatment on Body Composition and Metabolism
Authors: Gerver W.J.M. , De Bruin R. , Delemarre-van de Waal H.A. , Aldewereld B. , Theunissen P. , Westerterp K.R.
Published: April 2003

This study was directed to the investigation of two different aspects of growth hormone: What are the metabolic consequences following the discontinuation of treatment and are these metabolic effects correlated with the growth-promoting effects seen in the first year of treatment? The study was performed on 12 growth hormone-deficient (GHD) patients who reached their final height. Each patient was matched with a non-GHD person of the same sex and about the same age. Immediately after the discontinuation of treatment, and 6 weeks and 6 months later, the following anthropometric variables were assessed: height, weight, skinfold thicknesses (biceps, triceps, subscapular and suprailiacal), body volume (underwater weighing) and total body water (deuterium dilution). To describe energy metabolism, basal metabolic rate assessed by ventilated hood, and sleep metabolic rate assessed by respiration chamber, were studied. Body composition was calculated from weight, volume and total body water. Clear metabolic effects were found after the discontinuation of treatment in GHD children: there was a decrease in fat free mass and sleep metabolic rate. Also, a strong correlation between the above-mentioned effects and the growth-promoting effects of human growth hormone at the beginning of the treatment was observed. The fact that this correlation exists poses the interesting question of whether the results from a test treatment lasting some weeks could be used to predict the long-term effects of hGH.
Insulin-Like Growth Factor-Binding Protein-2 Levels in Pediatric Patients with Growth Hormone Deficiency, Eating Disorders and Acute Lymphoblastic Leukemia
Authors: Barrios V. , Buño M. , Pozo J. , Muñoz M.T. , Argente J.
Published: April 2003

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) is altered in different diseases and might be used as an indication of its severity. The aims of our study were to investigate: (1) the developmental pattern of the serum IGFBP-2 concentration at birth and during childhood and adolescence; (2) whether the serum IGFBP-2 level could be a marker for the diagnosis and evolution of diseases where the growth hormone (GH)-IGF axis is altered, and (3) whether this binding protein shows a relationship with IGF-I, its free fraction, IGFBP-1 and -3. We report reference values for 55 normal full-term newborns and 221 normal children who were divided into 5 groups according to their Tanner stage. Serum levels were higher in newborns when compared with Tanner stages I–V (p < 0.001, ANOVA), with no further changes throughout development. Furthermore, we studied IGFBP-2 levels in 24 children with congenital GH deficiency (GHD), 26 with acute lymphoblastic leukemia (ALL), 75 obese children, and 60 girls with anorexia nervosa (AN) at diagnosis and during a follow-up period. IGFBP-2 at diagnosis was increased in GHD, ALL and AN, and decreased in obesity (p < 0.05, ANOVA). During the follow-up, IGFBP-2 concentrations tended to normalize. IGFBP-2 correlated positively with IGFBP-1 and negatively with IGF-I and IGFBP-3 in normal subjects and at diagnosis of the pathologies studied. Although IGFBP-2 functions are not well understood, these results suggest a possible role for this protein in diseases where the GH-IGF axis is altered.
A Novel Arginine Vasopressin-Neurophysin II Mutation Causes Autosomal Dominant Neurohypophyseal Diabetes insipidus and Morphologic Pituitary Changes
Authors: Skordis Nicos , Patsalis Philippos C. , Hettinger Joe A. , Kontou Maria , Herakleous Eleni , Krishnamani M.R.S. , Phillips III J.A.
Published: April 2003

To determine the genetic basis of autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) in a Cypriot family, we ascertained and studied a large, four-generation kindred in which all participating family members had arginine vasopressin-neurophysin II (AVP-NP-II) gene analyses done. A G to A transition was found by DNA sequence analysis at position 1773 (G1773A) of the AVP-NPII gene which is predicted to encode a substitution of tyrosine for cysteine in codon 59 (CYS59TYR). The mutation was confirmed by restriction endonuclease analysis of PCR amplification products that contain the corresponding segment of the AVP-NPII gene. To clarify the morphologic status of the pituitaries of family members, 12 affected and 3 nonaffected members had magnetic resonance imaging (MRI) studies. The bright spot of the posterior pituitary lobe was completely absent in 75% and faintly identified in 25% of the affected members who were examined with MRI. We conclude that (1) a novel G1773A transition in exon 2 of the AVP-NPII gene causes ADNDI in the large Cypriot kindred studied, (2) this mutation is predicted to encode a CYS59TYR substitution in NPII, and (3) MRI studies of the posterior pituitary lobes of affected family members show either a decreased intensity or a complete absence of the bright spot in all cases studied.
Dissociation between Plasma Adrenocorticotropin and Serum Cortisol Level during the Early Postoperative Period after Gastrectomy
Authors: Cho Y.M. , Kim S.Y. , Cho B.Y. , Lee H.K. , Yang H.K. , Lee K.U.
Published: April 2003

We demonstrated the dissociation between plasma adrenocorticotropin (ACTH) and serum cortisol levels during the early recovery period after radical gastrectomy in 9 of 31 patients with gastric adenocarcinoma. Patients with the dissociation between plasma ACTH and serum cortisol levels (DAC) showed a sustained elevation of serum cortisol level on the first or second postoperative day, while the plasma ACTH level returned to its preoperative state. These patients also had more advanced cancers (p < 0.05) and suffered from more postoperative complications (p < 0.05) than those without DAC. In these patients with DAC, serum cortisol and interleukin (IL)-6 levels remained higher on the second postoperative day than in those of the patients without DAC (21.80 ± 1.57 vs. 13.68 ± 0.72 μg/dl, p < 0.001, and 74.31 ± 15.65 vs. 18.75 ± 3.14 pg/ml, p < 0.001, respectively). On the second postoperative day, serum IL-6 levels showed a significant correlation with serum cortisol levels in all patients (r = 0.511, p < 0.01). These results suggest that the DAC during the early postoperative period after radical gastrectomy is associated with advanced stage of cancer and postoperative complication, and that the increased serum IL-6 level is at least in part responsible for maintaining the elevated serum cortisol.
Sensitization to Blomia tropicalis among Asthmatic Patients in Taiwan
Authors: Tsai Jaw-Ji , Wu Huai Hui , Shen Horng-Der , Hsu Err-Lieh , Wang Soo-Ray
Published: April 2003

House dust mites have been reported as one of the most important allergens in Taiwan especially in asthmatic patients. This study was conducted to determine the allergenicity of Blomia tropicalis and sensitization of asthmatic patients in Taiwan. Serial dust samples were collected every month between July 1993 and June 1994 from 13 houses of mite-allergic patients. About 1 m2 surface area of a quilt was vacuumed. The floating method was used to collect mites, then identification and counting were performed. Results showed that Dermatophagoides pteronyssinus and B. tropicalis were the two most common species of mites found in allergenic patients’ houses in Taipei. D. pteronyssinus accounted for 52.1% of the total number of mites and was found in every house. B. tropicalis, although not present in every sample, accounted for 44.3% of the total number of mites. The skin test positive reaction to B. tropicalis, D. pteronyssinus and Dermatophagoides farinae were 73.3, 88.3 and 85.0% as determined from 60 allergic patients who attended our allergy clinics. The extract prepared from B. tropicalis was used to determine the allergenicity and contained at least 30 protein components when silver stained. The most frequently detected allergens were proteins with molecular weights of 14.3, 106.5, 94.0, 72.0, 91.9, 63.7, 100.3, 43.6, 27.3, 62.0, 34.7, 18.3, 41.1 and 21.9 kD. The frequency of IgE binding of patient sera to those proteins were 87.0, 65.2, 56.5, 43.4, 39.1, 39.1, 34.8, 30.4, 30.4, 17.4, 17.4, 17.4, 13.0 and 8.7%. The results from immunoblot inhibition showed that there was IgE cross-reactivity among the B. tropicalis and D. pteronyssinus. However, there were two major allergenic components of B. tropicalis not inhibited by D. pteronyssinus with molecular weights of about 14.3 and 27.3 kD. The use of B. tropicalis extract for diagnostic purposes to identify patients with specific sensitivity should be considered in Taiwan.
The Th1/Th2 Paradigm and Experimental Murine Leishmaniasis
Authors: Lohoff Michael , Gessner André , Bogdan Christian , Röllinghoff Martin
Published: April 2003

In recent years, the Th1/Th2 concept has become of prime importance in the understanding of heterogeneous responses of the immune system and implications thereof for infectious and autoimmune diseases. Originally established on the basis of different cytokines produced by T cell clones, it is now known that the Th1/Th2 concept really defines totally different immune pathways that affect most if not all cells of the immune system. Murine experimental leishmaniasis was the first model to confirm the relevance of the Th1/Th2 concept in vivo. Herein, we summarize the current knowledge on the characteristics and generation of Th1 and Th2 cells, as well as on recent advances of the application of this concept to murine cutaneous leishmaniasis.
Exposure to Parakeets and Bronchiolitis obliterans
Authors: Daschner Alvaro , Moreno-Ancillo Alvaro , Barranco Pilar , López-Serrano Concepcio´n
Published: April 2003

Case report of a 64-year-old woman with increasing dyspnea and cough. She cared at home for 8 parakeets (Melopsittacus undulatus). Subsequent studies revealed a restrictive pulmonary defect and transbronchial biopsy, a histological bronchiolitis obliterans (BO). No significant elevated anti-avian IgG could be detected, probably because of a transient hypogammaglobulinaemia. The implication of antigenic exposure to avian antigens in the pathogenesis of BO is discussed.