bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoking and hormones in health and endocrine disorders
Authors: Kapoor D , Jones T H
Published: April 2005

Smoking has multiple effects on hormone secretion, some of which are associated with important clinical implications. These effects are mainly mediated by the pharmacological action of nicotine and also by toxins such as thiocyanate. Smoking affects pituitary, thyroid, adrenal, testicular and ovarian function, calcium metabolism and the action of insulin. The major salient clinical effects are the increased risk and severity of Graves’ hyperthyroidism and opthalmopathy, osteoporosis and reduced fertility. Smoking also contributes to the development of insulin resistance and hence type 2 diabetes mellitus. An important concern is also the effect of smoking on the foetus and young children. Passive transfer of thiocyanate can cause disturbance of thyroid size and function. Furthermore, maternal smoking causes increased catecholamine production, which may contribute to under perfusion of the foetoplacental unit.
Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement
Authors: Maghnie Mohamad , Aimaretti Gianluca , Bellone Simonetta , Bona Gianni , Bellone Jaele , Baldelli Roberto , de Sanctis Carlo , Gargantini Luigi , Gastaldi Roberto , Ghizzoni Lucia , Secco Andrea , Tinelli Carmine , Ghigo Ezio
Published: April 2005

Objective: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 μg/l based on a cohort of subjects with a mean age of 45 years.

Design and methods: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic–pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8±2.3 years, range 17–25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2±4.4 years, range 15.1–30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals.

Results: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8±2.0 μg/l, range 0.1–6.1 μg/l) compared with the 39 controls (18.5±15.5 μg/l, range 6.1–84.0 μg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 μg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 μg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of −1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I ≤ − 2.0 SDS showed a sensitivity of 62%.

Conclusion: Our data show that the cut-off value of the peak GH response to ITT of less than 3 μg/l or 5 μg/l and of IGF-I of less than −2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic–pituitary abnormalities.
The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5
Authors: Hofland Leo J , van der Hoek Joost , Feelders Richard , van Aken Maarten O , van Koetsveld Peter M , Waaijers Marlijn , Sprij-Mooij Diana , Bruns Christian , Weckbecker Gisbert , de Herder Wouter W , Beckers Albert , Lamberts Steven W J
Published: April 2005

Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing’s disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst1, sst2, sst3 and sst5 was recently introduced. We compared the in vitro effects of the sst2-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells.

Methods: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied.

Results: Corticotroph adenomas expressed predominantly sst5 mRNA (six out of six adenomas), whereas sst2 mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range −30 to −40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (− 28%). In AtT20 cells, expressing sst2, sst3 and sst5, SOM230 inhibited ACTH secretion with high potency (IC50 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst5 is relatively resistant to negative control by glucocorticoids.

Conclusions: The selective expression of sst5 receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing’s disease.
The clinical, metabolic and endocrine features and the quality of life in adults with childhood-onset craniopharyngioma compared with adult-onset craniopharyngioma
Authors: Kendall-Taylor Pat , Jönsson Peter J , Abs Roger , Erfurth Eva Marie , Koltowska-Häggström Maria , Price David Anthony , Verhelst Johan
Published: April 2005

Background: Craniopharyngioma is a parasellar tumour that, although benign, tends to behave aggressively. It can occur at any age but most commonly presents in childhood or adolescence.

Objectives: To investigate the frequency and severity of problems associated with craniopharyngioma, using the large international database (KIMS) for adult patients with GH deficiency (GHD), and to assess the differences between the adult onset (AO, aged 18 or above) disease and adults with childhood onset (CO) craniopharyngioma.

Design: Inclusion criteria were: an established diagnosis of craniopharyngioma, severe GHD and no recent GH treatment. These criteria were fulfilled by 393 (184 female, 209 male) patients; 241 had AO (mean age 28.7±8.7 years) and 152 had CO disease (age 42.0±12.3 years). Disease history, clinical features and anthropometric data were recorded at the time of enrolment in the database, and body composition, serum IGF-I, serum lipids and quality of life (QoL) were assessed.

Results: Peak age at onset of craniopharyngioma was 15–20 years. Ninety percent of patients had been treated surgically. CO patients were shorter than AO patients and had much lower IGF-I standard deviation scores (SDS). The majority had hypopituitarism and over 60% had diabetes insipidus. Body mass index (BMI) was higher in AO males (30.2±5.5) than in CO males (28.5±7.5); waist circumference was also greater. Obesity was more common in AO patients (51.8% vs 39.1%). Body composition did not differ between groups. Cholesterol and triglycerides were higher in AO than in CO patients, but high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol did not differ. Quality of life, assessed by Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Nottingham Health Profile, was markedly reduced in all groups with no significant differences between them; the QoL-AGHDA score correlated with age at onset of both craniopharyngioma and GHD, and also with BMI in AO patients.

Conclusions: These data emphasise the generally poor state of health of patients treated for craniopharyngioma, with respect to endocrine and metabolic function, and also the markedly reduced quality of life. In addition to GHD, most patients have evidence of hypothalamic damage with associated obesity, diabetes insipidus and hypopituitarism. Adults with CO craniopharyngioma were shorter, had lower IGF-I, lower BMI, less obesity and slightly lower blood lipid levels than patients with AO craniopharyngioma.
Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene
Authors: Riepe Felix G , Ahrens Wiebke , Krone Nils , Fölster-Holst Regina , Brasch Jochen , Sippell Wolfgang G , Hiort Olaf , Partsch Carl-Joachim
Published: April 2005

Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy.

Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright’s hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found.

Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gsα) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T > G in exon 5, leading to the amino acid substitution Ile-106 → Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient’s parents, both of whom showed normal Gsα protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely.

Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.
Ethinylestradiol and testosterone have divergent effects on circulating IGF system components in adolescents with constitutional tall stature
Authors: Rooman Raoul P A , De Beeck Lieve Op , Martin Manou , van Doorn Jaap , Mohan Subburaman , Du Caju Marc V L
Published: April 2005

Objective: Pharmacological doses of estrogens or testosterone are used to limit the final height of girls or boys with constitutional tall stature but the mechanism behind this growth inhibition is still debated. We therefore studied the changes in the circulating components of the insulin-like growth factor (IGF) system during high dose sex steroid therapy.

Design and methods: Twenty three girls and twenty boys with constitutional tall stature were treated with 100 μg ethinylestradiol per day or 250 mg testosterone ester every 14 days respectively. In 19 girls and 18 boys, the levels of IGF-I, free IGF-I, IGF-II, acid-labile subunit (ALS) and IGF binding proteins (IGFBP)-2 to -6 were measured before and 3–6 months after the start of therapy (group 1). In 18 girls and 11 boys, samples were collected at the end of therapy and 3 to 6 months afterwards (group 2). Fourteen girls and nine boys belonged to both groups. All parameters were measured by radioimmunoassay or ELISA.

Results: Levels of IGF-I were decreased significantly by estrogen treatment but remained unchanged during testosterone treatment. Free IGF-I decreased during estrogen treatment but increased during testosterone therapy. Estrogens increased IGF-II and testosterone reduced it. The important reduction of IGFBP-2 during estrogen therapy is not reproduced by androgen therapy, neither is the stimulation by estrogens of IGFBP-4. IGFBP-3 is not modulated by either sex steroid. We found that IGFBP-6 is up-regulated by testosterone but not by estrogens; the reverse is true for ALS, which increased during estrogen treatment but remained unchanged during testosterone treatment.

Conclusions: Our findings demonstrate that androgens and estrogens exert differential effects on the circulating levels of several IGF components.
Forskolin and dexamethasone synergistically induce aromatase (CYP19) expression in the human osteoblastic cell line SV-HFO
Authors: Watanabe Masatada , Ohno Shuji , Nakajin Shizuo
Published: April 2005

Objective: Recent progress supports the importance of local estrogen secretion in human bone tissues to increase and maintain bone mineral density. In a previous study, we reported that the expression of aromatase (CYP19) is dexamethasone (Dex)-dependent and oncostatin M (OSM) increases the expression synergistically with Dex. In the present study, we examined the effects of forskolin (FSK) as another potential synergistic factor.

Results: Co-administration of 100 nM Dex and 10 μM FSK increased aromatase activity 4-fold compared with Dex alone. The results of reverse transcriptase (RT)-PCR suggest that the amount of CYP19 gene transcript was also up-regulated by FSK synergistically with Dex, and that promoter I.4, which is not activated by FSK alone, is activated by FSK synergistically with Dex. The results of RT-PCR also suggest that promoter II, which responds to FSK, was not activated even in the presence of FSK in SV-HFO. The promoter I.4 sequence that was transfected into SV-HFO was activated by FSK synergistically with Dex.

Conclusions: Synergistic up-regulation of aromatase activity, CYP19 gene transcript, and promoter I.4 activity were Dex-dependent and not up-regulated by FSK alone. The results of this work may form the basis of bone-specific estrogen-replacement therapy that increases the estrogen concentration in bone tissue only.
Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway
Authors: Thams Peter , Anwar Mohammad R , Capito Kirsten
Published: April 2005

Objective: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K+ (K+ATP) channel-dependent insulin secretion and in glucose amplification of K+ATP channel-independent insulin secretion.

Methods: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay.

Results: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs–Ringer medium, the PKA inhibitors, H89 (10 μmol/l) and PKI 6–22 amide (30 μmol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion, but inhibited stimulation by the adenylyl cyclase activator, forskolin (10 μmol/l). In the presence of 60 mmol/l K+ and 250 μmol/l diazoxide, which stimulates maximum Ca2+ influx independently of K+ATP channels, H89 (10 μmol/l) inhibited Ca2+-evoked insulin secretion, but failed to prevent glucose amplification of K+ATP channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 μmol/l diazoxide, which cause modest Ca2+ influx, glucose amplification of K+ATP channel-independent insulin secretion was observed without concomitant Ca2+ stimulation of PKA activity. In islets cultured at 16.7 mmol/l glucose, glucose (16.7 mmol/l)-induced insulin secretion in physiological Krebs–Ringer medium was augmented and now inhibited by H89 (10 μmol/l), implicating that culture at 16.7 mmol/l glucose may increase Ca2+-sensitive adenylyl cyclase activity and hence PKA activity. In accordance, Ca2+-evoked insulin secretion at 60 mmol/l K+ and 250 μmol/l diazoxide was improved, whereas glucose amplification of K+ATP channel-independent insulin secretion was unaffected.

Conclusions: Glucose may activate PKA through triggering of the K+ATP channel-dependent pathway. Glucose amplification of K+ATP channel-independent insulin secretion, on the other hand, occurs by PKA-independent mechanisms.
Gonadal dysfunction in systemic diseases
Authors: Karagiannis Asterios , Harsoulis Faidon
Published: April 2005

Gonadal function is significantly affected in many acute and chronic systemic diseases. As the function of the testes and the ovaries is determined by the integrity of the hypothalamic–pituitary–gonadal axis, it is obvious that a systemic disease may affect one or more levels of the axis in such a manner that the gonadal dysfunction may have various clinical and laboratory manifestations. In this brief review, the most common disturbances seen in the main systemic diseases will be discussed.
Nitric oxide mediates abnormal responsiveness of thyroid arteries in methimazole-treated patients
Authors: Ortega Joaquín , Vila José M , Mauricio María Dolores , Segarra Gloria , Medina Pascual , Martínez-León Juan B , Lluch Salvador
Published: April 2005

Objective: We studied the intervention of nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor (EDHF) in mediating responses to acetylcholine in thyroid arteries from euthyroid and methimazole-treated (MT) patients.

Design and methods: Branches of the superior thyroid artery were obtained from 19 euthyroid patients and 17 MT patients (euthyroid at the time of surgery) undergoing total thyroidectomy or hemithyroidectomy. Artery rings were suspended in organ baths for isometric recording of tension.

Results and conclusions: Acetylcholine caused endothelium-dependent relaxation of greater magnitude in arteries from MT patients (pD2 (−log EC50) values were 7.68±0.19 in euthyroid and 8.17±0.26 in MT patients, P <0.05). The relaxation was unaffected by indomethacin and was partially reduced by the NO-synthase inhibitor NG-monomethyl-l-arginine (l-NMMA). This reduction was higher in arteries from MT patients (50±6%) as compared with euthyroid patients (36±6%) (P <0.05). Inhibition of K+ channels using apamin combined with charybdotoxin or high K+ solution abolished the relaxation resistance to l-NMMA and indomethacin. The maximal contraction response to noradrenaline (as a percentage of the response to 100 mM KCl) was lower in MT than in euthyroid patients (57±10 and 96±8 respectively, P < 0.05). The hyporesponsiveness to noradrenaline in arteries from MT patients was corrected by l-NMMA. The results indicate that: (i) thyroid arteries from MT patients show an increased relaxation response to acethylcholine and a decreased contraction response to noradrenaline due to overproduction of NO; (ii) EDHF plays a prominent role in acetylcholine-induced relaxation through activation of Ca2+-activated K+ channels; (iii) the abnormal endothelium-dependent responses in arteries from MT patients are not corrected by medical treatment.
Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation
Authors: Neumann Susanne , Claus Maren , Paschke Ralf
Published: April 2005

Objective: The molecular mechanisms of TSH receptor (TSHR) activation and intramolecular signal transduction are largely unknown. Deletion of the extracellular domain (ECD) of the TSHR results in increased constitutive activity, which suggests a self-inhibitory interaction between the ECD and the extracellular loops (ECLs) or the transmembrane domains (TMDs). To investigate these potential interactions and to pursue the idea that mutations in the ECD affect the constitutive activity of mutants in the ECLs or TMDs we generated double mutants between position 281 in the ECD and mutants in all three ECLs as well as the 6th TMD.

Design: We combined mutation S281D, characterized by an impaired TSH-stimulated cAMP response, with the constitutively activatingin vivomutations I486F (1st ECL), I568T (2nd ECL), V656F (3rd ECL) and D633F (6th TMD). Further, we constructed double mutants containing the constitutively activating mutation S281N and one of the inactivating mutations D474E, T477I (1st ECL) and D633K (6th TMD).

Results: The cAMP level of the double mutants with S281N and the inactive mutants in the 1st ECL was decreased below the level of the inactive single mutants, demonstrating that a constitutively activating mutation in the ECD cannot bypass disruption of signal transduction in the serpentine domain. In double mutants with S281D, basal and TSH-induced cAMP and inositol phosphate production of constitutively active mutants was reduced to the level of S281D.

Conclusion: The dominance of S281D and the dependence of constitutively activating mutations in the ECLs on the functionally intact ECD strongly suggest that interactions between these receptor domains are required for TSHR activation and intramolecular signal transduction.
Mini-Mental State Examination is superior to plasma glucose concentrations in monitoring patients with suspected hypoglycaemic disorders during the 72-hour fast
Authors: Wiesli Peter , Schwegler Beat , Schmid Beat , Spinas Giatgen A , Schmid Christoph
Published: April 2005

Objective: To determine whether systematic evaluation of cognitive function by the Mini-Mental State Examination (MMSE) allows the objective detection and documentation of cognitive deterioration in patients referred for evaluation of suspected hypoglycaemic disorders by the 72-h fast.

Design: Prospective case series.

Methods: In 50 patients referred for evaluation of suspected hypoglycaemic disorders, the MMSE score (maximum 30 points) was assessed at the start and at the end of the fast.

Results: The fast was terminated before 72 h in 14 patients because they developed neuroglycopenic symptoms due to hypoglycaemic disorders. Their MMSE score fell from a median of 29 points (range 20–30) at the beginning to 17 points (range 0–24) at the termination of the fast. The score dropped by ≥6 points in all patients with hypoglycaemic disorders. Median (range) plasma glucose concentration at the end of the fast was 2.1 (1.1–2.5) mmol/l. Thirty-six individuals developed no neuroglycopenic symptoms throughout the 72-h fast, their MMSE score remained between 27 and 30 throughout the fast and their median plasma glucose concentration dropped to 2.9 (2–3.6) mmol/l.

Conclusions: Systematic evaluation of cognitive function by the MMSE at the beginning and at the termination of the fast allows objective determination and documentation of the deterioration of the cognitive state in patients with hypoglycaemic disorders. A decline in the cognitive performance by ≥6 points in the MMSE score rather than a distinct plasma glucose concentration should be used as the criterion to terminate the prolonged fast before 72 h.
A steroidogenic cell line with differentiation potential from mouse granulosa cells, transfected with Ad4BP and SV40 large T antigen genes
Authors: Kamei Y , Aoyama Y , Fujimoto T , Kenmotsu N , Kishi C , Koushi M , Sugano S , Morohashi K , Kamiyama R , Asakai R
Published: April 2005

Several steroidogenic cell lines of granulosa cells (GC) have been used to elucidate differentiation mechanisms of GC during folliculogenesis. These cell lines, however, are of limited usefulness since they have lost some of their differentiation potential. The transcription factor adrenal-4 binding protein (Ad4BP), also known as steroidogenic factor-1 or NR5A1, is essential for the expression of all P-450 steroidogenic enzymes. By transfection with the Ad4BP gene together with SV40 DNA, we have generated several steroidogenic cell lines. One selective clone, named 4B2, retained its steroidogenic potential and was therefore analyzed in depth. This cell line responded to 8-Br-cAMP by displaying differentiation characteristics similar to those occurring in the differentiation process of primary cultured GC, including enhanced progesterone secretion, a cell shape change from a fibroblastic to epithelioid conformation, elongated mitochondria, increased gap junction formation and inhibition of cell proliferation. Prostaglandin E2 (PGE2), an intraovarian regulator of GC, stimulated cAMP production, and this eicosanoid, like 8-Br-cAMP, induced differentiation properties with the exception of cell conformation in 4B2 cells. These results suggest that expression of Ad4BP may provide the basis for a repertoire of cAMP-sensitive differentiation properties, including morphological alterations and growth inhibition. Thus, the 4B2 cell line may serve as a tool for elucidation of differentiation mechanisms that are under the control of Ad4BP.
Dehydroepiandrosterone (DHEA) modulates GHRH, somatostatin and angiotensin II action at the pituitary level
Authors: Suárez C , Vela J , García-Tornadú I , Becu-Villalobos D
Published: April 2005

In view of the present controversy related to the potential beneficial effects of clinical dehydroepiandrosterone (DHEA) treatments, and considering our own previous results that reveal an influence of this steroid in pituitary hyperplasia development in vivo in rats, we decided to evaluate the role of DHEA in prolactin and GH secretion, as well as in second messengers involved, in cultured rat anterior pituitary cells. DHEA (1 × 10−5 to 1 × 10−7 M) did not modify basal GH or prolactin release, and a prolactin inhibitory effect was observed only for androstenediol, a metabolite of DHEA. DHEA partially prevented dopamine (1 × 10−6 M)-induced prolactin inhibition and facilitated the prolactin-releasing effect of 10−8 M Ang II, without modifying the resulting Ca2+i mobilization. Furthermore, DHEA potentiated the GH release and cAMP production induced by 1 × 10−8 M GHRH. Finally, DHEA partially reversed the inhibitory effect of 1 × 10−8 M somatostatin on GH, but not prolactin, release. We conclude that DHEA in vitro, directly or indirectly through conversion into metabolites, is able to modulate the hormonal response of the pituitary to hypothalamic regulators. It can enhance pituitary prolactin release and induce GH secretion. These effects could help explain some of the side effects observed in prolonged DHEA treatments in vivo and should be taken into account when considering its use in human clinical trials.
Role of the RIP140 corepressor in ovulation and adipose biology
Authors: Steel Jennifer H , White Roger , Parker Malcolm G
Published: April 2005

RIP140 is a ligand-dependent corepressor for most, if not all, nuclear receptors. It is expressed widely in many different tissues, but the phenotype of mice devoid of RIP140 indicates that it plays a crucial role in the ovary and in adipose biology. Ovarian expression of RIP140 is cell-type-specific during follicular development and it is essential for oocyte release during ovulation, but not for luteinization of mature ovarian follicles. In adipose tissue, RIP140 is essential for normal fat accumulation and RIP140-null mice show decreased lipid storage even on a high-fat diet, with upregulation of mitochondrial uncoupling protein (UCP1) in some fat depots. Thus RIP140 plays a crucial role in female fertility and in energy homeostasis, and could be a target for infertility treatment, new contraceptive strategies or prevention of obesity.
Intragranular targeting of syncollin, but not a syncollinGFP chimera, inhibits regulated insulin exocytosis in pancreatic β-cells
Authors: Hays L B , Wicksteed B , Wang Y , McCuaig J F , Philipson L H , Edwardson J M , Rhodes C J
Published: April 2005

Several proteins play a role in the mechanism of insulin exocytosis. However, these ‘exocytotic proteins’ have yet to account for the regulated aspect of insulin exocytosis, and other factors are involved. In pancreatic exocrine cells, the intralumenal zymogen granule protein, syncollin, is required for efficient regulated exocytosis, but it is not known whether intragranular peptides similarly influence regulated insulin exocytosis. Here, this issue has been addressed using expression of syncollin and a syncollin-green fluorescent protein (syncollinGFP) chimera in rat islet β-cells as experimental tools. Syncollin is not normally expressed in β-cells but adenoviral-mediated expression of both syncollin and syncollinGFP indicated that these were specifically targeted to the lumen of β-granules. Syncollin expression in isolated rat islets had no effect on basal insulin secretion but significantly inhibited regulated insulin secretion stimulated by glucose (16.7 mM), glucagon-like peptide-1 (GLP-1) (10 nM) and glyburide (5μM). Consistent with specific localization of syncollin to β-granules, constitutive secretion was unchanged by syncollin expression in rat islets. Syncollin-mediated inhibition of insulin secretion was not due to inadequate insulin production. Moreover, secretagogue-induced increases in cytosolic intracellular Ca2+, which is a prerequisite for triggering insulin exocytosis, were unaffected in syncollin-expressing islets. Therefore, syncollin was most likely acting downstream of secondary signals at the level of insulin exocytosis. Thus, syncollin expression in β-cells has highlighted the importance of intralumenal β-granule peptide factors playing a role in the control of insulin exocytosis. In contrast to syncollin, syncollinGFP had no effect on insulin secretion, underlining its usefulness as a ‘fluorescent tag’ to track β-granule transport and exocytosis in real time.
1,25-dihydroxyvitamin D3 stimulates vesicular transport within 5 s in polarized intestinal epithelial cells
Authors: Sterling Tremaine M , Nemere Ilka
Published: April 2005

Controversy remains regarding whether the seco-steroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) enhances calcium and phosphate movement across the intestinal epithelial cell by facilitated diffusion or a vesicular transport mechanism. In this study we investigated whether membrane trafficking, as judged by confocal microscopy, was sufficiently rapid in comparison to hormone-stimulated uptake of phosphate (32P). Primary cultures of chick intestinal cells were established overnight either in Petri dishes (uptake studies) or chambered coverslips (confocal microscopy). Addition of 130 pM 1,25(OH)2D3 resulted in an apparent increase in 32P uptake within 1 min, relative to controls, that was statistically significant from 3–10 min of incubation. Using the endocytic marker dye, FM1–43, confocal microscopy revealed a profound decrease in membrane-associated fluorescence (apical> basal) within 10 s of hormone treatment, a return of fluorescence at 15–65 s, followed by another round of decreasing and increasing fluorescence. Between 3–9 min of incubation, fluorescence intensity increased 50% (apical region) and 20% (basal region) over control conditions. An antibody (Ab 099) directed against a putative membrane receptor for 1,25(OH)2D3 (1,25D3-MARRS) inhibited both 32P uptake, and changes in fluorescence. In addition, the protein kinase C (PKC) inhibitor, calphostin C, inhibited both 32P uptake and the observed 1,25(OH)2D3-mediated changes in fluorescence. At the microscopic level, calphostin C pretreatment abolished the very rapid redistribution of the endocytic marker dye, although a slight increase in fluorescence was still observed. We conclude that 1,25(OH)2D3-stimulated vesicular trafficking is mediated by the 1,25D3-MARRS protein, implicates a PKC signaling mechanism, and occurs in a time frame that is commensurate with a role in ion transport.
External ATP triggers Ca2+ signals suited for synchronization of pancreatic β-cells
Authors: Grapengiesser E , Dansk H , Hellman B
Published: April 2005

External ATP is supposed to trigger short-lived increases (transients) of cytoplasmic Ca2+ important for entraining insulin-secreting β-cells into a common rhythm. To get insight into this process, rises of the cytoplasmic Ca2+ concentration ([Ca2+]i) induced by external ATP were compared with those obtained with acetylcholine, another neurotransmitter with stimulatory effects on the inositol trisphosphate (IP3) production. A ratiometric fura-2 technique was used for measuring [Ca2+]i in individual β-cells and small aggregates isolated from ob/ob mouse islets and superfused with a medium containing methoxyverapamil. ATP and acetylcholine induced temporary rises of [Ca2+]I from a basal level manifested as solitary transients (<20 s) and bumps (≥20 s) superimposed or not with transients. Addition of ATP (1–100 μM) usually triggered transients whereas acetylcholine induced bumps lacking superimposed transients. After the initial rise there was a steady-state elevation of [Ca2+]i in β-cells exposed to acetylcholine but not to ATP. Similar differences were seen comparing the responses of rat β-cells to 100 μM ATP and acetylcholine. Inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump (with 50 μM cyclopiazonic acid) prevented both the ATP-induced rise of [Ca2+]i and the spontaneous firing of transients. Similar effects were seen after activation of protein kinase C (10 nM phorbol-12-myristate-13-acetate), whereas an inhibitor of this enzyme (2 μM bisindolylmaleimide) promoted the generation of transients. The results indicate that ATP fulfils the demands for a coordinator of the secretory activity of β-cells by generating distinct [Ca2+]i transients without sustained elevation of basal [Ca2+]i.
Effects of age and pregnancy on the circulatory activin response of sheep to acute inflammatory challenge by lipopolysaccharide
Authors: McClure L , O’Connor A E , Hayward S , Jenkin G , Walker D W , Phillips D J
Published: April 2005

The release of activin A in response to intravenous injection of the bacterial cell-wall component lipopolysaccharide (LPS) was investigated in an ovine model of acute inflammatory challenge in newborn and adult sheep, and in non-pregnant and pregnant ewes. Neonatal lambs (<20 days of age) showed a quantitatively similar response in terms of circulating concentrations of activin A, its binding protein follistatin and the cytokine interleukin-6 compared with adult ewes challenged with an equivalent dose (300 ng/kg bodyweight) of LPS. The fever response and plasma tumour necrosis factor-α release in response to LPS, however, were significantly (P < 0.01) less in lambs than in the adult group. Pregnant ewes in the last trimester of gestation had similar responses to LPS, in all aspects measured, compared with their non-pregnant counterparts, apart from an ablated fever response. Although the adult and neonatal sheep responded to LPS, a similar response was not apparent in the fetal circulation, possibly due to a protective effect of the placenta. A 10-fold increase in the dose of LPS (from 300 ng to 3 μg/kg bodyweight) given to neonatal lambs elicited an increase in several cytokine responses measured, with a significant (P< 0.05) increase in follistatin release. In contrast, the amount of activin released by the increased dose of LPS was similar to that invoked by the lower dose. The effect of tolerance to LPS was investigated by giving a second challenge of LPS 5 days after the initial injection. In all animals studied, there was an ablated (P < 0.05) response to the subsequent LPS injection, apart from a similar temperature-response profile. These data provide further evidence that activin A concentrations in the bloodstream are acutely responsive to inflammatory challenge in post-natal life and suggest that the response forms a significant component of the innate immune system.
Reciprocal regulation of activin A and inhibin B by interleukin-1 (IL-1) and follicle-stimulating hormone (FSH) in rat Sertoli cells in vitro
Authors: Okuma Y , Saito K , O’Connor A E , Phillips D J , de Kretser D M , Hedger M P
Published: April 2005

In several biological systems, the inhibin βA homodimer activin A is stimulated by, and in turn, inhibits the action of interleukin (IL)-1 (both IL-1α and IL-1β) and IL-6. The possibility that a similar regulatory relationship operates within the testis was investigated. Sertoli cells from immature (20-day-old) rats were cultured with human IL-1α or IL-1β, human IL-6 and/or ovine FSH or dibutyryl cAMP. Activin A and the inhibin dimers, inhibin A and inhibin B, were measured by specific ELISA. Immunoreactive inhibin (ir-inhibin) was measured by RIA. Activin/inhibin subunit mRNA expression was measured by quantitative real-time PCR. Both IL-1 isoforms, but not IL-6, stimulated activin A secretion through increased synthesis of βA-subunit mRNA. IL-1 also stimulated activin A secretion by testicular peritubular cells. In contrast to the effect on activin A, IL-1 suppressed inhibin βB-subunit and, to a lesser extent, α-subunit mRNA expression, thereby reducing basal and FSH-stimulated inhibin B secretion by the Sertoli cells. Conversely, FSH inhibited basal activin A secretion and antagonised the stimulatory effects of IL-1. Dibutyryl cAMP partially inhibited the action of IL-1 on activin A secretion, but had no significant effect on basal activin A secretion. Secretion of inhibin A was low in all treatment groups. These data demonstrate that IL-1 and FSH/cAMP exert a reciprocal regulation of activin A and inhibin B synthesis and release by the Sertoli cell, and suggest a role for activin A as a potential feedback regulator of IL-1 and IL-6 activity in the testis during normal spermatogenesis and in inflammation.
Protein tyrosine phosphatases and signalling
Authors: Stoker Andrew W
Published: April 2005

A cornerstone of many cell-signalling events rests on reversible phosphorylation of tyrosine residues on proteins. The reversibility relies on the coordinated actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), both of which exist as large protein families. This review focuses on the rapidly evolving field of the PTPs. We now know that rather than simply scavenging phosphotyrosine, the PTPs specifically regulate a wide range of signalling pathways. To illustrate this and to highlight current areas of agreement and contention in the field, this review will present our understanding of PTP action in selected areas and will present current knowledge surrounding the regulatory mechanisms that control PTP enzymes themselves. It will be seen that PTPs control diverse processes such as focal adhesion dynamics, cell–cell adhesion and insulin signalling, and their own actions are in turn regulated by dimerisation, phosphorylation and reversible oxidation.
Calcium, Phosphorus, Parathyroid Hormone, and Cardiovascular Disease in Hemodialysis Patients: The USRDS Waves 1, 3, and 4 Study
Authors: Slinin Yelena , Foley Robert N. , Collins Allan J.
Published: April 2005

Animal studies suggest that calcium-phosphorus homeostatic abnormalities cause cardiovascular disease in uremia; few observational studies in humans have explored this. Associations in the retrospective United States Renal Data System Waves 1, 3, and 4 Study of 14,829 patients who were on hemodialysis on December 31, 1993, were examined. Mean age and duration of renal replacement therapy were 60.0 and 3.2 yr, respectively; 40.7% had diabetes. Quintiles (Q1 to Q5) of (albumin-adjusted) calcium were ≤8.7, 8.8 to 9.2, 9.3 to 9.6, 9.7 to 10.2, and >10.2 mg/dl; phosphorus, ≤4.4, 4.5 to 5.3, 5.4 to 6.3, 6.4 to 7.5, and >7.5 mg/dl; calcium-phosphorus product, ≤40.9, 41.0 to 50.1, 50.2 to 59.2, 59.3 to 71.0, and >71.0 mg2/dl2; and parathyroid hormone (PTH), ≤37, 38 to 99, 100 to 210, 211 to 480, and >480 pg/ml. Higher calcium levels were associated with fatal or nonfatal cardiovascular events (adjusted hazards ratio, 1.08 for Q5,

versus

Q1) and all-cause mortality (Q2, 1.07; Q4, 1.11; Q5, 1.14). Phosphorus levels were associated with cardiovascular events (Q2, 1.06; Q3, 1.13; Q4, 1.14; Q5, 1.25) and mortality (Q4, 1.10; Q5, 1.19), calcium-phosphorus product was associated with cardiovascular events (Q3, 1.09; Q4, 1.14; Q5, 1.24) and mortality (Q4, 1.09; Q5, 1.19), and PTH levels were associated with cardiovascular events (Q5, 1.12) and mortality (Q5, 1.17). Despite limitations (including retrospective design; noncurrent study era; and lack of serial calcium, phosphorus, and PTH measurements), this study suggests that disorders of calcium homeostasis are associated with fatal and nonfatal cardiovascular events and all-cause mortality in hemodialysis patients.
Supermarkets and their impacts on the agrifood system of Brazil: The competition among retailers
Authors: Farina Elizabeth M.M.Q. , Nunes Rubens , Monteiro Guilherme F. de A
Published: April 2005

This article proposes an explanation for evidence that challenges the received knowledge in relation to the advance of large supermarket chains in the Brazilian food market. It was thought that the large, more efficient chains would eliminate the traditional stores and the smaller supermarkets as well, based on price competition. However, the evolution of the food retail structure in Brazil shows growth in the number of traditional firms and independent supermarkets in the last nine years, with little evidence of loss of importance in food sales, especially as to the independent supermarkets whose share in food sales has grown. [EconLit citation: L100, L130, Q130.] © 2005 Wiley Periodicals, Inc. Agribusiness 21: 133–147, 2005.
Determining the causality between retail price and consumer demand in a linear function when demand‐shift variables are missing but wholesale prices are available
Authors: Kuiper W. Erno , Meulenberg Matthew T.G.
Published: April 2005

A test procedure is proposed to test for the simultaneous nature of the relationship between price and quantity with respect to consumer demand of fresh products at the level of an individual retail chain. It is argued in the literature that, on the sector level, inverse demand systems in which quantities are exogenous and prices are the dependent variables are better able to describe consumer demand behavior in case of perishable products whose quantities may be treated as fully price inelastic in the short run. Nevertheless, applying our test procedure to six fresh vegetable products sold by a Dutch supermarket chain reveals that consumer demand for fresh products is better described by a simultaneous price–quantity relationship. [EconLit citations: C320, D420, Q110.] © 2005 Wiley Periodicals, Inc. Agribusiness 21: 167–176, 2005.
Branding and its consequences for German agribusiness
Authors: Hanf Jon H. , Kühl Rainer
Published: April 2005

Today there is a clear consensus that customer orientation is a competitive necessity in order to survive in a market. In this article, the authors will analyze questions addressing brand management, especially the activities of retailers who are developing their own brands. As evidenced by the steady increase in market share for retail brands, nowadays consumers see little significant difference between retail brands and processor brands. Being the trustee of credence characteristics of food items, brands have to guarantee the correctness of their products throughout the whole food supply chain. In order to ensure this, vertical coordination mechanisms have to be installed. This is leading to competition among retail chains in the area of vertical coordination to ensure quality and to build brand equity. [EconLit citations: L220, L660, Q130.] © 2005 Wiley Periodicals, Inc. Agribusiness 21: 177–189, 2005.
Vertical contractual relations in the Italian beef supply chain
Authors: Mora Cristina , Menozzi Davide
Published: April 2005

This paper focuses on the Italian beef market and chain organization after the bovine spongiform encephalopathy (BSE) crises. This food scare, on the one hand, strongly affected consumers' attitude, making meat safety one of the most important issues of product quality for both consumers and retailers and, on the other hand, had important effects on the supply chain organization. The coming into force of the European Regulations (EC) No. 1760/2000 and No. 1825/2000 on beef labeling has partly led to a reshaping of the structure and organization of the Italian beef chain. The new relationships and contracts along the chain have been analyzed, and the strategies set up by the retailers to improve beef safety and quality and reinforce market segmentation have been discussed. The experience of the COOP Italia, the most important Italian large‐scale retailer, has been studied and discussed considering its chain organization and contract designing for beef products. [EconLit citations: L140, Q130, L220.] © 2005 Wiley Periodicals, Inc. Agribusiness 21: 213–235, 2005.
Effects of the Swiss retailers' strategy on the governance structure of the fresh food products supply chains
Authors: Réviron Sophie , Chappuis Jean‐Marc
Published: April 2005

On the initiative of the two main retailers, the structure of the Swiss food supply chains has changed in depth, with the construction of “normed systems,” characterized by quality insurance guarantees and of “partnerships” with alliances of producers and processing companies. These new forms of vertical organizations are different types of hybrid forms, according to New Institutional Economic theory. We highlight that these new organizations were chosen because of the lower degree of acceptance by the retailers of the asymmetry of information on quality, generally to their discredit, and in order to protect their reputation. Nevertheless, even in the case of products where the risk of acquiring a bad batch is particularly problematic for retailers, the latter do not seek to create bilateral governances systems directly with the producers, a situation that can lead to high tensions with the producers. [EconLit citations: Q130, D810.] © 2005 Wiley Periodicals, Inc. Agribusiness 21: 237–252, 2005.
Vertical integration and non‐linear price adjustments: The Spanish poultry sector
Authors: Ben‐Kaabia Monia , Gil José M. , Ameur Mehrez
Published: April 2005

The analysis of asymmetries in the price‐transmission mechanism at different levels of the marketing chain provides a good indicator of market efficiency in vertically related markets. The objective of this paper is to investigate the non‐linear adjustments of prices in the poultry marketing chain in Spain. The methodology used is based on the multivariate approach to specify and estimate a threshold autoregressive model. Price relationships at feed industry, producer, and retail levels are considered. Results indicate that, in the long run, price transmission is perfect and any supply or demand shocks are fully transmitted to all prices in the system. In the short run, price adjustments between the feed and the farmer levels are fairly symmetric and are representative of a cost‐push transmission mechanism. On the other hand, retailers benefit from any shock, whether positive or negative, that affects supply or demand conditions when price spreads are increasing, while price behavior is closely related to competitive markets when faced with declining price spreads. [EconLit citations: C320, Q130.] © 2005 Wiley Periodicals, Inc. Agribusiness 21: 253–271, 2005.