bluuebunny/crossref_metadata_2025 huggingface dataset:
Friction stir welding of DH36 steel
Authors: Reynolds A. P. , Tang W. , Posada M. , Deloach J.
Published: December 2003

Hot rolled DH36 carbon steel, 6.4 mm in thickness, was friction stir welded at speeds of 3.4 mm s-1 (8 in min-1), 5.1 mm s-1 (12 in min-1), and 7.6 mm s-1 (18 in min-1). Single pass welds free of volumetric defects were produced at each speed. The relationships between welding parameters and weld properties are discussed. Optical microscopy, microhardness testing, and transverse and longitudinal tensile tests have been performed. Bainite and martensite are found in the nugget region of the friction stir welds whereas the base material is comprised of ferrite and pearlite. The maximum hardness is observed in the weld nugget, and the hardness decreases gradually from the weld nugget, through the heat affected zone, to the base metal. Tensile testing also indicates overmatching of the weld metal relative to the base metal. Maximum hardness and longitudinal (all weld metal) tensile strengths increase with increasing welding speeds. Weld transverse tensile strengths are governed by the base metal properties, as all transverse tensile bars fail in the base metal.
Friction stir welding of magnesium alloy AZ31B to aluminium alloy 5083
Authors: McLean A. A. , Powell G. L. F. , Brown I. H. , Linton V. M.
Published: December 2003

A preliminary investigation has been carried out into the application of friction stir welding for joining a magnesium alloy to an aluminium alloy. The work has shown that liquation during the welding process can lead to the formation of a brittle intermetallic at the joint interface. This intermetallic has a microstructure composed of a divorced lamellar eutectic containing Al12Mg17 and magnesium. The formation of this microstructure and its influence on mechanical properties are discussed in terms of solidification theory.
Sleep-related respiratory disturbances in patients with Duchenne muscular dystrophy
Authors: Barbe F , Quera-Salva MA , McCann C , Gajdos P , Raphael JC , de Lattre J , Agusti AG
Published: December 2003

Sleep-related respiratory disturbances (SRD) in patients with muscle diseases may have significant clinical implications, because the patients frequently die at night. The aims of the study were to :1) assess the presence and severity of sleep-related respiratory disturbances in patients with Duchenne muscular distrophy (DMD); and 2) investigate the relationship of sleep-related respiratory disturbances to daytime symptoms and pulmonary function. We studied six clinically stable patients with Duchenne muscular dystrophy, mean age (+/- SD) 18 +/- 2 yrs. Vital capacity was 27 +/- 19% of predicted and daytime arterial oxygen tension (PaO2) was 10.9 +/- 1 kPa (range 8.9-12.4 kPa). The presence of daytime somnolence, insomnia, headache, nightmares and/or snoring was recorded. Four patients (67%) showed symptoms that suggest sleep-related respiratory disturbances. At night, the apnoea-hypopnoea index (AHI) was 11 +/- 6. The patients with more symptoms during the daytime had the highest AHI scores. Most of the apnoeas (85%) were central, particularly during rapid eye movement (REM) sleep. Sleep architecture was well-preserved. Arterial desaturation (> 5% below baseline) occurred during 25 +/- 23% of total time. AHI correlated with daytime PaO2, and AHI in REM sleep correlated with age. A stepwise multivariate analysis showed that PaO2 and, to some extent, the degree of airflow obstruction were significantly correlated with AHI. We conclude that sleep-related respiratory disturbance are frequently present in patients with Duchenne muscular dystrophy. Therefore, physicians should look for symptoms related to sleep-related respiratory disturbances in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparison between the epithelial tight junction morphology of human extrapulmonary bronchi and rat trachea
Authors: Godfrey RW , Severs NJ , Jeffery PK
Published: December 2003

Animal models have been used to investigate the involvement of epithelial tight junctions in the pathogenesis of human airway disease. However, no previous study has compared the tight junction morphologies of human and animal species in order to relate findings in animal models to human disease. In the present study, we therefore undertook a comprehensive quantitative evaluation of tight junction morphology, to determine what similarities or differences may exist in rat and human airways. Human tissue was obtained from grossly and histologically normal extrapulmonary bronchi from lungs resected for pulmonary tumour (n = 8); rat tracheal epithelium was acquired from Sprague-Dawley specific pathogen-free animals (n = 12). The tight junction morphologies of the two species were compared with respect to junctional depth, number of strands and junctional complexity. The basic architectural arrangement of the tight junctions in both species was found to be similar; however, tight junctions in rat tissues were less deep, comprised fewer strands, and had fewer strand interconnections compared with those in the human samples. The number of strands per interconnection was similar in the two species. We conclude that, in spite of a general similarity of rat and human airway epithelial tight junctions, there are specific quantitative details of morphology which need to be considered when attempting to extrapolate to the human the results of studies of airway epithelial permeability conducted in the rat. The precise biological significance of these differences, as yet, remains unclear.
Increased PMA-induced chemiluminescence from whole blood of patients with bronchial hyperreactivity
Authors: Nordman S , Nyberg P , Linko L
Published: December 2003

Blood phagocytes from patients with asthma have an increased capacity to produce reactive oxygen metabolites. We studied whether whole blood luminol-dependent chemiluminescence could detect this phenomenon in patients with a normal spirometry but bronchial hyperreactivity as determined with a methacholine bronchial challenge test. Whole blood chemiluminescence, serum eosinophilic cationic protein (ECP), and serum myeloperoxidase (MPO) were determined from 50 patients referred for a methacholine challenge due to prolonged cough and/or dyspnoea. The chemiluminescence results were compared to those from 15 healthy persons. The hyperreactive patients (n = 18) had significantly higher phorbol 12-myristate 13-acetate (PMA)-induced whole blood chemiluminescence values (mean 18.8 mV.min-1; 95% confidence limits (C.L.) 16.3-21.3 mV.min-1) than the normoreactive patients (mean 14.2 mV.min-1; 95% C.L. 13.0-15.5 mV.min-1;) and the healthy controls (mean 12.8 mV.min-1; 95% C.L. 11.7-13.9 mV.min-1). There was no significant difference in PMA-induced chemiluminescence between the normoreactive patients and the controls. The hyperreactive patients had higher serum ECP values than the normoreactive patients, but there was no correlation between whole blood chemiluminescence and serum ECP levels or total eosinophil count. There was no significant difference in monocyte reactive oxygen metabolite production or serum MPO values between the normoreactive and the hyperreactive patients. We suggest that the increased PMA-induced whole blood chemiluminescence in bronchial hyperreactivity is due mainly to an activation of neutrophils, and that the assay might be useful as a systemic inflammatory marker in patients with pulmonary inflammatory processes resulting in bronchial hyperreactivity.
Nasal eosinophilia induced by PAF-acether is accompanied by the release of eosinophil cationic protein
Authors: Tedeschi A , Milazzo N , Miadonna A
Published: December 2003

It has been demonstrated that platelet-activating factor (PAF)-acether can induce nasal neutrophilia and eosinophilia, with a different degree of responsiveness in atopic and in nonatopic subjects. The aim of this study was to evaluate whether PAF can also induce the release of secondary mediators in the human nose. Ten patients with allergic rhinitis and 10 normal subjects underwent nasal challenge with PAF (500 nmol), lyso-PAF (500 nmol) and saline solution. Nasal lavages were performed before and after challenge to evaluate changes in nasal cytology and release of histamine, immunoreactive leukotriene (iLT) C4 and eosinophil cationic protein (ECP). PAF caused neutrophilia and eosinophilia, which appeared earlier in atopic than in nonatopic subjects (30 min vs 1 h), and peaked 3 h after challenge in both groups. Lyso-PAF caused mild neutrophilia, which appeared 3 h after challenge in both groups; an increase in eosinophil counts was observed 3 h after challenge in atopic subjects, but not in nonatopic subjects. PAF insufflation caused a significant release of ECP in nasal lavage fluids 30 min and 3 h after challenge in atopic subjects, and 3 h after challenge in nonatopic subjects. ECP levels in the nasal lavages collected 30 min and 3 h after challenge with PAF were higher in atopic than in nonatopic subjects. Eosinophil counts correlated with ECP levels in the nasal lavages collected 30 min after PAF challenge in atopic subjects. Nasal challenge with lyso-PAF did not provoke any release of ECP. No significant increase of histamine and iLTC4 levels in nasal lavages was found after challenge with either PAF or lyso-PAF.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypodense eosinophil number relates to clinical severity, airway hyperresponsiveness and response to inhaled corticosteroids in asthmatic subjects
Authors: Kuo HP , Yu TR , Yu CT
Published: December 2003

The phenotypically distinct low-density eosinophil, with its greater inflammatory potential, is increased in asthma. However, the role of hypodense eosinophils in the development of asthma is still unclear. We conducted a double-blind, placebo-controlled study to examine the effect of inhaled corticosteroids on the number of hypodense eosinophils in 27 asthmatic subjects and its relationship with clinical severity. The density profile of eosinophils in the peripheral blood was determined using Percoll density gradient fractionation. Eosinophils recovered from asthmatics were mainly in the lower density fractions (< 1.095 g.ml-1) (63 +/- 3%; n = 27), significantly different from those of normal subjects (27 +/- 2%; n = 7). The proportion of hypodense eosinophils was inversely related to the provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) value (r = -0.75). Patients with mild asthma had a lower percentage of hypodense eosinophils (45 +/- 4%; n = 14) than those with moderate asthma (67 +/- 3%; n = 13). Inhalation of budesonide (800 micrograms.day-1) (n = 15) for 4 weeks, but not placebo, significantly improved the PC20 values by 0.97 doubling dose, forced expiratory volume in one second (FEV1) % predicted by 17%, and peak expiratory flow rate (PEFR) by 15%, and decreased PEFR diurnal variability by 5.4%. The percentage of hypodense eosinophils was significantly decreased from 68 +/- 4 to 47 +/- 4% in the budesonide group (n = 15), but not in the placebo group (n = 12) (63 +/- 4 to 65 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro
Authors: Llewellyn-Jones CG , Stockley RA
Published: December 2003

Therapeutic agents which affect polymorphonuclear neutrophil (PMN) functions have the potential to reduce or increase PMN activation and, hence, influence the progression of lung inflammation. We have assessed the effects of the beta 2-agonist, terbutaline, and the methylxanthine, aminophylline, on PMN functions in vitro at both therapeutic and higher concentrations. At therapeutic levels, both agents increased PMN chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP) in a dose-dependent manner from a control value of 22.5 +/- 3.58 cells.field-1 to 26.1 +/- 4.73 cells.field-1 with 4 mg.l-1 terbutaline, and to 26.3 +/- 4.49 cells.field-1 with 20 mg.l-1 aminophylline. When the cells were preincubated with higher doses of the agents in separate experiments there was inhibition of chemotaxis from a control value of 31.1 +/- 2.06 cells.field-1 to 18.3 +/- 0.82 cells.field-1 at 160 mg.l-1 terbutaline, and to 16.1 +/- 0.77 cells.field-1 at 400 mg.l-1 aminophylline. A similar effect was seen when the PMNs were preincubated with terbutaline and aminophylline prior to assessment of superoxide anion generation, with stimulation of superoxide release at therapeutic levels of the drugs and inhibition at higher doses (19% increase from resting control cells at terbutaline 4 mg.l-1 and 53% reduction at 160 mg.l-1; 28% increase with aminophylline 20 mg.l-1 and 22% reduction at 400 mg.l-1). Both terbutaline and aminophylline had no effect on PMN degranulation, as assessed by the degradation of fibronectin.(ABSTRACT TRUNCATED AT 250 WORDS)
Deposition of inhaled particles in the mouth and throat of asthmatic subjects
Authors: Svartengren K , Lindestad PA , Svartengren M , Bylin G , Philipson K , Camner P
Published: December 2003

We previously studied the deposition of inhaled particles in the mouth and throat of asthmatic patients, and found large, reproducible differences among subjects. In the present study, we examined whether anatomical and/or functional differences in the pharynx and larynx could underlie this interindividual variation. Deposition in the mouth and throat, and in the lung was estimated in 16 asthmatic subjects after inhalation of 3.6 microns (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. The particles were inhaled at a flow rate of 0.5 l.s-1 with maximally deep breaths. Radioactivity was measured by external scanning over head and neck, lungs and stomach, immediately after the inhalation. Radioactivity in the lungs was also measured 24 h later. A measure of the total amount of particles deposited in the mouth and throat was obtained from the added activities in mouthwash, head and neck, and stomach, immediately after the inhalation of the test particles. Pharynx and larynx function was examined by fibreoptic laryngoscopy performed during a corresponding inhalation procedure. Deposition in the mouth and throat varied widely among the subjects, ranging 9-76% (median 12%). We found two subpopulations, 13 subjects in the range 9-34%, and 3 subjects with > 70% deposition. Deviations in pharyngeal configuration during inhalation were significantly related to high mouth and throat deposition, whereas functional differences in the larynx were not. Our study shows that mouth and throat deposition may be extremely high in some asthmatics, and that pharyngeal configuration affects deposition of particles in the mouth and throat.
Regional deposition of nebulized hypodense nonisotonic solutions in the human respiratory tract
Authors: Chan HK , Phipps PR , Gonda I , Cook P , Fulton R , Young I , Bautovich G
Published: December 2003

Deposition of nonisotonic therapeutic and diagnosis aerosols can cause changes in airway fluid composition and bronchoconstriction in sensitive subjects. "Hypodense" aerosols containing a relatively low concentration of droplets in the carrier air were used in the studies of regional deposition of radiolabelled nebulized solutions of hypo- and hypertonic saline, in order to investigate whether the number of droplets per volume of carrier can affect deposition. Solutions with and without 0.5% nedocromil sodium were nebulized in order to examine the effects of a potential modifier of the rates of heat and mass transfer. The deposition was quantified using penetration index (PI) calculated from images obtained by single photon emission computerized tomography (SPECT) in 11 healthy volunteers per study. There was an increase in the penetration index (10.9%, for the saline only; 15.5%, for the nedocromil study) of the hypotonic compared to the hypertonic aerosol, although the initial size distribution of both types of aerosols was very similar (mass median aerodynamic diameter (MMAD) 3.7 and 3.8 microns; geometric standard deviation (GSD) 1.8 and 1.5 for the hypo- and hypertonic aerosols, respectively). The present results confirm the effects of tonicity on deposition of aerosols found in a parallel study reported in this issue of the Journal. They also give support to the theory that, in addition to the concentration of the nebulized solutions, the number of droplets per volume of the carrier air is a factor affecting deposition of aqueous aerosols. The presence of 0.5% nedocromil sodium in the solutions did not appear to interfere with the processes of heat and water transfer in the airways.
Inhaled frusemide does not affect lung mucociliary clearance in healthy and asthmatic subjects
Authors: Hasani A , Pavia D , Spiteri MA , Yeo CT , Agnew JE , Clarke SW , Chung KF
Published: December 2003

Inhaled frusemide has been shown to protect against the bronchoconstrictor effect of several inhaled agents in asthmatic subjects by mechanism(s) that are unclear. Since loop diuretics can modulate Cl- transport in the airway epithelium, frusemide may alter the quality and/or the quantity of the periciliary layer, which in turn may affect lung mucociliary transport. We investigated the effect of a single inhalation of nebulized frusemide (40 mg) on lung mucociliary clearance in four healthy subjects and in seven stable, mild asthmatics using an objective radioaerosol technique. Frusemide or placebo was inhaled in a double-blind, randomized, cross-over manner half an hour after the inhalation of 5 microns polystyrene particles labelled with 99mTc, used for assessing mucociliary clearance. The pulmonary function and initial radioaerosol distribution were similar between frusemide and placebo runs within each of the two study groups. The areas under the tracheobronchial retention curves over the 6 h observation period were similar between frusemide and placebo runs for both groups. Our findings show inhaled frusemide, at a dose known to inhibit bronchoconstrictor responses, does not affect lung mucociliary clearance.
A method for the long-term exposure of rabbits to environmental pollutant gases
Authors: Douglas GJ , Price JF , Page CP
Published: December 2003

The aims of the present study were twofold. Firstly, we wanted to develop a system for the exposure of rabbits to pollutant gases that would monitor gas concentrations accurately, allow flexibility, be simple to operate, and could be constructed at relatively modest cost. Additionally, we wanted to determine whether the procedures necessary for the daily exposure of young rabbits had any detrimental effect on their development. Using the environmental exposure system that we developed, littermate New Zealand White rabbits, neonatally immunized to either Alternaria tenuis or house dust mite antigen were exposed 2 h daily, from within 24 h of birth until 3 months of age, to either 4 ppm nitrogen dioxide (NO2), or 5 ppm sulphur dioxide (SO2) or ambient air. The environmental exposure system consists of four sections; a stainless steel exposure chamber; an airflow monitoring and control system and gas delivery system; a gas detector and monitoring system; and an exhaust fan. Equilibration and wash-out times of gas were short and the gas mixing within the chamber atmosphere was uniform. Levels of gases were reliably maintained throughout the period of exposure within predetermined limits. The weights of the immunized, gas-exposed animals did not differ significantly from those of the immunized, air-exposed animals at any time throughout the 3 month period of exposure. At 3 months of age, the basal values for lung resistance and dynamic compliance did not differ between gas- and air-exposed rabbits. These values did not differ significantly from those obtained from naive animals of the same age. Our results suggest that we have developed a sensitive, reliable and simple environmental exposure and monitoring system. It is anticipated that the methodology described will allow the careful investigation of the effects of long-term exposure to pollutant gases from birth on the development of airways hyperresponsiveness.
Electronic cell counting to measure total cell numbers in bronchoalveolar lavage fluid
Authors: Heaney LG , McKirgan J , Stanford CF , Ennis M
Published: December 2003

Cell counting of bronchoalveolar lavage (BAL) fluid is performed manually in routine practice. This has both methodological and inherent errors; however, the accuracy and suitability of automated counting devices have been questioned. In this study, a Coulter Counter D Industrial model was calibrated and then used to measure the total cell count in unprocessed bronchoalveolar lavage fluid, and compared to a standard manual method. Bronchoalveolar lavage was performed on 34 patients undergoing routine bronchoscopy. An aliquot of unprocessed bronchoalveolar lavage fluid was taken for all counting procedures. Manual counts were performed blind by two experienced independent observers using improved Neubauer chambers. Electronic counting measured 1 ml aliquots suspended in 10 and 20 ml Isoton counting 0.5 and 1 ml duplicates. The correlation coefficients between electronic and manual counts were good. The coefficients of repeatability of electronic counts, for repeat counts, both on the same dilution (Intra-Coulter: 0.1 x 10(5) cells.ml-1) and different dilutions (Interdilution-Coulter: 0.48 x 10(5) cells.ml-1), were superior compared to those for repeat manual counts by the same observer (1.03 x 10(5) cells.ml-1), and counts between observers (1.82 x 10(5) cells.ml-1). This method offers a quick, precise and simple method for counting cells in unprocessed bronchoalveolar lavage fluid, which is both less labour intensive and subjective than manual counting.
Completely reversible respiratory insufficiency with persisting ultrastructural ciliary abnormalities
Authors: Malysse I , Jorissen M , Verbeken E , Vaerenberg C , Demedts M
Published: December 2003

A male nonsmoker, born in 1946, suffered from hypersecretory bronchitis and recurrent upper and lower respiratory tract infections since adolescence. In 1983 he developed pulmonary insufficiency. In 1984, some months after daily occupational exposure to printing inks and glues, forced expiratory volume in one second (FEV1) was 1.1 l (28% pred) and arterial oxygen tension (PaO2) 44 mmHg (5.9 kPa). Open lung biopsy showed a centri-acinar bronchiolitis-alveolitis suggestive of an airborne toxic pathology. Ultrastructural examination of the bronchial mucosa revealed microtubular abnormalities in about 10% of the cilia. Treatment consisted of stopping work from December 1985, oral corticosteroids until 1988, bronchodilators on a regular basis and intermittent antibiotics (1 week/month). The evolution was remarkable because: 1) from a severe pulmonary insufficiency, refractory to bronchodilators and corticosteroids for several years, lung function slowly improved to supernormal values, without residual functional signs of small airways disease; and 2) a repeat ultrastructural nasal mucosa examination in 1992 still showed persisting microtubular abnormalities in about 10% of the cilia, which disappeared on sequential monolayer-suspension culture, thus indicating secondary ciliary abnormalities.
A solitary pulmonary nodule due to eosinophilic granuloma
Authors: ten Velde GP , Thunnissen FB , van Engelshoven JM , Wouters EF
Published: December 2003

A symptomless 42 year old man with a smoking history of 40 pack-years presented with a solitary pulmonary nodule highly suggestive of lung cancer. Wedge resection proved it to be an eosinophilic granuloma. No other localizations of eosinophilic granuloma were found, and none developed during a 3 yr follow-up.
Epidermal Homeostasis: The Role of the Growth Hormone and Insulin-Like Growth Factor Systems
Authors: Edmondson Stephanie R. , Thumiger Susan P. , Werther George A. , Wraight Christopher J.
Published: December 2003

GH and IGF-I and -II were first identified by their endocrine activity. Specifically, IGF-I was found to mediate the linear growth-promoting actions of GH. It is now evident that these two growth factor systems also exert widespread activity throughout the body and that their actions are not always interconnected. The literature highlights the importance of the GH and IGF systems in normal skin homeostasis, including dermal/epidermal cross-talk. GH activity, sometimes mediated via IGF-I, is primarily evident in the dermis, particularly affecting collagen synthesis. In contrast, IGF action is an important feature of the dermal and epidermal compartments, predominantly enhancing cell proliferation, survival, and migration. The locally expressed IGF binding proteins play significant and complex roles, primarily via modulation of IGF actions. Disturbances in GH and IGF signaling pathways are implicated in the pathophysiology of several skin perturbations, particularly those exhibiting epidermal hyperplasia (e.g., psoriasis, carcinomas). Additionally, many studies emphasize the potential use of both growth factors in the treatment of skin wounds; for example, burn patients. This overview concerns the role and mechanisms of action of the GH and IGF systems in skin and maintenance of epidermal integrity in both health and disease.
Systemic and Local Regulation of the Growth Plate
Authors: van der Eerden B. C. J. , Karperien M. , Wit J. M.
Published: December 2003

The growth plate is the final target organ for longitudinal growth and results from chondrocyte proliferation and differentiation. During the first year of life, longitudinal growth rates are high, followed by a decade of modest longitudinal growth. The age at onset of puberty and the growth rate during the pubertal growth spurt (which occurs under the influence of estrogens and GH) contribute to sex difference in final height between boys and girls. At the end of puberty, growth plates fuse, thereby ceasing longitudinal growth. It has been recognized that receptors for many hormones such as estrogen, GH, and glucocorticoids are present in or on growth plate chondrocytes, suggesting that these hormones may influence processes in the growth plate directly. Moreover, many growth factors, i.e., IGF-I, Indian hedgehog, PTHrP, fibroblast growth factors, bone morphogenetic proteins, and vascular endothelial growth factor, are now considered as crucial regulators of chondrocyte proliferation and differentiation. In this review, we present an update on the present perception of growth plate function and the regulation of chondrocyte proliferation and differentiation by systemic and local regulators of which most are now related to human growth disorders.
The Calcimimetic Cinacalcet Normalizes Serum Calcium in Subjects with Primary Hyperparathyroidism
Authors: Shoback Dolores M. , Bilezikian John P. , Turner Stewart A. , McCary Laura C. , Guo Matthew D. , Peacock Munro
Published: December 2003

Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4–10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10–65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2–4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.
Glucocorticoids and Insulin Sensitivity: Dissociation of Insulin’s Metabolic and Vascular Actions
Authors: Perry C. G. , Spiers A. , Cleland S. J. , Lowe G. D. O. , Petrie J. R. , Connell J. M. C.
Published: December 2003

Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1–40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as d-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.
Exon 6 and 2 Peroxisome Proliferator-Activated Receptor-γ Polymorphisms in Polycystic Ovary Syndrome
Authors: Orio Francesco , Matarese Giuseppe , Di Biase Sebastiano , Palomba Stefano , Labella Donato , Sanna Veronica , Savastano Silvia , Zullo Fulvio , Colao Annamaria , Lombardi Gaetano
Published: December 2003

Obesity affects about 44% of women with polycystic ovary syndrome (PCOS). Peroxisome proliferator-activated receptor-γ (PPAR-γ) is one of the genes involved in the differentiation of adipose tissue. In an attempt to shed light on the high percentage of obesity in PCOS, we examined polymorphisms at exons 6 and 2 of the PPAR-γ gene in 100 PCOS patients and in 100 healthy controls matched for age and body mass index (BMI). The T allele frequency of exon 6 was significantly higher (P < 0.05) in PCOS patients compared with control women. In addition, the BMI and leptin levels were significantly higher (P < 0.05) in PCOS patients carrying the C→T substitution than in controls. There was no significant difference in leptin levels after normalization for BMI. The Pro12Ala polymorphism at exon 2 was unrelated to BMI and/or leptin levels in PCOS women. In conclusion, the higher frequency of the C→T substitution in exon 6 of the PPAR-γ gene in PCOS women suggests that it plays a role in the complex pathogenetic mechanism of obesity in PCOS, whereas the Pro12Ala polymorphism does not seem to affect BMI in PCOS women.
Identification of Adrenocorticotropin Receptor Messenger Ribonucleic Acid in the Human Pituitary and Its Loss of Expression in Pituitary Adenomas
Authors: Morris Damian G. , Kola Blerina , Borboli Ninetta , Kaltsas Gregory A. , Gueorguiev Maria , McNicol Anne Marie , Ferrier Roderick , Jones T. Hugh , Baldeweg Stephanie , Powell Michael , Czirják Sándor , Hanzély Zoltán , Johansson Jan-Ove , Korbonits Márta , Grossman Ashley B.
Published: December 2003

The ACTH receptor (ACTH-R) is the second member of the melanocortin (MC-2) receptor family that includes five seven-transmembrane G protein-coupled receptors and has been shown to be predominantly expressed in the adrenal cortex. It has been postulated that ACTH may regulate its own secretion through ultra-short-loop feedback within the pituitary. ACTH-secreting adenomas are characterized by resistance to glucocorticoid feedback, and they may have dysregulated ACTH feedback. We therefore investigated the ACTH-R in normal and adenomatous human pituitary tissue. We report here the identification of ACTH-R mRNA in the human pituitary gland, which was confirmed by direct sequencing. We studied the expression of the ACTH-R in 23 normal pituitary specimens and 53 pituitary adenomas (22 ACTH-secreting, nine GH-secreting, eight prolactin-secreting, one TSH-secreting, one FSH-secreting, 10 nonfunctioning, and two silent corticotroph adenomas), using the sensitive technique of real-time quantitative PCR. Contamination of ACTH-secreting adenomas and nonfunctioning pituitary adenomas with nonadenomatous tissue was excluded by lack of Pit-1 expression. ACTH-R mRNA was detected in all normal pituitary specimens, and in situ hybridization colocalized expression to ACTH staining cells only. However, ACTH-R mRNA levels were undetectable in 16 of 22 ACTH-secreting tumors and in both silent corticotroph tumors. Diagnostic preoperative plasma ACTH levels were significantly lower in the ACTH-R positive ACTH-secreting tumors, compared with those who were ACTH-R negative (P = 0.0006). Direct sequencing of the coding region of the ACTH-R in cDNA from three ACTH-secreting tumors positively expressing the receptor showed no mutations, as did sequencing of genomic DNA in three receptor negative ACTH-secreting tumors and the two silent corticotrophs. These results provide further evidence compatible with an ACTH feedback loop in the pituitary and suggest that loss of expression of the ACTH-R in corticotroph adenomas of patients with Cushing’s disease may play a role in the resistance to feedback of the pituitary-adrenal axis seen in these patients.
CYP21 Genotype, Adult Height, and Pubertal Development in 55 Patients Treated for 21-Hydroxylase Deficiency
Authors: Balsamo Antonio , Cicognani Alessandro , Baldazzi Lilia , Barbaro Michela , Baronio Federico , Gennari Monia , Bal Milva , Cassio Alessandra , Kontaxaki Krissi , Cacciari Emanuele
Published: December 2003

In a retrospective study we evaluated long-term growth, pubertal developmental patterns to final height (FH), and medication in 55 patients (35 females) affected by 21-hydroxylase deficiency. The patients were classified into 3 groups according to predicted mutation severity: group A (11 women and 9 men), homozygous or compound heterozygous for null or In2 splice mutations [residual enzymatic activity (RA), <1%]; group B (11 women and 4 men), homozygous for I172N or R341P or R426H mutations (RA, ∼2–3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, >30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 sd of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (<1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome.
Acute Exposure to Circularly Polarized 50-Hz Magnetic Fields of 200–300 μT Does Not Affect the Pattern of Melatonin Secretion in Young Men
Authors: Warman G. R. , Tripp H. , Warman V. L. , Arendt J.
Published: December 2003

Environmental exposure to time-varying (alternating current) magnetic fields (MFs) produced by electrical current flow is a perceived public health risk. Several epidemiological studies report correlations between MF exposure and carcinogenesis. It has been hypothesized that MF-induced suppression of melatonin could provide the mechanism by which this effect is mediated. Here, we describe results from a controlled laboratory-based study designed to detect changes in human melatonin secretion after a 2-h exposure to 200–300 microTesla, 50 Hz circularly polarized MF. Exposure was timed to occur before or during the nightly melatonin rise, and levels administered were some 4–6 times higher than the commonly encountered maximum levels. Results from 19 male subjects aged between 18 and 35 yr indicate that acute exposure to 50 Hz MFs of this nature does not result in significant suppression, alteration of peak levels, or a change in timing of the nighttime melatonin rise. We conclude that acute exposure to 50 Hz MFs does not have a significant effect on the normal nighttime production of melatonin in young men.
Leptin and Bone Mineral Density: A Cross-Sectional Study in Obese and Nonobese Men
Authors: Morberg Cathrine M. , Tetens Inge , Black Eva , Toubro Soeren , Soerensen Thorkild I. A. , Pedersen Oluf , Astrup Arne
Published: December 2003

Leptin has been suggested to decrease bone mineral density (BMD). This observational analysis explored the relationship between serum leptin and BMD in 327 nonobese men (controls) (body mass index 26.1 ± 3.7 kg/m2, age 49.9 ± 6.0 yr) and 285 juvenile obese men (body mass index 35.9 ± 5.9 kg/m2, age 47.5 ± 5.1 yr). Whole-body dual-energy x-ray absorptiometry scan measured BMD, fat mass, and lean mass. Fasting serum leptin (nanograms per milliliter) was strongly associated with fat mass (kilograms) in both controls (r = 0.876; P < 0.01) and juvenile obese (r = 0.838; P < 0.001). An inverse relation between BMD adjusted for body weight and serum leptin emerged in both the control group (r = −0.186; P < 0.01) and the juvenile obese group (r = −0.135; P < 0.05). In a multiple linear regression, fat mass, lean body mass, and occupational physical activity were positively associated with BMD in the control group, whereas in the juvenile obese, only lean body mass was positively associated with BMD and smoking negatively associated with BMD. Our study supports that leptin is inversely associated with BMD and may play a direct role in the bone metabolism in nonobese and obese Danish males, but it also stresses the fact that the strong covariation between the examined variables is a shortcoming of the cross-sectional design.
Puberty in Growth Hormone-Treated Children Born Small for Gestational Age (SGA)
Authors: Boonstra Venje , van Pareren Yvonne , Mulder Paul , Hokken-Koelega Anita
Published: December 2003

Seventy-five small for gestational age (SGA) children were studied in a randomized, double-blind, dose-response GH trial with either 1 or 2 mg GH/m2·d. Mean (sd) age at the start of GH therapy was 7.3 (2.2) yr. Data were compared with Dutch reference data.

In SGA boys, mean (sd) age at onset of puberty was 12.0 (1.0) and 11.6 (0.7) yr, and in SGA girls it was 10.9 (1.1) and 10.6 (1.2) yr when treated with 1 and 2 mg GH/m2·d, respectively. SGA boys treated with the lower GH dose started puberty later than the appropriate for gestational age (AGA) controls; for the other GH-dosage groups there was no significant difference in age at onset of puberty compared to AGA controls. The age at menarche and the interval between breast stage M2 and menarche were not significantly different for GH-treated SGA girls compared to their peers. The duration of puberty and pubertal height gain of GH-treated SGA boys and girls were not significantly different between the two GH-dosage groups and were comparable with untreated short children born SGA.

In conclusion, long-term GH therapy in short SGA children has no influence on the age at onset and progression of puberty compared to AGA controls, regardless of treatment with a dose of 1 or 2 mg GH/m2·d. Duration of puberty and pubertal height gain were not significantly different between the GH-dosage groups.
Cyclical Cushing’s Syndrome in a Patient with a Bronchial Neuroendocrine Tumor (Typical Carcinoid) Expressing Ghrelin and Growth Hormone Secretagogue Receptors
Authors: Arnaldi G. , Mancini T. , Kola B. , Appolloni G. , Freddi S. , Concettoni C. , Bearzi I. , Masini A. , Boscaro M. , Mantero F.
Published: December 2003

A 56-yr-old woman was referred with a diagnosis of Cushing’s disease. Hypertension and severe hypokalemia were present and high urinary free cortisol/cortisone ratio was detected, raising a suspicion of an ectopic ACTH syndrome. Inferior petrosal sinus sampling, thoracic computed tomography, and octreotide scans were negative. Remission and relapse periods lasting 3–4 months were observed during the 3.5 yr of follow-up. Finally a thoracic computed tomography scan showed a basal paracardic nodule in the left lung. After surgery, a well-differentiated neuroendocrine tumor (typical bronchial carcinoid) was diagnosed, staining positively for ACTH. RT-PCR revealed expression of proopiomelanocortin, CRH receptor, and V3 vasopressin receptor. Somatostatin receptor type 1, 2, 3, and 5 mRNA was detected only in tumoral tissue. Interestingly, we observed the simultaneous presence of ghrelin and both GH secretagogue (GHS) receptors (1a and 1b) mRNA in tumoral tissue but not in the normal lung. This finding correlates with the in vivo ACTH hyperresponsiveness to hexarelin (a GHS).

This is the first report of a cyclical ectopic ACTH-secreting tumor with an in vivo ACTH response to hexarelin coupled with the tumoral expression of ghrelin and GHS receptors. This finding might imply an autocrine/paracrine modulatory effect of ghrelin in bronchial ACTH-secreting tumors.
Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People
Authors: Toorians A. W. F. T. , Thomassen M. C. L. G. D. , Zweegman S. , Magdeleyns E. J. P. , Tans G. , Gooren L. J. G. , Rosing J.
Published: December 2003

The incidence of venous thrombosis associated with estrogen treatment in male-to-female (M→F) transsexuals is considerably higher with administration of oral ethinyl estradiol (EE) than with transdermal (td) 17-β-estradiol (E2).

To find an explanation for the different thrombotic risks of oral EE and td E2 use, we compared the effects of treatment of M→F transsexuals with cyproterone acetate (CPA) only, and with CPA in combination with td E2, oral EE, or oral E2 on a number of hemostatic variables [activated protein C (APC) resistance and plasma levels of protein S, protein C, and prothombin], all of which are documented risk factors for venous thrombosis. APC resistance was determined by quantification of the effect of APC on the amount of thrombin generated during tissue factor-initiated coagulation; plasma levels of total and free protein S were determined by standard ELISA; and levels of prothrombin and protein C were determined with functional assays after complete activation of the zymogens with specific snake venom proteases.

CPA-only, td-E2+CPA, or oral-E2+CPA treatment produced rather small effects on hemostatic variables, whereas oral EE treatment resulted in a large increase in APC resistance from 1.2 ± 0.8 to 4.1 ± 1 (P < 0.001), a moderate increase in plasma protein C (9%; P = 0.012), and a large decrease in both total and free plasma protein S (30%; P < 0.005). The large differential effect of oral EE and oral E2 indicates that the prothrombotic effect of EE is due to its molecular structure rather than to a first-pass liver effect (which they share). Moreover, these differences may explain why M→F transsexuals treated with oral EE are exposed to a higher thrombotic risk than transsexuals treated with td E2. Testosterone administration to female-to-male transsexuals had an antithrombotic effect.
High Risk of Adrenal Insufficiency in Adults Previously Treated for Idiopathic Childhood Onset Growth Hormone Deficiency
Authors: Lange Martin , Feldt-Rasmussen Ulla , Svendsen Ole Lander , Kastrup Knud William , Juul Anders , Müller Jørn
Published: December 2003

The aim was to reevaluate a group of adults treated for idiopathic childhood onset GH deficiency (GHD) after 18 yr without GH treatment.

Twenty-six (11 females) patients participated. All but two had isolated GHD. Childhood diagnosis was established by insulin tolerance test (ITT). The patients were retested with an ITT to evaluate adult GH status. In five patients, an arginine and a synacthen test were performed instead of an ITT.

Eleven of 25 patients had a subnormal cortisol response to ITT or synacthen. Ten patients had a GH peak less than 3.0 μg/liter (0.5. ± 0.5 μg/liter), whereas 16 patients displayed a normal GH response (12.3 ± 10.6 μg/liter) after ITT. IGF-I values were decreased in the patients with a pathological retest as well as in patients with a normal GH response compared with controls (P < 0.005).

In 26 idiopathic childhood onset GHD patients, 44% of the patients had developed adrenal insufficiency; 38.5% had persistent GHD in adulthood, using the same test in both childhood and adulthood. Patients having a normal GH test had decreased IGF-I levels, compared with controls, indicating impaired function of a seemingly normal GH axis. It is imperative that pituitary axes other than the GH axis are tested at regular intervals, even in the absence of GHD in adulthood.
Computed Tomography-Guided Percutaneous Acetic Acid Injection Therapy for Functioning Adrenocortical Adenoma
Authors: Minowada Shigeru , Fujimura Tetsuya , Takahashi Naoki , Kishi Hiroichi , Hasuo Kanehiro , Minami Manabu
Published: December 2003

We reported the outcomes of computed tomography (CT)-guided percutaneous acetic acid injection therapy for functioning adrenocortical adenomas. With the patient in a prone position, the puncture needle was inserted vertically downward into the adenoma with frequent CT scanning. After confirmation by pilot injection with contrast medium, a small aliquot of 40–50% acetic acid was injected and repeated. Between 1997 and 2002, 18 sessions of CT-guided injection therapy, including one session of ethanol injection, were performed on 10 patients (five patients with primary aldosteronism and five patients with Cushing’s or subclinical Cushing’s syndrome) without any complications except transient upper abdominal pain during the acetic acid injection. The follow-up period ranged from 5–69 months. The treatment resulted in almost an extirpation of the adrenocortical hyperfunction in seven patients after one or two sessions. CT-guided percutaneous acetic acid injection might be a simple, cost-effective, and far less invasive treatment for small functioning adrenocortical adenomas.