bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced expression and normal nucleotide sequence of androgen receptor gene coding and promoter regions in a family with partial androgen insensitivity syndrome
Authors: Choong Catherine S. , Sturm Marian J. , Strophair Julie A. , McCulloch Ross K. , Hurley David M. 
Published: November 2003

BACKGROUND AND OBJECTIVES Androgen insensitivity syndrome (AIS) is an X‐linked disorder of XY males characterized by varying degrees of impaired masculinization. In many AIS cases, mutations have been identified in the coding sequence of the human androgen receptor (AR) gene which impair receptor function. Cases have also been reported in which reduced AR mRNA expression may contribute to AIS in association with AR gene mutations. The purpose of this study was to define the molecular basis of AIS in members of a family with clinical and laboratory features of partial androgen insensitivity (PAIS).DESIGN Genital skin fibroblast (GSF) cultures were established from foreskin tissue for androgen receptor binding analysis. Genomic DNA was obtained from blood leucocytes for AR gene nucleotide sequence analysis. AR mRNA levels were determined in total RNA extracted from GSF cultures.PATIENTS  Three related subjects with perineo‐scrotal hypospadias, bifid scrotum and microphallus were studied. The family pedigree of these subjects suggested an X‐linked pattern of inheritance. Hormone assay results were consistent with AIS.MEASUREMENTS AR binding capacity and affinity were determined in three subjects and compared with unaffected male controls. The coding sequence and 1.4 kb of promoter region of the AR gene were amplified in overlapping fragments by polymerase chain reaction from genomic DNA and sequenced. GSF AR mRNA was measured by a competitive PCR technique.RESULTS In the PAIS subjects, AR affinity in cultured GSF was normal (Kd = 0.24, 0.30, 0.48 vs 0.27 ±0.07 (SD) nmol/l) but binding capacity was reduced (Bmax =0.31, 0.36, 0.27 vs 1.26 ±0.37 (SD) fmol/μg DNA). Sequence analysis of the CAG repeat polymorphism within exon 1 of the AR gene showed that both mothers were heterozygous at this locus, and that the three subjects had inherited the same allele. GSF AR mRNA levels were reduced in all three patients compared with controls (0.25, 0.74 and 0.74 vs 3.8 ±0.9 (SEM), range 1.8–7.3 amol/μg total RNA). The nucleotide sequences of the entire AR coding region and of a 1.4 kb segment containing the promoter region were normal.CONCLUSION Members of this family with clinical and biochemical evidence of X‐linked partial androgen insensitivity syndrome demonstrated normal androgen receptor binding affinity and androgen receptor gene nucleotide sequence but reduced androgen receptor binding capacity and reduced androgen receptor mRNA. These results suggest that partial androgen insensitivity syndrome in this family may be caused by reduced expression of a normal androgen receptor gene.
Pituitary size and function in children and adolescents with shunted hydrocephalus
Authors: Löppönen Tuija , Pääkkö Eija , Laitinen Juhani , Saukkonen Anna‐Liisa , Serlo Willy , Tapanainen Päivi , Ruokonen Aimo , Pirttiniemi Pertti , Poikela Aila , Knip Mikael 
Published: November 2003

OBJECTIVEMost previous reports of endocrine disorders in children with shunted hydrocephalus have been case reports and there is a lack of systematic information on pituitary anatomy and function among these children. We have obtained these data in a large group of individuals with shunted hydrocephalus.DESIGNA controlled cross‐sectional study.PATIENTSFifty‐four children and adolescents with shunted hydrocephalus were studied for pituitary anatomy and function. They had 54 age‐ and sex‐matched controls (group I). The mean age of the patients and controls was 12.6 years and the mean shunting period 10.6 years. There was a second control group (II) for the magnetic resonance imaging (MRI) and a third control group (III) for the radiography of the sella turcica.MEASUREMENTSThe anatomy was visualized by MRI of the pituitary gland and by radiography of the sella turcica. The functional evaluation included an arginine–insulin test and a combined stimulation test with corticotrophin releasing factor (CRF), GnRH and TRH.RESULTSThe patients were shorter (height 148.4 cm vs 153.7 cm, P < 0.05 and relative height −0.5 SDS vs 0.4 SDS, P < 0.05) and had a higher BMI than the control group I (20.6 kg/m2 vs 18.0 kg/m2, P < 0.001). They had also a greater pituitary height than the control group II (5.8 mm vs 5.1 mm, P < 0.01). The patients had significantly lower basal GH levels (P < 0.001) than controls I. Sixteen patients (30%) had a poor GH response (< 20 mU/l) in the arginine–insulin test. Pituitary height was significantly lower among these patients than in those with a normal response (4.7 mm vs 6.3 mm, P < 0.01), who had an increased pituitary height compared to controls II (5.1 mm, P < 0.01). The area under the curve (AUC) for GH correlated with the pituitary volume (r = 0.50, P < 0.001). The patients had higher basal FSH and LH concentrations than controls I (P < 0.001). The peak to basal ratios of FSH and LH were increased in the prepubertal patients and that of LH at Tanner pubertal stage II in the females. The basal FSH and LH levels correlated with the pituitary volume (r = 0.50 and r = 0.54, P < 0.001 for), as did FSH AUC and LH AUC (r = 0.48 and r = 0.75, P < 0.001 for both).CONCLUSIONSThese observations indicate that children with shunted hydrocephalus have an increased pituitary size on average. About one‐third of these patients had signs of reduced GH secretion and significantly lower pituitary height, which probably contributes to their poor linear growth. Increased pituitary size was associated with enhanced gonadotrophin secretion, which may result in early puberty in children with shunted hydrocephalus.
Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC‐1 in dermal fibroblasts from patients with syndromes of severe insulin resistance
Authors: Whitehead Jonathan P. , Humphreys Phillippa J. , Dib Karim , Goding James W. , O'Rahilly Stephen 
Published: November 2003

OBJECTIVETo date, mutations in the insulin receptor gene are the only clearly defined cause of extreme insulin resistance in man. Recently, however, some patients with severe insulin resistance have been reported to have marked over‐expression of the transmembrane glycoprotein PC‐1 in their cultured fibroblasts. This protein appears to act as an endogenous inhibitor of the insulin receptor tyrosine kinase which suggests that primary over‐expression of PC‐1 may play an aetiological role in some forms of insulin resistance. One sub‐type of extreme insulin resistance in which the insulin receptor gene has been reported to be normal is pseudo‐acromegalic insulin resistance. The main aim of this study was to determine whether overexpression of PC‐1 might contribute to the severe insulin resistance exhibited by some patients with pseudo‐acromegaly.DESIGN AND PATIENTSPC‐1 phosphodiesterase activity and PC‐1 protein and mRNA content were measured in cultured dermal fibroblasts from three severely insulin resistant pseudo‐acromegalic patients. These were compared with fibroblasts from normoinsulinaemic normoglycaemic controls and from subjects with known genetic defects in the insulin receptor or IRS‐1.RESULTSIn the fibroblasts from pseudo‐acromegalic insulin resistant subjects PC‐1 activity and PC‐1 protein and mRNA levels were indistinguishable from the normoinsulinaemic controls. Consistent with this observation, insulin receptor tyrosine kinase activity was similar in extracts from fibroblasts of pseudo‐acromegalic subjects and normal controls. Surprisingly, subjects with insulin receptor or IRS‐1 mutations had a profound reduction in PC‐1 activity (p ≤ 0.005), protein (p ≤ 0.05) and mRNA levels (P ≤ 0.005).CONCLUSIONSThe results indicate that PC‐1 overexpression does not appear to contribute to the insulin resistant state of pseudo‐acromegalic patients. The finding of normal insulin receptor tyrosine kinase activity in these subjects suggests that the site of defective insulin signalling is likely to be distal to the receptor. The unexpected finding that PC‐1 activity, protein and mRNA were all dramatically reduced in patients with lesions early in the insulin signalling cascade provides further evidence for a link, albeit as yet poorly understood, between cellular insulin action and the expression of PC‐1.
Inhaled beclomethasone dipropionate suppresses the hypothalamo–pituitary–adrenal axis in a dose dependent manner
Authors: Grebe Stefan K. G. , Feek Colin M. , Durham John A. , Kljakovic Marjan , Cooke Russell R. 
Published: November 2003

OBJECTIVELittle is known about the dose–response relationship of potential, unwanted, effects of inhaled beclomethasone (BDP) on the hypothalamo–pituitary–adrenal (HPA) axis, particularly in non‐specialist clinic settings. The purpose of our study was to investigate the dose–response relationship of inhaled BDP on the HPA axis in a general practice patient population. We also explored the optimal testing strategy in this population and correlated effects of inhaled BDP on the HPA axis with other systemic corticosteroid side effects.PATIENTS AND DESIGNControlled observational study employing 21 patients on inhaled BDP recruited from general practice, with minimal past and no present exposure to other corticosteroids, and 21 age and gender‐matched controls.MEASUREMENTSTwenty‐four‐hour urinary free cortisol excretion (UFC), serum cortisol before and 30 minutes after injection of 1 μg and 250 μg of tetracosactrin, serum IGF‐I and serum osteocalcin were measured. BDP use was estimated by inhaler weighing and prescription count.RESULTSIn subjects on inhaled BDP, 24‐hour UFC (P < 0.008), serum cortisol 30 minutes after 250 μg tetracosactrin (P < 0.05) and the serum cortisol rise after 250 μg tetracosactrin (P < 0.04) were significantly lower when compared with controls. Measurements of HPA function correlated inversely with BDP dose estimated by inhaler weighing (all P < 0.03). Serum IGF‐I and osteocalcin levels did not differ.CONCLUSIONSWe have demonstrated hypothalamo–pituitary–adrenal axis suppression in non‐specialist‐clinic asthma patients on moderate to large doses of inhaled beclomethasone dipropionate. When accurate measurements of inhaled steroid dose are used, there is an exponential relationship between dose and hypothalamo–pituitary–adrenal axis suppression. There appears to be no ‘safe’ threshold, and around 15% of patients may have clinically significant suppression. However, the significance of hypothalamo–pituitary–adrenal axis suppression as a marker for concomitant corticosteroid effects on other organ systems remains uncertain.
Anisomycin and verapamil influence the action of progesterone on regulation of term human myometrial contractile activity
Authors: Fu Xin , Moberg Christian , Bäckström Torbjörn , Ulmsten Ulf , Gylfe Erik 
Published: November 2003

OBJECTIVEProgesterone has been shown to have both stimulatory and inhibitory effects on term human myometrial contractile activity. The mechanisms involved in this action of progesterone are still poorly understood.DESIGNMyometrial tissues were obtained from the lower uterine segment at elective Caesarean section of 30 term pregnant women. The contractile activity of muscle strips was measured by a superfusion technique and protein synthesis evaluated by [3H]‐leucine incorporation.RESULTS[3H]‐leucine incorporation into term myometrial strips was not affected by progesterone (10 μmol/l), but was markedly reduced by the protein synthesis inhibitor anisomycin (P  <  0.05). However, progesterone increased frequency and tonus of contractions and reduced the activity‐area of contractions (P  <  0.01). Anisomycin (100 μmol/l) did not change these effects or the spontaneous contractile activity. Removal or extracellular Ca2+ or addition of the L‐type calcium channel blocker verapamil prevented the spontaneous as well as the progesterone‐induced contractions, but had less pronounced effects on contractions initiated by oxytocin.CONCLUSIONThe results indicate that the actions of progesterone on term myometrial contractile activity occur without protein synthesis and that increased Ca2+ influx or decreased outward transport of Ca2+ may play a possible role.
Suspected hypoglycaemia in out patient practice: accuracy of dried blood spot analysis
Authors: Parker David R. , Bargiota Alexandra , Cowan Fiona J. , Corrall Roger J. M. 
Published: November 2003

OBJECTIVEThe assay of dried blood spots on filter paper to determine blood glucose concentration has been used to detect hypoglycaemia in out patients. We assessed the accuracy of this approach in assaying blood glucose concentrations in the hypoglycaemic range.DESIGNVolunteers were rendered hypoglycaemic by intravenous infusion of insulin. The glucose concentration in simultaneously taken blood samples was measured either fresh or after drying on filter paper.PATIENTSTwenty‐four healthy young volunteers and 9 patients with insulin‐dependent diabetes were studied.MEASUREMENTSPlasma glucose concentrations were measured using a standard auto analyser glucose oxidase method. Whole blood taken simultaneously was placed on prepared filter paper and allowed to dry; glucose concentration was then measured using a well‐established technique. A correction factor was applied to convert the glucose concentration of plasma to that of whole blood. The relationship between glucose concentrations measured by the two methods was determined by regression coefficient.RESULTSIn the unequivocally hypoglycaemic range (plasma 2.5 mmol/l), corrected dried blood spot glucose concentrations significantly correlated with standard plasma glucose concentrations (r = 0.81; P < 0.001). The dried blood spot method had a sensitivity of 91%. In the range designated probable hypoglycaemia (plasma 3.3 mmol/l), there was also significant correlation (r = 0.90; P < 0.001) and the sensitivity was 96%. The specificity of the dried blood spot method was 100% in both ranges.CONCLUSIONSMeasurement of glucose concentrations in dried blood spots is specific and sensitive in the hypoglycaemic range. The present study indicates that hypoglycaemia may be excluded or confirmed respectively when levels in excess of 3.7 or below 2.8 mmol/l are found in uncorrected dried blood spot analysis.
L‐hydroxytryptophan amplifies pulsatile secretion of LH in the follicular phase of normal women
Authors: Lado‐Abeal J. , Rey C. , Cabezas‐Agrícola J. M. , Rodriguez A. , Camarero E. , Cabezas‐Cerrato J. 
Published: November 2003

OBJECTIVESThe hypothalamus possesses serotoninergic fibres which arise from neuronal cell bodies located in the raphe nuclei and have synapse on GnRH‐secreting neurones. Hitherto, no firm evidence has been produced to support a role for serotoninergic control of LH in humans. Our first objective was to investigate whether pulsatile administration of L‐5‐hydroxytryptophan—the immediate precursor of serotonin—affects pulsatile LH secretion in the medium–late follicular phase of normal women. Since the results of the first experiment suggest that L‐5‐hydroxytryptophan amplifies LH release, our second objective was to investigate whether, in the absence of GnRH, L‐5‐hydroxytryptophan can release LH. This was done by studying LH response in patients with hypogonadotrophic hypogonadism of hypothalamic origin.PATIENTSTwenty‐two normal women (18–25 years old) and 8 patients with hypogonadotrophic hypogonadism (2 men with Kallmann's syndrome and 6 women with anorexia nervosa).DESIGNSerum LH levels in the 22 subjects (reference population) were monitored at 10‐minute intervals over an 8‐hour period (1000–1800 h) during medium–late follicular phase. In 7 of these subjects, serum LH levels were monitored in their next medium–late follicular phase while L‐5‐hydroxytryptophan was administered at hourly intervals from 1000 to 1800 h; the peripheral conversion of L‐5‐hydroxytryptophan to serotonin was inhibited by 150 mg of benserazide at 0930 and 1430 h. To investigate whether, in the absence of GnRH, L‐5‐hydroxytryptophan can release LH, two patients with Kallmann's syndrome were monitored over a 7‐hour period and 6 patients with anorexia nervosa over a 9‐hour period. After a 2.5 hour control period the subjects received 150 mg of benserazide, and pulsatile L‐5‐hydroxytryptophan (every 30 minutes in the Kallmann's patients and every 45 minutes in the subjects with anorexia nervosa).MEASUREMENTSLH pulses were identified and analysed according to number, amplitude, interpulse interval and pulse duration.RESULTSIn the normal women, L‐5‐hydroxytryptophan increased pulse amplitude (mean ± SD: 3.02 ± 1.42 IU/l vs. 1.75 ± 0.98 IU/l before L‐5‐hydroxytryptophan and 1.90 ± 1.04 IU/l in the reference population; P < 0.01 in both cases), but had no significant effects on pulse duration, interpulse interval or number of pulses. L‐5‐hydroxytryptophan had no effect on LH in patients with Kallmann's syndrome. In the anorexia nervosa group, the mean serum LH level increased significantly after L‐5‐hydroxytryptophan (3.90 ± 2.46 IU/l vs. 3.06 ± 1.23 IU/l, P < 0.001) but, as in Kallmann's patients, the three women in this group without residual LH pulsatility did not respond to L‐5‐hydroxytryptophan.CONCLUSIONPulsatile administration of L‐5‐hydroxytryptophan increases LH pulse amplitude in the follicular phase of normal women. In the absence of GnRH, L‐5‐hydroxytryptophan does not stimulate pituitary LH secretion.
Effects of prolonged bisphosphonate therapy and its discontinuation on bone mineral density in post‐menopausal osteoporosis
Authors: Orr‐Walker Brandon , Wattie Diana J. , Evans Margaret C. , Reid Ian R. 
Published: November 2003

OBJECTIVE The bisphosphonates have proven efficacy in the management of post‐menopausal osteoporosis. However, the benefits of prolonged (<2 years) administration and the effects of discontinuation of bisphosphonate treatment are not clear. DESIGN We have previously reported a 2‐year, randomized, double‐blind, placebo‐controlled trial of pamidronate therapy (150mg/day) in women with established post‐menopausal osteoporosis. We now report the bone mineral density (BMD) changes in those women who continued for a third year of active treatment and were then observed off therapy for a further 12 months. PATIENTS Twenty‐two women (mean age 66 years) continued on pamidronate in year 3, and in 16 of these the effects of subsequent discontinuation of therapy for 12 months were studied. MEASUREMENTS BMD was measured in the total body, lumbar spine and proximal femur using a Lunar DPX‐L dual‐energy, X‐ray absorptiometer. RESULTS The third year of therapy with pamidronate was associated with a significant further gain in BMD only at the lumbar spine (2.1±0.8%, P=0.003), resulting in a total gain of 9.5±1.0% at that site over 3 years of treatment. In the total body, BMD tended to decline (−0.6±0.3%) in year 3. One year after discontinuation of pamidronate, there were significant losses of BMD in the total body (−1.9±0.3%, P<0.0001) and femoral trochanter (−2.7±0.9%, P=0.01), and non‐significant changes at the lumbar spine (−0.9±0.8%), femoral neck (−0.5±1.6%), and Ward's triangle (−2.9±3.7%). By the end of one year off therapy, BMD was greater than baseline only in the lumbar spine (71±1.1%, P<0.0001) and femoral trochanter (4.5±1.88%, P<0.03). In the total body, BMD was 0.3±0.7% below the values at the trial’s inception (P=0.7). CONCLUSIONS These data demonstrate that the rate of bone gain associated with bisphosphonate use slows over time, and that significant bone loss follows withdrawal of these agents. These findings have important implications for the duration of use of these novel drugs in the therapy of osteoporosis and suggest a need for close observation following their discontinuation.
Increased cerebrovascular mortality in patients with hypopituitarism
Authors: Bülow Birgitta , Hagmar Lars , Mikoczy Zoli , Nordström Carl‐Henrik , Erfurth Eva Marie 
Published: November 2003

OBJECTIVE An increased prevalence of atherosclerosis has been shown among patients with hypopituitarism. The aim of the present study was to assess whether patients with hypopituitarism experience increased cardiovascular, in particular cerebrovascular, mortality. DESIGN AND PATIENTS Retrospective cohort study of mortality, 1952–1992, in 344 patients, of whom 130 were female, receiving conventional hormone replacement for hypopituitarism following neurosurgery for pituitary tumours. The general population in the catchment area of southern Sweden from which the patients were recruited constituted the reference population. Expected mortality was obtained from cause, sex, calendar year, and 5‐year age‐specific death rates for the area. RESULTS Increased mortality from cerebrovascular disease (standardized mortality ratio (SMR) 3.39; 95% CI 2.27–4.99) was the main contributor to the increased overall cardiovascular mortality (SMR 1.75; 95% CI 1.40–2.19). The increase in mortality from cardiac diseases was much smaller (SMR 1.41; 95% CI 1.04–1.88). The risk for cerebrovascular death was higher in women (SMR 4.91) than in men (SMR 2.64). The relative risk for cerebrovascular death was independent of the time interval since diagnosis of pituitary insufficiency, but was greater in subjects diagnosed at an earlier age (<55 years). No increased mortality in malignant tumours was observed (SMR 0.95; 95% CI 0.60–1.48). CONCLUSION The increased cerebrovascular mortality may be due to GH deficiency, or to long‐term lack or inadequacy of substitution for other pituitary hormones. The observations that an early onset of pituitary insufficiency and female sex are predictors for a high risk for cerebrovascular mortality merit particular attention when treating this group of patients.
Mapping the soil resources of a recent alluvial plain in Greece using fuzzy sets in a GIS environment
Authors: Kollias V. J. , Kalivas D. P. , Yassoglou N. J. 
Published: November 2003

SummaryCollecting soil data is time‐consuming and costly, often exceeding practical possibilities. A methodology for the delineation of soil mapping units in an alluvial plain of Western Peloponnese, Greece, was investigated. A detailed soil survey of an area of 300 ha was used to obtain the basic soil data for evaluating the performance of the proposed methodology. The methodology consists of the following steps: (a) data collection from borings and representative soil profiles, (b) definition of the soil mapping units in the study area, (c) determination of the range of the diagnostic variables for each mapping unit from field observations and statistical analysis of the analytical data from representative soil profiles, (d) determination of the class of each diagnostic variable by observation at a network of boring points, (e) subjective assignment of numerical values to soil variables at the bore points, (f) estimation of the values of each soil variable at the points of a regular grid using the interpolation methods kriging and inverse squared distance, (g) application of the fuzzy set theory to the interpolated data and the production of thematic fuzzy maps, and (h) validation of the results through a number of independent test borings. The results obtained show that the proposed methodology can produce soil maps of recent alluvial plains with acceptable accuracy and cost.