bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep apnoea in treated acromegaly: relative frequency and predisposing factors
Authors: Rosenow Felix , Reuter Stefan , Deuß Ulrich , Szelies Brigitte , Hilgers Ralf‐Dieter , Winkelmann Werner , Heiss Wolf‐Dieter
Published: November 2003

OBJECTIVES Sleep apnoea is common in active acromegaly. It is associated with increased morbidity and mortality but can be treated effectively. The objective of this study was to determine the largely unknown relative frequency of, and the predictive factors for, sleep apnoea in treated acromegalic patients.

DESIGN Retrospective cohort study.

SETTING Tertiary referral hospital.

PATIENTS Fifty‐four of 100 patients with treated acromegaly. If sleep apnoea had been diagnosed before acromegaly, the patient was excluded.

MEASUREMENTS Sleep studies (using the MESAM‐4 device measuring oxyhaemoglobin saturation, heart rate, snoring sounds and body position to determine presence and severity of sleep apnoea); GH and IGF‐I levels; body mass index, neck and index‐finger circumference; daytime symptoms of sleep apnoea, duration of acromegaly before treatment, shoe and neck‐size difference since beginning of acromegaly; age, sex and treatment modes of acromegaly.

RESULTS The relative frequency of sleep apnoea was 39% in the 54 patients with sleep studies and at least 21% in the entire study population of 100 patients.

In patients with sleep apnoea, statistically significant higher values were observed for GH (P = 0.002), IGF‐I (P = 0.029), age (P = 0.014) and neck circumference (P = 0.016). An index‐finger circumference of ≥8.5 cm was associated with a significantly higher desaturation index (P = 0.012, Mann–Whitney Itest). Adenomectomy had been performed significantly less frequently in patients with sleep apnoea (P < 0.001, χ2 test). The body mass index was non‐significantly higher in the patients with sleep apnoea.

CONCLUSIONS The relative frequency of sleep apnoea in patients with treated acromegaly is at least 21%. Parameters of predictive value for the presence of sleep apnoea in this population are neck and index‐finger circumference as measures of soft tissue hypertrophy, age, GH and IGF‐I levels, and whether or not operative therapy was applied.
Urinary free cortisone and the assessment of 11β‐hydroxysteroid dehydrogenase activity in man
Authors: Palermo Mario , Shackleton Cedric H. L. , Mantero Franco , Stewart Paul M.
Published: November 2003

OBJECTIVE Two isoforms of 11β‐hydroxysteroid dehydrogenase (11β‐HSD) catalyse the interconversion of cortisol to hormonally inactive cortisone; defects in the 11β‐HSD2 isoform result in hypertension. The kidney, expressing high levels of 11β‐HSD2, is the principal source of cortisone in man. We have validated the measurement of urinary free cortisone (UFE) excretion in normals and in patients with disorders of the pituitary‐adrenal axis in an attempt to more accurately measure the activity of 11β‐HSD2 in vivo.

SUBJECTS Forty‐one normal adults, 12 normal children <12 years of age, 15 patients with Cushing’s syndrome, 12 with hypopituitarism on replacement hydrocortisone, 12 with the syndrome of apparent mineralocorticoid excess (AME) and 7 volunteers consuming liquorice.

MEASUREMENTS A complete 24‐hour urine collection was analysed by gas chromatography/mass spectrometry for ‘A‐ring’ reduced cortisol and cortisone metabolites, i.e. tetrahydrocortisols (THF and allo‐THF) and tetrahydrocortisone (THE). In addition, urinary free cortisol (UFF) and urinary free cortisone were quantified using deuterium‐labelled internal standards.

RESULTS In normal adults and children, UFE excretion exceeded that of UFF (UFF 30.4 ± 2.4 μg/24h (mean ± SE), UFE 54.6 ±4.1 μg/24h, adults) (for conversion to nmol/24h multiply E by 2.78 and F by 2.76 respectively). Thus the normal UFF/UFE ratio was 0.54 ± 0.05 in contrast to the (THF+allo‐THF)/THE ratio of 1.21 ± 0.06. UFE excretion was normal in hypopituitary patients on replacement hydrocortisone. Although UFE was elevated in all forms of Cushing’s syndrome, the UFF/UFE ratio was grossly elevated in patients with the ectopic ACTH syndrome (14.0 ± 6.7, n=6). UFE was below the lower limit of the assay (<1 μg/24h) in most patients with the so‐called type 1 variant of AME and significantly reduced in 4 patients described as having the type 2 variant of AME (10.5 ± 3.5 μg/h, P<0.05) and in 7 volunteers consuming liquorice (26.8 ± 10.0 μg/24h, P<0.01). In ectopic ACTH syndrome, AME, and liquorice ingestion the UFF/UFE ratio was more deranged than the (THF+ allo‐THF)/THE ratio.

CONCLUSION In normals the discrepant THF + allo‐THF/THE and UFF/UFE ratio suggests that much more of the UFE is derived from the kidney. Reduction in UFE excretion is seen following liquorice ingestion and in both variants of AME, though it is more profound in AME1. The high UFF/UFE ratio in the mineralocorticoid excess state seen in the ectopic ACTH syndrome is compatible with substrate‐saturation of renal 11β‐HSD2. The measurement of UFE and the UFF/UFE ratio is a significant advance in the analysis of human 11β‐HSD activity in vivo; in particular, the UFF/UFE ratio appears to be a more sensitive index than the (THF+allo‐THF)/THE ratio of renal 11β‐HSD2 activity.
HLA DRB1/DQA1/DQB1 haplotype determines thyroid autoimmunity in patients with insulin‐dependent diabetes mellitus
Authors: Chuang L.‐M. , Wu H.‐P. , Chang C.‐C. , Tsai W.‐Y. , Chang H.‐M. , Tai T.‐Y. , Lin B. J.
Published: November 2003

OBJECTIVE Thyroid autoimmunity is frequently associated with insulin‐dependent diabetes mellitus (IDDM). The genetic factors which contribute to thyroid autoimmunity and IDDM have been described but vary between different races. We have therefore investigated the effect of class II HLA genes at both loci and the HLA haplotypes on the presence of autoimmunity in patients with IDDM in Taiwan.

SUBJECTS AND MEASUREMENTS Eighty‐three patients with IDDM and 105 unrelated normal controls were recruited for the measurement of thyroid autoantibodies and for genotyping of HLA DRB1, DQA1 and DQB1 by polymerase chain reaction‐based DNA typing techniques.

RESULTS Among 83 patients with IDDM, 23 (27.7%) were positive for antithyroid autoantibodies. Compared to those without thyroid autoimmunity, there was a female preponderance for IDDM with thyroid autoimmunity (female: male, 3:20 vs 29:31). Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients. Upon detailed analysis of class II HLA haplotypes, the DRB1*0301/DQA1*0501/DQB1*0201 haplotype was found to be associated with an increased risk of IDDM regardless of thyroid autoimmunity, while DRB1*0405/DQA1*0301/DQB1*0401 was significantly increased only in the IDDM patients with thyroid autoimmunity. IDDM individuals with the HLA DRB1*0405/DQA1*0301/DQB1*0302 haplotype were not at risk of thyroid autoimmunity.

CONCLUSIONS Our data indicated that there was a generalized genetic factor within or associated with the DRB1*0301/DQA1*0501/DQB1*0201 haplotype, and a more restricted effect with the DRB1*0405/DQA1*0301/DQB1*0401 haplotype which led to thyroid autoimmunity in patients with insulin‐dependent diabetes mellitus.
Growth hormone, insulin‐like growth factor I and its binding proteins 1 and 3 in last trimester intrauterine growth retardation with increased pulsatility index in the umbilical artery
Authors: Larsen Torben , Main Katharina , Andersson Anne Marie , Juul Anders , Greisen Gorm , Skakkebæk Niels Erik
Published: November 2003

OBJECTIVE The interrelationships between maternal hormone levels and placental dysfunction in mothers bearing children with intrauterine growth retardation remain unclear. We have examined some endocrinological aspects of intrauterine growth retardation and, in particular, tested whether low levels of GH and IGF‐ I in maternal serum are associated with direct evidence of placental dysfunction.

DESIGN Prospective, descriptive and comparative.

PATIENTS Women with singleton pregnancies: 48 with a small for gestation fetus (SGA) (estimated fetal weight less than −1.5 standard deviation scores) and 28 with an appropriate for gestation fetus (AGA).

MEASUREMENTS Maternal serum GH, IGF‐I, IGFBP‐1 and 3 were determined, and fetal weight and umbilical artery pulsatility index (PI) was estimated by ultrasonography and Doppler ultrasound at 33 weeks gestational age.

RESULTS Serum IGF‐I was lower in the SGA group (246  vs 297 μg/l, P = 0.03) but GH and IGFBP‐1 and ‐3 did not differ between the groups. In the 16 SGA pregnancies with increased PI, IGF‐I concentration was low (218 μg/l, quartiles 149–265), whereas in the 32 with normal PI, IGF‐I was 269 μg/l, quartiles 219–382. Serum IGFBP‐1 was increased in the high PI group compared to the normal PI group (161 μg/l vs 113, P = 0.05).

CONCLUSION M aternal serum IGF‐I concentration was lower in small for gestational age pregnancieswith increased pulsatility of the umbilical artery blood flow, compared to small for gestational age pregnancies with normal umbilical blood flow, which in turn was close to the IGF‐I concentration in appropriate for gestational age pregnancies. Growth hormone concentrations did not differ among the groups.
Serum levels of insulin‐like growth factor I and insulin‐like growth factor‐binding protein 1 correlate with serum free testosterone and sex hormone binding globulin levels in healthy young and middle‐aged men
Authors: Erfurth Eva Marie , Hagm ar Lars , Sääf Maria , Hall Kerstin
Published: November 2003

OBJECTIVE Administration of testosterone has been reported to increase serum levels of IGF‐I in men with isolated hypogonadotrophic hypogonadism. An inverse relation between serum IGF‐I and sex hormone binding globulin (SHBG) is seen in GH deficient children. The biological action of IGF‐I is thought to be influenced by binding proteins, one of which is insulin‐like growth factor‐binding protein‐1 (IGFBP‐1), which is not only a carrier protein but also actively regulates the cellular actions of IGF‐I. These observations suggest associations between IGF‐I, IGFBP‐1, testosterone and SHBG in serum. The aim of the present study was to investigate these associations in normal healthy men.

DESIGN AND PATIENTS The associations between the serum levels of IGF‐I and IGFBP‐1 on one hand, and testosterone and SHBG on the other were investigated in 38 normal healthy young and middle‐aged men.

RESULTS Serum levels of IGF‐I decreased both with increasing age (r = − 0.66, P < 0.001) and increasing SHBG levels (r = − 0.46, P = 0.002), but increased with increasing free testosterone (f‐testosterone) (r = 0.42, P = 0.005). These associations remained after mutual simultaneous adjustments in a multiple regression analysis. IGFBP‐1 did not display any significant univariate correlation with age (r = − 0.25, P = 0.06) or SHBG (r = 0.18, P = 0.14), but showed a significant positive correlation with both f‐testosterone (r = 0.42, P = 0.004), and total testosterone (t‐testosterone) (r = 0.39, P = 0.008). In a multiple regression analysis IGFBP‐1 was positively correlated with both SHBG and f‐testosterone, but not with t‐testosterone.

CONCLUSION The present study suggests that among healthy young and middle‐aged men, there is an association between serum levels of free‐testosterone and SHBG on the one hand, and serum IGF‐I and IGFBP‐1 on the other.
Predicting the growth response to growth hormone in patients with intrauterine growth retardation
Authors: Frank Graeme R. , Cheung Pik‐To , Horn Jo Ann , Alfaro Mary Pat , Smith Eric P. , Chernausek Steven D.
Published: November 2003

OBJECTIVE Human GH treatment of short children who had intrauterine growth retardation (IUGR) results in a highly variable growth response. The object of this study was to test the hypothesis that differences in responsiveness to exogenously administered GH might reflect differences in endogenous GH secretion or sensitivity.

DESIGN Prospective study evaluating the growth response to GH therapy in short individuals with prior IUGR.

PATIENTS Ten short, prepubertal children with prior IUGR were studied. Mean age was 6 years (3.39–8.61). Mean bone age was 4.6 years (2.3–8.3). Mean body mass index was 13.2 kg/m2 (9.9–14.0; normal 13.5–19.0).

MEASUREMENTS  Overnight spontaneous GH release was measured using a constant withdrawal pump and stimulated GH release was measured following clonidine (0.15 mg/m2) administration. IGF‐I concentrations were measured at baseline and 12, 24, 36 and 48 hours after sequential doses of GH (0.05 and 0.2 mg/kg/dose) given 48 hour apart. Patients were treated with GH (0.125 mg/kg three times a week) and growth response was assessed. In the second and third year, attempts were made to improve the growth rate by nutritional supplementation and increasing the dose of GH to 0.25 mg/kg three times a week.

RESULTS All patients had normal integrated nocturnal GH secretion (>3 μg/l, 6mU/l) and normal peak GH secretion in response to clonidine (>7 μg/l). In the first year of the trial, mean growth velocity (GV) increased from 5.39 cm/year ± 0.29 to 7.32 cm/year ± 0.39 (P = 0.004). Changes in GV correlated inversely with integrated GH (r = − 0.69; P = 0038), baseline IGF‐I concentration (r =  − 0.88; P = 0.002) and baseline GV‐SDS (r =  − 0.68; P =  0.043). There was no correlation between change in GV and GH binding protein, baseline height SDS or age. The effect of GH waned in the second year, but tended to remain greater than the pretreatment growth rate (6.54 ± 0.49 vs 5.53 cm/year ± 0.29; P  = 0.09). No significant advancement of bone age over chronological age was observed over the first 2 years. Increasing nutritional intake by 17% did not result in significant weight gain nor increase in height velocity. Doubling the dose of GH in the second or third year did not result in a significant increase in GV.

CONCLUSION  The variable response to GH therapy in short children with a history of intrauterine growth retardation may partly reflect relative sufficiency or insufficiency of GH. Baseline IGF‐I levels and baseline growth velocity appear to be useful and practical predictors of response to GH.
Accelerated bone loss in post‐menopausal women with mild primary hyperparathyroidism
Authors: Grey Andrew B. , Stapleton Joanne P. , Evans Margaret C. , Reid Ian R.
Published: November 2003

OBJECTIVES Osteopenia is regarded as an indication for parathyroidectomy in primary hyperparathyroidism. However, uncertainty exists as to the extent and degree of the skeletal effects in those with mild disease. We sought to determine whether mild primary hyperparathyroidism affects the rate of bone loss in post‐menopausal women.

DESIGN Prospective 2‐year comparison of rates of bone loss throughout the skeleton in 17 post‐menopausal women with untreated mild asymptomatic primary hyperparathyroidism, and 48 age‐matched, eucalcaemic controls.

RESULTS The women with primary hyperparathyroidism had a greater annual rate of loss of bone mineral density (BMD) of the total body (mean ± SE, primary hyperparathyroidism −1.15 ± 0.31%, controls −0.39 ± 0.10%; P = 0.04) and its spine subregion (primary hyperparathyroidism −2.08 ± 0.88%, controls 0.04 ± 0.35%; P = 0.02). Lumbar spine BMD tended to decline in the primary hyperparathyroidism group (−0.35 ± 0.33%) in contrast to the control group (+ 0.28 ± 0.22%) (P = 0.10). There were no significant differences between the groups in rates of change of BMD in the legs or the proximal femur. In the primary hyperparathyroidism group, the rate of total body bone loss in the eight women known at study entry to have had long‐standing (>5 years) primary hyperparathyroidism was −1.52 ± 0.61%/year, similar to that of the whole group.

CONCLUSION Primary hyperparathyroidism is associated with an increased rate of loss of total body bone mineral density in post‐menopausal women. Prolonged disease duration is therefore likely to be associated with an increasing risk of osteopenia, such that skeletal surveillance and interventions designed to reduce bone loss should be considered.
Adrenal autoantibodies and organ‐specific autoimmunity in patients with Addison's disease
Authors: Söderbergh A. , Winqvist O. , Norheim I. , Rorsman F. , Husebye E. S. , Dolva Ø. , Karlsson F. A. , Kämpe O.
Published: November 2003

OBJECTIVE Autoimmune destruction of the adrenal gland is the major cause of idiopathic Addison's disease, but the significance of 21‐hydroxylase autoantibodies and their correlation with the presence of other autoantibodies have not so far been investigated in a larger population of patients with Addison's disease. We have now characterized a cohort of patients with idiopathic Addison’s disease (n=97) regarding the specificity of autoantibodies against the adrenal cortex and, as Addison's disease can be either an isolated condition or part of a polyendocrine disorder, we investigated the presence of organ‐specific polyendocrine autoimmunity in this patient population.

DESIGN Cross‐sectional study.

MEASUREMENTS Autoantibodies were analysed with indirect immunofluoresence (IF) on tissue preparations, ELISA and in Western blots using bacterially expressed proteins.

RESULTS Eighty‐four per cent (81/97) of the patient sera recognized the steroid‐producing cells of the adrenal cortex in indirect IF. The antigen was identified as 21‐hydroxylase by 72% (70/97) of the patient sera in Western blots. Seven sera that were negative on adrenocortical IF identified 21‐hydroxylase on Western blot, while eight IF‐positive sera were 21‐hydroxylase‐negative. Five sera weakly recognized 17α‐hydroxylase in Western blots, but all of these were also positive for 21‐hydroxylase. In 13 cases (12 women), the sera also reacted with testicular Leydig cells, and nine of these identified the side‐chain cleavage (SCC) enzyme. Other clinically evident organ‐specific autoimmune disorders were present in 40% of the 97 patients and abnormal titres of organ‐specific antibodies were found in 60% of the patients.

CONCLUSIONS In idiopathic Addison's disease, autoantibodies against 21‐hydroxylase are found in a majority of cases and this represents an important diagnostic tool. The enzyme 17α‐hydroxylase does not seem to constitute a major autoantigen in Addison's disease. In a subgroup of patients with autoantibodies to gonads, antibodies to SCC are produced, often in parallel with antibodies to 21‐hydroxylase. In yet another subgroup the specificity of autoantibodies giving positive immunofluorescence is still unknown. Three patients revealed a polyendocrine syndrome which clinically resembles autoimmune polyendocrine syndrome (APS) type I, but serologically corresponds to APS type II. Polyendocrine disorders are often associated with Addison's disease, and screening, including quantification of autoantibodies, may help to identify those at risk of developing associated autoimmune disorders.
Granulomatous hypophysitis associated with Takayasu's disease
Authors: Tóth M. , Szabó P. , Rácz K. , Szende B. , Balogh I. , Czirják S. , Slowik F. , Gláz E.
Published: November 2003

We report a case of Takayasu's disease, presenting with symptoms of fever, anaemia, elevated erythrocyte sedimentation rate, anterior pituitary failure and mild diabetes insipidus. A pituitary mass with suprasellar extension mimicking a pituitary adenoma was found, and histological examination revealed granulomatous hypophysitis. The diagnosis of Takayasu's disease was established after the development of a multiple arterial occlusive disease. We suggest that Takayasu's disease should be considered in the differential diagnosis of granulomatous hypophysitis of unknown origin.
Clinical examination is not an accurate method of defining the presence of goitre in schoolchildren
Authors: Lisbôa Hugo R. K. , Gross Jorge L. , Orsolin Ademir , Fuchs Sandra
Published: November 2003

OBJECTIVE There are few published data on thyroid size and body size variables in children. We aimed to develop an index for normal thyroid size in schoolchildren using ultrasonography and to evaluate the accuracy of clinical examination in the diagnosis of goitre.

DESIGN A study to screen and diagnose goitre

SUBJECTS A population based sample of 1094 schoolchildren aged 6–14 years (556 boys and 538 girls) were submitted to clinical examination of the thyroid. One hundred and nineteen were considered to have goitre. Ultrasonography was performed in 85 who agreed to participate in the study and in 62 schoolchildren selected randomly from those thought to have no goitre.

MEASUREMENTS Clinical examination and definition of goitre were performed according to WHO criteria. Thyroid volume was measured by ultrasonography (7.5 MHz transducer).

RESULTS The gland volume of 62 schoolchildren without goitre on clinical examination showed a positive correlation with body surface area, age and skinfold thickness. When these factors were entered in multiple regression analysis, only body surface area remained associated with thyroid volume. The upper limit (95th percentile) of the ratio of thyroid volume to body surface area (Ecobody index) was 6.2 ml/m2. Taking this index as the standard criterion, the performance parameters of clinical examination for the detection of goitre in the 1094 schoolchildren were: sensitivity 41%, specificity 91%, positive predictive value 27% and negative predictive value 95%.

CONCLUSIONS Clinical examination of the thyroid is unreliable in establishing the presence of goitre in schoolchildren because it tends to overestimate thyroid size. Nevertheless, it can be used as a screening test. Ultrasonography should be performed when the thyroid gland is thought to be enlarged.
Divergence between growth hormone responses to insulin‐induced hypoglycaemia and growth hormone‐releasing hormone in patients with non‐functioning pituitary macroadenomas and hyperprolactinaemia
Authors: Beentjes John A.M , Tjeerdsma Geert , Sluiter Wim J. , Dullaart Robin P.F.
Published: November 2003

OBJECTIVE The GH responses to the insulin tolerance test (ITT) and growth hormone‐releasing hormone (GHRH) may yield different results in patients with pituitary lesions. The GH responses to these stimuli were compared in patients with untreated non‐functioning pituitary macroadenomas, who represent an important cause of GH deficiency.

DESIGN Analysis of peak GH to ITT and to 100 μg GHRH in relation to an elevated PRL level (> 200 mIU/l for males and > 600 mIU/l for females) as an indication of hypothalamic‐pituitary dysregulation, as well as in relation to other anterior pituitary hormone deficiencies. A peak GH < 5 μg/l in either test indicated GH deficiency.

PATIENTS Twenty females and 14 males (median age 52 (23−77) years) evaluated preoperatively in a university hospital setting.

RESULTS In the whole group the median peak GH to GHRH (3.6 (0.9−26.3) μg/l) was higher than to ITT (1.6 (0.2−7.8) μg/l, P < 0.001). This difference was seen only in 19 patients with concomitant hyperprolactinaemia (P < 0.001). When hyperprolactinaemia was present, an insufficient GH peak was demonstrated by ITT in 16 cases and by GHRH stimulation in 7 cases (P < 0.01). The frequency of an insufficient GH peak by ITT (13 cases) and by GHRH (14 cases) was similar in the normoprolactinaemic patients. In addition, 9 of 10 patients with an impaired response to ITT and a normal response to GHRH were hyperprolactinaemic compared to 7 of 19 patients with GH deficiency as assessed by both stimuli (P < 0.02). Peak GH to ITT was lower in 24 patients with, compared to 10 patients without, other hormonal deficiencies (1.4 (0.2−5.6) vs 3.0 (1.0−7.8) μg/l, P < 0.02), but was not related to elevated PRL. In contrast, GHRH‐stimulated GH was higher in hyperprolactinaemic than in normoprolactinaemic patients (5.9 (1.6−26.3) vs 2.9 (0.9−5.4) μg/l, P < 0.001) and was not related to the presence of other pituitary hormone deficiencies. Analysis of covariance confirmed that peak GH to ITT was negatively associated with the presence of other pituitary hormone deficiencies (P < 0.01), whereas peak GH to GHRH was positively related to an elevated PRL level (P < 0.02). Basal GH was positively correlated with PRL (Rs = 0.36, P < 0.05).

CONCLUSIONS This study demonstrates that ITT and GHRH tests cannot be used interchangeably in diagnosing GH deficiency in patients with non‐functioning pituitary macroadenoma and hyperprolactinaemia. If the ITT is considered to be the reference test, GH deficiency as assessed by GHRH can be missed in patients with hyperprolactinaemia. This disparity is probably due to a different mechanism of action of these stimuli. Hyperprolactinaemia may be associated with a diminished somatostatin tone, leading to a higher basal and GHRH‐stimulated GH, without having an effect on peak GH to ITT.
Oral prednisolone supplement abolishes the acute adverse effects following initiation of depot bromocriptine therapy
Authors: Jenkins Paul J. , Jain Ajay , Jones Sharon L. , Besser G. M. , Grossman A. B.
Published: November 2003

OBJECTIVE Although an effective treatment for hyperprolactinaemia, initiation of bromocriptine therapy may be associated with significant acute side‐effects in some patients, particularly nausea, vomiting and postural hypotension. These may be minimized by initial treatment with i.m. depot bromocriptine (Parlodel‐LAR, Sandoz, Basel, Switzerland), but adverse effects following the first injection may still be a significant problem. Following the observation that cortisol deficient patients were subject to an increased incidence of severe side‐effects on initiation of bromocriptine therapy, we have evaluated whether concurrent administration of oral prednisolone to patients without cortisol deficiency might reduce adverse effects.

DESIGN Double‐blind placebo‐controlled trial with prednisolone (20 mg) prior to, and 16 hours after, depot injection of i.m. bromocriptine (50 or 100 mg).

PATIENTS Twenty‐one consecutive patients with hyperprolactinaemia (serum prolactin >1000 mU/l on 3 separate occasions) who were due to start depot bromocriptine and who had a normal cortisol response to insulin‐induced hypoglycaemia.

MEASUREMENTS Symptoms at 0, 16 and 40 hours after injection were assessed using visual linear analogue scales and both inter and intra‐group scores were compared by non‐parametric tests.

RESULTS Depot bromocriptine was associated with the significant occurrence of light‐headedness and lethargy in the placebo‐administered group by 16 hours, and also with nausea and nasal congestion by 40 hours. These symptoms did not occur in the prednisolone‐administered group.

CONCLUSIONS Concurrent oral administration of prednisolone significantly reduces the incidence of acute adverse effects following depot bromocriptine. Two 20 mg doses of prednisolone given at 12‐hour intervals may be used to avoid dopamine‐agonist‐induced adverse effects at the initiation of treatment with depot bromocriptine, and may also be of value in the treatment of side‐effects associated with other dopamine agonist drugs.
Body composition in growth hormone deficient adults over the age of 60 years
Authors: Toogood Andrew A , Adams Judith E , O'Neill Paul A , Shalet Stephen M
Published: November 2003

OBJECTIVE Elderly patients with hypothalamic‐pituitary disease exhibit a reduction in GH secretion distinct from the decline in GH secretion related to age. GH deficiency in young adults causes a change in body composition, with increased fat mass (FM) and reduced fat free mass (FFM), similar to that seen as a result of the normal ageing process. The aim of this study was to determine whether organic GH deficiency in elderly patients may cause changes in body composition beyond those due to ageing.

SUBJECTS Twenty‐one patients (15 male) with documented pituitary disease and 24 controls (17 male) matched for age, height, weight and BMI, all over the age of 60, in whom GH status had been defined by a 24‐hour GH profile and an arginine stimulation test.

MEASUREMENTS Serum was taken for fasting IGF‐I and IGFBP‐1 estimations. Total and regional FM and FFM were determined using dual‐energy X‐ray absorptiometry.

RESULTS FM (median (range)) was increased in the patients, 27.76 (19.25–50.24) vs 21.23 (8.81–49.15) kg in the controls (P < 0.005). FM was significantly increased in the arms, legs and trunk in the patients compared with the controls. The proportion of fat deposited centrally did not differ significantly between the two groups (57.0% (47.6–65.1) in the patients vs 55.3% (44.1–63.8) in the controls, P = 0.25). There was an inverse relation between total FM and serum IGFBP‐1 present in the patients, ρ = −0.632, P < 0.005, and in the controls ρ = −0.467, P < 0.05, but the relation between total FM and area under the GH profile was significant only in the controls (ρ = −0.651, P < 0.001) and not in the patients.

FFM (51.19 (26.96–69.18) kg in the patients vs 51.55 (32.35–60.53) kg in the controls, P = 0.99) and serum IGFBP‐1 levels did not differ significantly between the two groups.

CONCLUSION Organic growth hormone deficiency causes changes in body composition beyond the changes associated with the ageing process. These changes differ from those seen in younger GH deficient adults in that they are limited to an increase in FM with no change in FFM. These findings indicate that even in the elderly, in whom GH secretion is normally very low, the additional imposition of GH deficiency due to organic disease has significant biological impact.
Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure
Authors: Sheaves R. , Jenkins P. , Blackburn P. , Huneidi A. H. , Afshar F. , Medbak S. , Grossman A. B. , Besser G. M. , Wass J. A. H.
Published: November 2003

OBJECTIVE Previous studies of surgical treatment for acromegaly have used varied criteria for ‘cure’, but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer‐term outcome for patients not offered further treatment when post‐operative levels of GH < 5 mU/l were achieved.

DESIGN We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew’s Hospital between 1985 and 1993.

PATIENTS One hundred consecutive patients (53 male, mean age 46 years, range 18–68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5–8 years) after operation.

MEASUREMENTS GH levels are represented as a mean value from a four‐point day curve taken at 0830, 1300, 1700 and 1900h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured.

RESULTS Post‐operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post‐operative GH values < 5mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post‐operative GH levels of < 5 mU/l. Of the 42 patients considered in remission postoperatively (mean GH < 5 mU/l), 32 were available for long‐term follow‐up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow‐up of 3.8 years (range 0.5–8).  There were no peri‐operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post‐operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted.

CONCLUSIONS The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post‐operative GH < 5 mU/l are achieved.
Clinical and biochemical investigations and molecular analysis of subjects with mutations in the androgen receptor gene
Authors: Weidemann Wolfgang , Linck Birgit , Haupt Heike , Mentrup Birgit , Romalo Gabriela , Stockklauser Karin , Brinkmann Albert O. , Schweikert Hans‐Udo , Spindler Klaus‐Dieter
Published: November 2003

OBJECTIVE Androgen insensitivity syndromes (AIS) in subjects with 46,XY karyotype and normal or even elevated androgen blood levels are characterized by various aberrations in male differentiation and virilization. AIS is often accompanied by a broad spectrum of abnormal binding characteristics of the androgen receptor (AR). In order to investigate the correlation between the degree of virilization defect and the type of androgen binding abnormalities and/or the nature of the mutation in the AR gene, we determined androgen binding characteristics of the AR protein and the sequence of the AR gene in clinically and biochemically well characterized patients with various degrees of androgen resistance.

DESIGN AND PATIENTS The activity of 5α‐reductase and the binding of androgen to its receptor (KD‐values, Bmax, thermolability) were determined in genital skin fibroblasts from 20 patients with various degrees of defects in virilization (2 CAIS, complete AIS; 18 PAIS, partial AIS patients). The AR gene of these 20 subjects was characterized by PCR‐SSCP analysis. In case of aberrant electrophoretic mobility the corresponding exon was sequenced.

RESULTS The 2 patients with CAIS and 7 with PAIS showed a mutation in the AR gene. In two, the mutation was in the DNA binding domain, and in all others in the ligand binding domain. In 11 patients with severe virilization defects no abnormal behaviour was detected in the PCR‐SSCP. Transcriptional activation studies of two mutant ARs revealed that an approximately tenfold higher androgen concentration (methyltrienolone) is necessary to achieve maximal response as compared to the wild type AR.

CONCLUSIONS There is no obvious relation between the degree of androgen resistance and the binding parameters of the AR and/or the nature of mutation in the AR gene. Androgen insensitivity syndrome can occur despite normal androgen binding and presumably non‐mutated AR genes. Even if there is abnormal binding of androgen and/or a mutation in the AR gene there is no clear‐cut relationship between these parameters and the degree of virilization defects. Thus, in a proportion of patients, neither the determination of binding parameters of the AR nor the detection of mutations in the AR gene are sufficient to understand the mechanisms underlying the androgen insensitivity syndrome.
Effects of oral and transdermal oestrogen replacement therapy on plasma levels of insulin‐like growth factors and IGF binding proteins 1 and 3: a cross‐over study
Authors: Helle S. I. , Omsjø I. H. , Cwyfan Hughes S. C. , Botta L. , Hüls G. , Holly J. M. P. , Lønning P. E.
Published: November 2003

OBJECTIVE Conflicting results have been reported on the effects of oral and transdermal oestrogen replacement therapy on IGF‐I, while little information exists regarding the effects on IGFBP ‐1 and ‐3. In this study we evaluated the effects of oral and transdermal oestrogens on these parameters in post‐menopausal women in a randomized cross‐over study.

PATIENTS A group of 14 post‐menopausal women were randomized to receive progestin‐opposed oestrogen replacement therapy administered orally (Trisekvens Novo: 17β‐oestradiol 2 mg daily on days 1–22 and 1 mg daily on days 23–28, norethisterone 1 mg days 13–22) or transdermally (Estracomb CIBA: oestradiol 50 μg/24 h on days 1–28, norethisterone 250 μg/24 h on days 15–28) for 6 months after which they were crossed over to the alternative treatment option. Fasting blood samples were obtained before treatment, and after 3, 6, 9 and 12 months on treatment.

MEASUREMENTS IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐3, oestradiol and norethisterone were analysed by radioimmunoassays. In addition, IGFBPs were evaluated with Western ligand blots (WLB) in a subgroup of 12 patients.

RESULTS Plasma levels of oestradiol were not significantly different during oral and transdermal treatment. Norethisterone levels were below the detection limit in all situations in 8 patients, while 6 patients had detectable levels in one or several samples during treatment. Oral treatment caused a significant decrease (16%, P<0.005) in IGF‐I and a non‐significant decrease in IGFBP‐3. A similar effect was observed when samples containing detectable levels of norethisterone were excluded from the analysis. No significant effect on IGFBP‐1 was observed when all samples were included in the analysis. However, when samples with detectable norethisterone were excluded IGFBP‐1 increased by 46% (P<0.01) during oral therapy. Contrary, transdermal treatment with oestrogens did not influence any of the parameters measured. None of the treatments had any effect on plasma IGF‐II levels or IGFBP profile evaluated by WLB.

CONCLUSIONS Treatment with oral hormone replacement therapy significantly suppresses plasma IGF‐I levels and increases plasma IGFBP‐1 while transdermal treatment had no influence. This may be due to the route of administration, as plasma oestradiol levels showed little difference between the groups. The effect of oral oestrogens on IGFBP‐1 seems to be attenuated by progestins.
Expression of RANTES mRNA in skin lesions of feline eosinophilic plaque
Authors: Kimura Tomoe , Kano Rui , Maeda Sadatoshi , Tsujimoto Hajime , Nagata Masahiko , Hasegawa Atsuhiko
Published: November 2003

Abstract One of the mechanisms of eosinophil infiltration is its induction by chemoattractants such as regulated upon activation, normal T‐expressed and secreted (RANTES) which is a cysteine–cysteine chemokine that mediates chemotaxis and activation of eosinophils in humans and mice. Skin lesions of feline eosinophilic plaque are characterized by a predominant infiltration of eosinophils. The mechanism(s) of eosinophilic infiltration in the skin and/or mucosa of cats is unknown. It is possible that RANTES is involved. To investigate the presence of RANTES in the skin of cats with eosinophilic plaques and nonaffected skin, we cloned and sequenced the full‐length feline RANTES cDNA gene, in order to determine whether it is present in the skin of cats with eosinophilic plaques and/or if it is present in normal adjacent skin. We were able to document the the expression of RANTES mRNAs in skin with feline eosinophilic plaque as well as in normal cat skin. The full‐length cDNA sequence of the RANTES gene (742 bp) contained a single open reading frame of 276 bp encoding a protein of 92 amino acids. The amino acid sequence of feline RANTES shared 67 and 74% sequence identity with that of bovine and mouse RANTES genes, respectively. RT–PCR analysis on RANTES mRNA in the skin of cats with eosinophilic plaque revealed that its expression was higher in the eosinophilic plaque skin lesions than in the normal skin. The result suggested that RANTES might play a role to induce eosinophil infiltration in feline eosinophilic plaque lesions.
A novel mannitol teichoic acid with side phosphate groups of Brevibacterium sp. VKM Ac‐2118
Authors: Potekhina Natalia V. , Shashkov Alexander S. , Evtushenko Lyudmila I. , Gavrish Ekaterina Yu. , Senchenkova Sofya N. , Stomakhin Andrey A. , Usov Anatolii I. , Naumova Irina B. , Stackebrandt Erko
Published: November 2003

The cell wall of Brevibacterium sp. VKM Ac‐2118 isolated from a frozen (mean annual temperature −12 °C) late Pliocene layer, 1.8–3 Myr, Kolyma lowland, Russia, contains mannitol teichoic acid with a previously unknown structure. This is 1,6‐poly(mannitol phosphate) with the majority of the mannitol residues bearing side phosphate groups at O‐4(3). The structure of the polymer was established by chemical methods, NMR spectroscopy, and MALDI‐TOF mass spectrometry.
Regulation of ascidian Rel by its alternative splice variant
Authors: Kawai Narudo , Shimada Masumi , Kawahara Hiroyuki , Satoh Noriyuki , Yokosawa Hideyoshi
Published: November 2003

The Rel/NF‐κB family of transcription factors play key roles in morphogenesis and immune responses. We reported previously that As‐rel1 and As‐rel2 of the ascidian Halocynthia roretzi are involved in notochord formation. The As‐rel1 protein is a typical Rel/NF‐κB family member, whereas the As‐rel2 protein is a novel truncated product of As‐rel1 that lacks a nuclear localization signal and the unique C‐terminal region. Here, we present conclusive evidence that As‐rel1 and As‐rel2 are generated from a single gene by alternative splicing. We analyzed the roles of As‐rel2 using cells transfected with As‐rel1 or As‐rel2 or both. As‐rel1 was localized in the nucleus and As‐rel2 in the cytoplasm when they were transfected individually. In contrast, when they were transfected simultaneously, both were localized in the nucleus because of the association of As‐rel2 with As‐rel1. In this case, the transcriptional activity of As‐rel1 was suppressed by As‐rel2. Ascidian IκB was found to sequester As‐rel1 in the cytoplasm and suppress its transcriptional activity when As‐rel1 and IκB were transfected simultaneously. In contrast, when As‐rel1 and IκB were transfected together with As‐rel2, As‐rel1 was transported into the nucleus and its transcriptional activity was rescued from inhibition by IκB, whereas As‐rel2 remained localized in the cytoplasm, suggesting IκB sequestration in the cytoplasm by As‐rel2. From these findings, we conclude that the alternative splice variant, As‐rel2, regulates the nuclear localization and transcriptional activity of As‐rel1.
Transphosphatidylation activity of Streptomyces chromofuscus phospholipase D in biomimetic membranes
Authors: El Kirat Karim , Prigent Annie‐France , Chauvet Jean‐Paul , Roux Bernard , Besson Françoise
Published: November 2003

The phospholipase D (PLD) from Streptomyces chromofuscus belongs to the superfamily of PLDs. All the enzymes included in this superfamily are able to catalyze both hydrolysis and transphosphatidylation activities. However, S. chromofuscus PLD is calcium dependent and is often described as an enzyme with weak transphosphatidylation activity. S. chromofuscus PLD‐catalyzed hydrolysis of phospholipids in aqueous medium leads to the formation of phosphatidic acid. Previous studies have shown that phosphatidic acid–calcium complexes are activators for the hydrolysis activity of this bacterial PLD. In this work, we investigated the influence of diacylglycerols (naturally occurring alcohols) as candidates for the transphosphatidylation reaction. Our results indicate that the transphosphatidylation reaction may occur using diacylglycerols as a substrate and that the phosphatidylalcohol produced can be directly hydrolyzed by PLD. We also focused on the surface pressure dependency of PLD‐catalyzed hydrolysis of phospholipids. These experiments provided new information about PLD activity at a water–lipid interface. Our findings showed that classical phospholipid hydrolysis is influenced by surface pressure. In contrast, phosphatidylalcohol hydrolysis was found to be independent of surface pressure. This latter result was thought to be related to headgroup hydrophobicity. This work also highlights the physiological significance of phosphatidylalcohol production for bacterial infection of eukaryotic cells.
Identification of CD4 and transferrin receptor antibodies by CXCR4 antibody‐guided Pathfinder selection
Authors: Sui Jianhua , Bai Jirong , St. Clair Tallarico Aimee , Xu Chen , Marasco Wayne A
Published: November 2003

To generate human antibodies against CXCR4, a seven‐transmembrane chemokine receptor and a principal coreceptor for HIV‐1, several rounds of Pathfinder and Step‐back selection from a large phage display antibody library were performed on Jurkat cells. A mAb against CXCR4 or biotinyated phage antibodies were used as guide molecules. Over 100 pan‐Jurkat‐cell‐positive antibodies were characterized, but none were CXCR4 specific. However, several antibodies against CD4 and the transferrin receptor were identified. Our results indicate that, although Pathfinder and Step‐back selection can be used to select phage antibodies on whole cells, the successful selection of certain targets is still complex and limited. The reason is probably, in part, due to the inaccessibility of the targeted extracellular structures and the range of the horseradish peroxidase‐labeled guide molecule. Refinements of these techniques are required to improve target specificity and selectivity.
Comparative importance in vivo of conserved glutamate residues in the EX7E motif retaining glycosyltransferase Gpi3p, the UDP‐GlcNAc‐binding subunit of the first enzyme in glycosylphosphatidylinositol assembly
Authors: Kostova Zlatka , Yan Benjamin C. , Vainauskas Saulius , Schwartz Roberta , Menon Anant K. , Orlean Peter
Published: November 2003

Saccharomyces cerevisiae Gpi3p is the UDP‐GlcNAc‐binding and presumed catalytic subunit of the enzyme that forms GlcNAc‐phosphatidylinositol in glycosylphosphatidylinositol biosynthesis. It is an essential protein with an EX7E motif that is conserved in four families of retaining glycosyltransferases. All Gpi3ps contain a cysteine residue four residues C‐terminal to EX7E. To test their importance for Gpi3p function in vivo, Glu289 and 297 in the EX7E motif of S. cerevisiae Gpi3p, as well as Cys301, were altered by site‐specific mutagenesis, and the mutant proteins tested for their ability to complement nonviable GPI3‐deleted haploids. Gpi3p‐C301A supported growth but membranes from C301A‐expressing cells had low in vitro N‐acetylglucosaminylphosphatidylinositol (GlcNAc‐PI) synthetic activity. Haploids harboring Gpi3p‐E289A proved viable, although slow growing but Gpi3‐E297A did not support growth. The E289D and E297D mutants both supported growth at 25 °C, but, whereas the E289D strain grew at 37 °C, the E297D mutant did not. Membranes from E289D mutants had severely reduced in vitro GlcNAc‐PI synthetic activity and E297D membranes had none. The mutation of the first Glu in the EX7E motif of Schizosaccharomyces pombe Gpi3p (Glu277) to Asp complemented the lethal null mutation in gpi3+ and supported growth at 37 °C, but the E285D mutant was nonviable. Our results suggest that the second Glu residue of the EX7E motif in Gpi3p is of greater importance than the first for function in vivo. Further, our findings do not support previous suggestions that the first Glu of an EX7E protein is the nucleophile and that Cys301 has an important role in UDP‐GlcNAc binding by Gpi3ps.
Unraveling the catalytic mechanism of lactoperoxidase and myeloperoxidase
Authors: Ghibaudi Elena , Laurenti Enzo
Published: November 2003

Although belonging to the widely investigated peroxidase superfamily, lactoperoxidase (LPO) and myeloperoxidase (MPO) share structural and functional features that make them peculiar with respect to other enzymes of the same group. A survey of the available literature on their catalytic intermediates enabled us to ask some questions that remained unanswered. These questions concern controversial features of the LPO and MPO catalytic cycle, such as the existence of Compound I and Compound II isomers and the identification of their spectroscopic properties. After addressing each of these questions, we formulated a hypothesis that describes an integrated vision of the catalytic mechanism of both enzymes. The main points are: (a) a re‐evaluation of the role of superoxide as a reductant in the catalytic cycle; (b) the existence of Cpd I isomers; (c) reciprocal interactions between catalytic intermediates and (d) a mechanistic explanation for catalase activity in both enzymes.