bluuebunny/crossref_metadata_2025 huggingface dataset:
Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene
Authors: Hiroi N. , Yakushiji F. , Shimojo M. , Watanabe S. , Sugano S. , Yamaguchi N. , Miyachi Y.
Published: June 2003

OBJECTIVE

Activating mutations of the ACTH receptor have not been previously described. We investigated a 69‐year‐old woman with normal blood cortisol but undetectable blood ACTH concentrations. The aim of this study was to evaluate her hypothalamo–pituitary–adrenal axis by measuring circadian variation in blood ACTH and cortisol, and by performing CRH and ACTH stimulation and dexamethasone suppression tests. We also examined biological activity of her circulating blood ACTH using bovine adrenocortical cell suspensions and ACTH receptor gene structure by Northern blotting analysis.

RESULTS

Random plasma cortisol concentrations ranged from 182 to 328 nmol/l, while ACTH concentrations were always undetectable. After an intravenous bolus injection of human CRH 100 μg, plasma ACTH rose slightly, while plasma cortisol increased appropriately. ACTH stimulation tests revealed that a small amount of ACTH (5 ng/kg b.w.) had the maximal cortisol stimulatory activity, and even smaller amounts of ACTH (0.5 and 0.05 ng/kg b.w.) produced significant increases in cortisol levels. ACTH bioassay of the patient's plasma demonstrated weak biological activity in the HPLC fractions which corresponded to the band of synthetic human ACTH 1–39. The ACTH receptor coding region was amplified by polymerase chain reaction using the leucocyte genomic DNA. There were two base mutations; cysteine 21 → arginine and serine 247 → glycine in the sequences coding for the first extramembranous N‐terminal domain and the third extramembranous loop of the ACTH receptor.

CONCLUSIONS

This patient with normal blood cortisol but undetectable ACTH levels showed increased adrenocortical sensitivity to ACTH and two point mutations in the ACTH receptor gene. This study, therefore, reports a previously undescribed syndrome—ACTH hypersensitivity syndrome—and provides insights into the molecular mechanism of ACTH receptor action.
The genetics of autoimmune endocrine disease
Authors: Tait Karen F. , Gough Stephen C. L.
Published: June 2003

The common autoimmune endocrinopathies result from an interaction between environmental factors and genetic predisposition. Several chromosomal gene regions have been shown to contribute to more than one disease, supporting the clinical observation that the autoimmune endocrine diseases cluster within individuals and families. Genetic studies have implicated the major histocompatability complex (MHC)‐human leucocyte antigen (HLA) genes on chromosome 6p21, although this chromosomal region does not explain all of the genetic contribution to the various disorders. Non‐MHC‐HLA genes, including disease‐specific loci, are beginning to be identified and the publication of the draft sequence of the human genome will undoubtedly expediate future discoveries. Combined with the establishment of large cohorts of subjects with disease and the development of technology capable of performing high‐throughput genotyping, genetic studies are likely to impact on the future treatment and prevention of the common autoimmune endocrine diseases.
Growth hormone secretory pattern and response to treatment in children with short stature followed to adult height
Authors: Radetti Giorgio , Buzi Fabio , Cassar Walburga , Paganini Claudio , Stacul Elisabetta , Maghnie Mohamad
Published: June 2003

objective To compare the relative utility of GH stimulation tests and assays of spontaneous GH secretion as predictors of change in height standard deviation score at the end of GH treatment in children with short stature.

patients and methods We retrospectively studied 116 children (67 boys and 49 girls) with subnormal growth rates and short stature, defined as a height of more than 2SD below the mean for age and sex. The patients were classified according to their pattern of findings on baseline pharmacological GH stimulation tests and a 12‐h assay of nocturnal spontaneous GH secretion. Twenty‐eight patients (24%) had normal hormone levels by both methods (group I); 14 (12%) had normal levels by stimulation tests but subnormal levels by the physiological assay (group II); 48 (41%) had subnormal levels on pharmacological stimulation, with normal physiologic levels (group III); and 26 (22%) had subnormal levels by both methods (group IV). All children in groups II and IV, and 27 in group III, designated IIIb, were treated with recombinant GH at 0·7 U (0·23 mg/kg) of body weight per week. GH secretory patterns were related to final height SD scores and other growth parameters, after the patients had attained their adult stature 6·7 ± 2·2 years (SD) after GH evaluation.

results The five groups were similar with respect to mean baseline height SD scores for chronological as well as bone age. Whether assessed as absolute or parentally adjusted (relative) values, mean gains in height SD scores were significantly greater in treated patients with physiologicial hormone deficiency (groups II and IV) than in those with normal hormone levels (group I, untreated controls). Relative height gains were 1·03 ± 1·45 cm (6·6 ± 9·28 cm) and 1·85 ± 1·21 cm (SDS; 11·8 ± 7·74 cm) in groups II and IV respectively, compared with only 0·11 ± 0·42 cm (0·7 ± 2·68 cm) in group I (P < 0·01 and P < 0·001). GH treatment failed to improve either the absolute or parentally adjusted final height of patients with GH deficiency by stimulation tests but normal levels by physiological assay.

conclusion Long‐term administration of GH to short children with normal spontaneous GH secretion is not associated with an appreciable increase in adult height.
A novel specific bioassay for the determination of glucocorticoid bioavailability in human serum
Authors: Vermeer H. , Hendriks‐Stegeman B. I. , Van Den Brink C. E. , Van Der Saag P. T. , Van Der Burg B. , Van Buul‐Offers S. C. , Jansen M.
Published: June 2003

objective Some patients develop side‐effects even on relatively low doses of topically administered glucocorticoids (GCs), while others appear to be less sensitive to GCs. We have developed and validated a bioassay which can measure glucocorticoid bioavailability directly from small amounts of human serum to help elucidate underlying mechanisms.

methods We have stably transfected the human embryonic kidney cell line HEK293 with a plasmid expressing the glucocorticoid receptor, and a plasmid containing the luciferase gene preceded by three concatenated steroid response elements, bringing luciferase expression under control of the liganded glucocorticoid receptor.

results The assay, with an intra‐ and interassay coefficient of variance (CV) better than 10%, showed the expected difference in potency between different GCs (fluticasone propionate > budesonide > dexamethasone > hydrocortisone). No cross‐reactivity was detected with other steroid hormones such as progesterone, testosterone and oestradiol. The bioassay easily detects the rise and subsequent fall of bioavailable GCs in human serum following ingestion of only 0·5 mg dexamethasone, and clearly reflects the diurnal cortisol rhythm. Moreover, systemic availability following inhalation of 2 × 250 µg fluticasone propionate using a pressure dose inhaler could be demonstrated.

conclusions This assay can be used to determine levels of bioavailable GCs in serum, both endogenous and administered, and thus may help in optimizing treatment regimens. The small amount of serum needed to perform an analysis makes this assay applicable even to infants.
Diagnostic reliability of a single IGF‐I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency
Authors: Aimaretti G. , Corneli G. , Baldelli R. , Di Somma C. , Gasco V. , Durante C. , Ausiello L. , Rovere S. , Grottoli S. , Tamburrano G. , Ghigo E.
Published: June 2003

objective Within an appropriate clinical context, GH deficiency (GHD) in adults must be demonstrated biochemically by a single provocative test. Insulin‐induced hypoglycaemia (ITT) and GH‐releasing hormone (GHRH) + arginine (ARG) are indicated as the tests of choice, provided that appropriate cut‐off limits are defined. Although IGF‐I is the best marker of GH secretory status, its measurement is not considered a reliable diagnostic tool. In fact, considerable overlap between GHD and normal subjects is present, at least when patients with suspected GHD are considered independently of the existence of other anterior pituitary defects. Considering the time and cost associated with provocative testing procedures, we aimed to re‐evaluate the diagnostic power of IGF‐I measurement.

design To this goal, in a large population [n = 237, 139 men, 98 women, age range 20–80 years, body mass index (BMI) range 26·4 ± 4·3 kg/m2] of well‐nourished adults with total anterior pituitary deficit including severe GHD (as shown by a GH peak below the 1st centile limit of normal response to GHRH + ARG tests and/or ITT) we evaluated the diagnostic value of a single total IGF‐I measurement. IGF‐I levels in hypopituitary patients were evaluated based on age‐related normative values in a large population of normal subjects (423 ns, 144 men and 279 women, age range 20–80 years, BMI range 18·2–24·9 kg/m2).

results Mean IGF‐I levels in GHD were lower than those in normal subjects in each decade, but not the oldest one (74·4 ± 48·9 vs. 243·9 ± 86·7 µg/l for 20–30 years; 81·8 ± 46·5 vs. 217·2 ± 56·9 µg/l for 31–40 years; 85·8 ± 42·1 vs. 168·5 ± 69·9 µg/l for 41–50 years; 82·3 ± 39·3 vs. 164·3 ± 60·3 µg/l for 51–60 years; 67·5 ± 31·8 vs. 123·9 ± 50·0 µg/l for 61–70 years; P < 0·0001; 54·3 ± 33·6 vs. 91·6 ± 53·5 µg/l for 71–80 years, P = ns). Individual IGF‐I levels in GHD were below the age‐related 3rd and 25th centile limits in 70·6% and 97·63% of patients below 40 years and in 34·9% and 77·8% of the remaining patients up to the 8th decade, respectively.

conclusions Total IGF‐I levels are often normal even in patients with total anterior hypopituitarism but this does not rule out severe GHD that therefore ought to be verified by provocative testing of GH secretion. However, despite the low diagnostic sensitivity of this parameter, very low levels of total IGF‐I can be considered definitive evidence of severe GHD in a remarkable percentage of total anterior hypopituitary patients who could therefore skip provocative testing of GH secretion.
Physiological testosterone replacement and arterial endothelial function in men
Authors: Sader Mark A. , Griffiths Kaye A. , Skilton Michael R. , Wishart Susan M. , Handelsman David J. , Celermajer David S.
Published: June 2003

objective The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long‐term physiological androgen replacement therapy, at trough and peak testosterone levels.

patients and design  We recruited nine hypogonadal men (aged 35 ± 4 years) receiving androgen replacement therapy, each treated with 800 mg testosterone (T) depot preparations every 6 months.

measurements Serum lipid and hormone levels and arterial reactivity were measured, prior to (trough T) and 2–4 weeks following testosterone administration (peak T). Each subject therefore served as their own control. Vessel diameter was measured by ultrasound at rest, during reactive hyperaemia [leading to flow‐mediated dilatation (FMD), an endothelium‐dependent response] and after sublingual nitroglycerin (GTN, an endothelium‐independent dilator).

results Serum T (13 ± 2 nmvs. 27 ± 3 nm for trough and peak serum T, respectively, P < 0·001; normal adult male range 11–35 nm), and free T (195 ± 23 pmvs. 510 ± 93 pm, P < 0·005) significantly increased following subcutaneous depot T administration, as did serum oestradiol (100 ± 10 pmvs. 175 ± 9 pm, P = 0·001; normal adult male range < 250 pm). There was a significant decrease in FMD (3·6 ± 1·1%vs. 3·0 ± 0·8%, P < 0·01), but GTN responses were similar (9·5 ± 0·8%vs. 10·4 ± 1·0%, P > 0·2). Lipid, blood pressure and vessel diameter measurements were also similar before and after testosterone administration.

conclusion Physiological replacement of testosterone is associated with decreased endothelium‐dependent dilatation, in hypogonadal men.
The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients
Authors: Di Blasio Anna Maria , Van Rossum Elisabeth F. C. , Maestrini Sabrina , Berselli Maria Elisa , Tagliaferri Mariantonella , Podestà Francesca , Koper Jan W. , Liuzzi Antonio , Lamberts Steven W. J.
Published: June 2003

objective  We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low‐dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity.

design Two hundred and seventy‐nine patients (mean BMI 45·9 ± 0·9 kg/m2) were genotyped using both PCR‐restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype.

results In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2·3%) and had significantly higher BMI (P < 0·04), resting energy expenditure (P < 0·03) and food intake (P < 0·01) when compared to wild‐type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI (P = 0·04), resting energy expenditure (P = 0·03) and food intake (P = 0·008) than obese women with the wild‐type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case–control study with homozygous wild‐type obese subjects which were age‐, sex‐ and BMI‐matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the BclI variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the BclI polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL‐cholesterol levels (P = 0·005 and P = 0·05, respectively).

discussion Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the BclI polymorphism as well, tend to have a slightly unfavourable cardiovascular profile.
Assessment of quality of life in adults receiving long‐term growth hormone replacement compared to control subjects
Authors: Malik I. A. , Foy P. , Wallymahmed M. , Wilding J. P. H. , MacFarlane I. A.
Published: June 2003

objective There are few studies of quality of life (QOL) in adults with growth hormone deficiency (GHD) compared to matched control populations without GHD. These have shown impairments in a variety of QOL measures, which improve but do not normalize after short‐term replacement with GH. There is little information on QOL in long‐term treated GHD patients compared with controls without GHD.

patients and methods A total of 120 adults with GHD who had received GH replacement for at least 1 year were identified from the neuroendocrine clinic. Patients were asked to complete eight QOL questionnaires and an Energy Visual Analogue Scale (VAS). Results were compared with 83 control subjects without GHD from the local population who agreed to complete seven of the QOL questionnaires (excluding Disease Impact scale) and the energy VAS. The eight questionnaires were a combination of generic and disease‐specific questionnaires used to assess health related QOL, namely: Short Form‐36 (SF‐36), Nottingham Health Profile (NHP), Disease Impact, Life Fulfilment and Satisfaction scales, Mental Fatigue Questionnaire (MFQ) and Self Esteem scale, Hospital Anxiety Depression (HAD) scale and QOL‐AGHDA (assessment of GHD in adults).

results Eighty‐nine patients returned questionnaires and 85 (71%) had complete data for analysis. The mean (SD) duration of GH replacement was 36·0 ± 26·4 (range 13–159) months. Mean age was 43·9 ± 15·8 years (37 males) in treated GHD patients compared to a mean age 41·7 ± 10·5 years (32 males) in the controls. Mean IGF‐1 levels were 22·5 ± 13·6 nmol/l in the GHD patients and the mean dose of GH replacement was 1·2 ± 0·4 IU daily. Analysis of the QOL questionnaires from the GH treated patients revealed highly significant impairments in all measures (most P ≤ 0·0001, except life fulfilment‐material, P = 0·33) compared to the control population.

conclusions This large population with treated GH deficiency have significant impairments in multiple aspects of QOL despite replacement with GH and other pituitary hormones for at least 1 year (mean 3 years). It is likely therefore that other factors in addition to GH deficiency must influence QOL in these patients. Further strategies to improve QOL in these individuals should therefore be considered, e.g. psychological support and treatments and physical treatments (such as exercise programmes).
Interleukin‐2 given to asymptomatic HIV‐infected individuals leads to an exaggerated response of the pituitary gland to the action of CRH
Authors: Witzke Oliver , Winterhagen Toni , Kribben Andreas , Philipp Thomas , Mann Klaus , Reinhardt Walter
Published: June 2003

background and aims Studies investigating the impact of interleukin‐2 (IL‐2) on the corticotroph axis have shown that IL‐2 can stimulate cortisol and ACTH secretion. However, the site, the time course and the mechanisms of IL‐2 stimulation of the corticotroph axis are still not known. The aim of this study was to gain insight into the mechanisms of IL‐2 stimulation of the corticotroph axis.

patients and methods A total of 9 × 106 IU/day IL‐2 were given to 18 male HIV‐infected patients treated with a combination of HIV antiviral drugs (usually two reverse‐transcriptase inhibitors and one protease‐inhibitor) over a course of 4–5 days. Seven of these 18 patients received a second course of IL‐2.

results Cortisol levels increased significantly (P < 0·001) from baseline levels (427 ± 118 nmol/l) to 746 ± 132 nmol/l after 4 days of IL‐2 therapy with a gradual decrease to baseline within 10 days after the end of therapy. ACTH showed a similar pattern rising from 5·9 ± 1·9 pmol/l at baseline to 12·4 ± 4·6 pmol/l on day 4 (P < 0·001). The cortisol response after CRH application (carried out at 15·00 h) was significantly more pronounced at the end of IL‐2 application (CRH test B, baseline: 330 ± 59 nmol/l, peak 774 ± 134 nmol/l, 135% increase) when compared to pretreatment (CRH test A, baseline: 226 ± 73 nmol/l, peak 459 ± 103 nmol/l, 103% increase, P ≤ 0·0001). The cortisol response 9 days after the end of IL‐2 administration showed a similar pattern when compared to pretreatment values. The ACTH response after CRH was essentially paralleled by the cortisol response (CRH test B, baseline: 6·1 ± 2·8 pmol/l, peak 16·0 ± 4·4 pmol/l, 170% increase; CRH test A, baseline: 4·3 ± 1·9 pmol/l, peak 9·2 ± 3·1 pmol/l, 110% increase, P = 0·0005). Furthermore, we observed higher ACTH and cortisol concentrations in the morning when compared to late afternoon values during treatment with IL‐2 [cortisol: baseline: 426 ± 73 nmol/l (8·00 h); 226 ± 73 nmol/l (15·00 h)]; day 4: [746 ± 132 nmol/l (8·00 h); 339 ± 59 nmol/l (15·00 h)]; ACTH: baseline: [5·9 ± 1·9 pmol/l (8·00 h); 4·3 ± 1·9 pmol/l (15·00 h)]; day 4: [12·4 ± 4·7 pmol/l (8·00 h); 6·1 ± 2·8 pmol/l (15·00 h)].

conclusion The data from this in vivo study suggest that IL‐2 most likely resulted in corticotroph hyperplasia leading to an exaggerated response of the pituitary gland to the action of CRH.
Growth without growth hormone: growth pattern and final height of five patients with idiopathic combined pituitary hormone deficiency
Authors: Lazar Liora , Dan Sivan , Phillip Moshe
Published: June 2003

background Growth without GH has been reported in patients with organic combined pituitary hormone deficiency (CPHD) after resection of craniopharyngiomas and hypothalamic tumours or in septo‐optic dysplasia.

methods This study describes the growth pattern and final height of five children (four boys, one girl) with idiopathic CPHD (GH, TSH, ACTH, LH and FSH) who maintained normal growth despite persistent GH deficiency throughout the growth period.

results Presenting findings were borderline small penis in two children diagnosed at ages 3 and 9 years, and absence of pubertal signs in three adolescents diagnosed at age 12·8–13·7 years. The latter three patients also exhibited acromegaloid features. The height of all patients was within the 10–25th percentiles, and weight at the 25–50th percentiles. Although they were moderately overweight, accelerated weight gain was not observed. Prepubertal growth rate was 4–5 cm/year. The pubertal growth period, starting after initiation of sex hormone therapy (chronological age 15·9–16·3 years and bone age 12·5–14·5 years) continued for 4–5·5 years. Total pubertal growth was 6–11·7 cm with reduced growth spurt. Final height, which was attained at an advanced age (19–22 years), was 170–179 cm in the boys and 164 cm in the girl, equal to or exceeding the target height range. Repeated hormonal evaluations revealed undetectable GH and IGF‐I levels, and no evidence of hyperprolactinaemia or hyperinsulinism.

conclusions Final height attainment within or above target height range may occur in patients with idiopathic CPHD despite persistent GHD. As this was not mediated by GH, IGF‐I, insulin or prolactin, some other growth factors probably played a growth‐promoting role.
Increased fracture rates in Turner's syndrome: a nationwide questionnaire survey
Authors: Gravholt Claus Højbjerg , Vestergaard Peter , Hermann Anne Pernille , Mosekilde Leif , Brixen Kim , Christiansen Jens Sandahl
Published: June 2003

background and objectives Reduced bone mineral content (BMC) and bone mineral density (BMD) have previously been reported in Turner's syndrome, although appropriate GH treatment and early induction of puberty seem to permit normal bone mass accumulation. Furthermore, an increased risk of fractures and osteoporosis have been reported in a registry study. The aim of the present study was to further characterize the risk of fractures in TS and to explore risk factors, in a historical follow‐up survey based on a self‐administered questionnaire.

study groups The questionnaire was issued to all females with TS (n = 632) in Denmark and to 1888 randomly selected controls (C) matched for age and geographical region. A total of 322 patients (51%) and 1169 controls (62%) returned the questionnaire.

results TS women were younger than C (30 years, range: 1–73 years vs. 34 years, range 2–82 years, P < 0·0005), smoked less often (17%vs. 27%, P < 0·0005), and had less frequent spontaneous menstruation (18%vs. 86%, P < 0·0005). In contrast, they used hormonal replacement therapy (HRT) more often (71%vs. 7%, P < 0·0005). The median age at start of HRT was 16 years (range 8–59 years) in TS vs. 42 years (range 12–53 years) in C (P < 0·0005). Above the age of 15 years, 83% of TS and 8% of C used HRT. GH had been used by 37% of TS but only 0·2% of C. Both type 1 and 2 diabetes were increased sevenfold among TS. Altogether, 77 individuals with TS had 109 fractures. The fracture risk was increased in TS [hazard ratio (HR, status) 1·35, confidence interval (CI) 1·04–1·75, P = 0·025]. Time to first fracture was reduced in TS (53 ± 2 vs. 63 ± 1; log‐rank P = 0·03). Spontaneous menstruation was protective in females above 13 years of age (HR: 0·70, CI 0·54–0·93, P = 0·012). A history of parental fractures increased the risk (HR 1·92, CI 1·62–2·27, P < 0·001). Fractures of the forearm was more frequent among TS (P = 0·02).

conclusion The present nationwide survey, based on questionnaires, confirms an increased risk of early fractures in TS, especially in those without ovarian function and with a positive family history of fracture and osteoporosis. It thereby emphasizes the need for being vigilant with respect to BMD measurements in these patients.
Relationship between leptin levels and bone mineral density in the elderly
Authors: Zoico Elena , Zamboni Mauro , Adami Silvano , Vettor Roberto , Mazzali Gloria , Tosoni Paolo , Bissoli Luisa , Bosello Ottavio
Published: June 2003

objective To assess the relationship between circulating leptin levels, bone mineral content and density in the elderly.

design A cross‐sectional study.

patients A cohort of 92 men and 171 women, with ages ranging from 68 to 75 years, selected as a healthy and normal functioning group, in the city centre of Verona.

measurements Plasma leptin levels were determined in each participant. Body composition was evaluated with dual energy X‐ray absorptiometry (DXA). Bone mineral content (BMC) and bone mineral density (BMD) were measured at whole‐body, hip and femoral neck level in all subjects.

results In both men and women a significant relationship between fat mass and whole‐body BMC or BMD was found. The strength of this association was consistently reduced after adjustment for plasma leptin. A significant association between circulating leptin levels, whole‐body, total hip and femoral neck BMC and BMD was found in both sexes. This association retained the statistical significance after adjustment for fat mass percentage, especially in women. In stepwise multiple linear regression analyses, leptin was shown to be a significant predictor of whole‐body, total hip and femoral neck BMC and BMD, independently of age and the percentage of body fat in both sexes. The circulating levels of leptin accounted for a variance in whole‐body BMC of 8·9% in men and 18·2% in women, and in whole‐body BMD of 10·6% in women.

conclusion Our data show a significant relationship between leptin, bone mineral mass and density in healthy elderly men and women.
Left ventricular mass index and ventricular septum thickness are associated with serum dehydroepiandrosterone‐sulphate levels in hypertensive women
Authors: Szathmári Miklós , Treszl András , Vásárhelyi Barna
Published: June 2003

objective  Several data indicate that endogenous sex steroids might influence left ventricular mass. Our aim was to examine the association between dehyroepiandrosterone‐sulphate (DHEAS) levels and left ventricular mass index (LVMI) and ventricular septal thickness (VST) in pre‐ and in postmenopausal women with treated essential hypertension.

patients and methods  LVMI and VST were related to serum DHEAS in 26 pre‐ and in 34 postmenopausal women. The associations between DHEAS and LVMI, VST were adjusted for body mass index, duration of hypertension, systolic blood pressure, serum cholesterol and testosterone levels using a multiple regression model.

results  In premenopausal women there was a significant linear correlation between DHEAS and LVMI (P < 0·02) after adjustment for confounding variables. In contrast, DHEAS was inversely correlated with LVMI and VST in postmenopausal women (r = −0·49, P < 0·02, r =−0·42, P < 0·02, respectively). These associations also remained significant (P = 0·04, P = 0·03, respectively) after adjustment for confounding variables.

conclusion  DHEAS might be an independent determinant of LVMI and VST. Its effect on the heart may depend on hormonal milieu. In premenopausal women, DHEAS might have androgenic effects and might enhance fibroblast proliferation; while during the postmenopausal period it is dominantly oestrogenic in action, with antiproliferative effect on cardiac cells.
Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH‐secreting pituitary adenoma cells in vitro
Authors: Florio Tullio , Thellung Stefano , Corsaro Alessandro , Bocca Liliana , Arena Sara , Pattarozzi Alessandra , Villa Valentina , Massa Alessandro , Diana Fabrizio , Schettini Daria , Barbieri Federica , Ravetti Jean Louis , Spaziante Renato , Giusti Massimo , Schettini Gennaro
Published: June 2003

objective Somatostatin is an endogenous inhibitor of hormone secretion and cell proliferation. Treatment with somatostatin analogues in humans causes a reduction in size and secretory activity of endocrine tumours, including GH‐secreting pituitary adenomas. This study was aimed to characterize the intracellular mechanisms mediating the in vitro antiproliferative and antisecretory effects of somatostatin and its analogue lanreotide, on primary cultures of GH‐secreting pituitary adenoma cells.

design Thirteen GH‐secreting pituitary adenoma postsurgical specimens were analysed for somatostatin receptor (SSTR) mRNA expression and a subset of them was analysed in vitro for the effect of somatostatin on cell proliferation, assessed by means of [3H]‐thymidine uptake, and GH release, using an immunoradiometric assay. Moreover, the intracellular signalling involved in such effects has been studied.

results All the adenomas analysed expressed at least one somatostatin receptor subtype mRNA. SSTR2 mRNA was identified in 77% of the adenomas, SSTR1 and SSTR3 in 69% and SSTR5 in 60%. Somatostatin and lanreotide inhibited cell proliferation in phorbol ester (PMA)‐stimulated conditions (10/13 adenomas), as well as after fetal calf serum (3/3 adenomas) or IGF‐I stimulation (2/2 adenomas). Conversely, GHRH or forskolin treatments did not significantly affect DNA synthesis in adenoma cells in the presence or absence of somatostatin (2/2 and 4/4 adenomas, respectively). Vanadate pretreatment reversed somatostatin inhibition of PMA‐induced DNA synthesis suggesting an involvement of tyrosine phosphatase in this effect (2/2 adenomas); this was confirmed by the direct induction of tyrosine phosphatase activity in two adenomas after somatostatin treatment. Somatostatin and also lanreotide caused significant inhibition of phorbol ester, forskolin, GHRH and KCl‐dependent increase of GH secretion in the culture medium. Moreover, voltage‐sensitive calcium channel activity induced by 40 mm KCl depolarization in microfluorimetric analysis, was significantly reduced (5/5 adenomas).

conclusions These data show that somatostatin and lanreotide inhibit human GH‐secreting pituitary adenoma cell proliferation and hormone release in vitro, and suggest that the activation of tyrosine phosphatases may represent intracellular signals mediating the antiproliferative effects and that the inhibition of the voltage‐dependent calcium channels and adenylyl cyclase activities may control GH secretion.
Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese
Authors: Tso A. W. K. , Rong R. , Lo C. Y. , Tan K. C. B. , Tiu S. C. , Wat N. M. S. , Xu J. Y. , Villablanca A. , Larsson C. , Teh B. T. , Lam K. S. L.
Published: June 2003

objective Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland.

design In order to define the prevalence of MEN1 germ‐line mutations in Southern Chinese patients with MEN1 syndrome, we performed direct sequencing of the entire open reading frame of the MEN1 gene for 12 index patients and their first‐degree relatives.

results Six patients had familial MEN1 syndrome and six had apparently sporadic disease. Nine different germ‐line mutations at the MEN1 gene were identified, including three novel mutations [248–249delTT in exon 2, K559X(AAG → TAG) in exon 10 and IVS 2nt + 2(G → T) in intron 2]. All patients with familial MEN1 syndrome were heterozygous carriers of a germ‐line mutation and MEN1‐related disorders were only evident in their first‐degree relatives who also carried the mutation. All patients with an enteropancreatic lesion were mutation carriers and the absence of mutation in three apparently sporadic MEN1 patients with only hyperparathyroidism and pituitary microadenoma might represent the presence of MEN1 phenocopy.

conclusions The finding of MEN1 germ‐line mutation in all patients with familial MEN1 syndrome suggests that genetic screening should be useful in our population to identify affected individuals within a kindred and allow early detection of MEN1‐related tumours.
The effect of cryptorchidism on inhibin B in a subfertile population
Authors: De Gouveia Brazao C. A. , Pierik F. H. , Erenpreiss Y. , De Jong F. H. , Dohle G. R. , Weber R. F. A.
Published: June 2003

objective Prepubertal cryptorchidism may cause fertility problems in adulthood, due to impaired spermatogenesis. Serum inhibin B has emerged as an accurate marker of spermatogenesis. The aim of this study was to evaluate the impact of a history of cryptorchidism on serum inhibin B levels and other markers of spermatogenesis in subfertile men.

patients and measurements  In a retrospective study, the effect of cryptorchidism on inhibin B, FSH, LH, free testosterone, testicular volume and semen parameters was assessed in a case–control study within a population of 2613 subfertile men. Of these, 161 and 102 subjects had a history of, respectively, unilateral and bilateral cryptorchidism that was treated by orchiopexy in childhood. Hormone data were complete for 64 cryptorchid patients (32 unilateral and 32 bilateral). A group of 128 patients was randomly selected out of the remaining group of 2350 men with idiopathic subfertility. An additional control group consisted of 32 fertile men from the general population.

results In cryptorchid subfertile men, inhibin B concentrations were significantly lower than in noncryptorchid subfertile men and fertile men (103 ng/l, 143 ng/l and 148 ng/l, respectively; P < 0·01). The FSH concentration was significantly higher in cryptorchid men vs. noncryptorchid men and controls (6·1 IU/l vs. 3·3 and 2·9 IU/l, respectively; P < 0·01).Testicular volumes and sperm concentration of cryptorchid men were significantly lower than in noncryptorchid subfertile men (12 vs. 15 ml, P < 0·01 and 3·8 × 106 sperm/ml vs. 17·4 × 106 sperm/ml; P < 0·05). A significantly higher inhibin B level and sperm concentration was observed in men undergoing orchiopexy at an early age (1–4 years) compared with men treated between 5 and 9 years or later (P < 0·05).

conclusion Spermatogenesis is more impaired in cryptorchid subfertile men compared to men with idiopathic subfertility, as reflected by a lower inhibin B concentration.
Role of protein binding in renal elimination of leptin
Authors: Landt Michael , Ludbrook Philip A. , Billadello Joseph J.
Published: June 2003

objective Leptin, a hormone produced by fat which signals to the brain the extent of fat stores, is known to be eliminated from circulation primarily by the kidney. The hormone circulates in both free and protein‐bound forms, but there is little information concerning the inter‐relationship of these forms of leptin, or which form is influenced by physiological processes such as renal elimination. We studied total, free and bound concentrations of leptin in ambulatory adults undergoing catheterization for diagnosis/management of congenital cardiac disease.

design Blood specimens were collected from both the arterial circulation and the renal vein, for determination of the fractional extraction of leptin resulting from a single pass through the kidney.

patients Thirteen subjects were studied.

measurements Total leptin concentrations were measured by radioimmunoassay, and free/protein‐bound leptin concentrations were quantified by an high‐performance liquid chromatography method. Adequacy of renal vein sampling was assessed by comparing the creatinine concentration of arterial and venous specimens.

results Mean fractional extraction of creatinine was 28 ± 7% in the 13 subjects studied. Fractional extraction of total leptin was 18 ± 8%, significantly less than that for creatinine. Fractional extraction of total leptin was not related to arterial leptin concentration or the fractional extraction of creatinine. Both free and bound fractions of leptin were significantly reduced by passage through the kidney, with fractional extractions of 22% and 25%, respectively. Efficiency of extraction was not influenced by the relative proportion of free or bound leptin fractions. Leptin‐binding capacity (a measure of the concentrations of leptin‐binding proteins) was not altered by passage through the kidney.

conclusions Both free and bound leptin are metabolically active with regard to elimination. Protein‐bound leptin equilibrates with the free leptin fraction in circulation as the result of a dynamic equilibrium. The data are consistent with either glomerular filtration or active uptake as mechanisms of elimination. Leptin‐binding proteins are apparently neither eliminated or produced by the kidney.
Alzheimer's Disease: Current Pharmacotherapy in the Context of Patient and Family Needs
Authors: Geldmacher David S.
Published: June 2003

The objective of this paper is to review current evidence and treatment patterns for pharmacotherapy in Alzheimer's disease (AD), with an emphasis on outcomes considered important to patients and families. The sources for the information are the peer‐reviewed literature, Food and Drug Administration‐approved package labeling for acetylcholinesterase inhibitors (AChEIs), expert opinions expressed at the First Annual Dementia Congress, and clinical experience. Three AChEI agents are in routine use in the United States. They are considered part of the standard of care for patients with mild‐to‐moderate AD. There are differences in metabolism, pharmacokinetics, side effects, and ease of use that may influence the prescriber's choice of agent and dosage. The three approved agents have similar outcomes in cognition and global clinician ratings of effectiveness in double‐blind placebo controlled trials. Persistent therapy with effective doses of AChEIs is associated with reduced risk for, or delayed, nursing home placement, which is a stated priority of AD caregivers. Agents from this class of drugs have also been shown to be associated with statistically significant preservation of daily function and benefits in treatment of adverse behaviors in AD. Numerous additional choices are available to the clinician for pharmacotherapy of adverse behaviors. Community‐based psychoeducational support is also of value to caregivers.
Drought and aquatic community resilience: the role of eggs and seeds in sediments of temporary wetlands
Authors: Brock M. A. , Nielsen Daryl L. , Shiel Russell J. , Green John D. , Langley John D.
Published: June 2003

1. A long‐lived bank of propagules consisting of eggs, seeds and spores is one mechanism that allows aquatic communities to survive drought. A drying (drought) event is, for aquatic organisms in a temporary wetland, a phase from which communities must recover. Such a dry phase is often considered a disturbance but should not be considered adverse or catastrophic for the organisms that have evolved to live in temporarily wet habitats.

2. This paper explores the parallels between the egg bank of zooplankton and the seed bank of aquatic plants as means of survival in temporary wetlands. The resilience of communities in temporary wetland ecosystems is assessed by examining dormancy, hatching, germination, establishment and reproduction of animals and plants from the egg and seed banks of wetlands with a range of wetting and drying regimes.

3. Both the zooplankton and aquatic plants of the temporary wetlands studied rely on their egg and seed banks as a means for surviving drying. These communities recover after the disturbance of drying by means of specific patterns of dormancy, dormancy breakage, hatching, germination, establishment and reproduction. Spatial and temporal patterns of species richness allow resilience through dormancy, as not all species are present at all sites and not all species hatch and germinate at the same time. Multiple generations in the egg and seed bank and complexity of environmental cues for dormancy breakage also contribute to the ecosystem's ability to recover after a drying event. A persistent egg and seed bank allows species‐rich communities to hatch, germinate and develop rapidly once dormancy is broken. Rapid establishment of species‐rich communities that reproduce rapidly and leave many propagules in the egg and seed bank also facilitates community recovery on flooding of a temporary wetland after a drying event.

4. To maintain the diversity of temporary wetland communities through droughts and floods we need to manage the dry and wet phases of wetlands. To conserve a wide range of wetland types, we need to maintain a variety of hydrological patterns across the landscape.
Ecological effects of perturbation by drought in flowing waters
Authors: Lake P. S.
Published: June 2003

Knowledge of the ecology of droughts in flowing waters is scattered and fragmentary, with much of the available information being gathered opportunistically. Studies on intermittent and arid‐zone streams have provided most of the information.

Drought in streams may be viewed as a disturbance in which water inflow, river flow and water availability fall to extremely low levels for extended periods of time. As an ecological perturbation, there is the disturbance of drought and the responses of the biota to the drought.

Droughts can either be periodic, seasonal or supra‐seasonal events. The types of disturbance for seasonal droughts are presses and for supra‐seasonal droughts, ramps.

In droughts, hydrological connectivity is disrupted. Such disruption range from flow reduction to complete loss of surface water and connectivity. The longitudinal patterns along streams as to where flow ceases and drying up occurs differs between streams. Three patterns are outlined: ‘downstream drying’, ‘headwater drying’ and ‘mid‐reach drying’.

There are both direct and indirect effects of drought on stream ecosystems. Marked direct effects include loss of water, loss of habitat for aquatic organisms and loss of stream connectivity. Indirect effects include the deterioration of water quality, alteration of food resources, and changes in the strength and structure of interspecific interactions.

Droughts have marked effects on the densities and size‐ or age‐structure of populations, on community composition and diversity, and on ecosystem processes.

Organisms can resist the effects of drought by the use of refugia. Survival in refugia may strongly influence the capacity of the biota to recover from droughts once they break.

Recovery by biota varies markedly between seasonal and supra‐seasonal droughts. Faunal recovery from seasonal droughts follows predictable sequences, whilst recovery from supra‐seasonal droughts varies from one case to another and may be marked by dense populations of transient species and the depletion of biota that normally occur in the streams.

The restoration of streams must include the provision of drought refugia and the inclusion of drought in the long‐term flow regime.
Drought in an evolutionary context: molecular variability in Flannelmouth Sucker (Catostomus latipinnis) from the Colorado River Basin of western North America
Authors: Douglas Marlis R. , Brunner Patrick C. , Douglas Michael E.
Published: June 2003

Summary 1. Fishes can often rebound numerically and distributionally from short‐term (i.e. seasonal) drought, yet their capacity to recover from decades or centuries of drought is less apparent. An exceedingly warm and dry period swept the intermontane west of North America ca. 7500 years BP, concomitant with an abrupt extinction of >35 mammal species. Were larger fishes in mainstem rivers also impacted by this drought?

2. The Colorado River Basin encompasses seven states in western North America and drains 600 000 km2. Its endemic mainstem fish community is ancient (i.e. Miocene) but depauperate.

3. We evaluated one widely distributed candidate species (flannelmouth sucker, Catostomus latipinnis) for basin‐wide genetic and geographic structure at three fast‐evolving mitochondrial (mt) DNA genes, ND2 with 589 bp and ATPase 8 and 6 with 642 bp. It is hypothesized that a concomitant signature would be present in the mtDNA of this species, if indeed it had been seriously bottlenecked by post‐Pleistocene drought. A total of 352 individuals were sequenced from 24 populations (4–40 individuals/population; average of 14.7).

4. Only 49 unique haplotypes were found, 53% of which represented single individuals. Haplotype diversity was high (0.905 ± 0.007) whereas nucleotide diversity was low (0.002 ± 0.000).

5. A significant and positive geographical cline (P < 0.001) in nucleotide diversity was observed as sampling locations progressed upstream from southwest to northeast. These results divided the Colorado River Basin into three reaches: the lower reach with six populations and 83 individuals; the upper reach with seven populations and 83 individuals; and the middle reach with 11 populations and 186 individuals. An analysis of molecular variance (amova) revealed that 81.5% of the total genetic variation was within populations, 16% among populations within reaches and 2.5% among reaches. Only the last was significant. Populations from the three reaches diverged from one another by 3400–11 000 years BP. Haplotype distribution suggested populations in the upper Colorado River are expanding.

6. The lack of genetic variation and recent coalescence of lineages in C. latipinnis are unusual given its fossil history, broad geographical sampling, the rapid rate of mtDNA evolution and the number (and evolutionary rate) of the genes examined. The most parsimonious explanation for these data is a rapid expansion following a recent period of low effective population size at the end of the Pleistocene.

7. The intense drought is suggested at the end of the Pleistocene (late‐to‐mid‐Holocene), severely impacted not only large mammals but also larger fishes in western North American rivers. These perspectives have important implications for management of endangered and threatened species in this region.