bluuebunny/crossref_metadata_2025 huggingface dataset:
Dehydroepiandrosterone sulphate is increased and dehydroepiandrosterone‐response to corticotrophin‐releasing hormone is decreased in the hyperthyroid state compared with the euthyroid state
Authors: Yamakita Noriyoshi , Murai Toshihiro , Kokubo Yoshiaki , Hayashi Makoto , Akai Akifumi , Yasuda Keigo
Published: March 2003

OBJECTIVE Dehydroepiandrosterone (DHEA) and DHEA‐sulphate (S) have been suggested to play protective roles in many pathological states, some of which are observed in hyperthyroidism. If DHEA and DHEA‐S levels change in hyperthyroidism, they might participate as a possible causative link with such pathophysiological changes in hyperthyroidism. However, the CRH–ACTH–DHEA system in hyperthyroidism has not been clearly defined. We examined plasma levels of DHEA and DHEA‐S together with ACTH and cortisol in both hyperthyroid (Hyper) and euthyroid states (Eu).

METHODS Eighteen patients (5 men and 13 women, aged 46·9 ± 2·8 years) with Graves' disease were studied before treatment and again in the euthyroid state following treatment with methimazole. A 100 µg hCRH stimulation test and a low‐dose (0·5 µg) 1–24 ACTH stimulation test were performed on separate days. Basal levels and Δ area under the response curve (AUC) were compared between Hyper and Eu.

RESULTS DHEA‐S was higher in Hyper than in Eu. However, basal DHEA did not differ between Hyper and Eu. The ratio of DHEA to DHEA‐S was lower in Hyper than in Eu. ΔAUC of DHEA during a CRH test was lower in Hyper than in Eu. However, ΔAUC of DHEA during an ACTH test was similar in both Hyper and Eu. Basal ACTH was higher in Hyper than in Eu. In both CRH and ACTH tests, ΔAUC of cortisol response was lower in Hyper than in Eu, although the basal cortisol level was not different.

CONCLUSION The balance of the conversion between DHEA‐S and DHEA in the hyperthyroid state favoured DHEA‐S. Similar to cortisol, the DHEA response in the CRH test in hyperthyroidism seemed to be insufficiently compensated for by increased ACTH, although the DHEA response to low‐dose ACTH was similar in the hyperthyroid and euthyroid states. Increased DHEA‐S might play some role in the pathological states in many organs in hyperthyroidism.
CTLA‐4 gene A–G polymorphism and childhood Graves’ disease
Authors: Yung E. , Cheng P. S. , Fok T. F. , Wong G. W. K.
Published: March 2003

objective Graves’ disease is associated with a polymorphism at position 49 in exon 1 of the cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) gene in Caucasians and Japanese. A high incidence of childhood Graves’ disease has been documented in Hong Kong Chinese. The aims of this study were to investigate the CTLA‐4 gene A–G polymorphism association in Chinese children with Graves’ disease.

patients and design One hundred and twenty‐three Chinese children with Graves’ disease (104 girls and 19 boys) and 158 racially matched healthy controls were recruited for the study. Genomic DNA was extracted from venous blood samples. The dimorphism at position 49 A–G was analysed by polymerase chain reaction, single‐strand conformation polymorphism and restriction fragment‐length polymorphism analysis.

results The genotype distribution and allele frequencies of children with Graves’ disease differed significantly from those of the controls (P = 0·0023 and P = 0·022, respectively). The presence of at least one G allele (GG or AG) was associated with an increased risk of Graves’ disease (OR = 6·8, 95% CI = 2·0–36·1; P = 0·001).

conclusions This study confirms that CTLA‐4 49 A–G polymorphism is associated with Graves’ disease in Chinese children. The CTLA‐4 49 G allele confers an increased risk of childhood Graves’ disease.
Subjective health status in Norwegian patients with Addison’s disease*
Authors: Løvås Kristian , Loge Jon Håvard , Husebye Eystein S.
Published: March 2003

objective  Many patients with Addison’s disease have complaints that might be related to the disease or to its treatment. However, only a few studies have addressed the subjective health status of patients with adrenocortical failure. The aim of the present study was to assess the subjective health status with special emphasis on fatigue among patients with Addison’s disease.

subjects, design and measurement   In a postal survey, 79 patients with confirmed primary adrenal failure (Addison’s disease) completed the Short Form 36 (SF‐36) and the Fatigue questionnaires. The subjective health status in Addison’s disease was compared with normative data from the general population.

results  General health and vitality perception were most consistently impaired in the patients with Addison’s disease. The scores on physical functioning and role‐physical were low in women. Social functioning and role‐emotional scores were also lower than normal in the female patients, but this was confined to the patients with autoimmune polyendocrine syndromes. Patients with autoimmune polyendocrine syndromes tended to have lower scores than patients with solitary Addison’s disease. The level of fatigue was higher than normal for both men and women. Working disability at ages 18–67 years was 26%, compared with 10% in the corresponding general Norwegian population. The high working disability increased with age and was higher in subgroups with concomitant endocrine diseases. Most subjective health parameters were lower among the disabled compared to the patients in work.

conclusions  Patients with Addison’s disease under replacement therapy with cortisone acetate and fludrocortisone have reduced general health perception and vitality, and increased fatigue. Female patients reported reduced physical function, which might be due to adrenal androgen depletion. Mental health seems more influenced by concomitant endocrine diseases, but mental fatigue might be a specific feature in adrenal failure. The patient population is heterogeneous, with normal findings in a substantial proportion but markedly reduced subjective health status and working ability in many others. Thus, there might be potential for further refinement of replacement therapy.
Erythrocyte Na+,K+‐ATPase and nasal potential in pseudohypoaldosteronism*
Authors: Bistritzer Tzvy , Kerem Eitan , Berkovitch Matitiahu , Rapoport Micha J. , Evans Sandra , Aladjem Mordechai
Published: March 2003

objectives Pseudohypoaldosteronism type 1 (PHA1) is a rare inherited disorder characterized by salt‐wasting due to target organ unresponsiveness to mineralocorticoids. PHA1 comprises two clinically and genetically distinct entities; isolated renal and systemic forms.

design The aim of this study was to investigate red blood cell (RBC) Na+,K+‐ATPase activity and nasal potential difference (PD) in two pairs of unrelated dyzygous twins; one with the systemic form of the disease (PHA1‐S) and the second with the isolated renal form (PHA1‐R). Total and ouabain‐sensitive ATPase activities were measured spectrophotometrically by a method that couples ATP hydrolysis with NADH oxidation. Maximal PD and response to amiloride perfusion were evaluated by a standard technique.

results In the twins with PHA1‐S, persistently low activity of RBC Na+,K+‐ATPase was found during a 6‐year follow‐up. Normalization of plasma renin activity (PRA) and plasma aldosterone was observed at the end of the first year of life. Maximal nasal PD was low and there was no significant response to amiloride. In the twins with PHA1‐R, RBC Na+,K+‐ATPase activity was very low at the time of diagnosis and normalized at the age of 6–8 months. PRA reverted gradually to normal values, whereas aldosterone levels remained high during the 6 years of follow‐up. Maximal nasal PD and response to amiloride were normal.

conclusions The observed differences in RBC Na+,K+‐ATPase activity and nasal PD response to amiloride between the two pairs of twins support the contention of different basic pathogenic mechanisms in the two forms of PHA1.
Trisomy of the short stature homeobox‐containing gene (SHOX), resulting from a duplication‐deletion of the X chromosome
Authors: Adamson K. A. , Cross I. , Batch J. A. , Rappold G. A. , Glass I. A. , Ball S. G.
Published: March 2003

The Turner syndrome (TS) is a complex disorder associated with almost invariant short stature and gonadal dysgenesis, as well as a variety of other major organ malformations. Recently, a homeobox‐containing gene entitled short‐stature homeobox‐containing gene (SHOX), was isolated from a minimal short stature gene interval from the pseudoautosomal region of Xp (and Yp). Together with the demonstrable escape of SHOX from X‐inactivation, this suggested SHOX to be a strong candidate gene for the short stature component of TS, and as SHOX haploinsufficiency appears to be the molecular basis of a mesomelic short statured skeletal dysplasia (Leri–Weill syndrome), this suggested that SHOX protein expression levels may confer a dosage effect on human stature. However, in this communication we report a normal statured female with gonadal dysgenesis, due to the inheritance of a recombinant duplication‐deletion X‐chromosome. The karyotype of the proband was 46,X,rec(X)dup(Xp)inv(X)(p11·22q21·2)mat and fluorescentin situhybridization of her metaphases with a SHOX cosmid confirmed the proband to be trisomic forSHOX. This communication suggests the relationship between levels of SHOX expression and human stature to be more complex than envisaged previously. The presence of normal stature in our patient rather than tall stature is likely to represent the natural variation seen in patients with transcription factor disorders.
Low‐dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome
Authors: Murray R. D. , Wieringa G. E. , Lissett C. A. , Darzy K. H. , Smethurst L. E. , Shalet S. M.
Published: March 2003

objective Adult growth hormone deficiency (AGHD) is associated with an adverse lipid profile. The majority of previous studies of GH replacement have used supraphysiological doses and reported favourable changes in the lipid profile. Whether this beneficial effect is the result of pharmacological GH therapy, or occurs in response to low‐dose GH replacement aimed at normalization of the serum IGF‐I, has not been fully elucidated.

study design We studied 67 patients with GH deficiency using a low‐dose individualized GH replacement regimen. GH was commenced at a dose of 0·27 mg/day and the GH dose titrated until the serum IGF‐I was normalized. Serum lipids were assessed at baseline, 12 and 24 months.

results A reduction in total cholesterol (TC) was observed at 12 (6·01 vs. 5·77 mmol, P = 0·04) and 24 months (6·01 vs. 5·56, P = 0·09). The reduction in LDLC failed to reach significance at 12 months (3·97 vs. 3·8, P = 0·09), but was significant at 24 months (3·97 vs. 3·50, P = 0·02). Levels of HDLC did not change significantly at 12 or 24 months. Significant improvements in the TC/HDLC ratio were observed at both 12 (5·68 vs. 5·29, P = 0·01) and 24 months (5·68 vs. 4·86, P = 0·007). A significant fall in triglycerides (TG) was present at 12 months (2·07 vs. 1·83, P = 0·01), and was maintained at 24 months, but was no longer significant (2·07 vs. 1·89, P = 0·28). At 12 months there was no correlation between improvements in lipid parameters and either the change in IGF‐I SD score or the GH dose. Using multivariate analysis the change in TC, LDLC and the TC/HDLC ratio with 12 months GH replacement were determined by the baseline TC, LDLC and TC/HDLC levels (R2 = 0·18, P = 0·004; R2 = 0·20, P = 0·006; and R2 = 0·33, P < 0·0001), respectively.

conclusions Low‐dose individualized GH replacement aimed at normalization of the serum IGF‐I is associated with significant improvements in TC, LDLC, TGs and the TC/HDLC ratio. The greatest improvements are observed in patients with the most adverse lipid profiles at baseline. Improvements are independent of changes in the IGF‐I SDS and GH dose.
Changes in adiposity and excess body weight correlate with growth responses but not with decreases in low‐density lipoprotein cholesterol levels during GH treatment in GH‐deficient children
Authors: Kuromaru Ryuichi , Kohno Hitoshi , Hara Toshiro
Published: March 2003

background and aims GH has profound effects on body composition and lipid metabolism in children as well as in adults. The relationship between such metabolic effects and the growth‐promoting effects of GH has not been studied thoroughly in children with GH deficiency. This prospective study was designed to determine the relationship between growth and lipid metabolism during long‐term GH treatment.

patients and methods Twenty‐two boys with idiopathic GH deficiency were studied. Height, per cent overweight (%OW), per cent body fat (%BF) and serum low‐density lipoprotein (LDL) cholesterol levels were determined every 6 months during 3 years of GH treatment.

results After 3 years of GH treatment, the mean height SD score had increased significantly from −2·70 SD to −1·59 SD (P < 0·0001), while the mean %OW and LDL cholesterol level had decreased significantly from 7·0% to 1·3% (P < 0·0001) and from 2·69 mmol/l to 2·04 mmol/l (P < 0·0001), respectively. The mean %BF fell significantly from 15·5% to 11·1% during the first 6 months of GH treatment (P < 0·0001). The 6‐month reduction in %BF correlated significantly with the 3‐year increase in height SD score (r = −0·58, P = 0·008). The decrease in %OW also correlated negatively with the change in height SD score (r = −0·48, P = 0·03). However, there was no correlation between the changes in LDL cholesterol levels and those in %BF, %OW or height SD score.

conclusion We conclude that the growth‐promoting effects of GH correlate significantly with the reductions in %BF and %OW but not with the decrease in LDL cholesterol level in children with GH deficiency. The changes in LDL cholesterol did not correlate with any of the changes in body composition parameters, suggesting that the various actions of GH may have different mechanisms of regulation.
Combination therapy for postmenopausal osteoporosis
Authors: Compston Juliet E. , Watts Nelson B.
Published: March 2003

A number of agents have been shown to reduce the risk of fractures in patients with postmenopausal osteoporosis. However, the additional benefits of combination therapy as opposed to monotherapy are uncertain. We performed a MEDLINE search and reviewed the published randomized trials of agents used in combination. Combination therapy results in greater gains in bone mineral density than monotherapy and possibly greater effects on bone turnover. However, none of these studies are large enough or of sufficient duration to determine whether a greater reduction in fracture is achieved. Combination therapy has important cost implications and is likely to be associated with an increased prevalence of adverse events, reduced tolerability and a reduction in adherence. Furthermore, over‐suppression of bone turnover as a result of combination antiresorptive therapy might have adverse effects on bone strength, particularly with long‐term treatment. Thus, the use of combination therapy for treatment of osteoporosis cannot be recommended on the basis of currently available evidence.
The influence of human leucocyte antigen (HLA) genes on autoimmune thyroid disease (AITD): results of studies in HLA‐DR3 positive AITD families
Authors: Ban Yoshiyuki , Davies Terry F. , Greenberg David A. , Concepcion Erlinda S. , Tomer Yaron
Published: March 2003

objective Population‐based, case–control studies have consistently shown association of Graves’ disease (GD) with human leucocyte antigen (HLA)‐DR3 in Caucasian populations. HLA association studies in Hashimoto's thyroiditis (HT) have also suggested an association with DR3, as well as with other HLA alleles. In contrast, HLA linkage studies in autoimmune thyroid disease (AITD) have been largely negative. The aim of the present study was to investigate the role of HLA in AITD and to explain the observed associations, but lack of linkage, by examining only AITD families with the associated allele, DR3.

patients We studied 99 probands (60 with GD and 39 with HT) from 99 multiplex, multigenerational Caucasian AITD families, and 135 age‐ and sex‐matched Caucasian controls in association studies. In addition, a dataset of 34 Caucasian AITD families (out of the 99 families) with HLA‐DR3 positive probands were analysed in linkage studies.

design HLA typing was performed using the technique of group‐specific polymerase chain reaction‐amplification with restriction enzyme digestion. Whole genome screening was performed using the ABI microsatellite panels. For fine mapping of the HLA region, we used the following markers: D6S276, D6S464, D6S439, D6S273, tumour necrosis factor α and D6S1610. LOD scores were calculated using the LIPED and GeneHunter programs.

results Case–control association analyses using the probands from our 99 Caucasian families showed an association of GD with DRB1*03 [P = 0·00032, relative risk (RR) = 3·4]. Linkage analysis for the HLA region in the 34 DR3 positive AITD families showed negative LOD scores throughout the region. The two‐point LOD score at marker D6S273 (the closest to HLA‐DRB1) was −3·0, and the multipoint LOD score was −7·6, demonstrating strong evidence against linkage to the HLA region in the subset of DR3 positive families. Whole genome screening in the subset of 34 DR3 positive families revealed one locus showing evidence for linkage to AITD: D3S1580 on chromosome 3q27 with a maximum two‐point LOD score of 2·1.

conclusions The HLA locus did not cosegregate with disease in DR3 positive families, suggesting that HLA genes are not major genes for AITD expression even within DR3 positive families; Hence, although HLA‐DR3 was associated with GD in the probands, it was most likely a modulating gene and not causative; and, as the DR3 positive families showed evidence for linkage with D3S1580, it may imply that the DR3 gene modulated the effect of a susceptibility gene within the D3S1580 locus.
Endocrine consequences of premature pubarche in post‐pubertal Caucasian girls
Authors: Meas Taly , Chevenne Didier , Thibaud Elisabeth , Léger Juliane , Cabrol Sylvie , Czernichow Paul , Lévy‐Marchal Claire
Published: March 2003

background It has been postulated that intrauterine undernutrition may predispose to serious endocrine consequences, including precocious pubarche (PP), functional ovarian hyperandrogenism and insulin resistance syndrome.

objective The aim of this study was to determine whether a history of PP was associated with the development of hyperandrogenism and/or metabolic consequences and to evaluate the effect of birth weight on this association.

patients The study population comprised 27 Caucasian girls with a history of PP and 25 healthy girls of similar age (17·4 ± 1·3 vs. 17·7 ± 0·9 years).

results Gynecological age, irregular menses and oral contraceptive use were similar in the two groups. PP girls showed an increased Ferriman‐Gallway Score [median (range) 8 (4–17) vs. 6 (2–10), P = 0·02] and tended to have more previous history of acne. No statistical differences were found between the groups for mean testosterone (1·7 ± 0·7 vs. 1·4 ± 0·7 nmol/l, P = 0·49) and dehydroepiandrosterone sulphate concentrations (7·2 ± 3·7 vs. 5·8 ± 2·0 µmol/l, P = 0·15), but mean Δ4‐androstenedione concentrations (7·3 ± 2·4 vs. 4·9 ± 2·1 nmol/l, P = 0·007) and free androgen index (8·5 ± 9·7 vs. 3·6 ± 3·9 IU, P = 0·003) were significantly increased in the PP group. All girls showed normal glucose tolerance with an oral glucose tolerance test. Derived insulin resistance parameters were not statistically different between the two groups and fasting lipids were comparable in both groups. There was no significant effect of birth weight on androgen levels in the PP girls. Moreover, none of the PP girls demonstrated the above‐described association.

conclusions Precocious pubarche could be the first sign of future functional ovarian hyperandrogenism but a link between this condition and intrauterine undernutrition or insulin resistance could not be demonstrated in this study.
Effects of a growth hormone receptor antagonist on bone markers in acromegaly
Authors: Fairfield W. P. , Sesmilo G. , Katznelson L. , Pulaski K. , Freda P. U. , Stavrou S. , Kleinberg D. , Klibanski A.
Published: March 2003

objective Excess GH secretion, as occurs in acromegaly, is associated with abnormalities in bone turnover markers and bone mineral density (BMD). GH administration in GH deficient patients causes an increase in bone turnover. IGF‐I mediates many of the metabolic actions of GH, although GH may have direct effects upon bone. In patients with acromegaly who are treated with a GH receptor antagonist, selective blockade of the GH receptor results in a decrease in circulating IGF‐I levels in the majority of cases. We hypothesized that, in acromegaly, antagonism of GH receptors would result in a decrease in serum markers of bone turnover, including serum procollagen I carboxy‐terminal propeptide (PICP), osteocalcin and N‐telopeptide (NTx).

design and subjects Twenty‐seven patients with acromegaly were enrolled as part of a multicentre 12‐week trial of a GH receptor antagonist and were randomized to placebo (n = 7) or 10, 15 or 20 mg of pegvisomant (n = 20).

measurements Serum markers of bone turnover were determined at baseline and 12 weeks.

results Baseline bone turnover markers were above the upper limit of normal in 23%, 19% and 32% of subjects for osteocalcin, PICP and NTx, respectively. During the 12‐week placebo‐controlled period, there were significant decreases in serum markers of bone formation, osteocalcin (−2·2 ± 0·44 vs. placebo +0·01 ± 0·39 nmol/l, P = 0·009) and PICP (−23·6 ± 9·6 vs. placebo +18·1 ± 12·8 µg/l, P = 0·022) and a serum marker of bone resorption, NTx (−4·4 ± 1·4, placebo +1·0 ± 0·3 nm, P = 0·024).

conclusions Using a specific GH receptor antagonist, we found that normalization of IGF‐I is associated with rapid reductions in markers of both bone formation and resorption, and that these processes remain coupled. These data confirm the highly significant effects of GH and IGF‐I in modulating bone turnover. The independent contributions of GH and IGF‐I to these effects and the long‐term effects on BMD in this population remain to be determined.
Intraoperative gamma probe detection of insulinoma in an elderly patient with pancreatic cystic lesions
Authors: Rosière Alain , Ernst Yves J. , Roelants Véronique , Vander Borght Thierry , Michel Luc , Donckier Julian E.
Published: March 2003

Insulinoma is a rare endocrine tumour in the elderly. We report the case of an 81‐year‐old woman suffering from grand mal seizures. Insulinoma was suspected because plasma glucose and insulin levels were 1·5 mmol/l and 80·4 pmol/l, respectively. A pancreatic computerized tomography (CT) scan, magnetic resonance imaging (MRI) and arteriography were normal but 111In‐DTPA‐octreotide scintigraphy detected a hotspot in the pancreatic tail. Intraoperative pancreatic ultrasonography and palpation were non‐contributory due to multiple pancreatic cysts and nodular lesions. However, a gamma‐detecting probe localized a small tumour, labelled preoperatively with 111In‐DTPA‐octreotide. Intraoperative insulin measurements in portal venous blood confirmed the successful removal of an insulinoma that was 6 mm in diameter histologically. Pancreatic cystic lesions increase with age and make the intraoperative localization of the insulinoma difficult. Intraoperative gamma probe detection of the tumour labelled with 111In‐DTPA‐octreotide might therefore constitute a useful surgical tool.
Neck circumference a good predictor of raised insulin and free androgen index in obese premenopausal women: changes with weight loss
Authors: Dixon John B. , O'Brien Paul E.
Published: March 2003

Objective Severe obesity can be associated with evidence of androgen excess and insulin resistance, which are features of the metabolic and polycystic ovary syndromes (PCOS). In this study, we examined the association between clinical and biochemical features of these syndromes and assess changes with weight loss.

Design A consecutive series of 107 severely obese premenopausal women presenting for obesity surgery.

Measurements Pre‐operative assessment included details of clinical comorbidity, anthropometric measures and biochemical measures, including fasting insulin, glucose, lipid profile and sex hormone analysis. Changes in these measures for 42 of 52 (81%) patients at 1 year post surgery are reported.

Results Neck circumference and younger age were independent predictors of higher free androgen index (FAI) (combined r2 = 0·36). If neck circumference is not included, then younger age, higher body mass index and raised fasting insulin levels were all independent predictors of FAI (r2 = 0·29). Waist to hip ratio showed no predictive value (r = 0·14). Neck circumference was also a good clinical predictor of menstrual irregularity, hirsutism, infertility, insulin resistance and the PCOS. Neck circumference of less than 39, 39–42 and greater than 42 cm reflect a low, intermediate and high risk of the metabolic and PCOS syndromes in obese premenopausal women. For 42 patients who were followed for 1 year after surgery, the weight loss was associated with reduction of FAI, less insulin resistance and improved menstrual regularity and resolution of the PCOS in 11 of 12 cases.

Conclusions Neck circumference is a good predictive measure of hyperinsulinaemia and raised androgens in obese premenopausal women. Weight loss following surgery improves ovarian function and vasculopathic risk.
Increased serum leptin concentrations correlate with soluble tumour necrosis factor receptor levels in patients with cirrhosis
Authors: Lin Shih Yi , Wang Ya Yu , Sheu Wayne Huey‐Herng
Published: March 2003

Objective Several reports have documented the involvement of hyerleptinaemia in malnutrition associated with liver cirrhosis. However, the mechanisms of elevated leptin levels remains unclear. Serum concentrations of tumour necrosis factor‐α (TNF‐α), and two soluble TNF receptors (sTNF‐RI and sTNF–RII) are increased in patients with liver cirrhosis. In rodents, administration of TNF‐α has been shown to stimulate plasma leptin concentration, suggesting that a cytokine–leptin link may mediate anorexia and weight loss during chronic inflammation. In this study, we investigate the potential interaction of the TNF‐α system with leptin in the development of malnutrition in liver cirrhosis.

Study Design A total of 26 male patients with liver cirrhosis and 25 healthy people were recruited at an outpatient clinic at the Veterans General Hospital in Taiwan. Serum biochemistry and anthropometric measurement by bioelectrical impedance analysis were used to assess nutrition status, and immunoassay was used to determine serum leptin, TNF‐α sTNF‐RI and sTNF‐RII concentrations.

Results In cirrhotic patients, the body fat mass (FM) and serum albumin levels were both lower than control subjects [15·8 (13·2–19·5) kg vs. 18·9 (16·2–20·1) kg; 35 (33–41) g/l vs. 43 (41–45) g/l, respectively; P < 0·05]. Serum TNF‐α sTNF‐RI and sTNF‐RII were significantly elevated in cirrhotic patients compared to healthy controls [9·8 (7·2–13·5) ng/l vs. 4·3 (3·4–7·3) ng/l; 1682·1 (1344·8–2179·4) ng/l vs. 1319·6 (1037·7–1632·1) ng/l; 4462·2 (3748·5–5159·4) ng/l vs. 3559·8 (2506·9–3988·9 ng/l, respectively; P < 0·01] and correlated with disease severity (graded by Pugh–Child's scores). An inverse correlation was observed between circulating sTNF‐RI and sTNF‐RII to serum albumin levels (r =−0·42, r = −0·398; P < 0·05). The serum leptin levels in cirrhotic patients were significantly higher [6·0 (3·6–7·7) (g/l vs. 3·4 (2·9–4·3) (g/l; P < 0·01) and correlated with body FM (r = 0·52; P < 0·01]. Using a multiple linear regression analysis with leptin as dependent variable and FM and TNF‐α, sTNF‐R as independent variables, FM and serum sTNF‐RI concentrations were found to predict independently the leptin levels in cirrhotic patients.

Conclusion Our study demonstrated that serum levels of TNF‐α, sTNF‐RI, sTNF‐RII and leptin were all elevated in cirrhotic patients. The severity of liver cirrhosis was an important factor for the activation of TNF‐α system. The activated TNF‐α system conjointly with hyperleptinaemia might mediate malnutrition in patients with liver cirrhosis.
Demonstration of human telomerase reverse transcriptase (hTERT) in human parathyroid tumours by in situ hybridization with a new oligonucleotide probe
Authors: Kammori Makoto , Nakamura Ken‐Ichi , Ogawa Toshihisa , Mafune Ken‐Ichi , Tatutomi Yusuke , Obara Takao , Onoda Naoyoshi , Fujiwara Mutsunori , Izumiyama‐Shimomura Naotaka , Mori Masaki , Kaminishi Michio , Takubo Kaiyo
Published: March 2003

background and objective Telomerase activity is present in most malignant tumours and might provide a mechanism for unlimited replication of neoplastic cells. Expression of the gene encoding human telomerase reverse transcriptase (hTERT), the telomerase catalytic subunit gene, is associated with telomerase activity, and it is overexpressed in most parathyroid carcinomas. We have therefore studied hTERT expression in parathyroid tumours.

methods In the present study, we assayed telomerase activity by the telomeric repeat amplification protocol (TRAP) and used in situ hybridization (ISH) to study hTERT mRNA expression in four parathyroid metastatic cancers, six adenomas and two parathyroid hyperplasia tissue specimens.

results Telomerase activity was detected by the TRAP assay in all of the parathyroid cancers (100%) but in none of the eight parathyroid benign lesions. hTERT gene expression was detected in the nuclei of the parathyroid cancer cells in all of the lesions (100%) but in none of the eight parathyroid benign lesions.

conclusions Our results demonstrate a correlation between telomerase activity and hTERT gene expression measured by ISH (P < 0·001) in parathyroid tumours. We succeeded in very clearly and sensitively demonstrating hTERT mRNA in parathyroid tissues by using a new probe.
Significant ethnic variation in total and free testosterone concentration
Authors: Heald Adrian H. , Ivison Fiona , Anderson Simon G. , Cruickshank Kennedy , Laing Ian , Gibson J. Martin
Published: March 2003

objective Measurement of serum testosterone is an integral part of the assessment of men presenting to endocrine clinics. Little is known about the variation of total bound or bioavailable testosterone by ethnic group. The principal determinant of testosterone bioavailability is SHBG, which itself is a marker for insulin sensitivity. Our aim was to examine variations in testosterone and SHBG levels across three ethnic groups in relation to ethnic differences in insulin sensitivity.

design Men of three ethnic groups living in Manchester, UK, were sampled randomly from population registers being of white European (n = 55), Pakistani (n = 50) and African‐Caribbean (AfC) origin (n = 75). Circulating serum testosterone and SHBG concentrations were measured and free testosterone calculated. Insulin sensitivity (HOMA‐S) and insulin secretory capacity (HOMA‐B) were determined from fasting plasma intact insulin and glucose values.

results Testosterone levels were lower in Pakistani men (mean 14·6 nmol/l, 95% confidence interval 12·6–16·6 nmol/l) than in Europeans (18·7, 16·8–20·6 nmol/l) or AfCs (18·0, 16·4–19·6 nmol/l) (F = 4·8, P = 0·009). Despite SHBG levels also being lower in Pakistani men (22·9, 19·4–26·5 nmol/l) compared with Europeans (28·7, 25·7–31·8 nmol/l) and AfCs (26·9, 23·9–30·0 nmol/l) (F = 3·0, P < 0·05), circulating free testosterone was significantly lower in the Pakistani group (367, 326–408 pmol/l) than in Europeans (455, 416–494 pmol/l) or AfCs (458, 424–492 pmol/l) (F = 6·8, P = 0·001).

Pakistani men were on average 4 cm shorter than other groups. However, the lower free testosterone persisted even when adjusted for height or waist–hip ratio. The lower SHBG in the Pakistani men was paralleled by a lower HOMA‐S (0·40, 0·25–0·56) compared with Europeans (0·77, 0·61–0·93) and AfCs (0·80, 0·66–0·93) (F = 8·2, P < 0·0001). SHBG correlated positively with HOMA‐S (ρ = 0·28, P < 0·001) and strongly with total testosterone (ρ = 0·54, P < 0·001). There was no difference in insulin secretory capacity (HOMA‐B) in Pakistani men compared with Europeans and AfCs.

Multiple linear regression analysis showed that total testosterone was independently and negatively related to ln fasting insulin (β = −0·28, P < 0·001) and age (β =−0·17, P = 0·02) and positively to ln SHBG (β = 0·23, P < 0·001) and height (β = 0·22, P = 0·001). There was no relationship with ethnicity or waist–hip ratio.

conclusion Both total bound and calculated free testosterone were lower in Pakistani men. SHBG levels were also lower in Pakistani men, in keeping with poorer insulin sensitivity. We propose that further work is necessary to establish ethnic‐specific ranges for the interpretation of total circulating and free testosterone levels in men.
Both fasting‐induced leptin reduction and GH increase are blunted in Cushing's syndrome and in simple obesity
Authors: Grottoli S. , Gauna C. , Tassone F. , Aimaretti G. , Corneli G. , Wu Z. , Strasburger C. J. , Dieguez C. , Casanueva F. F. , Ghigo E. , Maccario M.
Published: March 2003

background  Simple obesity and Cushing's syndrome (CS) are two clinical models of leptin hypersecretion coupled with GH hyposecretion. Fasting inhibits leptin while stimulating GH secretion in normal human subjects.

objectives  To clarify the effect of fasting on leptin and GH secretion in obesity and CS.

patients and protocol  We studied six women with CS [age 17–66 years; body mass index (BMI) 28·6 kg/m2], seven women with visceral obesity (OB; 20–41 years; BMI 42·9 kg/m2) and seven normal women (NS; 25–31 years; BMI 19·3 kg/m2). The effects of 36‐h fasting on 8‐h diurnal mean leptin, GH, insulin and glucose concentrations (mLEPTc, mGHc, mINSc and mGLUc) as well as on the IGF/IGFBP system were studied.

results  Before fasting, mLEPTc in OB and in CS were similar and both were higher (P < 0·01) than in NS. OB and CS showed similar mGHc, which were lower (P < 0·05) than in NS. Fasting induced a reduction in mLEPTc that was significant in NS and CS (P < 0·04) but not in OB. The mLEPTc in OB and CS after fasting remained higher (P < 0·05) than in NS. After fasting, OB and CS showed no increase in mGHc, although this clearly increased (P < 0·02) in NS. IGF‐I but not IGFBP‐3 levels decreased in all groups (P < 0·05). Fasting reduced mINSc and mGLUc while increasing IGFBP‐1 in all groups. After fasting, mINSc in OB and CS remained higher (P < 0·03) than in NS.

conclusions  Short‐term fasting has less inhibitory effect on leptin and no stimulatory effect on GH secretion in patients with Cushing's syndrome as well as simple obesity. After fasting, insulin levels in hypercortisolaemic and also in obese patients remained higher than in normal subjects suggesting that hyperinsulinism could play a role in the altered response of leptin and GH to starvation in these conditions.
Hormone replacement therapy: current controversies
Authors: Davison Sonia , Davis Susan R.
Published: March 2003

Postmenopausal hormonal therapy is used to manage the climacteric symptoms that impair the quality of life of a substantial number of women. The difficulty is achieving the desired effects with minimal side‐effects and no adverse health risks. Fundamental to this is understanding the physiology of oestrogen in women and the metabolism of the therapeutic compounds. Although the effects of oral oestrogen therapy have been studied extensively, there is insufficient evidence to assess adequately the independent effects of progestin use, other oestrogen compounds, differing doses and duration of treatment. We have reviewed some basic concepts of oestrogen physiology and how these relate to exogenous oestrogen administration, the risks of greatest concern, and the role of androgens and newer treatment alternatives.
Calf vein compliance increases following bed rest after aortocoronary bypass surgery
Authors: Leftheriotis G. , Legrand M. S. , Abraham P. , Kamuanga‐Subayi J. B. , Jardel A. , Saumet J. L.
Published: March 2003

Early post‐operative ambulation (<3 days) is expected to decrease the risk of venous thrombosis, whereas late ambulation (>7 days) increases the risk of orthostatic hypotension. The effect of post‐operative bed rest on calf vein compliance was studied before (D − 1) and 7 days (D + 7) after aortocoronary bypass surgery in 50 patients (41 men and nine women, 65 ± SD 10 years). Calf vein compliance was measured by strain gauge plethysmography and stepwise increases in thigh congestive pressure from 20 to 60 mmHg. Calf compliance [median (25 percentile–75 percentile)] increased significantly by 48% from D − 1 to D + 7 [0·044 (0·039–0·051) vs. 0·065 (0·048–0·083) ml (100 ml mmHg)−1,P<0·001]. This increase was reflected as increased calf volume for the 50 mmHg [D − 1 2·10 (1·75–2·65) vs. D + 7 2·60 (1·70–3·00) ml 100 ml−1,P<0·01] and 60 mmHg [D − 1 2·50 (2·10–2·95) vs. D + 7 3·20 (2·30–4·00) ml 100 ml−1,P<0·001] occlusion pressure levels. The associated pathologies (diabetes and arterial hypertension) and NYHA grades had no significant influence on the increase in compliance. Among the vasoactive therapeutic regimens, calcium channel blockers contributed significantly to the increased calf compliance, but only on D − 1. The increase in venous compliance following aortocoronary bypass surgery is multifactorial but should be considered for prophylactic management of these patients.
Myocardial perfusion scintigraphy (SPECT) during adenosine stress can be performed safely early on after thrombolytic therapy in acute myocardial infarction
Authors: Bouvier  , Höjer  , Hulting  , Ruiz  , Samad  , Jensen‐Urstad
Published: March 2003

The objective of this study was to evaluate the safety of myocardial perfusion scintigraphy with Tc‐99 m sestamibi during adenosine stress in patients with recent thrombolytically treated myocardial infarction. Eighty‐four patients with thrombolytically treated myocardial infarction, 59 males and 25 females, aged 62·9 ± 8·4, were eligible for myocardial perfusion scintigraphy during adenosine provocation. Exclusion criteria for adenosine stress were hypotension, unstable angina pectoris, cardiac failure, pericarditis and atrioventricular block (AV block) II–III. Adenosine‐stress and resting myocardial perfusion scintigraphy was performed 2–5 days after thrombolysis. Scintigraphy at rest was done 24 h after the stress study.

Sixty patients (71%) experienced some kind of side‐effects during adenosine infusion. The most frequent side‐effects were dyspnoea in 43/84 patients (51%) and unspecific chest discomfort in 26/84 patients (31%). During infusion, ST depressions or elevations on ECG were seen in 9 patients (11%), 5 of whom experienced atypical chest discomfort. Five patients (6%) described typical angina but none of them showed electrographic signs of myocardial ischaemia during infusion. Six patients (7%) developed transient AV block I–II. Reversible scintigraphic perfusion defects were seen in 67 patients (79%). No serious complications, such as death, reinfarction or severe arrhythmias, occurred during adenosine infusion or during a 3‐day clinical follow‐up period.

In conclusion, MIBI‐SPECT during adenosine stress is a safe diagnostic method that can be performed in most patients early on after thrombolytically treated acute myocardial infarction. Side‐effects are common but benign, and not different from those seen in patients with chronic coronary artery disease.
Finger skin blood flow in response to indirect cooling in normal subjects and in patients before and after sympathectomy
Authors: Bornmyr  , Svensson  , Söderström  , Sundkvist  , Wollmer
Published: March 2003

Finger skin blood flow was measured in 80 healthy subjects, using laser Doppler imaging during basal vasodilatation at a local temperature of 40°C. The response to cooling of the contralateral hand at 15°C was studied. A vasoconstriction index was calculated in all subjects and a nomogram was constructed, taking age into consideration. Compared with these normal subjects, four patients operated on with transthoracic endoscopic sympathectomy due to hand hyperhidrosis showed clearly attenuated responses. The results indicate that the test can be used to assess disturbances in the sympathetic regulation of the peripheral blood flow.
Compression‐induced pulsatile blood flow changes in human legs
Authors: Mayrovitz
Published: March 2003

Initial and sustained (7‐h) impacts of foot‐to‐knee compression bandaging on leg arterial pulsatile blood flow were assessed by nuclear magnetic resonance flowmetry in eight healthy supine subjects. A widely used bandaging method (zinc impregnated gauze + Coban) and a slight variant (Coban only) were applied one week apart to one leg. Blood flow was measured on each day of bandage application before and after bandaging and after 7 h of normal activity. Initial mean sub‐bandage pressures (lateral gaiter) were between 28·4 and 28·9 mmHg but were significantly reduced after 7 h to 16·3–19·4 mmHg. Overall below‐knee pulsatile blood perfusion was initially significantly increased by both methods mainly due to increased proximal blood flow. Bandaging was also associated with a decrease in blood perfusion of the nonbandaged control leg mainly due to a decrease in distal blood flow. Neither of these effects were sustained after 7 h. The fact that neither sub‐bandage pressure nor blood flow was sustained may indicate a causal linkage, a concept consistent with the finding of a linear relationship between afternoon blood flow and sub‐bandage pressure reductions. The implications of the present findings for venous ulcer therapy are speculative and based on the concept that arterial pulsatile flow augmentation is a positive feature. If so, more frequent bandage changes to provide transient flow stimulation or use of bandages to better maintain sub‐bandage pressure to sustain flow increases may be useful.
High blood pressure and muscle morphology/metabolism – causal relationship or only associated factors?
Authors: Krotkiewski  , Lithell  , Shono  , Wysocki  , Holm
Published: March 2003

As muscle tissue constitutes a main target organ for glucose metabolism and is responsible for the development of insulin resistance, it seems plausible to elucidate the relationship between blood pressure and muscle morphology and metabolism. The association between blood pressure and capillarization/morphology of the vastus lateralis muscle and metabolic variables was evaluated in 24 perimenopausal obese women [body mass index (BMI) 34·9 ± 1·1; waist–hip ratio (WHR) 0·90 ± 0·02]. The muscle enzyme activity of lipoprotein lipase (LPL), citrate synthase and glycogen synthase was determined. There was a significant negative correlation between the percentage of type I fibres and relative fibre area of type I on the one hand and systolic and diastolic blood pressure on the other. There was a negative correlation between the capillary density (i.e. number of capillaries/muscle fibre) and a positive correlation between the diffusion distance (fibre area supplied by one capillary) and diastolic blood pressure. The activities of LPL and citrate synthase were positively correlated with the percentage of type I and negatively correlated with the percentage of type II muscle fibres. The activity of LPL was also negatively correlated with plasma glucose and the insulin/C‐peptide ratio. The insulin/C‐peptide ratio was positively correlated with the percentage of type II muscle fibres. In stepwise multiple regression analyses, 20–30% of the variation in systolic and diastolic blood pressure could be explained by the variables of muscle fibre distribution. Excluding muscle morphological variables from the regression model, the insulin/C‐peptide ratio accounted for 13% of the variation in systolic and diastolic blood pressure. The results of the study show the close association between muscle morphology and blood pressure. It remains to be elucidated whether this association indicates a causal relationship.
Ankle–brachial index after maximum exercise in treadmill and cycle ergometers in athletes
Authors: Abraham P. , Desvaux B. , Saumet J. L.
Published: March 2003

Previous works have focused on the normal ankle and arm pressure response to maximum bicycle exercise or moderate walking tests. The aim of the present work was to compare the normal ankle and arm pressure and ankle–brachial index response to incremental maximum bicycle and treadmill exercise in 13 athletes (11 men, two women, 24 ± 11 years) No difference was found at rest on both ankle pressure 139 ± 21 vs. 163 ± 22 mmHg and ankle–brachial index 1·18 ± 0·09 vs. 1·17 ± 0·10 between bicycle and treadmill tests respectively (mean ± SD). One minute after maximum exercise, no difference in arm pressure was found between bicycle (182 ± 16 mmHg) and treadmill tests (190 ± 17 mmHg), whereas ankle pressure was 139 ± 21 vs. 163 ± 22 mmHg respectively (P<0·05). As a result, a significant difference was found in the ankle–brachial index 0·76 ± 0·10 vs.0·86 ± 0·10 (P<0·05) between bicycle and treadmill ergometers during the first minute of the recovery period. Although performed at comparable workloads, a significant difference was noted between running and cycling tests. Thereby, the limit cut‐off point for the diagnosis of lower extremity arterial disease in athletes defined for maximum bicycle tests may not apply to maximum incremental treadmill tests.
Ventilatory inefficiency for carbon dioxide during exercise in patients with pulmonary hypertension
Authors: Reybrouck T. , Mertens L. , Schulze‐Neick I. , Austenat I. , Eyskens B. , Dumoulin M. , Gewillig M.
Published: March 2003

The purpose of this study was to analyse the ventilatory efficiency for carbon dioxide (CO2) in the assessment of exercise tolerance in patients with pulmonary hypertension. Two groups of patients were studied. One group consisted of 37 patients with normal pulmonary artery pressure who underwent surgical closure of a left‐to‐right shunt. Another group was composed of 10 patients with pulmonary hypertension. Both patient groups were compared with the mean value of an age‐matched pool of normal control subjects. Aerobic exercise performance was assessed by determination of the ventilatory threshold. The ventilatory efficiency for CO2 was assessed by calculating the slope of ventilation over carbon dioxide below the ventilatory threshold. The slope of ventilation vs. carbon dioxide output in patients with pulmonary hypertension (48 ± 12) was steeper than the slope (31·3 ± 7·0) in patients with normal pulmonary artery pressure (P<0·05). Significant correlations (P<0·05) were found between the pulmonary artery pressure and the slope of pulmonary ventilation over carbon dioxide (r = 0·92) and also with the physiological dead space–tidal volume ratio at maximal exercise (r = 0·55). This was associated with a severe reduction in exercise performance in patients with pulmonary hypertension, whereas in patients with normal pulmonary artery pressure it was only slightly below the lower limit of normal. These results demonstrate that patients with pulmonary hypertension have an inefficient ventilatory response to metabolically produced CO2 during exercise, which severely limits exercise tolerance.