bluuebunny/crossref_metadata_2025 huggingface dataset:
Pituitary apoplexy induced by corticotrophin‐releasing hormone in a patient with Cushing's disease
Authors: Rotman‐Pikielny Pnina , Patronas Nicholas , Papanicolaou Dimitris A.
Published: December 2004

Pituitary apoplexy can occur spontaneously or following anterior pituitary stimulation tests. Apoplexy is a rare complication of Cushing's disease.

 We report a 19‐year‐old woman who was admitted to the National Institutes of Health for evaluation of possible Cushing's syndrome. Her symptoms and initial laboratory work were suggestive of Cushing's disease. Magnetic resonance imaging (MRI) revealed a macroadenoma of the pituitary gland. As part of her evaluation she received corticotrophin‐releasing hormone (CRH). Two days later she developed severe headache, accompanied by nausea and vomiting, followed by meningismus, ptosis and diplopia. A diagnosis of pituitary apoplexy was made and she was treated conservatively with dexamethasone. Her neurological symptoms resolved shortly afterwards. By the time of discharge her anterior pituitary function was suppressed. All symptoms and signs of Cushing's syndrome resolved thereafter.

 This is the first case to demonstrate that CRH administration can induce pituitary apoplexy in a patient with Cushing's disease. Therapy with glucocorticoids was effective in our case, suggesting that conservative treatment can be successfully and safely applied in certain cases with pituitary apoplexy.
Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects
Authors: Elbers Jolanda M. H. , Giltay Erik J. , Teerlink Tom , Scheffer Peter G. , Asscheman Henk , Seidell Jacob C. , Gooren Louis J. G.
Published: December 2004

objective Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex‐specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood.

design Prospective, intervention study.

subjects In 37 young (age range 16–36 years), nonobese [body mass index (BMI) < 29], transsexual subjects, effects of ethinyl oestradiol (100 µg/day) + cyproterone acetate (100 mg/day) administration were evaluated in 20 male‐to‐female transsexuals and of testosterone‐ester administration [250 mg intramuscularly (i.m.)/2 weeks] in 17 female‐to‐male transsexuals.

measurements We studied lipid spectrum, postheparin hepatic lipase (HL) and lipoprotein lipase (LPL) activity, blood pressure, glucose utilization (by euglycaemic hyperinsulinaemic clamp), and fat areas (by magnetic resonance imaging) at baseline and during 1‐year cross‐sex hormone administration.

results Oestrogens + antiandrogens increased high‐density lipoprotein (HDL)‐cholesterol and decreased LDL‐cholesterol, and HL activity, which are considered beneficial. But this combination also increased triglycerides, blood pressure, subcutaneous fat and visceral fat, and decreased the LDL‐particle size, LPL activity and insulin sensitivity, which are all considered detrimental. Testosterone reduced HDL‐cholesterol and the LDL‐particle size, and increased triglycerides and HL activity. An android fat distribution was induced (i.e. decreased subcutaneous and increased visceral fat). Blood pressure, total and LDL‐cholesterol, LPL activity and insulin sensitivity were mainly unaffected.

conclusions The effects of cross‐sex hormone treatment – in the dosages used in this study – in healthy, nonobese, young transsexual subjects do not show unequivocally that female sex steroids, given in large amounts to male subjects, have beneficial effects on cardiovascular profile and that high dose testosterone administration to female subjects is detrimental with respect to cardiovascular risk.
Oral administration of the growth hormone secretagogue NN703 in adult patients with growth hormone deficiency
Authors: Svensson J. , Monson J. P. , Vetter T. , Hansen T. K. , Savine R. , Kann P. , Bex M. , Reincke M. , Hagen C. , Beckers A. , Ilondo M. M. , Zdravkovic M. , Bengtsson B‐Å. , Korbonits M. ,   the NN703 Clinical Research Group
Published: December 2004

objective Little is known of the usefulness of GH secretagogues (GHSs) in GH‐deficient (GHD) adults. The objective of this study was to determine the number of responders to treatment with NN703 in GHD adults.

design A multicentre, randomized, double‐blind, and placebo‐controlled study.

patients Ninety‐seven GHD adults were included.

measurements The GH response before and after 1 week of oral treatment with NN703 (n = 83) or placebo (n = 14) was determined. The first and last dose of NN703 was 3 mg/kg, whereas the dose of NN703 was 1·5 mg/kg/day during the 6 days between the first and last doses. Furthermore, all 97 patients received 1 µg/kg GH‐releasing hormone (GHRH) 3 weeks after the last dose of NN703.

results Serum GH peak and area under curve (AUC) values after the first NN703 administration were greater than those after placebo administration (P < 0·05). However, after correction for the lower body mass index (BMI) in the NN703 group, this difference lost statistical significance. After 1 week of therapy, GH peak and AUC values were similar following the final doses of NN703 and placebo. Serum peak and AUC values of other anterior pituitary hormones were similar between the NN703 and placebo groups both after the first and last administration of study drug. Nine of the 83 patients (11%) responded with a serum peak GH concentration ≥ 5 µg/l after the first and/or last NN703 administration, whereas no patient responded after placebo administration. Serum IGF‐I was unaffected by 1‐week NN703 treatment, whereas serum IGFBP‐3 was increased (P < 0·05 vs. placebo) also after correction for BMI. Mean serum peak GH concentration after GHRH administration was 2·1 µg/l (±0·3, SEM), which was higher than that after the first NN703 administration (1·32 ± 0·3, P < 0·05).

conclusion NN703 administration was generally well tolerated. Eleven per cent of the GHD adult patients responded with a peak GH response ≥ 5 µg/l after the first and/or last administration of oral NN703. Although a majority of GHD adults will not respond to NN703, the present results suggest that oral NN703 treatment could be useful in some adult patients with moderately severe GHD. These patients may be identified by a test dose of GHS.
Iodine sufficiency and measurements of thyroid function in maternal hypothyroidism
Authors: Mitchell M. L. , Klein R. Z. , Sargent J. D. , Meter R. A. , Haddow J. E. , Waisbren S. E. , Faix J. D.
Published: December 2004

objectives To test the hypothesis that thyroglobulin (Tg) and free T4 (FT4) concentrations more than 2SD from the control mean are not increased in pregnancy in an iodine replete area in the absence of elevated TSH concentrations. The second hypothesis to be tested was that if such abnormalities in FT4 and Tg in the absence of elevated TSH concentrations were to exist they would not be associated with lowered IQs in the progeny.

design Cross‐sectional study in New England comparing TSH, Tg, antibodies to Tg and FT4 in volunteer nonpregnant women 20–40 years old with those in hypothyroid mothers and matched euthyroid control mothers. The results are contrasted with those from similar studies reported from iodine deficient areas.

subjects Sera obtained at 17 weeks gestation and stored at −20 °C for 8 years were retrieved and analysed from 62 mothers with subclinical hypothyroidism and 124 matched euthyroid mothers. The diagnosis of hypothyroidism was made by finding a TSH concentration > 97·7 percentiile for 25 000 consecutive pregnant women. Sera were also analysed from 53 healthy nonpregnant volunteer women aged 20–40 years.

measurements TSH, Tg and Tg antibodies were measured in the sera of the nonpregnant volunteers, and Tg and Tg antibodies in the sera of the pregnant women who had previously been analysed for TSH and FT4. The incidence of FT4 concentrations below the 2·3 percentile of nonpregnant laboratory controls was compared for the euthyroid and hypothyroid mothers and the laboratory normal controls.

results Thirty‐one per cent of the 62 hypothyroid mothers had FT4 concentrations below the 2·3 percentile compared with only one (0·8%) of the euthyroid mothers. Mean Tg concentrations did not differ between the nonpregnant controls and the euthyroid pregnant women, 14 ± 10 vs. 16 ± 10 µg/l. Tg concentration in the hypothyroid mothers was 44 ± 61, significantly greater than for either of the euthyroid control groups, P < 0·005. Positive antibodies to Tg were found in 9% and 10% of the control groups and 57% of the hypothyroid mothers, P < 0·0005. When TSH is included as an independent variable in multiple linear and logistic regressions, FT4 and Tg no longer correlate significantly with IQs.

conclusions The incidences of FT4 concentrations more than 2SD below the control mean and of Tg > 2SD above the control mean are significantly increased in hypothyroid mothers in iodlne‐sufficient New England. However, in the absence of elevated TSH concentrations, the incidences of such abnormalities in FT4 and TG are negligible. Indeed, concentrations for FT4, Tg and Tg antibodies for nonpregnant and pregnant controls in our iodine‐replete area do not differ significantly from each other or from previously reported normative concentrations with the methods used. Thus, pregnancy in New England neither increases Tg nor lowers FT4 concentrations.
Serum concentrations of remnant‐like particles in hypothyroid patients before and after thyroxine replacement
Authors: Ito Mitsuru , Takamatsu Junta , Matsuo Takashi , Kameoka Keiichi , Kubota Sumihisa , Fukata Shuji , Tamai Hajime , Miyauchi Akira , Kuma Kanji , Hanafusa Toshiaki
Published: December 2004

objectives  Remnant‐like particles (RLPs) reflect chylomicron remnants and very‐low‐density lipoprotein remnants, which are most likely to be atherogenic particles. To investigate the effect of thyroxine replacement on the metabolism of RLPs in hypothyroidism, we measured serum concentrations of RLPs during an oral fat‐loading test in patients with hypothyroidism before and after thyroxine replacement.

patients and methods  Thirteen patients with hypothyroidism, having serum‐free thyroxine (FT4) of 4·25 ± 2·23 pmol/l (mean ± SD) and TSH of 72·5 ± 27·7 mU/l, participated in the study. Two‐hundred grams of cream containing 32·9% of fat were given to each patient followed by blood draws every 2 h for 8 h. The patients became euthyroid after 3 months of T4 replacement, and the fat‐loading tests were then repeated.

results  Fasting levels of serum total cholesterol and low‐density lipoprotein cholesterol were remarkably decreased after T4 therapy (P < 0·0005). Serum high‐density lipoprotein cholesterol and triglyceride were also decreased by T4 therapy, not so remarkably but significantly (P < 0·05). Activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) increased 52% and 85%, respectively, from the pretreatment values. Serum concentrations of remnant‐like particle cholesterol (RLP‐C) and remnant‐like particle triglyceride (RLP‐TG), measured by immunoseparation assays, significantly decreased from 0·14 ± 0·03 to 0·09 ± 0·03 mmol/l (P < 0·0005) and from 0·19 ± 0·11–0·11 ± 0·07 mmol/l (P < 0·01), respectively. In the fat‐loading test, serum low‐density lipoprotein cholesterol concentrations were not changed, while serum RLPs concentrations were increased and remained high throughout the test, with the peak value at 6 h in a hypothyroid condition. In an euthyroid condition after T4 therapy, the peak values of RLPs were obtained at 4 h, and the concentrations were decreased rapidly. As the result, areas under the curve of serum RLPs were decreased remarkably after T4 therapy.

conclusions  Hypothyroidism seems to be associated with a decrease in metabolism of serum RLPs. Such altered metabolism of RLPs may be related to the decreased activities of LPL and HTGL and can be corrected by T4 replacement therapy.
Molecular analysis of 5α‐reductase type 2 gene in eight unrelated egyptian children with suspected 5α‐reductase deficiency: prevalence of the G34R mutation
Authors: Mazen Inas , Gad Yehia Z. , Hafez Mona , Sultan Charles , Lumbroso Serge
Published: December 2004

objective Analysis of the 5α‐reductase type 2 (SRD5A2) gene in Egyptian patients with suspected 5α‐reductase (5αR) deficiency.

patients and methods Eight unrelated patients, originating from different geographical areas of Egypt, were referred to the Department of Pediatrics. Six prepubertal and two postpubertal patients presented with ambiguous genitalia. Four were being reared as females while the others were being reared as males. Six patients were products of consanguineous marriages. All patients had 46,XY karyotype. Basal and post‐human chorionic gonadotrophin (hCG) stimulation plasma levels of testosterone and dihydrotestosterone were determined. Sequencing of five exons of the SRD5A2 gene was carried out.

results All patients had normal male testosterone levels, both basal and post‐hCG stimulation. The T/DHT ratio was available for six patients and showed values that ranged from normal to high. Three different homozygous mutations were identified. One patient carried a Y235F substitution and two had a N160D substitution. Interestingly, all five of the other patients had the G34R mutation. The parents were heterozygous for the mutations, although the mother of one patient was homozygous for the G34R mutation.

conclusion Among eight unrelated Egyptian children with 5α‐reductase deficiency, the G34R mutation was identified in five patients. The high consanguinity rate in Egypt suggests a common ancestor with a founder gene effect in cases of G34R mutation.
Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction
Authors: Aversa Antonio , Isidori Andrea M. , Spera Giovanni , Lenzi Andrea , Fabbri Andrea
Published: December 2004

objectives We have recently shown that, in men with erectile dysfunction (ED), free testosterone (FT) directly correlates with penile arterial inflow. This led us to further investigate the effect(s) of androgen administration on cavernous arteries in patients failing sildenafil treatment.

design Prospective randomized placebo‐controlled pilot study.

patients Twenty patients with arteriogenic ED as evaluated by dynamic colour duplex ultrasound (D‐CDU) studies, normal sexual desire but testosterone (T) and FT in the lower quartile of normal range (low‐normal), not responding to sildenafil treatment (100 mg) on six consecutive attempts.

measurements All patients had D‐CDU, hormonal [LH, prostate‐specific antigen (PSA), total and free testosterone, sex hormone‐binding protein (SHBG), oestradiol], biochemical [haematocrit, low‐density lipoprotein (LDL) and HDL cholesterol, triglycerides], and sexual evaluations [International Index of Erectile Function (IIEF)] before and after 1 month of therapy with transdermal testosterone (5 mg/day, n = 10) or placebo along with sildenafil treatment on demand. Measurement of flow parameters by D‐CDU on cavernous arteries was the primary endpoint of the study. Improvement of erectile function was assessed using the IIEF questionnaire and the Global Assessment Question (GAQ).

results One month treatment with transdermal testosterone led to a significant increase in T and FT levels (23·7 ± 3·3 SD vs. 12·8 ± 2·1 nmol/l and 473 ± 40·2 vs. 260 ± 18·1 pmol/l, P < 0·01, respectively). In addition testosterone administration induced a significant increase in arterial inflow to cavernous arteries measured by D‐CDU (32 ± 3·6 vs. 25·2 ± 4 cm/s, P < 0·05), with no adverse effects. Also, a significant improvement in erectile function domain score at IIEF was found in the androgen but not in the placebo‐treated patients (21·8 ± 2·1 vs. 14·4 ± 1·4, P < 0·05) which was associated with significant changes in the GAQ score (80%vs. 10%, P < 0·01).

conclusions In patients with arteriogenic ED and low‐normal androgen levels, short‐term testosterone administration increases T and FT levels and improves the erectile response to sildenafil likely by increasing arterial inflow to the penis during sexual stimulation.
Growth hormone treatment improves body composition in adults with Prader–Willi syndrome
Authors: Höybye Charlotte , Hilding Agneta , Jacobsson Hans , Thorén Marja
Published: December 2004

objective Low growth hormone (GH) secretion and hypogonadism are common in patients with Prader–Willi syndrome (PWS). In this study we present the effects of GH treatment on body composition and metabolism in adults with PWS.

patients and measurements Nineteen patients with clinical PWS were recruited, 13 had PWS genotype. They were randomised to treatment with placebo or GH (Genotropin®, Pharmacia Corporation, Sweden) 0·8 IU (0·2 mg) daily for 1 month and then 1·6 IU (0·5 mg) daily for 5 months. Thereafter patients recieved open label treatment so that all had 12 months of active GH treatment. Doses were individually titrated to keep serum IGF‐I within the normal range for age. Body composition using dual energy X‐ray absorptiometry (DXA), metabolic and endocrinological parameters, including oral glucose tolerance test (OGTT), were studied every 6 months. Seventeen patients, nine men and eight women, 17–32 years of age, with a mean body mass index (BMI) of 35 ± 3·2 kg/m2 completed the study.

results Compared to placebo, GH treatment increased IGF‐I (P < 0·01) levels and decreased body fat (P = 0·04). When all patients recieved GH treatment a mean reduction in body fat of 2·5% (P < 0·01) concomitant with a mean increase in lean body mass of 2·2 kg (P < 0·05) was seen. Significant changes in body composition were only seen in the patients with the PWS genotype. Lipid profiles were normal in most patients before treatment and did not change. OGTT was impaired in five patients at 12 months, but two of these patients increased in fat mass. Insulin levels were unchanged. According to homeostasis model assessment (HOMA), insulin resistance did not change. Side‐effects attributed to water retention occurred in three patients, one of whom had to be given increased diuretic therapy.

conclusion This study shows beneficial effects of GH treatment on body composition in adult PWS patients without significant side‐effects. Consequently, further studies are encouraged.
Giant prolactinomas in men: efficacy of cabergoline treatment
Authors: Corsello S. M. , Ubertini G. , Altomare M. , Lovicu R. M. , Migneco M. G. , Rota C. A. , Colosimo C.
Published: December 2004

objective The term ‘giant prolactinoma’ can be used for tumours larger than 4 cm in diameter and/or with massive extrasellar extension. Cabergoline (CAB), a long‐lasting dopamine agonist (DA), safe and well tolerated, is effective in normalizing PRL levels and inducing tumour shrinkage in micro‐ and macroprolactinomas. The purpose of this prospective study was to evaluate the efficacy and safety of CAB also for giant prolactinomas.

patients and methods Ten men with giant prolactinomas with a median age of 44·8 years were treated with CAB. Before CAB, four patients had previously undergone transsphenoidal surgery without modifying the parasellar extension of the tumour or their visual defects. Pretreatment serum prolactin (PRL) levels ranged between 1230 and 22 916 µg/l (mean ± SEM: 5794 ± 1996) and tumour volume was between 21·8 and 105·5 cm3 (mean ± SEM: 50·7 ± 8·8).

CAB was administered at an initial low dose of 0·5 mg three times a week and, in five patients who did not achieve serum PRL normalization, the dose was progressively increased up to 10·5 mg/week. The duration of treatment was 13–68 months (mean 38·9). PRL levels and pituitary target organ hormones were assayed before, after 30 days and then every 3 months after the beginning of CAB treatment. Magnetic resonance imaging (MRI) was carried out before, after 1–3 months, after 6 months and then every 10–12 months to evaluate tumour shrinkage.

results In every patient, a significant PRL decrease (P = 0·0086) of at least 96% of the pretreatment values occurred (from 5794 ± 1996 to 77 ± 38, mean ± SEM); a persistent normalization of PRL levels was achieved in five out of 10 patients (50%) beginning from the first 3–6 months of CAB treatment (only one patient needed 12 months of therapy). A significant tumour shrinkage (P = 0·0003) was achieved after 12 months of therapy in nine out of 10 patients (90%), with a volume reduction greater than 95% in three, of 50% in four and 25% in two patients. Tumour volume decreased from 50·7 ± 8·8 to 28·6 ± 9·4 and then to 22·3 ± 8·8 cm3 (mean ± SEM) after 6 and 12 months of CAB treatment, respectively. An improvement of visual field defects (VFD) was obtained in six of the seven patients presenting visual impairment before CAB treatment. Among the eight patients presenting libido and potency (L‐P) failure, five normalized their PRL levels. In two of these a complete restoration of libido and potency was observed. Three patients with secondary hypoadrenalism and a patient with secondary hypothyroidism were treated with substitutive therapy during all the study time. The drug was well tolerated by all patients and no one discontinued the therapy.

conclusions These data suggest that, in giant, aggressive prolactinomas, CAB represents a first‐line therapy effective in reducing PRL levels and determining tumour shrinkage.
Adrenarche – physiology, biochemistry and human disease
Authors: Auchus Richard J. , Rainey William E.
Published: December 2004

Adrenarche refers to the onset of dehydroepiandrosterone (DHEA) and DHEA‐sulphate (DHEA‐S) production from the adrenal zona reticularis that can be detected at around 6 years of age. The phenotypic result of adrenarche is pubarche or the development of axillary and pubic hair that occurs in both girls and boys at about age 8. The phenomenon of adrenarche is unique to human beings and to some Old World primates, and a reversal of adrenarche appears to occur in the ageing process. Premature and exaggerated adrenarche can be indicative of future onset of adult diseases, thus increasing the clinical relevance of adrenarche. The physiological triggers of adrenarche and the role(s) of DHEA‐S remain speculative. However, the biochemical pathways that define adrenarche have been characterized in detail, and the appearance of key enzymes and cofactors in the adrenal zona reticularis track with the progression of adrenarche. This article reviews the clinical manifestations of adrenarche, the biochemistry of the enzymes involved in DHEA‐S production, and the cell biology of the adrenal zona reticularis.
Management of adrenocortical carcinoma
Authors: Allolio Bruno , Hahner Stefanie , Weismann Dirk , Fassnacht Martin
Published: December 2004

Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Patients present with signs of steroid hormone excess (e.g. Cushing's syndrome, virilization) or an abdominal mass. Tumour size at presentation (mean diameter at diagnosis > 10 cm) is the most important indicator of malignancy. In addition, computed tomography (CT) typically demonstrates an inhomogeneous adrenal lesion with irregular margins and variable enhancement of solid components after intravenous contrast media. Magnetic resonance imaging (MRI) is equally effective as CT and is particularly helpful to visualize invasion into large vessels. Complete tumour removal (R0 resection) offers by far the best chance for long‐term survival and therefore surgery is the treatment of choice in stage I–III ACC. Despite tumour resection for cure most patients will eventually develop local recurrence or distant metastases. Thus adjuvant treatment options need to be evaluated in high‐risk patients (e.g. radiation therapy of the tumour bed and/or chemotherapy). In tumour recurrence re‐operation should always be considered. In metastatic disease (stage IV ACC) not amenable to surgery mitotane (o,p′DDD) remains the first‐line therapy. Drug monitoring is needed for effective treatment aiming at concentrations between 14 and 20 mg/l. Patients not responding to mitotane may benefit from cytotoxic chemotherapy (23% partial remissions, 4% complete remissions). Only large prospective multicentre trials comparing different treatment options will allow to make systematic progress in the management of ACC.
Early postoperative indicators of late outcome in acromegalic patients
Authors: Takahashi Jun A. , Shimatsu Akira , Nakao Kazuwa , Hashimoto Nobuo
Published: December 2004

objective  According to current criteria, normalised serum IGF‐1 and glucose‐suppressed GH < 1 ng/ml are indicators of biochemical cure in acromegalic patients. We performed a retrospective study to assess whether the attainment of these values in the early postoperative period was predictive of future IGF‐1 normalisation and disease inactivity.

patients, measurements and results  Between 1978 and 1999, 78 acromegalic patients underwent resection for pituitary adenomas. At the end of the mean follow‐up period of 7 years, 43 (55·1%) showed normalised IGF‐1 levels and no disease activity. In 51 cases, both IGF‐1 and glucose‐suppressed GH were examined within the first postoperative month. Of this group, all 19 patients who had early glucose‐suppressed GH < 1 ng/ml and were treated by surgery alone maintained normal IGF‐1 levels throughout the follow‐up; four of them demonstrated delayed (i.e. more than 30 days after the operation) IGF‐1 normalisation. In 19 patients with early glucose‐suppressed GH levels of 1–4 ng/ml, seven of 11 patients with early normalised IGF‐1 and two of eight patients with early IGF‐1 elevation manifested eventual IGF‐1 normalisation. However, none of the 13 patients with early glucose‐suppressed GH > 4 ng/ml attained IGF‐1 normalisation. Both univariate and multivariate analyses indicated that early glucose‐suppressed GH was a significant factor for predicting late normalised IGF‐1; the cut‐off value was 1·5 ng/ml (sensitivity: 0·97; specificity: 0·75; odds ratio: 90).

conclusion  The attainment of both normalised IGF‐1 and glucose‐suppressed GH < 1 ng/ml, even during the early postoperative period, suggests absolute cure in acromegalic patients. However, even in patients who do not meet both criteria within the first postoperative month, glucose‐suppressed GH < 1·5 ng/ml, or glucose‐suppressed GH < 4 ng/ml coupled with early IGF‐1 normalisation indicate the possibility of eventual normalisation of IGF‐1 and disease inactivity without adjuvant therapy. These postoperative parameters may be useful for assessing the desirability of further treatment.
Successful treatment of childhood‐onset Cushing's disease is associated with persistent reduction in growth hormone secretion
Authors: Carroll P. V. , Monson J. P. , Grossman A. B. , Besser G. M. , Plowman P. N. , Afshar F. , Savage M. O.
Published: December 2004

objective  Although Cushing's disease (CD) rarely occurs in childhood, affected children commonly fail to achieve predicted adult height. Hypercortisolaemia results in reduced GH secretion and GH‐deficiency may persist or demonstrate delayed recovery after successful treatment of CD in adults. Whether recovery of spontaneous GH secretion occurs following treatment of childhood CD has yet to be established.

design and patients  We performed a retrospective analysis of the GH status of 13 children (10 males; 12·8 ± 1·0 years, mean ± SE) who had undergone successful treatment of CD that occurred prior to the completion of linear growth. Each underwent transsphenoidal hypophysectomy, resulting in satisfactory control of glucocorticoid levels in 7/13 (54%). The remaining six patients (46%) received fractionated external beam irradiation (4500 Gy). At the time of GH assessment, circadian dynamics of cortisol were normal in eight patients and five were receiving titrated glucocorticoid replacement.

measurements  GH status was assessed using the peak response to a provocative stimulus. Eleven out of 13 underwent testing with insulin‐induced hypoglycaemia (nadir plasma glucose ≤ 2·2 mmol/l) and glucagon provocation was used in 2/13. Severe GH‐deficiency was defined as a peak GH response < 9 mU/l, and a normal response as > 30 mU/l. Intermediate values were taken to represent subnormal GH status. Assessment of GH status was performed 39 ± 10 months (median ± SE) following successful treatment (range 9–108 months).

results  Using these criteria 4/13 (31%) patients had severe GH‐deficiency. Only 2/13 (15%) had a normal response. 7/13 (54%) achieved peak GH levels in the subnormal range. Those with multiple pituitary hormone deficiencies were most likely to have lower peak GH levels, but there was no clear effect of pituitary irradiation or relationship between duration post cure and peak GH response.

conclusion   GH‐deficiency is common and may persist for many years following successful treatment of CD prior to completion of linear growth. External radiotherapy does not necessarily result in severe GH‐deficiency in the short term. Assessment of GH status and consideration of GH treatment should be considered following treatment of CD in childhood and adolescence in order to maximize the opportunities to achieve a satisfactory final adult height. In those with subnormal GH responses, continued assessment is necessary to determine whether the GH axis subsequently recovers or if these patients develop features of the adult GH‐deficiency syndrome.
Effects of oral contraceptives on circulating osteoprotegerin and soluble RANK ligand serum levels in healthy young women
Authors: Hofbauer Lorenz C. , Schoppet Michael , Schüller Per , Viereck Volker , Christ Michael
Published: December 2004

objective  Osteoprotegerin (OPG) represents a secreted cytokine which regulates bone mass by blocking receptor activator of nuclear factor‐κB ligand (RANKL), the principal regulator of osteoclast function. In vitro, OPG production is upregulated by oestrogens in osteoblastic lineage cells, a mechanism that has been discussed as a protective paracrine mechanism of oestrogens on the skeleton. To define the effects of oestrogens on the RANKL/OPG system in vivo, we evaluated OPG and both free and total soluble RANKL (sRANKL) serum levels in healthy young women with or without oral contraceptives.

design and patients  Serum levels of OPG and sRANKL were prospectively assessed in a cohort of healthy young women with (n = 30) or without (n = 25) combined oestrogen–progestin‐based oral contraceptives.

measurements  OPG, total and free sRANKL serum levels were determined by enzyme‐linked immunosorbent assays (ELISA).

results  In women using oral contraceptives, OPG serum levels were significantly higher (2·71 ± 1·42 pmol/l) compared to nonusers (1·35 ± 1·02 pmol/l; P = 0·0003), whereas free (P = 0·55) and total (P = 0·24) sRANKL serum levels did not differ between both groups. This resulted in an increased OPG/free sRANKL ratio (P = 0·02) in women on oral contraceptives. During the ovarian cycle, OPG (P = 0·22) and free sRANKL (P = 0·99) serum levels remained unchanged in women without oral contraceptives (n = 19), while total sRANKL levels were higher in the follicular than in the luteal phase (P = 0·02).

conclusions  Intake of oral contraceptives is associated with increased OPG serum levels, but not sRANKL levels, resulting in a higher OPG/sRANKL ratio. This may contribute to the positive effects of oral contraceptives on the skeleton.
Effects of conjugated oestrogen and droloxifene on the renin–angiotensin system, blood pressure and renal blood flow in postmenopausal women
Authors: Seely Ellen W. , Brosnihan K. Bridget , Jeunemaitre Xavier , Okamura Kyoko , Williams Gordon H. , Hollenberg Norman K. , Herrington David M.
Published: December 2004

objective  The aim of this study was to evaluate the effect of conjugated equine oestrogen (CEE), and droloxifene, a selective oestrogen receptor modulator (SERM) on individual components of renin–angiotensin–aldosterone (RAAS) and blood pressure (BP) in postmenopausal women.

design and patients  Twenty‐one normotensive (NT) and 10 hypertensive (HT) postmenopausal women received either CEE (0·625 mg/day) or droloxifene (60 mg/day) for 6 weeks and, after a 4‐week washout, were restudied on the alternate medication.

measurements  Hormones of the RAAS and supine BP were measured prior to and at the end of each drug treatment in all subjects. In a subgroup of the NT (n = 10), 24 h ambulatory BP was performed and renal blood flow was determined by PAH clearance both basally and in response to 45‐min angiotensin II (Ang II) infusion (3 ng/kg/min).

results  CEE significantly increased angiotensinogen, decreased active renin and angiotensin‐converting enzyme (ACE), and maintained plasma immunoreactive (ir) angiotensin I (Ang I) levels compared to baseline. With droloxifene, angiotensinogen, active renin and Ang I remained unchanged. Both CEE and droloxifene significantly increased plasma ir–Ang II levels (pmol/l) in NT (baseline: 25·7 ± 2·5, CEE: 36·6 ± 3·4, droloxifene: 33·3 ± 3·1, P < 0·002) and HT women (baseline: 17·9 ± 2·3, CEE: 27·9 ± 3·2, droloxifene: 25·9 ± 4·9, P < 0·005). Renal blood flow was lower on CEE (P = 0·02) compared with baseline. Systemic BP (supine and 24‐h ambulatory) was unchanged during both treatments.

conclusion  This study demonstrates higher circulating levels of ir–Ang II with CEE and droloxifene.
Kidney size estimation in piglets using dimercaptosyccinic acid (DMSA) scintigraphy
Authors: Wallin L. , Thörne J. , Palmer† J. , Bajc M.
Published: December 2004

The objective of this study was to validate kidney size measurements obtained by DMSA scintigraphy in kidneys of sizes relevant in paediatric practice. Kidney length, width and volume were measured by DMSA scintigraphy in 10 piglets in vivo and compared with measurements on excised kidneys using callipers, planar scintigraphy and submersion in water. In addition, a kidney phantom was constructed and placed in a torso phantom. The length, width and volume of the kidney phantom were compared with planar and tomographic scintigraphic measurements. The mean overestimation of kidney length by scintigraphy was 1·7% (± 1·2%) on excised kidneys and 3·9% (± 2·4%) in vivo. The corresponding figures for width measurements were 7·0% (± 3·9%) and 7·8% (± 4·4%). Tomography volume estimation overestimated the submersion volume by 23% (± 12%). Scintigraphic measurements on the phantom overestimated length by 5%, width by 8% and volume by 11%. Scintigraphic renal length measurements are reliable and differ from the anatomical length by <4% compared with excised kidneys and <8% in vivo. Scintigraphic width measurements and volume estimations, especially on small kidneys, are less reliable.
Stiffness of the common carotid artery in healthy 50‐year‐old subjects
Authors: Jonason T. , Henrikssen E. , Kangro T. , Nilsson H. , Vessby B. , Ringqvist I.
Published: December 2004

We examined whether, in a group of healthy 50 year‐old subjects, there was a relation between the stiffness of the common carotid artery and risk factors for atherosclerosis and, further, if there was a sex difference in these healthy individuals. A group of 248 healthy subjects (123 men and 125 women), all 50 years of age, were examined. The elastic properties of the common carotid artery, measured in terms of stiffness index, were investigated with an ultrasound technique. Men had significantly higher stiffness index than women (5·46 ± 1·32 vs. 5·04 ± 1·05, P<0·01). The arterial diameter was significantly larger in men. When comparing stiffness index in a subgroup of 38 men and women with similar arterial diameters, no significant difference in stiffness index was found. Multivariate analysis showed that smoking habits, measured as pack–years, insulin levels and the low‐density lipoprotein (LDL)‐/high‐density lipoprotein (HDL)‐cholesterol ratio was independently significantly associated with the stiffness index. Sex did not emerge as a significant variable. In conclusion, there is a relation between the stiffness of the carotid arteries and risk factors for atherosclerosis such as smoking, insulin levels and LDL‐/HDL‐cholesterol ratio in healthy 50‐year‐old subjects. The stiffness is higher in men than in women, probably dependent on differences in arterial size and possibly also on risk factors.
Morbid obesity does not preclude successful renal transplantation
Authors: Bennett William M , McEvoy Kevin M , Henell Karen R , Valente John F , Douzdjian Viken
Published: December 2004

Abstract: Many renal transplantation centers arbitrarily deny transplantation to patients with morbid obesity usually defined as body mass index >35. We present a series of 173 primary renal transplant patients in a new transplant program that accepted all recipients with 3 yrs or greater life expectancy and no active malignancy or infection. When the patient outcomes are divided into groups by body mass index, it can be seen as expected that patients with body mass index >30 have an increased prevalence of wound infections (p < 0.05). However, aside from this complication there are no statistically significant outcome differences between the three groups realizing the possibility of type II statistical error because of small numbers. Graft survival, patient survival and other surgical complications are the same in all groups regardless of body mass index. At the end of the 3‐yr interval with a minimum transplant follow‐up of 3 months, 169 of 173 patients were alive and 163 of 173 transplants were functioning. Based on our experience, morbid obesity should not be used to exclude patients arbitrarily from transplantation anymore than advanced age or diabetes should.
Post‐liver transplant acute renal failure: factors predicting development of end‐stage renal disease*
Authors: Paramesh Anil S , Roayaie Sasan , Doan Yvette , Schwartz Myron E , Emre Sukru , Fishbein Thomas , Florman Sander , Gondolesi Gabriel E , Krieger Nancy , Ames Scott , Bromberg Jonathan S , Akalin Enver
Published: December 2004

Abstract:  Background:  Acute renal failure (ARF) occurs in 5–50% ofpatients undergoing orthotopic liver transplantation (OLT). The aim of this study was to determine factors that might predict the development of end stage renal disease (ESRD) in patients who had ARF after OLT.

Methods:  We studied all OLT recipients between 9/1/1988 through 12/31/2000.

Results:  A total of 1602 patients underwent OLT during the study period. About 350 patients (22%) developed ARF requiring dialysis post‐operatively. One hundred and twenty‐three (39.8%) died within a year after OLT. Median follow up was 5.8 yr (range 1–12 yr). Forty‐three patients (23%) developed ESRD over median of 3.79 yr (range 1–8 yr). Multivariate logistic regression analysis revealed creatinine levels >1.7 mg/dL at 1 yr (p < 0.001), cyclosporine as immunosuppression (p = 0.026), and the presence of diabetes pre‐OLT (p < 0.001) to be associated with the development of ESRD. The development of ESRD did not decrease patient survival (p = 0.111). ESRD patients who received subsequent kidney transplantation had significantly improved survival rates (p = 0.005).

Conclusions:  Serum creatinine levels at 1 yr, cyclosporine as immunosuppression, and the presence of diabetes pre‐OLT are independent predictive factors for the development of ESRD. ESRD patients who received kidney transplantation had higher10‐yr survival rates when compared with patients maintained on dialysis.
Cardiovascular and renal phenotyping of genetically modified mice: A challenge for traditional physiology
Authors: Fitzgerald Sharyn M , Gan Liming , Wickman Anna , Bergström Göran
Published: December 2004

1. The advent of techniques to genetically modify experimental animals and produce directed mutations in both a conditional and tissue‐specific manner has dramatically opened up new fields for physiologists in cardiovascular and renal research.

2. A consequence of altering the genetic background of mice is the difficulty in predicting the phenotypic outcome of the genetic mutation. We therefore suggest that physiologists may need to change their current experimental paradigms to face this new era. Hence, our aim is to propose a complementary research philosophy for physiologists working in the post‐genomic era. That is, instead of using strictly hypothesis‐driven research philosophies, one will have to perform screening studies of mutant mice, within a field of interest, to find valuable phenotypes. Once a relevant phenotype is found, in‐depth studies of the underlying mechanisms should be performed. These follow‐up studies should be performed using a traditional hypothesis‐driven research philosophy.

3. The rapidly increasing availability of mutated mouse models of human disease also necessitates the development of techniques to characterize these various mouse phenotypes. In particular, the miniaturization and refinement of techniques currently used to study the renal and cardiovascular system in larger animals will be discussed in the present review. Hence, we aim to outline what techniques are currently available and should be present in a laboratory to screen and study renal and cardiovascular phenotypes in genetically modified mice, with particular emphasis on methodologies used in the intact, conscious animal.
Nucleotides modulate renal ischaemia–reperfusion injury by different effects on nitric oxide and superoxide
Authors: López‐Martí J , Sola A , Pi F , Alfaro V , Marco A , Hotter G
Published: December 2004

1. The present study investigated the effects of kidney ischaemia duration on nitric oxide (NO) and superoxide (O2–) generation at reperfusion and the role of xanthine and adenosine as mediators of NO/O2– generation.

2. The effect of the duration of ischaemia on renal nucleotide levels was studied in two ischaemic groups (10 and 30 min). The role of adenosine and xanthine was studied in ischaemic–reperfused groups (subjected to 10 and 30 min ischaemia and 60 min reperfusion).

3. Tissue levels of adenosine decreased significantly after 30 min ischaemia, whereas xanthine/hypoxanthine levels increased concomitantly with renal dysfunction and histological damage.

4. Nitric oxide production increased significantly after 10 min ischaemia and 60 min reperfusion, whereas lipoperoxidation increased significantly after 30 min ischaemia and 60 min reperfusion. The administration of theophylline (40 mg/kg, i.p.) reversed the early increase in NO production.

5. Xanthine supplementation decreased renal function and increased lipoperoxidation.

6. In conclusion, NO/O2– production and the subsequent renal injury/dysfunction may be modified by changes in the adenosine and xanthine levels of the injured kidney, although the present data show a significant in vivo role only for xanthine.
Low‐affinity neurotrophin receptor with targeted mutation of exon 3 is capable of mediating the death of axotomized neurons
Authors: Murray Simon S , Bartlett Perry F , Lopes Elizabeth C , Coulson Elizabeth J , Greferath Una , Cheema Surindar S
Published: December 2004

1. In vivo studies have shown that the low‐affinity 75 kDa neurotrophin receptor (p75NTR) is involved in axotomy‐induced cell death of sensory and motor neurons. To further examine the importance of p75NTR in mediating neuronal death in vivo, we examined the effect of axotomy in the p75NTR‐knockout mouse, which has a disrupted ligand‐binding domain.

2. The extent of sensory and motor neuron loss in the p75NTR‐knockout mouse following axotomy was not significantly different to that in wild‐type mice. This suggests that disruption of the ligand‐binding domain is insufficient to block the cell death process in axotomized neurons.

3. Immunohistochemical studies showed that axotomized neurons continue to express this mutant receptor with its intracellular death‐signalling moiety intact.

4. Treatment with antisense oligonucleotides targeted against p75NTR resulted in significant reduction in the loss of axotomized neurons in the knockout mouse.

5. These data suggest that the intracellular domain of p75NTR is essential for death‐signalling and that p75NTR can signal apoptosis, despite a disrupted ligand‐binding domain.
Effects of dietary Angelica keiskei on lipid metabolism in stroke‐prone spontaneously hypertensive rats
Authors: Ogawa Hiroshi , Nakashima Seiji , Baba Kimiye
Published: December 2004

1. The effect of dietary Angelica keiskei on lipid metabolism was examined in stroke‐prone spontaneously hypertensive rats (SHRSP).

2. Six‐week‐old male SHRSP were fed diets containing 0.2% A. keiskei extract (ethyl acetate extract from the yellow liquid of stems) for 6 weeks with free access to the diet and water.

3. Elevation of systolic blood pressure tended to be suppressed on and after 2 weeks; however, this effect was not statistically significant.

4. Serum levels of cholesterol and phospholipid in SHRSP were significantly elevated after treatment with A. keiskei extract and this effect was accompanied by significant increases in serum apolipoprotein (Apo) A‐I and ApoE concentrations. These changes in the serum were due to increases in high‐density lipoprotein (HDL) containing ApoA‐I and ApoE.

5. In the liver, significant decreases in relative weight and triglyceride content were observed in SHRSP after treatment with A. keiskei extract. An investigation of mRNA expression of enzymes involved in hepatic triglyceride metabolism indicated a decreased level of hepatic Acyl‐coenzyme A synthetase mRNA expression.

6. In conclusion, dietary A. keiskei produces elevation of serum HDL levels and a reduction of liver triglyceride levels in SHRSP.
WF‐536 INHIBITS METASTATIC INVASION BY ENHANCING THE HOST CELL BARRIER and INHIBITING TUMOUR CELL MOTILITY
Authors: Nakajima Masahide , Katayama Ken‐ichi , Tamechika Ichiro , Hayashi Kazutaka , Amano Yusaku , Uehata Masayoshi , Goto Nobuharu , Kondo Takao
Published: December 2004

1. Rho‐associated coiled‐coil forming protein serine/threonine kinase (ROCK) is involved in the development of tumour metastasis. Wf‐536, (+)‐(R)‐4‐(1‐Aminoethyl)‐N‐(4‐pyridyl) benzamide monohydrochloride, a novel inhibitor of ROCK, inhibits tumour metastasis in some animal models. To metastasise, tumour cells have to disturb the tight intercellular junctions and the basement membrane matrix of the host tissue, which, respectively, create an intercellular barrier and the extracellular membrane. To clarify the mechanism of Wf‐536 in inhibition of tumour metastasis, we analysed the effect of Wf‐536 on the transition of tumour cells through the host cell layer and the basement membrane in in vitro systems.

2. In a coculture system of human fibrosarcoma HT1080 cells plated on a monolayer of human ECV304 cells, Wf‐536 (0.3–3 µmol/L) inhibited the paracellular infiltration of tumour cells.

3. Wf‐536 (3–30 µmol/L) inhibited the invasion of tumour cells through the reconstituted basement membrane (Matrigel) layer.

4. Wf‐536 (10–30 µmol/L) inhibited the migration of tumour cells. At 0.3–3 µmol/L, Wf‐536 also restrained hepatocyte growth factor/scatter factor (HGF)‐induced increases in paracellular permeability of the ECV304 cell layer.

5. These results suggest that Wf‐536 suppresses tumour metastasis by both enhancing the barrier function of host cell layers and inhibiting tumour cell motility at the stage of host tissue penetration by metastatic tumour cells.