bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies
Authors: Suzuki Takashi , Sasano Hironobu , Takeyama Junji , Kaneko Chika , Freije William A. , Carr Bruce R. , Rainey William E. 
Published: March 2003

Adrenarche is considered to occur as a result of intra‐adrenal changes in steroidogenic enzymes involved in C19 steroid production. The present study was conducted because developmental changes in steroidogenic enzymes have not been examined well in human postnatal adrenal.Twenty‐four specimens of nonpathological human adrenals from 7 months to 62 years retrieved from autopsy files. Immunohistochemistry for P450 side‐chain cleavage (P450scc), 17α hydroxylase (P450c17), dehydroepiandrosterone sulfotransferase (DHEA‐ST), P450 oxidoreductase, cytochrome b5, and 3β‐hydroxysteroid dehydrogenase (3βHSD) was per‐formed in these specimens, and the immuno‐intensity was evaluated using CAS 200 computed image analysis system.Immunoreactivity of P450scc was marked in the zona glomerulosa, fasciculata and reticularis in the adrenal glands of all the cases examined. P450c17 and DHEA‐ST immunoreactivity was weak in the zona fasciculata and reticularis in the adrenals of age 7 months to 5 years, but thereafter became prominent in the zona reticularis. Immunoreactivity of P450 oxidoreductase and cytochrome b5, components of the electron transfer system hypothesized to regulate the 17–20 lyase activity of P450c17, was weak in all three zones of adrenal cortex from 7 months to 5 years, and became more marked in the zona reticularis after age 5 years. 3βHSD immunoreactivity was marked in all three zones of the adrenal cortex from 7 months to 8 years but thereafter decreased in the zona reticularis.These data suggest that the human adrenal zona reticularis markedly begins to develop morphologically and functionally at around 5 years of age. The increased level of P450c17, DHEA‐ST, P450 oxidoreductase, and cytochrome b5, and the decreased level of 3βHSD in the reticularis is likely to contribute to increased C19 steroid production during adrenarche.
Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study
Authors: Kalmijn Sandra , Mehta Kala M. , Pols Huibert A. P. , Hofman Albert , Drexhage Hemmo A. , Breteler Monique M. B. 
Published: March 2003

We investigated the prospective relationship between thyroid status and the risk of dementia and Alzheimer's disease among a random sample of 1843 participants, aged 55 years and over, from the population‐based prospective Rotterdam Study.Thyroid status was measured at baseline (1990–93), through assessment of serum antibodies to thyroid peroxidase (TPO‐Abs, positive: >10 IU/ml), serum TSH levels, and when TSH was abnormal (<0·4 or >4·0 mU/l), serum thyroxin levels (T4). At baseline and at follow up, after on average 2 years, participants were screened for dementia. Diagnoses were based on international criteria.Persons with reduced TSH levels at baseline had a more than threefold increased risk of dementia (RR = 3·5, 95%CI: 1·2–10·0) and of Alzheimer's disease (RR = 3·5, 95%CI: 1·1–11·5), after adjustment for age and sex. Among persons with reduced TSH levels, T4 levels appeared to be positively related to the risk of dementia (RR per SD increase = 2·9, 95%CI: 0·7–12·2), although none of those who became demented had a T4 level above the normal range (>140 nmol/l). The risk of dementia was especially increased in subjects with low TSH who were positive for TPO‐Abs (RR = 23·7, 95%CI: 4·0–140).This is the first prospective study to suggest that subclinical hyperthyroidism in the elderly increases the risk of dementia and Alzheimer's disease.
Non‐functioning pituitary adenomas: indications for postoperative radiotherapy
Authors: Woollons Andrew C. , Hunn Martin K. , Rajapakse Yasantha R. , Toomath Robyn , Hamilton David A. , Conaglen John V. , Balakrishnan V. 
Published: March 2003

To determine the indications for postoperative radiotherapy after surgical resection of a nonfunctioning pituitary macroadenoma.A retrospective chart review of 72 patients with histologically proven chromophobe adenoma who presented for pituitary surgery between January 1985 and June 1998, with a minimum follow‐up period of 12 months. The study endpoint was tumour recurrence or progression detected either by routine follow‐up imaging or by clinical progression with subsequent confirmation by imaging. A proportional hazards model was used to determine independent prognostic factors.Mean follow‐up was 64 months. In the radiotherapy group 13 of 50 recurred (or progressed) (26%), while in the nonradiotherapy group 10 of 22 recurred (46%), logrank test, P = 0·025. In patients assessed as having complete excision of tumour (n = 20) only two recurred (10%), both in patients without radiotherapy. No further treatment has been required in either case to date. In patients with residual tumour (n = 52), 41 had radiotherapy with 13 recurrences (32%), while 11 patients had no radiotherapy with eight subsequent recurrences (73%); logrank test, P = 0·007. Further treatment has been required in the majority of these cases. Cox's proportional hazards model analysis showed that only complete tumour removal and postoperative radiotherapy were independent favourable prognostic factors.The goal of surgery should be complete surgical excision where possible. The risk of recurrence in patients with no residual tumour on postoperative imaging is low enough to justify withholding routine postoperative radiotherapy in this group. In patients with residual tumour, conventional external beam radiotherapy administered within 12 months of surgery is effective at reducing recurrence or progression.
Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism
Authors: Diekman M. J. M. , Van Der Put N. M. , Blom H. J. , Tijssen J. G. P. , Wiersinga W. M. 
Published: March 2003

OBJECTIVEHyperhomocysteinaemia is a risk factor for premature atherosclerotic vascular disease and venous thrombosis. The aim of the present study was to assess plasma total homocysteine (tHCys) concentrations in hypo‐ as well as hyperthyroid patients before and after treatment, and to evaluate the role of potential determinants of plasma tHCys levels in these patients.DESIGNProspective follow up study.PATIENTSFifty hypothyroid and 46 hyperthyroid patients were studied in the untreated state and again after restoration of euthyroidism.MEASUREMENTSFasting plasma levels of tHCys and its putative determinants (plasma levels of free thyroxine (fT4), folate, vitamin B12, renal function, sex, age, smoking status and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene were measured before and after treatment.RESULTSRestoration of the euthyroid state decreased both tHCys (17·6 ± 10·2–13·0 ± 4·7 µmol/l; P < 0·005) and creatinine (83·9 ± 22·0–69·8 ± 14·2 µmol/l; P < 0·005) in hypothyroid patients and increased both tHCys (10·7 ± 2·5–13·4 ± 3·3 µmol/l; P < 0·005) and creatinine (49·0 ± 15·4–66·5 ± 15·0 µmol/l; P < 0·005) in hyperthyroid patients (values as mean ± SD). Folate levels were lower in the hypothyroid group compared to the hyperthyroid group (11·7 ± 6·4 and 15·1 ± 7·6 nmol/l; P < 0·05). Pretreatment tHCys levels correlated with log fT4 (r = − 0·47), folate (r = − 0·21), plasma creatinine (r = 0·45) and age (r = 0·35) but not with C677T genotype. Multivariate analysis indicated that pretreatment log(fT4) levels and age accounted for 28% the variability of pre‐treatment tHCys (tHCys = 14·2–5·50 log(fT4) + 0·14 age). After treatment the logarithm of the change (Δ) in fT4 (expressed as the post‐treatment fT4/pre‐treatment fT4 ratio) accounted for 45% of the variability in change of tHCys ( tHCys =− 0·07–4·94 log ( fT4)); there was no independent contribution of changes in creatinine which was, however, strongly related to changes in tHCys (r = 0·61).CONCLUSIONSPlasma tHCys concentrations increased in hypothyroidism and decreased in hyperthyroidism. Plasma fT4 is an independent determinant of tHCys concentrations. Lower folate levels and a lower creatinine clearance in hypo‐thyroidism, and a higher creatinine clearance in hyperthyroidism only partially explain the changes in tHCys.
Oestradiol improves arterial endothelial function in healthy men receiving testosterone
Authors: Sader Mark A. , McCredie Robyn J. , Griffiths Kaye A. , Wishart Susan M. , Handelsman David J. , Celermajer David S. 
Published: March 2003

OBJECTIVETo assess prospectively the effects of low dose oestradiol on arterial endothelial and smooth muscle function in healthy men. Oestrogen use is associated with reduced cardiovascular disease in oestrogen‐deficient women, however, the vascular effects of low‐dose oestradiol in healthy men have not been investigated previously.PATIENTS and DESIGNTwenty‐three men (aged 32 ± 8 years) were randomized to receive depot implants of testosterone (T) alone (group 1, n = 10), or T with either 10 mg (group 2, n = 7) or 20 mg (group 3, n = 6) of oestradiol (E).MEASUREMENTSHormone levels, lipids and vascu‐lar reactivity were measured before, 1 month and 6 months after hormone implantation. Using high‐resolution ultrasound, brachial artery diameter was measured at rest, during reactive hyperaemia (leading to flow‐mediated dilatation, FMD, which is endothelium‐dependent) and after sublingual nitroglycerin (GTN, an endothelium‐independent dilator).RESULTSOestradiol produced a dose‐dependent increase in plasma oestradiol (at 1 month 96 ± 7, 149 ± 6, 192 ± 23 pmol/l in the 3 groups, respec‐tively, P < 0·001 by anova for trend). Minor side‐effects (gynaecomastia, nipple tenderness) indicated that 20 mg oestradiol was the maximum tolerated dose. There was also a dose‐dependent increase in FMD with oestradiol dose: at 1 month, − 0·2, + 0·2 and + 1·8% for groups 1–3, respectively (P = 0·31 by anova for trend); and at 6 months, − 0·8, + 0·4 and + 2·2% (P = 0·02). The rise in oestradiol levels following treatment correlated with the improvement in FMD (P = 0·01). GTN responses were similar in the 3 groups throughout the study.CONCLUSIONIn healthy young men, oestradiol supplementation is associated with enhanced arterial endothelial function, a key marker of vascular health.
Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men
Authors: Pfeifer Marija , Kanc Karin , Verhovec Renata , Kocijančič Andreja 
Published: March 2003

OBJECTIVE The within subject variability of the insulin tolerance test (ITT) for assessment of growth hormone (GH) status and cortisol reserve has rarely been examined, particularly in patients with hypopituitarism. This becomes important when biochemical criteria are used to determine which adults with hypopituitarism should receive GH and/or cortisol replacement. In the present study we assessed the reproducibility of GH and cortisol responses in repeated ITTs. Baseline insulin‐like growth factor 1 (IGF‐1) levels were also assessed for reproducibility on each occasion.DESIGN and PATIENTS Three consecutive ITTs were performed in seven normal adult men (ages 22–27 years) and two ITTs in 11 men with hypopituitarism and suspected GH deficiency (ages 23–48 years).MEASUREMENTS Serum GH and IGF‐1 were measured by immunoradiometric and cortisol by immunofluorimetric assays.RESULTS In normal men group peak GH responses did not differ between the three tests. There was no correlation between individual peak values. The within subject peak GH variability was between 4·6 and 59·3%, and the overall variability in 21 tests was 35%. The lowest peak GH concentration was 70 mU/l (27 µg/l). All hypopituitary men had severe GH deficiency (all peak GH concentrations < 4 mU/l (1·5 µg/l) in both tests). There was a highly significant correlation between individual peak GH values (r = 0·95, P < 0·0001). Basal IGF‐1‐values in normal and hypopituitary men were highly correlated between tests (r = 0·98, P < 0·0001). The overall within subject variability of IGF‐1‐values was 11·9% in normal and 22·7% in hypopituitary men. In normal men group peak cortisol responses were not different between the three tests. There was a good correlation between individual peak cortisol responses in the three ITTs. The within subject peak cortisol variability (median 8·3%; range 0·7–21·5%) was significantly less than that of GH (P < 0·03) in two of three test comparisons. In hypopituitary men the within subject peak cortisol variability (median 41·6%; range 3·5–92·7%) was significantly greater (P < 0·001) than in normal men. All patients were correctly classified as cortisol deficient or normal in both ITTs.CONCLUSION The cortisol response to repeated hypoglycaemia is very reproducible in normal men but the GH response is less so. In hypopituitary men the reproducibility of the GH response is good while that of the cortisol response is poor. However, a single ITT did not misclassify hypopituitary patients who are severely GH and/or ACTH deficient and was therefore adequate for clinical decisions regarding GH and/or cortisol replacement. Nevertheless, it remains possible that a single ITT could misclassify some hypopituitary patients with partial GH or ACTH deficiency.
Effects of insulin and glucocorticoids on the leptin system are mediated through free leptin
Authors: Lewandowski K. , Randeva H.S. , O'Callaghan C.J. , Horn R. , Medley G.F. , Hillhouse E.W. , Brabant G. , O'Hare P. 
Published: March 2003

OBJECTIVE Insulin and glucocorticoids are known to increase total leptin levels. However, the effects of insulin and glucocorticoids on the components of the leptin system – free leptin (FL), bound leptin (BL) and soluble leptin receptor (SR) – have not been elucidated. The aim of this study was to determine if there is a differential effect of insulin and glucocorticoids on the leptin system.MATERIAL AND METHODS In the first of two studies (study 1), we measured free leptin (FL), bound leptin (BL), a soluble leptin receptor (SR) and insulin, by specific RIA methods, in six healthy subjects on a control day, and subsequently during a hyperinsulinaemic euglycaemic clamp study. In the second study (study 2) we measured the same parameters in six healthy subjects, before (day 1) and during administration of dexamethasone over 3 consecutive days.RESULTS In study 1, on the control day FL levels rose over the 16 h monitoring period (P = 0·057) and SR levels declined (P < 0·001), but there was no change of BL levels. Even after accounting for diurnal variation, FL levels increased even more substantially over 12 h of insulin infusion than observed on the control day (P < 0·001). In study 2, mean FL concentration doubled from day 1 to day 2 (P = 0·01) and remained elevated subsequently. In contrast to FL, BL and SR levels remained unchanged during the study. Fasting insulin levels (pmol/l) increased from day 1 to day 2, but this rise only approached significance on day 4 (P = 0·05).CONCLUSION We conclude that insulin and dexamethasone increase free leptin levels, but do not change the concentrations of bound leptin and soluble leptin receptor. Furthermore, the dexamethasone‐induced rise in leptin levels is (at least partially) independent of the effects of glucocorticoid‐induced hyperinsulinaemia.
Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma
Authors: Schott Matthias , Feldkamp Joachim , Lettmann Melanie , Simon Dietmar , Scherbaum Werner A. , Seissler Jochen 
Published: March 2003

OBJECTIVE Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell‐based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin‐producing pancreatic carcinoma.DESIGN Autologous dendritic cells (DCs) were generated from peripheral blood monocytes in the presence of granulocyte/macrophage colony‐stimulating factor, interleukin‐4 and tumour necrosis factor α. DCs were loaded with tumour‐derived lysate (TL), and were delivered by subcutaneous injections in 4‐week intervals.RESULTS Three weeks after first treatment, the patient developed a strong delayed‐type hypersensitivity (DTH) skin reaction with an erythema and induration after the challenge with TL‐pulsed DCs, which indicates the efficient generation of antigen‐specific memory T‐cells. Immunohistochemical analysis of skin biopsy demonstrated a strong perivascular and epidermal infiltration by T‐helper (CD4 positive) and cytotoxic T cells (CD8 positive). Stimulation with TL revealed a dose‐dependent T‐cell proliferation with a stimulation index of 1·1–5·7 compared to 1·1–1·4 before vaccination (P < 0·01). Most strikingly, DC‐based vaccination was accompanied by a steady decrease of the tumour marker chromogranin A from 2.93 umol/l initially to below the detection limit of 0.15 umol/l within 9 months of therapy. The ultrasound examination revealed a tumour regression of the metastasis in the right lobe of the liver.CONCLUSIONS Our data indicate that vaccination with tumour lysate‐pulsed DCs induced a significant antitumour immune response in a neuroendocrine carcinoma of the pancreas. This approach represents an alternative strategy for the treatment of advanced neuroendocrine carcinomas that are resistant to conventional therapy.
Efficacy of radiotherapy in normalizing serum IGF‐I, acid‐labile subunit (ALS) and IGFBP‐3 levels in acromegaly
Authors: Epaminonda Paolo , Porretti Silvia , Cappiello Vincenzo , Beck‐Peccoz Paolo , Faglia Giovanni , Arosio Maura 
Published: March 2003

OBJECTIVE Radiotherapy (RT) has been used for many years in order to complete the cure of unsuccessfully operated acromegalic patients. Several studies have shown its efficacy in normalizing GH levels, while reports about IGF‐I normalization are conflicting. Moreover, data regarding other markers of disease activity, such as IGFBP‐3 and acid‐labile subunit (ALS), i.e. the other two components of the circulating 150 kDa complex, are lacking.DESIGN Retrospective study.PATIENTS AND MEASUREMENTS Sixty‐seven acromegalic patients (20 males and 47 females, aged 40 ± 6 years) who underwent postoperative RT (in fractionated doses for a total of 40–75 Gy) were followed‐up for 11 ± 6 years (range: 1–26 years, median: 10 years). Serum GH and IGF‐I levels off medical therapy were measured in all patients; ALS and IGFBP‐3 were measured in 11 patients with normalization of IGF‐I concentrations. Computed tomography or nuclear magnetic resonance imaging periodically assessed possible development of pituitary deficiency along with imaging of the hypothalamic‐pituitary region.RESULTS Forty‐one out of 67 patients (58%) achieved GH levels < 2·5 µg/l by 1–15 years after RT (mean 8 ± 6) and 37/67 patients (55%) had normal or low IGF‐I levels 1–26 years after RT (mean: 12 ± 6), a normalization of both parameters being seen in 37 patients. GH < 2·5 µg/l and normal IGF‐I levels were achieved in 17/26 (65%) patients followed‐up for at least 15 years. ALS and IGFBP‐3 concentrations paralleled IGF‐I levels in all patients studied. With respect to secondary pituitary insufficiency, acquired ACTH deficiency was found in 25 patients, TSH deficiency in 20, gonadotropin deficiency in 23 and GH deficiency in seven. In total, two cases of meningioma and one pineal tumour, possibly related to RT, were seen 9–22 years after RT.CONCLUSIONS RT is an effective, although slow‐acting, therapeutic tool for acromegaly, with ‘safe’ GH levels and normal IGF‐I concentrations being achieved in 65% of patients after 15 years. IGF‐I levels normalize more slowly than GH levels. Radiotherapy is able to normalize the concentration of all three components of the circulating 150 kDa complex. Checks for loss of pituitary function and appearance of second brain tumours must be carried out life‐long.
Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with 131I‐meta‐iodobenzylguanidine (131I‐mIBG)
Authors: Mukherjee J. J. , Kaltsas G. A. , Islam N. , Plowman P. N. , Foley R. , Hikmat J. , Britton K. E. , Jenkins P. J. , Chew S. L. , Monson J. P. , Besser G. M. , Grossman A. B. 
Published: March 2003

OBJECTIVE Meta‐iodo‐benzyl‐guanidine labelled with 131‐iodine (131I‐mIBG) has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non‐catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of 131I‐mIBG, we have reviewed all patients who had received this form of treatment in our department.DESIGN Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with131I‐mIBG and were followed‐up according to a defined protocol in a given time frame.PATIENTS Thirty‐seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with 131I‐mIBG over a 15‐year period were included in this analysis.MEASUREMENTS The symptomatic, hormonal and tumoural responses before and after 131I‐mIBG therapy over a median follow‐up duration of 32 months (range 5–180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18–81 years), 15 were treated with 131I‐mIBG alone whereas the other 22 received additional therapy.RESULTS A total of 116 therapeutic 131I‐mIBG doses were administered [mean cumulative dose 592 mCi (21·9 GBq); range 200–1592 mCi (7·4–58·9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with 131I‐mIBG alone and 84% who received additional therapy showed stable disease over the period of follow‐up. Overall survival during the period of the study was 71%. The overall 5‐year survival rate was 85% (95% confidence interval, 72–99%) for all patients and 78% (95% confidence interval, 55–100%) for the carcinoid group alone, according to Kaplan–Meier analysis. Symptomatic control was achieved in all the patients treated with 131I‐mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. 131I‐mIBG therapy was safe and well tolerated. Serious side‐effects necessitating the termination of 131I‐mIBG therapy were seen in only 2 of our patients.CONCLUSIONS  131I‐mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.