bluuebunny/crossref_metadata_2025 huggingface dataset:
Urocortin expression in the human central nervous system
Authors: Iino Kazumi , Sasano Hironobu , Oki Yutaka , Andoh Noriaki , Shin Ryong‐Woon , Kitamoto Tetsuyuki , Takahashi Kazuhiro , Suzuki Hiroyoshi , Tezuka Fumiaki , Yoshimi Teruya , Nagura Hiroshi
Published: March 2003

OBJECTIVE AND STUDY DESIGN

Urocortin is a recently identified neuropeptide of the corticotrophin‐releasing factor (CRF) family in the mammalian brain and has been demonstrated to stimulate ACTH secretion from pituitary cells, but its expression in human brain tissue including the hypothalamus has not been examined. In this study, we first examined urocortin expression in the hypothalamus (20 cases) and pituitary stalks (17 cases) of human brain obtained from autopsy using immunohistochemistry and mRNA in situ hybridization.

RESULTS

Neither urocortin immunoreactivity nor mRNA hybridization signals were detected in the hypothalami and pituitary stalks while CRF immunoreactivity was detected in the paraventricular nuclei of the hypothalami in 10/20 cases and in nerve fibres of the stalks in 17/17 cases. These results indicate that urocortin does not act on the hypothalamo‐pituitary‐adrenal axis, at least not in the same manner as CRF in humans. We then examined urocortin expression in various portions of the brain in 7 cases. Both urocortin immunoreactivity and mRNA hybridization were detected in Purkinje cells of the cerebellum and anterior horn cells of the spinal cord in specimens examined. Urocortin expression was, however, variably seen in superior olivary nuclei (two out of six cases examined) and in the Edingar‐Westphal nuclei (one out of three cases examined).

CONCLUSIONS

The distribution of urocortin in the human central nervous system suggests that urocortin may work as a neurotransmitter like other neuropeptides in the human.
Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas
Authors: Hensen Johannes , Henig Anja , Fahlbusch Rudolf , Meyer Martin , Boehnert Markus , Buchfelder Michael
Published: March 2003

OBJECTIVE

Disturbances of osmoregulation, leading to diabetes insipidus and hyponatraemia are well known complications after surgery in the sella region. This study was performed to examine the prevalence and predictors of polyuria and hyponatraemia after a complete and selective removal of pituitary adenomas was attempted via the transnasal–transsphenoidal approach.

DESIGN

1571 patients with pituitary adenomas (238 Cushing's disease, 405 acromegaly, 534 hormonally inactive adenomas, 358 prolactinoma, 23 Nelson's syndrome, and 13 thyrotropinoma) were daily examined within a 10‐day postoperative inpatient observation period. Prevalence of patterns of polyuria (> 2500 ml) and oliguria/hyponatraemia (< 132 mmol/l) were surveyed as well as predictors of postoperative morbidity.

RESULTS

487 patients (31%) developed immediate postoperative hypotonic polyuria, 161 patients (10%) showed prolonged polyuria and 37 patients (2.4%) delayed hyponatraemia. A biphasic (polyuria‐hyponatraemia) and triphasic (polyuria‐hyponatraemia‐polyuria) pattern was seen in 53 (3.4%) and 18 (1.1%) patients, respectively. Forty‐one patients (2.6%) displayed immediate postoperative (day 1) hyponatraemia. Altogether, 8.4% of patients developed hyponatraemia at some time up to the 10th day postoperative, with symptomatic hyponatraemia in 32 patients (2.1%). Risk analysis showed that patients with Cushing's disease had a fourfold higher risk of polyuria than patients with acromegaly and a 2.8‐fold higher risk for postoperative hyponatraemia. Younger age, male sex, and intrasellar expansion were associated with a higher risk of hypotonic polyuria, but this was not considered clinically relevant.

CONCLUSIONS

The analysis illustrates that disturbances in osmoregulation resulting in polyuria and pertubations of serum sodium concentration are of very high prevalence and need observation even after selective transsphenoidal surgery for pituitary adenomas, especially in patients with Cushing's disease.
Blood pressure and Turner syndrome
Authors: Nathwani  , Unwin  , Brook  , Hindmarsh
Published: March 2003

INTRODUCTION

Elevated blood pressure (BP) is an important predictor of morbidity and mortality from cardiovascular disease. Patients with Turner syndrome (TS) have a higher morbidity and mortality in middle age than the normal population. As BP in childhood or early adulthood is predictive of BP later in adult life, we assessed manual and 24 h ambulatory BP in patients with TS to determine whether the BP pattern is altered at an early stage in these patients who are known to be at risk of cardiovascular disease.

PATIENTS AND METHODS

We studied manual and 24 h ambulatory BP profiles in 75 girls with Turner syndrome, age range 5.4–22.4 years. A monitor with an oscillometric device (SpaceLabs model 90207) and an appropriate sized cuff was used. BP was measured during the day‐time (0800–2000 h) and the night‐time periods (2200–0800 h). The BP measured were compared with population standards. The effect of different growth promoting agents on BP was also evaluated.

RESULTS

Mean manual and 24 h ambulatory BP measurements were 118/77 mmHg (range 95/60–140/102) and 115/70 mmHg (range 93/57–154/99), respectively. There was minimal difference between the two methods with a positive bias of 2.4 mmHg for diastolic BP and a negative bias of 2.1 mmHg for systolic BP. The mean standard deviation scores (SDS) corresponding to the mean BP recordings were 24 h systolic + 0.81 (range − 1.26 to + 4.45), 24 h diastolic + 0.43 (range − 0.85 to + 3.42), day‐time systolic + 1.08 (range − 0.95 to + 4.72), day‐time diastolic + 0.70 (range − 0.94 to + 3.71), night‐time systolic + 0.22 (range −2.2 to + 3.64) and night‐time diastolic − 0.18 (range −2.0 to + 2.43). The SDS for both the mean 24 h and day‐time systolic and diastolic BP were shifted to the right of the normal distribution. 57% of the girls had less than the normal 10% reduction in nocturnal systolic blood pressure. 17% had diastolic and 21% had systolic blood pressure above the 95th percentile for age and sex. There was no significant difference in the BP SDS between girls on no treatment and those receiving treatment.

CONCLUSION

Over 50% of girls with Turner syndrome have an abnormal BP circadian rhythm, which is similar to adult patients with secondary hypertension. Patients with Turner syndrome have higher blood pressure measurements compared to published population standards, as evidenced by the shift to the right of both the systolic and diastolic BP SDS. These findings suggest that girls with Turner syndrome should be carefully monitored in childhood and adulthood for blood pressure and other cardiovascular risk factors.
Influence of different genotypes on 17‐hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21‐hydroxylase deficiency
Authors: Bachega Tânia A. S. S. , Billerbeck Ana E. C. , Marcondes José A. M. , Madureira Guiomar , Arnhold Ivo J. P. , Mendonca Berenice B.
Published: March 2003

OBJECTIVE

The diagnosis of the nonclassical form of 21‐hydroxylase (NC‐21OH) deficiency, established before molecular studies, is based on basal 17OH‐progesterone (17OH‐P) values > 15 nmol/l or ACTH‐stimulated 17OH‐P values > 30 nmol/l. This disease is caused by mutations in the structural gene that can be grouped into three categories: A, B and C, according to the predicted level of enzymatic activity. So, the genotype of the nonclassical form is a combination of mutations that cause moderate impairment of enzymatic activity in one allele and mutations which cause total (A), severe (B: 3%) or moderate (C: 20–60%) impairment of enzymatic activity in the other allele.

DESIGN

We analysed the influence of the different genotypes on 17OH‐P levels in 58 patients with the nonclassical form of 21OH deficiency.

RESULTS

After screening for 18 mutations through Southern blotting, allele‐specific polymerase chain reaction (PCR) and enzyme restriction, mutations were identified in 73% of the alleles. Patients with mutations identified in both alleles were divided into groups A/C (n = 18), B/C (n = 3) and C/C (n = 15). The basal and ACTH‐stimulated 17OH‐P levels in patients with A/C genotype ranged from 1.2 to 153 and 72–363 nmol/l, and in C/C genotype ranged from 0.9 to 72 and 51–363 nmol/l, respectively (P < 0.05 for stimulated levels). The lowest value of ACTH‐stimulated 17OH‐P levels in fully genotyped patients was 51 nmol/l. Patients with the A/C genotype presented androgen excess symptoms earlier than patients with the C/C genotype.

CONCLUSIONS

These data suggest an influence of genotype on phenotype and on 17OH‐P levels. The high frequency of unidentified mutant alleles in nonclassical 21‐hydroxylase deficiency suggests that ACTH‐stimulated values of 17OH‐P between 30 and 51 nmol/l have overestimated this diagnosis. Genotyping more patients with nonclassical 21‐hydroxylase deficiency will help to redefine the cut‐off value for ACTH‐stimulated 17OH‐P for correct diagnosis of this disease.
Embolization in combination with radioiodine therapy for bone metastases from differentiated thyroid carcinoma
Authors: Van Tol K. M. , Hew J. M. , Jager P. L. , Vermey A. , Dullaart R. P. F. , Links T. P.
Published: March 2003

BACKGROUND

The outcome for patients with bone metastases from differentiated thyroid carcinoma is worse compared to the overall prognosis of patients with differentiated thyroid carcinoma. The aim of this study is to evaluate the effect of embolization with concomitant radioiodine treatment on the serum thyroglobulin (Tg) level, pain and neurological symptoms in patients with large bone metastases from differentiated thyroid carcinoma.

PATIENTS AND METHODS

Five symptomatic patients, who presented with a large unresectable bone metastasis of differentiated thyroid carcinoma were treated with radioiodine and embolization. The effect of this combined treatment was compared to the effect of radioiodine without embolization in a previously treated control group of 6 patients. Serum Tg levels, pain and neurological symptoms were scored. Both groups were treated similarly with total thyroidectomy followed by ablation with 5.55 GBq 131I and a second dose of 5.55 GBq 131I three months later, except for embolization in the embolization group, which took place between the 2 radioiodine treatments.

RESULTS

In the embolization group, serum Tg at the second 131I therapy had decreased by 88.7% (median, range: 77.1–99.3%), which was significantly more compared to the decrease of serum Tg in the control group (18.6%, range: −4.7–95%, P < 0.05). CT‐scanning showed a median volume reduction of the metastasis after radioiodine treatment combined with embolization of 52.5% (range: 39–80%). Both strategies resulted in a rapid relief of pain and neurological symptoms. Embolization was not accompanied with severe complications.

CONCLUSIONS

This preliminary study suggests that embolization of bone metastases of differentiated thyroid carcinoma in combination with radioiodine treatment results in a significant initial reduction of serum Tg level compared to radioiodine treatment alone. This suggests a beneficial reduction in tumour burden. In this patient category, embolization appears to be a safe and well tolerated procedure.
Low birth weight is not associated with clinically overt thyroid disease: a population based twin case‐control study
Authors: Brix Thomas Heiberg , Kyvik Kirsten Ohm , Hegedüs Laszlo
Published: March 2003

OBJECTIVE

In recent years low birth weight has been proposed as a risk factor for the development of several chronic diseases in adult life, including diabetes and subclinical autoimmune thyroid disease. The association could, however, also be due to genetic or environmental factors affecting both birth weight and adverse health outcomes in adult life. Moreover, it is at present unknown whether or not low birth weight is associated with an increased risk of developing clinically overt thyroid disease. The aim of the present study was to investigate the impact of birth weight and several other birth characteristics on the development of clinically overt thyroid disease.

DESIGN

A twin case‐control study of same sex twin pairs.

PATIENTS

One hundred and thirty‐one same sex twin pairs (262 twin individuals) discordant for clinically overt thyroid disease, ascertained from a population based nation‐wide twin register.

MEASUREMENTS

Information about birth weight, birth length, birth order (first vs. second born), and prematurity was obtained from the original midwife records.

RESULTS

Forty‐nine twin pairs were discordant for clinically overt autoimmune thyroid disease (Graves' disease = 35 and Hashimoto's thyroiditis = 14) and 82 pairs were discordant for overt nonautoimmune thyroid disease (Simple goitre = 79 and toxic nodular goitre = 3). Overall, there was no difference in birth weights between probands and the healthy co‐twins in monozygotic (MZ, n = 39) or in dizygotic (DZ, n = 92) pairs (MZ: mean ± SE: 2619 ± 93 g vs. 2553 ± 89 g, P = 0.40; DZ: 2576 ± 45 g vs. 2585 ± 49, P = 0.86). By means of logistic regression, the impact of other birth characteristics such as birth length, birth order (first vs. second born), and prematurity was tested. None of the variables reached statistical significance. Subdividing the twin pairs into those discordant for clinically overt Graves' disease, Hashimoto's thyroiditis, and nonautoimmune thyroid disease did not change the results.

CONCLUSIONS

This is the first study of the effect of birth weight and other birth characteristics on the subsequent development of clinically overt thyroid disease in which maternal, socioeconomic, and to a high degree, genetic factors have been controlled for. Our study did not show any effect of birth weight or any of the other birth characteristics on the risk of developing clinically overt autoimmune or nonautoimmune thyroid disease.
Gigantism due to growth hormone excess in a boy with optic glioma
Authors: Drimmie F. M. , Maclennan A. C. , Nicoll J. A. R. , Simpson E. , McNeill E. , Donaldson M. D. C.
Published: March 2003

True gigantism is rare in early childhood and is usually due to excess GH secretion from a pituitary adenoma. We report a case in which the endocrine abnormality is secondary to an optic glioma. Careful endocrine evaluation has shown that GH peak amplitude was not increased but rather there was failure of GH levels to suppress to baseline and a lack of pulsatility. There is no evidence of a direct secretory role for the tumour and we postulate that the tumour is affecting GH secretion through an effect on somatostatin tone. Specific tumour therapy is not indicated for this patient in the absence of mass effect or visual disturbance. The GH excess is being treated with somatostatin analogue (Octreotide) and as he has developed precocious puberty he is also receiving long acting GnRH analogue (Zoladex). This boy appears likely to have neurofibromatosis type 1 (NF1) which raises the question of subtle GH excess in NF1 patients with tall stature.
Urinary GH and IGF‐I excretion in nine year‐old children: relation to sex, current size and size at birth
Authors: Fall C. H. D. , Clark P. M. , Hindmarsh P. C. , Clayton P. E. , Shiell A. W. , Law C. M.
Published: March 2003

OBJECTIVES

To study the relationship of 24‐hour urinary growth hormone (GH) and IGF‐I excretion in childhood to sex and body size. To test the hypothesis that small size at birth followed by postnatal catch‐up growth is associated with elevated IGF‐I production.

DESIGN AND SUBJECTS

Follow‐up study of a cohort of 183 healthy children born in Salisbury, UK.

MEASUREMENTS

Weight and height, 24‐h urinary growth hormone (uGH) and IGF‐I (uIGF‐I) excretion, and systolic and diastolic blood pressures.

RESULTS

At 9 years of age, 24‐h uIGF‐I excretion, but not uGH excretion, was strongly related to current weight (P < 0.001) and height (P < 0.001). Urinary GH and IGF‐I excretion were positively correlated (r = 0.15, P = 0.05). Boys excreted more uIGF‐I per unit uGH than girls (uIGF‐I/uGH molar ratio 32.1 compared to 21.0; P for difference = 0.002). There were no significant relationships of uGH, uIGF‐I or uIGF‐I/uGH molar ratio with birthweight, birthlength or head circumference at birth, nor with blood pressure at 9 years. ‘Catch‐up’ growth, indicated by an increase in height SD scores between birth and 9 years, was associated with higher IGF‐I excretion (P = 0.01) and occurred in children with taller parents (P < 0.001).

CONCLUSIONS

Boys appear to be more sensitive to GH than girls, generating more uIGF‐I in relation to uGH. Urinary IGF‐I excretion at 9 years is related to both absolute height and to the degree of catch‐up in height from birth. Our results suggest that IGF‐I production is strongly influenced by genetic factors, but also by either the degree to which intrauterine growth falls short of genetic growth potential, or the process of postnatal catch‐up growth that follows.
Over‐expression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma
Authors: Ramirez Raul , Hsu Daniel , Patel Aneeta , Fenton, Cydney , Dinauer Catherine , Tuttle R. Michael , Francis Gary L.
Published: March 2003

OBJECTIVE

The study determined if hepatocyte growth factor/scatter factor (HGF/SF) or the HGF/SF receptor (cMET) might be important for metastasis in thyroid cancer.

DESIGN

We examined HGF/SF and cMET expression by immunohistochemistry in a retrospective group of benign and malignant thyroid lesions from children and young adults, and correlated the intensity of expression with clinical outcome.

PATIENTS

Patients included 42 children and young adults with papillary thyroid carcinomas (PTC), seven with follicular thyroid carcinomas (FTC), two with medullary thyroid carcinomas (MTC), 14 with benign thyroid disorders, and two with normal thyroids.

MEASUREMENTS

Expression of cMET was graded from 0 (absent) to 4 (intense); and HGF/SF expression was graded from 0 (absent–minimal) to 3 (diffuse and intense).

RESULTS

cMET staining was greater in PTC (mean intensity 2.3 ± 0.4 vs. 0.8 ± 0.2, P < 0.005) and FTC (2.4 ± 0.6 vs. 0.8 ± 0.2, P = 0.04) than benign lesions (0.8 ± 0.2) or normal thyroids (0.4 ± 0.5). PTC with intense cMET staining had shorter disease free survival (P = 0.05) and increased HGF/SF staining (r = 0.39, P = 0.017). HGF/SF correlated with the extent of disease at diagnosis (r = 0.33, P = 0.049). Patients with PTC were stratified into quartiles based on combined cMET and HGF/SF staining. Those with intense cMET and HGF/SF staining were younger (P = 0.05), and had reduced disease free survival (P = 0.03).

CONCLUSIONS

We conclude that increased cMET and HGF/SF expression is associated with a high risk for metastasis and recurrence in children and young adults with papillary thyroid carcinoma.
Immunohistochemical detection of somatostatin receptor types 1–5 in medullary carcinoma of the thyroid
Authors: Papotti Mauro , Kumar Ujendra , Volante Marco , Pecchioni Carla , Patel Yogesh C.
Published: March 2003

BACKGROUND We have analysed the distribution of the five somatostatin receptors (sst1–5) by immunohistochemistry in a large retrospective series of 51 medullary carcinoma of the thyroid (MCT) specimens and correlated the pattern of sst expression with expression of somatostatin (SRIF) peptide, tumour pathology and clinical outcome.

MEASUREMENTS Immunohistochemistry was performed with rabbit polyclonal antipeptide antibodies directed against the extracellular domains or cytoplasmic tail of human (h) sst1–5. SRIF immunoreactivity was investigated in parallel paraffin sections.

RESULTS Eighty‐five percent of the tumours were positive for one or more sst, localized to both tumour cells as well as surrounding peritumoural structures, especially blood vessels. Forty‐nine percent of the tumours were positive for sst1, 43% for sst2, 47% for sst3, 4% for sst4, and 57% for sst5. Fifty‐one percent of tumours expressed one or two sst subtypes; 33% were positive for three or more sst isoforms. All five sst receptors were detected in only two cases. Tumours expressing octreotide sensitive subtypes (sst2,3,5) accounted for 75% of the series. 50% of the tumours co‐expressed SRIF suggesting tumour cell regulation by endogenous SRIF via paracrine/autocrine circuits. There was no correlation between sst1–5 expression and age, sex, tumour size or stage, histological type or clinical outcome. Simultaneous analysis of primary tumour and lymph node metastases revealed a similar pattern of sst immunoreactivity indicating that sst expression is not modified in the course of disease progression.

CONCLUSIONS With the exception of sst4, medullary carcinoma of the thyroid display a rich but heterogeneous expression of sst subtypes. Immunohistochemical typing of sst receptor expression using specific antireceptor antibodies represents an ideal approach for characterizing sst subtype expression in medullary carcinoma of the thyroid for optimizing receptor targeted diagnosis and therapy with somatostatin analogs.
The release of leptin and its effect on hormone release from human pituitary adenomas
Authors: Korbonits Márta , Chitnis Meenali M. , Gueorguiev Maria , Norman Dennis , Rosenfelder Nicola , Suliman Mohamed , Jones T. Hugh , Fabbri Kate Noonan Andrea , Besser G. Michael , Burrin Jacky M. , Grossman Ashley B.
Published: March 2003

BACKGROUND Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary.

AIM The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT‐PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin.

RESULTS Leptin receptor long isoform expression was detected in 2/4 GH‐secreting adenomas, 12/17 non‐functioning adenomas, 5/9 ACTH‐secreting adenomas, 1/2 prolactinomas, 2/2 FSH‐secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH‐secreting adenomas, 9/14 non‐functioning adenomas, 2/3 ACTH‐secreting adenomas, 1/3 prolactinomas and 1/3 FSH‐secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non‐tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and α‐subunit secretion from a non‐functioning adenoma and TSH secretion from a somatotroph adenoma.

CONCLUSION We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.
Hormone replacement therapy may improve hepatic function in women with Turner's syndrome
Authors: Elsheikh M. , Hodgson H. J. F. , Wass J. A. H. , Conway G. S.
Published: March 2003

OBJECTIVE Women with Turner's syndrome (TS) have recently been shown to be at an increased risk of developing chronic liver disease. There has been some concern that oestrogen replacement therapy may exacerbate hepatic dysfunction. The aim of this study was to assess hepatic function in women with TS and to determine the effect of oral oestradiol valerate on liver enzymes.

DESIGN AND PATIENTS A retrospective review of liver enzymes of 80 women with TS, followed by a prospective study looking at serum liver enzyme concentrations in 20 women with TS following 3 months on and off hormone replacement therapy (HRT) (oestradiol valerate, 2 mg/levonorgestril 75 µg).

MEASUREMENTS Liver enzymes (gamma glutamyl transferase, aspartate transaminase and alkaline phosphatase), albumin and bilirubin were measured on and off HRT. Viral hepatitis serology and liver autoantibodies were tested in patients with abnormal liver function.

RESULTS Thirty‐five out of 80 women (44%) had elevated serum liver enzyme concentrations. Two women (2·5%) had a mildly raised serum bilirubin, but protein synthesis was normal in all subjects. HRT resulted in a significant fall in all liver enzymes (P < 0·05) but did not affect serum protein concentrations

CONCLUSIONS Women with Turner's syndrome often have elevated liver enzymes. Oestrogen/progestagen therapy using oestradiol valerate improves liver function in this group of patients. The mechanisms behind this are unclear.
Distinct clonal composition of primary and metastatic adrencorticotrophic hormone‐producing pituitary carcinoma
Authors: Zahedi Afshan , Booth Gillian L. , Smyth Harley S. , Farrell William E. , Clayton Richard N. , Asa Sylvia L. , Ezzat Shereen
Published: March 2003

The pathogenetic mechanisms underlying pituitary tumorigenesis are largely unknown. Previous reports have suggested that aggressive pituitary adenomas and/or carcinomas may be associated with genetic alterations that are distinct from those responsible for the more common and less aggressive pituitary adenomas. Here, we describe the clonal composition of a pituitary carcinoma, its recurrence and its metastasis. The samples studied were from a 48‐year‐old woman who presented with recurrent Cushing's syndrome. During the 8‐year course of her disease, she had an ACTH‐producing pituitary carcinoma requiring two transsphenoidal procedures and resection of a metastatic cervical lymph node. Her disease remained active despite surgical resection, external beam irradiation and medical treatment with ketoconazole. Ultimately, bilateral adrenalectomy was performed to control the hypercortisolism. Morphological and immunohistochemical studies revealed that the primary and recurrent pituitary tumours and the metastatic lesion were an endocrine tumour with ACTH and growth hormone immunoreactivity. Primary, recurrent and metastatic tumour DNAs were analysed for X‐chromosome inactivation and loss of heterozygosity (LOH) at several microsatellite loci on chromosomes 9,10, 11, 13 and 22. All three lesions were monoclonal in composition as suggested by the pattern of X chromosome inactivation of the PGK‐1 allele. Moreover, the primary, recurrent and metastatic lesions demonstrated LOH at the microsatellite allelic markers PYGM and D10S217. In contrast, however, the metastatic lesion showed a loss‐to‐retention pattern at two distinct loci (IFNA and D22S156) compared to the primary and recurrent pituitary tumours. These findings, while consistent with a clonal composition of the primary and metastatic pituitary lesions, show each clone to be distinct. This is the first description of a metastatic pituitary carcinoma with a distinct clonal composition from its primary source.
The atherogenic plasma remnant‐like particle cholesterol concentration is increased in the fasting and postprandial state in active acromegalic patients
Authors: Twickler TH. B. , Dallinga‐Thie G. M. , Zelissen P. M. J. , Koppeschaar H. P. F. , Erkelens D. W.
Published: March 2003

BACKGROUND Premature atherosclerosis is a clinical feature in untreated acromegaly. Increased postprandial lipoprotein remnant levels are associated with premature atherosclerosis. In most studies, remnants have been measured indirectly using retinyl esters (RE) as a chylomicron core label. Remnants can also be directly quantified by immunoseparation using monoclonal antibodies to apolipoprotein (apo) AI and apo B100 to remove nonremnant lipoproteins. Cholesterol is quantified in the remaining apo E‐rich remnant fraction (RLP‐C).

OBJECTIVE The aim of the present study was to investigate the role of postprandial lipaemia in patients with acromegaly to further define abnormalities leading to increased susceptibility for atherosclerosis.

PATIENTS In a case–control study, the plasma postprandial lipoprotein remnant fraction (RLP‐C and RE) were analysed in six patients with active acromegaly [two females, four males; aged 53 ± 9 years; body mass index (BMI), 29 ± 4 kg/m2] and in six normolipidaemic control subjects (matched for age, gender, BMI and apo E genotype). They underwent an oral vitamin A fat loading test.

RESULTS Baseline plasma triglycerides (TG) were not significantly different in patients (1·75 ± 0·71 mm) and controls (1·15 ± 0·46 mm). Lipoprotein lipase activity was significantly lower in patients than in controls (108 ± 21 vs. 141 ± 19 U/l, respectively; P < 0·05). Baseline plasma apo E levels were higher in patients (60·8 ± 7·9 mg/l) than in controls (48·3 ± 5·9 mg/l; P < 0·05). No differences were found in the area under the postprandial TG curve (AUC–TG), the incremental AUC–TG (ΔAUC–TG) and AUC–RE in the Sf < 1000 remnant fraction. However, fasting plasma RLP‐C concentrations, isolated by immunoseparation, were increased in patients with active acromegaly (0·41 ± 0·13 mm) compared to control subjects (0·20 ± 0·07 mm; P < 0·05). Incremental postprandial RLP‐C response (corrected for fasting values) was also significantly elevated in patients (2·14 ± 1·19 mm/h/l) compared to controls (0·86 ± 0·34 mm/h/l; P < 0·05). In both groups, the maximal RLP‐C concentration was reached between 2 and 4 h.

CONCLUSIONS In conclusion, the atherogenic postprandial remnants, represented by RLP‐C, were significantly elevated at baseline and in the postprandial period, whereas the larger‐sized remnants, represented by retinyl esters (Sf < 1000), were not different from controls. The disturbances in the postprandial RLP‐C response increased the susceptibility for premature atherosclerosis as observed in patients with acromegaly.
Controversies in the clinical evaluation of active thyroid‐associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment
Authors: Dickinson A. Jane , Perros Petros
Published: March 2003

Despite many learned publications over recent decades, the assessment of active thyroid‐associated orbitopathy (TAO) remains difficult and controversial. There are no biochemical, immunological or imaging investigations which can identify active disease reliably, and clinical assessment is still of paramount importance. We therefore review the strengths and weaknesses of all methods of clinical assessment. A new atlas for clinical assessment of soft tissue signs has been developed, and its reproducibility assessed. It details a suggested protocol that could help standardize descriptions of TAO and allow more objective assessment of its activity and severity. This is relevant to general endocrinologists, who have a crucial role in the identification of patients who require ophthalmological assessment. Certain aspects are more relevant to ophthalmologists and endocrinologists who have a special clinical and research interest in TAO. Unless a reproducible system of assessment is devised and widely adopted, it will remain difficult to interpret research meaningfully, particularly if results appear to contradict.
Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1
Authors: Ouyang Bin , Knauf Jeffrey A. , Ain Kenneth , Nacev Benjamin , Fagin James A.
Published: March 2003

objective Thyroid follicular adenomas (FA) and carcinomas (FC) have a high prevalence of aneuploidy. We examined the contribution of mitotic checkpoint dysfunction and mutations of BUB1 or BUBR1, components of the spindle assembly checkpoint pathway, to chromosomal instability in thyroid cancer.

design The integrity of the mitotic checkpoint was studied in 8 aneuploid thyroid tumour cell lines. All cell lines as well as 9 FA, 9 FC, and 1 aneuploid papillary carcinoma were screened for mutations of BUB1 by SSCP and direct sequencing. Cell lines were also examined for mutations of BUBR1.

results Neither FRO, NPA nor WRO cells arrested in mitosis after treatment with nocodazole, whereas other aneuploid cell lines paused appropriately following microtubule disruption. One FC had a 2‐bp somatic deletion (G2480/A2481) of BUB1 leading to a frameshift, and one FC had a silent polymorphism at nucleotide 1049 (TGT‐TGC). There was a silent polymorphism of BUBR1 (G1271A) in one sample.

conclusion Some, but not all thyroid cancer cell lines with aneuploidy have an abnormal mitotic checkpoint, indicating that chromosomal instability may arise through alternative cell cycle defects. Moreover, mutations of BUB1 or BUBR1 are infrequent in follicular neoplasms, and do not account for aneuploidy in thyroid cancer.
Effect of low‐ and high‐dose levothyroxine on thyroid nodule volume: a crossover placebo‐controlled trial
Authors: Koc Mehmet , Ersoz H. Onder , Akpinar Ihsan , Gogas‐Yavuz Dilek , Deyneli Oguzhan , Akalin Sema
Published: March 2003

objective The efficacy and the effective dose of levothyroxine suppressive therapy in the treatment of benign thyroid nodules are controversial. In this study, we aimed to determine the response of solitary thyroid nodules to low‐ or high‐level TSH suppression in a placebo‐controlled, randomized crossover trial.

design Forty‐nine patients with solitary thyroid nodules on palpation were randomized to high‐level and low‐level TSH suppression groups. In each group, patients were further randomized to placebo and active levothyroxine subgroups. Patients in each subgroup were crossed over to placebo or active levothyroxine at the end of the first year and were then followed up for an additional year.

methods TSH levels were suppressed to 0·4–0·6 mIU/ml and ≤ 0·01 mIU/ml in the low‐level and high‐level TSH suppression groups, respectively. Nodule volumes were measured at baseline and every 6 months after the desired level of TSH was reached if the patients were in the active levothyroxine treatment group or every 6 months if they were in the placebo group.

results In high‐level TSH suppression groups, nodule volume decreased significantly at the end of the active treatment periods (4·99 ± 2·02 ml vs. 3·20 ± 1·50 ml, P < 0·01, in Group 1; and 3·72 ± 1·79 ml to 2·05 ± 0·64 ml, P < 0·001, in Group 2). In the low‐level TSH suppression groups, nodule volume also decreased significantly at the end of the active treatment periods (4·43 ± 1·76 ml vs. 3·04 ± 1·32, P < 0·05, in Group 3; and 3·59 ± 0·89 ml to 2·22 ± 0·59 ml, P < 0·01, in Group 4). Nodule volumes regained their original volumes during the placebo treatment periods. The percentage decline in clinically relevant nodule volume reduction (≥ 50%) was similar in the low‐level and high‐level TSH suppression groups.

conclusion Low‐ and high‐level TSH suppression were equally effective in reducing nodule volume and thus, considering the complications of high‐level TSH suppression, low‐level TSH suppression should be used if one considers levothyroxine suppressive therapy to reduce thyroid nodule size.
Accuracy of a novel real‐time microprocessor QRS detector for heart rate variability assessment
Authors: Loimaala  , Sievänen  , Laukkanen  , Pärkkä  , Vuori  , Huikuri
Published: March 2003

Assessment of heart rate variability from 24‐h recordings requires a high‐quality Holter, expensive equipment and multistage processing of recordings. We compared a new personal computer‐based digital QRS detector system with a Holter recorder, and found the two methods to be equally accurate in time and frequency domain measures of heart rate variability.
Altered skeletal muscle glucose transport and blood lipid levels in habitual cigarette smokers
Authors: Rincón  , Krook  , Galuska  , Wallberg‐Henriksson  , Zierath
Published: March 2003

We determined whether habitual cigarette smoking alters insulin‐stimulated glucose transport and GLUT4 protein expression in skeletal muscle. Vastus lateralis muscle was obtained from 10 habitual cigarette smokers and 10 control subjects using an open muscle biopsy procedure. Basal 3‐O‐methylglucose transport was twofold higher (P > 0·01) in muscle from habitual smokers (0·05 ± 0·08 vs. 1·04 ± 0·19 μmol ml−1 h−1; controls vs. smokers respectively). Insulin (600 pmol l−1) increased glucose transport 2·6‐fold (P > 0·05) in muscle from control subjects, whereas no significant increase was noted in habitual smokers. Skeletal muscle GLUT4 protein expression was similar between the groups. FFA levels were elevated in the smokers (264 ± 49 vs. 748 ± 138 μmol l−1 for control subjects vs. smokers; P < 0·05), and serum triglyceride levels were increased in the smokers (0·9 ± 0·2 vs. 2·3 ± 0·6 mmol l−1 for control subjects vs. smokers; P < 0·05). Skeletal muscle carnitine palmitil (acyl) transferase activity was similar between the groups, indicating that FFA transport into the mitochondria was unaltered by cigarette smoking. In conclusion, cigarette smoking appears to have a profound effect on glucose transport in skeletal muscle. Basal glucose transport is markedly elevated, whereas insulin‐stimulated glucose transport is impaired. These changes cannot be explained by altered protein expression of GLUT4, but may be related to increased serum FFA and triglyceride levels. These findings highlight the importance of identifying habitual cigarette smokers in studies aimed at assessing factors that lead to alterations in lipid and glucose homeostasis in people with non‐insulin‐dependent diabetes mellitus (NIDDM).
Interstitial lactate levels in human skin at rest and during an oral glucose load: a microdialysis study
Authors: Petersen Lars J.
Published: March 2003

In vitro data have suggested that the skin is a significant lactate source. The purpose of the present study was to measure lactate and glucose concentrations in intact human skin in vivo using the microdialysis technique. Microdialysis fibres of 216 μm were inserted intradermally and perfused at a rate of 3 μl min–1. In the first experimental protocol, dialysis fibres were calibrated by the method of no net flux in eight subjects. Skin lactate concentrations of 2·48 ± 0·17 mmol l–1 were significantly greater than lactate concentrations of 0·84 ± 0·15 mmol l–1 in venous plasma (P<0·01). Glucose concentrations in skin and venous plasma were similar (5·49 ± 0·18 vs. 5·26 ± 0·24 mmol l–1). In the second experimental protocol, changes in lactate and glucose levels were studied in 10 subjects after an oral glucose tolerance test (OGTT). After the OGTT, plasma glucose and lactate levels increased by 54% and 39% to peak levels at 30 and 60 min respectively. In comparison, skin glucose and lactate increased by 41% and 18% at 60 and 90 min. No changes in skin blood flow were observed during the OGTT. The data suggest that resting skin is a significant lactate source with no significant lactate production during OGTT. The cellular source of lactate in the skin remains undetermined to date.
Volumetric measurements of peripheral oedema in clinical conditions
Authors: Brijker  , Heijdra  , Van Den Elshout  , Bosch  , Folgering
Published: March 2003

Water‐displacement volumetry can be used for quantifying the volume of the leg. However, not much is known about its application in patients with peripheral oedema of cardiopulmonary origin. We measured the reproducibility of a water‐displacement apparatus with a solid object and in ten non‐oedematous clinical patients (group A). The day‐to‐day variability of the leg volume was assessed in the same group. The diurnal variability was assessed in ten patients with persisting peripheral oedema (group B). The effect of treatment on the severity of peripheral oedema was evaluated in another nine patients with peripheral oedema, who were in need of diuretic treatment (group C). Volumetric results were compared to the ankle circumference method and the body weight method. The coefficient of variation was 0·16% in the fixed object and 0·47% in group A. The day‐to‐day variability was 1·52% after 1 day and 1·76% after a mean interval of 4·8 days. In group B, leg volume and circumference increased during the day (5·9%, P<0·001, and 2·4%, P<0·01, respectively), while body weight remained unchanged. In group C, leg volume, circumference and body weight decreased significantly after treatment (13·1%, P<0·01, 7·1%, P<0·05, and 5·9%, P<0·05). The correlation between the changes in volume and body weight was poor (r=0·37, P=0·33). In conclusion, (1) water‐displacement volumetry is highly reproducible, (2) a diurnal variability of peripheral oedema was found, and (3) volumetry is a suitable tool for monitoring peripheral oedema, while the body weight method appears to be less accurate.
Physical activity, aerobic capacity and selected markers of oxidative stress and the anti‐oxidant defence system in healthy active elderly men
Authors: Kostka  , Drai  , Berthouze  , Lacour  , Bonnefoy
Published: March 2003

The relationship of oxidative stress and the anti‐oxidant defence system to maximal oxygen consumption (V˙O2max) and habitual physical activity was assessed in 26 elderly men (71·0 ± 4·2 years) and compared to that of 12 young men (22·1 ± 5·1 years). Physical activity was assessed by a questionnaire. Malondialdehyde (MDA), plasma total anti‐oxidant status (TAS), the levels of red blood cell (RBC) superoxide dismutase (SOD) and glutathione peroxidase (GPX), as well as serum GPX activities were determined under resting conditions. The older and young men had similar TAS and RBC SOD, while MDA, RBC GPX and plasma GPX were higher, and RBC SOD/GPX ratio was significantly lower in the older men. Neither MDA nor anti‐oxidants were associated with any of the physical activity/aerobic capacity measures in the elderly men. We conclude that in healthy elderly men with a good nutritional status, indicators of the anti‐oxidant defence system are not lower in comparison with young men. Increased RBC and plasma GPX coupled with a high level of lipid peroxidation marker may indicate an adaptation of anti‐oxidant defences to sustained oxidative stress. Furthermore, the results of the present study suggest that the level of habitual physical activity and aerobic capacity have no major influence on the resting balance between radical generation and blood anti‐oxidant potential in healthy older men.
Automated standardized pupillometry with optical method for purposes of clinical practice and research
Authors: Fotiou F. , Fountoulakis K. N. , Goulas A. , Alexopoulos L. , Palikaras A.
Published: March 2003

The aim of the current study was the introduction and standardization of two experimental conditions for dynamic pupillometry. Pupillometry is a method that can provide valuable data concerning the functioning of the autonomous nervous system. The system for recording the pupil reaction was developed in the Laboratory of Clinical Neurophysiology of the 1st Department of Neurology of Aristotle University of Thessaloniki, in co‐operation with the Laboratory of Fluid Mechanics of the Aristotle University of Thessaloniki. This system is fully automated. It includes an infra‐red video camera, which has the capacity to record in complete darkness, and an SLE (clinical photic stimulator) lamp. A software application automatically performed all the procedures. During the first experiment, one flash was administered. During the second experiment, a series of 25 flashes (1 Hz frequency) was administered. Fifty physically and mentally healthy subjects aged 23–48 years took part in the study. Means, standard deviations and ranges for all variables characterizing normal subjects during both experimental conditions are reported. Test/re‐test results and comparisons of the two eyes are also reported. The combined use of these two experimental conditions in dynamic pupillometry may be a very useful tool in medical research. There are already reports on the usefulness of pupillometry in the research of various diseases, including depression and Alzheimer’s disease. It is expected that it will also be a valuable research tool in the study of diabetes, alcoholism, myasthenia gravis, cancer, multiple sclerosis, etc.
The influence of local heating on skin microcirculation in pressure ulcers, monitored by a combined laser Doppler and transcutaneous oxygen tension probe
Authors: Schubert Vivianne
Published: March 2003

In a prospective, controlled study the skin microcirculation and transcutaneous oxygen tension were evaluated in 28 elderly patients (85 ± 0·8 years) with grade 2 and 3 pressure ulcer. Laser Doppler fluxmetry and transcutaneous oxymetry techniques were used together in a combined probe to simultaneously evaluate the influence of heat stress at 44°C, at the same time and in the same area of the ulcer edge. Total skin microcirculation was already increased at rest before heating, and increased even more during a fast and then a more gradually heat‐induced hyperaemia response compared with undamaged skin. The increase showed a biphasic manner. On the other hand, the oxygen diffusibility from the capillaries to the skin surface was significantly reduced, compared with undamaged skin. One hypothesis may be that in ageing skin the main part of the increased skin microcirculation in a pressure ulcer were passing through thermoregulatory vessels in subpapillary tissue layers. Interactions between the increased blood flow and metabolic activity at the ulcer edge might be oxygen‐consuming, leading to reduced oxygen content passing through the capillaries and contributing to tissue ischaemia. Disturbances of the local skin microcirculation and tissue oxygenation will influence the ulcer healing rate and may affect the healing progress.
Air pollutants and tear film stability – a method for experimental evaluation
Authors: Zhao Jiang , Wollmer Per
Published: March 2003

Instability of the pre‐ocular tear film causes symptoms of dry eyes. Tear film instability may be caused by exposure to air pollutants, but identification of causative agents is often difficult. We describe an in vitro technique for assessment of putative agents on the surface activity of Meibomian lipids. The lipids were obtained from bovine eyelids and dissolved in chloroform. Surface activity of the solution was assessed on a Wilhelmy balance. After addition of benzalkonium chloride, minimum surface tension of the lipids increased and maximum surface tension fell. After addition of quartz particles, both maximum and minimum surface tension increased. The method can be used to screen substances suspected to cause dry eyes, providing a basis for selection of substances for in vivo studies.