bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation and tissue distribution of the human sodium iodide symporter gene
Authors: Ajjan R. A. , Kamaruddin N. A. , Crisp M. , Watson P. F. , Ludgate M. , Weetman A. P.
Published: March 2003

OBJECTIVE

Iodide uptake by the thyroid gland is mediated by the sodium iodide symporter (NIS). In the present report, we have analysed the factors that modulate human NIS mRNA expression and iodide uptake in primary thyroid follicular cell (TFC) cultures. In addition, NIS mRNA tissue distribution was investigated.

METHODS

Primary thyroid follicular cell cultures were treated with human recombinant TSH with or without cytokines for 72 h. Subsequently, NIS gene expression and iodide uptake were analysed using reverse transcription–polymerase chain reaction (RT–PCR) and 125I uptake, respectively. Human tissue samples were investigated for NIS gene expression using both RT–PCR and Northern blotting.

RESULTS

Human TSH increased both NIS gene expression and iodide uptake in TFC cultures in a dose‐dependent manner. Using concentrations of 0.1 U/l of hTSH, a minor increase in NIS gene expression was detected without a detectable increase in iodide uptake. IL‐1α,TNFα and IFNγ at concentrations of 105 U/l all inhibited TSH‐induced NIS gene expression and iodide uptake. In these experiments, there was a good correlation between NIS mRNA expression and iodide uptake. Using RT–PCR higher levels of NIS mRNA were detected in Graves' disease (GD) compared to multi‐nodular goitre tissue samples. Stomach and salivary gland tissue also expressed NIS mRNA, whereas low levels were found in the mammary gland and extraocular muscle tissue. No expression was detected in the ovary, oesophagus, colon, extraocular fat or skin. In contrast, Northern blot analysis failed to detect NIS in stomach, salivary gland, intestinal fat or non‐toxic multi‐nodular goitre tissue samples, although this was present in GD thyroid tissue.

CONCLUSION

TSH upregulates sodium iodide symporter gene expression and iodide uptake in primary thyroid follicular cell cultures, and this induction is modulated by cytokines. Variable levels of sodium iodide symporter mRNA are present in different tissue samples, with high expression evident in Graves' disease thyroid tissue.
Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults
Authors: Welch Dinauer Catherine A. , Michael Tuttle  , Robie Daniel K. , McClellan Donald R. , Svec Rita L. , Adair Carol , Francis Gary L.
Published: March 2003

OBJECTIVE

Differentiated thyroid cancer (DTC), including papillary (PTC) and follicular (FTC) variants, is unusual in children and accounts for only 10% of all cases. For that reason, knowledge of the clinical features which predict recurrence is limited. We reviewed 170 cases of childhood DTC to determine if specific clinical or pathological findings were associated with increased risk of recurrence.

DESIGN

This was a retrospective study of children and adolescents with DTC registered in the Department of Defense Automated Centralized Tumor Registry.

PATIENTS

We reviewed 137 cases of PTC and 33 cases of FTC diagnosed between 1953 and 1996 at ≤ 21 years of age.

RESULTS

In the PTC group (median follow‐up 6.6 years, range 2 month — 39.5 years), only one patient died, but 21 developed local and 6 developed distant recurrence. By univariate analysis, recurrence was more common in patients with multifocal (odds ratio 7.5) or large tumours (odds ratio 4.1), and in those with palpable cervical lymphadenopathy (odds ratio 3.0) or metastasis at diagnosis (odds ratio 2.8). By multivariate analysis focality was the best predictor of recurrence (P = 0.0019). In the FTC group (median follow‐up 5 years, range 6 month — 38.1 years), no patient died of disease, but 5 developed recurrence. As with PTC, recurrence was more likely in patients with multifocal tumours (odds ratio 22.0).

CONCLUSIONS

Differentiated thyroid cancer in children and adolescents has low mortality, but a high risk of recurrence. Young patients with large, multifocal tumours that are already metastatic at diagnosis have the greatest risk of recurrence.
Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle: association with changes in ovarian and uterine Doppler blood flow
Authors: Agrawal Rina , Conway G. S. , Sladkevicius P. , Payne N. N. , Bekir J. , Campbell S. , Tan S. L. , Jacobs H. S.
Published: March 2003

OBJECTIVE

To investigate whether changes in circulating serum vascular endothelial growth factor (VEGF) concentrations during the menstrual cycle are associated with changes in blood flow within the ovaries and uterus.

PATIENTS AND MEASUREMENTS

Serum VEGF concentrations were measured and pulsed and colour Doppler blood flow waveforms recorded within the ovarian stroma and uterine arteries during the early follicular, the immediate preovulatory and the mid‐luteal phases of the menstrual cycle of 14 healthy women.

RESULTS

Mean (±SD) serum VEGF concentrations rose from 2.44 ± 0.1 ng/ml in the early follicular phase to 3 ± 0.8 ng/ml in the pre‐ovulatory phase and to 4.4 ± 0.9 ng/ml in the mid‐luteal phase (P < 0.0001) of the menstrual cycle. Mean peak systolic blood flow velocity (PSV) and time‐averaged maximum flow velocity (TAMXV) were higher within the ovarian stroma of the ovary bearing the dominant follicle and the uterine arteries in the pre‐ovulatory and mid‐luteal phase than in the same sites during the early follicular phase of the menstrual cycle. PSV rose significantly from the early follicular phase (11 ± 6 cm/s) to 14 ± 4 cm/s in the pre‐ovulatory phase and further in the mid‐luteal phase (26 ± 7 cm/s, P = 0.0001). Within the uterine arteries, mean PSV rose significantly from 28 ± 9 cm/s in the early follicular phase to 31 ± 8 cm/s in the pre‐ovulatory phase and further in the mid‐luteal phase (44 ± 11 cm/s, P < 0.005). Serum VEGF correlated with serum progesterone concentrations in the luteal phase (r = 0.85, P < 0.001), with serum oestradiol concentrations in the early follicular (r = 0.67, P = 0.009), pre‐ovulatory (r = 0.57, P = 0.03) and luteal phases (r = 0.68, P < 0.005) and with serum testosterone in the early follicular phase (r = 0.63, P = 0.01).

CONCLUSIONS

Cyclical changes in serum vascular endothelial growth factor concentrations are associated with coincident changes in ovarian and uterine blood flow.
Multiple endocrine neoplasia type 1 (MEN1): clinical heterogeneity in a large family with a nonsense mutation in the MEN1 gene (Trp471Stop)
Authors: Valdés N. , Pérez de Nanclares G. , Alvarez V. , Castaño L. , Díaz‐Cadórniga F. , Aller J. , Coto Eliecer
Published: March 2003

OBJECTIVE

Familial multiple endocrine neoplasia type 1 (MEN1) is an hereditary dominant trait characterized by tumours of the parathyroids, anterior pituitary and endocrine pancreatic glands, among others. The MEN1 gene has recently been cloned, and MEN1‐mutations have been identified in several families as well as in a number of sporadic cases. The aim of this study was to search for mutations in a large MEN1‐family in order to define the clinical heterogeneity among mutation‐carriers. We also analysed DNA from several tumour tissues in order to test the ‘two hit’ model for inactivation of the MEN1 gene.

PATIENTS AND METHODS

We searched for mutations in the MEN1‐gene in members of a large MEN1‐family. A total of 11 affected and 4 healthy at risk individuals were analysed. DNA was obtained and exons 1 to 10 of the MEN1‐gene were PCR‐amplified and subjected to automated‐direct sequencing. In addition, we isolated DNA from parathyroid tumours of two family members, and compared this DNA with that of the normal tissue counterpart to define if the normal copy of the MEN1‐gene was deleted.

RESULTS

G to A change at nucleotide 7640 (exon 10) that would convert Trp to Stop at codon 471 was found. This mutation was identified in eleven affected individuals, as well as in four healthy (asymptomatic) family members. These patients showed a wide spectrum of clinical symptoms and ages of presentation. Comparison of normal and tumour DNAs showed the loss of the normal (non‐mutated) copy of MEN1 gene in the tumour tissue.

CONCLUSION

The different ages of disease presentation and the heterogeneity of symptoms among carriers of the Trp471Stop mutation, which would lead to the synthesis of a truncated non‐functional protein, suggest that clinical heterogeneity is a characteristic of MEN1 independent of the type of mutation. Finally, the lack of amplification of the normal MEN1‐allele on DNA from parathyroid tumours of two family members indicates that MEN1 is a tumour suppressor gene, the second hit that inactivates the normal copy in mutation carriers being a deletion.
A trial of growth hormone therapy in well‐controlled hypophosphataemic rickets
Authors: Cameron  , Sochett  , Daneman  , Kooh
Published: March 2003

OBJECTIVE

Conventional therapy of hypophosphataemic rickets (HR) with oral phosphate and calcitriol does not always result in normal linear growth. Recombinant human growth hormone (rhGH) offers theoretical advantages as an adjunctive therapy. We aimed to determine the effects of adjunctive rhGH therapy in children with well‐controlled HR.

PATIENTS

In this report, 5 prepubertal children (aged 3.5–10.9 years) with well‐controlled HR on conventional therapy were given adjunctive standard dose rhGH therapy for one year.

DESIGN AND MEASUREMENTS

Height, growth velocity, metabolic markers of calcium and phosphate metabolism, body composition, bone mineral density, wrist and knee X‐rays, and renal sonography were assessed at regular intervals. Height and growth velocities were also calculated 12 months after ceasing rhGH therapy.

RESULTS

After 12 months therapy with rhGH, no significant biochemical or radiological benefits were observed. A significant increase in height SD score was observed (P = 0.023), but this was not associated with any increase in the growth velocity SD score and appears to have been due to catch‐up growth caused by conventional therapy alone. When rhGH therapy was ceased, no significant decreases in mean height SD or growth velocity SD scores were observed.

CONCLUSIONS

In well‐controlled hypophosphataemic rickets patients receiving conventional therapy, adjunctive therapy with standard dose rhGH offers no benefits in linear growth or rachitic disease markers.
The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism
Authors: Wichers Maria , Springer Wolfram , Bidlingmaier Frank , Klingmüller Dietrich
Published: March 2003

OBJECTIVE

Hydrocortisone replacement regimes remain rather empirical and produce serum cortisol profiles very different from normal physiology. We have analysed the effects of different dosages of hydrocortisone (HC) replacement therapy on the health perception and general well‐being of patients with secondary hypocortisolism. We also evaluated the effects of these regimens on bone metabolism.

DESIGN

In a prospective randomized double‐blind study, 3 groups of 3 patients were treated with 3 different dosages of HC (15, 20 and 30 mg/day), in different sequences, each sequence for two weeks.

PATIENTS

Nine adult patients with complete secondary hypocortisolism.

MEASUREMENTS

Serum cortisol, ACTH, aldosterone, renin, alkaline phosphatase, bone specific alkaline phosphatase, osteocalcin, PTH, C‐telopeptides of type‐I collagen, sodium, potassium, phosphate; urinary free cortisol, pyridinium cross‐links, urine sodium, potassium and phosphate were measured at the beginning and after each week of the study.

For quality of life assessment the patients completed three different questionnaires, the Basler Befindlichkeits‐Skala (BBS), the Befindlichkeits‐Skala (Bf‐S), the Beschwerde‐Liste (BL) each week.

RESULTS

With increasing doses of 15, 20 and 30 mg hydrocortisone a significant increase of free urinary cortisol was achieved (298 ± 26 nmol/day, 454 ± 43, 819 ± 59, respectively; P < 0.01). The mean scores of the psychological questionnaires did not change significantly during the whole study (BBS 81.8 ± 3.9; 82.8 ± 3.9, 83.6 ± 3.9; Bf‐S 15.9 ± 3.4, 11.3 ± 2.6, 12.5 ± 2.8; BL 15.7 ± 2.3, 14.4 ± 2.5, 14.8 ± 2.6, respectively). Osteocalcin decreased significantly (2.3 ± 0.49, 2.1 ± 0.42, 1.8 ± 0.38, P < 0.01) with increasing HC doses but remained within the normal range. The other investigated parameters were within or nearly within the normal range in all patients at the beginning and did not change during the study.

CONCLUSION

Dosages of 15, 20 or 30 mg hydrocortisone/day have equivalent effects on quality of life in patients with secondary hypocortisolism. With 15 or 20 mg hydrocortisone/day the patients feel nearly as well and content as normal healthy individuals. Since long‐term treatment with a high replacement dose of glucocorticoids (hydrocortisone 30 mg/day) induces bone loss, this risk can be avoided with a substitution dosage of 20 mg or even 15 mg hydrocortisone/day, without influencing the well‐being of the patient.
The effects of testosterone on osteoporosis in men
Authors: Francis
Published: March 2003

Although the pathogenesis of osteoporosis in men is multi‐factorial, testosterone is known to play an important role in the maintenance of the male skeleton. This role, however, appears complicated as it may be mediated in part by aromatization to oestradiol. Testosterone replacement therapy improves bone density in men with hypogonadal osteoporosis, particularly if the epiphyses are still open. There is no well‐established treatment for idiopathic osteoporosis in men, but testosterone supplementation may prove to be useful. Further studies are required to confirm the safety and efficacy of this treatment in eugonadal men with osteoporosis.
Ontogeny of serum leptin concentrations in the human
Authors: Geary M. , Herschkovitz R. , Pringle P. J. , Rodeck C. H. , Hindmarsh P. C.
Published: March 2003

OBJECTIVE

Serum leptin concentrations reflect the fat mass of an individual. Fetal growth is rapid and it might be expected that major changes in circulating leptin concentrations in the fetus and neonate take place. We have studied the ontogeny of serum leptin concentrations in cord blood samples obtained by cordocentesis between 14 and 32 weeks of gestation and in samples obtained at term.

PATIENTS

Cordocentesis samples from 10 appropriately grown for gestational age (AGA) and 10 intrauterine growth restricted (IUGR) fetuses. The results were compared with cord serum leptin concentrations obtained in 39 term healthy pregnancies.

RESULTS

In the AGA and term pregnancies serum leptin concentrations changed little up until 38 weeks of gestation when there was an increase in concentration (Pre 38 weeks 3.5 μg/l (SEM 0.3); Post 38 weeks 5.6 μg/l (SEM 0.7): Mann Whitney P = 0.03). Serum leptin concentrations were similar in the AGA and IUGR fetuses (AGA 5.9 μg/l (SEM 3.0); IUGR 4.2 μg/l (SEM 1.5): Mann–Whitney P = ns). Serum leptin was strongly related to birth weight (r = 0.58; P < 0.001) and birth length (r = 0.32; P = 0.05) in the term babies but not in the AGA or IUGR groups.

CONCLUSION

Serum leptin concentrations in the fetus appear to be independent of gestational age and only rise towards the end of gestation. This late change probably reflects the changes in the accretion of body fat. There appears to be little difference in serum leptin concentrations between AGA and IUGR fetuses.
Growth hormone and exercise
Authors: Jenkins Paul J.
Published: March 2003

This review summarizes the interactions between GH and exercise. Not only does exercise have profound effects upon the GH/IGF‐I axis per se, but there is increasing evidence that such physiological perturbations might be influential in the performance responses to repeated training. However, the effects of systemic administration of rGH in restoring exercise capability and muscle strength in GH deficient adults and the ergogenic benefits of GH doping amongst athletes remain unproven. What is certain is that these issues will be of increasing relevance to clinical endocrinologists.
The impact of mild Leydig cell dysfunction following cytotoxic chemotherapy on bone mineral density (BMD) and body composition
Authors: Howell S. J. , Radford J. A. , Adams J. E. , Shalet S. M.
Published: March 2003

BACKGROUND

Overt testosterone deficiency is associated with a reduction in BMD and alteration in body composition. However, there are few data concerning the impact of mild hypogonadism on these parameters.

PATIENTS AND METHOD

We have identified a cohort of 36 men aged < 55 years with mild Leydig cell impairment, defined by a raised LH level (LH ≥ 8 IU/l) in the presence of a testosterone level in the lower half of the normal range or frankly subnormal (< 20 nmol/l), following treatment with procarbazine‐containing chemotherapy regimens or high‐dose chemotherapy for haematological malignancy. These men underwent measurements of BMD (measured by dual‐energy X‐ray absorptiometry (DXA), single energy X‐ray absorptiometry (SXA) and quantitative CT (QCT)), body composition (DXA), markers of bone turnover, serum lipids and serum IGF‐1. To allow for changes that may be directly attributable to the underlying disease or its treatment, results were compared with those obtained in 14 men who had received the same chemotherapy for the same diseases but had normal LH and testosterone levels (controls).

RESULTS

When data from all 50 men were considered together there were significant reductions in BMD of the lumbar spine both by DXA (Z = − 0.34, P = 0.01) and QCT (Z = − 1.5, P < 0.0001), at the femoral neck (Z = − 0.52, P < 0.0001) and distal forearm (Z = − 0.21, P = 0.05). Mean femoral neck BMD was significantly lower in patients compared with controls (Z = − 0.68 vs. Z = − 0.11, P = 0.05) and there was a nonsignificant trend towards lower lumbar spine BMD measured by QCT (Z = − 1.64 vs. Z = − 1.10; P = 0.09). In addition, serum testosterone level and testosterone:LH ratio significantly correlated with femoral neck BMD (r = 0.28, P = 0.05 and r = 0.37, P = 0.008, respectively). There were no significant differences in lean body mass, fat mass and percentage fat between the patients and controls. There was, however, a difference in the distribution of body fat with a propensity for the patients to accrue truncal fat, and the serum testosterone level significantly inversely correlated with percentage of truncal fat (r = − 0.29, P = 0.04). There were no significant differences in lipid levels, IGF‐1 levels or markers of bone turnover between the patients and controls.

CONCLUSIONS

These data suggest that mild Leydig cell impairment may have significant effects on bone mineral density and may result in subtle body composition changes, although in men who have received cytotoxic chemotherapy, other factors also contribute to the observed osteopenia. Testosterone replacement may be beneficial in some of these men and this requires further evaluation.
Increased prevalence of thyroid autoimmunity in patients successfully treated for Cushing's disease
Authors: Colao Annamaria , Pivonello Rosario , Faggiano Antongiulio , Filippella Mariagiovanna , Ferone Diego , Di Somma Carolina , Cerbone Gaetana , Marzullo Paolo , Fenzi Gianfranco , Lombardi Gaetano
Published: March 2003

BACKGROUND

Cushing's disease is characterized by abnormalities of immune function.

OBJECTIVE

To evaluate the prevalence of autoimmune thyroid diseases in patients with Cushing's disease (CD), after successful treatment and the possible association between previous nodular goitre or positive thyroid autoantibodies during the active phase of CD and the subsequent development of autoimmune thyroid diseases after cure.

SUBJECTS AND METHODS

Twenty patients with CD and 40 sex‐ and age‐matched healthy controls were considered for the study. In CD patients, thyroid ultrasonography and measurement of circulating free thyroxine (fT4), free triiodothyronine (fT3), thyroid stimulating hormone (TSH), antithyroglobulin (anti‐Tg) and antithyroperoxidase (anti‐TPO) antibodies were performed at diagnosis and 6 months after disease cure while in controls they were performed only at study entry.

RESULTS

Serum fT3, and fT4 levels were similar in patients, either during the active phase or after cure of the disease, and controls. Conversely, in the patients, serum TSH levels were significantly lower during active disease (0.4 ± 0.05 mU/l, P = 0.001) and significantly higher after disease cure (4.7 ± 0.1 mU/l, P < 0.001) than in controls (2.3 ± 0.4 mU/l). Four patients (20%) and 11 controls (27.5%) had positive anti‐Tg and/or anti‐TPO titre at study entry, while eight patients (40%) developed positive anti‐Tg and/or anti‐TPO titre after disease cure. The prevalence of positive antithyroid antibodies titre in cured CD patients was significantly higher than that observed in the same patients during the active disease (P = 0.008) and in controls (P = 0.031). A significantly higher prevalence of autoimmune thyroiditis was found in patients cured from CD (35%) than in patients with active CD (0%) (P = 0.016) and in controls (10%) (P = 0.031). A significant association was found between the presence of autoimmune thyroiditis after CD cure and the presence of a previous nodular goitre (P = 0.017) or positive thyroid autoantibodies titre (P = 0.007) during the active phase of the disease.

CONCLUSION

Patients successfully treated for Cushing's disease have an increased prevalence of thyroid autoimmunity and autoimmune thyroiditis as compared to a control population. Therefore, patients with hypercortisolism need an accurate evaluation of thyroid function after remission of the disease in order to prevent the eventual onset of subclinical or overt post‐thyroiditis hypothyroidism.
Thyroperoxidase (TPO) immunostaining of the solitary cold thyroid nodule
Authors: Christensen Lise , Blichert‐Toft Mogens , Brandt Mathilde , Lange Martin , Bjerregaard Sneppen Simone , Ravnsbæk Joan , Mollerup Charlotte L. , Strange Lise , Jensen Flemming , Kirkegaard Jørgen , Sand Hansen Hanne , Sørensen Sven Sølvsten , Feldt‐Rasmussen Ulla
Published: March 2003

OBJECTIVE

To evaluate the value of immunostaining using the monoclonal antibody (MoAB47) against thyroperoxidase (TPO) in distinguishing between benign and malignant tumour cells in fine needle aspiration cytology (FNAC) samples obtained from a solitary cold nodule of the thyroid gland for the purpose of strengthening the indication for thyroid surgery.

DESIGN

A prospective, immunocytochemical study of FNACs taken from patients with solitary cold thyroid nodules who presented to Rigshospitalet, Copenhagen, Denmark, during the period April 1993 to May 1996. The first sample series was taken perioperatively in order to test the utility of the method. In the second part of the study samples were obtained preoperatively by ultrasonic guided aspiration. Tissue sections from the nodules obtained during a subsequent operation served as controls.

PATIENTS

One hundred and eighty‐one patients, 150 women and 31 men, were studied. The age range was 14–89 years with a median age of 44 years. Fifty‐seven patients were excluded from the study for various reasons leaving us with a total of 124 nodules from 124 patients for final evaluation.

METHODS

FNAC cells and corresponding nodular tissue were stained by immunocyto– and immuno‐histochemistry using MoAb47 and by routine staining methods. Samples were considered benign if 80% or more of the epithelial‐looking cells of both the FNACs and the histological tissue sections of the nodule were stained by TPO. Consequently, samples were considered malignant if more than 20% of the epithelial‐looking cells failed to stain for TPO. Routinely stained tissue cells and sections served as diagnostic controls.

RESULTS

A pattern with negative TPO staining was found in all lesions which, by conventional histological staining, were subsequently proven to be malignant. A universal and reliable, positive TPO staining pattern was found in all subsequently proven benign lesions, with the exception of one out of 26 follicular adenomas. This gave the method a sensitivity of 1.0 (negative TPO staining = malignancy in 27 out of 27) and a specificity of 0.99 (positive TPO staining = benign lesion, in 96 out of 97). Positive and negative predictive values were 0.96 and 1.00 respectively.

CONCLUSION

Thyroperoxidase immunostaining of fine needle aspirates from solitary, scintigraphically cold nodules of the thyroid gland has proved to be an important and reliable diagnostic tool for distinguishing between benign and malignant nodules. Thus, patients might be spared further surgery if not otherwise indicated.
Prolonged activation of the hypothalamus– pituitary–gonadal axis in a child with X‐linked adrenal hypoplasia congenita
Authors: Takahashi Ikuko , Takahashi Tsutomu , Shoji Yasuko , Takada Goro
Published: March 2003

X‐linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder of the human adrenal cortex that is caused by a mutation of the DAX‐1 gene, a member of the nuclear hormone receptor superfamily. Hypogonadotrophic hypogonadism is frequently associated with this disease and the DAX‐1 mutation is known to impair gonadotrophin production by acting at both the hypothalamic and pituitary levels. However, three recent studies reported that the hypothalamic–pituitary–gonadal axis was active in six infants with AHC, suggesting that a difference exists in the central regulation of hypothalamic–pituitary–gonadal activity between infant boys and pubertal boys. To determine the effect of the DAX‐1 gene mutation on the axis in early childhood, we measured testosterone, LH, and FSH and performed LH‐releasing hormone tests on a boy with AHC from birth to 3 years of age. Surprisingly, our findings showed that the axis was active from the infantile period to 3 years of age. This delayed initiation of the prepubertal pause, or prolonged activation of the axis, indicates that the DAX‐1 gene is related to the control mechanism of the prepubertal restraint of gonadotrophin secretion.
Low dose (1 μg) ACTH test in the evaluation of adrenal dysfunction in pre‐clinical Addison's disease
Authors: Laureti Stefano , Arvat Emanuela , Candeloro Paola , Di Vito Lidia , Ghigo Ezio , Santeusanio Fausto , Falorni Alberto
Published: March 2003

OBJECTIVE

The presence of 21‐hydroxylase autoantibodies (21OHAb) is a marker of adrenal autoimmunity and can be used to identify subjects with pre‐clinical Addison's disease. The low‐dose (1 μg) ACTH test (LDT) is more sensitive than the high‐dose (250 μg) test (HDT) for the diagnosis of pituitary adrenal insufficiency, but no information is available on the use of a LDT in subjects with autoimmune adrenalitis and primary adrenal insufficiency. The aim of our study was to evaluate the clinical use of the LDT in the diagnosis of early adrenocortical dysfunction in patients with adrenal autoantibodies.

DESIGN AND METHODS

Firstly, we evaluated the cortisol responses to both a LDT and a HDT in a group of 12 healthy volunteers. We then performed a LDT in 11 subjects positive for 21OHAb, but without clinical signs of Addison's disease identified by screening 920 patients with one or more organ‐specific autoimmune diseases. In all cases, the LDT was followed by a sequential HDT which was used as a control test of the sensitivity and specificity of the LDT.

RESULTS

In healthy subjects, the peak cortisol levels after the LDT were similar to those after the classical HDT. In 21OHAb‐positive subjects, the LDT showed a pathological response in five out of 11 (45%) cases and the diagnostic concordance between the results of the LDT and those of the HDT was 100%. All the five cases with pathological LDT were also positive for adrenal cortex autoantibodies (ACA) and 4/5 had high levels of basal ACTH. One subject with pathological LDT developed clinical Addison's disease 4 months after the test had been performed.

CONCLUSIONS

Our study demonstrates that the low dose ACTH test has a high diagnostic sensitivity and specificity for primary adrenal insufficiency and suggests that it can accurately identify subjects with pre‐clinical adrenal dysfunction.
Expression of CYP27A, a gene encoding a vitamin D‐25 hydroxylase in human liver and kidney
Authors: Gascon‐Barré Marielle , Demers Christian , Ghrab Olfa , Theodoropoulos Catherine , Lapointe Réal , Jones Glenville , Valiquette Luc , Ménard Daniel
Published: March 2003

Vitamin D3 (D3) is not active but must be hydroxylated at C‐25 in liver before acquiring its hormonal potential in the kidney. The sterol‐27 hydroxylase (gene symbol: CYP27A) catalyses the oxidation of sterol side chain in bile acid synthesis but the enzyme is also known as a D3−25 hydroxylase.

The study examined the expression of the gene encoding CYP27A in adult and fetal human livers and kidneys.

Thirty‐nine adults (18 men and 21 women; mean age 58 years in men and 57 years in women) and three normal fetuses gestational age 17–19 weeks were studied.

Tissue CYP27A mRNA and serum 25OHD concentrations were measured.

Normal specimens: CYP27A transcript was found to be higher in adult than in fetal livers but its expression was similar in adult and fetal kidneys. In fetuses, no difference was observed between CYP27A levels in livers and kidneys. In adult livers CYP27A levels were higher in women than in men. Hepatic CYP27A mRNA and serum 25OHD concentrations were both found to be higher in summer than in winter. Multiple linear regression analyses indicate that the season of the year and the serum 25OHD concentrations (but not 1,25(OH)2D concentrations) are the best predictors of CYP27A mRNA abundance in normal adult livers. In situ hybridization illustrates a clear label in hepatocytes which increases in intensity in the perivenous region of the hepatic acinus. Pathological specimens: In one man with an hepatic carcinoma there was a very large increase in CYP27A (> 1000 fold) compared to the level found in the normal liver. In that patient, serum 25OHD concentrations were found to be high considering the level of CYP27A mRNA in the normal hepatic area suggesting that the neoplastic tissue contributed to the C‐25 hydroxylation of vitamin D. Specimens obtained from two patients suffering from focal hepatic hyperplasia indicate that in one case the level of CYP27A mRNA was twice as high in the pathological than in the normal area while in the other its levels were similar in both areas. No difference in the CYP27A transcript was observed between specimens obtained from normal areas and those obtained form either an hepatic adenoma or from two intrahepatic colonic metastases.

CYP27A is present not only in the human adult liver but also in the adult kidney, and in the fetal liver and kidney. Our findings illustrate that CYP27A can be significantly upregulated in certain pathological situations such as in hepatic carcinoma and that the neoplastic tissue could contribute to the circulating concentration of 25OHD.
A luminescent bioassay for thyroid blocking antibodies
Authors: Jordan N. J. , Rinderle C. , Ashfield J. , Morgenthaler N. G. , Lazarus J. , Ludgate M. , Evans C.
Published: March 2003

Thyroid blocking antibodies (TBAb) have a role in the development of hypothyroidism and in the neonate are responsible for transient hypothyroidism. Specific measurement of TBAb requires a bioassay, but current methods are lengthy and cumbersome. We describe a rapid luciferase‐based method for the detection of TBAb using the lulu* cell line which is suitable for the provision of a clinical service

Chinese hamster ovary (CHO) cells were transfected with human TSH‐R together with G418 resistance and a cAMP responsive luciferase construct. Stable pools of transfected cells were selected and clones identified by limiting dilution. Clone lulu* gave the best response to stimulation by TSH and was used to develop a bioassay for TBAb. The luminescent bioassay conditions have been optimized and validated using 12 serum samples from patients found to be TBAb positive in a bioassay using an established method quantifying cAMP by radioimmunoassay (RIA). The effect of thyroid stimulating antibodies (TSAb) on the calculation of Inhibition Index (InI) using two previously described formulae have been investigated and we have used serum containing both TSAb and TBAb to investigate detection of TBAb in samples containing more than one type of activity.

Lulu* displays a dose dependent increase in luciferase expression in response to stimulation with bovine (b) TSH which is more effective in serum free medium than in salt free buffer. TSH stimulated luciferase expression can be inhibited by TBAb in either serum or an immunoglobulin preparation. Using optimized assay conditions, challenging 10% serum against 1 U/l bTSH in culture medium, we have tested 31 euthyroid sera to determine a reference range: InI values >23% were considered positive. Twelve samples previously shown to contain TBAb by an established method quantifying cAMP by RIA were positive by the luciferase‐based assay. Of control sera, 20/20 systemic lupus erythematosus, 13/14 rheumatoid arthritis, 12/12 multinodular goitre were negative.

We demonstrated that if more complex formulae are used to calculate InI, false positive TBAb results can be obtained in samples containing only TSAb. Finally, when sera contain both TSAb and TBAb, the net activity of stimulating and blocking antibodies is detected in the bioassay. Where TSAb are also present, analysis of serum may be required at several dilutions to detect TBAb.

We describe the production of a new cell line, lulu*, and its use to develop a luminescent bioassay for TBAb suitable for clinical use. Comparing two established methods of calculating TBAb, we found that they do not give identical results. In light of this, the high prevalence reported for TBAb in some studies has to be considered with caution.
Increasing incidence of childhood Graves' disease in Hong Kong: A follow‐up study
Authors: Wong Gary W. K. , Cheng P. S.
Published: March 2003

OBJECTIVE Childhood Graves' disease has been reported to be rare but preliminary epidemiological data on its incidence appeared to be high in Hong Kong Chinese children. The aim of this study is to determine the incidence of childhood Graves' disease in Hong Kong and to analyse whether there is an increasing trend of the incidence.

PATIENTS AND DESIGN We established a registry of childhood Graves' disease at our centre to collect cases from four districts in Hong Kong. The diagnosis of Graves' disease was based on clinical features, diffused enlargement of thyroid gland, raised free thyroxine or triiodothyronine levels, suppressed TSH levels, and the presence of thyroid receptor antibodies. Confirmed cases of Graves' disease who resided in any of the four districts were used to calculate the incidence for the study period between 1989 and 1998.

RESULTS One hundred and eighteen Chinese children under 15 years of age had a confirmed diagnosis of Graves' disease during the study period from January 1989 to December 1998. There were 11 boys and 107 girls giving a male to female ratio of 1 : 9·7. The overall incidence rates were 3·2/100 000/year and 6·5/100 000/year for the two periods 1989–93 and 1994–98, respectively. The incidence rates for girls have increased significantly (P < 0·001) from 3·8/100 000/year in 1989 to 14·1/100 000/year in 1998. The current incidence of childhood Graves' disease in our population is about eight times that reported in Danish children.

CONCLUSIONS This study confirms the high incidence of childhood Graves' disease in Hong Kong and documents an increasing trend for girls. Further studies are required to reveal possible genetic or environmental factors responsible for such epidemiology in Hong Kong Chinese children.
Growth hormone‐releasing hormone (GHRH) and GHRH receptor (GHRH‐R) isoform expression in ectopic acromegaly
Authors: Othman Nor Hayati , Ezzat Shereen , Kovacs Kalman , Horvath Eva , Poulin Eric , Smyth Harley S. , Asa Sylvia L.
Published: March 2003

Bronchial endocrine neoplasms causing acromegaly due to ectopic production of growth hormone (GH)‐releasing hormone (GHRH) have been reported. We describe the case of a 39‐year‐old man with clinical and biochemical acromegaly. Magnetic resonance imaging revealed an enlarged pituitary, which was confirmed histologically to harbour somatotroph hyperplasia. Further investigations identified a circumscribed central mass in the right lung which was surgically resected and histologically confirmed to be an endocrine tumour with strong immunopositivity for GHRH, synaptophysin and chromogranin; the lesion also exhibited mild positivity for peptide YY, calcitonin gene‐related peptide (CGRP), glucagon‐like peptide (GLP)−1, corticotrophin‐releasing hormone (CRH), tyrosine hydroxylase, vasoactive intestinal peptide (VIP) and enkephalin. S100 protein was identified in stellate cells surrounding nests of epithelial tumour cells. The MIB‐1 antibody labelled about 10% of the tumour cells. We established that the tumour not only produced GHRH but the GHRH‐receptor (GHRH‐R) as well. GHRH and GHRH‐R mRNA were identified and the latter was characterized as two variants, a full‐length transcript and a truncated splice variant that has been described in human pituitary somatotroph adenomas. We suggest that GHRH expression by this tumour and the presence of its receptor may be responsible for enhanced growth. The expression of a truncated splice variant that is unable to transduce GHRH signalling may be implicated in the less aggressive behaviour of well‐differentiated endocrine tumours that produce GHRH compared with small‐cell lung carcinomas that are very responsive to GHRH growth stimulation.
Double‐blind placebo‐controlled trial of oral dehydroepiandrosterone in patients with advanced HIV disease
Authors: Piketty C. , Jayle D. , Leplege A. , Castiel P. , Ecosse E. , Gonzalez‐Canali G. , Sabatier B. , Boulle N. , Debuire B. , Le Bouc Y. , Baulieu E.‐E. , Kazatchkine M. D.
Published: March 2003

OBJECTIVE Plasma levels of dehydroepiandrosterone sulphate (DHEA‐S) decrease with the progression of HIV disease. Here, we report on the efficacy and safety of the oral administration of DHEA as replacement therapy, in patients with advanced HIV disease, in a trial that was primarily aimed at assessing quality of life.

DESIGN The trial was randomized and double‐blind. Thirty‐two patients were allocated to either DHEA 50 mg per day for 4 months (n = 14) or a matching placebo (n = 18). Clinical data, virological and immunological surrogate markers of HIV infection, plasma levels of DHEA‐S and the Medical Outcomes Study HIV Health Survey (MOS‐HIV) quality of life scale were recorded every month.

RESULTS The mean age of the patients was 40 ± 11 years. The mean CD4 cell count at baseline was 32·5 ± 32·4 × 106/l. The mean DHEA‐S plasma level at baseline was 5·23 ± 0·76 µmol/l. No side‐effects related to DHEA occurred during the study. A statistically significant increase in the levels of DHEA‐S was observed in the treated group throughout the study (P < 0·01). A significant improvement in the Mental Health and Health Distress dimension of MOS‐HIV was observed in the DHEA treated group; P = 0·001 and 0·004, respectively. No change in CD4 cell counts was seen during follow‐up.

CONCLUSIONS The administration of DHEA in patients with advanced HIV infection results in improved mental function scores as assessed by the MOS‐HIV quality of life scale.
Relationship between the number and impact of stressful life events and the onset of Graves' disease and toxic nodular goitre★
Authors: Matos‐Santos A. , Nobre E. Lacerda , Costa J. Garcia E , Nogueira P. J. , Macedo A. , Galvão‐Teles A. , De Castro J. Jácome
Published: March 2003

BACKGROUND In the last few decades, several studies have suggested a possible association between Stressful Life Events (SLEs) and the onset of Graves' Disease (GD). However, others have criticised this association and it has not yet been possible to prove it unequivocally. At present, we are not aware of studies correlating SLE and non autoimmune thyrotoxicosis.

OBJECTIVE To assess possible associations between SLEs, the onset of GD and the onset of non autoimmune thyrotoxicosis (toxic nodular goitre, TNG).

DESIGN A case–control retrospective study.

PATIENTS This study included 93 subjects, divided into three groups of 31 each: GD, TNG and control (CG). The GD and TNG patients had thyroid disease diagnosed within the last 12 months, with clinical and biochemical confirmation. In the CG, psychopathological and endocrine disturbances had been ruled out. All three groups consisted of nine males (29%) and 22 females (71%). The mean age was 38·4 ± 10·9 years in the GD group, 48·3 ± 11·1 years in the TNG group and 41·1 ± 11·8 years in the CG group. SLEs were evaluated (number and impact) for the 12 months preceding the onset of symptoms of thyroid disease.

MEASUREMENTS SLE occurrences and their impact on each group of cases were measured. To assess SLEs, we used the Life Experiences Survey (LES). Our statistical analysis included descriptive techniques and parametric and/or nonparametric comparative tests. P < 0·01 was considered statistically significant. Odds ratios were also calculated.

RESULTS Patients with GD had a significantly greater number of SLEs compared to the TNG group and the CG (P < 0·001). The number and impact of negative SLEs were significantly higher in GD compared to TNG and CG (P < 0·001). The difference between TNG and CG was not significant (P > 0·01). GD had a higher impact of positive SLEs than TNG (P = 0·004), and no significant differences were found between the GD group and CG. Neutral SLEs were similar in the three groups.

CONCLUSIONS These results suggest that SLEs are a precipitating factor of the onset of GD. We also demonstrated that SLEs do not seem to have any conclusive relationship with the onset of TNG.
Association between lithium use and thyrotoxicosis caused by silent thyroiditis
Authors: Miller Karen K. , Daniels Gilbert H.
Published: March 2003

OBJECTIVE To determine the incidence of silent thyroiditis in lithium users and characterize lithium‐associated thyrotoxicosis.

DESIGN Retrospective record review.

PATIENTS 400 consecutive patients (300 with Graves' disease and 100 with silent thyroiditis) who underwent radioiodine scanning of the thyroid.

MEASUREMENTS Odds of lithium exposure.

RESULTS The odds of lithium exposure were increased 4·7‐fold in patients with silent thyroiditis compared with those with Graves' disease (95% CI: 1·3, 17). Lithium‐associated silent thyroiditis occurred with an incidence rate of approximately 1·3 cases per 1000 person‐years, and lithium‐associated thyrotoxicosis occurred with an incidence rate of approximately 2·7 cases per 1000 person‐years, higher than the reported incidence rates of silent thyroiditis (< 0·03–0·28 cases per 1000 person‐years) and of thyrotoxicosis (0·8–1·2 cases per 1000 person‐years) in the general population.

CONCLUSION Thyrotoxicosis caused by silent thyroiditis might be associated with lithium use.
Is pituitary gene therapy realistic?
Authors: Davis Julian R. E. , McNeilly Alan S.
Published: March 2003

Current therapies for pituitary tumours are moderately successful in many cases but still suffer from significant limitations, with relatively poor long‐term rates of endocrine cure from surgery, and long‐term hypopituitarism after radiotherapy. Even in the case of the most readily treatable tumours, prolactinomas, medical therapy with dopamine agonists is limited by lack of response or side‐effects in up to 10% of patients. This has led to increasing interest in the application of our knowledge of pituitary cell and molecular biology to evaluate the potential of gene therapy. Various vectors are available to facilitate gene delivery, and recombinant adenoviruses have been studied in detail because of their ability to transduce the postmitotic, nondividing cells of the pituitary gland. Various studies with reporter genes such as β‐galactosidase have demonstrated high efficiency and long lasting expression of adenoviral transgenes in cultured pituitary cells in vitro. The feasibility of high level transgene expression has also been shown in vivo, but so far this requires stereotaxic intrapituitary injection to achieve adequate transduction. Ablation of pituitary cells has been demonstrated in cultured cell lines and in subcutaneous tumours in nude mice, though alternative animal models will be required to evaluate efficacy in more slowly proliferating tumours as found in man. Inflammatory responses have been documented in the pituitary gland as in other tissues, and this will require the evaluation of modified vectors to avoid significant adverse effects before human applications can be considered. In summary, gene therapy for pituitary disease is likely to be feasible in the future, but will require careful and extensive evaluation of efficacy and safety, using a variety of possible methods of gene delivery.
Normal VLDL metabolism despite altered lipoprotein composition in type 1 diabetes mellitus
Authors: Christ E. R. , Carroll P. V. , Albany E. , Umpleby A. M. , Lumb P. J. , Wierzbicki A. S. , Simpson H. L. , Sönksen P. H. , Russell‐Jones D. L.
Published: March 2003

OBJECTIVES Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.

PATIENTS This study examined overnight VLDL apoB metabolism and VLDL composition in six lean patients with type 1 diabetes during euglycaemia (controlled by a varying insulin infusion) and in six age‐, sex‐ and BMI‐matched control subjects.

METHODS VLDL apoB kinetics were determined using a primed constant 1–13C leucine infusion, and VLDL apoB enrichment was measured by gas‐chromatography mass‐spectrometry. Fasting lipid profile, IGF‐I, IGFBP‐3, overnight GH profiles and free insulin concentrations were also assessed.

RESULTS Fasting concentrations of triglycerides (TG), total cholesterol (TC), HDL‐cholesterol (HDL‐C) and LDL‐cholesterol (LDL‐C) were similar in both groups. The VLDL apoB secretion and metabolic clearance rates were not significantly different between the two groups, but the VLDL‐TG/VLDL apoB and the VLDL‐C/VLDL apoB ratios were significantly increased in those with diabetes (P < 0·02 and P < 0·03, respectively). Total IGF‐I concentrations were similar between the two groups; however, the GH area under the curve and free insulin concentrations were increased in patients with type 1 diabetes (GH: diabetes: 94·8 ± 15·1 vs. controls: 45·6 ± 10·6, mU/L/h, P < 0·04; free insulin: diabetes: 78·4 ± 5·0 vs. controls: 28·3 ± 3·26, pmol/l, P < 0·001). IGFBP‐3 concentrations were lower in diabetic patients (diabetes: 2454·2 ± 68·7 vs. controls: 3219·4 ± 76·4, ng/ml, P < 0·001). In the control group overnight GH secretion correlated negatively with fasting TC (P < 0·01) and LDL‐C (P < 0·03) concentrations, whereas free insulin concentrations correlated positively with fasting TG concentrations (P < 0·009). No significant correlations were found in the patients with diabetes.

CONCLUSION This study suggests that in euglycaemic conditions patients with type 1 diabetes mellitus have normal VLDL apoB kinetics but altered VLDL composition. The altered VLDL composition may be associated with accelerated atherogenesis. We speculate that the disrupted hormonal balance and, in particular, the increased GH secretion might be responsible for the compositional changes of VLDL particles in type 1 diabetes mellitus.