bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitrodendritic cell-induced T cell responses to B cell chronic lymphocytic leukaemia enhanced by IL-15 and dendritic cell–B-CLL electrofusion hybrids
Authors: GODDARD R V , PRENTICE A G , COPPLESTONE J A , KAMINSKI E R
Published: March 2003

HLA class II-restricted proliferative and cytotoxic T cell (CTL) responses to B cell chronic lymphocytic leukaemia (B-CLL) can be generated using autologous dendritic cells (DCs) pulsed with tumour cell lysate. In this study a number of different approaches were used to optimize further the in vitro system. First, the effects of a variety of maturation agents were studied. The addition of TNF-α, polyriboinosinic polyribocytidylic acid (Poly(I:C)) and LPS to autologous DCs resulted in the emergence of only a small percentage of CD83+ DCs, IFN-α having no demonstrable effect. Only the addition of Poly(I:C) to DCs resulted in modestly increased specific cytotoxicity to B-CLL targets, IFN-α and LPS having no effect. Secondly, T cells were pretreated with IL-15, prior to culturing with lysate-pulsed autologous DCs. A significant increase in T cell activation (P = 0·038), IFN-γ secretion (P = 0·030) and specific cytotoxicity to B-CLL targets (P = 0·006) was demonstrated compared to untreated T cells. Thirdly, monocyte derived DCs electrofused with B-CLL B cells were compared with lysate-pulsed DCs. T cells stimulated by fused DCs generated higher levels of specific cytotoxicity to autologous B-CLL B cell targets than those stimulated by lysate pulsed DCs (P = 0·013). Blocking studies demonstrated inhibition of this cytotoxicity by both anti-CD4 (P = 0·062) and anti-CD8 monoclonal antibodies (P = 0·018), suggesting the generation of both HLA class I- and HLA class II-restricted CTL responses. In summary, in vitro B-CLL-specific T cell responses can be enhanced further by preincubating T cells with IL-15 and using autologous fused DC–B-CLL hybrids instead of autologous lysate-pulsed DCs. These preliminary data require confirmation with larger numbers of patients. Such an approach, however, may eventually provide effective immunotherapy for treatment of B-CLL.
Respiratory syncytial virus infection suppresses IFN-γproduction ofγδT cells
Authors: AOYAGI M , SHIMOJO N , SEKINE K , NISHIMUTA T , KOHNO Y
Published: March 2003

The immunological mechanisms by which respiratory syncytial virus (RSV) contributes to the development of asthma are poorly understood. γδ T cells are important in mucosal defence, and may contribute to the establishment of primary immune responses by producing cytokines early during respiratory infections. Thus, we used flow cytometry and intracellular cytokine staining to investigate the expression of interferon (IFN)-γ and interleukin (IL)-4 by mitogen-stimulated γδ T cells from the peripheral blood of 15 hospitalized infants with RSV bronchiolitis, seven rotavirus-infected infants and eight normal controls. γδ T cells from RSV-infected infants had a lower proportion of IFN-γ-producing cells (median, 4.00%; range, 0.58–6.60%) and a slightly but significantly higher proportion of IL-4-producing cells (median, 0.40%; range, 0.13–2.76%) than rotavirus-infected infants (median, 32.10%; range, 14.43–61.21%; P < 0·01, median, 0.00%; range, 0.00–0.00%; P < 0·05) in the acute phase. By contrast, differences in cytokine production by total CD3+ T cells did not differ significantly between patient groups. Thus, reduced IFN-γ-production by γδ T cells in the peripheral blood of RSV-infected infants is accompanied by increased Th2 cytokine production during the acute phase of disease. At follow-up, eight children had recurrent episodes of wheezing. The frequencies of IFN-γ-producing γδ T cells were significantly lower in patients who developed recurrent wheezing (median, 0.65%; range, 0.02–1.75%) than in patients without recurrent wheezing (median, 6.90%; range, 5.25–10.98%; P < 0·005). Cytokine production by γδ T cells may therefore be important in the pathogenesis of acute RSV disease, and play a part in the development of recurrent childhood wheezing after bronchilolitis.
Selective up-regulation of functional CXCR4 expression in erythroid cells by HIV-1 Tat protein
Authors: GIBELLINI D , RE M C , VITONE F , RIZZO N , MALDINI C , LA PLACA M , ZAULI G
Published: March 2003

CXCR4 is the high affinity receptor for the SDF-1α chemokine and represents the main coreceptor for HIV-1 T-tropic strains. The surface expression of CXCR4 was analysed in CD34+ haematopoietic progenitors, induced to differentiate along the erythroid or granulocytic lineages, in liquid cultures supplemented or not with HIV-1 Tat protein. At concentrations as low as 1–10 ng/ml, synthetic Tat protein significantly increased the surface expression of CXCR4 in erythroid but not in granulocytic cells. The Tat-mediated up-regulation of surface CXCR4 was accompanied by a concomitant increase of CXCR4 mRNA and total CXCR4 protein content in cells developing along the erythroid lineage after 6–10 days of culture. Moreover, addition of SDF-1α (200 ng/ml) induced a significant higher rate of apoptosis in Tat-treated erythroid cells in comparison with control cells. These results demonstrated for the first time a direct positive role in haematopoietic gene regulation of Tat protein, and suggest the possible involvement of Tat in HIV-1-induced anaemia.
The octreotide suppression test and [111In‐DTPA‐D‐Phe1]‐octreotide scintigraphy in neuroendocrine tumours correlate with responsiveness to somatostatin analogue treatment
Authors: Shi  , Buchanan  , Johnston  , Larkin  , Ong  , Ferguson  , Laird
Published: March 2003

OBJECTIVE

The somatostatin analogue octreotide (Sandostatin, Novartis, Basle) significantly improves the syndromes suffered by most patients with neuroendocrine tumours (NETs). The use of [111In‐DTPA‐D‐Phe1]‐octreotide scintigraphy ([111In]‐pentetreotide) to predict the response to octreotide treatment has been described. Short‐term hormone inhibition by a single injection of octreotide has also been reported. This study aimed to compare the effects of the suppression test with the response to long‐term somatostatin analogue treatment, and to seek a correlation between the short‐term suppression test, [11In]‐pentetreotide observations and long‐term somatostatin analogue treatment.

DESIGN AND MEASUREMENTS

Short octreotide suppression test and octreotide scintigraphy. Blood samples were collected before (0900, 0930 h), at (1000 h), and after (1030, 1100, 1200, 1300 h) the injection of 50 μg octreotide subcutaneously. Plasma hormones relevant to the syndrome were analysed by radioimmunoassay. The short suppression effects, the [111In]‐pentetreotide observations and the response to long‐term treatment with somatostatin analogue were evaluated and compared.

PATIENTS

Twenty‐six patients with metastatic NETs were evaluated, including 14 carcinoid tumours, 10 pancreatic endocrine tumours and 2 medullary carcinomas of thyroid (MCTs). Twelve patients had received octreotide treatment before the study, another 4 patients were treated subsequently with somatostatin analogue.

RESULTS

During the short suppression test, hormones relevant to the syndromes were suppressed in 24 patients (those with carcinoids and pancreatic endocrine tumours). There was no suppression in the 2 patients with MCT. [111In]‐pentetreotide observations closely correlated with the short suppression response to octreotide. Fourteen patients were treated with somatostatin analogue, and responded clinically; they had a positive short inhibition test and positive tumour uptake. Two patients with MCT did not respond to the treatment and had a negative suppression test and a negative [111In]‐pentetreotide.

CONCLUSION

Our results suggest that a consistent relationship exists between the short suppression test and the response to somatostatin analogue treatment in the majority of the patients with neuroendocrine tumours. The octreotide suppression test and octreotide scintigraphy together will be helpful in selecting appropriate patients for clinical treatment with somatostatin analogues.
Plasma sex hormones are significantly associated with plasma leptin concentration in healthy subjects
Authors: Paolisso Giuseppe , Rizzo Maria Rosaria , Mone Concetta Maria , Tagliamonte Maria Rosaria , Gambardella Antonio , Riondino Mariangela , Carella Carlo , Varricchio Michele , D'Onofrio Felice
Published: March 2003

OBJECTIVE

In humans a sexual dimorphism of plasma leptin concentration has been demonstrated but its significance remains to be established. Sex hormones may have a role.

PATIENTS

Eighty healthy, non‐obese subjects (41M/39F) were studied.

MEASUREMENTS

In the whole group of subjects plasma sex hormones, leptin and insulin concentrations were determined, body fat content assessed by bioimpedance analysis, body fat distribution evaluated and insulin‐mediated glucose uptake measured by euglycemic hyperinsulinemic glucose.

RESULTS

After adjustment for age, gender, amount of body fat, waist/hip ratio (WHR) and fasting plasma insulin concentration, fasting plasma leptin was still significantly correlated with plasma DHEAS (r =−0.30, P < 0.006), oestradiol (r = 0.53, P < 0.001) and testosterone (r = −0.43, P < 0.001) in all subjects (n = 80). Independently of age, amount of body fat and WHR, fasting plasma leptin concentration correlated with plasma oestradiol (r = 0.38, P < 0.01) and total testosterone (r = −0.58, P < 0.001) in males (n = 41) and with fasting plasma oestradiol (r = 0.48, P < 0.002) in females (n = 39). To investigate the independent contribution of anthropometric and hormonal variables to fasting plasma leptin concentration, a multivariate stepwise regression analysis with fasting plasma leptin concentration as dependent variable was made. In the entire group (n = 80), the whole model explained 43% of fasting plasma leptin concentration with fasting plasma insulin, total testosterone and oestradiol concentrations significantly and independently associated with plasma leptin concentration. In this model, fasting plasma DHEAS, testosterone and oestradiol explained 25% of the variability in plasma leptin concentration.

CONCLUSION

Our study demonstrates that plasma sex hormone concentrations are associated with plasma leptin concentration.
Positive association between circulating free thyroxine and insulin‐like growth factor I concentrations in euthyroid elderly individuals
Authors: Seck Thomas , Scheidt‐Nave Christa , Ziegler Reinhard , Pfeilschifter Johannes
Published: March 2003

OBJECTIVE

Previous studies have shown marked changes in circulating insulin‐like growth factor‐I (IGF‐I) levels in hypo‐ and hyperthyroid patients. In this study we examined whether the circulating concentration of IGF‐I may also be affected by normal thyroid hormone levels.

DESIGN

A cross‐sectional study of thyroid hormones and plasma IGF components in a population‐based sample.

PATIENTS

50–80 year‐old men (n = 262) and women (n = 218) with normal concentrations of serum free thyroxine (f T4), free triiodothyronine (f T3) and thyrotrophin (TSH).

MEASUREMENTS

Plasma concentrations of IGF‐I, IGF‐II and IGFBP‐3, and serum concentrations of TSH, f T3 and f T4.

RESULTS

Serum f T4 values were weakly positively correlated and serum TSH levels were inversely correlated with circulating IGF‐I concentrations. The associations persisted after adjustment for age and ideal body weight.

CONCLUSIONS

Our data demonstrate that thyroid hormones are positively correlated to IGF‐I plasma levels even under physiological conditions. However, thyroid hormones explain only 1–2% of the normal variability of circulating IGF‐I.
TSH receptor antibody‐associated thyroid dysfunction following subacute thyroiditis
Authors: Iitaka Makoto , Momotani Naoko , Hisaoka Toshihiko , Noh Jaeduk Yoshimura , Ishikawa Naofumi , Ishii Jun , Katayama Shigehiro , Ito Kunihiko
Published: March 2003

OBJECTIVE

Autoimmunity plays an important role in the development of thyrotrophin (TSH) receptor antibodies and the pathogenesis of Graves' disease and Hashimoto's thyroiditis. On the other hand, subacute thyroiditis is a self‐limited inflammatory disease of presumed viral aetiology. The aim of this study was to examine whether subacute thyroiditis triggers TSH receptor antibody‐associated thyroid disorders.

PATIENTS

We reviewed 1,697 patients with subacute thyroiditis seen between 1985 and 1995.

DESIGN AND MEASUREMENTS

We measured antibodies which inhibit the TSH binding to the TSH receptor (TBIAb), thyroid stimulating antibodies (TSAb) and antibodies that block TSH action (TBAb). Other thyroid autoantibodies were also determined.

RESULTS

TBIAb became positive in 38 patients following subacute thyroiditis. Thyroid function after the development of TBIAb appeared to be influenced by the bioactivity of the antibody. Hyperthyroidism developed in the presence of TSAb, and so did hypothyroidism in the presence of TBAb, although 21 patients did not have thyroid dysfunction despite high titres of TBIAb. Fifteen out of 17 patients recovered from hyperthyroidism or hypothyroidism after the disappearance of TBIAb sometimes even without medication. TBIAb‐positive patients had a high incidence of a family history of thyroid disease and positive anti‐thyroid microsomal antibodies. An ophthalmopathy similar to Graves' disease was also observed in 3 patients.

CONCLUSIONS

Subacute thyroiditis may trigger autoreactive B cells to produce TSH receptor antibodies, resulting in TSH receptor antibody‐associated thyroid dysfunction in some patients.
Carcinoid tumours presenting as breast cancer: the utility of radionuclide imaging with 123I‐MIBG and 111In‐DTPA pentetreotide
Authors: Kaltsas G. A. , Putignano  , Mukherjee J. J. , Satta M. A. , Lowe D. G. , Britton K. E. , Monson J. P. , Grossman A. B. , Besser G. M.
Published: March 2003

Secondary tumours of any type in the breast are rare. A review of the literature demonstrated only 23 cases of carcinoid tumours with associated breast metastasis, as distinct from primary carcinoid tumours of the breast. Distant metastases from carcinoid tumours are correlated with poor prognosis and survival. Although both primary and metastatic mammary carcinoid tumours are uncommon, the recognition of the true origin of the tumours may be of importance owing to the different clinical management and prognosis of the two conditions. Recently, radionuclide‐labelled imaging techniques have been applied to the localization of such lesions, based on isotope uptake by receptors present in these neuroendocrine tumours. We report two new cases of carcinoid tumours with breast metastases, the primaries being in the ileocaecal valve and the bronchus, respectively. The diagnosis of a carcinoid tumour was based on the clinical, biochemical, histopathological and immunostaining features. Furthermore, these patients had both 123I‐MIBG and 111In pentetreotide scintigraphy performed. These radionuclides play a useful role in the localization and potentially in the management of carcinoid tumours and their distant metastases.
Dose response with fluticasone propionate on adrenocortical activity and recovery of basal and stimulated responses after stopping treatment
Authors: Wilson Andrew M. , Sims Erika J. , Lipworth Brian J.
Published: March 2003

OBJECTIVE

To evaluate the dose–response relationship for adrenocortical activity with fluticasone propionate (FP) and to assess basal and dynamic markers after stopping treatment for 3 days.

PATIENTS AND DESIGN

Fourteen asthmatic patients were recruited: mean age 33.3 years, forced expiratory volume in 1 s (FEV1): 91.3% predicted, forced mid expiratory flow rate (FEF25–75): 58.1% predicted. A single blind study design was used comparing a placebo run‐in with sequentially low, medium and high doses of FP and a placebo washout. All active treatments, placebo and washout were each for 3 days. FP was given at steady‐state with twice daily divided dosing at 0800 h and 2200 h at doses of 375 μg, 875 μg, and 1750 μg per day.

MEASUREMENTS

A 100 μg iv bolus hCRF test was performed at 0800h after the run‐in and washout periods. Blood samples were taken for 0800h serum cortisol and osteocalcin as well as an overnight 10 h urine collection for cortisol/creatinine excretion after the run‐in period, each dose of active treatment and washout.

RESULTS

For serum cortisol (pre and post hCRF stimulation) there was no significant difference between placebo and washout values. Mean (SE) cortisol (nmol/1) values pre hCRF were run‐in: 644.5 (59.7), washout: 550.3 (42.8) and post hCRF were run‐in: 690.9 (42.9), washout: 719.1 (43.8). There was a significant (P < 0.05) difference between run‐in vs medium and high doses for 0800 h serum cortisol, overnight urinary cortisol and overnight urinary cortisol/creatinine excretion; and vs high dose for serum osteocalcin. The fold difference (95% CI for difference) between run‐in and high dose was: 2.2 (1.5–3.2) for overnight urinary cortisol, 2.5 (1.5–4.1) for overnight urinary cortisol/creatinine, 2.0 (1.1–3.6) for serum cortisol, and 1.2 (1.1–1.3) for serum osteocalcin.

CONCLUSION

Fluticasone propionate exhibited dose related adrenal suppression with treatment. The suppressive effects of fluticasone propionate on adrenocortical activity were greater than those observed on osteocalcin.
Cardiac function at rest in hypothyroidism evaluated by equilibrium radionuclide angiography
Authors: Tielens Emile T. , Pillay Marrmuthoo , Storm Corstiaan , Berghout Arie
Published: March 2003

OBJECTIVE

Previous studies have suggested that hypothyroidism affects both systolic and diastolic cardiac function. We have applied equilibrium radionuclide angiography to the study of heart function at rest in hypothyroidism.

DESIGN

A prospective study, evaluating cardiac function at rest in primary hypothyroidism.

METHODS

Cardiac function was studied by means of equilibrium radionuclide angiography. Screening echo‐Doppler examinations were performed on each patient.

PATIENTS

Twenty‐six consecutive untreated hypothyroid patients without clinical or echocardiographic cardiac disease and 20 healthy matched controls.

RESULTS

Between patients and controls, the time to peak emptying rate (161 ± 6 msec vs. 144 ± 6 msec, P < 0.05) and the time to peak filling rate (188 ± 6 msec vs. 170 ± 5 msec, P < 0.05), were the only discriminatory parameters. In hypothyroid patients, a trend towards a decrease in diastolic cardiac function, expressed as peak filling rate, was observed: 2.6 ± 0.1 End Diastolic Volume (EDV)/s vs. 3.0 ± 0.1 EDV/s, P = 0.06. Within the hypothyroid patient group, the time to peak emptying rate was more prolonged in patients with lower free thyroxine levels (R = − 0.60, F = 13.5, P < 0.001). Peak filling rate was decreased in patients with lower free thyroxine levels (R = 0.51, F = 8.4, P < 0.01) whereas the time to peak filling rate was more prolonged (R = − 0.62, F = 15, P < 0.001).

CONCLUSION

In a large group of consecutive patients presenting with primary hypothyroidism, even in the absence of clinical cardiac disease and echocardiographic abnormalities, clear changes in myocardial performance at rest were observed. The most obvious effect of thyroid hormone deficiency on the heart was a lengthening of both systolic and early diastolic time characteristics. Diastolic rather than systolic cardiac function was influenced by hypothyroidism.
Parathyroid hormone gene polymorphisms in primary hyperparathyroidism
Authors: Kanzawa Michiko , Sugimoto Toshitsugu , Kobayashi Tatsuya , Kobayashi Akira , Chihara Kazuo
Published: March 2003

OBJECTIVE

Genetic contributions to bone mineral density (BMD) and bone turnover are well known. In the present study, we analysed the relationship between restriction fragment length polymorphisms of the PTH gene and the development of primary hyperparathyroidism (pHPT) as well as its severity.

PATIENTS

Seventy‐nine pHPT patients and 104 age‐matched healthy controls were analysed.

DESIGN AND MEASUREMENTS

PTH genotypes were determined by polymerase chain reaction and BstB I or Dra II restriction fragment length polymorphisms. The presence and absence of BstB I or Dra II restriction sites of the PTH gene were indicated by B and b or D and d, respectively. BMD levels at the lumbar spine and at the radius were measured in all subjects. Serum levels of calcium, phosphorus, alkaline phosphatase and intact PTH were measured in pHPT patients.

RESULTS

There were no differences in the frequencies of these PTH genotypes between pHPT patients and controls. In control subjects, lumbar BMD was significantly higher in BB genotype than in Bb/bb genotypes. In pHPT patients, there was no difference of BMD between BB and Bb/bb genotypes. In pHPT patients, serum calcium level was significantly higher in those with the BB genotype than Bb/bb genotypes. On the other hand, there was no association between DraII polymorphism and BMD in both controls and pHPT patients, but serum intact PTH level was significantly higher in DD genotype than Dd/dd genotype in pHPT patients. Moreover, serum levels of ALP and intact PTH were significantly higher in the PTH BBDD haplotype, compared to those in haplotypes other than BBDD.

CONCLUSIONS

The present study suggests that the BstB I polymorphism of PTH gene is closely related to bone mineral density and that PTH gene polymorphisms do not seem to affect the development of primary hyperparathyroidism but may relate to the severity of primary hyperparathyroidism.
GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety
Authors: Abs Roger , Bengtsson Bengt‐Åke , Hernberg‐Ståhl Elizabeth , Monson John P. , Tauber Jean‐Pierre , Wilton Patrick , Wüster Christian
Published: March 2003

OBJECTIVE

Long‐term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long‐term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting.

PATIENTS

The present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years.

RESULTS

Prior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease‐specific questionnaire (QoL‐AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non‐naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF‐I indicated that overtreatment with GH was markedly more common in non‐naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment.

CONCLUSIONS

Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well‐tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.
Acidic isoforms of chorionic gonadotrophin in European and Samoan women are associated with hyperemesis gravidarum and may be thyrotrophic
Authors: Jordan Vanessa , Grebe Stefan K. G. , Cooke Russell R. , Ford Henry C. , Larsen Peter D. , Stone Peter R. , Salmond Clare E.
Published: March 2003

OBJECTIVE

There is conflicting evidence concerning the role of human chorionic gonadotrophin (hCG) in the aetiology of hyperemesis gravidarum (HG); particular isoforms of hCG may be the critical factor. Ethnic differences in HG prevalence and putative thyrotrophic effects of hCG may also relate to differences in hCG isoform profiles. To address these issues we examined the relationship of hCG isoforms to HG and thyroid function tests in two groups of women from ethnic backgrounds with significantly different HG prevalence rates.

PATIENTS AND DESIGN

We enrolled 10 European and 10 Samoan women with HG and an equally sized non‐hyperemetic, gestational stage matched control group.

MEASUREMENTS

We administered a questionnaire, generated serum hCG charge‐isoform profiles by chromatofocusing and measured the serum concentrations of total hCG, oestradiol (E2), thyrotrophin (TSH) and free thyroxine (FT4).

RESULTS

The mean serum total hCG levels were highest in the Samoan hyperemetics (176 268 IU/l), and overall higher in hyperemetics compared with controls (159 770 IU/l vs. 86 420 IU/l, P < 0.001). When compared with controls, hyperemetics displayed increased hCG concentrations in the more acidic half (pH < 4) of the chromatofocusing pH range (89 843 IU/l vs. 41 146 IU/l, P < 0.003). Serum E2 levels did not differ between the four groups, but correlated with the hCG concentration between pH 5.2 and 4.01. Mean serum TSH levels were significantly lower in hyperemetics than in controls (0.33 mIU/l vs. 1.19 mIU/l, P < 0.001) and correlated with the hCG concentration between pH 4.6 and 2.8, while serum FT4 correlated with the hCG concentration below pH 4.0.

CONCLUSIONS

Acidic isoforms of hCG may play a role in the aetiology of HG and gestational thyrotoxicosis. Minor ethnic differences in hCG isoform profiles were observed, but the relationship of acidic hCG isoforms to HG and serum thyroid hormone levels was largely independent of the patients' ethnicity. The mechanisms by which acidic isoforms might provoke nausea remain uncertain, but do not seem to involve E2, while the longer half‐life of acidic hCG isoforms may result in increased in vivo TSH receptor cross‐talk with resultant thyrotrophic effects.
Reduced foetal growth and growth hormone secretion in adult life
Authors: Flanagan Daniel E , Moore Vivienne M , Godsland Ian F , Cockington Richard A , Robinson Jeffrey S , Phillips David I W
Published: March 2003

OBJECTIVES

Recent studies suggest that growth restriction or other adverse influences acting in utero or during early infancy lead to permanent alterations in growth hormone (GH) secretion. As GH secretion is known to predict cardiovascular risk, alterations in GH may contribute to the association between reduced foetal growth and cardiovascular disease. We have therefore assessed the relationship between birth size and GH secretion in a prospective study of young adults whose birth size was recorded and who have had their current blood pressure and glucose tolerance measured.

DESIGN

Prospective cohort study

PATIENTS

153 healthy men and women, aged 20–21 years.

MEASUREMENTS

Subjects carried out a timed overnight urinary collection for analysis of GH excretion. Insulin sensitivity and insulin secretion were measured using the intravenous glucose tolerance test with minimal model analysis. Blood pressure, height, weight, usual level of exercise, smoking habits, alcohol consumption, and socio‐economic status were also recorded.

RESULTS

GH excretion ranged from 0.01 to 41.8 μU per subject. It did not differ according to gender but was markedly reduced in obese subjects (P < 0.0001) Low birthweight was strongly associated with low GH excretion at age 20 years (P = 0.002). Low placental weight and short body length also predicted low GH (P = 0.02 and P = 0.04, respectively). These relationships were independent of other confounding factors including obesity. GH excretion was not independently related to current levels of blood pressure, insulin sensitivity or insulin secretion.

CONCLUSIONS

Body size at birth predicts GH excretion in adult life. Low GH excretion in people who were small at birth may be one mechanism explaining their increased risk of cardiovascular disease.
Type 1 multiple endocrine neoplasia (MEN1): contribution of genetic analysis to the screening and follow‐up of a large French kindred
Authors: Waterlot  , Porchet  , Bauters  , Decoulx  , Wémeau  , Proye  , Degand  , Aubert  , Cortet  , Dewailly
Published: March 2003

OBJECTIVE

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal genetic disorder, the clinical phenotype of which includes tumours of the parathyroids and/or anterior pituitary and/or endocrine pancreas. The genetic defect has been mapped to the chromosome 11q13 and the MEN1 gene has been recently identified, thus allowing genetic screening in affected kindreds. The aim of this study was to establish the usefulness of genetic screening in the follow‐up of a large MEN1 kindred.

PATIENTS

We describe a large kindred of 91 members, of whom 56 had clinical, biochemical and genetic screening. Twenty eight of them have been tested annually for the last 5 years.

RESULTS

Although the precise mutation is still undetermined in this kindred, genotypic determination confirmed linkage with the MEN1 gene in affected members and excluded 28 members from annual testing. By drawing our attention to susceptible subjects, genetic screening improved the evaluation of age‐related penetrance of the disease in the 3 generations from this kindred. For instance, annual screening showed conversion from unaffected to affected phenotype in 4 subjects aged 14, 14, 15, and 17 years. Moreover, genetics helped us to evaluate the specificity of clinical or biochemical markers, and thus to discard useless investigations. So far however, the genetics have not helped to explain the phenotypic heterogeneity and particularly low incidence of pancreatic tumours in this kindred.

CONCLUSION

Genetic screening is very useful in detecting high risk individuals for MEN 1, since it avoids time‐consuming and expensive investigations in non‐affected subjects. By providing better understanding of the age‐related penetrance of this syndrome, it improves the efficiency of screening. Genetic studies allow differentiation between clinical and biochemical features that are useful in follow‐up and other confusing or unhelpful parameters.
Extrusion of testosterone pellets: a randomized controlled clinical study
Authors: Kelleher  , Turner  , Howe  , Conway  , Handelsman
Published: March 2003

BACKGROUND

It has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side‐effect. The present study aimed to reduce the extrusion rate.

OBJECTIVE

To determine whether the washing of testosterone pellets to remove potentially surface‐adherent particles decreased the rate of extrusion of pellet implants.

DESIGN

Prospective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group.

PATIENTS

The study included 251 testosterone implantation procedures in men with known androgen deficiency.

MEASUREMENTS

The primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end‐points included peri‐procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow‐up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors.

RESULTS

In the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1.09 [95% CI 0.47–2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44–3.9], bleeding/bruising (8.8%, 1.23 [0.47–3.3]) and infection (4.0%, 1.54 [0.35–7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77).

CONCLUSIONS

The pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow‐up or a secular trend.
Thyroid suppression test with L‐thyroxine and [99mTc] pertechnetate
Authors: Ratnos Celso D. , Zantut‐Wittmann Denise E. , Tambascia Marcos A. , Assumpção Lígia , Etchebehere Elba C. S. C. , Camargo Edwaldo E.
Published: March 2003

OBJECTIVE The thyroid suppression test is still used in some centres as an adjunt in the diagnosls of autonomous functioning thyroid nodules. With the purpose of minimizing the disadvantages of the original T3 suppression test, we have evaluated the efficacy of a method using L‐thyroxine as TSH suppression agent and [99mTc] pertechnetate as radio‐pharmaceutical.

DESIGN Open nonrandomized prospective study MATERIALS AND METHODS A control group of 15 normal volunteers (11 males, 4 females; 21–35 years, mean 26–4 years) and a patient group of 20 patients (18 females, 2 males: 27–83 years, mean 53.6 years) divided into 4 subgroups, were studied: 7 patients with autonomous functioning nontoxic nodules, 3 with autonomous functioning toxic nodules, 7 with Graves disease and 3 with nonautoimmune diffuse toxic goitre. Baseline thyroid uptake and imaging were begun 20 minutes after an intravenous injection of 370 MBq (10mCi) of [99mTc] pertechnetate. This was followed by a single daily intake of 2μg/kg of L‐thyroxine, for 10 days. Thyroid imaging and uptake were then repeated.

RESULTS In the control group [99mTc] pertechnetate uptake after L‐thyroxine suppression had a mean reduction of 75.8 ± 7.69% (58–47%) in comparison to the baseline level. All subjects were euthyroid by clinical and laboratory criteria and none complained of side‐effects, despite significant suppression of TSH levels. In the patient group, thyroid uptake after suppression decreased in 10 patients (maximum reduction 39%), was unchanged In 2 patients and increased in the remaining 8 patients. CONCLUSION The method described was efficient for demonstration of autonomous thyroid tissue, since none of the patients showed significant reduction of thyroid uptake after L‐thyroxine suppression compared with the control group. This test was as effective as the original T3 suppression test, but more convenient to the patient: no side‐effects, ease of hormonal intake, low dosimetry and short stay in the nuclear medicine laboratory.
Analysis of the peroxisome proliferator activated receptor γ (PPARγ) gene in HAIRAN syndrome with obesity
Authors: Globerman H. , Zauberman Y. , Makarov T. , Beamer B. A. , Yen C‐J. , Shuldiner A. R. , Harel C. , Karnieli E.
Published: March 2003

OBJECTIVES To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor γ (PPARγ), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARγ and the degree of insulin resistance.

DESIGN A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype. PATIENTS Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non‐diabetic non‐obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non‐diabetic non‐obese individuals. MEASUREMENTS Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARγ isoforms (PPARγ1 and PPARγ2) for single‐stranded conforma‐tional polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique. RESULTS A synonymous substitution in codon 477 (CACHis← CAFHis) was found in one patient. A missense mutation in codon 12 of PPARγ2 (CCApro← GCAAla) was found in another patient, but not in any of 25 non‐diabetic, non‐obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied. CONCLUSIONS Mutations in the PPARγ gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.
New breakpoints in both the H4 and RET genes create a variant of PTC‐1 in a post‐Chernobyl papillary thyroid carcinoma
Authors: Elisei Rossella , Romei Cristina , Soldatenko Pavel P. , Cosci Barbara , Vorontsova Tatiana , Vivaldi Agnese , Basolo Fulvio , Cherstvoy Evgeny D. , Pinchera Aldo , Pacini Furio
Published: March 2003

Two main types of RET/PTC oncogene, named RET/PTC‐1 and 3, occur in papillary thyroid carcinomas especially in those from Belarus children after the Chernobyl nuclear accident. Several variants of RET/PTC‐3 have also been found, having different break points with respect to the classical RET/PTC‐3. To our knowledge, no variant of RET/PTC‐1 has been described up to now. We found a post‐Chernobyl papillary thyroid carcinoma with an RET/PTC‐1 rearrangement characterized by a transcript longer than expected. Sequence analysis of the PCR product obtained after RT‐PCR revealed new fusion points between H4 and RET genes. The genomic sequence showed new breakpoints in both H4 intronic and in RET exonic regions. The RET gene breakpoint occurred within exon 11, at variance with the classical form of RET/PTC‐1, in which it is in intron 11. As a consequence of this new fusion point, the transcript included 132 nucleotides of exon 11, coding for 44 amino acids of RET protein. Regarding the H4 gene, the classical breakpoint is in the first intron and the cDNA contains a fragment of 339 nucleotides. In our case the cDNA had a longer fragment of H4 involving a total of 1266 nucleotides. Sequencing of genomic DNA revealed a rearrangement breakpoint at position 886 of a new H4 intron located downstream of the 1266 coding region. Furthermore, as a consequence of the activation of a cryptic splicing site, 132 nucleotides of this intron were spliced between the H4 and RET genes. Sequence analysis of the new chimera showed that the original frames of H4 and RET were joint with the intronic sequence without disruption of the open reading frame (ORF). Moreover, the genomic DNA of this case showed transforming activity in the DNA‐mediated transfection assay using NIH‐3T3 cells. In conclusion, we describe here the first variant of RET/PTC‐1 oncogene, which we have termed ‘long’‐PTC‐1, characterized by new breakpoints of both genes involved in the rearrangement and having transforming activity. Similar to previously reported PTC‐3 variants, long‐PTC‐1 has been found in a post‐Chernobyl papillary thyroid carcinoma confirming that RET/PTC rearrangements other than the classical forms (RET/PTC‐1 and ‐3) are specifically associated with radiation‐induced papillary thyroid cancer.
Vitamin D receptor gene start codon polymorphism (FokI) and bone mineral density in healthy male subjects
Authors: Kanan R. M. , Varanasi S. S. , Francis R. M. , Parker L. , Datta H. K.
Published: March 2003

OBJECTIVE

The genetic factors determining peak bone mineral density (BMD) in men are not well characterized. Recent studies have investigated the relationship between the start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene and BMD in different populations. We have now examined the relationship between SCP of the VDR gene and BMD in a group of healthy Caucasian men from the north‐east of England.

SUBJECTS

Ninety‐six healthy men (median age 50, range 40.0–77.0 years).

MEASUREMENTS

Analysis of the FokI genotypes of SCP of the VDR and measurements of BMD at the femoral neck and lumbar spine were performed.

RESULTS

FF, Ff and ff VDR FokI genotypes were found to have the highest, intermediate and the lowest lumbar spine BMD, respectively (Mean ± SD, for FF 1.07 ± 0.14, Ff 1.05 ± 0.16 and ff 0.95 ± 0.10 g/cm2). There was a significant difference in spine BMD between FF and ff genotypes (P < 0.05, analysis of variance [anova]), but no such difference was apparent between Ff and ff (P > 0.05, anova). Interestingly, there was no association between FokI polymorphism and femoral neck BMD (Mean ± SD, for FF 0.85 ± 0.12, Ff 0.87 ± 0.15 and ff 0.83 ± 0.15 g/cm2). The distribution of FokI VDR genotypes approached Hardy–Weinberg equilibrium and was similar to that reported for women from different ethnic groups, as the prevalence of FF and ff genotypes was 44% and 16%, respectively.

CONCLUSION

The study shows that in this population of healthy men there is a weak association between lumbar spine bone mineral density and FokI restriction fragment length polymorphism at the translation initiation site of the vitamin D receptor gene.
Reduced vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis
Authors: Sudhaker Rao  , Han  , Phillips Evelyn R. , Palnitkar Saroj , Parfitt
Published: March 2003

BACKGROUND AND OBJECTIVES

Parathyroid adenomas discovered fortuitously grow very slowly and their cell birth rate greatly declines, features explicable by an initial increase in secretory set‐point. In the nodules of severe uraemic parathyroid hyperplasia, there is an increased set‐point and decreased expression of both the calcium sensing receptor (CaSR) and the vitamin D receptor (VDR). Accordingly, we examined VDR and CaSR expression in parathyroid adenomas.

PATIENTS AND DESIGN

We studied 24 patients with primary hyperparathyroidism with a wide range of vitamin D nutritional status (plasma 25‐hydroxyvitamin D range 10–107 nmol/l). Eighteen patients discovered by biochemical screening were enrolled in a natural history or treatment option study, and six additional US patients matched a group studied concurrently in India with low plasma 25‐hydroxyvitamin D level (< 37 nmol/l).

MEASUREMENTS

Receptor expression was determined by immunocytochemistry in each tumour and in 11 cases also in adjacent nonadenomatous tissue. VDR expression was reported as the proportion of positive cells (strongly rather than weakly stained) determined by systematic random sampling and CaSR expression as grey scale values of staining intensity in arbitrary units determined by image analysis.

RESULTS

The mean (SD) proportion of cells positive for VDR was 2.93 (2.17)% in the parathyroid adenomas and 95.7 (5.10)% in the nonadenomatous tissue. In about two‐thirds of the cases VDR positive cells could have been remnants of a normal gland, but in the remaining one‐third they were too numerous to be accounted for by this explanation. The mean (SD) intensity of CaSR expression was 151 (4.71) units in parathyroid adenomas and 218 (5.0) units in nonadenomatous tissue (P < 0.001). The frequency of VDR loss and the changes in CaSR immunohistochemistry were unrelated to race, sex, or disease severity, except that the reduction in CaSR was significantly greater in patients with normal vitamin D nutrition (32.1% vs. 29.0%).

CONCLUSIONS

(1) There is reduction of vitamin D receptor expression in almost all cells in parathyroid adenomas. This defect was probably present in the founder cell of the tumour clone in the majority of cases. Since mutations in the vitamin D receptor gene have been sought but not found, possible explanations include inhibition of vitamin D receptor gene transcription, decreased amount of the corresponding mRNA, or failure of normal translation. (2) Reduction in calcium sensing receptor could be either the primary defect or (more commonly) secondary to loss of vitamin D receptor and is of sufficient magnitude to account for the increase in secretory set‐point and consequent asymptotic growth and stable clinical course.
Postoperative radiotherapy in acromegaly is effective in reducing GH concentration to safe levels
Authors: Biermasz Nienke R. , Dulken Hans van , Roelfsema Ferdinand
Published: March 2003

OBJECTIVE

Several studies have established that in treated acromegaly mortality is only normalized in patients achieving a serum GH concentration below 5 mU/l. Few studies however, have addressed results of radiotherapy using this strict criterion. The aim of our study was to assess the efficacy of postoperative radiotherapy in reducing serum GH concentration below 5 mU/l.

PATIENTS AND METHODS

Forty acromegalic patients who underwent radiotherapy for postoperative persistent disease after transsphenoidal surgery were studied. Mean time of follow‐up after radiotherapy was 123 ± 11.1 months. A serum GH concentration of <5 mU/l was used to define remission.

RESULTS

Following surgery mean GH concentration decreased from 120.8 ± 21 mU/l to 24.4 ± 5.2 mU/l and mean GH concentration prior to radiotherapy, administered after a mean of 8.2 ± 2.7 (0.5–96) months postoperatively was 26.0 ± 5.1 mU/l.

Using individual regression plots, GH was reduced to 50% by radiotherapy after a mean of 27 ± 5 months (range 3–105 months). The observed mean GH concentration as measured at follow‐up visits was reduced by 55% (−36–95%) after the first year, by 65% (−29–97.3%) after 2 years and by 78% (−29–99%) after 5 years. We could not demonstrate a significant correlation between a normalized GH concentration on the one hand and tumour size, preradiotherapy GH concentration or duration of follow‐up on the other hand. During follow‐up, GH‐suppressive medical therapy was used in 11 patients, five of whom were still using medication at the end of follow‐up. Eight patients had a follow‐up of less than 5 years and three of them had a serum GH concentration of <5 mU/l at their latest follow‐up visit (38%). At 5 years of follow‐up after radiotherapy, 24 out of 32 patients had a GH level of <5 mU/l without medication (75%). At 10 years following irradiation, 16 of 21 patients (76%) had a GH level of <5 mU/l without medical treatment. At 15 years follow‐up, a serum GH concentration of <5 mU/l was observed in 13 out of 15 patients (87%) without GH suppressive medication. At the latest follow‐up visit, serum GH concentration below 5 mU/l was present in 75% of patients (30 out of 40) without medical therapy after a mean of 10.4 ± 0.9 years, but five patients required octreotide up to the end of follow‐up. Twenty‐seven out of 37 patients with available IGF‐I data had normal IGF‐I at the end of follow‐up (73%). Fifty percent of patients needed substitution therapy for (partial) hypopituitarism after 10 years and 75% after 15 years of radiotherapy.

CONCLUSION

In our group of patients who were incompletely cured by surgery, but had a significant postoperative decrease of serum GH concentrations, radiotherapy was able to achieve ‘safe’ serum GH concentrations in the majority in the long term.