bluuebunny/crossref_metadata_2025 huggingface dataset:
IgG subclass response toHelicobacter pyloriand CagA antigens in children
Authors: DZIERZANOWSKA-FANGRAT K , RAEISZADEH M , DZIERZANOWSKA D , GLADKOWSKA-DURA M , CELINSKA-CEDRO D , CRABTREE J E
Published: December 2004

Specific serum IgG subclass antibodies against Helicobacter pylori antigens and recombinant CagA were analysed in 75 symptomatic children with histologically confirmed H. pylori infection. H. pylori stimulated an IgG1 predominant response, and IgG3 titres showed a positive association with peptic ulcer disease, chronicity of antral inflammation and density of H. pylori colonization. Two methods used for assessing serum IgG CagA antibody status, i.e. Western blotting and enzyme-linked immunosorbent assay (ELISA), were concordant. CagA stimulated an IgG1 and IgG3 predominant humoral response. Total CagA IgG titres were higher in children with active and more severe chronic antral inflammation. These findings suggest that in children the systemic humoral immune response to H. pylori infection may reflect gastroduodenal pathology.
Nasal-associated lymphoid tissue (NALT): frequency and localization in young children
Authors: DEBERTIN A S , TSCHERNIG T , TÖNJES H , KLEEMANN W J , TRÖGER H D , PABST R
Published: December 2004

In mucosal immunology nasal-associated lymphoid tissue (NALT) is taken as a constitutive structure of the nasal immune system and as a target tissue in strategies of local defence and an induction site for vaccination. These concepts are based on findings in rodents, but it has not been investigated systematically whether NALT also is present in humans and if so in which amount and localization. In a postmortem study the presence of NALT in humans is documented as a morphologically distinct structure additional to the lymphoid structures of the Waldeyer's ring. Human nasal tissue blocks of 150 children who had died in the first two years of life either of sudden infant death (n = 109) without signs of respiratory tract infections or of different traumatic (n = 22) and natural causes of death (n = 19) were obtained using a specific autopsy-technique and were investigated systematically using histology. Clearly in contrast to rodents human NALT was found disseminated in the nasal mucosa with typical morphological features in 38% of all children, mainly in the middle concha, with similar morphology and frequency in the examined groups. No correlation was found between the presence of NALT and the cause of death and especially the grade of inflammation in general. Therefore, NALT might be the morphological basis for inhalative vaccination strategies in young children and play a role in mucosal host defence.
Polarity of helper T cell subsets represents disease nature and clinical course of experimental autoimmune myocarditis in rats
Authors: FUSE K , KODAMA M , ITO M , OKURA Y , KATO K , HANAWA H , AOKI S , AIZAWA Y
Published: December 2004

The mechanisms of progression, remission and relapse of myocarditis remain unclear. To clarify these mechanisms, we focused on T helper-1 (Th1)/T helper-2 (Th2) subsets balance of peripheral lymphocytes and serum cytokine levels during disease progression in rats with experimental autoimmune myocarditis (EAM). Lewis rats were immunized with cardiac myosin on day 0. Blood samples were collected on days 0, 7, 15, 18, 21, 28, 35, 42, 49 and 56 following immunization. We examined percentages of interferon (IFN)-γ and/or interleukin (IL)-4 producing cells in stimulated peripheral CD4-positive lymphocytes using flow cytometry analysis. Serum IFN-γ, IL-2, IL-6 and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA). The percentage of Th1/Th2 subsets in EAM on days 0, 15, 28 and 56 were 2·5 ± 0·5/0·5 ± 0·1%, 19·4 ± 3·2/1·6 ± 0·3%, 2·0 ± 0·5/22·1 ± 5·7% and 3·0 ± 0·4/1·7 ± 0·3%, respectively. Serum levels of Th1 cytokines, IFN-γ and IL-2 significantly increased in the acute phase (from day 15–18) and immediately decreased in the early recovery phase. On the other hand, serum levels of Th2 cytokine, IL-10 significantly increased in the early recovery phase (from day 24–30). These results suggest that induction of acute myocarditis might be associated with systemic Th1 dominance, while recovery is related to systemic Th2 polarity. Thus, analysis of Th1/Th2 balance in peripheral T cells may be useful in disease monitoring in patients with myocarditis and postmyocarditic dilated cardiomyopathy.
Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves’ disease
Authors: PICHURIN P , ALIESKY H , CHEN C-R , NAGAYAMA Y , RAPOPORT B , MCLACHLAN S M
Published: December 2004

The role of B cells as antigen-presenting cells is being recognized increasingly in immune responses to infections and autoimmunity. We compared T cell responses in wild-type and B cell-deficient mice immunized with the thyrotrophin receptor (TSHR), the major autoantigen in Graves’ disease. Three B cell-deficient mouse strains were studied: JHD (no B cells), mIgM (membrane-bound monoclonal IgM+ B cells) and (m + s)IgM (membrane-bound and secreted monoclonal IgM). Wild-type and B cell-deficient mice (BALB/c background) were studied 8 weeks after three injections of TSHR or control adenovirus. Only wild-type mice developed IgG class TSHR antibodies and hyperthyroidism. After challenge with TSHR antigen, splenocyte cultures were tested for cytokine production. Splenocytes from TSHR adenovirus injected wild-type and mIgM-mice, but not from JHD- or (m + s)IgM- mice, produced interferon (IFN)-γ in response to TSHR protein. Concanavalin A and pokeweed mitogen induced comparable IFN-γ secretion in all groups of mice except in the JHD strain in which responses were reduced. The absence in (m + s)IgM mice and presence in mIgM mice of an anamnestic response to TSHR antigen was unrelated to lymphoid cell types. Surprisingly, although TSHR-specific antibodies were undetectable, low levels of serum IgG were present in mIgM- but not (m + s)IgM mice. Moreover, IFN-γ production by antigen-stimulated splenocytes correlated with IgG levels. In conclusion, T cell responses to TSHR antigen developed only in mice with IgG-secreting B cells. Consequently, in the TSHR–adenovirus model of Graves’ disease, some normal B cells appear to be required for the development of memory T cells.
Chemokines, chemokine receptors and adhesion molecules on different human endothelia: discriminating the tissue-specific functions that affect leucocyte migration
Authors: HILLYER P , MORDELET E , FLYNN G , MALE D
Published: December 2004

The selective accumulation of different leucocyte populations during inflammation is regulated by adhesion molecules and chemokines expressed by vascular endothelium. This study examined how chemokine production and the expression of adhesion molecules and chemokine receptors vary between endothelia from different vascular beds. Human saphenous vein endothelium was compared with lung and dermal microvascular endothelia and with umbilical vein endothelium and a bone-marrow endothelial cell line. All endothelia produced CCL2 and CXCL8 constitutively, whereas CXCL10 and CCL5 were only secreted after tumour necrosis factor (TNF)-α or interferon (IFN)-γ stimulation. In combination with TNF-α, IFN-γ suppressed CXCL8 but enhanced CCL5 and CXCL10, whereas transforming growth factor (TGF)-β reduced secretion of all chemokines. Basal chemokine secretion was higher from umbilical vein than other endothelial cells. Chemokine receptors, CXCR1, CXCR3 and CCR3, were present on all endothelia but highest on saphenous vein. CCR4, CCR5, CCR6, CXCR2, CXCR4 and CXCR5 were also detected at variable levels on different endothelia. The variation between endothelia in chemokine secretion was much greater than the variations in adhesion molecules, both on resting cells and following cytokine stimulation. These results indicate that it is the tissue-specific variations in endothelial chemokine secretion rather than variations in adhesion molecules that can explain the different patterns of inflammation and leucocyte traffic seen in non-lymphoid tissues.
Gliadin and tissue transglutaminase complexes in normal and coeliac duodenal mucosa
Authors: CICCOCIOPPO R , DI SABATINO A , ARA C , BIAGI F , PERILLI M , AMICOSANTE G , CIFONE M G , CORAZZA G R
Published: December 2004

Tissue transglutaminase (tTG) seems to be the target self-antigen for endomysial antibodies in coeliac disease (CD) and to catalyse the critical deamidation of gliadin which strengthens its recognition by HLA-restricted gut-derived T cells. To date, it has not been demonstrated whether gliadin is cross-linked to tTG within the gut wall, a phenomenon known to occur in vitro. We therefore investigated the putative presence of tTG and gliadin complexes directly in duodenal mucosa. The immunoprecipitation and Western blotting experiments were performed on mucosal biopsies obtained from untreated, treated CD patients and biopsied controls, by using either anti-tTG or anti-gliadin antibodies, in both denaturating/reducing or nondenaturating/nonreducing conditions. A subset of experiments was performed by using anti-tTG antibodies purified by affinity chromatography from sera of untreated coeliac patients. The localization of tTG and gliadin was studied by immunofluorescence at confocal laser microscopy on seriate sections of diseased and normal duodenal mucosa by using the same antibodies of the coimmunoprecipitation section. The amounts of tTG and gliadin coimmunoprecipitated with anti-tTG monoclonal antibody in untreated CD mucosa were significantly increased compared to those of the other two groups. When performing the experiments in nondenaturating/nonreducing conditions, a high molecular weight band formed by both molecules, was evidenciated. Also the anti-tTG antibodies purified from patients’ sera turned out to be able to coimmunoprecipitate the two molecules. The analysis by confocal microscopy showed that tTG colocalizes with gliadin at the epithelial and subepithelial levels in active CD, and only in the lamina propria of the villi in normal mucosa. Our findings firstly demonstrated that gliadin was directly bound to tTG in duodenal mucosa of coeliacs and controls, and the ability of circulating tTG-autoantibodies to recognize and immunoprecipitate the tTG-gliadin complexes.
A pilot study of the safety and efficacy of thymosinα1 in augmenting immune reconstitution in HIV-infected patients with low CD4 counts taking highly active antiretroviral therapy
Authors: CHADWICK D , PIDO-LOPEZ J , PIRES A , IMAMI N , GOTCH F , VILLACIAN J S , RAVINDRAN S , PATON N I
Published: December 2004

To study the safety and efficacy of thymosin α1 in stimulating immune reconstitution in combination with highly active antiretroviral therarpy (HAART), a phase II randomized, controlled open-label trial of subcutaneous thymosin α1 was undertaken for 12 weeks. Twenty clinically stable patients with viral loads <400 copies/ml and CD4 counts less than 200 cells/µl were randomized to receive 3·2 mg thymosin α1 subcutaneous injections twice weekly or no injections for 12 weeks. CD4 and CD8 counts, CD45 RO+ and RA+ subsets and signal joint T cell receptor excision circles (sjTREC) in peripheral blood mononuclear cells (PBMCs) were measured every 2 weeks. Thirteen patients received thymosin α1 and seven were controls. Thymosin α1 was well tolerated and there were no serious adverse events. There was no significant difference between the thymosin α1 and control groups in CD4, CD8 and CD45 lymphocyte subset changes at week 12; however, PBMC sjTREC levels increased significantly in the thymosin α1-treated patients compared to controls at week 12. In conclusion, the increase in PBMC sjTREC levels in patients taking thymosin α1 may represent enhanced immune reconstitution; however, the clinical benefits and long-term consequences remain to be determined.
Cortisol levels and mortality in severe sepsis
Authors: Sam Susan , Corbridge Thomas C. , Mokhlesi Babak , Comellas Alejandro P. , Molitch Mark E.
Published: December 2004

objective  Serum cortisol levels rise in response to the stress of critical illness but the optimal range of serum cortisol in such settings is not clearly defined. The objectives of this study were to determine the range of serum cortisol levels in a group of medical intensive care unit patients with severe sepsis/septic shock using uniform criteria, and to correlate serum cortisol levels to mortality.

design and patients  In a prospective observational fashion, 100 medical intensive care unit patients at Northwestern Memorial Hospital in Chicago were enrolled within 48 h of developing severe sepsis/septic shock as defined by the American College of Chest Physicians/Society of Critical Care Medicine.

measurements  A serum cortisol level was measured during the morning hours in the first 48 h of developing severe sepsis/septic shock. The severity of critical illness was measured by the Acute Physiology and Chronic Health Evaluation II (APACHE II) score.

results  The average patient age was 63 ± 17 years, 54 patients were men. The average APACHE II score for all patients was 23 ± 7. In‐hospital and 90‐day mortality were 51% and 60%, respectively. Four patient groups were defined a priori based on morning serum cortisol levels and their in‐hospital mortalities were as follows: group 1 (cortisol ≤ 345 nmol/l), n = 11, mortality 54%; group 2 (cortisol 345–552 nmol/l), n = 19, mortality 53%; group 3 (cortisol 552–1242 nmol/l), n = 54, mortality 41%; and group 4 (cortisol ≥ 1242 nmol/l), n = 16, mortality 81% (P < 0·01).

conclusions  Cortisol levels were elevated in most patients with septic shock. Cortisol levels less than 552 nmol/l occurred in 30% of patients with septic shock but the mortality in these patients was not significantly increased. Serum cortisol levels ≥ 1242 nmol/l were associated with significantly higher mortality.
Expression, subcellular localization and phosphorylation status of annexins 1 and 5 in human pituitary adenomas and a growth hormone‐secreting carcinoma
Authors: Mulla Abeda , Christian Helen C. , Solito Egle , Mendoza Nigel , Morris John F. , Buckingham Julia C.
Published: December 2004

objective  Annexin 1 (ANXA1), a 37‐kDa protein, plays an important role as a mediator of glucocorticoid action in the anterior pituitary gland and has been implicated in the processes of tumorigenesis in a number of other tissues. As a prelude to examining the potential role of ANXA1 in the pathophysiology of pituitary tumours, this study examined the expression, phosphorylation status and distribution of ANXA1 and the closely related protein, annexin 5 (ANXA5), in a series of pituitary adenomas and in two carcinomas.

patients and design  Forty‐two human pituitary adenomas were examined. Parallel studies were performed on normal pituitary tissue, obtained postmortem, a GH‐secreting carcinoma and a grade 4 astrocytoma.

measurements  The tissue was processed for analysis of ANXA1 mRNA and protein expression by reverse transcriptase polymerase chain reaction (RT‐PCR), Western blot analysis and immunogold electron‐microscopic histochemistry. Parallel measures of ANXA5 mRNA and protein were also made.

results  ANXA1 mRNA and protein were detected in all but three adenomas studied; the protein was localized mainly, but not exclusively, to nonendocrine cells. ANXA5 expression was more variable and was contained within both endocrine and nonendocrine cells of these tumours. In comparison with the adenomas, the GH‐secreting carcinoma showed abundant expression of both ANXA1 and ANXA5, with intense ANXA1 staining in some but not all tumour/endocrine cells. A serine‐phosphorylated species of ANXA1 was detected in all pituitary tumours studied; by contrast, tyrosine‐phosphorylated ANXA1 was detected in only four adenomas and in the GH carcinoma. ANXA1 and ANXA5 were also expressed in abundance in the astrocytoma.

conclusions  The results demonstrate expression of both ANXA1 and ANXA5 in human pituitary tumours and thus raise the possibility that these proteins influence the growth and/or functional activity of the tumours.
Obese patients with obstructive sleep apnoea syndrome show a peculiar alteration of the corticotroph but not of the thyrotroph and lactotroph function
Authors: Lanfranco F. , Gianotti L. , Pivetti S. , Navone F. , Rossetto R. , Tassone F. , Gai V. , Ghigo E. , Maccario M.
Published: December 2004

objective  Obstructive sleep apnoea syndrome (OSAS) is strongly associated with obesity (OB) and is characterized by several changes in endocrine functions, e.g. GH/IGF‐I axis, adrenal and thyroid activity. It is still unclear whether these alterations simply reflect overweight or include peculiar hypoxia‐induced hormonal alterations. Hormonal evaluations have been generally performed in basal conditions but we have recently reported that OSAS is characterized by a more severe reduction of the GH releasable pool in comparison to simple obesity. We aimed to extend our evaluation of anterior pituitary function to corticotroph, thyrotroph and lactotroph secretion under dynamic testing in OSAS in comparison with simply obese and normal subjects.

subjects and methods  In 15 male patients with OSAS [age, mean ± SEM 43·5 ± 1·6 years; body mass index (BMI) 39·2 ± 3·1 kg/m2; apnoea/hypopnoea index, (AHI) 53·4 ± 8·7], 15 male patients with simple obesity (OB, age 39·7 ± 1·2 years; BMI 41·2 ± 2·0 kg/m2; AHI 3·1 ± 1·2 events/h of sleep) and in 15 normal lean male subjects (NS, age 38·2 ± 1·4 years; BMI 21·2 ± 0·8 kg/m2; AHI 1·9 ± 0·8 events/h of sleep) we evaluated: (a) the ACTH and cortisol responses to CRH [2 µg/kg intravenously (i.v.)] and basal 24 h UFC levels; (b) the TSH and PRL responses to TRH (5 µg/kg iv) as well as FT3 and FT4 levels.

results  Twenty‐four‐hour UFC levels in OSAS and OB were similar and within the normal range. Basal ACTH and cortisol levels were similar in all groups. However, the ACTH response to CRH in OSAS (Δpeak: 30·3 ± 3·8 pmol/l; ΔAUC: 682·8 ± 128·4 pmol*h/l) was markedly higher (P < 0·001) than in OB (Δpeak: 9·3 ± 1·4 pmol/l; ΔAUC 471·5 ± 97·3 pmol*h/l), which, in turn, was higher (P < 0·05) than in NS (Δpeak: 3·3 ± 0·9 pmol/l; ΔAUC 94·7 ± 76·7 pmol*h/l). On the other hand, the cortisol response to CRH was not significantly different in the three groups. Basal FT3 and FT4 levels as well as the TSH response to TRH were similar in all groups. Similarly, both basal PRL levels and the PRL response to TRH were similar in the three groups.

conclusions  With respect to patients with simple abdominal obesity, obese patients with OSAS show a more remarkable enhancement of the ACTH response to CRH but a preserved TSH and PRL responsiveness to TRH. These findings indicate the existence of a peculiarly exaggerated ACTH hyper‐responsiveness to CRH that would reflect hypoxia‐ and/or sleep‐induced alterations of the neural control of corticotroph function; this further alteration is coupled to the previously described, peculiar reduction of somatotroph function.
Stimulation of thyroid‐stimulating hormone (TSH) receptor antibody production following painless thyroiditis
Authors: Iitaka Makoto , Morgenthaler Nils G. , Momotani Naoko , Nagata Atsuo , Ishikawa Naofumi , Ito Koichi , Katayama Shigehiro , Ito Kunihiko
Published: December 2004

objective  Development or recurrence of Graves’ disease (GD) following painless thyroiditis (PT) has been documented. Therefore, we measured titres of TSH receptor antibodies (TSHR Ab) using a novel sensitive TSHR Ab assay in patients with PT to determine whether PT enhances TSHR Ab production, possibly triggering the development or recurrence of GD.

design and measurements  Ninety‐two patients who developed PT were studied. Group G consisted of 40 patients with a history of GD (19 patients in remission, 21 who had stopped taking antithyroid drugs during pregnancy). Group P consisted of 52 patients with no history of GD. Serum thyroid hormone levels, thyroid autoantibodies including TSHR Ab, and 123I uptake at 24 h (RAIU) were measured in these patients at the time of PT onset. TSHR Abs were measured by radioreceptor assay using porcine TSH receptors (pTBII) or human TSH receptors (hTBII).

results  There were no significant differences in serum thyroid hormone levels or pTBII values between groups G and P. Nor was there any significant difference between p‐ and h‐TBII values in group P. There was also no significant difference in pTBII levels before, compared to at the time of PT onset in group G patients. However, hTBII values at the PT onset were significantly higher in the group G than in the group P (7·7 ± 9·8%vs. 1·4 ± 5·4%, P = 0·0014). The rate of hTBII positivity was also significantly higher in group G than in group P (12/40 vs. 3/52, P = 0·002). Furthermore, the RAIU in group G patients was significantly higher than that in group P patients (2·8 ± 2·4%vs. 1·3 ± 0·9%, P = 0·0002). GD recurrence was observed in seven patients in group G, whose hTBII levels were significantly higher than those of other patients in this group (17·0 ± 11·8%vs. 5·7 ± 8·2%, P = 0·02). Of these seven with relapses, five had hTBII values exceeding 15%.

conclusions  TBII elevation at the onset of PT in patients with a history of GD was detected by a sensitive hTBII assay. Destruction of the thyroid by PT may trigger GD recurrence in patients with a history of GD.
N‐terminal‐pro‐B‐type natriuretic peptide (NT‐pro‐BNP) in different thyroid function states
Authors: Schultz Marianne , Faber Jens , Kistorp Caroline , Jarløv Anne , Pedersen Frants , Wiinberg Niels , Hildebrandt Per
Published: December 2004

objective  N‐terminal B‐type natriuretic peptide (NT‐pro‐BNP) is secreted from the cardiac ventricles in response to volume expansion and pressure overload, and serum levels are elevated in systolic heart failure. The aim of this study was to evaluate the influence of thyroid function on NT‐pro‐BNP.

design  Patients with overt or subclinical thyroid disease were evaluated before and after treatment for their dysthyroid state.

patients  Seventeen overt and 21 subclinical hypothyroid patients together with six subclinical and 13 overt hyperthyroid patients without cardiac disease were included. Subclinical states had, by definition, free T4 and free T3 estimates within reference ranges.

measurements  Serum levels of NT‐pro‐BNP and thyroid hormones were measured, and in 31 patients resting cardiac output was measured by impedance cardiography in the untreated state.

results  NT‐pro‐BNP levels were more than four times higher in hyperthyroid than hypothyroid patients, with mean values of 30 and 7 pmol/l, respectively (P < 0·001). Serum NT‐pro‐BNP levels correlated to the thyroid function (vs. free T4 estimate: r = 0·52, P < 0·0001, n = 57). Treatment resulted in significant increases in NT‐pro‐BNP in both hypothyroid groups, and decreases in both hyperthyroid groups. A multiple linear regression analysis demonstrated that free T4 and free T3 (P < 0·001) estimates were independently associated with a high serum NT‐pro‐BNP, whereas cardiac output and resting pulse rate were not.

conclusions  Serum NT‐pro‐BNP levels are affected by thyroid function. This seems due to a direct stimulatory effect of thyroid hormones.
Relationship of GnRH‐stimulated LH release to episodic LH secretion and baseline endocrine‐metabolic measures in women with polycystic ovary syndrome
Authors: Patel Ketan , Coffler Mickey S. , Dahan Michael H. , Malcom Pamela J. , Deutsch Reena , Chang R. Jeffrey
Published: December 2004

background and objective  In polycystic ovary syndrome (PCOS) inappropriate gonadotrophin secretion is characterized by increased pulse frequency and amplitude, elevated 24‐h mean serum concentrations, and greater responses to GnRH. While the mechanism(s) responsible for this increased release of LH are not well understood, enhanced LH secretion has been attributed to increased pituitary sensitivity to GnRH and feedback influences from circulating steroid hormones. To address these considerations, we conducted a study to examine the relationships between GnRH‐stimulated LH responses, episodic gonadotrophin secretion, and baseline measurements of endocrine‐metabolic function in PCOS.

patients  Serum LH responses to sequential multidose GnRH administration and pulsatile gonadotrophin secretion were examined in 13 PCOS and 13 normal women.

measurements  Serum LH, steroid hormone, insulin and glucose levels were determined in blood samples obtained during assessment of episodic gonadotrophin secretion and LH responses to GnRH stimulation.

design  Each subject was studied on two consecutive days. On study day 1 each subject underwent frequent blood sampling every 10 min for 12 h. On study day 2 each received sequential doses of GnRH, 2 µg, 10 µg and 20 µg, administered intravenously at 4‐h intervals over a continuous 12‐h period.

results  Serum LH responses following GnRH were markedly greater in PCOS compared to normal women, as expected. In individual PCOS, peak LH responses to GnRH were significantly correlated with corresponding basal LH and LH pulse amplitude, but not LH pulse frequency. In the PCOS group, LH responses were positively correlated with serum oestradiol (E2) and inversely related to body mass index (BMI). Between‐group differences in LH responsiveness disappeared when controlling for serum testosterone (T) levels.

conclusions  These results indicate that the absolute LH increment following GnRH is largely dependent on baseline LH levels and may account for the well‐documented difference in LH responsiveness between PCOS and normal women. That neither LH responses to GnRH nor LH pulse amplitude were correlated to LH pulse frequency suggests involvement of other factors along with GnRH to account for increased LH secretion in PCOS. In addition to E2 and BMI, serum testosterone appears to be, at least in part, responsible for differences in LH secretion and release between PCOS and normal women.
FSH and LH responses to GnRH after ovariectomy in postmenopausal women
Authors: Dafopoulos K. C. , Kotsovassilis C. P. , Milingos S. D. , Kallitsaris A. T. , Georgadakis G. S. , Sotiros P. G. , Messinis I. E.
Published: December 2004

objective  Whether the postmenopausal ovary is still playing a role in the control of gonadotrophin secretion in response to GnRH has not been investigated. The aim of the present study was to test this hypothesis by examining changes in basal and GnRH‐induced gonadotrophin secretion in postmenopausal women after bilateral ovariectomy.

design  The responses of LH and FSH to GnRH [10 µg intravenously (i.v.)] were investigated in postmenopausal women from 2 days before to 8 days after total abdominal hysterectomy plus bilateral ovariectomy.

patients  Nine postmenopausal women aged 52–67 years and between 5 and 15 years after menopause. In all cases the ovaries were histologically normal.

measurements  Pituitary responses to GnRH were calculated every 12–24 h as the net increases in LH (ΔLH) and FSH (ΔFSH) at 30 min above the basal values. Basal values of oestradiol (E2) and testosterone were also measured.

results  Basal values of FSH showed a significant decrease on postoperative days 2 (P < 0·01) and 8 (P = 0·03) as compared to day 0, while at the same time points after the operation LH values were marginally lower than on day 2 (P = 0·05). Serum E2 values showed a gradual increase up to postoperative day 1 (P = 0·04) and a gradual decline thereafter. Basal testosterone concentrations decreased gradually and significantly after ovariectomy and were significantly lower on day 8 than on day 0 (P < 0·01). ΔFSH and ΔLH responses to GnRH did not change significantly with time. A temporary increase at 12 h after the operation was not significant.

conclusions  These results demonstrate for the first time that the removal of the ovaries in postmenopausal women does not affect GnRH‐induced gonadotrophin secretion in the short term. It is suggested that the postmenopausal ovary is not a dominant regulator of hypothalamic–pituitary interactions.
Hypertriglyceridaemia in Alström's syndrome: causes and associations in 37 cases
Authors: Paisey R. B. , Carey C. M. , Bower L. , Marshall J. , Taylor P. , Maffei P. , Mansell P.
Published: December 2004

objective  To document frequency of severe hypertriglyceridaemia in Alström's syndrome (AS) and its relationship to hepatic and renal function, glycaemia and insulin resistance.

patients and methods  Thirty‐seven subjects with AS aged 5–35 years, 51% male, were assessed at multidisciplinary clinics in Canada, UK and Italy. Diagnostic criteria were: severe cone/rod dystrophy leading to severe visual impairment in early childhood, sensorineural deafness, moderate overall obesity and normal intelligence. Three patients were treated with thyroxine for primary hypothyroidism and one female patient for secondary amenorrhoea with 20 µg ethinyloestradial combined oral contraceptive. Two male patients were receiving monthly intramuscular testosterone enanthate for secondary hypogonadism. Fasting bloods were taken for serum insulin, serum glucose, serum triglycerides, hepatic and renal function and glycosylated Hb. Triglyceride levels > 8 mmol/l and fasting serum insulin levels > 16 microunits/ml were considered to represent severe hypertriglyceridaemia and severe insulin resistance, respectively. All subjects with (23) hypertriglyceridaemia also had high insulin resistance, as measured by HOMA modelling. However, there was no significant correlation between log tyriglyceride and log serum insulin or HOMA in the whole group (P = 0·2 and 0·14, respectively). There was no clear relationship between serum triglyceride levels and age, body mass index (BMI), hepatic or renal impairment or glycaemia.

conclusion  The first overview of serum triglyceride levels in a significant number of reported cases of Alström Syndrome shows an overlap between severe hypertriglyceridaemia and severe hyperinsulinism, but not a direct correlation between the two nor with insulin resistance measured by HOMA. Triglyceride levels were not related to glycaemia, hepatic or renal dysfunction.
Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus
Authors: Christensen Jane H. , Siggaard Charlotte , Corydon Thomas J. , Robertson Gary L. , Gregersen Niels , Bolund Lars , Rittig Søren
Published: December 2004

objective and study design  Two different mutations in the arginine vasopressin (AVP) gene associated with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) predict Y21H (AVP2) and V67A (NP36) amino acid substitutions of the AVP prohormone. They are unique in that they change, respectively, the AVP moiety and a region of the neurophysin II domain not so far affected by any mutations. To test whether they affect the cellular handling of the AVP prohormone in a similar manner to previously investigated mutations, they were examined by heterologous expression in cell lines.

results  Both mutations resulted in significantly reduced amounts of immunoreactive AVP in the cell culture medium as determined by radioimmunoassay analysis. Metabolic labelling combined with immunoprecipitation demonstrated that processing and secretion of the mutant prohormones was reduced but not prevented. Finally, confocal laser scanning microscopy showed that normal AVP prohormone and/or its processed products were localized in the tips of the cellular processes, whereas both mutant prohormones were accumulated in the endoplasmic reticulum (ER) and in the case of the V67A prohormone, also in perinuclear structures outside the ER.

conclusion  Both mutations result in reduced AVP prohormone processing and secretion probably due to retention in the ER. This supports, at least partly, the hypothesis that the mutations lead to the production of a mutant hormone precursor that fails to fold and/or dimerize properly and, as a consequence, is retained by the ER protein quality control machinery. Perinuclear accumulation of the V67A prohormone outside the ER indicates that additional mechanisms could be involved.
Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor
Authors: Park S.‐M. , Clifton‐Bligh R. J. , Betts P. , Chatterjee V. K. K.
Published: December 2004

objective  We wished to ascertain whether mutations in the TSH receptor (TSHR) gene were present in two siblings with congenital hypothyroidism with no parental consanguinity.

design  The pituitary–thyroid axis and thyroid gland morphology were investigated in both affected siblings and their parents. The TSHR gene was analysed in each subject.

measurements  Basal thyroid function together with circulating thyroglobulin levels were measured in each subject. In addition, a TRH stimulation test was undertaken in each parent. All family members underwent thyroid ultrasonography. The TSHR gene was amplified from genomic DNA using the polymerase chain reaction and receptor mutations were identified by sequence analysis.

results  Two siblings were diagnosed with severe congenital hypothyroidism (total T4 19–21 nmol/l, TSH 160–230 mU/l on neonatal screening). Although radioiodine scanning showed no tracer uptake and ultrasound imaging in both individuals failed to demonstrate thyroid tissue, suggesting complete athyreosis, circulating thyroglobulin levels were measurable. The thyroid status of the parents was discordant: in the father, baseline thyroid function (FT4 13 pmol/l, TSH 4 mU/l), the peak TSH level after TRH stimulation (30 mU/l) were normal and he exhibited an appropriate rise in circulating thyroid hormones in response to the elevated TSH; in contrast, in the mother, baseline thyroid function was abnormal (FT4 10 pmol/l, TSH 15 mU/l), the TSH response to TRH was exaggerated (110 mU/l), with no subsequent rise in circulating thyroid hormones. An eutopic, slightly hypoplastic thyroid gland was visualized on ultrasonography in the mother and her thyroid antibody status was negative. Both children were compound heterozygotes for missense (alanine to threonine at codon 553, A553T) and premature stop (tryptophan at codon 546, W546X) mutations in the fourth transmembrane domain of the TSH receptor. The mother and father were heterozygous for W546X and A553T mutations, respectively. Each mutation is known to abolish the function or cellular surface expression of the TSH receptor.

conclusions  Inactivating mutations in the TSH receptor can be associated with severe TSH resistance presenting as congenital hypothyroidism with apparent athyreosis. Our observations also suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia.
Aggregation of thyroid autoantibodies in first‐degree relatives of patients with autoimmune thyroid disease is mainly due to genes: a twin study
Authors: Heiberg Brix Thomas , Skov Hansen Pia , Ohm Kyvik Kirsten , Hegedüs Laszlo
Published: December 2004

background Family studies have repeatedly shown aggregation of thyroid autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) in first‐degree relatives of patients with autoimmune thyroid disease (AITD). This phenomenon has generally been interpreted as evidence of a genetic component in the development of thyroid autoantibodies. However, family studies cannot determine whether the observed familial aggregation of these antibodies is due to shared genes or shared environment.

aim To test the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined.

design A cross‐sectional study of healthy twin siblings to twins with AITD.

participants Thirty‐eight healthy twin siblings to twins with AITD and a control group of 76 healthy twins, matched for age, sex and zygosity, but without AITD among their first‐degree relatives.

main outcome measures Prevalence of TPOab, Tgab and TSH‐receptor antibodies (TSHRab).

methods All antibodies were measured by routine commercial kits. TPOab, Tgab and TSHRab were regarded as positive if > 60 U/ml, > 60 U/ml and > 1·0 U/l, respectively. Zygosity was established by DNA fingerprinting.

results The prevalence of TPOab, Tgab and TSHRab in the 38 healthy twin siblings was 34% (13/38), 26% (10/38) and 13% (5/38), respectively, which was higher than the corresponding prevalences in the control population, 9% (7/76;P = 0·002), 7% (5/76;P = 0·006) and 1·3% (1/76;P = 0·015), respectively. Combination of two or more thyroid autoantibodies was also significantly more common among index subjects (10/38 or 26%) than in the control group (2/76 or 3%),P = 0·0001. Among the healthy monozygotic twin siblings, 53%, 47% and 20% had TPOab, Tgab and TSHRab, respectively, compared with 22% (P = 0·045), 13% (P = 0·02) and 9% (P = 0·36), respectively, in the dizygotic twin siblings. Significantly more monozygotic twin siblings were positive for two or more autoantibodies than dizygotic twin siblings (8/15vs.2/23;P = 0·006).

conclusion Healthy first‐degree relatives to patients with AITD show significant clustering of thyroid autoantibodies. Moreover, healthy monozygotic and dizygotic twin siblings to twins with AITD differ in prevalence of thyroid autoantibodies. These observations strongly support the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined.
Marked and sustained increase in bone mineral density after parathyroidectomy in patients with primary hyperparathyroidism; a six‐year longitudinal study with or without parathyroidectomy in a Japanese population
Authors: Nomura Rikako , Sugimoto Toshitsugu , Tsukamoto Tatsuo , Yamauchi Mika , Sowa Hideaki , Chen Qingxiang , Yamaguchi Toru , Kobayashi Akira , Chihara Kazuo
Published: December 2004

objective  Although many reports have demonstrated the sustained increase in bone mineral density (BMD) at trabecular sites in primary hyperparathyroidism (pHPT) after parathyroidectomy (PTX), there have been no data available on BMD changes over the long‐term in pHPT patients with and without PTX in Japanese population. The present study was designed to investigate long‐term BMD changes at both trabecular and cortical sites in Japanese pHPT patients with or without PTX.

methods  The subjects were 97 patients who had been followed up in Kobe University Hospital for at least 1 year up to 6 years with or without PTX. PTX was recommended to all patients whose pathological parathyroid gland(s) could be determined by image diagnosis. BMD was measured at the lumbar spine (L2–L4) and at distal one‐third of the radius (R1/3) by dual energy X‐ray absorptiometry (QDR2000). Serum levels of calcium, alkaline phosphatase and parathyroid hormone (PTH) were determined at the time of the BMD measurement.

results  Significant increases in any of the indices of BMD from the baseline values were observed within three months after PTX, followed by sustained increases over 6 years at L2–L4 even in postmenopausal women. Radial BMD also showed a marked increase six years after PTX. L2–L4 eventually reached the normal BMD but R1/3 did not. The percentage changes in L2–L4 were positively and significantly correlated with the preoperative PTH levels over the study period. However, the percentage changes in R1/3 showed a significant correlation with the preoperative PTH levels only 5 and 6 years after PTX. In the patients without PTX, no obvious changes in biochemical indices and BMD were observed over the six years.

conclusion  We demonstrated that PTX led to marked and sustained increases in BMD not only at L2–L4 but also at R1/3 in Japanese pHPT patients, including postmenopausal women. The preoperative PTH level could be a clinically useful index for predicting long‐term BMD changes after PTX.
Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy
Authors: Lanfranco Fabio , Zitzmann Michael , Simoni Manuela , Nieschlag Eberhard
Published: December 2004

objective  Adiponectin is an adipocyte‐specific secretory protein which exhibits antiatherogenic, anti‐inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy.

subjects and methods  In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean ± SEM: 36·5 ± 2·4 years; body mass index (BMI) 24·6 ± 0·8 kg/m2] and 29 weight‐matched eugonadal men (EM; age 30·8 ± 1·5 years; BMI 23·4 ± 0·6 kg/m2). In 13 HM (age 33·9 ± 3·2 years; BMI 24·2 ± 0·9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects.

results  Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4·4 ± 0·4 nmol/l, 78·4 ± 10·9 pmol/l and 36·1 ± 3·0 pmol/l, respectively, in HM vs. 21·9 ± 0·7 nmol/l, 507·9 ± 13·8 pmol/l and 65·2 ± 1·8 pmol/l, respectively, in EM, P < 0·0001), while SHBG levels in HM were higher than in EM (54·4 ± 7·5 vs. 30·9 ± 2·2 nmol/l, P < 0·005). Serum adiponectin levels in HM were significantly higher than in EM (9·53 ± 0·73 vs. 6·80 ± 0·55 µg/ml, P < 0·01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = −0·38, P < 0·05). Serum adiponectin levels were negatively correlated with body weight (r = −0·41, P < 0·05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6·37 ± 0·93 vs. 9·26 ± 1·01 µg/ml, P < 0·01) and similar to those recorded in EM.

conclusions  Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.
Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women
Authors: Godsland I. F. , Manassiev N. A. , Felton C. V. , Proudler A. J. , Crook D. , Whitehead M. I. , Stevenson J. C.
Published: December 2004

objective  Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes.

design  Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol‐17 beta with 5 or 10 mg/day dydrogesterone for days 17–28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol‐17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9).

measurements  Patients underwent measurement of glucose, insulin and C‐peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured.

results  In both groups there were significant reductions in fasting glucose, insulin and C‐peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P < 0·01). Insulin elimination was increased at both the peripheral (16% to 43%, P < 0·05) and hepatic (18% to 31%, P < 0·05) levels. Insulin sensitivity was unaffected. Low density lipoprotein (LDL) cholesterol was reduced and high density lipoprotein (HDL) cholesterol increased with treatment.

conclusions  Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause‐associated changes in insulin secretion and elimination.
Baseline characteristics and the effects of two years of growth hormone replacement therapy in adults with growth hormone deficiency previously treated for Cushing's disease
Authors: Johannsson Gudmundur , Sunnerhagen Katharina Stibrant , Svensson Johan
Published: December 2004

objective  To determine baseline characteristics and the effects of 2 years of GH replacement therapy on body composition, muscle strength, bone mass, and metabolic indices in GH‐deficient (GHD) adults previously treated for pituitary‐dependent Cushing's disease.

design  A single‐centre, open‐labelled, prospective study.

patients  Fifteen consecutive GHD adults previously treated for pituitary‐dependent Cushing's disease (CD group) and 15 closely matched GHD adults with previous nonfunctioning hypopituitary disease (NF group) were included. All patients had adult‐onset GH deficiency.

results  The mean dose of GH was similar in both study groups during the 2‐year treatment. At baseline, diastolic blood pressure was higher, and lumbar (L2–L4) bone mineral density (BMD) was lower, in the CD group than in the NF group. The increase in lean mass in response to GH therapy, as measured by dual‐energy X‐ray absorptiometry (DEXA), was less marked in the CD group. GH replacement therapy reduced diastolic blood pressure only in the CD group. The patients in the CD group had greater treatment response in lumbar (L2–L4) spine BMD and in isometric and isokinetic knee extension strength than the patients in the NF group. At study end, no difference remained between the two study groups.

conclusions  This study revealed differences in the baseline characteristics between GHD patients previously treated for Cushing's disease as compared with closely matched GHD patients with previous nonfunctioning hypopituitary disease. The 2‐year GH replacement therapy eliminated all the differences between the two study groups.