Pituitary function in patients with hereditary haemochromatosis.

Haemochromatosis may impair the function of endocrine organs, amongst others the pituitary gland. It was the aim of this study to determine pituitary function in adult patients with genetically defined hereditary haemochromatosis in a prospective diagnostic study using a standardised stimulation test. Therefore, 22 patients (7 females, 15 males; age at diagnosis of haemochromatosis 48.1 ± 7.9 years; age at study inclusion 50.7 ± 7.7 years) with genetically defined hereditary haemochromatosis were investigated by a combined pituitary stimulation test (CRH, GHRH/arginine, GnRH, TRH). In 11 patients (50% of the study population; 2 females, 9 males), pituitary insufficiencies were detected [isolated corticotrophic insufficiency (peak cortisol < 181.25 µg/l/500 nmol/l) n=10 (2 females, 8 males); combined corticotrophic and borderline gonadotrophic insufficiency (basal testosterone 2.4-3.0 µg/l without basal LH-elevation) in 1 male]. Somatotrophic pituitary insufficiencies were not found. IFG-1 concentrations below -2 standard deviations in 7 patients (32%) may be attributed to impaired hepatic IGF-1 synthesis. Hypopituitarism, particularly corticotrophic insufficiency, seems to be prevalent in a considerable number of middle-aged patients with hereditary haemochromatosis. Despite normal somatotrophic function, low IGF-1 serum concentrations may be found in a subgroup of haemochromatosis patients.

Vascular endothelial growth factor confers endothelial resistance to apoptosis through poly(ADP-ribose) polymerase.

BACKGROUND: Vascular endothelial growth factor (VEGF) inhibits the endothelial apoptosis that is induced by caspases during vascular remodeling; however, the underlying mechanisms have not been completely elucidated. OBJECTIVES: We hypothesized that VEGF upregulates poly(ADP-ribose) polymerase-1 (PARP) as a caspase mediator, and sought to investigate the link between apoptosis inhibition by VEGF and PARP regulation in the human vasculature. METHODS: Human endothelial cells (primary cells, macrovascular/microvascular lines) were incubated with 100 pg mL(-1) to 1 µg mL(-1) VEGF-A(165) in the absence or presence of PARP small interfering RNA (siRNA). Apoptosis induced by integrin inhibition was measured by flow cytometry, trypan blue exclusion, and nuclear morphology. PARP expression and activity were determined by real-time RT-PCR, Western blot, and ribosylation assay. VEGF receptors and signal transduction were analyzed by inhibitor experiments, enzyme assays, western blot, and immunofluorescence microscopy. Immunohistochemistry was applied to a vascular culture model and to 24 atherosclerotic and 10 normal human arteries. RESULTS: VEGF-A(165) induced resistance to apoptosis caused by caspase activation in endothelial cells in a time-dependent manner. VEGF, but not fibroblast growth factor-2 or transforming growth factor-ß, time-dependently and dose-dependently induced PARP expression and activity, involving VEGF receptor-2 colocalized with neuropilin-1 as well as the signal transduction molecules c-Jun N-terminal kinase and Akt. The antiapoptotic effect of VEGF was abrogated by PARP siRNA. The relationship between local VEGF influence and endothelial PARP expression was confirmed in human arteries and the vascular culture model. CONCLUSIONS: VEGF exerts its antiapoptotic effect on the endothelium through the regulation of PARP expression. PARP has been attributed an ambiguous role in apoptosis; here, we show that PARP promotes vascular endothelial integrity in VEGF-associated processes.

A case-control study of the relation between plasma selenium and asthma in European populations: a GAL2EN project.

BACKGROUND: There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. METHODS: The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. RESULTS: All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). CONCLUSION: This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.

Endothelin-1 and vasopressin plasma levels are not associated with the insertion/deletion polymorphism of the human angiotensin I-converting enzyme gene in patients with coronary artery disease.

The objective was to investigate whether the renin-angiotensin (RA) system and related peptides endothelin-1 (ET-1) and vasopressin (VP) influence the development of coronary artery disease (CAD). Angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism has been associated with the risk of CAD. The ACE I/D polymorphism determines ACE activity, but plasma levels of other RA system components remain unchanged. However, ET-1 and VP production could be increased by RA system-dependent stimulation, continually promoted by paracrine stimulation and sustained by neointimal growth. ET-1 and VP have not been associated with the ACE I/D polymorphism so far. The present study investigated the association of the ACE I/D polymorphism with plasma concentrations of ET-1 and VP, as well as with renin, angiotensin-II (AT-II) and ACE activity in 98 Caucasian individuals with CAD. ACE I/D polymorphism showed no association with plasma levels of VP, ET-1, AT-II or renin. These parameters were also not associated taking into consideration different patient variables, such as diabetes mellitus, hypertension or severity of CAD. Only plasma ACE activity was associated with the D allele. In conclusion, the ACE I/D polymorphism could not be related to plasma concentrations of VP, ET-1, renin or AT-II, but as previously demonstrated, it could only be related to ACE activity in patients with CAD. Differences in ACE activity between ACE I/D genotype subgroups are probably compensated within the RA system itself or within non-ACE pathways, so that plasma concentrations of the related peptides ET-1 and VP remain unaffected.

The insertion of the lesser and greater gastric omenta and its significance for the T classification of gastric carcinomas (UICC).

The problem of T classification of proximal gastric carcinomas is becoming increasingly important due to a rise in the incidence of these tumors. The aim of this study was to examine the gastric insertion of the lesser and greater omenta and its role in the T classification of gastric carcinomas. The stomach and greater and lesser omenta were removed from 76 fixed cadavers and 12 measurements each were done in defined localizations. The lesser omentum extended to the gastric wall in 98% of the cases. This junction as well as the omental thickness and thus the retroperitoneal part are especially pronounced in the cardiac region. According to the current UICC classification, even advanced tumors extending into the gastric wall can be classified T2 as long as they do not penetrate the visceral peritoneum. This results in "understaging" and a seemingly poorer prognosis for cardiac carcinomas. Our study results support the recommendation of Hermanek and Wittekind [5] to subdivide the T2 stage of gastric carcinomas on the basis of infiltration depth.

[Rate of complications with systematic exposure of the recurrent laryngeal nerve and parathyroid glands in operations for benign thyroid gland diseases]. / Die Komplikationsrate bei systematischer Darstellung des Nervus recurrens und der Epithelkörperchen für Operationen benigner Schilddrüsenerkrankungen.

OBJECTIVE: The influence of the operation technique on the complication rate of thyroid operations is still a subject of discussions. In this study, we analysed therefore the most important complications, i.e. palsy of the recurrent laryngeal nerve and hypoparathyroidism, specially under the aspect of routine exposition of the recurrent laryngeal nerve and parathyroids. METHODS: 116 patients with goiter operations of the year 1995 (12 different surgeons) were analysed. Age of patients was between 7 and 72 years, mean age 45 years. The operations performed were 70 subtotal resections (benign goiter), 33 near-total-resections (diffuse autonomy or Graves' disease), 33 hemithyroidectomies (scintigraphically "cold" nodules), 4 adenoma resections with combinations of these resections in 24 cases. RESULTS: 4.3% of the patients (5/116 patients) developed an unilateral recurrent nerve palsy immediately after operation. Persisting recurrent nerve palsy occurred only in 1.7% (2/116) of these cases. Postoperative nerve palsy was mainly found after extensive resections (2/33 near-total-resections) or operations of recurrent goiter (2/6 re-operations), rarely after routine operations (1/70 subtotal resections). Hypocalcemia was found in 9.5% of the patients (11/116), of which 9 cases were asymptomatic (7.8%) and 2 symptomatic by tetany (1.7%). Persisting hypocalcemia for longer than one week was found in 3.5% (4/116), permanent hypoparathyroidism in 1.7% (2/116) of the patients. CONCLUSIONS: Routine systematic exposure of recurrent laryngeal nerves and parathyroids reduces the incidence of complications in thyroid surgery to a minimum. The risk of recurrent nerve palsy increases with extent and difficulty of the operation, with the highest risk for nerve lesions seen in re-operations and near-total-resections.

Activity of acetylcholinesterase and unspecific cholinesterase during differentiation of somites in mouse embryos.

During the development of somites in mouse embryos, widespread activity of unspecific cholinesterase (BuChE) was demonstrated after prolonged incubation. Independent of their position, all somite cells and their derivatives (dermatome, myotome and sclerotome) exhibited enzyme activity in the perinuclear space and in the endoplasmic reticulum. The plasmalemma did not show any enzyme activity. Differentiation of the sclerotome into vertebrae was accompanied by a reduction of BuChE. However, a low enzyme reaction was still present in the first typical differentiated chondroblasts. Notochordal cells were detectable by their high BuChE content. This was also found in cells already showed severe degeneration. In addition to BuChE, acetylcholinesterase (AChE) was first visible of day 9 of embryonic development in newly formed myotubes of the myotomes. Some hypotheses on the functional significance of of embryonic BuChE are discussed in the light of these results.