The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure.

The expression of the nuclear protein Ki-67 (pKi-67) is strictly correlated with cell proliferation. Because of this, anti-Ki-67 antibodies can be used as operational markers to estimate the growth fraction of human neoplasia in situ. For a variety of tumours, the assessment of pKi-67 expression has repeatedly been proven to be of prognostic value for survival and tumour recurrence, but no cellular function has yet been ascribed to the Ki-67 protein. This study shows that a C-terminal domain of pKi-67 (Kon21) is able to bind to all three members of the mammalian heterochromatin protein 1 (HP1) family in vitro and in vivo. This interaction can be manipulated in living cells, as evidenced by ectopic expression of GFP-tagged HP1 proteins in HeLa cells, which results in a dramatic relocalization of endogenous pKi-67. Taken together, the data presented in this study suggest a role for pKi-67 in the control of higher-order chromatin structure.     

Endothelin-like immunoreactivity in aqueous humor of patients with primary open-angle glaucoma and cataract

Background: Experimental evidence suggests a role of endothelin-1 (ET) in the regulation of intraocular pressure (IOP). Method: Therefore, inpatients undergoing cataract surgery, ET-like immunoreactivity (STIR) was measured by radioimmunoassay in pooled samples of aqueous humor of eyes with primary open-angle glaucoma (POAG) and normotensive eyes with cataract only. Results: ETIR was significantly (P < 0.05) higher in patients with cataract and POAG (20.5 ± 1.8 pg/ml,n = 12; preoperative IOP 21.4 ± I.1 mmHg,n = 33) than in patients with cataract only (15.8 ± 1.6 pg/m1,n = 15; preoperative IOP 16.0 ± 0.6 mmHg,n = 77). Conclusion: This finding may indicate a role of ET in POAG or ocular antihypertensive treatment, and its relevance should be further investigated.     

Asthma und asthmatypische Beschwerden bei Schulkindern: Vergleich von Gebieten in Deutschland und Osterreich

Conclusion

Geographical differences in morbidity of asthma and asthmalike complaints were ascertained and remained stable after adjustment for potential confounders. However, the choice of the way of presentation (relative risk versus deviation from the weighted mean of the prevalences) can provoke different suggestive effects.     

Hippocampal loss of the GABAA receptor α1 subunit in patients with chronic pharmacoresistant epilepsies

Alterations of gamma aminobutyric acid (GABA)-mediated neurotransmission have been implicated in the pathogenesis of epilepsies. Here we examine the distribution of the GABA_A receptor in the hippocampus of 78 surgical specimens from patients with chronic pharmacoresistant focal epilepsies. The receptor was localized immunohistochemically with the monoclonal antibody bd-24 which selectively recognizes the ₁ subunit of the GABA_A receptor. The results were compared with the receptor distribution of 28 normal hippocampal specimens obtained at autopsy. In the great majority of the surgical specimens a loss of GABA_A receptor immunoreactivity was present in CA1 (92.3%), CA4 (78.2%), the dentate granular cell layer (70.5%) and the molecular layer of the dentate gyrus (65.4%). The subiculum revealed a normal staining pattern in all but 4 cases. In no instance did we observe an increase of immunoreactivity in any region or cell population. The decrease of GABA_A receptor immunoreactivity was closely related to neuronal loss in the respective specimen and to Ammon's horn sclerosis. There was no correlation between GABA_A receptor loss and the patient's age at surgery, duration of seizures, age at onset of seizures and to the presence or absence of secondary generalized tonic clonic seizures. The data suggest that the observed loss of GABA_A receptor immunoreactivity is a secondary phenomenon rather than an event that is relevant for the pathogenesis of epileptic seizures.     

Intramedullary epidermoid cyst. A case report

The authors add to the literature a case report of a 32-year-old man with an intramedullary epidermoid cyst at the level of D 3/4, that was successfully operated on. There are several previous reports in the literature, but only five of these include MRI studies.     

Relation of dehydroepiandrosterone and dehydroepiandrosterone sulfate with cardiovascular disease risk factors in women: longitudinal results from the Massachusetts Women's Health Study

Low circulating levels of the adrenal steroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are thought to be associated with increased risk of cardiovascular disease (CVD) in men. In women, either a positive or null association with CVD has been found. The nature of the relation between DHEAS and CVD risk factors in women is unclear and is based on cross-sectional data. We present results from a longitudinal investigation of serum DHEA and DHEAS and cardiovascular disease risk factors in 236 women, initially 50-60 years old, from a population-based prospective (1986-1995) study of the menopausal transition. We used generalized estimating equations to model the relation of serum DHEA and DHEAS to systolic and diastolic blood pressure and serum levels of total cholesterol, high density lipoprotein cholesterol, and apolipoproteins A and B, adjusting for other factors related to CVD. Both DHEA and DHEAS were positively related to diastolic and systolic blood pressure, and DHEAS was negatively related to apolipoprotein A. DHEA and DHEAS were also positively related to smoking, alcohol use, estrone, and estradiol levels, and inversely related to age. Our results suggest that higher levels of DHEA and DHEAS in middle-aged women may indicate increased CVD risk.     

Striatal dopamine transporter density in major depression

Rationale: There are no previous data available regarding [¹²³I]β-CIT binding to the dopamine transporter sites in the basal ganglia in depressed patients. Objective: The present study tested the hypothesis that the brain DAT density in depressed patients is lower than that in matched healthy controls. Methods: Fifteen drug-naive outpatients with major depression and 18 healthy controls were investigated using single photon emission computerized tomography (SPECT) with a high-affinity dopamine transporter specific radioligand, ¹²³I-labeled β-CIT (2β-carbomethoxy-3β-(4-iodophenyl)-tropane). Results: We found a significantly higher [¹²³I]β-CIT uptake in both sides of the basal ganglia in patients with major depression than in the controls (Mann-Whitney U-test, P = 0.002 on the right and P = 0.003 on the left). Conclusions: The radioligand uptake reflecting the DAT density was significantly higher among the patients than in the controls. This finding is unexpected, since it is generally believed that monoaminergic neurotransmission is lower in depression, and therefore it could be assumed that a reduction in dopamine transmission would lead to secondary down-regulation of DAT density. However, it is possible that up-regulation of the DAT may be the primary alteration, which leads to lower intrasynaptic dopamine concentration and to lower dopamine neural transmission. Received: 20 October 1998/Final version: 25 January 1999     

SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain

Summary Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [¹²³I]-2--carbomethoxy-3--(4-iodophenyl)-tropane ([¹²³I]-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamusmidbrain area. Here, we report on the regional kinetic uptake of [¹²³I]-CIT in the brain of 4 normal volunteers and 2 patients with Parkinson's disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinson's disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only mildly diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinson's disease. Consequently, in Parkinson's disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [¹²³I]-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.     

Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man

Summary In vitro experiments were performed with cytosolic and microsomal fractions of human liver specimens in order to investigate which enzyme forms of sulfotransferase (ST) and UDP-glucurosyltransferase (GT) are involved in the metabolism of digitoxin (dt-3) and/or its cleavage products. It was found that the cytosolic STs preferentially react with digitoxigenin (dt-0) whereas microsomal GTs conjugate digitoxigenin-monodigitoxoside (dt-1) and in traces the bisdigitoxoside (dt-2). Dt-3 and dt-0 cannot be glucuronidated. By separation of different sulfotransferases it was found that the hydroxysteroid-ST is responsible for dt-0 and 3-epidigitoxigenin (epi-dt-0) sulfation. The hydroxysteroid-ST could be purified and characterized (apparent K_m and V_max for dt-0 sulfation: approx. 17 mol/l and 2.7 nmol/min mg protein, respectively). Of various model substrates and endogenous compounds (steroids, bilirubin) none caused a competitive inhibition of the microsomal dt-1 glucuronidation except dt-2 and dt-3. Therefore it can be supposed that a new GT form catalyses this reaction. It is characterized by an extraordinarily high affinity towards dt-1 with K_m values ranging between 0.7 and 27 mol/l.Abbreviations DHEA dehydroepiandrosterone - dg-0 digoxigenin - dg-1 digoxigenin-monodigitoxoside - dt-0 digitoxigenin - dt1 digitoxigenin-monodigitoxoside - dt-2 digitoxigenin-bisdigitoxoside - dt-3 digitoxigenin-trisdigitoxoside, digitoxin - epi-dt-0 3-epi-digitoxigenin - GT UDP-glucuronosyltransferase - PAPS 3-phosphoadenosine-5-phosphosulfate - ST sulfotransferase - UDPGA UDP-glucuronic acid Send offprint requests to A. Schmoldt at the above address     

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal -oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid -oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.