Modulation of noradrenaline release from the sympathetic nerves of human right atrial appendages by presynaptic EP3- and DP-receptors

Strips of human right atrial appendages were preincubated with [³H]noradrenaline and then superfused with physiological salt solution containing inhibitors of uptake₁ and uptake₂. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz). Prostaglandin E₂ (PGE₂) inhibited the electrically evoked tritium overflow; at the highest concentration investigated, tritium overflow was reduced by about 80% and the pIC_50% value was 7.14. The effect of PGE₂ was not affected by rauwolscine, which, by itself, increased the evoked overflow. Naproxen failed to affect the evoked tritium overflow and its inhibition by PGE₂. The inhibitory effect of PGE₂ on the electrically evoked tritium overflow was mimicked by prostaglandin E₁, the EP₁/EP₃-receptor agonist sulprostone and the EP₂/EP₃-receptor agonist misoprostol with the rank order of potency (pEC_50%): sulprostone (7.68) > misoprostol (7.10) > PGE₁ (6.39). In contrast, PGF_2α, the IP/EP₁-receptor agonist iloprost and the stable thromboxane A₂ analogue U46619 (9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F_2α) did not change evoked tritium overflow. PGD₂ caused facilitation. These results suggest that the sympathetic nerve fibres innervating human atrial appendages are endowed with presynaptic inhibitory EP₃ and facilitatory DP-receptors. The EP₃-receptors appear not to be tonically activated and do not interact with the α₂-autoreceptors. Received: 11 May 1998 / Accepted: 29 July 1998     

Cognitive impairment and depression in the oldest old in a German and in U.S. communities

Data on cognitive impairment in the oldest old is reported comparing two different samples, one in Munich, Germany, and the other in the United States (Epidemiologic Catchment Area [ECA] study). In both studies the Mini Mental State Examination (MMSE) was used for assessing cognitive impairment. The Munich sample consisted of 402 and the ECA sample of 827 very old people aged 85 years and above. The results indicate that approximately 40% of each sample scored below 24 points in the MMSE indicating at least mild cognitive impairment. Severe cognitive impairment was found in 13.4% of the Munich and in 14.6% of the American sample. The prevalence of major depression was 1.4% in Munich and 2.0% in the ECA study, and dysthymia was found in 5.1% in the Munich and in 2.0% in the ECA sample aged 85 years and above. Persons living in institutions in both studies more frequently showed signs of cognitive impairment than those living in private households. The ECA sample, but not the Munich sample, showed a significantly higher prevalence of cognitive impairment for females and for the oldest age cohort above 90 years of age. Major depression was more frequent in Munich in persons living in institutions and in the ECA study among the oldest age cohort above 90 years of age. Dysthymia in both studies did not show any association with sociodemographic factors. Most of the excess comorbidity (cognitive impairment and depression) was observed among subjects with mild (and not with severe) cognitive impairment. Very similar prevalence rates were generally found not only for MMSE-based cognitive impairment, but contrary to our expectations, also for major depressive disorder. Out data partially confirm a further increase in the prevalence of cognitive impairment in very old age.     

Purinergic substances promote murine keratinocyte proliferation and enhance impaired wound healing in mice

As membrane-bound receptors for adenosine, purines, and pyrimidines, purinoceptors are expressed in nearly all cell types throughout the mammalian organism. Previous studies showed that purinoceptors are involved in the regulation of proliferation and differentiation of most target cells. The present study was performed to elucidate their role in keratinocyte proliferation and wound healing. The expression of the mRNA of several adenosine and P2Y receptors was shown in the immortalized murine keratinocyte cell line MSC-P5 and primary cultured keratinocytes of four different mouse strains. The nonselective adenosine receptor agonist 5'-(N-ethyl)-carboxamidoadenosine enhanced the growth of MSC-P5 cells in vitro via the A2B receptor. The proliferative stimulus of adenosine triphosphate and uridine triphosphate on this cell line was mediated by the P2Y2 receptor. The mitogenic effect of the purinergic substances was inhibited by simultaneous treatment with respective antagonists. Studies in a mouse model of dexamethasone-induced impaired wound healing showed the in vivo efficacy of the purinoceptor agonists. These studies confirm that pharmacological actions via purinoceptors offer an intriguing possibility in the treatment of impaired wound healing. Nevertheless, further investigations are needed to elucidate fully the role of purinergic mechanisms involved in wound healing.     

Changing aspects of psychiatric inpatient treatment

This paper presents data obtained in a one-day census investigation in five European countries (Austria, Hungary, Romania, Slovakia, Slovenia). The census forms were filled in for 4191 psychiatric inpatients. Concerning legal status, 11.2% were hospitalised against their will (committed) and 21.4% were treated in a ward with locked doors. There was only a small correlation between commitment and treatment in a locked ward. More frequent than treatment of committed patients in locked wards was treatment of committed patients in open wards (Austria, Hungary) and treatment of voluntary patients in closed wards (Slovakia, Slovenia). Concerning employment, 27.7% of patients aged 18-60 held a job before admission. The vast majority of patients (84.8%) had a length of stay of less than 3 months. A comparison of these data with the results of a study performed in 1996 and using the same method shows a decrease of rates of long-stay patients. In 1996 the rates of employment were significantly higher in Romania (39.3%) and Slovakia (42.5%) compared to Austria (30.7%). These differences disappeared in 1999 due to decreasing rates of employment in Romania and Slovakia. The numbers of mental health personnel varies between types of institution (university or non-university) and countries, being highest in Austria and lowest in Romania. A considerable increase in the numbers of staff was found in Slovakia.     

Synthesis and Neuropeptide Y Y1 Receptor Antagonistic Activity of N,N-Disubstituted ω-Guanidino- and ω-Aminoalkanoic Acid Amides

Potent arpromidine-type histamine H₂ receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y₁ receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr³⁶ in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y₁ antagonists in human erythroleukemia (HEL) cells (Ca²⁺ assay) achieving pKB values in the range of 6.3–6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H₂ receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y₁ antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.     

Isoform of Fibronectin Mediates Bone Loss in Patients With Primary Biliary Cirrhosis by Suppressing Bone Formation

Osteoporosis is a major cause of morbidity and decreased quality of life in patients with chronic cholestatic liver disease. It is established that this osteoporosis results from decreased bone formation, but the mechanisms for the interaction between liver and bone remain elusive. The aim of this study was to test the hypothesis that an increase in the production of cellular fibronectins during liver disease may result in decreased osteoblast‐mediated mineralization and thus explain the decrease in bone formation. We performed a prospective cross‐sectional study in patients with primary biliary cirrhosis and matched controls, followed by experiments on human and mouse osteoblasts in culture and injections in mice in vivo. In patients with primary biliary cirrhosis, the oncofetal domain of fibronectin correlated significantly with the decrease in osteocalcin, a marker of bone formation (r = ?0.57, p < 0.05). In vitro, amniotic fluid fibronectin (aFN) containing mainly the oncofetal domain and EIIIA domain resulted in decreased osteoblast‐mediated mineralization in human osteoblasts (69% decrease at 100 μg/ml; p < 0.01) and mouse osteoblasts (71% decrease; p < 0.05). Removing the EIIIA domain from aFN similarly suppressed mineralization by osteoblasts (78% decrease; p < 0.05). Injection of labeled aFN in mice showed that it infiltrates the bone, and its administration over 10 days resulted in decreased trabecular BMD (17% drop; p < 0.05), mineralizing surface (30% drop; p < 0.005), and number of osteoblasts (45% drop; p < 0.05). Increased production of a fibronectin isoform containing the oncofetal domain and its release in the circulation in patients with primary biliary cirrhosis is at least partially responsible for the decrease in bone formation seen in these patients. This establishes that a molecule that has thus far been viewed as an extracellular matrix protein exerts hormone‐like actions.     

Transmission and scanning electron microscopy investigations on the structure of the ultrafilter of glomeruli in human acute renal failure

In 4 cases of human acute renal failure (ARF) with oligo-anuria, normuria and polyuria the following findings were made. (1) The diameter of endothelial cell fenestrae is on average larger than that of the control values, but not significantly. (2) In ARF the ratio of the endothelial cell fenestral area to the total endothelial area is not significantly lower than in control kidneys. (3) In ARF the average density of fenestrae per unit of area is not significantly lower than in control kidneys. (4) The structure of the podocytes does not differ from that of control kidneys.