Relationship between serum concentrations of interleukin-6 and tumor necrosis factor alpha in female Turkish subjects with normal and impaired glucose tolerance.

Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) concentrations were measured in subjects during two-hour glucose loading in order to investigate the effects of glucose on serum IL-6 and TNFalpha concentrations. Twenty-six female subjects (mean age 60 +/- 10 years) had normal glucose tolerance (NGT) and nineteen female subjects (mean age: 63 +/- 9 years) had impaired glucose tolerance (IGT) according to WHO criteria. Serum IL-6 and TNFalpha concentrations were measured by chemiluminescent immunometric assay. Subjects with IGT have higher fasting serum TNFalpha levels than subjects with NGT (p < 0.01). Serum IL-6 and TNFalpha concentrations were elevated during glucose loading (for each comparison, p < 0.01). The increase in serum TNFalpha concentrations in IGT was greater than in NGT (p < 0.01). Serum IL-6 and TNFalpha concentration significantly correlated with insulin and glucose in IGT group (for each comparison, p < 0.01). The correlation between serum glucose and cytokines concentrations was significant in IGT (for each comparison, p < 0.01). There was also a positive correlation between serum IL-6 and TNFalpha in NGT and IGT (for each comparison, p < 0.01). In conclusion, hyperglycemia is associated with increased circulating cytokine concentrations and fasting TNFalpha concentrations seem to be more associated with IGT than IL-6.

A new side stream process for easily degradable industrial waste waters to avoid sludge bulking.

A new treatment scheme for the treatment of easily biodegradable industrial waste waters has been developed. The side stream treatment of dairy waste water with the excess sludge from the domestic treatment line of the regional treatment plant Bad Vöslau has been operated successfully for a period of three years during which the industrial load stemming from the dairy increased from 800 kg COD/d to 2,500 kg COD/d with peak loads up to 5,000 kg/d. Despite of the increased load to the treatment plant the total aeration tank volume had not been increased. This treatment is performed in an existing aeration tank of the WWTP (V = 1,800 m3) which is now used as contact tank for the combined aeration of dairy waste water and excess sludge from the domestic treatment line (volume aeration tank = 15,000 m3). In this tank the easily degradable substrate from the industrial waste is mainly adsorbed to the biological sludge and after a mechanical dewatering transferred to the anaerobic digester where it yields in an increased gas production. The filtrate of the dewatering process is completely free from biodegradable material and can without danger of bulking be fed to the aeration tank of the domestic treatment line. The new process has proven to be extremely flexible since already now daily peak loads exceeding the design load by more then 60% could be treated in the plant without any problems. Compared to other alternatives for the dairy waste water treatment that were investigated during this study, the new side stream process is very advantageous. No other pre-treatment process for industrial waste water could have been operated under comparable loading conditions without severe operating problems.

Application of neurosonography to experimental physiology.

When Horsley and Clark invented the stereotaxic technique they revolutionized experimental neurobiology. For the first time it became possible to repeatably place experimental or surgical probes at precise locations within the skull. Unfortunately, variations in the position and size of neuroanatomical structures within the cranium have always limited the efficiency of this technology. Recent advances in diagnostic medical ultrasonography, however, allow for the real-time visualization of anatomical structures, in some cases with resolutions of up to 150 microm. We report here that commercially available ultrasonographs can be used in the laboratory to generate real-time in vivo images of brain structures in both anesthetized and awake-behaving animals. We found that ultrasonic imaging is compatible with many types of experimental probes including single neuron recording electrodes, microinjection pipettes, and electrodes for producing electrolytic lesions. Ultrasonic imaging can be used to place, monitor and visualize these probes in vivo. In our hands, commercially available ultrasonic probes designed for pediatric use allowed us to visualize anatomical structures with sub-millimeter resolution in primate brains. Finally, ultrasonic imaging allowed us to reduce the risk of accidentally damaging major blood vessels, greatly reducing the incidence of stroke as an unintended complication of an experimental neurosurgical procedure. Diagnostic ultrasound holds the promise of reducing the uncertainty associated with stereotaxic surgery, an improvement which would significantly improve the efficiency of many neurobiological investigations, reducing the number of animal subjects employed in this research. While this demonstration focuses on sonographic imaging in non-human primates, similar advances should also be possible for studies in other species, including rodents.

'No-show' for initial screening at a community mental health centre: rate, reasons and further help-seeking.

INTRODUCTION: The aim of this study was to investigate aspects of the phenomenon of 'no-show' for initial screening in a community mental health centre (CMHC). First, the 'no-show' rate was assessed and possible differences between the 'show' and 'no-show' populations were studied. The 'no-show' individuals were then approached to ask about their reasons for their no-show and about any subsequent help seeking. METHODS: Included in this study were all adults referred to the Maastricht CMHC between December 1995 and April 1997. The 'no-show' rate was assessed for the referrals in 1996. In May 1997 a brief questionnaire, concerning the 'no-show' reason and further help-seeking was sent to all 202 individuals who failed to keep the first appointment in the 15-month period. RESULTS: The 'no-show' rate in 1996 was 9.6% (165 out of 1716 individuals). The most prevalent reasons for 'no-show' were the waiting list, lack of motivation and resolution of the mental health problem. The presenting complaint was still present in 78.7% of the 'no-show' subjects. Most of them had received treatment from their GP, social worker or a private practice. Despite persistence of their problem, 29% didn't seek further treatment. An equal number of subjects solved their problem before the screening interview. CONCLUSIONS: The 'no-show' rate in this population was very low. Measures to reduce this rate (e.g. reducing the waiting list, sending appointment reminders) may be counterproductive as they can discourage successful active problem coping. Additionally, it is doubtful whether if these measures increase the show-rate of less motivated individuals.

Locating biologically active compounds in medium-sized heterogeneous datasets by topological autocorrelation vectors: dopamine and benzodiazepine agonists.

Electronic properties located on the atoms of a molecule such as partial atomic charges as well as electronegativity and polarizability values are encoded by an autocorrelation vector accounting for the constitution of a molecule. This encoding procedure is able to distinguish between compounds being dopamine agonists and those being benzodiazepine receptor agonists even after projection into a two-dimensional self-organizing network. The two types of compounds can still be distinguished if they are buried in a dataset of 8323 compounds of a chemical supplier catalog comprising a wide structural variety. The maps obtained by this sequence of events, calculation of empirical physicochemical effects, encoding in a topological autocorrelation vector, and projection by a self-organizing neural network, can thus be used for searching for structural similarity, and, in particular, for finding new lead structures with biological activity.

Pyridyl-substituted tetrahydrocyclopropa[a]naphthalenes: highly active and selective inhibitors of P450 arom.

The synthesis and biological evaluation of substituted exo-1-(4-pyridyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene s as inhibitors of estrogen biosynthesis is described [H (1); 4-OCH3 (2); 5-OCH3 (3); 6-OCH3 (4); 1-CH3, 6-OCH3 (5); 4-OCH3, 7-Br (6); 6-OCH3, 5-Br (7); 4-OH (8); 5-OH (9); 6-OH (10)]. The synthetic key step--the formation of the cyclopropyl ring--was accomplished using the conditions of a modified Wolff-Kishner reduction (N2H5OH/KOH; delta T) and yielded exclusively the exo-configurated diastereomers. The racemic compounds 1-10 showed an inhibition of human placental aromatase (P450 arom) exhibiting relative potencies (rp) from 3.7 to 303 (compounds 8 and 4, respectively; rp of aminoglutethimide (AG) identical to 1, fadrozole = 359). The enantiomers of 4 and 7 were separated by LPLC on tribenzoyl cellulose and by crystallization of the diastereomeric tartrates (4). (1aS,2S,7bS)-(+)-4 (absolute configuration determined by X-ray crystallographic analysis) is the active P450 arom inhibiting enantiomer of 4 and shows a rp value of 617. Compound 4 is a reversible inhibitor showing a competitive type of inhibition and a type II difference spectrum. In vitro 4 influenced other steroidogenic P450 enzymes either not at all (bovine adrenal P450 scc) or only marginally (rat testicular P450 17, bovine adrenal P450 18). In ACTH-stimulated rat adrenal tissue, 4 was less active, inhibiting corticosterone and aldosterone formation compared to AG and fadrozole, respectively. In vivo 4 was not superior to AG as far as the inhibition of the uterotrophic activity of androstenedione (juvenile SD rats) and the reduction of the plasma estradiol concentration (pregnant mares' serum gonadotropin-primed SD rats) are concerned. Compound 4 shows marked antitumor activity in the dimethylbenzanthracene-induced mammary carcinoma of the SD rat: in the postmenopausal model it is at least as active as AG; in the premenopausal experiment it is clearly superior to AG. No induction of hepatic P450 enzymes was observed in the latter experiment. The rp value of 4 toward rat ovarian P450 arom, i.e., 23 (rp of AG identical to 1), is markedly decreased compared to the human enzyme (rp value of 303). From this fact it must be concluded that 4 should be more active in the human than in the rat.

Analysis of immunoassays to detect antibodies to hepatitis A virus (anti-HAV) and anti-HAV immunoglobulin M.

Two newly developed anti-HAV tests were assessed, using a total of 1835 sera. These two tests are being distributed under the trademarks Enzymun-Test anti-HAV and Enzymun-Test IgM anti-HAV. The anti-HAV test was compared to anti-HAV tests from other manufacturers and featured a high sensitivity combined with a high level of reproducibility and specificity. In terms of sensitivity, reproducibility and specificity, the IgM test proved to be comparable to other IgM anti-HAV tests used for the diagnosis of acute type A hepatitis. Combining both tests was shown to be useful to recognize an acute or past hepatitis A virus infection. In addition, the high sensitivity of the anti-HAV test makes this test extremely useful to assess the immunoresponse to the hepatitis A vaccine.

Aromatase inhibitors. Syntheses and structure-activity studies of novel pyridyl-substituted indanones, indans, and tetralins.

The (E)-2-(4-pyridylmethylene)-1-indanones(E)-1-(E)-5[(E)-1,H;(E)-2,4- OCH3; (E)-3,5-OCH3; (E)-4,4-OH;(E)-5,5-OH] were obtained by aldol condensation of the corresponding 1-indanones with 4-pyridinecarboxaldehyde, and in case of the OH compound (E)-4 subsequent ether cleavage of (E)-2. The synthesis of the (Z)-isomers (Z)-1-(Z)-3[(Z)-1,H;(Z)-2,4-OCH3; (Z)-3,5-OCH3] was accomplished by UV irradiation of the corresponding (E)-isomers. Catalytic hydrogenation of (E)-1-(E)-3 gave the 2-(4-pyridylmethyl)-1-indanones 6-8 (6, H; 7,4-OCH3; 8,5-OCH3). The 2-(4-pyridylmethyl)-substituted indans 11-13 (11,H; 12,4-OCH3; 13,5-OCH3) and the tetralins 16-19 (16,H;17,5-OCH3;18,6-OCH3;19,7-OCH3) were obtained by reduction of the corresponding ketones using N2H4/KOH. The 2-(4-pyridylmethyl)-substituted indanones 9 (4-OH) and 10 (5-OH), indans 14 (4-OH) and 15 (5-OH), and tetralins 20-22 (20,5-OH; 21,6-OH; 22,7-OH) were synthesized by ether cleavage of the corresponding OCH3 compounds. All compounds showed inhibition of human placental aromatase exhibiting relative potencies from 0.9 [(E)-4] to 163 [18; aminoglutethimide (AG) potency identical to 1]. Compounds 13 and 18 showed competitive type of inhibition and a type II difference spectrum, indicating the interaction of the pyridyl-N with the central Fe(III) ion of the cytochrome P450 heme component.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis of human immunodeficiency virus (HIV) infection: multicenter evaluation of a newly developed anti-HIV 1 and 2 enzyme immunoassay.

A new anti-human immunodeficiency virus type 1 and 2 (anti-HIV 1 and 2) test is described. It uses recombinant p24 and peptides covering gp32, gp41, and gp120 to identify HIV-1 and HIV-2 infections. This test has been shown to be specific (99.5%) and sensitive (99.8%). In this respect, the assay was equal or superior to anti-HIV 1 and 2 tests run as references. The test was able to discriminate sera from patients with HIV infections from those from uninfected individuals with excellence; it also exerted high intra- and interassay precisions. The "modular" concept of the test allows the use of single components (gp32 or gp41) to separate between HIV-2 and HIV-1 infections, respectively.

Boehringer Mannheim modular test concepts in HIV and hepatitis immunoassays.

Anti-HIV-antibody and hepatitis C virus (HCV)-antibody screening tests have to be able to detect a variety of virus antibodies. On the other hand, HIV-antigen specific antibody tests that detect only one kind of antibody are needed for prognosis of disease or for distinguishing infection by different virus subtypes. Usually in an enzyme-linked immunosorbent assay for each individual test an individual solid phase has to be created. For our Boehringer Mannheim Enzymun-Test Diagnostics Assay we used a single universal biotin-binding solid phase in all tests and biotin-labeled specific antigens for the individual tests. The modular system for the antibody tests is a convenient tool for the development of a broad test menu for different viruses. We show that the modular system is suited for screening tests for HIV1, HIV2, or HCV antibodies, as as well as for virus typing or for detection of HIV/p24-specific antibodies in a quantitative assay with high precision.

[New inhibitors of aromatase: synthesis and biological activity of pyridyl-substituted phenanthrenone derivatives]. / Neue Hemmstoffe der Aromatase: Synthese und biologische Aktivität pyridyl-substituierter Phenanthrenonderivate.

The phenanthrenone derivatives 3-6 were synthesized and tested for their aromatase and desmolase inhibitory potency. Compounds 5 and 6 show a stronger inhibition of aromatase than aminoglutethimide not exceeding, however, the activity of the parent compounds 1 and 2. Compounds 4 and 5 do not inhibit desmolase.

[Pyridyl-substituted tetralone derivatives: a new class of nonsteroidal aromatase inhibitors]. / Pyridyl-substituierte Tetralonderivate: Eine neue Klasse nichtsteroidaler Aromatase-Inhibitoren.

Structural modification of flavone and flavanone, two weak inhibitors of aromatase, led to the new compounds 1-7, the syntheses of which are described as well as the evaluation of their aromatase and desmolase inhibitory potency. With the exception of 2 all compounds show a stronger inhibition of aromatase than the parent compounds and are more effective inhibitors than aminoglutethimide (AG), the only commercially available compound. In contrast to AG compounds 1 and 3-7 exhibit no desmolase inhibitory activity. In case of AG this effect leads to undesirable side effects.

New aromatase inhibitors. Synthesis and biological activity of pyridyl-substituted tetralone derivatives.

The (E)-2-(4-pyridylmethylene)-1-tetralones 1-7 (1, H; 2, 5-OCH3; 3, 6-OCH3; 4, 7-OCH3; 5, 5-OH; 6, 6-OH; 7, 7-OH) were obtained by aldol condensation of the corresponding 1-tetralones with 4-pyridinecarboxaldehyde, and in the case of the OH compounds 5 and 7 subsequent ether cleavage of the OCH3-substituted 2-(4-pyridylmethylene)-1-tetralones. Catalytic hydrogenation of 1-4 gave the 2-(4-pyridylmethyl)-1-tetralones 8-11 (8, H; 9, 5-OCH3; 10, 6-OCH3; 11, 7-OCH3). Subsequent ether cleavage of 9-11 led to the corresponding OH compounds 12-14 (12, 5-OH; 13, 6-OH; 14, 7-OH). The enantiomers of 11 and 12 were separated semipreparatively by HPLC on triacetylcellulose. All compounds (1-14) showed an inhibition of human placental aromatase exhibiting relative potencies from 2.2 to 213 [compounds 6 and (+)-12, respectively; aromatase inhibitory potency of aminoglutethimide (AG) = 1]. The compounds exhibited no or only a weak inhibition of desmolase [cholesterol side chain cleavage enzyme; maximum activity shown by 12, 23% inhibition (25 microM); AG, 53% inhibition (25 microM)]. In vivo, however, the compounds were not superior to AG as far as the reduction of the plasma estradiol concentration and the mammary carcinoma (MC) inhibiting properties are concerned (PMSG-primed SD rats as well as DMBA-induced MC of the SD rat, pre- and postmenopausal experiments, and the transplantable MXT-MC of the BD2F1 mouse). This is due to a fast decrease of the plasma E2 concentration inhibiting effect as could be shown by a kinetic experiment. In addition, select compounds inhibited rat ovarian aromatase much less than human placental aromatase (12, factor of 10). Estrogenic effects as a cause for the poor in vivo activity of the test compounds could be excluded, since they did not show affinity for the estrogen receptor.

Phosphorylation sites of the nicotinic acetylcholine receptor. A novel site detected in position delta S362.

The delta-subunit of the nicotinic acetylcholine receptor from Torpedo californica electric tissue isolated form receptor purified in the absence of protein phosphatase inhibitors contains a total of four phosphate groups. Three of these are shown to represent phosphoserine groups. The fourth possible represents phosphotyrosine. The phosphate groups are localized within the primary structure: We found phosphoserine in positions delta S361 and delta S377, the predicted sites phosphorylated by PKA and PKC, respectively. In addition, we found that position delta S362 is also phosphorylated. Phosphorylation experiments with the synthetic peptide delta L357-delta K368 show that phosphorylation of this novel site can be catalyzed by PKA and by PKC. It is concluded that the delat-subunit of the acetylcholine receptor is stably and not transiently phosphorylated. Implications for the physiological functions of receptor phosphorylation are discussed.

[Medical, moral, ethical and legal problems in modern obstetrics]. / Medizinische, moralisch-ethische und juristische Probleme in der modernen Geburtshilfe.

This paper addresses the problems which have arisen in connection with the improved intensive care of neonates and the possibility of prenatal diagnosis and therapy. Medical problems consist of difficulties in determining the indications. Ethical problems result from the right of decision of the pregnant woman, of her family and of the society beyond the normal physician-patient relationship and there are expert and legal questions, too. A more public evaluation of the patient material may lead to solution of the problems. Ethical and legal principles can be derived from these basic considerations. No new morals and ethics must evolve even if damage to the fetus or malformations can now be recognized antenatally instead of only postnatally as before. Malformations incompatible with life are indications for termination if the pregnant woman so desires. Every other type of malformation is something which the pregnant woman, her family and society must come to terms with. Prenatal medicine is able to soften the consequent burdens for the family and society.

Safety and long-term benefit of carotid endarterectomy in the asymptomatic patient.

In order to determine the safety and long-term salutary effects of carotid endarterectomy in the asymptomatic patient, we retrospectively reviewed all asymptomatic patients who underwent carotid endarterectomy from 1980 through 1986. There were 60 carotid endarterectomies performed in 54 patients, 53 men and one woman. The mean age was 64 years. Arteriography revealed a high grade stenosis of 70% or greater in 46 carotid arteries (77%), ulceration in five (8%), and both in nine (15%). Risk factors included coronary artery disease in 60% of patients, smoking in 87%, hypertension in 67%, and diabetes in 22%. Perioperative morbidity included three cranial nerve injuries, one myocardial infarction and one contralateral stroke. There were no deaths. Mean follow-up was 47 months with only two patients being lost to follow-up. During follow-up three patients suffered ipsilateral transient ischemic attacks without recurrent carotid stenosis and one patient had a transient ischemic attack secondary to contralateral carotid occlusion. There was one ipsilateral stroke occurring two years after operation secondary to restenosis that required reoperation and four late contralateral strokes. Ten patients died in the follow-up period. Causes of death were stroke (1), cardiac (4), malignancy (2), pulmonary (2), and unknown (1). All surviving patients were evaluated by duplex scan at a mean interval following surgery of 47 months. Restenosis of endarterectomized arteries was seen at the following rates: less than 50% in 41 (87%); 50-75% in four (8.5%); 80% in one (2%); and 90% in one (2%). Life table analysis revealed a 98% ipsilateral stroke-free rate at five and eight years.(ABSTRACT TRUNCATED AT 250 WORDS)

[Assessment of peripheral hemodynamics of the fetus using Doppler ultrasound]. / Die Einschätzung der peripheren Hämodynamik des Feten mittels Dopplerultraschall.

Analysis of foetal haemodynamics using Doppler ultrasound is widely applicable in obstetrics in assessing foetal well-being. To evaluate the parameters of foetal circulation we examined 205 pregnant women to ascertain normal velocity ranges of the foetal internal carotid artery and the foetal renal artery. By establishing the ratio between the pulsatility indices of the foetal internal carotid artery, the foetal aorta and the renal artery of the foetus, standards of these were obtained. From this it seems to be possible to gain information on the extent and degree of the centralisation of foetal blood circulation.