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The objective of this investigation was to show that the low nitrate bend in the redox potential curve is in fact the result of nitrite inhibition of oxygen uptake. The oxygen sensor used indicated traces of oxygen at the time of the observed low nitrate bend which supports the hypothesis. However, an oxygen sensor with a lower measuring range is needed in order to show conclusively that this hypothesis is true. At higher oxygen concentrations it was observed that nitrite inhibition of oxygen uptake had a marked effect on the appearance of both the oxygen concentration curve and the redox potential in activated sludge. Therefore a complete model of the redox potential in activated sludge must include nitrite inhibition of oxygen uptake. As part of the investigation, the response time of the redox electrode was found to be 5 times longer than the response time of the oxygen sensor. This indicates that the diffusion barrier between the bulk liquid in the sludge and the redox electrode surface is greater than the diffusion barrier of the oxygen sensor's membrane.

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Corrosion of concrete sewer pipes caused by hydrogen sulphide is a problem in many sewer networks. The mechanisms of production and fate of hydrogen sulphide in the sewer biofilms and wastewater as well as its release to the sewer atmosphere are largely understood. In contrast, the mechanisms of the uptake of hydrogen sulphide on the concrete surfaces and subsequent concrete corrosion are basically unknown. To shed light on these mechanisms, the uptake of hydrogen sulphide from a sewer gas phase was compared to the biological hydrogen sulphide removal potential of the concrete corrosion products. The results showed that both microbial degradation at and sorption to the concrete surfaces were important for the uptake of hydrogen sulphide on the concrete surfaces.

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The activity of hydrogen sulfide oxidizing bacteria within corroded concrete from a sewer manhole was investigated. The bacteria were exposed to hydrogen sulfide starvation for up till 18 months, upon which their hydrogen sulfide oxidizing activity was measured. It was tested whether the observed reduction in biological activity was caused by a biological lag phase or by decay of the bacteria. The results showed that the bacterial activity declined with approximately 40% pr. month during the first two months of hydrogen sulfide starvation. After 2-3 months of starvation, the activity stabilized. Even after 6 months of starvation, exposure to hydrogen sulfide for 6 hours a day on three successive days could restore the bacteriological activity to about 80% of the initial activity. After 12 months of starvation, the activity could, however, not be restored, and after 18 months the biological activity approached zero. The long-term survival aspect of concrete corroding bacteria has implications for predicting hydrogen sulfide corrosion in sewer systems subject to irregular hydrogen sulfide loadings, e.g. as they occur in temperate climates where hydrogen sulfide often is a summer-problem only.

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Treatment of lake inlets or lake sediments with aluminum (Al) is being increasingly used for lake restoration but only few studies exist concerning competitive substances that might influence phosphate (PO(4)(3-)) removal from lake water. Therefore, chemical interferences of several ions (magnesium, silicate, chloride and humic acid) on PO(4)(3-) adsorption to Al(OH)(3) were studied. Interference of each ion was studied in artificial lake water, and the complex interactions occurring in natural water were studied in water from 30 Danish lakes at pH 7 in both cases. In the artificial lake water Al:P ratio was high as sediment P-pools were the targets while in the natural lake water Al addition was generally lower as only P present in the water was targeted (i.e. inlet water). The single-ion experiments evidenced that silicate (>200 microM) and humic acids significantly decreased the effectiveness of PO(4)(3-) adsorption to Al(OH)(3) by 10-13% at 450 microM Si and 17% at 1 mM C, respectively. NaCl did not influence adsorption of PO(4)(3-) to Al(OH)(3), however, PO(4)(3-) removal was slightly reduced in seawater, mainly due to the presence of Mg(2+). The studies on interferences in natural lake water showed that as long as the PO(4)(3-) concentration was low (<5 microM), silicate competed with PO(4)(3-) for adsorption sites on Al(OH)(3) but at higher PO(4)(3-) concentrations, color and DOC (as indicators of HA) were the main variables decreasing PO(4)(3-) removal from lake water. Inhibition of PO(4)(3-) precipitation in natural lake water appeared complex and did not allow for a simple calculation of Al dose from the concentration of potentially competitive ions. Recommendation for lake management is therefore still that precipitation assays should be carried out for any type of inlet or lake water prior to Al application.

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BACKGROUND AND PURPOSE: Glycogen synthase kinase-3 (GSK-3) affects neuropathological events associated with Alzheimers disease (AD) such as hyperphosphorylation of the protein, tau. GSK-3beta expression, enzyme activity and tau phosphorylated at AD-relevant epitopes are elevated in juvenile rodent brains. Here, we assess five GSK-3beta inhibitors and lithium in lowering phosphorylated tau (p-tau) and GSK-3beta enzyme activity levels in 12-day old postnatal rats. EXPERIMENTAL APPROACH: Brain levels of inhibitors following treatment in vivo were optimized based on pharmacokinetic data. At optimal doses, p-tau (Ser(396)) levels in brain tissue was measured by immunoblotting and correlated with GSK-3beta enzyme activities in the same tissues. Effects of GSK inhibitors on p-tau, GSK-3beta activities and cell death were measured in a human neuronal cell line (LUHMES). KEY RESULTS: Lithium and CHIR98014 reduced tau phosphorylation (Ser(396)) in the cortex and hippocampus of postnatal rats, while Alsterpaullone and SB216763 were effective only in hippocampus. AR-A014418 and Indirubin-3'-monoxime were ineffective in either brain region. Inhibition of p-tau in brain required several-fold higher levels of GSK inhibitors than the IC(50) values obtained in recombinant or cell-based GSK-3beta enzyme activity assays. The inhibitory effect on GSK-3beta activity ex vivo correlated with protection against cell death and decrease of p-tau- in LUHMES cells, using low microM inhibitor concentrations. CONCLUSIONS AND IMPLICATIONS: Selective small-molecule inhibitors of GSK-3 reduce tau phosphorylation in vivo. These findings corroborate earlier suggestions that GSK-3beta may be an attractive target for disease-modification in AD and related conditions where tau phosphorylation is believed to contribute to disease pathogenesis.

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Alternative uses of pig manure are being considered, including separation and eventual incineration of the solid fraction to produce energy and ash. The efficiency of a screw press, a decanting centrifuge and chemical treatment in transferring N, P and heavy metals from slurry to a solid fraction were compared. Chemical treatment by coagulants and flocculants removed heavy metals most efficiently; they were transferred to the solid fraction in the order Zn > Cu > Cd by all three types of equipment. With centrifugation the heavy metal load on land where the solid fraction was applied was very low, whereas on land where the liquid fraction was applied it was only slightly less than that from un-separated manure. Conversely, chemical treatment resulted in a heavy metal load similar to that from un-separated manure with the solid fraction, while with the liquid fraction it was reduced to 20% of that from un-separated manure. Incineration of the solid fraction produces bottom ash and fly ash containing high levels of P. Most of the P and less than 10% of Cd is present in the bottom ash, producing an ash low in Cd content and a fly ash high in Cd. However, Cu and Ni tend to accumulate in the bottom ash. Chemical extraction procedures revealed that P-availability was high in all liquid and solid fractions except the bottom ash from incineration where approximately 80% of the P was transformed into a form of apatite. Since more bottom ash than fly ash is being formed, significant amounts of P may be immobilized by incineration of solid fractions.

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(RS)-2-Amino-3-(5-tert-butyl-3-hydroxy-4-isothiazolyl)propionic acid (thio-ATPA), a 3-isothiazolol analogue of (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), has previously been shown to be a relatively weak AMPA receptor agonist at native (S)-glutamic acid ((S)-Glu) receptors (EC(50)=14 microM), comparable in potency with ATPA (EC(50)=34 microM). Recent findings, that (S)-ATPA is a potent (EC(50)=0.48 microM) and selective agonist at homomerically expressed ionotropic GluR5, prompted us to resolve thio-ATPA using chiral chromatography and pharmacologically characterize the two enantiomers at native as well as cloned ionotropic glutamate receptors. The enantiomers, (S)- and (R)-thio-ATPA, were obtained in high enantiomeric excess, and their absolute stereochemistry established by an X-ray crystallographic analysis. Electrophysiologically, the two enantiomers were evaluated in the rat cortical wedge preparation, and the S-enantiomer was found to be an AMPA receptor agonist (EC(50)=8.7 microM) twice as potent as the racemate, whereas the R-enantiomer was devoid of activity. In accordance with this, (S)-thio-ATPA proved to be an agonist at homomerically expressed recombinant AMPA receptors (GluR1o, GluR3o, and GluR4o) with EC(50) values of 5, 32 and 20 microM, respectively, producing maximal steady state currents of 78--168% of those maximally evoked by kainic acid, and 120-1600% of those maximally evoked by (S)-ATPA. At homomerically expressed GluR5, (S)-thio-ATPA was found to be a potent agonist (EC(50)=0.10 microM), thus being approximately five times more potent than (S)-ATPA. (R)-Thio-ATPA induced saturating currents with an estimated EC(50) value of 10 microM, most likely due to a contamination with (S)-thio-ATPA. At heteromerically expressed GluR6+KA2 receptors, (S)-thio-ATPA showed relatively weak agonistic properties (EC(50)=4.9 microM). Thus, (S)-thio-ATPA has been shown to be a very potent agonist at GluR5, and may be a valuable tool for the investigation of desensitization properties of AMPA receptors.

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We have previously shown that (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (2-Me-Tet-AMPA) is a selective agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, markedly more potent than AMPA itself, whereas the isomeric compound 1-Me-Tet-AMPA is essentially inactive. We here report the enantiopharmacology of 2-Me-Tet-AMPA in radioligand binding and cortical wedge electrophysiological assay systems, and using cloned AMPA (GluR1-4) and kainic acid (KA) (GluR5, 6, and KA2) receptor subtypes expressed in Xenopus oocytes. 2-Me-Tet-AMPA was resolved using preparative chiral HPLC. Zwitterion (-)-2-Me-Tet-AMPA was assigned the (R)-configuration based on an X-ray crystallographic analysis supported by the elution order of (-)- and (+)-2-Me-Tet-AMPA using four different chiral HPLC columns and by circular dichroism spectra. None of the compounds tested showed detectable affinity for N-methyl-D-aspartic acid (NMDA) receptor sites, and (R)-2-Me-Tet-AMPA was essentially inactive in all of the test systems used. Whereas (S)-2-Me-Tet-AMPA showed low affinity (IC(50) = 11 microM) in the [(3)H]KA binding assay, it was significantly more potent (IC(50) = 0.009 microM) than AMPA (IC(50) = 0.039 microM) in the [(3)H]AMPA binding assay, and in agreement with these findings, (S)-2-Me-Tet-AMPA (EC(50) = 0.11 microM) was markedly more potent than AMPA (EC(50) = 3.5 microM) in the electrophysiological cortical wedge model. In contrast to AMPA, which showed comparable potencies (EC(50) = 1.3-3.5 microM) at receptors formed by the AMPA receptor subunits (GluR1-4) in Xenopus oocytes, more potent effects and a substantially higher degree of subunit selectivity were observed for (S)-2-Me-Tet-AMPA: GluR1o (EC(50) = 0.16 microM), GluR1o/GluR2i (EC(50) = 0.12 microM), GluR3o (EC(50) = 0.014 microM) and GluR4o (EC(50) = 0.009 microM). At the KA-preferring receptors GluR5 and GluR6/KA2, (S)-2-Me-Tet-AMPA showed much weaker agonist effects (EC(50) = 8.7 and 15.3 microM, respectively). It is concluded that (S)-2-Me-Tet-AMPA is a subunit-selective and highly potent AMPA receptor agonist and a potentially useful tool for studies of physiological AMPA receptor subtypes.

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C-reactive protein (CRP) is a reliable biochemical marker for tissue destruction, necrosis and inflammation. CRP is an essential human acute phase reactant produced in the liver as response to systemic stimuli. The biological half-life of CRP is not influenced by age, liver- or kidney function or pharmacotherapy. CRP values in acute bacterial infections have been appreciated for 70 years. The new standardized CRP analyses yield the possibilities of longitudinal monitoring of chronic inflammatory diseases and help identify complications. The more sensitive measures of the area of reference also supplies new information: As a prognostic marker for microvasculitis, CRP is at present re-writing the agenda for today's research in inflammation, angina pectoris, vascular insults and atherosclerosis.

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We present a case of a 52 year-old female treated with high dose chemotherapy for a malignant lymphoma. After a six month period on maintenance chemotherapy the patient developed a cytomegalovirus induced retinitis which was first suspected to be a lymphoma relapse. She went blind, despite treatment with ganciclovir.

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The clinical diagnoses and gross diagnoses of acute pulmonary infections were investigated for 100 consecutively performed hospital autopsies, and the diagnoses were compared with the histological findings. We found 34 cases of pneumonia and one case of tuberculosis. Of these, 29 infections represented principal diagnoses, i.e. as causative of or contributive towards death. The predictive values, the sensitivities and specificities were estimated. The predictive value for gross diagnostics was low with a value of 42.9% against 58.8% for clinical diagnostics. The sensitivities for both clinical diagnostics and gross diagnostics were about 30% and the specificities about 85%. The study shows that sampling for histology from all pulmonary lobes is essential for correct autopsy diagnoses, either from areas that appear to be infected on gross examination or from the peripheral parts. Furthermore autopsy performance is still of great value for clinical diagnostics and for medical statistics.

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The sensitivity, specificity and clinical accuracy of clinical diagnoses were determined and compared for two periods of time: 1.7.1980-30.6.1981 and 1.7.1990-30.6.1993 based on the analysis of 286 and 138 autopsies respectively. The autopsy rate decreased from 82.7% in the first period to 11.2% in the second. The first period shows a generally higher sensitivity and accuracy for positive diagnosis. Both periods reveal the lowest sensitivity for pulmonary embolism and the lowest accuracy for positive clinical diagnosis of pneumonia/bronchopneumonia. For malignancies and arteriosclerotic heart diseases significant discrepancy between the periods was demonstrated using the chi 2-test. The results are influenced by low autopsy rates causing fewer true-positive diagnoses and a declining sensitivity. This type of study is a useful tool for demonstrating changes in the diagnostic procedure. The present investigation demonstrates a need for further analysis of malignancies to explain the simultaneous decrease in sensitivity, specificity and accuracy in spite of an increasing number of malignancies in autopsy findings.

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We report the development of the first radioimmunoassay for YKL-40, a M(r) = 40 kDa protein which is secreted at high levels by human synovial cells and articular cartilage chondrocytes, and by the human osteosarcoma cell line MG63. This assay uses YKL-40 purified from the conditioned medium of MG63 cells as standard and tracer, and as antigen for immunizing rabbits. With this assay we have discovered high levels of YKL-40 antigen in serum and SF. The molecular weight of serum and SF YKL-40 is identical to purified YKL-40. To evaluate the possible utility of YKL-40 in the assessment of joint disease, we measured YKL-40 in serum and SF of 49 patients with various forms of inflammatory and degenerative joint disease and in the serum of 50 normal adults. The YKL-40 level in serum was significantly higher (P < 0.001) in the patients compared to the normal adults, but there was no difference in serum YKL-40 between the patients with inflammatory joint diseases and OA. The SF levels of YKL-40 were 15-fold higher than serum levels and there was a significant correlation (r = 0.55, P < 0.001) between YKL-40 concentration in SF and serum. Although the tissue distribution of YKL-40 secretion is presently unknown, these observations suggest that a major portion of serum YKL-40 in fact arises from the joint.(ABSTRACT TRUNCATED AT 250 WORDS)

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Activation of human monocytes in rheumatic disorders includes the production of substances active in immunologic interactions, inflammatory responses, and tissue remodelling. This review discusses the cell surface-related elastolytic activity of live human monocytes, as determined by a newly developed elastin assay. Elastase activity was not found to be depressed by patient treatment with glucocorticoids or slow-acting disease modifying drugs nor enhanced by phagocytosis, but was increased by immune complexes in vitro and in patients with rheumatoid arthritis or giant cell arteritis. The leucocyte elastase content seems to be influenced by systemic factors before the monocytes are released into the blood. The enzyme expression of elastase is determined by local factors acting after the cells have left the circulation. Monocyte expression may therefore be a link between immune activation and proteolytic activity.

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Elastolytic activity by live human monocytes (M phi) is mainly caused by cell surface related leucocyte elastase, capable of degrading matrix components. In order to examine the possible correlation between enzyme activity and tissue turnover in the joint, we examined 24 synovial fluids for M phi elastolytic activity, using the levels of synovial fluid interleukin-6 and serum C reactive protein as additional markers of cell activation. Proteoglycan levels were measured as an indication of cartilage degradation and the types I and III procollagen propeptides as markers of synovial membrane turnover. We found that elastolysis by live M phi and the levels of interleukin-6 and C reactive protein correlated significantly with proteoglycan concentrations but not with the procollagen propeptides. These findings suggest that human M phi elastolytic activation is a biologically relevant factor in cartilage degradation, but is unrelated to the collagen metabolism of the synovial membrane.

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Synovial fluid (SF) and blood from 24 patients with non-traumatic, sterile hydarthron were examined for monocyte elastolysis (MøE) and for levels of interleukin 6 (IL-6) and of soluble interleukin 2 receptor (sIL-2R). Six patients had osteoarthrosis (OA) and 18 patients had inflammatory hydarthron (IH), 10 of whom had rheumatoid arthritis (RA). Blood MøE was lower in OA than in IH, both measured as basal MøE activity and after in vitro stimulation with immune complexes and phorbol myristate acetate (PMA). SF MøE was higher than MøE in blood (p less than 0.01). This increase in SF MøE could be mimicked in vitro by prestimulation of blood Mø with low levels of IC. SF IL-6 and sIL-2R were also elevated (p less than 0.01). All three parameters correlated to the degree of joint inflammation evaluated by SF leucocyte level, complement activation, blood C Reactive Protein, and to the clinical evaluation of the joint. The increase in SF MøE, IL-6 and sIL-2R in patients with IH, points to a stimulation of Mø and lymphocytes in the joint.

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The leucocyte elastase of human blood monocytes was investigated by applying a new monoclonal antibody which did not block the enzyme activity against elastin. In a fixed population of mononuclear cells (MNC) and using fluorescence activated cell sorting (FACS), the human leucocyte elastase (HLE) antibody identified a subgroup of CD14+ cells which contained all the elastase activity and which could be blocked by a specific chloromethylketone elastase inhibitor. By anti-CD14 labelling the HLE positive cells were identified as monocytes and amounted to 88% of this cell type (median: range 72-96%). In a parallel study of patients with active rheumatoid arthritis (RA) and control donors the elastolytic capacity of PMA-stimulated live MNC was higher for RA patients than for controls (p less than 0.02). For control donors the number of HLE+ cells correlated well to the elastolysis in the same MNC sample (Spearman's rho:0.83, p less than 0.05); in the samples from RA patients no correlation was found between the normal number of HLE+ cells and the increased elastolysis (rho: 0.54, p greater than 0.20).

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Elastase from phagocytes are neutral proteolytic enzymes and potent destructors of elastic fibres, proteoglycan and collagen. Using soluble 3H-elastin as substrate in a cell culture assay we examined the ability of live, adherent human blood neutrophils and monocytes to release elastolytic activity following immune complex (IC) stimulation. While monocytes increased their elastolysis 2 1/2 times in response to IC (p less than 0.01), neutrophils did not but released lactoferrin and produced superoxide. Both cell types could be stimulated by phorbol myristate acetate (PMA) to increase elastolysis (p less than 0.02) and produce superoxide. Thus, when in contact with the elastin substrate, the in vitro response of monocytes and neutrophils to IC differed with respect to elastolytic release. These findings might be of interest in the understanding of cartilage destruction in immunocomplex-mediated diseases such as rheumatoid arthritis.

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The elastolytic capacity of live human blood monocytes was studied in patients with giant cell arteritis (GA) and in age-matched controls. Despite normalized acute-phase reactants during glucocorticoid (GC) therapy, the basic activity of monocytes from patients with newly diagnosed GA was elevated compared with controls (80 vs. 39 ng/h, p less than or equal to 0.01). The maximum response was enhanced by stimulation with immune complexes (224 vs. 125 ng/h, p less than or equal to 0.01) and with phorbol myristic acetate (324 vs. 214 ng/h, p less than or equal to 0.01). No age difference was found between healthy young and old people. Cell surface related human monocyte elastolytic activity could act as a sensitive marker of cell activation in vivo.

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