Employment, attitudes toward work, and quality of life among people with schizophrenia in three countries.

This study examines attitudes toward work, work incentives, and the impact of work on quality of life for people with schizophrenia, and investigates whether these findings differ among Western countries. We interviewed 24 randomly selected subjects with schizophrenia and schizoaffective disorder (12 employed and 12 unemployed) at each of three sites: Boulder, Colorado, United States; Berlin, Germany; and Berne, Switzerland. No significant differences were found in the subjects' attitudes toward work or subjective well-being, although Swiss patients had a higher cost-of-living-adjusted income. Unemployed subjects reported a lower subjective reservation (minimum financially worthwhile) wage than employed subjects in Berlin and Berne, whereas the reverse was true in Boulder. When subjects from all sites were combined, employed patients displayed less psychopathology and significant advantages in terms of objective and subjective measures of income and well-being: They were also more likely to stress the importance of work. The results suggest that work is associated with a markedly better quality of life for people with schizophrenia, but that disability pension programs in the United States might introduce work disincentives.

Biocompatibility differences with respect to the dialyzer sterilization method.

The impact of the method of sterilization (steam vs. ethylene oxide, ETO) on indices of biocompatibility is investigated using polysulfone membranes. Eight patients were treated with a random choice of the high-flux membranes F60S (steam) and F60 (ETO) and the low-flux membrane F6 (ETO). Blood samples were taken prior to and 5, 15, 30, 60, and 180 min after the start of hemodialysis. White blood cell count, platelet count, and plasma concentrations of polymorphonuclear neutrophil elastase, complements C3a and C5a, and beta2-microglobulin were determined. The dialysis procedure was associated with a significant decrease in white blood cell count and beta2-microglobulin level and a significant increase in polymorphonuclear neutrophil elastase and complement C3a and C5a levels. However, the steam-sterilized F60S membrane had a significantly lower impact on the biocompatibility indices than the ETO-sterilized F60 and F6 membranes (p < 0.05 or p < 0.001 for the individual markers). We conclude that using steam instead of ETO for sterilization may improve the biocompatibility of membranes.

Epilepsy in a population of 6000 re-examined: secular trends in first attendance rates, prevalence, and prognosis.

It is important to document changes in the vital statistics of epilepsy in the general population so that the success or failure of prevention and treatment can be assessed and health provisions planned. A population of 6000 persons was studied 10 years apart to determine secular trends in the prevalence and prognosis of epilepsy. The lifetime prevalence of all patients with one or more afebrile seizures was 20.3/1000 (95% CI 16.9-24.3) in 1983 and 21.0/1000 (95% CI 17.6-25.1) in 1993. The prevalence of active epilepsy was 5.3/1000 (95% CI 3.6-7.5) in 1983 and 4.3 (95% CI 2.8-6.3) in 1993. To assess trends in incidence rates the annual first attendance rates were measured from 1964 to 1993. Annual first attendance rates in children (age < 20 years) have declined from 152.4/100,000 (90% CI 106.0-212.9) in the years 1974-83, to 60.9/100,000 (90% CI 33.0-103.3) in the years from 1984-93, suggesting that the incidence of epilepsy in children is falling. Also noteworthy was the first attendance rates for epilepsy in elderly people (61-80 years) in the years 1984-93, of 82.0 (90% CI 38.5-154.0), higher than in any other age group. This increase in the number of elderly patients with epilepsy is important, and has health planning implications, especially with the overall increase in the total elderly population. There was, however, no evidence that prognosis has significantly altered in the past 40 years.

Protein S degradation in vitro by neutrophil elastase.

Human protein S is degraded by neutrophil elastase. The characteristics of cleavage are compared in a purified protein S preparation, a concentrate of vitamin K-dependent proteins (PPSB) and in normal plasma as well as in alpha-proteinase inhibitor (alpha PI)- deficient plasma. Elastase incubation of purified human protein S (molar enzyme-to-substrate-ratio 1:5500-1:55) reduces the molar mass of the native protein S (81-83 kDa) to about 79 kDa by cleavage of a small peptide. Incubation with very high elastase concentrations (molar enzyme-to-substrate-ratio 1:5.5) completely degrades protein S into small fragments. The elastase incubated protein S has a higher isoelectric point than the native form (Ip 5.9 vs. 5.3). Protein S in a PPSB coagulation factor concentrate is degraded in the same way as isolated protein S. By immunoblotting also smaller split products of molar masses between 34 and 70 kDa are demonstrated. In normal plasma protein S is not degraded by elastase concentrations up to 14 mumol l-1. In plasma of a patient with alpha 1-proteinase inhibitor deficiency protein S can be degraded by elastase. The native 82 kDa protein is degraded to a 72 kDa protein. PEG precipitation of the protein S- C4b- binding protein-complex shows that elastase predominantly splits the free protein S.

Granulocyte-monocyte colony-stimulating factor levels during hemodialysis-induced leukopenia.

Hemodialysis (HD), especially with cellulosic membranes, leads regularly to a transient but marked drop of peripheral neutrophils. Such neutropenia during the initial 10-30 min of HD is followed by a reincrease in granulocyte count up to a mild leukocytosis. Although this phenomenon accounts for the best documented side effect of HD, little is known about the underlying regulatory mechanisms. Therefore in this study the blood levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured during HD. Previous investigations have demonstrated that GM-CSF plays the central role in controlling the homeoiostasis of leukocytes by up- and downregulation of proliferation and efflux of cells out of the maturation compartment within the bone marrow. Three patients with chronic renal failure underwent HD with cuprophane membranes. In all cases a significant drop of peripheral granulocytes occurred, but GM-CSF levels remained unchanged and were found in the normal range during the whole period of the treatment. It is therefore concluded that GM-CSF may not be significantly involved in the regulation of peripheral leukocytes during HD.

Stimulation of neutrophil functions by C5a(desArg): an in vitro model of haemodialysis.

Cuprophane membranes during haemodialysis significantly increase the plasma levels of C5a(desArg) (maximal 55 mug C5a(adesArg)/1 blood after 30 min) whereas Hemophane or Polysulphonemembranes induce only low plasma levels of C5a(desArg). C5a(desArg) generated in vitro by yeast incubation of autologous plasma stimulates PMN chemotaxis and oxidative metabolism but has no effect on enzyme release. Preincubation of whole blood with C5a(desArg) causes aggregation and changed oxidative burst activity of the isolated PMN. These changes are similar to those found in cells from patients after haemodialysis with cuprophane membranes. So the elevated plasma levels of C5a(desArg) after haemodialysis explain some of the changes in PMN functions, but additional mechanisms have to be assumed.

Regulation of neutrophil functions by elastase-generated IgG fragments.

IgG is split by neutrophil elastase into Fc and Fab fragments. These IgG fragments influence the functions of stimulated neutrophils such as chemotaxis, oxidative burst, and enzyme release. FMLP stimulated leukocyte chemotaxis is specifically inhibited by the elastase generated Fc fragments. Seven nmol Fc/10(6) PMN totally inhibit the chemotaxis stimulated by 16 to 125 nM FMLP. Native IgG and Fab fragments show no effect. FMLP-stimulated superoxide anion generation is specifically inhibited by Fc fragments with half maximal inhibition by 1.2 nmol/10(6) PMN. The generation of hydrogen peroxide is concomitantly stimulated, resulting in a superoxide dismutase-like effect. FMLP-stimulated elastase and myeloperoxidase release are enhanced by Fab fragments (10 nmol/10(6) PMN) to 206 and 155%, respectively, of reference values by 25 nM FMLP, while Fc and native IgG stimulate to a less extent. Consequently, elastase-generated Fc fragments have an inhibitory effect on inflammation by reducing chemotaxis and oxidative burst of stimulated neutrophils. The release stimulating activity of Fab fragments results in an up-regulation of elastase induced IgG degradation.

Protein C degradation in vitro by neutrophil elastase.

Purified protein C is completely degraded into small peptides by in vitro incubation with purified elastase. Protein C is a rather sensitive substrate as degradation is already accomplished by low elastase concentrations (molar enzyme-to-substrate ratio 1:510) and short incubation periods (5 min-60 min). Protein C in a PPSB coagulation factor concentrate is equally degraded and similar split products are detected by blotting techniques. The protein C activity (measured by a chromogenic substrate) is faster reduced by elastase than the protein C concentration (measured by an ELISA). Incubation of normal plasma with high elastase concentrations (5.7 nmol/ml plasma) results in reduction of the protein C band while no split products are detectable. The pathophysiologic significance of the effects of elastase on protein C remains to be elucidated.

Polymorphonuclear neutrophil chemiluminescence in periodontal disease.

The oxidative metabolism of polymorphonuclear leukocytes (PMNs) in rapidly progressive periodontitis (RPP, n = 19), localized juvenile periodontitis (LJP, n = 10), adults periodontitis (AP, n = 10) and healthy control subjects (HS, n = 39) was compared using the luminol chemiluminescence (CL) method. Possible influences of the isolation procedure on CL were circumvented by replacing starch with Haemaccell 35 as the sedimentation agent. In all groups, CL was significantly higher with autologous serum than with normal pooled serum (NPS) and there was a significant linear relationship between the two values. Comparisons of both pooled and autologous serum between patient groups and their matched controls were not statistically significant. There was a suggestion of serum-induced defects in 2 patients and 1 control. The range of individual values within each group was very heterogeneous, probably because of the many factors that are able to influence both the production of CL and the basal levels of CL observed.

Inhibition of neutrophil chemotaxis by elastase-generated IgG fragments.

IgG1 is cleaved in vitro by granulocyte elastase into Fc and Fab fragments. The elastase-specific Fc fragment has been previously detected in vivo. Biological activity of the fragments has been described in modulating neutrophil oxidative metabolism and enzyme release. To investigate further effects granulocyte chemotaxis (CT) was tested. The CT was assayed in Boyden chambers and the chemotactic index (CI) was calculated which represents the mean distance travelled by the activated cells. Stimulation of leucocyte CT by casein, activated serum and FMLP gives maximal values of delta CI = 46.7, 26.4 and 7.2 microns, respectively. Native IgG1 and the elastase-produced IgG fragments do not stimulate leucocyte CT. FMLP-stimulated CT is specifically inhibited by the elastase-produced Fc fragments. Addition of 7 nmol Fc to stimulus concentrations of 16 to 125 nM FMLP results in total inhibition of chemotaxis demonstrated by CI values which are lower than those for unstimulated cells. The inhibition of CT is concentration dependent in the range of 2 to 7 nmol Fc/10(6) PMN. Number and affinity of FMLP receptors are not influenced by Fc fragments, so Fc binds neither to FMLP nor the FMLP receptor. CT stimulated by casein shows a large portion of chemokinesis. Only at suboptimal casein concentrations do Fc and IgG have an inhibitory effect on CT (0.63 mg casein/ml, 10 nmol peptide/10(6) PMN). C5a-stimulated CT is not influenced by IgG or IgG fragments which indicates that the samples are not cytotoxic. So the FMLP and casein-stimulated CT is specifically inhibited by the elastase-produced Fc fragments in a low concentration range.

The role of membrane contact in hemodialysis-induced granulocyte activation.

Besides complement, interleukin-1 and beta 2-microglobulin, activation of granulocyte function has been found out to be the major parameter in the determination of dialyzer biocompatibility. Unfortunately, the term 'granulocyte activation' has been widely used without restriction to distinct functions or definition of the related metabolic pathways. Therefore, the present study aims to elucidate the influence of hemodialysis (HD) pure membrane contact on granulocyte O2- release. The activation of this metabolic pathway which is also known as the so-called oxidative burst has been generally accepted as the initial signal in the granulocyte inflammatory activation cascade. Two membranes which have been previously shown to differ most widely in biocompatibility, cuprophane and polysulfone, have been selected. During HD with cuprophane the stimulatable O2- release was initially decreased, whereas polysulfone HD was effectless on granulocyte oxidative metabolism. The inhibition was due to a prestimulation of the granulocyte by pure interaction of the cell with the surface of the dialyzer membrane which could be proved by evaluating a plasma-free model. Activation of oxidative metabolism was strongly correlated with granulocyte adherence, showing a significantly higher rate of cell adherence in the case of cuprophane. Nevertheless, sheer forces were able to prevent granulocytes becoming adherent directly to the dialyzer membrane, but sheer forces were not able to influence the oxidative burst reaction, suggesting that the membrane-related stimulation of oxidative metabolism occurs immediately after a very short, possibly a single and hasty contact of the cell to the surface of the dialyzer membrane.

High affinity binding of immunoglobulin G fragments to human polymorphonuclear leukocytes.

Human neutrophil elastase splits IgG into Fc, Fabc, and Fab fragments. The Fc and Fabc fragments bind with high affinity (KD 2.1 and 2.5 nM respectively) to a small number of binding sites (1175 and 1370 sites/cell respectively) on untreated human polymorphonuclear leukocytes. Molecular mass determination of the binding site by crosslinking of Fc fragments to the neutrophils followed by SDS electrophoresis yields one band corresponding to a molecular mass of 67 kDa for the binding site. Incubation of neutrophils with rIFN-gamma (50 ng/ml, 18 h, 37 degrees C) enhances the expression of binding sites by about 6 fold to about 14,500 sites/cell, while the binding affinity and the molecular mass of the ligand receptor complex remain constant. By comparison with known affinities of leukocyte Fc receptors it is concluded that IgG fragments bind to the high affinity FcRI receptor of human neutrophils.

Latent inhibition of granulocyte function by cyclosporine A.

According to the literature, Cyclosporine A (CsA) is said to suppress specifically the activity of T and B cells. A significant influence on phagocyte function has been neglected. However, aggravated courses of bacterial and fungal infections have been frequently reported under the treatment with CsA, suggesting that a latent depression of phagocytic activity may possibly occur under clinical circumstances. Therefore, this study set out to assess whether CsA can also change granulocyte function under therapy conditions or not. Thirty-seven patients, 3 months-10 years after kidney transplantation being under immunosuppressive treatment with CsA + Prednisolone (n = 25), Azathioprine + Prednisolone (n = 6) and under Prednisolone alone (n = 6) underwent the study. 18 healthy persons served as a normal control group. Granulocyte function was tested ex vivo by chemiluminescence (CL) after stimulation with phorbolmyristate acetate (PMA) and with zymosan (zym) activated autologous or pool-serum. The obtained data were correlated to corresponding serum or plasma levels of CsA, human leukocyte elastase (HLE) and neopterin. Comparing the three therapy groups with the healthy control and with each other no differences could be seen in median CL values; but there was a significant (p = 0.05) negative correlation between CsA blood levels and maximum CL values of PMN. Such inhibition of CL could be calculated for zym but not for PMA stimulated PMN; suggesting that the CsA mediated inhibition of granulocyte function may be only partial and restricted to phagocytosis. In addition, a positive correlation between serum levels of human leukocyte elastase (HLE) and neopterin could be found. This indicates a simultaneous influence of CsA on both PMN and macrophages.

Stimulation of neutrophil elastase and myeloperoxidase release by IgG fragments.

Human leucocyte elastase (HLE) cleaves IgG into Fab and Fc fragments. The Fc fragment bears an elastase-specific antigen and has previously been reported to be found in synovial fluid during rheumatoid arthritis. In addition, biological activity of elastase-specific Fc fragments has been described in modulating granulocyte oxidative metabolism. To investigate further regulatory effects of the elastase-induced IgG cleavage products, we tested the elastase and myeloperoxidase release of granulocytes. IgG fragments induce no enzyme release of unstimulated neutrophils. But elastase and myeloperoxidase release of cytochalasin b/FMLP-treated neutrophils is stimulated in a dose-dependent manner by the Fab fragments. The extent of stimulation depends on stimulus concentration and is at its maximum for low (e.g. 2.5 x 10(-8) M) FMLP concentration. Ten nanomoles Fab/4 x 10(6) PMN augment elastase release to 206% and myeloperoxidase release to 155% after pre-stimulation with 2.5 x 10(-8) M FMLP. Fc fragments stimulate elastase release to 162% but no MPO release. Untreated IgG1 and analog Fab and Fc fragments produced by papain cleavage react similarly. Elastase-generated IgG fragments may therefore up-regulate their concentration by simulating elastase release. The concomitantly stimulated release of myeloperoxidase may influence bactericidal activity and termination of oxidative burst.

Inhibition of neutrophil oxidative burst by elastase-generated IgG fragments.

IgG1 is cleaved in vitro by granulocyte elastase into Fc, Fab and Fabc fragments. The cleaved products have been isolated by a series of chromatographic procedures and characterized with regard to molecular mass and isoelectric point. The Fc fragment has been previously shown to express at its N-terminal site a neoantigen which is specific for elastase (Kolb, G., Eckle, I., Heidtmann, H.-H., Neurath, F. & Havemann, K. (1988) Scand. J. Rheumatol. S75, 179-189). The production of superoxide radical anions in prestimulated neutrophils is inhibited dose-dependently by the elastase-generated Fc and Fabc fragments. Native IgG1 and Fab fragments show no inhibitory effect, nor do papain-generated Fc fragments. The degree of inhibition depends on the stimulus applied: half-maximal inhibition is obtained by 6 microM Fc after stimulation with 4 beta-phorbol and 2.4 microM after stimulation with fMet-Leu-Phe; neutrophils stimulated with serum-activated zymosan are not inhibited by IgG fragments. The effect of Fc is purely cellular; no inhibition of O2 generation can be produced by applying Fc to the xanthine oxidase/xanthine system. The fragments have no effect on the activation or activity of crude NADPH oxidase, which is the O2-forming enzyme system of neutrophils. Possible mechanisms are discussed by which Fc acts on stimulated neutrophils.

Detection of granulocyte elastase specific IgG split products in rheumatoid synovial fluid.

In vitro granulocyte elastase is known to cleave a large number of substrates e.g. complement components, fibrinogen, collagen and IgG. In vivo the enzyme is rapidly complexed by the plasma inhibitors a1proteinase inhibitor (a1PI) and a2macroglobulin. Therefore in biological fluids elastase is measured as the inactive a1PI-complex. We present a radioimmunoassay for elastase specific IgG split products as marker for the elastase activity in vivo. Elastase splits human IgG1 in Fab and Fc fragments and low molecular weight peptides. We produced specific antibodies against the elastase induced Fc fragment by immunization with an elastase generated peptide. After purification of the antibodies there is no crossreactivity with native IgG nor with similar Fc fragments produced by plasmin or papain. The elastase specific IgG split products are detected in synovial fluid samples of patients with rheumatoid arthritis. The measured concentrations are higher in the RA group than in control groups of patients with other inflammatory joint diseases.

Neoantigenic group on Fc fragments in rheumatoid arthritis synovial fluids.

Expression of neoantigens during denaturation of IgG by oxygen radicals or proteolysis was assumed to be a possible mechanism for stimulation of rheumatoid factor (RF) formation and/or granulocyte dependent inflammative joint destruction. The so-called human leukocyte elastase (HLE) regularly released by stimulated neutrophils f.e. into the RA synovial fluid is known to split IgG in vitro into papain like fragments and low molecular weight peptides. The n-terminal site of the HLE related Fc is bearing a neoantigenic group which is located near the hinge region but not expressed by the native IgG. The neoantigen itself is represented by the low molecular weight peptides produced by prolonged HLE-IgG proteolysis. Detection of HLE generated Fc in synovial fluids was performed by radioimmunoassay specific for the neoantigen. Patients were divided into the three groups; I RA (n = 23), II inflammative joint effusions except RA (n = 23), III osteoarthritis and trauma (n = 19). The biological effect of the neoantigen on to granulocyte oxidative metabolism was tested by Cytochrome C reduction and chemiluminescence. Neoantigen bearing Fc could be detected in 15 of 23 cases of group I, in group II in 11 of 23 cases and only in 7 of 19 cases in group III. The median concentrations were 0.62 micrograms in group I and zero in II and III. The HLE derived Fc were able to inhibit the oxidative metabolism of activated granulocytes in vitro. The O2- production of stimulated granulocytes was depressed dose dependent by the neoantigen. The neoantigenic group itself does not react with RF as proved by nephelometric titration of HLE derived Fc, neoantigenic peptide and native IgG against a RF standard.