The evolution of depression and suicidality in first episode psychosis.

OBJECTIVE: To have a clearer understanding of the ebb and flow of depression and suicidal thinking in the early phase of psychosis, whether these events are predictable and how they relate to the early course of psychotic symptoms. METHOD: Ninety-two patients with first episode psychosis (FEP) completed measures of depression, including prodromal depression, self-harm and duration of untreated psychosis. Follow-up took place over 12 months. RESULTS: Depression occurred in 80% of patients at one or more phases of FEP; a combination of depression and suicidal thinking was present in 63%. Depression in the prodromal phase was the most significant predictor of future depression and acts of self-harm. CONCLUSION: Depression early in the emergence of a psychosis is fundamental to the development of future depression and suicidal thinking. Efforts to predict and reduce depression and deliberate self-harm in psychosis may need to target this early phase to reduce later risk.

Radiation inactivation of ribonucleotide reductase, an enzyme with a stable free radical.

Herpes simplex virus ribonucleotide reductase (RR) is a tetrameric enzyme composed of two homodimers of large R1 and small R2 subunits with a tyrosyl free radical located on the small subunit. Irradiation of the holoenzyme yielded simple exponential decay curves and an estimated functional target size of 315 kDa. Western blot analysis of irradiated holoenzyme R1 and R2 yielded target sizes of 281 kDa and 57 kDa (approximately twice their expected size). Irradiation of free R1 and analysis by all methods yielded a single exponential decay with target sizes ranging from 128-153 kDa. For free R2, quantitation by enzyme activity and Western blot analyses yielded simple inactivation curves but considerably different target sizes of 223 kDa and 19 kDa, respectively; competition for radioligand binding in irradiated R2 subunits yielded two species, one with a target size of approximately 210 kDa and the other of approximately 20 kDa. These results are consistent with a model in which there is radiation energy transfer between the two monomers of both R1 and R2 only in the holoenzyme, a radiation-induced loss of free radical only in the isolated R2, and an alteration of the tertiary structure of R2.

Randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of AS-013, a prostaglandin E1 prodrug, in patients with intermittent claudication.

BACKGROUND: Intermittent claudication due to peripheral arterial occlusive disease (PAOD) is a common cause of pain and disability in the middle-aged. Clinical trials of the potent vasodilator prostaglandin E1 have been disappointing. This is the first report of a controlled clinical trial of AS-0:3, a novel prodrug of prostaglandin E1 incorporated into lipid microspheres that has been developed to improve delivery of the active compound to blood vessel walls. METHODS AND RESULTS: Eighty patients with stenosis or occlusion, symptoms of intermittent claudication, and maximum walking distance of > or = 30 and < or = 300 m on a standard treadmill test were randomized to placebo or one of three dosage regimens of AS-013. Drug was administered by intravenous injection 5 d/wk for 4 weeks. Treadmill tests and other assessments were completed at weeks 0, 4, and 8. A statistically significant increase in maximum walking distance was observed at 4 weeks (for placebo: median, 4.5 m; interquartile range [IQR], 20; for active treatment: median, 28.0 m; IQR, 81; P < .01, Mann-Whitney test). A similar response was seen at 8 weeks (for placebo; median, -11.2 m; IQR, 35; for active treatment: median, 35 m; IQR, 68; P < .01, Mann-Whitney test). Dose-related improvements in pain-free walking distance and quality of life were observed. No serious safety issues were noted. CONCLUSIONS: These promising clinical data indicate that AS-013, a new prodrug of prostaglandin E1, could provide an effective and acceptable treatment for patients with intermittent claudication. Studies to investigate the optimal dosing regimen, duration of clinical benefit, and effects in more severe forms of peripheral arterial disease are warranted.

Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process.

We investigated the nature of cytokines synthesized by human osteoarthritic (OA) synovium, particularly interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) to block the synthesis of metalloproteases (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthritis (OA) synovium. Human OA synovium were incubated in the presence or absence of lipopolysaccharide (LPS) or increasing concentrations of rhIL-1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-1ra in culture medium were carried out using specific ELISA. Although both IL-1 isoforms and TNF alpha could be produced by OA synovium, IL-1 beta was the predominant cytokine synthesized either in the presence or absence of LPS. Treatment of the OA synovium with an increasing concentration of rhIL-1ra (0-10 micrograms/ml) showed a dose dependent reduction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated synovium also showed a consistent suppression of metalloproteases and IL-6, although a higher IL-1ra concentration was required. Conversely, IL-1 beta production was not inhibited by IL-1ra, irrespective of the concentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine involved in the stimulation of metalloproteases and IL-6 synthesis in OA synovium.

Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis.

BACKGROUND: In an attempt to identify the factor(s) involved in the modulation of the degradative pathway of articular cartilage, we previously reported a possible imbalance between the levels of biologically active forms of metalloproteases and tissue inhibitor of metalloprotease (TIMP) in osteoarthritis (OA) cartilage. EXPERIMENTAL DESIGN: We extended our analysis on the protein level and the synthesis of stromelysin-1, collagenase, TIMP-1, and TIMP-2 in normal, OA, and RA cartilages, and provided information on the synthesis pattern of these proteins in respect to the action of interleukin-1 (IL-1). These protein concentrations were determined by specific sandwich EIA assays. RESULTS: This study allowed us to establish that the concentration of stromelysin-1 and collagenase is elevated in both OA and rheumatoid arthritis (RA) cartilages when compared with normal, with significantly higher levels of collagenase found in OA (p < 0.0003) and RA (p < 0.0001), and of stromelysin-1 in RA (p < 0.02). In all cases, the level of stromelysin-1 significantly exceeded (a few 100-fold) the collagenase level. The cartilage TIMP-1 level was notably enhanced only in RA, whereas TIMP-2 was increased in both OA and RA cartilage. RA patients with active disease had a higher level of metalloproteases and TIMP than those patients with inactive disease. Moreover, patients taking steroids alone or in combination with methotrexate had a markedly lower metalloprotease level without any changes in the TIMP-1 level. In culture cartilage explants, the synthesis of stromelysin-1 was enhanced in RA cartilage, whereas the level of collagenase was increased both in OA and RA explants. When compared with normal patients, the TIMP-1 synthesis was essentially unchanged in arthritic explants, whereas the level of TIMP-2 was decreased in RA explants when compared to OA. IL-1 induced a statistically significant increased synthesis of metalloproteases with the highest level found in arthritic explants. IL-1 also significantly decreased the TIMP-1 synthesis in OA and RA explants, and the TIMP-2 synthesis in OA. CONCLUSIONS: This study demonstrates that stromelysin-1 is the predominant metalloprotease synthesized in human articular cartilage and that both TIMP-1 and TIMP-2 are present in this tissue. The differential regulation of metalloprotease and TIMP syntheses by IL-1 suggests that this cytokine, during inflammatory conditions, may promote cartilage degradation by creating an imbalance between the level of these enzymes and their inhibitors.

Regulation of human normal and osteoarthritic chondrocyte interleukin-1 receptor by antirheumatic drugs.

OBJECTIVE: To determine the effect of antirheumatic drugs and corticosteroids on interleukin-1 receptor (IL-1R) levels in, and IL-1-stimulated metalloprotease synthesis and expression by, normal and osteoarthritic (OA) human articular chondrocytes. METHODS: IL-1R affinity and density of human chondrocytes were determined using radioligand binding experiments. Collagenase and stromelysin synthesis activities were analyzed by 14C-labeled type I collagen and Azocoll assays, respectively. Their messenger RNA (mRNA) levels were determined by Northern blot analysis. IL-1 alpha, IL-1 beta, IL-1 receptor antagonist, and beta 2-microglobulin were measured using enzyme-linked immunosorbent assays. Protein synthesis was determined by 3H-leucine incorporation. RESULTS: Antirheumatic drugs reduced the IL-1R level in normal and OA chondrocytes in a dose-dependent manner. In normal chondrocytes, tenidap reduced the IL-1R level by 44% at 5 micrograms/ml to 88% at 100 micrograms/ml (50% inhibition constant [IC50] 10.1 micrograms/ml), indomethacin reduced IL-1R by 6% at 1.5 micrograms/ml to 43% at 60 micrograms/ml, and naproxen reduced IL-1R by 10% at 10 micrograms/ml to 41% at 300 micrograms/ml; the effects observed with indomethacin and naproxen occurred only when the drugs were used at levels above their therapeutic concentrations. In OA chondrocytes, the effect of indomethacin and naproxen on the IL-1R level was greatly reduced, whereas tenidap still had a marked effect (IC50 22.5 micrograms/ml). Dexamethasone and hydrocortisone had no consistent effect on the IL-1R level. At a therapeutic concentration (20 micrograms/ml), tenidap was found to reduce the IL-1R level in a time-dependent manner, with maximum inhibition (98%) by 48 hours. Tenidap was also found to markedly reduce collagenase and stromelysin synthesis and mRNA levels in IL-1-stimulated chondrocytes. CONCLUSION: The suppressive effects of tenidap on IL-1-stimulated metalloprotease synthesis and expression in OA and normal chondrocytes are likely related to a decrease in IL-1R levels. At therapeutic concentrations, tenidap has a greater effect on the IL-1R level than is seen with indomethacin or naproxen, and glucocorticoids have no effect on IL-1R.

Cytokines and inflammation in cartilage degradation.

Since the discovery of humoral factors such as cytokines, which could modulate connective tissue metabolism, questions have arisen concerning their involvement in the pathophysiology of osteoarthritis. At least three cytokines, interleukin (IL-1), tumor necrosis factor, and interleukin-6, were identified in articular tissue and suggested to play a role during inflammation. Osteoarthritic chondrocytes have a higher sensitivity to stimulation by IL-1 with respect to metalloprotease production than normal chondrocytes that seem to be related to an increase in the level of IL-1 receptors. Natural antagonists capable of directly counteracting cytokine action on joint cells have been identified; however, their role in osteoarthritis remains to be determined, particularly in the context of their use for therapeutic intervention.

The synthesis of IL-1 receptor antagonist (IL-1ra) by synovial fibroblasts is markedly increased by the cytokines TNF-alpha and IL-1.

The regulation of inhibitors which block the action of IL-1 has significant implications in the control of inflammation. Different modulators of cellular metabolism were studied for their effect on the synthesis of IL-1 receptor antagonist (IL-1ra). Among the different growth factors and cytokines studied, only the inflammatory mediators IL-1 and TNF-alpha and one growth factor, PDGF-BB, were found to significantly increase, in an additive manner, the synthesis and secretion of IL-1ra.

The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function.

OBJECTIVE: To identify and investigate the kinetic binding properties of interleukin-1 receptors (IL-1R), and examine the abilities of the 2 IL-1 isoforms to stimulate metalloprotease synthesis, in normal and osteoarthritic (OA) chondrocytes. METHODS: Receptor affinity and density were determined using radioligand binding experiments and flow cytometry. Immunocytochemical analysis and affinity cross-linking studies were performed for characterization of IL-1R. RESULTS: While no difference in receptor affinity between normal and OA chondrocytes was noted in binding studies (Kd approximately 30 pM), a 2-fold increase in receptor density was found in OA chondrocytes as compared with normal chondrocytes (mean 4,069 sites/cell versus 2,315 sites/cell). Flow cytometry experiments also showed a significant increase in receptor density in OA cells, as well as an enhancement in the percentage of positive cells in diseased cartilage compared with normal. Binding data for both IL-1 isoforms revealed a single class of binding sites and receptor specificity. Factors such as IL-2, interferon-gamma, tumor necrosis factor alpha, and bovine insulin did not compete with IL-1 beta. By covalent ligand cross-linking and electrophoretic analysis, only type I IL-1R, a protein of 80 kd, was detected on chondrocytes. By immunocytochemical analysis, IL-1R was identified at the cell membrane level, in both normal and OA chondrocytes. The presence of nuclear staining was also observed, but only in OA chondrocytes. Recombinant human IL-1 (alpha and beta) induced the secretion of stromelysin and collagenase in a dose-dependent manner. The IL-1 concentration required for half-maximal metalloprotease stimulation was 3-4 times lower in OA chondrocytes than in normal cells. CONCLUSION: These results indicate that OA chondrocytes have a higher sensitivity to the stimulation of metalloprotease synthesis by IL-1 than do normal cells. This could be related to the increased levels of IL-1R expressed in the OA cells. The implications of these findings with regard to the possible roles of IL-1 and IL-1R in the pathogenesis of OA are discussed.

Effects of tiaprofenic acid on plasminogen activators and inhibitors in human OA and RA synovium.

The effect of therapeutic and pharmacological concentrations of tiaprofenic acid, a non-steroidal anti-inflammatory drug (NSAID), on the synthesis of the plasminogen activators, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), and the plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2), by human synovial membranes isolated from osteoarthritis (OA) and rheumatoid arthritis (RA) sufferers was evaluated. Both forms of plasminogen activator (PA) and PA inhibitor (PAI) were synthesized by the arthritic synovium. PAI-1 and PAI-2 were both synthesized in greater amounts than the plasminogen activators. Tiaprofenic acid induced a dose-dependent decrease in uPA synthesis in both OA and RA, particularly in OA synovium, but had no true effect on tPA. Tiaprofenic acid also exerted a suppressive effect on the synthesis of PAI-1 in both OA and RA synovial membranes, and on the release of PAI-2 in RA synovium. The results of this study indicate that a decrease in uPA synthesis may be one of the mechanisms by which tiaprofenic acid could exert its effects on the arthritic process. The suppressive action of tiaprofenic acid on PAI is not likely to have a significant impact on the balance of plasminogen activators and plasminogen activator inhibitors, as plasminogen activator inhibitors are synthesized in greater amounts than plasminogen activators.

Plasmin, plasminogen activators and inhibitor in human osteoarthritic cartilage.

Osteoarthritis (OA) is characterized by a progressive erosion of cartilage, which is mediated by the protease degradation of the extracellular matrix components. Plasmin, plasminogen activators (PA) and the inhibitor of plasminogen activator (PAI) are thought to play an important role in the regulation of the OA pathophysiology process. Our study determined the activity of plasmin and PA in OA and normal cartilage. Moreover, the presence and the content of each form of PA, uPA and tPA, as well as the inhibitor PAI-1, were determined using immunohistological techniques and ELISA. Our studies were carried out on fresh cartilage, cultured tissue explants and chondrocytes. OA cartilage demonstrates about 5 times more plasmin activity than the controls (p less than 0.001). Moreover, a statistically significant correlation was found between the plasmin activity and the free collagenolytic form in OA specimens showing severe lesions (r = 0.50; p less than 0.05). Our study revealed that PA content and activity increase in OA cartilage following culture explant experiments. Immunohistochemical studies showed the presence of both uPA and tPA forms in OA cartilage lesions only. Protein determinations revealed uPA as the predominant form. PAI-1 was significantly decreased (p less than 0.04) in OA, and was located mainly extracellularly. Chondrocyte cultures showed the ability to synthesize both forms of PA and PAI-1. Our study demonstrated an increased level of plasmin activity in OA cartilage. This is likely related to increased PA activity, in which the urokinase type appeared to be predominant in OA.(ABSTRACT TRUNCATED AT 250 WORDS)

Are cytokines involved in osteoarthritic pathophysiology?

The putative role and mechanism of action of cytokines in the progression of arthritic diseases such as osteoarthritis (OA) has received particular attention because of the important interaction between articular cartilage and synovium in the pathophysiology of the diseased state. Maintaining matrix homeostasis in the normal adult cartilage phenotype requires normal turnover of matrix components, principally collagen and proteoglycan. Chondrocytes and synovial fibroblasts are targeted, via specific cell-surface receptors, by cytokines like interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) to produce matrix proteases and to suppress the synthesis of collagen and proteoglycan. Thus, cytokines not only favor tissue destruction, but also inhibit tissue repair. A structurally heterogeneous group of factors capable of directly antagonizing cytokine action is described, which acts either by blocking cytokine-receptor binding, inhibiting local cytokine synthesis, or complexing the cytokine into an inactive form. Furthermore, many growth factors, such as transforming growth factor-beta (TGF-beta), can counteract the net effect of cytokines by stimulating the synthesis of matrix components or natural inhibitors of cartilage degrading enzymes.

Regulation of interleukin 1 receptors in human articular chondrocytes.

Interleukin 1 (IL-1) exerts pronounced effects on articular cartilage by increasing matrix molecule turnover and metalloprotease synthesis. These effects are believed to be mediated through a high affinity cell surface receptor (IL-1R) present on chondrocytes. Normal human chondrocytes express about 3,000-5,000 sites/cell. The downregulation of IL-1R could potentially reduce the biological effectiveness of IL-1 and as a result influence inflammatory conditions. Agents which modulate the number of IL-1R were investigated. Cytokines, such as IL-1 alpha (1 ng/ml) and IL-1 beta (1 ng/ml), were found to reduce the chondrocyte IL-1R level by about 78% versus the control. Other cytokines tested, IL-2 (20 ng/ml) and tumor necrosis factor-alpha (1 ng/ml), also reduced IL-1R levels but to a lesser extent; 52 and 69% inhibition were recorded, respectively. The growth factor bFGF (50 ng/ml) induced a 48% reduction versus the basal level, and a therapeutic dosage of indomethacin (1.5 micrograms/ml) elicited only a slight reduction (10%). Hydrocortisone had a variable effect on the IL-1R level.

Geriatric rehabilitation: a family practice approach.

Geriatric patients require rehabilitative measures that restore function and prevent further loss, with the goal of preserving independence. Assessment of functional ability and problems contributing to the disability (there are frequently more than one in elderly patients) help to make realistic goals for treatment. Functional scales provide rational evaluation of baseline status, progress made during treatment, and when remission has occurred.

HLA in two islands of French Polynesia.

The HLA-A, B, and C antigens of 243 individuals from two Polynesian islands, Maiao and Hiva Oa, have been characterized. 328 haplotypes were defined by family analysis. Most frequent antigens were A2, A11, Aw24, A26 , Aw34 ; Bw38, Bw39 , Bw48 , Bw55 , Bw56 , Bw60 ; Cwl, Cw3, and Cw4. Several other antigens were present at low frequency or were present on only one island. New variants of Bw22 and B40 were found. Despite an overall similarity in antigens of the two islands, the combination of HLA-A, B and C antigens on the haplotype were distinctive. Of 328 total haplotypes identified, 65 were unique. Thirteen of these (20%) were present on both islands. Twenty-eight (43%) were unique to Hiva Oa and 24 (37%) were unique to Maiao . Significant, positive linkage disequilibrium values (delta) for HLA-A, B and HLA-B, C antigens were also different for the two populations.

Some observations on viral hepatitis.

Epidemiologic patterns of viral hepatitis continue to change over time. Our understanding of its behavior began to change with the recognition that multiple distinct etiologic agents (hepatitis viruses A, B, and non-A/non-B) produce similar clinical syndromes and that there is a broad variability of age-related host response to infection with a given agent. Dorothy Horstmann was among the first to point to the relative mildness of symptoms in children and to the potential epidemiologic significance of such infections. Although hepatitis type A appears to be on a steady decline in overall national incidence, there is an increasing recognition of adult cases epidemiologically related to relatively mild or inapparent infections among infants and children attending day-care centers.

A validation procedure for air sampling-analysis systems.

Validation of solid sorbent air sampling-analytical systems used to evaluate employee exposures to substances in the work place air is a fundamental part of any industrial hygiene air sampling program. In April, 1977, the National Institute for Occupational Safety and Health (NIOSH) published "Documentation of the NIOSH Validation tests", as part of the Standards Completion Project. This paper presents an alternative validation procedure which is more easily understood, is more rigorous, and provides for greater accuracy and precision.

A randomized, double blind controlled trial of the efficacy of immune serum globulin for the prevention of post-transfusion hepatitis. A Veterans Administration cooperative study.

A double blind, randomized, controlled trial has been conducted in 11 Veterans Administration hospitals during a 49-month period to compare the relative efficacies of immune serum globulin (ISG) and an albumin placebo for the prevention of post-transfusion hepatitis (PTH). A total of 2204 patients, of whom 1094 received ISG, participated in the study. The results indicate that ISG significantly reduced the incidence of icteric type non-B hepatitis only (inferred to be also type non-A hepatitis). Adverse reactions were rare, and the ISG did not significantly alter the incubation period or duration of the disease. The data suggest, however, that a similar reduction in type non-A, non-B hepatitis would have occurred had commercial blood been excluded from use. Analysis of the 241 patients who developed hepatitis indicates that type B hepatitis constituted less than 20% of the cases each year of the study. Furthermore, the efficacy of the ISG, manufactured in 1944, against apparent type non-A, non-B hepatitis suggests that this overlooked disease has existed from at least that time. Host- and transfusion-related factors that might have modified the development of PTH were examined. The use of commercial blood was observed to be the most important risk factor. It is concluded that the PTH incidence can be most effectively reduced by eliminating commercial donor blood, and continuing to screen volunteer donors for hepatitis B surface antigen (HBsAg) by sensitive procedures. Of prime importance is the need to define the agent(s) responsible for type non-A, non-B hepatitis.