Intra-articular tissue factor/factor VII complex induces chronic arthritis.

OBJECTIVE: Fibrin accumulation in the joint cavity is a common feature of chronic arthritides, such as rheumatoid arthritis (RA). Complex formation between tissue factor (TF) and factor VII (FVII) is the initial step in such a fibrin formation. METHODS: To assess the role of the TF/FVII complex in the pathogenesis of joint inflammation, 1) the levels of TF/FVII complex were measured in synovial fluid of RA patients; 2) the complex was injected to healthy mice intra-articularly. RESULTS: Morphological analysis of the joints 4 days after TF/FVII injection revealed influx of CD4-Mac1+ mononuclear leukocytes into synovial tissue followed by cartilage and bone destruction. Inflammation induced by TF/FVII complex was more profound than that caused by each of the proteins separately, both with respect to frequency, severity and duration of arthritis. Interaction between macrophages and lymphocytes in sustaining joint inflammation was proved by the requirement of the combined lymphocyte/ monocyte depletion to abolish TF/FVII induced arthritis. Induction of monocyte attracting chemokines (MIP-1 alpha and RANTES) was shown to be one of the potential mechanisms for TF/FVII complex triggered inflammatory cell influx. Interestingly, TF/FVII complexes were detected in synovial fluid of 20/40 patients with RA. CONCLUSIONS: Altogether these findings indicate that TF/FVII complexes, frequently found intra-articularly in joints of RA patients, may be an important component in both induction and progression of chronic destructive arthritis.

Service delivery and community: social capital, service systems integration, and outcomes among homeless persons with severe mental illness.

OBJECTIVES: This study evaluated the influence of features of community social environment and service system integration on service use, housing, and clinical outcomes among homeless people with serious mental illness. STUDY SETTING: A one-year observational outcome study was conducted of homeless people with serious mental illness at 18 sites. DATA SOURCES: Measures of community social environment (e.g., social capital) were based on local surveys and voting records. Housing affordability was assessed with housing survey data. Service system integration was assessed through interviews with key informants at each site to document interorganizational transactions. Standardized clinical measures were used to assess clinical and housing outcomes in face-to-face interviews. RESEARCH DESIGN: Structural equation modeling was used to determine the relationship between (1) characteristics of the social environment (social capital, housing affordability); (2) the level of integration of the service system for persons who are homeless in each community; (3) access to and use of services by individual clients; and (4) successful exit from homelessness or clinical improvement. PRINCIPAL FINDINGS: Social capital was associated with greater service systems integration, which was associated in turn with greater access to assistance from a public housing agency and to a greater probability of exiting from homelessness at 12 months. Housing affordability also predicted exit from homelessness. Neither environmental factors nor systems integration predicted outcomes for psychiatric problems, substance abuse, employment, physical health, or income support. CONCLUSION: Community social capital and service system integration are related through a series of direct and indirect pathways with better housing outcomes but not with superior clinical outcomes for homeless people with mental illness. Implications for designing improved service systems are discussed.

In vivo activity of amphotericin B lipid complex in immunocompromised mice against fluconazole-resistant or fluconazole-susceptible Candida tropicalis.

We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.

The influence exerted by a restricted phospholipid microenvironment on the expression of tissue factor activity at the cell plasma membrane surface.

Phosphatidylserine (PhtdSer) is an anionic aminophospholipid necessary for the development of optimal tissue factor (TF) activity at the cell surface. This study investigates the implication of a restricted lipid environment with respect to PhtdSer availability on TF expression and activity. K562 cells, showing a reduced ability to externalize PhtdSer, were transfected with human TF cDNA. PhtdSer exposure and TF activity were examined in transfected cells and compared to monocytic THP-1 cells expressing constitutive and inducible TF or megakaryocytic HEL cells showing a high PhtdSer externalization potency. TF expression was evidenced by flow cytometry and its activity measured using functional assays. PhtdSer exposure was monitored by enzymatic prothrombinase assay. One clone (DC9) expressed a stable amount of TF antigen without global modification of its membrane status. Despite a noticeable TF expression level, clone DC9 presented only a weak TF activity even after ionophore stimulation. The apparent Km, relative to factor X (FX) activation by TF-factor VIIa (FVIIa) complex, was 335 nM versus 70 nM for THP-1 cells. The velocity of the reaction was found 3-fold slower in DC9 than THP-1 cells. Ionophore treatment resulting in slightly enhanced amounts of available PhtdSer abolished this difference. The DC9 clone appears suitable for further investigations on the biology of TF expressed at the surface of cells where the contribution of PhtdSer is significantly attenuated. Such cells should enable further assessment of the role of TF as a receptor coupled to intracellular signaling pathways and its fate during apoptotic cell death.

Fungal resistance to plant antibiotics as a mechanism of pathogenesis.

Many plants produce low-molecular-weight compounds which inhibit the growth of phytopathogenic fungi in vitro. These compounds may be preformed inhibitors that are present constitutively in healthy plants (also known as phytoanticipins), or they may be synthesized in response to pathogen attack (phytoalexins). Successful pathogens must be able to circumvent or overcome these antifungal defenses, and this review focuses on the significance of fungal resistance to plant antibiotics as a mechanism of pathogenesis. There is increasing evidence that resistance of fungal pathogens to plant antibiotics can be important for pathogenicity, at least for some fungus-plant interactions. This evidence has emerged largely from studies of fungal degradative enzymes and also from experiments in which plants with altered levels of antifungal secondary metabolites were generated. Whereas the emphasis to date has been on degradative mechanisms of resistance of phytopathogenic fungi to antifungal secondary metabolites, in the future we are likely to see a rapid expansion in our knowledge of alternative mechanisms of resistance. These may include membrane efflux systems of the kind associated with multidrug resistance and innate resistance due to insensitivity of the target site. The manipulation of plant biosynthetic pathways to give altered antibiotic profiles will also be valuable in telling us more about the significance of antifungal secondary metabolites for plant defense and clearly has great potential for enhancing disease resistance for commercial purposes.

Service system integration, access to services, and housing outcomes in a program for homeless persons with severe mental illness.

OBJECTIVES: This study evaluated the hypothesis that greater integration and coordination between agencies within service systems is associated with greater accessibility of services and improved client housing outcomes. METHODS: As part of the Access to Community Care and Effective Services and Supports program, data were obtained on baseline client characteristics, service use, and 3-month and 12-month outcomes from 1832 clients seen at 18 sites during the first year of program operation. Data on interorganizational relationships were obtained from structured interviews with key informants from relevant organizations in each community (n = 32-82 at each site). RESULTS: Complete follow-up data were obtained from 1340 clients (73%). After control for baseline characteristics, service system integration was associated with superior housing outcomes at 12 months, and this relationship was mediated through greater access to housing agencies. CONCLUSIONS: Service system integration is related to improved access to housing services and better housing outcomes among homeless people with mental illness.

Efficacy of LY303366 against amphotericin B-susceptible and -resistant Aspergillus fumigatus in a murine model of invasive aspergillosis.

LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.

An empirical assessment of rural community support networks for individuals with severe mental disorders.

The community support network has been well-established as a requirement for community treatment of individuals with severe mental disorders. This network generally consists of a multidisciplinary set of organizations that interrelate in some manner with individuals in the community. The question of coordination within this network has been much discussed; however little published research has empirically examined the types and extent of coordination among network organizations. In particular, little attention has been given to community support networks in rural communities. In each of seven rural counties, information was obtained on inter-actions among organizations in the community support network. These networks were analyzed to yield information on network density and centralization. Using measures of centrality, the most central organizations in each network were identified. Exchanges of information were the most common type of interaction among organizations in each network. Client referrals occurred less frequently, and sharing of resources was an even rarer phenomenon. Network analysis of community support networks provides an objective perspective on the structure of community support networks. An understanding of exchange among organizations within these networks is of value to administrators, clinicians, and planners interested in achieving greater effectiveness, as well as to patients, their families, and advocacy groups concerned with access and quality of care.

Embracing change. The only thing you can count on in healthcare is that nothing will stay the same.

From more woes for managed-care firms to continued hospital mergers, particularly among not-for-profits, the staff of Modern Healthcare makes its predictions for the healthcare industry in the new year. And--which should come as no surprise to seasoned executives--1998 should turn out to be memorable, possibly invigorating and most certainly full of change.

Making the pieces fit. After assembling their care networks, systems' next big challenge is to build a unifying information infrastructure.

Five years into a manic pace of consolidation, hospital-based health delivery systems across the country are feeling the pressure to establish computer networks to unite all sites and services. In the campaign to lift healthcare out of an era of paper and pencil, organizations have spent freely on healthcare software applications. But computer pros say that's not enough.

Service system performance and integration: a baseline profile of the ACCESS demonstration sites. Access to Community Care and Effective Services and Supports.

OBJECTIVE: Networks of agencies at the 18 demonstration sites in the Access to Community Care and Effective Services and Supports (ACCESS) program for homeless persons with serious mental illness were surveyed to profile baseline levels of systems performance and integration as part of a longitudinal evaluation of systems change and client outcomes. METHODS: Interviews were conducted with a representative from each of 875 agencies in the 18 service networks. Information was obtained about the perceived performance of the service system and the extent of systems integration as measured by client referrals, funds exchanges, and information sharing between agencies. Measures consisted of two multi-item scales assessing the accessibility and coordination of services for the target population in each community and four indexes of interagency relationships. RESULTS: Services at baseline for homeless mentally ill persons at the program sites were rated as relatively inaccessible, and the coordination of services between agencies was rated as even more problematic. Interagency ties were largely based on client referrals and information exchanges, with very few instances of funding transfers in the form of contracts or grants. On average, at baseline agencies that had received an ACCESS grant were better connected to their local service network than were other agencies. CONCLUSIONS: Consistent with the premise of the ACCESS demonstration, services for persons who are homeless and mentally ill in urban America are fragmented and not very accessible. The longitudinal design of the evaluation will allow for an assessment of efforts to improve services and systems integration and of the effects of these improvements on client outcomes.

Outlook 1997. Batten down the hatches. Execs need to prepare for scrutiny of deals by citizens, regulators and the media.

Our reporters make their prognostications for a dozen major segments of the healthcare industry in 1997. A common thread runs through them: as mergers and consolidations continue to sweet through the industry, communities and regulators are becoming increasingly concerned about whether the public interest is being served. And, our reporters say, scrutiny of such deals is going to get even more intense.