Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis

Increased intracranial pressure (ICP) plays an important role in the morbidity and mortality of cryptococcal meningoencephalitis. The microbial and host factors that contribute to the development of increased ICP are poorly understood. We found that phenotypic switch variants of Cryptococcus neoformans (smooth and mucoid) differed in their abilities to promote increased ICP in a rat model of cryptococcal meningitis. Rats infected with the mucoid variant developed increased ICP, whereas rats infected with the smooth parent did not. This trend correlated with a shorter survival time and a higher cerebrospinal fluid (CSF) fungal burden for mucoid variant-infected rats, although brain fungal burdens were comparable between mucoid variant- and smooth parent-infected rats. Magnetic resonance imaging revealed enhanced T2 signal intensity over the surfaces of the brains of mucoid variant-infected rats. In addition, more polysaccharide accumulated in the CSF and brains of mucoid variant-infected rats. The accumulation of glucorunoxylomannan was associated with elevated levels of MCP-1 (CCL2) and, accordingly, a more pronounced but ineffective monocytic inflammatory response in the meninges of mucoid variant-infected rats. In summary, these findings suggest that strain-specific characteristics can influence the development of increased ICP and indicate a manner in which phenotypic switching could influence the outcome of a central nervous system infection.     

Demonstration of complex dysregulation of anti-cytomegalovirus T-cellular immunity in Kaposi's sarcoma following renal transplantation

An increased incidence of Kaposi's sarcoma is well known in renal transplant recipients in whom it may represent up to 3 p. 100 of all de novo tumours. This sarcoma has a close relationship with the potential oncogenicity of the cytomegalovirus (CMV) and with chronic immunological deficiency. Anti-CMV immunity is based on the integrity of cytotoxic cellular functions such as those of cytotoxic T lymphocytes (CTL), "natural killers" cells, and K cells which function in the antibody-dependent cell cytotoxicity (ADCC) system. Two cases of Kaposi's sarcoma were observed out of a total of 700 renal transplant recipients; they underwent the following investigations: lymphocyte sub-group counts by murine monoclonal antibodies, lymphocyte proliferation to lectins and allogenic cells, NK activity and generation of specific auxiliary and cytotoxic anti-CMV cells. Both cases of Kaposi's sarcoma were seropositive for CMV and seronegative for LAV. In one case, an abnormal number of peripheral OKT9 + lymphocytes (normally a thymocytic marker) was observed with small numbers of OKT4/OKT8, a reduced proliferative response to mitogens and allogenic cells. All these in vitro changes persisted despite reduction of immunosuppressive therapy and clinical improvement. A clinical and biological cure was only obtained after withdrawal of immunosuppressive therapy and return to haemodialysis. In the second case of Kaposi's sarcoma, the initial biochemical changes were minimal and a clinical cure was obtained by decreasing the immunosuppressive therapy. These two cases illustrate the complex dysregulation of the immune system in Kaposi's sarcoma.     

Induction of capsule growth in Cryptococcus neoformans by mammalian serum and CO(2)

The pathogenic fungus Cryptococcus neoformans has a polysaccharide capsule that is essential for virulence in vivo. Capsule size is known to increase during animal infection, and this phenomenon was recently associated with virulence. Although various conditions have been implicated in promoting capsule growth, including CO(2) concentration, osmolarity, and phenotypic switching, it is difficult to reproduce the capsule enlargement effect in the laboratory. In this study, we report that serum can induce capsule growth, and we describe the conditions that induce this effect, not only by serum but also by CO(2). Capsule enlargement was dependent on the medium used, and this determined whether the strain responded to serum or CO(2) efficiently. Serum was most effective in inducing capsule growth under nutrient-limited conditions. There was considerable variability between strains in their response to either serum or CO(2), with some strains requiring both stimuli. Sera from several animal sources were each highly efficient in inducing capsule growth. The cyclic AMP (cAMP) pathway and Ras1 were both necessary for serum-induced capsule growth. The lack of induction in the ras1 mutant was not complemented by exogenous cAMP, indicating that these pathways act in parallel. However, both cAMP and Ras1 were dispensable for inducing a partial capsule growth by CO(2), suggesting that multiple pathways participate in this process. The ability of serum to induce capsule growth suggests a mechanism for the capsular enlargement observed during animal infection.     

Comparing case-mix systems for nursing home payment

Case-mix systems for nursing homes use resident characteristics to predict the relative use of resources. Seven systems are compared in structure, accuracy in explaining resource use, group homogeneity, and ability to identify residents receiving heavy care. Resource utilization groups, version II (RUG-II), was almost uniformly the best system, although management minutes and the Minnesota case-mix system were also highly effective. Relative weights for case-mix groups were sensitive to cost differences and should be recomputed for new applications. Multiple criteria should be used in choosing a case-mix system, including consideration of inherent incentives and how residents' characteristics are defined.     

Reducing the need and demand for medical care: implications for quality management and outcome improvement

Reduction in medical need (illness burden) and demand (variability in resource use) can improve health, reduce medical care costs, and move us toward the goal of becoming a healthy society. Health promotion, redefined, works to enhance individual autonomy. The underlying conceptual bases and the abundant empiric documentation of the effectiveness of need and demand reduction are summarized here.     

Maximizing worksite survey response rates through community organization strategies and multiple contacts

BACKGROUND. Worksites are natural settings for health promotion. In many cases, the effectiveness of such interventions is appraised by surveying employees to assess worksite-wide changes in the targeted behavior. Little attention has been paid to increasing worksite survey response rates. One way is to utilize community organization strategies, which involve enlisting the individuals within a group to work together with researchers to affect the social environment. METHODS. Community organization strategies and multiple contacts were used to obtain responses from employees in five worksites involved in a smoking cessation project. Employee Advisory Board members in each worksite reviewed, adapted, and revised the survey distribution method, the messages that accompanied the survey, and the survey content. Three major survey waves were undertaken: a worksite effort, a home mailing (in the pilot worksite only), and a telephone call to nonrespondents. RESULTS. Response rates to a worksite-wide survey in one worksite the first year and four additional worksites the next year yielded 99.3% and 98.4% response rates, respectively. In the pilot worksite, 273 employees were eligible for the survey with 366 eligible employees in the four other worksites. Chi-square or analysis of variance computations were used, as appropriate, to test for differences in characteristics of respondents in the various data collection waves. DISCUSSION. These results suggest that there may be merit in adapting such community organization intervention methods for research applications.     

Health risk changes with a low-cost individualized health promotion program: effects at up to 30 months

BACKGROUND AND PURPOSE. Health promotion programs are increasingly important components of health care in an era of predominantly chronic illness preceded by identified health risk behaviors. We report a large and relatively long experience with a low-cost intervention delivered through the mail and using sequential time-oriented risk appraisal and personalized recommendations, each six months, together with self-management materials. METHODS. We performed a prospective, longitudinal, observational study of 103,937 consecutive program participants observed for at least six months and up to 30 months. The primary study endpoint is overall health risk score, with secondary analysis of individual risk behaviors. A concurrent comparison group utilizes the initial scores of new participants by calendar time over the study period. RESULTS. Strong overall positive effects were observed, with improvement in computed health risk scores over 18 months of 14.7% (p less than .0001) in those 65 and over and 18.4% (p<.0001) in those under 65. At 30 months, improvement was 18.8% (p less than .0001) and 25.7% (p less than .0001), respectively. There was improvement in self-report scores for all targeted health risk behaviors, except for pounds over ideal weight, including smoking; dietary fat, salt, and fiber; alcohol; exercise; cholesterol; and reported stress. There was progressive improvement approximating 5% each six-month period. Results were consistent across age groups 16-35, 36-50, 51-65, and over 65 and over different educational level. Results could not be accounted for by sequential changes in initial health habits of participants over time. DISCUSSION.(ABSTRACT TRUNCATED AT 250 WORDS)