A venture capital view of challenges, opportunities, and innovation in biomedical research.

Small biotech companies have been an important source of innovation, pipelines, and new products for the pharmaceutical industry, and are primarily financed by venture capital (VC). The significant changes happening within the VC industry have broad implications for these small companies. This includes a shift to financing later-stage programs with increasing interest in orphan or specialty indications. Nontraditional sources of capital and innovative risk-sharing structures can enable early-stage companies.

Prostanoid modulation of synovial antigen-specific CD4+ T-cell cytotoxic function in rheumatoid arthritis.

The recent demonstration of cytolytic mediators within synovial CD4+ T-cells of patients with rheumatoid arthritis (RA) has suggested an additional role for these cells in the pathogenesis of the disease. In this study we have investigated the function and regulation of antigen-specific class II-restricted cytotoxic T-cells from the synovial fluid (SFMNC) and peripheral blood (PBMNC) of 20 seropositive RA patients, and correlated in vitro findings with clinical data. Regulatory factors including prostaglandin E2 (PGE2), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured in cell supernatants. A diversity in SFMNC antigen-specific cytotoxicity that correlated with therapy and PGE2 production was found, and shown to be mediated by synovial prostanoid (products of cyclooxygenase metabolism) inhibition of effector function. Our findings indicate that SFMNC cytotoxicity may be important in the pathogenesis and treatment of RA. Cyclooxygenase inhibition as the sole treatment early in RA may reduce the potentially beneficial inhibitory effect of synovial prostanoids on antigen-specific SFMNC cytotoxicity.

Reduced NK activity correlates with active disease in HIV- patients with multidrug-resistant pulmonary tuberculosis.

There has been a global increase in the incidence of multidrug-resistant pulmonary tuberculosis (TB). As there are no previous reports of immune function in HIV- patients with multidrug-resistant pulmonary TB, a comprehensive assessment of cellular immunity in this setting was undertaken. This involved a prospective, case-controlled study which included five patients with active multidrug-resistant pulmonary TB and five matched controls with active non-resistant infection, and documented the changes in immune parameters which occurred upon clinical resolution. Patients with multidrug-resistant TB had significantly lower fresh natural killer (NK) cell activity than matched controls with non-resistant pulmonary TB (P < 0.05). This was a specific abnormality, as there were no significant differences in antigen-specific cytotoxicity or lymphocyte proliferation in the case-controlled study. Follow-up assessment of the patients with multidrug-resistant infections indicated that clinical improvement correlated with a moderate increase in NK cell activity. Impaired NK cell function may be involved in the pathogenesis of multidrug-resistant TB.

Reduced natural killer cell activity in multi-drug resistant pulmonary tuberculosis.

Cellular immune status in five patients with multi-drug resistant pulmonary tuberculosis was investigated and compared with five matched controls with non-resistant tuberculosis. A significant reduction in fresh natural killer (NK)-cell activity was found in the resistant group (P less than 0.005). There were no significant differences between the two groups in lymphocyte phenotype, proliferation or PPD-specific cytotoxicity. Reduced NK-cell function may play a role in the pathogenesis of multi-drug resistant pulmonary tuberculosis.