Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

Objective. To measure, and seek clinical correlates with, levels of substance P (SP) in the cerebrospinal fluid (CSF) of fibromyalgia syndrome (FMS) patients.Methods. CSF from 32 FMS patients and 30 normal control subjects was tested for SP by radioimmunoassay . Clinical measures included tender point examination and standardized questionnaires.Results. CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001), but they correlated only weakly with tenderness found on examination. Concfusion. SP is significantly elevated in FMS CSF, but other abnormalities must exist in FMS to more fully explain the symptoms.Fibromyalgia syndrome (FMS) is a chronic, painful, musculoskeletal disorder commonly seen in rheumatology practice (14). Prevalence studies in Norway, Denmark, Germany, and South Africa have shown that 3-10% of the general population is affected, which would make FMS more common than rheumatoid arthritis (5). The comparison with rheumatoid arthritis is pertinent because the severity of the

In situ hybridization was used to localize and quantify gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Collagenase, tissue inhibitor of metalloproteinases (TIMP), HLA–DR, and complement (C2 and C3) gene expression was studied in synovial tissue from 23 patients with RA, OA, or other inflammatory arthropathies. Gene expression was highly compartmentalized: Collagenase, TIMP, and C2 messenger RNA (mRNA) were localized primarily to the synovial lining layer; HLA–DR mRNA was prominent in the lining and in some sublining lymphoid aggregates; the C3 probe hybridized only to sublining lymphoid aggregates. Relative mRNA levels were quantified using computer‐assisted image analysis. There was significantly more collagenase, C2, C3, and HLA–DR mRNA in RA compared with OA patients. However, TIMP mRNA levels were similar in RA and OA. Expression of collagenase, TIMP, C2, C3, and HLA–DR genes correlated with the degree of synovial inflammation. The effect of intraarticular corticosteroid injection on synovial tissue gene expression was studied using serial percutaneous synovial biopsy samples from the knees of 3 RA patients. Joints were biopsied, injected with triamcinolone, and rebiopsied 1–2 weeks later. Histologic inflammation scores were lower in posttreatment synovia. Collagenase and TIMP mRNA, although abundant in presteroid samples, were nearly undetectable in post‐steroid tissues. HLA–DR mRNA levels also were significantly decreased. C2 and C3 hybridization significantly decreased in 2 of 3 patients and 1 of 3 patients, respectively. Hence, clinical response to intraarticular steroid therapy was accompanied by histologic improvement and decreased expression of genes that play a role in articular destruction. This study demonstrates the power of quantitative in situ hybridization as a tool for studying drug efficacy and mechanism.

Two-dimensional (2-D) gel analysis was used to examine differences in the levels of 19 plasma proteins: before and after an acute inflammatory reaction (parenteral typhoid vaccination) in normal subjects, between rheumatoid arthritis (RA) patients and normals and in RA patients treated with tenidap (120 mg) and piroxicam (20 mg). Typhoid vaccination increased levels of SAA, haptoglobin alpha1, haptoglobin alpha2, haptoglobin beta and alpha1-anti-chymotrypsin but decreased transthyretin and apolipoprotein E. In RA patients, serum amyloid A (SAA), haptoglobin alpha2, haptoglobin beta, alpha1-antichymotrypsin and C3 proactivator levels were elevated while apolipoprotein A-I, apolipoprotein A-IV, transthyretin, Gc-globulin, alpha2-HS glycoprotein, alpha2-macroglobulin and alpha1-B glycoprotein levels were decreased, compared to normals. Compared to piroxicam, tenidap lowered levels of alpha1-antiprotease and SAA but raised the levels of transthyretin, Gc-globulin, alpha2-HS-glycoprotein and alpha2-macroglobulin in RA patients. C-reactive protein (CRP) could not be quantified on 2-D gels but, when measured by rate nephelometry, levels were reduced after treatment with tenidap compared to piroxicam. The general pattern of the acute phase protein response to an acute inflammatory response to typhoid vaccination is similar to that in the chronic inflammatory condition, RA. The impact of tenidap on both positive and negative acute-phase proteins in RA patients could clearly be distinguished from that of piroxicam.

Attempts to correlate developmental outcome with medical complications affecting the fetus and infant have focused on the prenatal, intrapartum, and postnatal periods. The time beyond the newborn stage has not been explored in detail. The aim of this study was to relate events occurring during the gestational and neonatal periods as well as the infancy periods to later performance by the use of four medical scales. A total of 126 preterm infants were followed up prospectively from birth to 2 years of age. Medical complications occurring during the prenatal, intrapartum, and postnatal periods as well as the first nine months of life were recovered. No relationship was found between obstetric and neonatal events and developmental outcome. Significant correlations were seen between medical events of later infancy and development at 2 years of age.

Translational medicine is the integrated application of innovative pharmacology tools, biomarkers, clinical methods, clinical technologies and study designs to improve disease understanding, confidence in human drug targets and increase confidence in drug candidates, understand the therapeutic index in humans, enhance cost-effective decision making in exploratory development and increase phase II success. Translational research is one of the most important activities of translational medicine as it supports predictions about probable drug activities across species and is especially important when compounds with unprecedented drug targets are brought to humans for the first time. Translational research has the potential to deliver many practical benefits for patients and justify the extensive investments placed by the private and public sector in biomedical research. Translational research encompasses a complexity of scientific, financial, ethical, regulatory, legislative and practical hurdles that need to be addressed at several levels to make the process efficient. Several have resisted the idea of supporting translational research because of its high costs and the fear that it may re-direct funds from other biomedical disciplines. Resistance also comes from those more familiar with traditional clinical research methods. In this review, we argue that translational research should be seen as enabled by ongoing efforts in basic and clinical research and not competing with them. Translational research provides the knowledge necessary to draw important conclusions from clinical testing regarding disease and the viability of novel drug mechanisms. Advancing translational research requires education and new sources of funding. This could be achieved through public and congressional education by a joint coalition of patients' advocacy groups, academia, drug regulatory agencies and industry.

Experimental medicine is the use of innovative measurements, models and designs in studying human subjects for establishing proof of mechanism and concept of new drugs, for exploring the potential for market differentiation for successful drug candidates, and for efficiently terminating the development of unsuccessful ones. Humans are the ultimate 'model' because of the uncertain validity and efficacy of novel targets and drug candidates that emerge from genomics, combinatorial chemistry and high-throughput screening and the use of poorly predictive preclinical models. The in-depth investigation of the effects of drugs and the nature of disease progression is becoming ever more feasible because of advances in clinical biomarkers.

Human monocytes and animal peritoneal macrophages have been demonstrated to produce various complement components including C2, C3, C4, and properdin factor B (1-3). Production of complement components by monocytes or macrophages is enhanced by prolonged culture on glass cover slips (1) and by phagocytosis of bacteria or bacterial products (2), factors that have been shown to activate macrophages by other criteria (4, 5). Activation of monocytes and macrophages, manifested by increased bactericidal or tumoricidal activity, inhibition of migration, and alterations in size and shape can also be induced by soluble mediators from antigen-stimulated lymphocytes (6). To determine whether or not lymphokine-mediated monocyte activation is associated with enhanced production of complement components, we studied the synthesis of C2 by monocytes co-cultured with lymphocytes with and without specific antigens and by monocytes cultured with lymphokine-rich supernates. We report here that monocytes cultured with lymphocytes in the presence of antigen produce hemolytically active C2 earlier and in larger amounts than do control cultures without antigen. Further, increased C2 production by adherent monocytes is mediated by a soluble substance present in lymphokine-rich supernates from antigen-stimulated cultures but not by supernates from unstimulated control cultures. Materials and MethodsCell Separations ana Cultures. Ficoll-separated peripheral blood mononuclear cells were obtained as previously described (7). These cells were washed three times with Hanks' balanced salt solution (HBSS, 1 Microbiological Associates, Bethesda, Md.) and resuspended in medium 199 (TC 199, Microbiological Associates) at 1 × 107 cells/ml. 2-ml cultures of mononuclear cells were performed in 15 × 100-ram round bottom screw cap culture tubes with 1 × 107 cells in 15% heatinactivated (56°C, 60 min) AB+ serum-TC 199. Either streptokinase-streptodornase antigen (dialyzed Varidase, Lederle Labs, Pearle River, N. Y.) at a final concentration of 50 U/ml or purified protein derivative antigen (kindly supplied by the U. S.-Japan Cooperative Science