Cardiohemodynamic effect of FK409, a novel highly potent nitrovasodilator, in anesthetized dogs.

The cardiohemodynamic effect of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), a novel potent vasodilator, was studied in anesthetized open-chest dogs. FK409 (1 to 10 micrograms/kg, i.v.) decreased mean blood pressure, cardiac output and venous return (sum of the flow through the inferior and the superior vena cava). These changes accompanied decreases in left ventricular pressure, in its maximum rate of rise and in right atrial pressure. This cardiovascular profile of FK409 is very similar to those of classical nitrates.     

Central nervous system lesion in myotonic dystrophy--demonstrated by X-ray computed tomography and magnetic resonance imaging]

We made an attempt to detect organic brain lesions in eight patients with myotonic dystrophy (MyD) using X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The patients comprised seven men and one woman with ages ranging from 41 to 58 years (average 47 +/- 5.3 years). Seven patients had intellectual impairment assessed using an intelligence quotient test (WAIS-R < 70). CT scans were obtained in the axial plane with a slice thickness of 10 mm, and MRI scans were performed on a 1.5 tesla system in the axial and coronal sections with a slice thickness of 8 mm. CT scans displayed both marked sulcal and prominent ventricular enlargement in 6 of the 8 patients, indicating the presence of brain atrophy, and 3 cases had a few paraventricular low density area in the cerebral hemispheres. In contrast to CT, MRI study revealed more widespread brain parenchymatous lesions in all the 8 cases, showing the multiple foci of high signal intensity with varying size in the white matter on T2-weighted images and proton density-weighted images. No visible changes were detected on CT or MRI in the brain stem and cerebellum. The present study demonstrated that there exist organic cerebral lesions, predominantly located in the white matter in patients with MyD, regardless of focal neurological symptoms. The parenchymatous lesions in the brain can be detected with MRI, and lesser extent with CT, and are considered to be intimately correlated with intellectual deterioration commonly seen in patients with MyD.     

Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma.

We report the results of reduced-intensity unrelated cord blood transplantation (RI-UCBT) in patients with advanced malignant lymphoma. Twenty patients (median age, 46.5 years; range, 27-66 years) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2 , melphalan 80 mg/m 2 , and 4 Gy of total body irradiation. The median infused total cell dose was 2.75 x 10(7)/kg (range, 2.3-3.4 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Fifteen patients achieved primary neutrophil engraftment after a median of 20 days. Eight patients developed grade II to IV acute GVHD, and 2 developed chronic GVHD. Of the 16 patients with evaluable disease, 10 achieved a complete response. Primary disease recurred in 1 patient, and transplant-related mortality within 100 days occurred in 8 of 20 patients. The estimated 1-year probability of progression-free survival was 50%. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack an HLA-matched donor.     

Cell type-specific involvement of RIG-I in antiviral response

Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, was also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. We show by gene targeting that RIG-I is essential for induction of type I interferons (IFNs) after infection with RNA viruses in fibroblasts and conventional dendritic cells (DCs). RIG-I induces type I IFNs by activating IRF3 via IkappaB kinase-related kinases. In contrast, plasmacytoid DCs, which produce large amounts of IFN-alpha, use the TLR system rather than RIG-I for viral detection. Taken together, RIG-I and the TLR system exert antiviral responses in a cell type-specific manner.     

Aberrant B1 cell migration into the thymus results in activation of CD4 T cells through its potent antigen-presenting activity in the development of murine lupus

B1 cells have different origin and function from conventional B (B2) cells and are considered to be involved in autoantibody production in the development of autoimmune disease. We found that B1 cells preferentially accumulated in the target organs including thymus in aged BWF1 mice, a murine model for systemic lupus erythematosus, and that B lymphocyte chemoattractant (BLC/CXCL13) expression was increased in the thymus before the onset of lupus nephritis, while stromal cell-derived factor-1 (SDF-1/CXCL12) and secondary lymphoid tissue chemokine (SLC/CCL21) expression remained unchanged. Adhesion molecules such as peripheral node addressin (PNAd), ICAM-1, and VCAM-1 were also expressed on endothelial cells in the enlarged thymic perivascular space (PVS) in aged BWF1 mice. BLC protein and PNAd were co-localized on these high-endothelial-venules-like vessels in enlarged PVS. B1 cells expressed higher level of costimulatory molecules and showed a potent antigen-presenting activity in allogeneic mixed lymphocyte reaction comparable to splenic dendritic cells. Interestingly, B1 cells stimulated proliferation of autologous thymic CD4 T cells in the presence of IL-2. These results indicate that aberrant B1 cell trafficking into the thymus due to ectopic high expression of BLC may result in an activation of self-reactive T cells in the development of murine lupus.