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.     

Conserved tRNA gene cluster in starfish mitochondrial DNA

Summary Partial sequencing of mtDNA from four long-diverged species of starfish reveals the existence of a conserved cluster of 13 tRNA genes, organized in a manner similar to that of the tRNA cluster of sea urchin mtDNA, but located at a position distant from the presumed replication origin. These findings suggest that a clustered organization of tRNA genes may have been present in the ancestral mitochondrial genome, and raise the possibility that tRNAs may have catalyzed the dispersal rather than the accumulation of the genes which encode them.     

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.     

Tumor necrosis factor-alpha in the placenta is not elevated in pre-eclamptic patients despite its elevation in peripheral blood

PROBLEM: Tumor necrosis factor-alpha (TNF-alpha) is present in human placental and uterine cells at the early and late stages of gestation and promotes the regulation of trophoblast growth and invasion. We evaluated whether TNF-alpha levels in the placenta and blood of pre-eclamptic women differed from those with normal pregnancies. METHOD OF STUDY: The subjects were 39 pregnant women carrying single fetuses (21 normal-pregnant and 18 pre-eclamptic patients). Their average gestational age at entry was 38-39 weeks. Peripheral blood was collected before the onset of labor and separated serum was stored at -20 degrees C. A tissue segment of the placenta was cut and frozen in liquid nitrogen immediately after delivery at -80 degrees C. The frozen placental tissue was added to phosphate-buffered saline. The tissue was fully homogenized and centrifuged. Separated supernatant was stored at -80 degrees C. TNF-alpha levels in separated serum and TNF-alpha and total protein (TP) levels in separated supernatant were measured. The presence of TNF-alpha in the placenta was evaluated by immunohistochemistry in five pre-eclamptic and five normal-pregnant patients. RESULTS: Serum TNF-alpha levels were higher in pre-eclampsia than in normal pregnancies. However, TNF-alpha/TP levels in the placenta did not differ significantly between the two groups. As for TNF-alpha immunostaining of trophoblastic cells in the placenta, it was weak in three and moderate in two of the normal pregnancies, while it was absent in two, weak in one, and moderate in two in the pre-eclampsia group. CONCLUSIONS: We demonstrated no significant increase in TNF-alpha/TP levels in the placenta in pre-eclampsia despite a significant increase in serum TNF-alpha levels. There was no strong immunostaining for TNF-alpha detected by immunohistochemistry in the pre-eclampsia group. These findings suggest that TNF-alpha in the placenta is not a key cytokine to interfere with normal trophoblast invasion into the myometrium in pre-eclampsia, and that sources other than the placenta may contribute to the elevated levels of TNF-alpha found in the circulation of pre-eclamptic patients.     

Pulmonary hypertension due to tumor emboli: A report of three autopsy cases with morphological correlations to radiological findings

Three cases of pulmonary hypertension caused by tumor emboli to the lungs are described. Two of the three cases had a clinical diagnosis of pulmonary thromboembolism until surgical embolectomy, and the other had a diagnosis of primary pulmonary hypertension. Autopsy disclosed chondrosarcoma, choriocarcinoma and gastric cancer as the primary tumors, respectively. Pulmonary vascular obstruction due to tumor embolism leading to pulmonary hypertension is a previously rare clinical entity, and obstructed pulmonary vessels are believed to tend to be small vessels. We compared the autopsy and radiological findings and concluded that pulmonary tumor embolism involved not only the small peripheral arteries but also the segmental and/or lobar arteries.