Genetic analysis of adult leukoencephalopathy patients using a custom-designed gene panel.

Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.

Synergistic enhancement of class I major histocompatibility complex antigen expression in K562 cells induced by recombinant human interferon-gamma and tumor necrosis factor in combination.

The effects of recombinant preparations of human interferon-gamma (rIFN-gamma) and tumor necrosis factor (rTNF), alone or in combination, on class I or class II major histocompatibility complex (MHC) antigen induction were studied using K562, a multipotent hematopoietic precursor cell line. Class I antigens were weakly induced by rIFN-gamma; however, rTNF at any concentration examined (1-1000 U/ml) showed no effect on the induction of class I or class II antigens in the cells. rIFN-gamma (600 U/ml) induced approximately 20% of the cells to express class I antigens after 72-h exposure, whereas 81% of the cells demonstrated class I antigens on their cell surfaces when the cells were simultaneously exposed to 600 U/ml of rIFN-gamma and 1000 U/ml of rTNF. The class II MHC antigens were not induced by the treatments with rIFN-gamma or rTNF, alone or in combination. A synergistic increase of mRNA for class I MHC molecules was demonstrated by treatments of the cells with rIFN-gamma and rTNF in combination. rTNF, but not rIFN-gamma, weakly induced granulocyte-monocyte antigens on the cell surface; however, no synergism was observed on the induction of these antigens by the combined treatments with rIFN-gamma and rTNF. These results indicate that class I MHC antigen expression on K562 cells can be induced by IFN-gamma in cooperation with TNF in a manner different from myeloid antigen expression.

Effects of nisoldipine on cytosolic calcium, platelet aggregation, and coagulation/fibrinolysis in patients with coronary artery disease.

The effect of nisoldipine, a dihydropyridine Ca2+ antagonist, on the platelet cytosolic Ca2+ concentration ([Ca2+]i), platelet aggregation, and various coagulation and fibrinolysis parameters was assessed in normotensive patients with coronary artery disease (CAD). Eleven patients with angiographically confirmed CAD (4 men, 7 women aged 67.3 +/- 5.4 years) were administered nisoldipine at 10 mg/day for two weeks. The [Ca2+]i was determined by use of fura2-loaded platelets, platelet aggregation was measured with an aggregometer, and coagulation/fibrinolysis parameters were measured by standard methods. Nisoldipine did not significantly affect blood pressure or heart rate. However, the [Ca2+]i decreased significantly (P<0.05) and platelet aggregation was also significantly inhibited. Plasma D-dimer levels decreased significantly (P<0.01). Thus, nisoldipine not only suppressed platelet activation but also affected the coagulation system, suggesting that it is not only a vasodilator and platelet inhibitor but also an antithrombotic agent.