The facilitative effects of bilobalide,a unique constituent of <Emphasis Type="Italic">Ginkgo biloba</Emphasis>, on synaptic transmission and plasticity in hippocampal subfields

Bilobalide, a unique constituent of Ginkgo biloba, has been reported to potentiate population spikes in hippocampal CA1 pyramidal cells and to protect the brain against cell death. In this study, the effects of bilobalide on synaptic transmission and its plasticity in rat hippocampal subfields were electrophysiologically investigated. Bilobalide (50 μM) significantly potentiated the input–output relationship at Schaffer collateral (SC)-CA1 synapses but not at medial perforant path (MPP)-dentate gyrus (DG), lateral perforant path (LPP)-DG, or mossy fiber (MF)-CA3 synapses. Facilitative effects of bilobalide on synaptic plasticity were only observed at MPP-DG synapses, in which the induction of long-term depression was blocked in the presence of bilobalide. However, no effect on synaptic plasticity was observed at SC-CA1 synapses. These results suggest that bilobalide has differential effects on synaptic efficacy in each hippocampal subfield.     

Type of skin eruption is an independent prognostic indicator for adult T-cell leukemia/lymphoma

Cutaneous involvement is seen in ~ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1.     

Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells

Polycomb-group (PcG) proteins are essential regulators of hematopoietic stem cells (HSCs). In contrast to Bmi1, a component of Polycomb repressive complex 1 (PRC1), the role of PRC2 and its components in hematopoiesis remains elusive. Here we show that Ezh2, a core component of PRC2, is essential for fetal, but not adult, HSCs. Ezh2-deficient embryos died of anemia because of insufficient expansion of HSCs/progenitor cells and defective erythropoiesis in fetal liver. Deletion of Ezh2 in adult BM, however, did not significantly compromise hematopoiesis, except for lymphopoiesis. Of note, Ezh2-deficient fetal liver cells showed a drastic reduction in trimethylation of histone H3 at lysine 27 (H3K27me3) accompanied by derepression of a large cohort of genes, whereas on homing to BM, they acquired a high level of H3K27me3 and long-term repopulating capacity. Quantitative RT-PCR revealed that Ezh1, the gene encoding a backup enzyme, is highly expressed in HSCs/progenitor cells in BM compared with those in fetal liver, whereas Ezh2 is ubiquitously expressed. These findings suggest that Ezh1 complements Ezh2 in the BM, but not in the fetal liver, and reveal that the reinforcement of PcG-mediated gene silencing occurs during the transition from proliferative fetal HSCs to quiescent adult HSCs.     

Novel monoclonal antibodies against pancreatic juice from pancreatic cancer patients and their possible application in differential diagnosis

Pancreatic cancer (PC) has a poor clinical prognosis with a <10% 5-year survival rate. Because there are no specific biomarkers of PC, it is difficult to detect small PC tumors and most patients are diagnosed at an advanced stage. Specific biomarkers are useful tools for the early detection of cancer. However, PC-related biomarkers, such as CA19-9 lack specificity and sensitivity. In this study, we took an immunological approach to establish novel monoclonal antibodies (mAbs) specific for the pancreatic juice from PC patients, which would be potentially useful in the diagnosis of PC. Mice were immunized by subtractive immunization using mixed pancreatic juices from chronic pancreatitis and PC patients as the tolerogen and the immunogen, respectively. After screening by Western blotting, four mAbs were obtained: 2P-1-2-1, 2P-1-17-1, 6P-3-2-4 and 7P-9-11-6. The mAb 2P-1-2-1 showed reactivity against the tolerogen at 115 and 120 kDa, but only the 120-kDa antigen was also reactive to the immunogen. The mAb 2P-1-17-1 showed an intense smear reactivity at ~150 kDa against the immunogen. Finally, the mAbs 6P-3-2-4 and 7P-9-11-6 showed PC-specific reactivity to the immunogen at >250 kDa and at ~70 kDa, respectively. We propose that investigation of pancreatic juice samples with these mAbs may enable us to perform reliable differential diagnosis of benign and malignant diseases. Furthermore, we demonstrated that subtractive immunization is a useful method for producing mAbs specific for the pancreatic juice from PC patients.     

Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan

To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.     

Antihypertensive medication versus health promotion for improving metabolic syndrome in preventing cardiovascular events: a success rate-oriented simulation study

Background  

In practice, it is difficult to compare the effectiveness of traditional antihypertensive treatment with that of health promotion in reducing incidence rate of cardiovascular disease (IR_CVD, events/year). This simulation study compared the effectiveness of two approaches to reducing IR_CVD in a sample population: a traditional approach, in which high-risk patients are treated with conventional antihypertensive medications, and a population-based approach, in which subjects participate in a health promotion program.