Flavonol glycosides from Epimedium sagittatum and their neurite outgrowth activity on PC12h cells

The MeOH extract of Epimedium sagittatum was found to show neurite outgrowth activity on cultured PC12h cells. Bioassay-guided fractionation of the MeOH extract yielded six prenylated flavonol glycosides, ikarisoside A (1), icarisid II (2), epimedoside A (3), icariin (4), epimedin B (5), and epimedokoreanoside-I (6) as the active ingredients.     

Proarrhythmic effects of fluoroquinolone antibacterial agents: in vivo effects as physiologic substrate for torsades

Drug-induced prolongation of the QT interval is often associated with the onset of Torsades de Pointes (TdP) resulting in a life-threatening ventricular arrhythmia. The potential of the proarrhythmic effects of the new fluoroquinolone antibacterial agents, levofloxacin and sparfloxacin, was examined in the chronic complete atrioventricular block dogs with stable idioventricular automaticity using Holter ECG monitoring in conscious state (Experiment 1). Next, to better analyze the mechanisms of the proarrhythmic property, the cardiovascular effects of these two drugs were compared in the halothane-anesthetized dogs under the monitoring of ECG, His bundle electrogram, systemic and left ventricular pressure, monophasic action potential, cardiac output, and effective refractory period (Experiment 2). In Experiment 1, oral administration of 6 mg/kg (n = 4) as well as 60 mg/kg (n = 4) of levofloxacin did not induce any ventricular premature depolarization. On the other hand, oral administration of 60 mg/kg of sparfloxacin (n = 4) induced TdP leading to ventricular fibrillation in all animals within 24 h, while 6 mg/kg of sparfloxacin (n = 4) did not induce any ventricular premature depolarization. In Experiment 2, intravenous administration of 0.3 mg/kg as well as 3.0 mg/kg of levofloxacin slightly increased cardiac output, but no significant changes were detected in the other parameters (n = 6). On the other hand, intravenous administration of 0.3 mg/kg of sparfloxacin prolonged the effective refractory period. Additional administration of 3.0 mg/kg of sparfloxacin decreased the heart rate and prolonged the effective refractory period and ventricular repolarization phase in a similar extent, but no significant changes were detected in the other parameters (n = 6). These results suggest that backward shift of the relative repolarization period in a cardiac cycle may be the mechanism responsible for the torsadegenic effect of sparfloxacin.     

Differential effects of omega-conotoxin GVIA, tetrodotoxin and prolonged cold storage on purinergic and adrenergic transmission in isolated canine splenic artery

Double-peaked vasoconstrictions (biphases of vasoconstrictions) were readily induced in the conditions of 30 s trains of pulses at 1 Hz in the isolated, perfused canine splenic artery. P2X purinoceptors have previously been shown to be involved mainfy in the first-peaked response and alpha1-adrenoceptors mostly in the second. The treatment with 10 nM omega-conotoxin GVIA (omega-CTX) produced a parallel inhibitory effect on the first- and second-peaked vasoconstrictor responses to nerve stimulation. A submaximal concentration of tetrodotoxin (TTX) (3 nM) did not affect the first peak of constriction, but strongly inhibited the second peak, although a larger dose of TTX (30 nM) abolished either the first- or second-peaked response. On the other hand, after cold storage at 4 degrees C for 7 days, the first-peaked vasoconstriction markedly decreased, whereas the second-peaked response was not significantly modified. In conclusion: (1) omega-CTX-sensitive calcium channels may produce a parallel modulation of purinergic and adrenergic components of sympathetic cotransmission; (2) TTX-sensitive sodium channels may have a more important role in controlling the adrenergic rather than purinergic transmission; and (3) the function of purinergic transmission of sympathetic nerve might be affected more strongly than that of adrenergic transmission in the cold-stored canine splenic artery.     

Role of PET/CT in tuberculosis--can we distinguish tuberculoma from lung cancer by PET/CT examination

Differentiating lung cancers from tuberculoma is very important, because in Japan, lung granulomas arise mostly from tuberculosis. However, diagnosis of tuberculoma is very difficult, because of its nonspecific radiographic appearances and the difficulty of bacteriological confirmation of the disease. 18F-FDG PET have contributed significantly to the diagnosis of lung cancer, but FDG is not a cancer-specific agent, so tuberculoma also have been reported to accumulate. Recently, 18F-FDG PET is useful as tools in evaluation of disease activity or for monitoring the response to chemotherapy in patients with tuberculoma. It may be possible to distinguish patients with tuberculoma from those with lung cancer by serial 18F-FDG PET examination (ie, before and after specific treatment of antituberculous treatment for several months).     

Skip mediastinal nodal metastases in non-small cell lung cancer

Objective: To reveal the incidence and clinical significance of mediastinal nodal metastases without N1-station nodal metastases (‘skip-N2 metastases’) in non-small cell lung cancer (NSCLC). Methods: A total of 450 NSCLC patients who underwent tumor resection with a systemic mediastinal nodal dissection were retrospectively reviewed. p53 status and proliferative activity represented as proliferative index (PI) were also examined immunohistochemically. Results: Skip-N2 metastases were documented in 49 (13%) patients of all 450 patients; among 334 patients without N1-nodal involvement, 18% patients had skip-N2 metastases. The postoperative survival of skip-N2 patients was almost same as that for patients with metastases to both N1 and N2 nodes. Skip-N2 metastases were significantly more frequent in male patients and squamous cell carcinoma patients. In addition, the mean PI for tumor with skip-N2 metastases was significantly higher than that for any other pathologic nodal (pN)-status diseases. Combined with histologic type and PI, the incidences of skip-N2 metastases for adenocarcinoma showing lower PI were only 5% (7/137) of all patients and 7% (7/94) of patients without N1-nodal involvement. Conclusions: N1 nodal status is not a useful predictor of N2 nodal status in NSCLC, because skip-N2 metastases were documented in 18% patients showing no N1-nodal involvement. However, N1 node-guided dissection might be performed in patients with adenocarcinoma showing lower PI, because the incidence of skip-N2 metastases was extremely low.     

Combination tumor immunotherapy with radiotherapy and Th1 cell therapy against murine lung carcinoma

Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 cells or OVA alone showed no significant therapeutic activity against LLC-OVA. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 cells and OVA was superior to induce the generation of OVA/H-2^b tetramer⁺ tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 cell/vaccine therapy may become a practical strategy for cancer treatment. Hiroshi Yokouchi and Kenji Chamoto are equally contributed.     

Pathogenesis of gastric and duodenal ulcer in the elderly

In the elderly, H. pylori infection and nonsteroidal anti-inflammatory drug(NSAID) use are most important risk factors for peptic ulcer disease. It is now recognized that, in patients with H. pylori infection, nonatrophic antral-predominant gastritis results in increased acid secretion, which is seen in duodenal ulcer patients, whereas corpus-predominant gastritis and pangastritis result in decreased acid secretion, that are seen in patients with proximal gastric ulcer and gastric cancer. These physiological changes are considered to be related to disease outcome. On the other hand, NSAIDs induced gastrointestinal toxicity is primarily due to the inhibition of mucosal prostaglandin synthesis in the gastric mucosa, which subsequently impairs the gastric cytoprotective factors. These two factors may independently, or even synergistically, cause the development of peptic ulcer disease in the elderly.     

Risk factor for cerebral hemorrhage for the patient with lacunar infarction: investigation of 5 cases associated with both of symptomatic hemorrhagic and ischemic strokes]

BACKGROUND AND PURPOSE: Microangiopathy is regarded as an important cause of intracerebral hematoma(ICH) and lacunar infarction. Dot-like low intensity spots on T2-weighted echo planar image(EPI) have been regarded as hemosiderin deposit associated with microangiopathy. However, clinical significance of dot-like hemosiderin spot(dotHS) is still debated. Therefore, we analyzed the number of dotHS on EPI of symptomatic lacunar infarction associated with ICH. METHODS: To investigate how the dotHS or risk factors contributed to hemorrhagic strokes for patients with lacunar infarction, the number of dotHS and various risk factors were made a comparison between 20 cases with symptomatic lacunar infarctions(lacunar group) and 5 cases with both symptomatic lacunar infarction and symptomatic ICH(complicated group). In addition to EPI, fluid attenuated inversion recovery image, and T1- and T2-weighted MR images were performed for differential diagnosis of dot HS. RESULTS: EPI demonstrated that asymptomatic ICH was significantly more frequent in complicated group (60%) than in lacunar group(10%), and dotHS were significantly more frequent in complicated group(100%) than in lacunar group(50%). The number of dotHS of complicated group was 14.6 +/- 4.3, which was significantly larger than that of lacunar group(4.1 +/- 9.2). No significant difference between two groups were founded in other risk factors including hypertension, diabetes mellitus, hyperlipidemia, and smoking. CONCLUSION: These results suggested that dotHS was one of the risk factors for ICH for patients with symptomatic lacunar infarction, and an increasing number of dotHS was one of the predictive factors of symptomatic and/or asymptomatic ICH.