Sinomenine and magnoflorine,major constituents of Sinomeni Caulis et Rhizoma,show potent protective effects against membrane damage induced by lysophosphatidylcholine in rat erythrocytes

The effects of the water extract of Sinomeni Caulis et Rhizoma (SCR-WE) and its major constituents, sinomenine (SIN) and magnoflorine (MAG), on moderate hemolysis induced by lysophosphatidylcholine (LPC) were investigated in rat erythrocytes and compared with the anti-hemolytic effects of lidocaine (LID) and propranolol (PRO) as reference drugs. LPC caused hemolysis at concentrations above the critical micelle concentration (CMC), and the concentration of LPC producing moderate hemolysis (60 %) was approximately 10 μM. SCR-WE at 1 ng/mL–100 μg/mL significantly inhibited the hemolysis induced by LPC. SIN and MAG attenuated LPC-induced hemolysis in a concentration-dependent manner from very low to high concentrations (1 nM–100 μM and 10 nM–100 μM, respectively). In contrast, the inhibiting effects of LID and PRO on LPC-induced hemolysis were observed at higher concentrations (1–100 μM) but not at lower concentrations (1–100 nM). Neither SIN nor MAG affected micelle formation of LPC, nor, at concentrations of 1 nM–1 μM, did they attenuate the hemolysis induced by osmotic imbalance (hypotonic hemolysis). Similarly, SCR-WE also did not modify micelle formation or hypotonic hemolysis, except at the highest concentration. These results suggest that SIN and MAG potently protect the erythrocyte membrane from LPC-induced damage and contribute to the beneficial action of SCR-WE. The protective effects of SIN and MAG are mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance.

     

ROS‐generating oxidases Nox1 and Nox4 contribute to oncogenic Ras‐induced premature senescence

Activated oncogenes induce premature cellular senescence, a permanent state of proliferative arrest in primary rodent and human fibroblasts. Recent studies suggest that generation of reactive oxygen species (ROS) is involved in oncogenic Ras‐induced premature senescence. However, the signaling mechanism controlling this oxidant‐mediated irreversible growth arrest is not fully understood. Here, we show that through the Ras/MEK pathway, Ras oncogene up‐regulated the expression of superoxide‐generating oxidases, Nox1 in rat REF52 cells and Nox4 in primary human lung TIG‐3 cells, leading to an increase in intracellular level of ROS. Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including β‐galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16^Ink4a. This suggests that Nox‐generated ROS transduce senescence signals by activating the p53 and p16^Ink4a pathway. Furthermore, Nox1 and Nox4 siRNAs inhibited both Ras‐induced DNA damage response and p38MAPK activation, whereas overexpression of Nox1 and Nox4 alone was able to induce senescence. The involvement of Nox1 in Ras‐induced senescence was also confirmed with embryonic fibroblasts derived from Nox1 knockout mice. Together, these findings suggest that Nox1‐ and Nox4‐generated ROS play an important role in Ras‐induced premature senescence, which may involve DNA damage response and p38MAPK signaling pathways.     

Cilostazol may improve cognition better than clopidogrel in non-surgical adult patients with ischemic moyamoya disease: subanalysis of a prospective cohort

ABSTRACT

Objective: Adult patients with ischemic moyamoya disease (MMD) who receive treatment with antiplatelet drugs reportedly show improvements in neuropsychological test scores after around 2 years. The purpose of the present study subanalyzing the same patient cohort used in a previous study was to determine which antiplatelet drug, clopidogrel or cilostazol, results in better improvement of cognitive function among non-surgical adult patients showing ischemic MMD without severe hemodynamic compromise.

Methods: Sixty-six patients without cerebral misery perfusion on ¹⁵O gas positron emission tomography were treated with pharmacotherapy alone. Patients ≥50 years old and <50 years old initially received clopidogrel and cilostazol, respectively. Any patient suffering side effects of the antiplatelet drug switched to the other antiplatelet drug. Neuropsychological tests were performed at study entry and at the end of the 2-year follow-up, and differences in each neuropsychological test score between the two time points (second test score – first test score) were calculated and defined as Δ scores.

Results: Among the five neuropsychological tests, Δ scores for two tests were significantly greater in patients treated with cilostazol (n = 36) than in those treated with clopidogrel (n = 30), and Δ scores of the remaining three tests did not differ between patient groups. Based on Δ scores, 15 patients (23%) were defined as showing interval cognitive improvement. On multivariate analysis, cilostazol administration (95% confidence interval, 1.19–193.98; P = 0.0361) represented an independent predictor of interval cognitive improvement.

Conclusions: Cilostazol may improve cognition better than clopidogrel in non-surgical adult patients with ischemic MMD.     

Driving license of patients with epilepsy, management of their oral drugs and suppositories by non-medical professionals, and the role of pediatric neurologists

In June 2002, the following new driving regulations were enforced in Japan: 1. A person with epilepsy may be granted a driving license after a seizure-free period of two years. 2. A person with simple partial seizures that would not impair driving safety may be granted a driving license if no other seizures that may impair driving safety have occurred over a period of at least one year. 3. A person with seizures occurring only in sleep may be granted a driving license if no seizures have occurred in waking over a period of at least two years. 4. In case that the above requirements are going to be met within 6 months, driving should be prohibited for 6 months. 5. A person with epilepsy is recommended to apply for a license to drive heavy and/or public vehicles only after a seizure-free period of 5 years without medication. The committee for legal problems of the Japan Epilepsy Society proposed a guideline for non-medical teaching or caring professionals to give children with epilepsy antiepileptic medication or to insert suppositories, if needed, at schools or care institutions. The guideline indicated the following preconditions as important: 1. There must be a wish and consent of the patient or his/her family. 2. Drugs or suppositories are usually taken or used at home and regarded as a safe procedure. 3. Attending doctor should provide clear information about the use and risk of the medication or suppository. 4. Privacy of the patient should be protected. Pediatric neurologists are expected to play an important role on these issues.     

Asking for cooperation with parents and special staff

There is no doubt that the purpose of pediatric neurologic medicine is to improve the quality of life of children with neurologic diseases and disabilities by medical care based on scientific evidence. It is also necessary to help these children to live in their families and society from a professional viewpoint. The course of social activity of the Japanese Society of Child Neurology will be decided by Social Activity and Public Relations Committee, to which appropriate information should be provided by accumulation of social activities of individual members. This paper illustrates the individual activity through my own experience.     

Prognostic model for hepatocellular carcinoma with time-dependent factors

The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n=336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n=227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.     

Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma

We conducted a multicenter retrospective analysis to evaluate the efficacy of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We enrolled 36 patients with pathologically proven, unresectable combined hepatocellular and cholangiocarcinoma treated with systemic chemotherapy. The log‐rank test determined the significance of each prognostic factor. Elevated alpha‐fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19‐9 levels were observed in 58.3%, 16.7% and 38.9% of patients, respectively. First‐line chemotherapy included platinum‐containing regimens consisting of gemcitabine/cisplatin (n = 12) and fluorouracil/cisplatin (n = 11), sorafenib (n = 5) and others (n = 8). The median overall and progression‐free survival times were 8.9 and 2.8 months, respectively, with an overall response rate of 5.6%. Prognostic factors associated with negative outcomes included poor performance status, no prior primary tumor resection, a Child‐Pugh class of B, and elevated carcinoembryonic antigen levels with a hazard ratio of 2.25, 2.48, 3.25 and 2.84 by univariate analysis, respectively. The median overall survival times of the gemcitabine/cisplatin, fluorouracil/cisplatin, sorafenib and other groups were 11.9, 10.2, 3.5 and 8.1 months, respectively. Multivariate analysis revealed that the overall survival of patients within the sorafenib monotherapy group was poor compared with platinum‐containing regimens (HR: 15.83 [95% CI: 2.25‐111.43], P = .006). All 7 patients in the sorafenib group had progressive disease, including 2 patients with second‐line therapy. In conclusion, the platinum‐containing regimens such as gemcitabine/cisplatin were associated with more favorable outcomes than sorafenib monotherapy for unresectable combined hepatocellular and cholangiocarcinoma.     

Scrub typhus mimicking the clinical course of infectious mononucleosis: a case report

Objective: Scrub typhus is a relatively common life-threating disease; its symptoms are non-specific and similar to those of other viral infections. Therefore, scrub typhus might be underdiagnosed.Patient: Herein, we report a patient with scrub typhus whose clinical course mimicked that of infectious mononucleosis. A 63-year-old male patient with hypertension presented to our hospital complaining of symptoms including prolonged fever, pharyngeal discomfort, and a mild headache. He showed the appearance of a rash after amoxicillin administration. At the same time, he did not show a crusted rash on his body surface.Results: After a comprehensive examination, Epstein-Barr virus and cytomegalovirus infections were ruled out. We suspected that this patient suffered from scrub typhus on the basis of his usual lifestyle. Finally, polymerase chain reaction analysis showed a positive result for deoxyribonucleic acid of Orientia tsutsugamushi in his blood sample. Fortunately, he recovered naturally with only supportive treatment during his hospitalization.Conclusion: We should observe and monitor patients with infectious mononucleosis-like symptoms and emphasize the importance of a clinical interview.     

Sediment Metal Contamination in the Kafue River of Zambia and Ecological Risk Assessment

Zambia’s Kafue River receives wastes from various sources, resulting in metal pollution. This study determined the degree of contamination of 13 metals (Al, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Cd, Hg and Pb) in Kafue River sediment and the associated ecological risks at six sites in three different seasons. The level of contamination for most metals showed significant site and seasonal differences. The contamination factor and pollution load index indicated that concentrations of most metals particularly copper (Cu), cobalt (Co), manganese (Mn) and arsenic (As) were very high at sites within the Copperbelt mining area. The geoaccumulation index showed an absence of anthropogenic enrichment with Cd and Hg at all the study sites and extreme anthropogenic enrichment with Cu at sites in the Copperbelt mining area. Potential ecological risk showed that Cu and As were likely to cause adverse biological effects to aquatic organisms in the Copperbelt mining region of the Kafue River.