Silibinin protects rat pancreatic β‐cell through up‐regulation of estrogen receptors' signaling against amylin‐ or Aβ1–42‐induced reactive oxygen species/reactive nitrogen species generation

Amylin and amyloid‐β (Aβ) were found to induce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in rat pancreatic β‐cell line, INS‐1 cells, leading to cell death. In this study, we report on reciprocal relationship between the expression of estrogen receptors (ERs) α and β (ERα and ERβ) and generation of ROS/RNS in amylin/Aβ_1–42‐treated INS‐1 cells. That is, pharmacological activation of ERs in INS‐1 cells significantly decreases ROS/RNS generation, but blockage of ERs increases ROS/RNS generation. Silibinin is a natural polyphenolic flavonoid isolated from milk thistle with phytoestrogen activities, also known as silybin. Treatment with silibinin down‐regulated ROS/RNS production induced by treatment with amylin/Aβ_1–42 in the cells. Silencing ERs expression with siRNAs targeting ERs showed that the protective effect of silibinin was markedly weakened, indicating that silibinin protection is largely attributed to activation of ERs' signaling. The binding of silibinin to ERs implies that the protective effect of silibinin on amylin/Aβ_1–42‐treated INS‐1 cells owes to down‐regulation of ROS/RNS through the activation of ERs phosphorylation. Amylin and Aβ_1–42 cotreatment enhanced furthermore ROS/RNS generation and cytotoxicity through further down‐regulation of ERs phosphorylation, and this was reversed by silibinin. Silibinin also protects INS‐1 cells from amylin and Aβ_1–42 cotreatment. These results indicate that protective effect of silibinin is mediated by enhancement of ERs phosphorylation that depresses ROS/RNS generation in amylin/Aβ_1–42‐treated INS‐1 cells.     

Gemcitabine and paclitaxel chemotherapy as a second-line treatment for advanced or metastatic urothelial carcinoma

OBJECTIVES: We report that a combination of gemcitabine and paclitaxel will effectively treat patients with advanced urothelial carcinoma (UC) who have been previously treated with methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). The objective of this study was to assess the tumor responses, toxicity, and overall survival of these patients as second-line treatment. METHODS: Ten eligible patients were enrolled in this study. All patients had been previously treated with MVAC. Patients received paclitaxel 200 mg/m(2) on day 1 and gemcitabine 1000 mg/m(2) on days 1, 8, and 15. The treatment was repeated every 21 days. Tumors were assessed every two cycles by imaging study. RESULTS: The median number of treatment courses was 4 (range 2-7). Two patients had complete response and five patients had partial response after two courses of treatment. Median overall survival was 10.3 months. Median overall survival from the first MVAC was 19.1 months. Median progression-free survival was 4.1 months. Of the seven responders, median progression-free survival was 7.4 months. Myelosuppression was the most common toxicity. Nonhematologic toxicity consisted of hypersensitivity reactions to paclitaxel. There were no therapy-related deaths. CONCLUSIONS: Gemcitabine and paclitaxel chemotherapy is a favorable therapeutic alternative for patients with advanced or metastatic UC who have previously been treated with MVAC chemotherapy. Given the safety and benefit profile seen in this study, a large prospective research study is warranted to consider the potential role of gemcitabine and paclitaxel chemotherapy as a second-line treatment for urothelial cancer.     

Using crutches during walking possibly reduces gait imagery accuracy among healthy young and older adults

[Purpose] Although crutches are widely used in the field of rehabilitation to improve gait performance, patients usually have difficulties using them, and this may increase their risks for falls. This study aimed to define the accuracy of gait imagery during walking with and without crutches, in healthy young and older adults, using the mental chronometry method. [Participants and Methods] Overall, 99 healthy young (mean age, 20.2 ± 1.0 years) and 39 healthy older adults (mean age, 71.3 ± 2.9 years) performed the imagery and execution tasks, which involved walking through a distance of 10 meters both with and without crutches. Using the mental chronometry method, the accuracy of the motor imagery was defined as the difference between the imagery time and the actual execution time. Two-way analysis of variance and one-sample t-tests were performed to evaluate the accuracy of the gait imagery. [Results] Both the young and older adults significantly overestimated their gait speeds when using crutches; the overestimation was larger among the older adults. [Conclusion] The overestimations indicate that participants estimated their gait speeds with crutches to be faster than their actual speeds. Therefore, using crutches decreased the accuracy of gait imagery and might therefore increase an individual’s risk of falling during walking.     

Reconstruction of health service systems in the post-conflict Northern Province in Sri Lanka

Public health problems in armed conflicts have been well documented, however, effective national health policies and international assistance strategies in transition periods from conflict to peace have not been well established. After the long lasted conflicts in Sri Lanka, the Government and the rebel LTTE signed a cease-fire agreement in February 2002. As the peace negotiation has been disrupted since April 2003, a long-term prospect for peace is yet uncertain at present. The objective of this research is to detect unmet needs in health services in Northern Province in Sri Lanka, and to recommend fair and effective health strategies for post-conflict reconstruction. First, we compared a 20-year trend of health services and health status between the post-conflict Northern Province and other areas not directly affected by conflict in Sri Lanka by analyzing data published by Sri Lankan government and other agencies. Then, we conducted open-ended self-administered questionnaires to health care providers and inhabitants in Northern Province, and key informant interviews in Northern Province and other areas. The major health problems in Northern Province were high maternal mortality, significant shortage of human resources for health (HRH), and inadequate water and sanitation systems. Poor access to health facilities, lack of basic health knowledge, insufficient health awareness programs for inhabitants, and mental health problems among communities were pointed by the questionnaire respondents. Shortage of HRH and people's negligence for health were perceived as the major obstacles to improving the current health situation in Northern Province. The key informant interviews revealed that Sri Lankan HRH outside Northern Province had only limited information about the health issues in Northern Province. It is required to develop and allocate HRH strategically for the effective reconstruction of health service systems in Northern Province. The empowerment of inhabitants and communities through health awareness programs and the development of a systematic mental health strategy at the state level are also important. It is necessary to provide with the objective information of gaps in health indicators by region for promoting mutual understanding between Tamil and Sinhalese. International assistance should be provided not only for the post-conflict area but also for other underprivileged areas to avoid unnecessary grievance.     

Engraftment and dissemination of T lymphocytes from primary haemophagocytic lymphohistiocytosis in scid mice

Although primary haemophagocytic lymphohistiocytosis (HLH) is a genetic disorder of T lymphocytes, it remains unclear why T lymphocytes of primary HLH patients preferentially infiltrate the central nervous system and peripheral blood, in addition to the reticuloendothelial systems. We engrafted Herpesvirus saimiri (HVS)-immortalized T-lymphocyte lines established from primary HLH patients into severe combined immunodeficient (scid) mice and examined their capacity to infiltrate mouse organs. A diffuse infiltration of human T lymphocytes was detected in each organ of scid mice treated with 1 x 10(6) T lymphocytes from all four primary HLH patients assessed, whereas no infiltration of T lymphocytes from healthy individuals was observed in any organ. The infiltration of T lymphocytes was mainly observed in the lung, brain and peripheral blood, in association with haemophagocytosis. These cells were positive for HLA-DR, CD3 and either CD8 or CD4, but negative for CD68. Certain markers of proliferation and apoptotic activities were highly positive in these cells. There was no difference between the infiltration pattern of T lymphocytes of primary HLH patients with a perforin deficiency and those without. By Southern blot analysis, T lymphocytes infiltrating mouse organs were observed to be polyclonal. These findings suggest that our murine model implementing HVS-immortalized human T lymphocytes is suitable to clarify the pathogenesis of primary HLH.     

Natural saline-flush is sufficient to maintain patency of immobilized-urokinase double-lumen catheter used to provide temporary blood access for hemodialysis

BACKGROUND: Thrombotic occlusion is a frequent complication of central venous catheters used to provide temporary blood access on hemodialysis therapy. Heparin-lock is conventionally used to maintain patency of the catheter, but the necessity of heparin-lock has not been determined yet. METHODS: After the immobilized-urokinase double-lumen central venous catheter was inserted into 48 Japanese hemodialysis patients, 22 patients randomized to the heparin group received a 20-ml saline-flush, followed by 2 ml of 1,000 U/ml heparin-lock, and 26 patients randomized to the saline group received only the 20-ml saline-flush once a day for each lumen. RESULTS: Thrombotic occlusion was observed in only 1 out of 22 patients in the heparin group and 1 out of 26 patients in the saline group. No significant difference of the catheter survival was observed between the two groups (p = 0.8599). CONCLUSIONS: Natural saline-flush is sufficient for maintaining the patency of an immobilized-urokinase double-lumen central venous catheter.     

Implications of Mechanical Stretch on Wound Repair of Gastric Smooth Muscle Cells In Vitro

Gastric smooth muscle cells continually receive repetitive physical stretching by food storage, peristalsis and fasting contraction; therefore mechanical stretch can not be disregarded in gastric events. The aim of this study was to clarify the effects of mechanical stretch on wound repair using a rabbit gastric smooth muscle cell sheet. Mechanical stretch was imposed on adherent cells on a flexible membrane in order to increase elongation by an average of 5% and 10%, respectively, at 5 cycles per minute after artificial wounding. Adherent cells not subjected to mechanical stretch served as controls. The restoration process was monitored by measuring wound size for 48 h. Proliferation was assessed by BrdU staining and the influence on the cytoskeletal system was assessed by actin staining. The speed of restoration was highest in controls and lowest in the 10% stretch groups. Proliferation was almost equal to that of controls in the stretch groups. Under the condition of mechanical stretch, stress fibers appeared weakened and the direction of fibers was not consistent but random. In conclusion, mechanical stretch inhibited the migration of gastric smooth muscle cells, leading to cytoskeletal dysfunction. It is suggested that physical stretch, such as mechanical stretch, might be an important factor in the process of gastric wound repair.