Kinetic simulation of signal transduction system in hippocampal long-term potentiation with dynamic modeling of protein phosphatase 2A.

We modeled and analyzed a signal transduction system of long-term potentiation (LTP) in hippocampal post-synapse. Bhalla and Iyengar [Science 283(1999) 381] have developed a hippocampal LTP model. In the conventional model, the concentration of protein phosphatase 2A (PP2A) was fixed. However, it was reported that dynamic inactivation of PP2A was essential for LTP [J. Neurochem. 74 (2000) 807]. We introduced a dynamic modeling of PP2A; inactivation (phosphorylation) of PP2A by calcium/calmodulin-dependent protein kinase II (CaMKII) in the presence of calcium/calmodulin, self-activation (autodephosphorylation) of PP2A, and inactivation (dephosphorylation) of CaMKII by PP2A. This model includes complex feedback loops; both CaMKII and PP2A are autoactivated, while they inactivate each other. Moreover, we proposed an analysis strategy for model validation by applying the results of sensitivity analysis. In our system, calcineurin (CaN) played an essential role, rather than the activation of protein kinase C (PKC) as documented in the conventional model. From results of the analysis of our model, we found the following robustness as characteristics of bistability in our model: (1). PP2A reactions against calcium ion (Ca(2+)) perturbation; (2). PP2A inactivation against PP2A increase; (3). protein phosphatase 1 (PP1) activation against PF2A increase; and (4). PP2A reactions against PP2A initial concentration. These properties facilitated LTP induction in our system. We showed that another mechanism could introduce bistable behavior by adding dynamic reactions of PP2A.     

Recovery of extensor muscle strength in athletes after anterior cruciate ligament reconstruction

We investigated the effects of the use of different autograft materials on the early postoperative recovery of extensor muscle strength after anterior cruciate ligament (ACL) reconstruction. Reconstruction was performed in 172 athletes with ACL-deficient knees; in 32, a quadriceps tendon-patellar tendon substitute (QTS) was used; in 79, semitendinosus and gracilis tendons (STG) were used; and in 61, a bone-patellar tendon-bone graft (BTB) was used. For QTS and STG autografts, a ligament augmentation device was used. Each group received the same accelerated rehabilitation program. Muscle strength was measured periodically 3–18 months after the operation, using a Cybex II dynamometer (Cybex Division of Lumex, Ronkonkoma, NY, USA). Knee extensor strength was evaluated, using the side-to-side ratio and the body weight ratio, to give a precise assessment of permissible sporting activity. After a period of 1 year, the percentage of athletes who recovered their extensor muscle strength at a level more than 80% of that in the uninvolved knee was 15.6% for those with QTS grafts, 41.0% for those with BTB grafts, and 77.9% for those with STG grafts (P<0.001 between QTS and STG,P<0.05 between QTS and BTB, andP<0.001 between BTB and STG). The body weight ratio in men showed that, after reconstruction, recovery of extensor muscle strength sufficient for participation in vigorous sport required 6 months for STG grafts, 12 months for BTB grafts, and 18 months for QTS grafts.     

Cerebellar superoxide dismutase expression in Menkes' kinky hair disease: an immunohistochemical investigation

This comparative immunohistochemical study deals with the expression of the cytosolic Cu/Zn-binding and mitochondrial Mn-dependent superoxide dismutases (SODs) in the cerebella of five patients with Menkes' kinky hair disease (MKHD) and five age-matched controls. Several cell types, including Purkinje cells and reactive astrocytes, of all MKHD patients examined were intensely stained by an antibody to Mn SOD, but not by an anti-Cu/Zn SOD antibody. By contrast, the cells of the five controls reacted very weakly or not at all with the anti-Mn SOD antibody, but were strongly reactive with the antibody to Cu/Zn SOD. These results suggest that the increased Mn SOD immunoreactivity in MKHD reflects enzyme induction as a protective mechanism against the highly toxic superoxide anion generated under the disease conditions.     

Salivary flow rates during relaxing, clenching, and chewing-like movement with maxillary occlusal splints.

The purpose of this study was to test the hypothesis that the application of occlusal splints increases the diurnal salivary flow rate both in bruxism patients and in normal subjects. Salivary flow rates in 16 adult volunteers (8 bruxism patients and 8 sex- and age-matched control subjects) were measured with the spitting method. There was no significant difference in the salivary flow rate with or without splints between the control and bruxism groups. In all subjects, the salivary flow rates with splints were significantly higher than those without splints during relaxing, clenching, and chewing-like movement. The salivary flow rate during the chewing-like movement was significantly higher than that during relaxing and clenching, irrespective of splint application. The results suggest that maxillary occlusal splints might stimulate salivary secretion, particularly during chewing-like movement, in both bruxism patients and normal subjects.     

Tolerability and safety of classic cyclophosphamide, methotrexate, and fluorouracil treatment in japanese patients with early Breast Cancer

BACKGROUND: Few reports have addressed the feasibility and safety of classic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) therapy in Japanese female breast cancer patients. METHODS: Twenty-four Japanese patients who received classic CMF, identical to the originally described treatment regimen were studied in terms of treatment dose, treatment delay, and toxicity. RESULTS: Classic CMF was not discontinued in any of the cases. The median delay in treatment was 14 days, and the mean administered dose of cyclophosphamide was 98.2% of the planned dose. None of the patients suffered severe side-effects such as febrile neutropenia; however, in 22 patients in whom the effect of CMF on hair loss could be assessed, 7 (31.8%) had to wear hats or wigs. CONCLUSIONS: Classic CMF is a feasible and safe regimen in Japanese breast cancer patients. In Japan, this regimen is still available for some specific groups of early breast cancer patients.     

Novel vaccine development strategies for inducing mucosal immunity

To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed.