An interactive simulator to deepen the understanding of Guyton's venous return curve.

Mean circulatory filling pressure, venous return curve, and Guyton's graphical analysis are basic concepts in cardiovascular physiology. However, some medical students may not know how to view and interpret or understand them adequately. To deepen students' understanding of the graphical analysis, in place of having to perform live animal experiments, we developed an interactive cardiovascular simulator, as a self-learning tool, as a web application. The minimum closed-loop model consisted of a ventricle, an artery, resistance, and a vein, excluding venous resistance. The simulator consists of three modules: setting (parameters and simulation modes), calculation, and presentation. In the setting module, the user can interactively customize model parameters, compliances, resistance, Emax of the ventricular contractility, total blood volume, and unstressed volume. The hemodynamics are calculated in three phases: filling (late diastole), ejection (systole), and flow (early diastole). In response to the user's settings, the simulator graphically presents the hemodynamics: the pressure-volume relations of the artery, vein, and ventricle, the venous return curves, and the stroke volume curves. The mean filling pressure is calculated at approximately 7 mmHg at the initial setting. The venous return curves, linear and concave, are dependent on the venous compliance. The hemodynamic equilibrium point is marked on the crossing point of venous return curve and the stroke volume curve. Users can interactively do discovery learning, and try and confirm their interests and get their questions answered about hemodynamic concepts by using the simulator.

Bone marrow ring sideroblasts in hematological diseases: an analysis of consecutive 1300 samples in a single institution.

The incidence of MDS-RS in Japan has been recognized as about 5% which is lower than that in European countries. Insufficient use of iron staining tests in Japan has been noted as one conceivable factor contributing to this apparently lower prevalence. To investigate this issue, we analyzed the proportion of ring sideroblasts (RS) in 1300 bone marrow samples from patients with hematological diseases at Kitasato University Hospital, including iron staining of all samples. Sixteen of 96 patients with MDS (16.7%) were diagnosed with MDS-RS, and this accounted for 26.2% of MDS without excess blasts. Some MDS-EB (22.9%) and AML-MRC (13.8%) patients also had ≥ 15% RS. In contrast, RS were rarely found in myeloid neoplasms without dysplasia and non-myeloid diseases: only 1 in 46 (2.2%) patients with AML without dysplasia, 2 in 93 (2.2%) with MPN, and 8 in 984 (0.8%) with non-myeloid diseases had ≥ 5% RS. These results indicate that prevalence of MDS-RS in Japan may be higher than conventionally recognized and that RS are principally restricted to myelodysplastic disorders. Further multicenter studies using consecutive bone marrow samples with iron staining tests will be required to confirm our findings.

[Acute leukemia developing in the second trimester of pregnancy].

Acute leukemia (AL) during pregnancy poses a substantial risk to both mothers and fetuses. Treatment for leukemia should be initiated promptly; however, the management of AL in pregnant women and fetuses is usually challenging, especially during the second trimester. Here, we report two cases of AL that developed during the second trimester of pregnancy. In one case, chemotherapy was initiated while continuing the pregnancy; in the second case, a cesarean section was performed prior to chemotherapy initiation. As per current medical records, both infants are thriving without any medical problems. The optimal strategy for the treatment of AL during pregnancy typically includes chemotherapy after delivery. However, if fetal development is not sufficient for ex utero survival, the only alternatives available are the initiation of treatment while continuing the pregnancy or treatment after therapeutic abortion (if it is legally allowed). According to previous studies and as per the results from our first case, the initiation of chemotherapy while sustaining the pregnancy may be an acceptable option if it is conducted with appropriate informed consent. The treatment of AL in the second trimester of pregnancy should be carefully decided, while taking into account the medical, legal, and social aspects, such as gestational weeks, maternal and fetal status, and wishes of the patients and their families.

KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis.

Fibrosis involves the production of extracellular matrix proteins in tissues and is often preceded by injury or trauma. In pleural fibrosis excess collagen deposition results in pleural thickening, increased stiffness and impaired lung function. Myofibroblasts are responsible for increased collagen deposition, however the molecular mechanism of transportation of procollagen containing vesicles for secretion is unknown. Here, we studied the role of kinesin on collagen-1 (Col-1) containing vesicle transportation in human pleural mesothelial cells (HPMCs). Among a number of cargo transporting kinesins, KIF5A was notably upregulated during TGF-ß induced mesothelial-mesenchymal transition (MesoMT). Using superresolution structured illumination microscopy and the DUO-Link technique, we found that KIF5A colocalized with Col-1 containing vesicles. KIF5A knock-down significantly reduced Col-1 secretion and attenuated TGF-ß induced increment in Col-1 localization at cell peripheries. Live cell imaging revealed that GFP-KIF5A and mCherry-Col-1 containing vesicles moved together. Kymography showed that these molecules continuously move with a mean velocity of 0.56 µm/sec, suggesting that the movement is directional but not diffusion limited process. Moreover, KIF5A was notably upregulated along with Col-1 and α-smooth muscle actin in pleural thickening in the carbon-black bleomycin mouse model. These results support our hypothesis that KIF5A is responsible for collagen transportation and secretion from HPMCs.

Antibacterial and anti-biofilm efficacy of fluoropolymer coating by a 2,3,5,6-tetrafluoro-p-phenylenedimethanol structure.

Fluorinated polymers generally function as antibacterial agents, but their anti-biofilm effect remains unresolved. This study investigates the efficacy of fluoropolymers containing 2,3,5,6-tetrafluoro-p-phenylenedimethanol (TFPDM) in preventing biofilm formation by Bacillus subtilis and Escherichia coli (Gram-positive and Gram-negative bacterial species). To this end, TFPDM-based acrylate and epoxy polymers (AF and EF, respectively) and their structural analogues without TFPDM (A and E, respectively) were synthesized. All polymers were coated onto polyethylene terephthalate (PET) sheets. Relative to pristine PET, sheets coated with AF reduced the initial bacterial adhesion (72h) and biofilm formation (30days) of B. subtilis by 27.6% and 68.7% and of E. coli by 89.2% and 93.8%, respectively. The comparable antibacterial and anti-biofilm efficacies were obtained by sheets with EF. The biofilm detachment was substantially facilitated from the AF, compared with the structural analogue without TFPDM (A). In this comprehensive study, the bacterial adhesion and subsequent biofilm formation were prevented by TFPDM-containing polymers effectively.

Rac1 regulates myosin II phosphorylation through regulation of myosin light chain phosphatase.

Phosphorylation of regulatory light chain (MLC) activates myosin II, which enables it to promote contractile and motile activities of cells. We report here a novel signaling mechanism that activates MLC phosphorylation and smooth muscle contraction. Contractile agonists activated Rac1, and Rac1 inhibition diminished agonist-induced MLC phosphorylation, thus inhibiting smooth muscle contraction. Rac1 inhibits the activity of MLC phosphatase (MLCP) but not that of MLC kinase, through a phosphatase that targets MYPT1 (a regulatory subunit of MLCP) and CPI-17 (a MLCP specific inhibitor) rather than through the RhoA-Rho dependent kinase (ROCK) pathway. Rac1 inhibition decreased the activity of protein kinase C (PKC), which also contributes to the change in CPI-17 phosphorylation. We propose that activation of Rac1 increases the activity of PKC, which increases the phosphorylation of CPI-17 and MYPT1 by inhibiting the phosphatase that targets these proteins, thereby decreasing the activity of MLCP and increasing phosphorylation of MLC. Our results suggest that Rac1 coordinates with RhoA to increase MLC phosphorylation by inactivation of CPI-17/MYPT1 phosphatase, which decreases MLCP activity thus promoting MLC phosphorylation and cell contraction.

[Efficacy and safety of piperacillin-tazobactam for febrile neutropenic patients in Japan].

The IDSA guideline for management of febrile neutropenic patients updated in 2010 recommends monotherapy with anti-pseudomonal-lactam agents, including piperacillin-tazobactam (PIPC/TAZ) for high-risk patients. However, clinical studies of PIPC/TAZ are limited in Japanese patients. In this study, we conducted an open-labeled non-randomized prospective trial to examine the efficacy and safety of PIPC/TAZ as an empirical treatment for Japanese patients with febrile neutropenia. Forty-nine febrile episodes in neutropenic patients excluding those undergoing allogeneic stem cell transplantation (high risk 36, low risk 13) were analyzed. The overall response rate was 71%, and no significant differences between the high-risk and the low-risk group were observed (high risk 72%, low risk 69%). Neither PS nor usage of G-CSF affected the response rate. No major side effects were observed in the study. The efficacy and the safety profile of PIPC/TAZ treatment were comparable to those in other previous Western studies. In conclusion, this study suggests PIPC/TAZ is effective and well tolerated as an initial empirical treatment for febrile neutropenic Japanese patients.

CD3- and CD4-positive plasmablastic lymphoma: a literature review of Japanese plasmablastic lymphoma cases.

Plasmablastic lymphoma (PBL) is a very rare and recently-described subtype of diffuse large B-cell lymphoma. A maxillary tumor in an 84-year-old HIV-negative Japanese-man was referred. The biopsied specimen showed a diffuse proliferation of mature plasma cells, expressing CD3 (+), CD4 (+), CD20 (-), CD138 (+) and EBER (+) by immunohistochemistry. He was diagnosed as a plasmablastic lymphoma; radiation therapy (RT) was started, but the response to the RT was only a partial response. To our knowledge, this is the first report of a patient with PBL expressing CD3 and CD4.