Application of quantum computing to a linear non-Gaussian acyclic model for novel medical knowledge discovery.

Recently, the utilization of real-world medical data collected from clinical sites has been attracting attention. Especially as the number of variables in real-world medical data increases, causal discovery becomes more and more effective. On the other hand, it is necessary to develop new causal discovery algorithms suitable for small data sets for situations where sample sizes are insufficient to detect reasonable causal relationships, such as rare diseases and emerging infectious diseases. This study aims to develop a new causal discovery algorithm suitable for a small number of real-world medical data using quantum computing, one of the emerging information technologies attracting attention for its application in machine learning. In this study, a new algorithm that applies the quantum kernel to a linear non-Gaussian acyclic model, one of the causal discovery algorithms, is developed. Experiments on several artificial data sets showed that the new algorithm proposed in this study was more accurate than existing methods with the Gaussian kernel under various conditions in the low-data regime. When the new algorithm was applied to real-world medical data, a case was confirmed in which the causal structure could be correctly estimated even when the amount of data was small, which was not possible with existing methods. Furthermore, the possibility of implementing the new algorithm on real quantum hardware was discussed. This study suggests that the new proposed algorithm using quantum computing might be a good choice among the causal discovery algorithms in the low-data regime for novel medical knowledge discovery.

Impact of a Clinical Text-Based Fall Prediction Model on Preventing Extended Hospital Stays for Elderly Inpatients: Model Development and Performance Evaluation.

BACKGROUND: Falls may cause elderly people to be bedridden, requiring professional intervention; thus, fall prevention is crucial. The use of electronic health records (EHRs) is expected to provide highly accurate risk assessment and length-of-stay data related to falls, which may be used to estimate the costs and benefits of prevention. However, no studies to date have investigated the extent to which hospital stays could be shortened through fall avoidance resulting from the use of prediction tools. OBJECTIVE: We first estimated the extended length of hospital stay caused by falls among elderly inpatients. Next, we developed a model that predicts falls using clinical text as input and evaluated its accuracy. Finally, we estimated the potentially shortened hospital stay that would be made possible by appropriate interventions based on the prediction model. METHODS: Patients aged 65 years or older were selected as subjects, and the EHRs of 1728 falls and 70,586 nonfalls were subjected to analysis. The extended-stay lengths were estimated using propensity score matching of 49 associated variables. Bidirectional encoder representations from transformers and bidirectional long short-term memory methods were used to predict falls from clinical text. The estimated length of stay and the outputs of the prediction model were used to determine stay reductions. RESULTS: The extended length of hospital stay due to falls was estimated to be 17.8 days (95% CI 16.6-19.0), which dropped to 8.6 days when there were unobserved covariates at an odds ratio of 2.0. The accuracy of the prediction model was as follows: area under the receiver operating characteristic curve, 0.851; F-value, 0.165; recall, 0.737; precision, 0.093; and specificity, 0.839. When assuming interventions with 25% or 100% effectiveness against cases where the model predicted a fall, the stay reduction was estimated at 0.022 and 0.099 days/day, respectively. CONCLUSIONS: The accuracy of the prediction model using clinical text is considered to be higher than the prediction accuracy of conventional assessments. However, our model's precision remained low at 9.3%. This may be due, in part, to the inclusion of cases in which falls did not occur because of preventative interventions during hospitalization. Nonetheless, it is estimated that interventions for cases when falls were predicted will reduce medical costs by 886 Yen/day (~US $6.50/day) of intervention, even if the preventative effect is 25%. Limitations include the fact that these results cannot be extrapolated to short- or long-term hospitalization cases, and that this was a single-center study.

Facility and Regional Factors Associated With the New Adoption of Electronic Medical Records in Japan: Nationwide Longitudinal Observational Study.

BACKGROUND: The rate of adoption of electronic medical record (EMR) systems has increased internationally, and new EMR adoption is currently a major topic in Japan. However, no study has performed a detailed analysis of longitudinal data to evaluate the changes in the EMR adoption status over time. OBJECTIVE: This study aimed to evaluate the changes in the EMR adoption status over time in hospitals and clinics in Japan and to examine the facility and regional factors associated with these changes. METHODS: Secondary longitudinal data were created by matching data in fiscal year (FY) 2011 and FY 2014 using reference numbers. EMR adoption status was defined as "EMR adoption," "specified adoption schedule," or "no adoption schedule." Data were obtained for hospitals (n=4410) and clinics (n=67,329) that had no adoption schedule in FY 2011 and for hospitals (n=1068) and clinics (n=3132) with a specified adoption schedule in FY 2011. The EMR adoption statuses of medical institutions in FY 2014 were also examined. A multinomial logistic model was used to investigate the associations between EMR adoption status in FY 2014 and facility and regional factors in FY 2011. Considering the regional variations of these models, multilevel analyses with second levels were conducted. These models were constructed separately for hospitals and clinics, resulting in four multinomial logistic models. The odds ratio (OR) and 95% Bayesian credible interval (CI) were estimated for each variable. RESULTS: A total of 6.9% of hospitals and 14.82% of clinics with no EMR adoption schedules in FY 2011 had adopted EMR by FY 2014, while 10.49% of hospitals and 33.65% of clinics with specified adoption schedules in FY 2011 had cancelled the scheduled adoption by FY 2014. For hospitals with no adoption schedules in FY 2011, EMR adoption/scheduled adoption was associated with practice size characteristics, such as number of outpatients (from quantile 4 to quantile 1: OR 1.67, 95% CI 1.005-2.84 and OR 2.40, 95% CI 1.80-3.21, respectively), and number of doctors (from quantile 4 to quantile 1: OR 4.20, 95% CI 2.39-7.31 and OR 2.02, 95% CI 1.52-2.64, respectively). For clinics with specified EMR adoption schedules in FY 2011, the factors negatively associated with EMR adoption/cancellation of scheduled EMR adoption were the presence of beds (quantile 4 to quantile 1: OR 0.57, 95% CI 0.45-0.72 and OR 0.74, 95% CI 0.58-0.96, respectively) and having a private establisher (quantile 4 to quantile 1: OR 0.27, 95% CI 0.13-0.55 and OR 0.43, 95% CI 0.19-0.91, respectively). No regional factors were significantly associated with the EMR adoption status of hospitals with no EMR adoption schedules; population density was positively associated with EMR adoption in clinics with no EMR adoption schedule (quantile 4 to quantile 1: OR 1.49, 95% CI 1.32-1.69). CONCLUSIONS: Different approaches are needed to promote new adoption of EMR systems in hospitals as compared to clinics. It is important to induce decision making in small- and medium-sized hospitals, and regional postdecision technical support is important to avoid cancellation of scheduled EMR adoption in clinics.

Board certification and urban-rural migration of physicians in Japan.

BACKGROUND: The board certification system serves as a quality assurance system for physicians, and its design and operation are important health policy issues. In Japan, board certification was established and operated independently by academic societies and has not been directly linked to reimbursement systems. The phenomenon of younger physicians seeking specialist careers has raised concerns about acceleration of the tendency of fewer physicians working in rural areas and the maldistribution of physicians. Little is known about the associations between physicians' geographical migration patterns and board certification status changes or between the continuation of urban/rural practice and the maintenance of board certification. This study aimed to identify these associations and to discuss their policy implications. METHODS: We analyzed 2012 and 2014 data from the Survey of Physicians, Dentists, and Pharmacists, a national census survey. To analyze geographical migration patterns, transitions in practice location (rural, intermediate, and urban) were analyzed by board certification status change (new, lost, consistently certified, and consistently uncertified). Logistic regression analysis was conducted to assess whether the odds of migrating to more urban/rural municipalities were associated with board certification status changes, adjusting for covariates, and whether practicing in a rural area was associated with maintaining board certification. RESULTS: Among 18,726 newly board-certified physicians, 94.9% (13,435/14,150) of those working in urban areas before certification remained in urban areas, whereas 64.6% (393/608) of those working in rural areas stayed in rural areas. Those who were newly certified had higher odds of moving to more urban areas, adjusting for covariates. Those who stayed in rural areas showed lower odds of maintaining board certification, adjusting for covariates. CONCLUSIONS: Newly board-certified physicians are more likely to migrate to other types of areas, particularly more urban areas, than other physicians. Allocating more training quotas to rural areas could be one option for leveling the distribution of specialists. It also appeared that those practicing in rural areas have difficulty maintaining their certification, so the need to establish a support system for already-certified physicians in rural areas should be emphasized.

A stable pulsed power supply for multi-beamline XFEL operations.

Since an X-ray Free Electron Laser (XFEL) facility is a linac-based single-user machine, a multi-beamline mode of operation, which improves the efficiency of user experiments, is critical for accommodating users' rapidly increasing demand for beamtime. A key supporting technology is a highly stable pulsed power supply (PS), which enables stable XFEL operations by precisely switching the beam route. We developed a high-power pulsed PS to drive a kicker magnet installed in a SACLA's beam switching system. SiC MOSFETs were adapted as switching elements to reduce the required size and to increase the electric power efficiency. The PS we developed provides two key capabilities: (i) a high current stability of 20 ppm (peak-to-peak) at a peak power of 0.24 MW and (ii) generation of controllable, bipolar, and trapezoidal current waveforms at 60 Hz. This paper describes the overall concept, the detailed design, the performance achieved, and the initial beam test results.

Regional differences in electronic medical record adoption in Japan: A nationwide longitudinal ecological study.

PURPOSE: Regional differences in the adoption of electronic medical records (EMR) are a major problem, yet little is known about these differences internationally. We analyzed regional differences in EMR adoption in Japan and evaluated factors associated with these differences. METHODS: This nationwide ecological study used secondary data from all secondary medical service areas (SMSAs) in fiscal years 2008 (n = 348) and 2014 (n = 344). For each SMSA we collected the following information from a Japanese national database: the number of medical facilities that had adopted EMR, the population density, the average per capita income, the number of working doctors per 1000 people, and the proportion of interns to all working doctors. To adjust for medical facility characteristics in each SMSA, such as number of beds, public versus private hospital, and hospital type (psychiatric or other), we estimated the standardized adoption ratio (SAR) for EMR adoption, modeled on the standardized mortality ratio. We calculated Moran's I for the SAR and investigated whether the SAR had spatial autocorrelations. We evaluated the association between the SAR and regional factors with a conditional autoregressive model. We compared these results in 2008 and 2014, for both hospitals and clinics. RESULTS: While the EMR adoption rate in SMSAs increased, Moran's I of the SAR in hospitals was close to 1 in both 2008 and 2014, and Moran's I of the SAR in clinics increased from 2008 to 2014. For hospitals, there was a significant association between the proportion of interns to all working doctors and the SAR only in 2008. For clinics, average income in the SMSA was positively associated with the SAR, whereas the number of working doctors was negatively associated with the SAR in both 2008 and 2014. Population density was positively associated with the SAR only in 2014. CONCLUSION: From 2008 to 2014, EMR adoption in Japan generally increased, but geographical differences did not improve. Regional factors associated with the SAR were different for hospitals than for clinics. Therefore, the government should take different approaches for clinics and hospitals to improve regional differences in EMR adoption, especially in providing financial and technical support.

Association between number of institutions with coronary computed tomography angiography and regional mortality ratio of acute myocardial infarction: a nationwide ecological study using a spatial Bayesian model.

BACKGROUND: Coronary computed tomography angiography (CTA) has demonstrated high diagnostic accuracy for detection of coronary artery stenosis, and healthcare providers can detect coronary artery disease in earlier stages before it develops into more serious clinical conditions such as acute myocardial infarction (AMI). We hypothesized that the mortality ratio of AMI in regions with a higher density of coronary CTA is lower than that in regions with a lower density of coronary CTA. METHODS: This ecological and cross-sectional study using secondary data targeted all secondary medical service areas (SMSAs) in Japan (n = 349). We obtained the numbers of cardiologists, institutions with coronary CTA, and institutions with a cardiac catheterization laboratory (CCL) as medical resources, socioeconomic factors, lifestyle factors, exercise habit factors, and AMI mortality data from a Japanese national database. We evaluated the association between the number of these medical resources and the standardized mortality ratio (SMR) of AMI in each SMSA using a hierarchical Bayesian model accounting for spatial autocorrelation (i.e., a conditional autoregressive model). We assumed a Poisson distribution for the observed number of AMI-related deaths and set the expected number of AMI-related deaths as the offset variable. RESULTS: The number of institutions with coronary CTA was negatively and significantly associated with the SMR of AMI (relative risk [RR] 0.900; 95% credible interval [CI] 0.848-0.953), while the SMR in each SMSA was not significantly associated with the number of either cardiologists (RR 0.997; 95% CI 0.988-1.004) or institutions with a CCL (RR 1.026; 95% CI 0.963-1.096). CONCLUSIONS: We observed a significant association between the number of institutions with coronary CTA and the SMR of AMI. Effective allocation of coronary CTA in each region is recommended, and it would be important to clarify the standing position of coronary CTA in regional networking for AMI treatment in the future.

Evaluation of cognitive and social functioning in patients requiring long-term inpatient psychiatric care using the International Classification of Functioning, Disability, and Health: a large-scale, multi-institutional observational study.

PURPOSE: We comprehensively evaluated cognitive and social functioning in patients requiring long-term inpatient psychiatric care using the International Classification of Functioning, Disability, and Health. METHOD: We surveyed 1967 patients receiving long-term inpatient psychiatric care. Patients were further categorized into an old long-stay group (n = 892, >5 years in hospitals) and a new long-stay group (n = 1075, 1-5 years in hospitals). We obtained responses for all the International Classification of Functioning, Disability, and Health items in domain b (Body Functions) and domain d (Activities and Participation). We estimated weighted means for each item using the propensity score to adjust for confounding factors. RESULTS: Responses were received from 307 hospitals (response rate of hospitals: 25.5%). Cognitive and social functioning in the old long-stay group was more severely impaired than in the new long-stay group. No statistically significant differences were observed regarding the International Classification of Functioning, Disability, and Health items associated with basic activities of daily living between the two groups. CONCLUSION: Combined therapy consisting of cognitive remediation and rehabilitation on social functioning for this patient population should be started from the early stage of hospitalization. Non-restrictive, independent environments may also be optimal for this patient population. Implications for rehabilitation Rehabilitation of cognitive and social functioning for patients requiring long-term inpatient psychiatric care should be started in the early stages of hospitalization. In psychiatric fields, the International Classification of Functioning, Disability, and Health checklist could facilitate individualized rehabilitation planning by allowing healthcare professionals to visually assess the comprehensive functioning of each patient using graphics such as radar charts.

Internal medicine board certification and career pathways in Japan.

BACKGROUND: Establishing and managing a board certification system is a common concern for many countries. In Japan, the board certification system is under revision. The purpose of this study was to describe present status of internal medicine specialist board certification, to identify factors associated with maintenance of board certification and to investigate changes in area of practice when physicians move from hospital to clinic practice. METHODS: We analyzed 2010 and 2012 data from the Survey of Physicians, Dentists and Pharmacists. We conducted logistic regression analysis to identify factors associated with the maintenance of board certification between 2010 and 2012. We also analyzed data on career transition from hospitals to clinics for hospital physicians with board certification. RESULTS: It was common for physicians seeking board certification to do so in their early career. The odds of maintaining board certification were lower in women and those working in locations other than academic hospitals, and higher in physicians with subspecialty practice areas. Among hospital physicians with board certification who moved to clinics between 2010 and 2012, 95.8% remained in internal medicine or its subspecialty areas and 87.7% maintained board certification but changed their practice from a subspecialty area to more general internal medicine. CONCLUSION: Revisions of the internal medicine board certification system must consider different physician career pathways including mid-career moves while maintaining certification quality. This will help to secure an adequate number and distribution of specialists. To meet the increasing demand for generalist physicians, it is important to design programs to train specialists in general practice.

Association between the Density of Physicians and Suicide Rates in Japan: Nationwide Ecological Study Using a Spatial Bayesian Model.

BACKGROUND: Regional disparity in suicide rates is a serious problem worldwide. One possible cause is unequal distribution of the health workforce, especially psychiatrists. Research about the association between regional physician numbers and suicide rates is therefore important but studies are rare. The objective of this study was to evaluate the association between physician numbers and suicide rates in Japan, by municipality. METHODS: The study included all the municipalities in Japan (n = 1,896). We estimated smoothed standardized mortality ratios of suicide rates for each municipality and evaluated the association between health workforce and suicide rates using a hierarchical Bayesian model accounting for spatially correlated random effects, a conditional autoregressive model. We assumed a Poisson distribution for the observed number of suicides and set the expected number of suicides as the offset variable. The explanatory variables were numbers of physicians, a binary variable for the presence of psychiatrists, and social covariates. RESULTS: After adjustment for socioeconomic factors, suicide rates in municipalities that had at least one psychiatrist were lower than those in the other municipalities. There was, however, a positive and statistically significant association between the number of physicians and suicide rates. CONCLUSIONS: Suicide rates in municipalities that had at least one psychiatrist were lower than those in other municipalities, but the number of physicians was positively and significantly related with suicide rates. To improve the regional disparity in suicide rates, the government should encourage psychiatrists to participate in community-based suicide prevention programs and to settle in municipalities that currently have no psychiatrists. The government and other stakeholders should also construct better networks between psychiatrists and non-psychiatrists to support sharing of information for suicide prevention.

Increased motility and invasiveness in tumor cells that survive 10 Gy irradiation.

Radiotherapy is an important noninvasive treatment for many types of cancer. However, it has been reported that the proliferative, invasive, and metastatic capacities of tumor cells can be increased in the repopulated tumors that survive radiotherapy. We have previously established a radiation-surviving cell model for the human non-small cell lung cancer cell line H1299 by harvesting relic cells 14 days after irradiation (IR cells). Here, we report that cell invasion, cell migration, and cell adhesion are enhanced in these surviving cancer cells. The mRNA expression levels of matrix metalloproteinases (MMPs), including mmp1, mmp2, and mmp9, were upregulated in IR cells compared with parental cells. A gelatin zymogram, wound healing assay, and invasion assay showed increased MMP activity, cell motility, and invasiveness in IR cells, respectively. Moreover, IR cells adhered more tightly to collagen-coated dishes than parental cells. Consistently, paxillin, phosphorylated FAK, integrin beta1, and vinculin were strongly localized at focal adhesions in IR cells, as visualized by immunofluorescence. In this report, we identify molecules responsible for the malignant properties of tumor cells that survive irradiation. These molecules may be important therapeutic targets for the control of repopulated tumors after radiotherapy.

Adaptor protein Crk induces Src-dependent activation of p38 MAPK in regulation of synovial sarcoma cell proliferation.

The adaptor protein Crk mediates intracellular signaling related to cell motility and proliferation and is implicated in human tumorigenesis. The role of Crk in the growth of human sarcoma has remained unclear, however. The present study shows that Crk-induced activation of Src and subsequent signaling by p38 mitogen-activated protein kinase (MAPK) contribute to the enhanced proliferation of human synovial sarcoma cells. Depletion of Crk by RNA interference markedly inhibited proliferation of the synovial sarcoma cell lines HS-SYII, SYO-1, and Fuji as well as prevented anchorage-independent growth. Conversely, reconstitution with CrkII by authentic small interfering RNA-resistant Crk gene restored proliferation in Crk-silenced SYO-1 cells. Crk-depleted synovial sarcoma cells manifested enhanced transcriptional activity and expression of the p16(INK4A) gene, resulting in their accumulation in G(1) phase of the cell cycle. In response to hepatocyte growth factor stimulation, Crk prominently induced the tyrosine phosphorylation of Grb2-associated binder 1 through activation of Src and focal adhesion kinase, and the Src family kinase inhibitor PP2 almost completely inhibited the proliferation of SYO-1 cells. Crk also induced the phosphorylation of p38 MAPK, and SB203580, a p38 MAPK-specific inhibitor, increased expression of p16(INK4A) gene in SYO-1 cells. Furthermore, SB203580 or depletion of p38 MAPK by small interfering RNA suppressed both the phosphorylation of Akt triggered by hepatocyte growth factor and the proliferation of SYO-1 cells. These results suggest that Crk promotes proliferation of human synovial sarcoma cells through activation of Src and its downstream signaling by a novel p38 MAPK-Akt pathway, with these signaling molecules providing potent new targets for molecular therapeutics.

Visualization of Ras-PI3K interaction in the endosome using BiFC.

Recent studies indicate the importance of spatiotemporal regulation in the diversity and specificity of intracellular signaling. Here, we show that Ras-PI3K signaling plays an important role in the local regulation of phosphatidylinositol metabolism in the endosome through live-cell imaging by using a bimolecular fluorescence complementation technique, in which molecular interaction is indicated by fluorescence emission. Using several possible combinations of Ras and the Ras-binding domain, we identified an optimal set of probe molecules that yielded the most significant increase in fluorescence intensity between the active and inactive forms of Ras. This combination revealed that, among the Ras effectors tested, phosphatidylinositol 3-kinase (PI3K) was specifically implicated in signaling in the endosome. We also found that full length PI3K was recruited to the endosome in EGF- and Ras-dependent manners, which appears to be essential for the activation of PI3K in this compartment. Taken together, these findings demonstrate that the spatiotemporal regulation of Ras-PI3K signaling may dictate the activation of PI3K and subsequent downstream signaling in the endosome.

Integral role of transcription factor 8 in the negative regulation of tumor angiogenesis.

Angiogenesis is involved in various physiologic and pathological conditions, including tumor growth, and is tightly regulated by the orchestration of proangiogenic and antiangiogenic factors. Inhibition of vascular endothelial growth factor (VEGF), the best-established antiangiogenic treatment in cancer, has shown some effectiveness; however, the identification of novel regulators, whose function is independent of VEGF, is required to achieve better outcomes. Here, we show that transcription factor 8 (TCF8) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator. Furthermore, TCF8 is specifically expressed in the endothelium of tumor vessels. Tcf8-heterozygous knockout mice are more permissive than wild-type mice to the formation of tumor blood vessels in s.c. implanted melanoma, which seems to contribute to the more aggressive growth and the lung metastases of the tumor in mutant mice. Suppression of TCF8 facilitates angiogenesis in both in vitro and ex vivo models, and displays comprehensive cellular phenotypes, including enhanced cell invasion, impaired cell adhesion, and increased cell monolayer permeability due to, at least partly, MMP1 overexpression, attenuation of focal adhesion formation, and insufficient VE-cadherin recruitment, respectively. Taken together, our findings define a novel, integral role for TCF8 in the regulation of pathologic angiogenesis, and propose TCF8 as a target for therapeutic intervention in cancer.

Transcription factor 8 activates R-Ras to regulate angiogenesis.

We have recently reported that transcription factor 8 (TCF8) negatively regulates pathological angiogenesis by regulating endothelial invasiveness by acting as a transcriptional attenuator of matrix metalloproteinase 1. TCF8 also modulates cell-matrix and cell-cell adhesion; however molecular mechanism of this TCF8 function remains obscure. Here, we provide evidence that TCF8 activates R-Ras, another class of angiogenic regulator, to suppress angiogenesis by a mechanism other than a transcriptional attenuator. Tube formation by human umbilical vein endothelial cells (HUVECs) facilitated by TCF8 suppression was significantly inhibited by the expression of constitutive active mutant of R-Ras. When we examined the mRNA expression levels of R-Ras regulators, no significant changes were observed to explain the R-Ras activation by TCF8. Interestingly, we found that TCF8 bound to CalDAG-GEFIII, an R-Ras activator, in the cytosol, indicating that TCF8 emanates signaling for R-Ras activation from cytosol to regulate angiogenesis negatively.

Pulsatile mechanical pressure promotes Angiotensin-converting enzyme expression in aortic smooth muscle cells.

BACKGROUND: Hypertension is a major risk factor for atherosclerosis, and elevated pressure (i.e., mechanical pressure stresses) has been known to modulate vascular remodeling, possibly by affecting the tissue renin-angiotensin system. METHODS: In the present study we applied pulsatile pressure to human aortic smooth muscle cells (HASMCs) and investigated whether mechanical pressure stress affects cell proliferation and/or the angiotensin-converting enzyme (ACE), and we tested whether the administration of an angiotensin II (AII) receptor blocker has a favorable effect. RESULTS: Three hours of pulsatile atmospheric pressure resulted in an approximately 8% increase in cell proliferation of human aortic smooth muscle cells. The cell surface ACE level, enzyme activity and mRNA expression were all elevated (37%, 110% and 17%, respectively) under pressurized conditions, and co-administration of AII reduced all these values. The reductions in these three parameters resulting from the administration of AII were all abolished by AII receptor blocker co-administration and values were increased (11%, 62% and 12%, respectively) under pressurized conditions. Pulsatile atmospheric pressure increased the amount of phosphorylated extracellular signal-regulated kinase (ERK) by approximately 54% in HASMCs. The administration of PD98059 (10 microM) resulted in a decrease in phosphorylated ERK and ACE activity in HASMCs compared to those of the pressurized control. CONCLUSION: From these observations, we conclude that pulsatile mechanical pressure is one of the mediators of ACE production in vascular smooth muscle cells and that AII receptor blocking may prevent negative feedback. The present findings may provide a potential therapeutical target beyond lowering blood pressure in hypertensive patients.

PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling.

Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer.

Functional identification of the primary motor area by corticospinal tractography.

OBJECTIVE: For quick and stable identification of the primary motor area (PMA), diffusion tensor imaging (DTI) data were acquired and corticospinal tractography was mathematically visualized. METHODS: Data sets of DTI, anatomic magnetic resonance imaging, and functional magnetic resonance imaging with finger-tapping tasks were acquired during the same investigation in 30 patients with a brain lesion affecting the motor system. Off-line processing of DTI data was performed to visualize the corticospinal tract, placing a seed area in the cerebral peduncle of the midbrain, where the corticospinal tract is densely concentrated. Somatosensory evoked magnetic fields and intraoperative cortical somatosensory evoked potentials were recorded with electrical stimulation of the median nerve to confirm the results of the corticospinal tractography. RESULTS: Functional magnetic resonance imaging and somatosensory evoked magnetic fields failed to identify the PMA in eight patients (16.7%) and one patient (3.8%) investigated, respectively, because of cortical dysfunctions caused by brain lesions. DTI data were acquired within 3 minutes without patient tasks. Using the appropriate seed area and fractional anisotropy, corticospinal tractography successfully indicated the PMA location in all patients. The suspected PMA and central sulcus locations were confirmed by the cortical somatosensory evoked potentials. CONCLUSION: Corticospinal tractography enables identification of the PMA and is beneficial, particularly for patients who present with dysfunction of the PMA.

Evidence for the involvement of the cyclooxygenase-metabolic pathway in diclofenac-induced inhibition of spontaneous contraction of rat portal vein smooth muscle cells.

The effects of diclofenac, a cyclooxygenase (COX) inhibitor, were investigated on spontaneous phasic contractions of longitudinal preparations of the rat portal vein. Diclofenac produced a concentration-dependent decrease in the amplitude of these spontaneous phasic contractions. Diclofenac (30 microM) decreased the amplitude of the spontaneous phasic increase in the F340/F380 ratio of Fura PE3, an indicator of intracellular Ca2+ concentration. It also reduced the number of action potentials in each burst discharge without changing the resting membrane potential of longitudinal smooth muscle cells. The extent of the distribution of Lucifer Yellow injected into a smooth muscle cell was decreased in the presence of diclofenac (30 microM). Both AH6809, a prostanoid EP receptor antagonist, and SQ22536, an adenylate cyclase inhibitor, decreased the amplitude of the spontaneous contractions. On the other hand, neither ozagrel, a thromboxane synthase inhibitor, nor SQ29548, a prostanoid TP receptor antagonist, significantly affected spontaneous contractions. These results indicate that diclofenac inhibits the amplitude of spontaneous contractions of the rat portal vein through inhibition of electrical activity, which may be related to an inhibition of the cyclooxygenase pathway.

Functional identification of the primary motor area by corticospinal tractography.

OBJECTIVE: For quick and stable identification of the primary motor area (PMA), diffusion tensor imaging (DTI) data were acquired and corticospinal tractography was mathematically visualized. METHODS: Data sets of DTI, anatomic magnetic resonance imaging, and functional magnetic resonance imaging with finger-tapping tasks were acquired during the same investigation in 30 patients with a brain lesion affecting the motor system. Off-line processing of DTI data was performed to visualize the corticospinal tract, placing a seed area in the cerebral peduncle of the midbrain, where the corticospinal tract is densely concentrated. Somatosensory evoked magnetic fields and intraoperative cortical somatosensory evoked potentials were recorded with electrical stimulation of the median nerve to confirm the results of the corticospinal tractography. RESULTS: Functional magnetic resonance imaging and somatosensory evoked magnetic fields failed to identify the PMA in eight patients (16.7%) and one patient (3.8%) investigated, respectively, because of cortical dysfunctions caused by brain lesions. DTI data were acquired within 3 minutes without patient tasks. Using the appropriate seed area and fractional anisotropy, corticospinal tractography successfully indicated the PMA location in all patients. The suspected PMA and central sulcus locations were confirmed by the cortical somatosensory evoked potentials. CONCLUSION: Corticospinal tractography enables identification of the PMA and is beneficial, particularly for patients who present with dysfunction of the PMA.