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Contact tracing for COVID-19 relies heavily on the cooperation of individuals with authorities to provide information of contact persons. However, few studies have clarified willingness to cooperate and motivation to provide information for contact tracing. This study sought to describe willingness to cooperate and motivation to report contact persons for COVID-19 contact tracing among citizens in Japan, and to assess any associated sociodemographic factors.Cross-sectional study.This was an online-based survey using quota sampling. Participants were asked about their willingness to cooperate in reporting contacts for COVID-19 contact tracing if they tested positive. Participants also responded to questions regarding their reasons for cooperating or not cooperating and provided sociodemographic data. Multiple logistic regression analysis was performed to clarify associations between sociodemographic factors and willingness to cooperate.This study included 2844 participants. The proportion of participants who were not willing to cooperate in reporting contacts was 27.6%, with their main reasons being concerns about causing trouble for the other person and being criticised for revealing their names. Willingness to cooperate was lower among men, young adults and those with an educational level less than a university degree.To improve the effectiveness of contact tracing, educational campaigns, such as reducing the fear and stigma associated with COVID-19, may be important. Furthermore, it is essential to understand that individuals may have contacts whom they do not wish to disclose to others and to be considerate when handling such situations.

Background: The number of individuals with obesity is growing worldwide and this is a worrying trend, as obesity has shown to cause pathophysiological changes, which result in the emergence of comorbidities such as cardiovascular disease, diabetes mellitus type 2 and cancer. In addition, cognitive performance may be compromised by immunometabolic deregulation of obesity. Although in more critical cases, the use of medications is recommended, a physically active lifestyle is one of the main foundations for health maintenance, making physical training an important tool to reduce the harmful effects of excessive fat accumulation. Aim: The purpose of this review of the literature is to present the impact of immunometabolic alterations on cognitive function in individuals with obesity, and the role of exercise training as a non-pharmacological approach to improve the inflammatory profile, energy metabolism and neuroplasticity in obesity. Method: An overview of the etiology and pathophysiology of obesity to establish a possible link with cognitive performance in obese individuals, with the executive function being one of the most affected cognitive components. In addition, the brain-derived neurotrophic factor (BDNF) profile and its impact on cognition in obese individuals are discussed. Lastly, studies showing regular resistance and/or aerobic training, which may be able to improve the pathophysiological condition and cognitive performance through the improvement of the inflammatory profile, decreased insulin resistance and higher BDNF production are discussed. Conclusion: Exercise training is essential for reestablishment and maintenance of health by increasing energy expenditure, insulin resistance reduction, anti-inflammatory proteins and neurotrophin production corroborating to upregulation of body function.

Probe electrospray ionization mass spectrometry (PESI-MS) is an ambient ionization-based mass spectrometry method that surpasses the original electrospray ionization technique in features such as the rapidity of analysis, simplicity of the equipment and procedure, and lower cost. This study found that the PESI-MS system with machine learning has the potential to establish a lipid-based diagnosis of breast cancer with higher accuracy, using a simpler approach. Rapid mass spectrometry for breast cancer.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

The use of azacitidine (AZA) has been known to lead to a high incidence of hematotoxic adverse events. The aims of this study were to identify the risk factors for thrombocytopenia after the administration of AZA and to analyze time to the initial platelet transfusion. Sixty-two patients with myelodysplastic syndrome (MDS), who were treated with AZA in Gifu Municipal Hospital between March 2012 and June 2020, were included in this study. The risk factors for thrombocytopenia were identified using univariate analysis of patient characteristics, disease type, and laboratory values immediately before the start of treatment. Variables with p0.2 identified in the univariate analysis were used as independent variables in the multivariate analysis. This analysis identified "creatinine clearance (CCr)60 mL/min" as a significant factor (odds ratio, 4.790; 95% confidence interval [CI], 1.380-16.70; p=0.014). Subsequently, time in days to the initial platelet transfusion after the initial administration of AZA was analyzed using the log-rank test. The overall median time in days to platelet transfusion was 370 days. The log-rank test was used to determine the influence of patient characteristics, disease type, and laboratory values immediately before the start of treatment. The subsequent Cox proportional hazard regression analysis using variables with p0.2 as independent variables identified "hemoglobin (Hb)8.0 g/dL" as a significant factor (hazard ratio, 2.143; 95% CI, 1.001-4.573; p=0.048). The results of this study led to the following clinical implications: first, patients with CCr of60 mL/min at the start of treatment should be treated with caution due to the risk of thrombocytopenia. Second, patients with Hb of8.0 g/dL at the start of treatment may require platelet transfusion in the early stage of treatment.

Importance: Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. Objective: To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime. Design, Setting, and Participants: Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Interventions: Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. Main Outcomes and Measures: The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause. Results: A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. Conclusions and Relevance: These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. Trial registration: ClinicalTrials.gov Identifier: NCT03036124.

Background The goal was to examine the feasibility of a randomized controlled trial (RCT) on the effect of a therapeutic foot-ankle training program to prevent injury in long-distance runners. First, we evaluated (i) the access to participants and recruitment success; (ii) participants' satisfaction and adherence to the program; (iii) the effect of the training program to improve foot muscle strength and change foot biomechanics; and, second, we used the collected data for a post hoc sample size calculation. Methods/design We randomized 31 healthy long-distance recreational runners to either an 8-week foot-ankle muscle strength-training program (intervention) or a stretching protocol (control). The recruitment rate was the number of eligible participants per week of recruitment; recruitment success, the ratio between scheduled baseline visits and initially eligible participants. Participant satisfaction was assessed by a questionnaire, and adherence to the training program was recorded in a Web-based software, both at the 8-week mark. Program effect was assessed by hallux and toe muscle strength using a pressure platform, foot muscle cross-sectional area using magnetic resonance imaging and foot kinematics during running using 3D gait analysis; assessments were done at baseline and after 8 and 16 weeks. A post hoc power analysis was performed on foot strength and the biomechanical data was collected. Results In two weeks of recruitment, 112 initially eligible subjects were screened, 81 of whom were deemed eligible and 31 had a baseline study visit, giving a recruitment rate of 40.5 subjects/week and recruitment success of 28%. Participants' adherence was 97%, and satisfaction scored a median >3 out of 5 on a Likert scale on all questions. The cross-sectional area of the abductor hallucis (P = 0.040) and flexor digitorum brevis (P = 0.045) increased significantly at 8 weeks in the intervention group. The post hoc sample sizes for almost all the strength and biomechanical parameters were below those of the 112 subjects calculated as the original sample size for clinical outcome (running-related injury). Conclusion Results show that this RCT is feasible, given an accessible study population that is willing to participate and that perceives the training program as positive and adheres to the program. The training program leads to several positive outcomes on muscle strength that justifies assessing clinical outcomes in this RCT.

Appropriate goal-oriented treatment strategies are important for optimal treatment outcomes and may prevent under-treatment. As treatment goals vary by patient, a study to examine treatment goals is more meaningful when patients and their physicians are paired. There has not been any study that examines alignment between paired psoriasis patients and physicians in real-world clinical practice using skin clearance as a treatment goal indicator. To evaluate treatment goal alignment between psoriasis patients and their paired physicians, and to quantitatively identify factors associated with goal misalignment. The study was a nationwide multicenter cross-sectional observational study. Subjects were physician-reported moderate to severe psoriasis patients with a history of systemic treatments, directly paired with their treating physicians. Subjects completed surveys independently. Treatment goals included seven categories and patient-physician pairs were grouped as "aligned" or "misaligned" when the answers were the same or different, respectively. A total of 425 pairs (mean response rate, 94.7%) of responses were collected from 54 sites (64.8% General Practitioners or clinics; 35.2% university or large hospitals). Treatment goal misalignment was found in 67.9% of the patient-physician pairs. The misalignment was mainly "patient predominant" (60.9%) indicating that patients had higher goals ("complete clearance") than physicians. In the multivariate logistic regression analyses, patients' treatment expectation for "complete clearance" (odds ratio [OR]: 1.927; 95% confidential interval [CI]: 1.232 to 3.016) and physician rating of "level of understanding on treatment options" being low (OR: 1.552, 95% CI; 1.082 to 2.227) were significant factors for treatment goal misalignment. The majority of treatment goal misalignment was found between paired psoriasis patients and their treating physicians in Japan. The most important contributing factors to misalignment were patients' treatment expectation for "complete clearance" and physicians' rating of their patients' "level of understanding on treatment options" being low. This article is protected by copyright. All rights reserved.

[Background] In this paper we propose the use of global Kalman filters (KFs) to estimate absolute angles of lower limb segments. Standard approaches adopt KFs to improve the performance of inertial sensors based on individual link configurations. In consequence, for a multi-body system like a lower limb exoskeleton, the inertial measurements of one link (e.g., the shank) are not taken into account in other link angle estimations (e.g., foot). Global KF approaches, on the other hand, correlate the collective contribution of all signals from lower limb segments observed in the state-space model through the filtering process. We present a novel global KF (matricial global KF) relying only on inertial sensor data, and validate both this KF and a previously presented global KF (Markov Jump Linear Systems, MJLS-based KF), which fuses data from inertial sensors and encoders from an exoskeleton. We furthermore compare both methods to the commonly used local KF., [Results] The results indicate that the global KFs performed significantly better than the local KF, with an average root mean square error (RMSE) of respectively 0.942° for the MJLS-based KF, 1.167° for the matrical global KF, and 1.202° for the local KFs. Including the data from the exoskeleton encoders also resulted in a significant increase in performance., [Conclusion] The results indicate that the current practice of using KFs based on local models is suboptimal. Both the presented KF based on inertial sensor data, as well our previously presented global approach fusing inertial sensor data with data from exoskeleton encoders, were superior to local KFs. We therefore recommend to use global KFs for gait analysis and exoskeleton control., This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), under Grant 2012/05552–9; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), under Grant 456089/2014–4; the HYPER project of the CONSOLIDER-INGENIO 2010 program of Spain, under Grant CSD2009–00067; the XoSoft project, Soft modular biomimetic exoskeleton to assist people with mobility impairments, contract H2020– ICT24–2016–688175; and by a grant from the Flemish agency for Innovation by Science and Technology (MIRAD, IWT–SBO 120057).

Background and objective Periodontal disease is a chronic inflammatory disease caused by bacterial infection that can lead to tooth loss. Gingival crevicular fluid can be collected easily and noninvasively. We previously discovered the presence of apolipoprotein B (apoB), the main constituent of low-density lipoprotein, and oxidized low-density lipoprotein (oxLDL) in the gingival crevicular fluid of healthy subjects. In this study, we investigated whether periodontal conditions affect the levels of apoB and oxLDL in gingival crevicular fluid. Material and methods The study population comprised 11 patients with chronic periodontitis. A pair of gingival crevicular fluid samples was collected from each patient at a healthy site and at a site with periodontitis (baseline samples). Thereafter, gingival crevicular fluid samples were collected from the same patients again at 4 and 8 wk after scaling and root planing (SRP). The levels of apoB, oxLDL, protein and cytokines in gingival crevicular fluid, in addition to gingival crevicular fluid volume, were measured. Results At baseline, the levels of apoB and oxLDL in gingival crevicular fluid were higher at the sites with periodontitis than at the healthy sites. The levels of apoB and oxLDL at periodontal sites decreased after SRP. The level of oxLDL in gingival crevicular fluid correlated well with the probing pocket depth. The oxLDL : apoB ratio in gingival crevicular fluid was significantly higher than that in plasma. Conclusions The levels of apoB and oxLDL in gingival crevicular fluid change according to the periodontal tissue conditions.

In clinical practice, pharmacists are continually required to improve their knowledge and expertise; however, the postgraduate education system for professional development cannot be confidently stated to be well established. The establishment of a systematic and multifaceted educational curriculum should be useful to improve home care and pharmacists' contribution; therefore, we developed a curriculum in collaboration with the university faculty of pharmaceutical sciences, department of pharmacy in hospital, and the Fukuoka Pharmaceutical Association. Class topics were extracted from the "Kanwa-Iryou-Yakugaku", edited by the Japanese Society for Pharmaceutical Palliative Care and Sciences. The items are necessary to perform palliative care as a pharmacist. A class schedule of 6 days (24 classes in total) was formulated. Questionnaires on comprehension degree before and after each class were provided to the participants. Comprehension was assessed on a scale of 1 to 10, where "I do not understand at all" was 1 and "I understand enough" was 10. The average recovery rates of questionnaires from each class were 92.6 % and 88.9 % before and after class, respectively. The average number of participants who completely answered the questionnaire before and after class was 45.6; therefore, these data were analyzed. Comprehension degree on each topic had significantly increased after attendance of all classes (

Introduction: The association between obesity and physical activity level is well established in the literature, as well as its consequences that lead to chronic noncommunicable diseases. In addition, it is also possible to obtain the immunometabolic mechanism that explains the pathway of associations between obesity, chronic noncommunicable diseases and level of physical activity. It also seems clear that treating illnesses has a financial impact on healthcare systems around the world, so it seems important to assess the financial impact on the healthcare system of individuals with immunometabolic dysfunction. Aim: To assess whether there is a correlation between metabolic and inflammatory markers and healthcare costs according to body adiposity and habitual physical activity (HPA). Methods: cross-sectional study, the sample consisted of men and women aged over 50. Participants underwent evaluations that included the following variables: i) immunometabolic markers, ii) healthcare costs, iii) obesity, iv) habitual physical activity, and v) history of personal illness. Statistical significance was set at values lower than 5% and the software used was BioEstat. Results: The correlation between metabolic and inflammatory markers and healthcare costs demonstrated a positive and significant relationship, adjusted for obesity and HPA, between glucose concentrations and exam costs (r = 0.343, p-value = 0.007) and total cost (r = 261; p-value = 0.043); HOMA index and cost of exams (r = 0.267; p-value = 0.038); and IL-10 and cost of medical consultation (r = 0.297; p-value = 0.020). Conclusion: Metabolic and inflammatory markers may be related to the costs of consultations and examinations, independent of obesity and HPA.

Chemotherapy for cancer is increasingly implemented in the outpatient setting. Pharmacists contribute to cancer treatment by conducting counseling during outpatient chemotherapy visits. They provide guidance on drug treatment, side effects, and side effect countermeasures on every visit. However, there have been few economic evaluations of pharmacist involvement in outpatient chemotherapy. Therefore, we performed a cost utility analysis. We assigned usual care (control) and pharmacist counseling to two groups of 19 patients receiving outpatient chemotherapy for breast cancer at Gifu Municipal hospital. Quality of life was measured at three timepoints before and during chemotherapy treatment using the EuroQol 5 dimension instrument (EQ-5D). EQ-5D values across the timepoints were 0.831, 0.757, and 0.791 for the control group, and 0.882, 0.883, and 0.921 for the pharmacist counseling group. The additional cost in the pharmacist counseling group was 2,227 yen per counseling session. The change in quality-adjusted life years (QALY) was a maximum of -0.021±0.186 in the control group and 0.007±0.199 in the pharmacist counseling group. The maximum cost for one QALY was 1,360,558 yen (≈12,460 US dollars). Pharmacists' counseling in outpatient cancer chemotherapy for breast cancer patients had an acceptable incremental cost-effect ratio, contributing to improved patient quality of life without significant additional expenditure to healthcare.

BACKGROUND The precise mechanism involved in the acquisition of the IL-17+ profile of γδT cells, the ligands responsible for this change, and whether this default is acquired during intrathymic maturation need to be elucidated. OBJECTIVE This study aimed to evaluate whether IL-17-producing γδT cells are present in the airways of tolerant offspring from allergen-sensitized mothers and the possible implication of maternal IgG in the generation of these cells. METHODS Female mice were immunized or not, and the allergic response, frequency of γδT cell subsets and cytokine production of the offspring were analysed by flow cytometry. The effects of passive in vivo transfer of purified IgG were investigated in offspring. A translational approach was employed to analyse γδT cells in the thymus and PBMCs from humans. RESULTS Maternal immunization reduced the frequency of spontaneous IL-17-producing γδT cells in the thymus, spleen and lung of offspring. This effect was mimicked by the in vivo treatment of females with purified IgG. IgG directly interacted with γδT cell membranes. The modulatory effect of human IgG on human infant intrathymic and adult peripheral γδT cells showed similarities to murine γδT cells, which is rarely reported in the literature. CONCLUSIONS & CLINICAL RELEVANCE Together, our results reveal that IgG from potentially tolerant atopic mothers can influence offspring thymic IL-17-producing γδT cell maturation. Furthermore, we suggest that IgG is an unprecedented modulatory factor of murine and human γδT cells. These observations may support the future development of IgG-based immunoregulatory therapeutic strategies.

Our group recently demonstrated that IgG modulates αβT cell cytokine production during the maturation process in the human thymus. The effects of this modulation are IgG repertoire dependent and can exert a systemic and long-term impact.To investigate whether IgG from atopic dermatitis (AD) patients can modulate cytokine production of infant intrathymic TCD4 and TCD8 cells in vitro.Thymic tissues were obtained from newborn children from nonatopic mothers, and thymocytes were cultured for 6 days with purified IgG from AD patients or with intravenous immunoglobulin (IVIG) or mock conditions as controls. Cells were gated as double positive T cells (TDPCompared to mock and IVIG culture conditions, IgG of AD individuals induced in vitro intracellular production of IL-17 and IL-10 by intrathymic TDP, TCD4, and TCD8 cells of infants. TGF-β was also detected at a higher frequency in response to AD IgG in TDP and TCD8 cells compared to mock and IVIG cultured conditions. An opposite effect was detected upon IFN-γ production in TCD4 cells, such that AD IgG reduced IFN-γ production compared to production under mock conditions but not under IVIG conditions.IgG of AD patients can stimulate cytokine production in infant thymocytes and thus resembles the peripheral profile observed in adults. These findings suggest a novel mechanism that can contribute to AD pathogenesis.

BACKGROUND This study aimed to analyze the effects of high-intensity intermittent training (HIIT) plus strength training on body composition, hormone related to energy balance (leptin), and hunger scores in physically active non-obese men. METHODS Sixteen men were allocated in two different groups, training group (N.=10) performed a combined HIIT (5 km, 1 minute of effort interspersed by 1 minute of rest in passive recovery) followed by strength exercise session (three sets, with load of 8-12 repetition maximum) twice a week, during 8 weeks, while control group (N.=6) did not suffer any intervention. Hunger scores, leptin concentrations and body composition were assessed. Body composition, fasting leptin and hunger score were compared through two-way analysis (group and period) with repeated measures in the second factor while leptin and hunger scores in exercise session pre- and post-8 weeks through two-way analysis (period and time of measurement) with repeated measures in the second factor. RESULTS The fasting leptin decreased pre- to post-8week in training group (7.7±4.9 to 2.9±2.1 ng/mL; P=0.012). For leptin response to exercise session there was main effect of training period, with higher values pre- (6.5±3.9 ng/mL) than post-training (2.6±2.1 ng/mL; P

Aims To evaluate the efficacy and safety of the selective sodium glucose co-transporter 2 inhibitor dapagliflozin in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by diet and exercise. Methods Patients received placebo or dapagliflozin (5 or 10 mg) once daily for 24 weeks. The primary outcome measure was change from baseline in glycated haemoglobin (HbA1c). Results Patients (N = 261) had modestly elevated baseline HbA1c (mean ≈ 7.5%) and most had mild or moderate renal impairment (estimated glomerular filtration rate range 43–103 ml/min/1.73 m2). Greater reductions in mean HbA1c level were observed with dapagliflozin (5 mg, −0.41%; 10 mg, −0.45%) than with placebo (−0.06%) at week 24 and these were greater in patients with higher baseline HbA1c levels. Fasting plasma glucose (FPG) was also significantly reduced with dapagliflozin (5 mg, −8.6 mg/dl; 10 mg, −13.7 mg/dl) compared with placebo (+5.8 mg/dl). Dapagliflozin significantly reduced body weight (5 mg, −2.13 kg; 10 mg, −2.22 kg) compared with placebo (−0.84 kg). Overall, 47.7 and 64.8% of patients with dapagliflozin 5 and 10 mg, respectively, and 51.7% with placebo experienced ≥1 adverse event, mostly mild or moderate, and unrelated to study treatment. Two patients on dapagliflozin 10 mg reported hypoglycaemia. Four patients across all groups reported events suggestive of genital infection and four of urinary tract infection. No events of pyelonephritis were reported. Conclusion Dapagliflozin (5 and 10 mg) was well tolerated and effective in reducing HbA1c, FPG and body weight over 24 weeks in Japanese patients with T2DM inadequately controlled by diet and exercise.

In this paper, we deal with Markov Jump Linear Systems-based filtering applied to robotic rehabilitation. The angular positions of an impedance-controlled exoskeleton, designed to help stroke and spinal cord injured patients during walking rehabilitation, are estimated. Standard position estimate approaches adopt Kalman filters (KF) to improve the performance of inertial measurement units (IMUs) based on individual link configurations. Consequently, for a multi-body system, like a lower limb exoskeleton, the inertial measurements of one link (e.g., the shank) are not taken into account in other link position estimation (e.g., the foot). In this paper, we propose a collective modeling of all inertial sensors attached to the exoskeleton, combining them in a Markovian estimation model in order to get the best information from each sensor. In order to demonstrate the effectiveness of our approach, simulation results regarding a set of human footsteps, with four IMUs and three encoders attached to the lower limb exoskeleton, are presented. A comparative study between the Markovian estimation system and the standard one is performed considering a wide range of parametric uncertainties.

Aim Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control. Methods Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and proportion of patients achieving HbA1c

An increased platelet count is often observed in lung cancer patients. Whether and how the platelets affect cancer progression have yet to be established. The aim of the study was to investigate the involvement of the platelet count and mean platelet volume (MPV) in the prognosis and progression of lung cancer patients. This retrospective study included 146 patients with newly diagnosed primary lung cancer. The platelet count and MPV were measured before invasive diagnostic procedures and treatment. These platelet indices, overall survival of the patients, and tumor metastases for each organ were analyzed. On Kaplan-Meier survival analysis, the overall survivals of patients with platelet counts ≤ 244.0 × 109/L or MPV > 9.7 fL were longer than those of patients with platelet counts > 244.0 × 109/L or MPV ≤ 9.7 fL. Cox regression analysis showed that poor performance status, increased platelet count, and increased C-reactive protein were independent prognostic factors. The platelet indices were associated with metastases to bone, soft tissue, and lymph node, in addition to malignant pleural effusion. Increased platelet count and decreased MPV were unfavorable prognostic factors for patients with lung cancer, and they were involved in bone, soft tissue, and lymph node metastases and malignant pleural effusion.

Inoue, DS, Panissa, VLG, Monteiro, PA, Gerosa-Neto, J, Rossi, FE, Antunes, BMM, Franchini, E, Cholewa, JM, Gobbo, LA, and Lira, FS. Immunometabolic responses to concurrent training: the effects of exercise order in recreational weightlifters. J Strength Cond Res 30(7): 1960-1967, 2016-The relationship between immunometabolic response and performance is not well understood. This study evaluated the influence of concurrent strength and high-intensity aerobic sequence of exercise order between sessions on strength performance, metabolic, and inflammatory response. Eleven recreational weightlifters underwent the following 2 randomized sessions: (a) strength-aerobic exercise order (SA) and (b) aerobic-strength exercise order (AS). Blood samples were collected before (Pre) and immediately after the first exercise (Post-1) and the second exercise (Post-2) of each session. The SA condition presented a higher number of repetitions (SA: 54 ± 15 vs. AS: 43 ± 12) and total volume (SA: 7,265 ± 2,323 vs. AS: 5,794 ± 1846 kg) than the AS condition (both p = 0.001). Glucose was higher in Pre when compared with post-1 in both orders (p ≤ 0.05); changes in lactate were time-dependent in the different orders (p ≤ 0.05); however, AS post-2 lactate was lower when compared with SA post-2 (p ≤ 0.05). Interleukin-6 levels showed time-dependent changes for both exercise orders (p ≤ 0.05). Tumor necrosis factor alpha (TNF-α) level was increased only in AS post-1 (AS: pre = 21.91 ± 35.47, post-1 = 26.99 ± 47.69 pg·ml vs. SA: pre = 25.74 ± 43.64, post-1 = 29.74 ± 46.05 pg·ml, p ≤ 0.05). These results suggest that concurrent training order exhibits different immunometabolic responses and, at least in part, can be associated with the acute decline in strength performance induced by concurrent exercise. Our results point to a possible role of TNF-α (post-1 AS condition) as a trigger to restore the energy demand by providing substrates to help maintain contractile activity in skeletal muscle.

Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-β-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-β-induced EMT, and found that TGF-β induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-β-mediated upregulation of δEF1 family proteins, δEF1 and SIP1. δEF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both δEF1 and SIP1, but not either alone, abolished the TGF-β-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of δEF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-β-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, δEF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-β-induced EMT and the progression of breast cancers.

Sakiyama Y, Kato R, Inoue S, Suzuki K, Itabe H, Yamamoto M. Detection of oxidized low-density lipoproteins in gingival crevicular fluid from dental patients. J Periodont Res 2009; doi: 10.1111/j.1600-0765.2009.01226.x. © 2009 John Wiley & Sons A/S Background and Objective: Oxidative modification of low-density lipoprotein (LDL) occurs in various diseased tissues and sites of local inflammation. For example, an increased plasma oxidized low-density lipoprotein (OxLDL) level is a well-known risk marker for cardiovascular diseases. Gingival crevicular fluid, the exudate from gingival tissues into the sulci, can be easily collected in a non-invasive manner. However, the possible presence of OxLDL in gingival crevicular fluid has not been studied. In this study, we established a procedure to measure OxLDL in human gingival crevicular fluid. Material and Methods: Human gingival crevicular fluid was sampled with paper points or paper strips. The gingival crevicular fluid samples from healthy gingival sulci (pocket depth

Tumour necrosis factor alpha (TNFalpha) has come to be regarded as a potential osteoporotic factor, because it has stimulatory effects on cells of the osteoclast lineage and has been implicated in the pathogenesis of bone loss associated with oestrogen deficiency. We recently described genetic linkage between the TNFalpha locus and human osteoporosis by sib-pair analysis. However, the molecular mechanism by which this locus regulates bone mineral density (BMD) remains unknown.We investigated whether the observed linkage reflects a sequence variation which might affect expression of the TNFalpha gene or alter the function of TNFalpha protein.We examined three single-nucleotide polymorphisms (SNPs) of the TNFalpha gene in a group of 390 postmenopausal Japanese women living in northern Japan. Minor-allele frequencies for the three SNPs (-1031C, -863A and -857T) in this population were 0.16, 0.13 and 0.20, respectively.Among the three SNPs examined, we observed a significant correlation only between the presence of a T allele at nt -1031 and decreased BMD, by analysis of variance. Among the three genotypic groups at nt -1031, mean BMD values were significantly higher in the T-negative genotype (C/C homozygotes; mean SD = 0.342 +/- 0.052 g cm(-2)), compared with T-positive genotypes (T/T homozygotes, 0.309 +/- 0.062 g cm(-2); p = 0.0253 and T/C heterozygotes, 0.305 +/- 0.062 g cm(-2); p = 0.0164).Given the lines of evidence from different genetic studies, we suggest that TNFalpha may play a role in pathogenesis of osteoporosis.

Objective The objective of this paper is to identify predictors for the response to treatment of acute lupus hemophagocytic syndrome (ALHS). Methods We reviewed seven cases with ALHS admitted to our hospital and published ALHS cases identified in the 2001–2014 Medline database, and then conducted univariate and multivariate analyses to identify predictors for the response to treatment. Results Review of our cases showed a significant and negative correlation between serum ferritin and anti-DNA antibody ( p = 0.0025). All three patients treated with cyclosporine A (CsA) were considered responders despite high serum ferritin and corticosteroid resistance. We also reviewed 93 patients with ALHS identified in 46 articles. Multiple logistic regression analysis identified C-reactive protein (CRP) (OR 0.83, p = 0.042) and hemoglobin (OR 1.53, p = 0.026) measured at diagnosis of ALHS as significant predictors of the response to corticosteroid monotherapy. Moreover, among 32 patients treated with CsA, serum ferritin was significantly higher in CsA responders (12163 ± 16864 µg/l, n = 22) than in non-responders (3456 ± 6267/µg/l, p = 0.020, n = 10). Leukocyte count was significantly lower in the CsA responders (1940.0 ± 972.3/µl) than in the non-responders (3253 ± 2198/µl, p = 0.034). Conclusion Low CRP and high hemoglobin can predict a positive response to corticosteroid monotherapy while high serum ferritin and low leukocyte count can predict a positive response to CsA in patients with ALHS and therefore, when corticosteroid monotherapy is not effective in such cases, CsA could be the first choice of an additional immunosuppressive agent.

In order to clarify the effects of medical education on attitudes towards mental illness among medical students, a follow-up study was conducted. All 100 students entering Kochi Medical School in 1988 were subjects. The initial questionnaire survey was conducted in 1988, and followed up in 1993. Response rate was 69% in the initial survey, and 83% in the follow-up study. By the time of the follow-up, all of the students had completed their medical education, including courses in psychiatry and mental health. Results were as follows: At the follow-up study, 1) a significantly higher percentage of students replied that they accepted the mentally ill as co-workers; 2) significantly favorable changes were observed in attitudes towards psychiatric services; 3) optimism about the effectiveness of treatment for mental illness at an early stage and prevention of mental illness had decreased; and 4) no change was observed in attitudes toward human rights of the mentally ill, except in the case of one item stating that the mentally ill should not have children in order to avoid hereditary handicaps, with which a lower percentage agreed. Conclusively, medical education can play an important role in attitudes towards mental illness.

The pathogenesis of osteoporosis is controlled by genetic and environmental factors. Considering the high prevalence of osteoporosis in homocystinuria, abnormal homocysteine metabolism would contribute to the pathogenesis of osteoporosis. It is known that the polymorphism of methylenetetrahydrofolate reductase (MTHFR), the enzyme catalyzing the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, correlates with hyperhomocysteinemia. In this study, we examined the association of this polymorphism with bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry (DXA) in 307 postmenopausal women. MTHFR A/V polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). We compared BMD, clinical characteristics, and bone metabolic markers among MTHFR groups (AA, AV, VV). The groups did not differ in terms of baseline data. The values of lumbar spine BMD and total body BMD were as follows: lumbar spine: AA, 0.91 +/- 0.18, AV, 0.88 +/- 0.16, VV, 0.84 +/- 0.14 g/cm(2); total body: AA, 0.97 +/- 0.11, AV, 0.96 +/- 0.11, VV, 0.93 +/- 0.09 g/cm(2). In the VV genotype, lumbar spine BMD values were significantly lower than those of the women with the AA genotype (P = 0.016) and total body BMD was significantly lower than those of the women with AA genotype (P = 0.03) and AV genotype (P = 0.04). This is the first report that suggests that the VV genotype of MTHFR is one of the genetic risk factors for low BMD.

To examine whether the relation between lifestyle and metacarpal bone mineral density (BMD) varied with life-stages.Cross-sectional study.Taking questionnaires related to lifestyle and examining metacarpal BMD by computed X-ray densitometry at a local health care center.Out of 750 Japanese women aged 40-69 y old who underwent screening for osteoporosis, we selected 535 healthy subjects without medical conditions or lifestyle factors known to affect bone metabolism.A cross-sectional comparison of BMD and years since menopause (YSM) resulted in a logarithmic regression model (BMD=2. 539-0.149xloge YSM, r2=0.418), indicating that a prominent reduction in metacarpal BMD appears up to 4-6 y after menopause. In premenopausal women with regular menstruation, those who engaged in regular physical activity during adolescence showed significantly greater BMD than those who did not. In 1-5-y postmenopausal women, those with current calcium intake of more than 800 mg/d, current milk intake greater than 900 ml/week, daily consumption of milk and/or dairy products, or frequent consumption of small fish showed significantly greater BMD. In 6-15-y postmenopausal women, those who took more than 6000 or 8000 steps/day showed significantly greater BMD.The relation between lifestyle and BMD differed with life-stages in Japanese women. It was suggested that to perform lifestyle modifications for the prevention of osteoporosis, life-stages should be taken into consideration.Grant for Research on Health Service from Ministry of Health and Welfare, Japan and grant from The National Dairy Promotion and Research Association of Japan. European Journal of Clinical Nutrition (2000) 54, 9-13

A sensitive method of HLA-DRB1 typing was devised using a semi-nested polymerase chain reaction (PCR) followed by a restriction fragment length polymorphism (RFLP) analysis (semi-nested PCR-RFLP method). The first-round amplification (30 cycles) of the semi-nested PCR was performed using DRB generic primer pairs and the second round of PCRs (20 cycles) were performed using DRB1 group-specific primers. The products of the second round PCRs were digested with restriction endonucleases for the typing of HLA-DRB1 alleles. By this method, HLA-DRB1 typing was possible from 10 pg of genomic DNA extracted from lymphocytes and from 0.5 microliter of 1,000 times diluted blood without DNA extraction. HLA-DRB1 alleles could be typed from a 2-mm long bloodstained cotton thread prepared from 10 times diluted blood and from a 2-mm thread of whole blood bloodstains stored at room temperature for 2 years. From the mixture of blood of two individuals with different genotypes, DRB1 alleles of the minor component were detected down to 1/1,000 of the major component. This semi-nested PCR-RFLP method is useful for HLA-DRB1 typing from extremely small amounts of DNA and from mixed samples.

BACKGROUND: Epstein's syndrome is defined as a subtype of Alport's syndrome, and is distinguished from the other subtypes by accompanying macrothrombocytopenia. Mutations in collagen IV genes are known to be involved in the pathogenesis of typical Alport's syndrome. However, the presence of an underlying genetic defect has not been demonstrated in Epstein's syndrome. AIM: To clarify the involvement of collagen IV in Epstein's syndrome. METHODS: The distribution of the alpha(IV) chain was studied in renal specimens obtained from three patients with Epstein's syndrome using chain specific monoclonal antibodies and an antigen retrieval procedure. RESULTS: The patients showed a normal distribution of alpha(IV) chains: alpha 1(IV) and alpha 2(IV) were expressed ubiquitously, whereas expression of alpha 3(IV) through to alpha 6(IV) chains was limited to the glomerular basement membrane, Bowman's capsular basement membrane, and/or a portion of the tubular basement membrane. CONCLUSIONS: These results suggest that genes other than those encoding alpha(IV) chains are responsible for the pathogenesis of Epstein's syndrome.

In order to analyze the role of the estrogen receptor (ER) gene allelic polymorphisms on bone mineral density (BMD), 173 pre- and postmenopausal women were divided into four groups according to their menstrual status (group A: premenopausal women; group B: late premenopausal women; group C: postmenopausal women who had menopause for 5 years or less; and group D: postmenopausal women who had menopause for more than 5 years), and the relationship between ER gene polymorphism and lumbar spine BMD, the percent annual change in BMD and biochemical markers were studied. The restriction fragment length polymorphism (RFLPs) were represented as Xx (XbaI) and Pp (PvuII), with upper case and lower case letters signifying the absence or presence of restriction sites, respectively. In group A, the Xx genotype had significantly higher BMD (p0.01) than the xx genotype, but the difference was lost in groups B, C, and D. Because the percent annual change in BMD of group A was 0.052% and was not statistically different among genotypes, it is suggested that RFLP by Xba I is closely linked with peak bone mass that was attained during the subject's late thirties. In group B, serum N-region osteocalcin (N-OC) levels and the percent annual change in BMD showed a significantly larger increase than that of group A, indicating postmenopausal bone loss had commenced. Because the N-OC level of the Xx genotype was significantly higher than that of the xx genotype (p0.05), and the percent annual change in BMD of the Xx genotype showed a tendency to increase (p = 0.072), it is suggested that the high BMD of the Xx genotype is rapidly lost during menopausal transition. There were no significant relationships between RFLP and BMD in groups C and D, and between RFLP and BMD in groups C and D, and between RFLP by PvuII and BMD. The present study suggests that the Xx genotype is involved in accretion of BMD during young adulthood, but the effect was lost during menstrual transition.

The combination of ifosfamide (I) and etoposide (E) was useful in salvaging patients with recurrent/resistant malignant solid tumors of childhood. Carboplatin (C), active against a number of pediatric cancers, was added to I and E to form a three-drug combination called ICE to improve the response rate.ICE, consisting of I 1.5 g/m2 plus E 100 mg/m2 i.v.q.d. x 3 plus C i.v. on day 3 only, was given in 21-28-day intervals. C was started at 300 mg/m2, and the dose was escalated in 25% increments, with three evaluable patients treated at each level.Ninety-two patients were enrolled in this phase I/II study between July 1990 and April 1993. A total of 331 courses of ICE was administered. Median courses of ICE received were three (range, 1-16). The maximum tolerated dose (MTD) for C when used in combination was found to be 635 mg/m2. The response rate for ICE at the MTD for C was complete response (CR) 26% and CR + partial response (PR) 53%. The response was even better in those who received C at the MTD: 32% achieving a CR and 63% a CR + PR. Pancytopenia was the dose-limiting toxicity. Thirteen episodes of bacterial infection were reported, none fatal. Only one patient developed a Fanconi-like syndrome.The MTD of C when used with I and E was found to be 635 mg/m2. The overall CR + PR rate for all patients treated at all C dose levels was 53%. Best responses were seen in non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcomas, and Wilms' tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

The glycoprotein laminin 5γ2 chain (LN-5γ2) has recently become a focus of increased interest and investigation as a marker of invasion in gastrointestinal malignancies. We investigated the significance of LN-5γ2 expression as a prognostic factor in superficial esophageal cancer. The study population consisted of 87 patients who had undergone a transthoracic esophagectomy and three-field lymphadenectomy for the treatment of superficial esophageal cancer at Tokai University Hospital. Formalin-fixed, paraffin-embedded sections of the resected specimens were examined using immunohistochemical staining and hematoxylin and eosin staining to assess the correlations between the LN-5γ2 expression pattern and the clinicopathological factors (age, sex, T-factor, N-factor, ly-factor, v-factor, degree of differentiation, infiltrative growth pattern, tumor node metastasis classification of malignant tumors [TNM] stage, etc.) and the patient outcome. The expression pattern of LN-5γ2 was classified into an extracellular type (E type), characterized by the staining of extracellular matrix such as the basement membrane and the stroma (31 cases, 35.6%), and a cytoplasmic type (C type), characterized by the staining of the cytoplasm in the cancer cells (56 cases, 64.6%). The expression pattern was not correlated with any of the clinicopathological factors that were assessed. However, univariate analyses of the survival analysis data showed that the N-factor (P = 0.011), TNM stage (P = 0.011), and LN-5γ2 C type (P = 0.017) were prognostic factors. A multivariate analysis revealed that the N-factor (P = 0.049) and LN-5γ2 C type (P = 0.048) were prognostic factors. In the survival analysis, a univariate analysis of the 75 T1b cases also showed that the N-factor (P = 0.048), TNM stage (P = 0.048), and LN-5γ2 C type (P = 0.029) were prognostic factors, while a multivariate analysis showed that the LN-5γ2 C type (P = 0.035) was a prognostic factor. The C type expression of LN-5γ2, i.e. confined to the cytoplasm, was correlated with an unfavorable outcome among the patients with superficial esophageal cancer in the present series. Observation of the LN-5γ2 expression pattern may be useful for the diagnosis of highly malignant tumors.

Aim To assess blood glucose control over 24 h and the safety of teneligliptin 10 and 20 mg, a novel dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Methods Ninety-nine patients were administered teneligliptin 10 or 20 mg or placebo before breakfast for 4 weeks in a randomized, double-blind, placebo-controlled, parallel-group study. Results Both teneligliptin-treated groups showed significantly smaller 2-h postprandial glucose (2-h PPG), 24-h mean glucose and fasting plasma glucose values than the placebo group. The differences between the teneligliptin 10 mg and placebo groups in changes in 2-h PPG after each meal were −50.7 ± 7.8, −34.8 ± 9.2 and −37.5 ± 7.5 mg/dl at breakfast, lunch and dinner, respectively [least-squares (LS) means ± standard error (s.e.), all, p

We previously reported that follistatin, an activin-binding protein, is produced in arteriosclerotic lesions. Here, the expression of activin-A which promotes the growth of vascular smooth muscle cells was examined in arteriosclerotic lesions of WHHL (Watanabe heritable hyperlipidemic) rabbits. Activin-A mRNA was detected in normal aorta by reverse transcriptase-polymerase chain reaction using specific primers for activin-A cDNA and was increased remarkably in arteriosclerotic lesions. In addition, using the cloned rabbit activin-A cDNA, RNA probe was prepared and in situ hybridization histochemistry was performed. Activin-A transcripts were detected abundantly in neointima of the diseased artery. Furthermore, immunohistochemistry also detected activin-A at the protein level. These observations suggest that activin-A is a cytokine expressed in arteriosclerotic lesions and might be involved in the pathogenesis of atherosclerosis.

The aim of this study is to compare the frequency of wound infection between bilateral and single internal thoracic artery (ITA) harvesting in coronary artery bypass grafting (CABG) cases. Two hundreds and thirty-four consecutive CABG cases performed harvesting either bilateral ITA (BITA) or single ITA (SITA) from January 2004 to December 2008, with or without concomitant surgery were studied. Harmonic Scalpel was used for the harvesting with skeletonization technique. The cases were divided into 2 groups: BITA group (n = 180) and SITA group (n = 54). The frequencies of wound infection were 3.7% in SITA group and 6.1% in BITA group. As to deep sternal infection, they were 1.9% in SITA group and 1.1% in BITA group. There was no significant difference between the 2 groups. Multivariate analysis of all patients showed that emergency cases, hypertension, congestive heart failure, and reopening for bleeding were identified as independent risk factors for wound infection. There were 113 diabetes mellitus (DM) patients out of all patients ; SITA group (n = 22) and BITA group (n = 91). Their wound infection rates were 4.5% and 6.6%, and those of deep sternal infection were 0% and 2.2%, respectively. There was no significant difference between them. In conclusion, BITA harvesting with skeletonized technique may be used as safely as SITA harvesting even in DM patients.

The transient receptor potential cation channel, subfamily V (TRPV), is expressed in the epidermis and considered to be a sensor of extrinsic stimuli such as temperature and other physical or chemical factors. In this study, we examined whether or not the activation of TRPVs by their agonists alters the epidermal tight junction (TJ) function in cultured human epidermal keratinocytes. Reverse transcription-polymerase chain reaction (RT-PCR) analyses showed that mRNA for TRPV1, 3 and 4 were expressed in differentiated keratinocytes in which TJs had formed. Stimulation of the keratinocytes with a TRPV4 agonist (4α-phorbol 12, 13-didecanoate, 4α-PDD) strengthened the TJ-associated barrier, analyzed by means of transepithelial electric resistance measurements and flux measurements of the paracellular tracer. Stimulation with TRPV1 and TRPV3 agonists did not have the same result. Simultaneously, the 4α-PDD-stimulated keratinocytes showed an upregulation of TJ structural proteins, occludin and claudin-4, and TJ regulatory factors, phospho-atypical PKCζ/ι. It was also observed that the amounts of occludin and phospho-atypical PKCζ/ι complex were higher in 4α-PDD stimulated keratinocytes. In conclusion, we demonstrated that the activation of TRPV4 strengthened the TJ-associated barrier of epidermal cells. It was also suggested that the upregulation of TJ structural proteins and/or the posttranslational modification of TJ structural proteins by phospho-atypical PKCζ/ι are responsible for the enhancement of TJ function. Our study supports the hypothesis that TJs change their function in response to a change in the external environment sensed through TRPVs.

OBJECTIVE: To use an accurate method of tooth visualization in magnetic resonance imaging (MRI) movie for the observation of spatio-temporal relationships among articulators. MATERIALS AND METHODS: The subjects were two volunteers. Each subject repeated a vowel-consonant-vowel syllable (ie, /asa/; /ata/), and the run was measured using a gradient echo sequence. A custom-made clear retainer filled with the jelly form of ferric ammonium citrate was then fit onto the dental arch, and a T1-weighted turbo-spin-echo sequence was taken. Landmarks were used for superimposition of the incisor boundary onto sequential images of MRI movie. Tracings were conducted to observe the spatio-temporal relationships among articulators. RESULTS: The incisor boundary was clearly visible in the magnetic resonance images. After superimposition, the contact distance of the tongue to palate/incisor was found to be longer during /t/-articulation than during /s/-articulation. There were prominent differences in images with and without tooth superimposition in the front oral cavity. CONCLUSIONS: The method could distinctly extract a tooth boundary in MRI. Detailed configurational relationships between the tongue and tooth were observed during the production of a fricative and a plosive in MRI movie using this method.

ER mRNA was detected as 6.0 kb band by Northern blot analysis in vascular smooth muscle cells (VSMC) derived from rat aorta. The presence of ER mRNA in VSMC was confirmed by reverse transcriptase-polymerase chain reaction using specific primers for rat ER cDNA. In addition, the immunocytochemistry of ER was performed in VSMC using a monoclonal anti-ER antibody which recognizes DNA-binding domain of ER. The immunoreactivity was distributed in the cytoplasm as well as in the nuclei. Thus, the expression of ER in VSMC was demonstrated at both the protein and the mRNA level. Furthermore, the expression of c-fos mRNA in VSMC was found up-regulated by 17 beta-estradiol treatment within 30 min. The observation that VSMC possess ER and respond to estrogen supports the idea that estrogen may directly influence vascular cell system through the ER.

We studied benign and malignant hepatic tumors with color Doppler sonography and arteriography in order to correlate color Doppler flow characteristics with tumor hemodynamics (vascularity, arteriovenous shunting, and portal vein involvement) shown by arteriography. We also evaluated the usefulness of color Doppler flow characteristics in discriminating between tumor types.We performed color Doppler sonography and hepatic arteriography in 58 patients with 72 hepatic lesions larger than 2.0 cm in diameter. Differences in pulsatile flow (peritumoral or intratumoral) and the highest systolic peak flow velocities reached were evaluated on color Doppler sonograms and compared with arteriographic findings.Color flow sonograms were obtained in 43 of 45 hepatocellular carcinomas, 15 of 16 cholangiocellular carcinomas or hepatic metastases, and six of 11 hemangiomas. Mixed peritumoral and intratumoral pulsatile flow was shown by arteriography in highly vascular tumors. The mean peak systolic flow velocity seen in hepatocellular carcinomas (0.52 m/sec) significantly exceeded the velocity seen in hemangiomas (0.16 m/sec), but not the velocity seen in other malignant hepatic tumors (0.51 m/sec). Six hepatocellular carcinomas, one cholangiocellular carcinoma, and two hepatic metastases with peak systolic flow velocities greater than 0.80 m/sec were each proved arteriographically to have arteriovenous shunting or portal vein involvement.Color Doppler sonography was useful for evaluating hepatic tumor hemodynamics as seen at arteriography, and peak systolic velocity may be useful in differentiating malignant hepatic tumors from hemangiomas.

The incidence and pattern of mutations of the ras oncogenes and the p53 tumor suppressor gene have been shown to differ among different cancer types and even among the same cancer types with different etiological backgrounds. For example, in a previous study we showed that not only the etiology but also the incidence of point mutation of the c-Ki-ras oncogene in cholangiocellular carcinomas (CCCs) differ between Japanese and Thai patients. In the study presented here, we examined the incidence of mutations in the ras gene family and the p53 gene in CCCs of both Japanese and Thai patients by single-strand conformation polymorphism and direct sequencing analyses and compared the pattern of p53 mutation between these two CCC groups. Although the incidence of ras mutation differed markedly between Japanese (seven of 12, 58%) and Thai (two of 26, 8%) cases, the incidence of p53 mutation was similar: four of 12 (33%) and nine of 26 (35%), respectively. Except for one case in which deletion-insertion was detected in the second exon of the N-ras gene, all ras mutations occurred at codon 12 or 13 of the c-Ki-ras gene. All p53 mutations but one were detected in a highly conserved region, and the predominant form of the mutations was G:C-->A:T transition at CpG sites in both Japanese and Thai cases, similar to that reported for colorectal cancers. Therefore, in contrast to the ras oncogenes, mutation of the p53 gene was frequently involved in the development of CCCs in both Japanese and Thai patients, irrespective of any difference in etiology.

The purpose of this study was to clarify the cytological features of neuroendocrine ductal carcinoma in situ (NE-DCIS) of the breast.We analysed the cytopathological findings in 22 fine needle aspiration (FNA) smears and 17 nipple discharge smears obtained from 32 Japanese patients with NE-DCIS.The background of the FNA smears was clear (59%), mucoid (23%), haemorrhagic (14%) or necrotic (5%). Most of the FNA smears (95%) showed high cellularity. Characteristically, NE-DCIS cells were loosely arranged in three-dimensional solid clusters or singly dispersed. Well-developed vascular cores with or without malignant cells were occasionally recognized. The tumour cells were polygonal or spindle-shaped with a fine granular, abundant cytoplasm. Nuclei with finely granular chromatin were round or oval and often eccentrically located (plasmacytoid appearance). Mitotic figures were infrequent. Nuclear grade was estimated to be low in 86%. Most nipple discharge smears had fairly low cellularity with poorly preserved cell clusters in a markedly haemorrhagic background, although two (12%) were extremely cellular with cytological characteristics similar to those of the FNA smears. Pre-operative cytological malignant diagnoses were made in 42% of FNA smears and 0% of nipple discharge smears. Immunohistochemistry for neuroendocrine markers (chromogranin A and synaptophysin) confirmed the neuroendocrine nature of this tumour in adequate cytological specimens.NE-DCIS has distinctive cytological features and can therefore be diagnosed as a neuroendocrine tumour in most FNAs and some nipple discharge smears by cytological examination employing immunohistochemical techniques. We emphasize that a breast lesion with these features may be in situ and not invasive, and also that there is a risk of under-diagnosis.

The therapeutic effectiveness of a new combination therapy--pretreatment with transcatheter arterial embolization (TAE) and subsequent percutaneous ethanol injection (PEI)--for solitary large (> 3.0 cm in diameter) primary hepatocellular carcinoma lesions was compared with that of TAE alone. With TAE alone, a partial response of the tumor was seen in only 10% of the patients, and the 1-, 2-, and 3-year survival rates were calculated to be 68%, 37%, and 0%, respectively. Histologic examination of specimens obtained at hepatectomy showed that TAE alone caused complete necrosis in only 20% of the tumors. In contrast, PEI combined with TAE significantly (P < .05) increased the partial response rate (45%) and significantly (P < .01) prolonged the 1-, 2-, and 3-year survival rates (100%, 85%, and 85%, respectively). Combination therapy caused complete histologic necrosis in 83% of the tumors. It also was significantly (P < .05) better than TAE alone in terms of rate of primary tumor recurrence during follow-up.

The conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase and the interconversion between DHT and 5 alpha-Androstane-3 alpha,17 beta-diol (3 alpha-diol) by 3 alpha-hydroxysteroid oxidoreductase (3 alpha-HSOR) were studied in fibroblasts derived from the genital skin of 15 prepubertal boys (2-10 yr), 17 young men (20-40 yr), 13 elderly men (60-78 yr) without clinically evident prostatic pathology, and 17 elderly men (61-88 yr) with benign prostatic hyperplasia (BPH). Respective DHT formations from testosterone (5 alpha-reduction) and 3 alpha-diol (3 alpha-HSOR oxidation) were not different among genital skin fibroblasts of the 4 groups. However, DHT degradation to 3 alpha-diol (3 alpha-HSOR reduction) was significantly lower in fibroblasts from elderly men with BPH than in those from the prepubertal boys (P less than 0.01), the young men (P less than 0.01), and the elderly men without BPH (P less than 0.05). 3 beta-HSOR reduction in fibroblasts of the BPH group was significantly lower (P less than 0.05) than in those of the elderly men without BPH; however, it did not differ from values for the prepubertal boys and the young men. (3 alpha + 3 beta)-HSOR reduction was also significantly lower (P less than 0.05) in the BPH group than respective values of the three other groups. These results indicate that DHT accumulation may occur in genital skin fibroblasts from elderly men with BPH, resulting from a shift in the overall balance of androgen metabolism, which favors the net formation of DHT.

Color Doppler sonographic findings on 38 lesions in 31 patients who had primary hepatocellular carcinoma were evaluated before and after transcatheter arterial embolization and compared with dynamic CT and hepatic arteriographic findings. All lesions that were observed with dynamic CT or arteriography were correctly identified on color Doppler sonography. Peritumoral pulsatile flow was the predominant color Doppler flow seen in all lesions. Mixed pulsatile and continuous flow were noted in larger tumors and in tumors with a higher degree of vascularity, as determined by arteriography. Two weeks after treatment, color Doppler flow was still identified in 18 lesions (47%), corresponding to dynamic CT or arteriographic findings documenting residual tumor. Histopathologic examination, performed in 10 other lesions, showed that the tumor was completely necrotic in five. These five necrotic tumors were not visible on color Doppler flow images after treatment. Viable tumor was observed in the five remaining lesions, all of which were shown on color Doppler flow images after treatment. During the 6- to 16-month follow-up period, color Doppler flow images showed recurrence of 13 (50%) of 26 lesions, corresponding to tumor recurrence as shown by CT and arteriography. We conclude that color Doppler sonography is useful for imaging hepatocellular carcinoma, for evaluating residual tumor after treatment, and for imaging tumor recurrence during follow-up.

Circulating angiogenic factors have been shown to be important in the pathophysiology of pre-eclampsia. Blood levels of adipocytokines differ in pre-eclampsia relative to controls and may also play an important role in disease pathogenesis. Differences in the circulating levels of these molecules were compared between matched normotensive controls and women with pre-eclampsia with onset before or at/after 32 weeks, and according to whether the women were of normal weight (18.5body mass index25) or overweight.A cross-sectional study of 110 pregnant Japanese women who visited the Department of Obstetrics and Gynecology, Okayama University Hospital, Okayama, Japan.Tertiary referral centre serving 2000 births.Serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin (sEng), adiponectin and leptin were measured in women with pre-eclampsia and in normotensive controls matched for age, gestational week, parity and body mass index. Main outcome measures Serum levels of sFlt-1, PlGF, the sFlt-1/PlGF ratio, sEng, adiponectin and leptin.The sFlt-1/PlGF ratio in early-onset pre-eclampsia was significantly higher than that in late-onset pre-eclampsia (112.0 +/- 30.2 versus 45.4 +/- 43.8, P = 0.037). There was a significant elevation of leptin in both subtypes relative to controls (early: 58.6 +/- 18.3 ng/ml versus 26.0 +/- 6.7 ng/ml, P = 0.001; late: 39.5 +/- 9.2 ng/ml versus 22.0 +/- 4.3 ng/ml, P = 0.005), but adiponectin was increased only in late-onset pre-eclampsia (36.5 +/- 13.4 microg/ml versus 12.0 +/- 4.3 microg/ml, P = 0.003). Significant differences in angiogenic factors and adiponectin were found between normal and overweight women only in late-onset pre-eclampsia.These data suggest that there are different profiles of angiogenic factors and adipocytokines between women who develop early- and late-onset pre-eclampsia.

To compare the analgesic efficacy of a lower (12.5 mg/mL) vs. higher (25 mg/mL) concentration of morphine with 0.2% ropivacaine for patient-controlled epidural analgesia (PCEA) following gynecological surgery.In a randomized double-blinded study, 40 ASA physical status I and II gynecological patients who were receiving combined general and epidural anesthesia for surgery and epidural analgesia for postoperative analgesia were assigned to receive 12.5 mg/mL (N=20) or 25 mg/mL (N=20) morphine with 0.2% ropivacaine for PCEA (continuous infusion 4 mL/h, bolus injection 2 ml, lockout interval 15 min). Maximum visual analogue pain scores (VAPS) at rest (VAPS-R max) and movement (VAPS-M max) during the previous 24 hours were assessed at 24 and 48 hours postoperatively, and the cumulative number of self-administrations in PCEA during the postoperative 48 h were also measured.There were no significant differences in VAPS at rest or with movement, and there were no differences in the cumulative boluses of PCEA between the groups. The incidences of nausea, vomiting, pruritus and leg numbness were greater in the 25 mg/mL morphine group, although statistically insignificant.PCEA using 0.2% ropivacaine and 12.5 mg/mL morphine compared with 0.2% ropivacaine and 25 mg/mL morphine provides equianalgesia with no differences in bolus administration. With respect to the analgesic efficacy and the potential risk for side effects, PCEA using 0.2% ropivacaine and 12.5 mg/ml morphine is a better choice for postoperative gynecological patients.