P = 0.01). Mean of functional support with considering the attainable range 0–384 was low (126.74  (SD = 76.97)). Social support of participants has been found to be associated with CD4 cell count (P = 0.000), sex (P = 0.049), and network size (P = 0.000)after adjusted for other variables in the final model. Totally, in this study, many of participants had the static social support network that contained large proportions of family and relatives. The findings contribute to the evidence for promotion of knowledge about social support network and social support of people living with HIV/AIDS.This study considers social network interactions as a potential source of support for individuals living with HIV/AIDS in Iran. This cross-sectional study was conducted on 224 people with HIV/AIDS who refer to behavioral counseling centers. Participants were randomly selected among all people with HIV/AIDS from these centers. Relatives were more reported as sources of support than nonrelatives. They were closer to participants, but there was difference between the closest type among relative and nonrelative supporters ( AIDS is a disease that affects not only physical health but also mental and social conditions of patients because of the negative attitude of society, discrimination, and stigmatization –3 especiSSN as a subset of a larger social network, consisting of some individuals who are linked to ego and roles such as emotional support, financial aid, guidance, and advice offered to him/her in a variety of situations , 20. SSNBCCs in Iran are the centers that provide free counseling, prevention, and treatment services for people with high-risk behaviors, HIV-positive and AIDS patient. Most people with HIV/AIDS are covered by these centers. Behavioral counseling centers of Tehran University of Medical Sciences were chosen as a study site.  This cross-sectional study was conducted from June to December of 2011. The 224 participants were randomly selected from all PLWHA referring to these centers. All of them have been receiveing antiretroviral therapy. Inclusion criteria were as follows: age over 15 years old, disclosing their HIV status at least to one person, and being aware of their infection/disease for at least the past six months. Because of self-administrated measure, illiterate people were excluded. Written informed consent was obtained from all participants at the time of the survey. This study was approved by the Research Ethics Board at the University Social Welfare and Rehabilitation of Tehran. Social support was measured by the Norbeck Social Support Questionnaire (NSSQ) which assesses supportive relation between the participants and the members of their social network. The questionnaire is composed of different types of social support: emotional support, instrumental support, functional support , structural support (network size plus duration and frequency of contact), and loss support. The reliability and validity of the NSSQ were confirmed in other studies , 28. RelThe questions of structural subscale in NSSQ were used for measuring characteristics of SSN . It is cFor network size, participants were asked to list people who they came in contact with in routine life and their relationship such as spouse, parent, and sibling (up to 24). Network composition was measured to determine which types of relations are more in the personal network of participants. It was categorized into two major groups: relative  and nonrelative . Network members are not necessarily a source of social support, unless the person perceives them as an available or suitable source of support for his/her needs. Network tie was used to refer to people in the personal network who have been providing support for participants. For instance, if a participant identified three supporters, three ties were produced for this participant. Then, it was asked that “how many of the people in your personal network provided support for you?” Frequency of contact was asked with questions like: “how often are you in contact with each of the listed people in your personal network?”. Four types of contact times  were specified. Type of contact was determined with three types of face-to-face, phone, and letter contact (by mail or e-mail). Tie duration refers to how long a tie among participants and their network members is there. Accordingly, the participants were asked about the duration of tie, which were categorized as “less than one year” (as short time), “one to five years” (as medium time), and “more than five years” (as long time).Demographic and disease characteristics of the participant including sex, age, marital status , number of years of education, number of household members (without considering the participant), CD4 cell counts, and route of transmission of HIV ) were also collected Also as a proxy of socioeconomic status, household level infrastructure was divided on the number of household members (considering participant) that it constructed area per capita of house. It was categorized into three groups: low (if the per capita was less than 10 meter), moderate (if the per capita was between 10 to 30 meter), and high (if the per capita was more than 30 meter) [Demographic characteristics and the size, composition, frequency of contact, and duration of tie of SSN were tabulated. Multiple linear regressions were also performed (considering the establishment of the required assumptions) to identify the association between demographic variables, characteristics of social network, and functional social support. Age, sex, number of household members, CD4 cell count, marital status, and number of years of education were used as independent variables. The following variables were entered into the model as the dummy variables: route of transmission of HIV and socioeconomic status. The baseline level for these variables was “sexual relationship,” “low,” respectively. Data were analyzed with using Statistical Package for the Social Sciences (SPSS) version 11.5. significant level was at 0.05.Response rate of 224 participants at the sampling was 96%. The mean of age of the participant was 35 (SD = 8.5) years, 68.3% were female and 31.7% male. Demographic characteristics of participants were presented in Personal network size of participants was shown in Majority of participants named relative  in their personal network (98.6%). Proportion of sibling was the most among relative composition (20.5%). Among nonrelatives, the proportion of friends was more than others in the personal network of PLWHA (20.2%). Composition of relation and sources of support (among participants and their network members) were shown in N = 1775) 1361 network members provided support for the participants. Overall proportion of the network tie was 77.5%. They are reported 72% relative and 28% nonrelative as a source of social support. It is apparent that relatives more frequently provided support than nonrelatives.The frequency of daily (45.1%) and face-to-face (69.4%) contact was greater than the other types of contact.Mean face-to-face contact was 5.87 (SD = 3.37), and mean of phone contact was 2.44 (SD = 2.5).  About duration of relationship, participants have known majority of their network members 78.9% for long time (more than five years), 15.9% for medium time (one to five year), and 5.2% for short time (less than one year). P = 0.036), CD4 (P = 0.02), route of transmission (P = 0.048), and number of household members (P = 0.045) were significant predictors of social support. In Model 2, network size (P = 0.000) was a significant predictor of social support. The final model revealed that marital status and number of household members, which were significant predictors of social support in the first model, were not shown significant association when networks' characteristics as network size and frequency of contact were added in the model, but the network size (P = 0.000), CD4 (P = 0.000), and sex (P = 0.049) remained a significant predictors of social support  . In thisAlso, the results showed that mean of social support of PLWHA considering the range of functional support score was very low. It is similar to that reported in the literature . In contR-squared = 0.05). However, the proposed models in this study have not explained a large percentage of the variance of social support, but our findings suggest the significant variables in models as determinants of social support in PLWHA. A reason for the low values of adjusted R2 could be the possible nonlinear association between the mentioned independent variables and social support. This issue also reveals the need to search for other social support predictors among PLWHA in future studies. Social support of PLWHA has been found to be associated with CD4 cell count, sex, and network size after being adjusted for other variables in the final model. In Model 1, however, there was a significant association between social support and some demographic variables  but they low explained the variability of social support (adjusted In summary, many of the PLWHA in this study had static SSN that contained large proportions of family and relatives. However, nearly the majority of participants did not have strong SSN with readily available sources of support. These findings highlighted the importance of addressing related factor to social support, especially importance of having more individuals as family, friends, and advisors members in support networks for PLWHA. Our study suggested that several sources of support which they can turn to if needed, may increase their perception of social support. Also the lower levels of the social support score of PLWHA in this study demands the relevant attention to these vulnerable people.The following limitations apply to the findings of this study. First, this study was a cross-sectional study, so causal links as well as true mediation between the variables could not be determined between characteristics' demographics, social network, and social support. In addition, this study did not address other possible factors that might have been related to social support and could explain more variance in the outcome. Further, because this study targeted PLWHA, who are referring to BCC of Tehran University of Medical Sciences, the findings cannot be generalized to other PLWHA. Other limitations are self-report measures. Despite these limitations, this study is one of only a few that has explored social support and its related factors among PLWHA who live in Iran. The findings of this study contribute to the evidence for promotion of knowledge about SSN of PLWHA.


We sought to assess vascularity in wrist tenosynovitis by using power Doppler ultrasound (PDUS) and to compare detection of intra- and peritendinous vascularity with that of contrast-enhanced grey-scale ultrasound (CEUS).Twenty-six tendons of 24 patients  with a clinical diagnosis of tenosynovitis were examined with B-mode ultrasonography, PDUS, and CEUS by using a second-generation contrast agent, SonoVue  and a low-mechanical-index ultrasound technique. Thickness of synovitis, extent of vascularized pannus, intensity of peritendinous vascularisation, and detection of intratendinous vessels was incorporated in a 3-score grading system (grade 0 to 2). Interobserver variability was calculated.P < 0.001). In terms of peri- and intratendinous vessels, CEUS was significantly more sensitive in the detection of vascularization compared with PDUS (P < 0.001). No significant correlation between synovial thickening and extent of vascularity could be found (P = 0.089 to 0.097). Interobserver reliability was calculated to be excellent when evaluating the grading score (κ = 0.811 to 1.00).With CEUS, a significantly greater extent of vascularity could be detected than by using PDUS (CEUS is a promising tool to detect tendon vascularity with higher sensitivity than PDUS by improved detection of intra- and peritendinous vascularity. Besides mechanical overloading and attrition, rheumatologic diseases are widespread causes of tenosynovitis and tendinosis. These chronic systemic inflammatory diseases lead to enormous costs for hospitalizations, physician visits, employee's illness, and invalidity pensions. They are caused not only by osseous destruction, but also by tendinosis and consecutive tendon rupture, which are not detectable by conventional imaging such as radiographs. Rheumatoid arthritis (RA), with a prevalence of 0.5% to 1%, the most common disease of this group . Flexor Angiogenesis is a hallmark of acute inflammation and exacerbation of chronic disease. Neovascularization in the synovial membrane is considered to be an important process in early pathogenesis as well as in the perpetuation and progression of RA ,7. DisorDespite the great involvement of tendons in RA, little research has been done into imaging of tendon disease. Color and power Doppler ultrasound (CDUS/PDUS) have been shown to be of diagnostic value in the detection of vascularity in synovial proliferation ,12. Doppet al. . These diagnoses are based on the 1987 revised criteria of the American College of Rheumatology , on the Blood tests were performed to determine serologic activity, including erythrocyte sedimentation rate  and rheumatoid factors . Fourteen (73.7%) of the ESR tests resulted in increased values . RFs were positive in 11 of the sera . Finally, nine patients were tested positive for anticyclic citrullinated peptide antibodies (anti-CCP).We used an MPX-Technos unit fitted with high-frequency transducers  for the US examinations.Grey-scale US was performed according to a standardized protocol by using 13.0 MHz and the musculoskeletal program presets, which remained fixed throughout the examination. PDUS was performed with standardized machine settings by using a frequency of 10.0 to 12.5 MHz with a pulse repetition frequency of 750 to 1,000 kHz, a low wall filter, and medium persistence. The window (colour box) was restricted to the vascular area studied. After visualization of colour-flow signals, pulsed wave spectral Doppler imaging was performed using the lowest filter setting and the smallest scale available that would display the Doppler waveforms as large as possible without aliasing. A spectral Doppler tracing was obtained to confirm that the PDUS signals represented true arterial or venous flow.Grey-scale US and PDUS were performed for adequate delineation of the tendon and to assess the presence of peritendinous effusion and tenosynovial thickening.Subsequently, PDUS was performed to detect tenosynovitis, which was defined as hypoechoic or anechoic thickened tissue, which is seen in two perpendicular planes and which may exhibit Doppler signal, according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria . If vasc≤ 0.1) technique, CnTI , was performed to ensure sufficient enhancement after bolus administration, allowing an examination window of up to 5 minutes.The agent was prepared in a standard manner with a dosage of 4.8 ml SonoVue flushed with 10 ml saline. Subsequently, US scanning by using a low-MI .Interobserver agreement was tested with the Cohen kappa statistics and was interpreted according to the guidelines of Landis and Koch as poor, ≤0.20; fair, 0.21 to 0.40; moderate, 0.41 to 0.60; good, 0.61 to 0.80; or excellent, 0.81 to 1.00.Differences between the CEUS and the PDUS groups regarding the severity scores were tested for significance by using the Wilcoxon test .Spearman rank correlation coefficients were used to assess a correlation between the different grading parameters .P < 0.05 was considered significant for all tests.A value of P = 0.063 to 0.080; rS = 0.350 to 0.370). Excellent interobserver reliability could be achieved (κ = 0.920).Tenosynovial thickening was detected in all tendons examined . 40.4%  were assessed with grade 1 (slight thickening of 2 to 4 mm), and 59.6% (16 of 26 and 15 of 26) showed sizable thickening of more than 4 mm (grade 2). A significant correlation between synovial thickening and extent of vascularity could not be found (Tendinous vascularization was detected in 20 (69.2%) of 26 tendons with PDUS and in 26 of 26 tendons (100%) with CEUS.P < 0.001) greater amount of vascularized synovitis could be detected than by with PDUS. Interobserver agreement was calculated to be excellent with PDUS (κ = 0.937) and CEUS (κ = 0.920).The extent of peritendinous vascularization was assessed in relation to the axial plane of the whole synovial proliferation (see Table P = 0.001). Interobserver reliability was calculated to be excellent by using both techniques (κ = 0.806 to 0.942).The comparison of the values regarding the detection of peri- and intratendinous vessels with PDUS and CEUS (see Table r = 0.25), whereas good to moderate correlation between PDUS and CEUS regarding the extent could be shown .No correlation between PDUS and CEUS regarding peri- and intratendinous vascularization was found  could be found between synovial thickness and the grade of tendinous in comparison with extratendinous enhancement. Perfect interobserver agreement could be achieved (κ = 1.00).Grading the intensity of tendinous vascularization by comparing tendinous enhancement with the enhancement in adjacent tissue showed the following results: grade 0, none; grade 1, 38.5%; and grade 2, 61.5%. Moderate correlation (P < 0.001). None of the patients showed adverse reactions to the contrast agent.Overall, interobserver reliability was calculated to be excellent in every scoring  because of its independence of the speed of flow . ComputeBecause vascularization correlates with the destructive behavior of chronic inflammation, vessel imaging also is of pivotal importance in tendons. As new therapeutic strategies like biologics attack at different points in the signal cascade that induces angiogenesis as part of the immune reaction, a growing necessity for exact detection and quantification of vascularization at the angiogenic level might be of importance for therapy follow-up.et al. [et al. [P = 0.0009; r = 0.66) and not for intratendinous vascularity detection. Good correlation but better sensitivity regarding CEUS and PDUS are in line with previously described vessel detection in joint synovitis. It can be speculated that, in more-advanced and aggressive disease, peritendinous synovitis invades the tendon, and CEUS enables earlier vessel detection in the tendon itself, reflecting progressive inflammation.Moreover, our results concur with a multicenter study comparing PDUS with CEUS in joint examinations of RA patients and with et al.  and Schü [et al. , which set al. [et al. [et al. [To our knowledge, this is the first study to compares CEUS and PDUS in the detection of vascularity in inflamed tendons. In the three studies of Adler et al. , Rudzki  [et al. , and Gam [et al. , brightn [et al. ,28,29, aHence, because of lack of definitions for a scoring system of CEUS examinations in tendons, we had to establish a scoring system to grade tenosynovitis in terms of vascularity to compare the sensitivity of PDUS and CEUS. Our scoring system is based on vascularization distribution, taking into account intratendinous, peritendinous, and extratendinous vascularity, overall resulting in an excellent interobserver reliability (κ = 0.811 to 1.00). A more-refined assessment of vascularity in inflammatory rheumatic disease by using the unique potential of CEUS might be of importance for treatment follow-up, especially when therapies target the angiogenic level.et al. [Morel et al.  offered The small diameter of the capillaries running through the tendon (<50 μm) is under the detection limit of PDUS, which might be a cause of contradictory results regarding the detection of vascularity in tendons. Different sensitivities of Doppler signal acquisition have been shown to have a great influence on US assessments, resulting in only moderate intermachine agreement ,31, whicTo our knowledge, no published study detected vascularity in tendons of extensors and flexors of the wrist by using CEUS. According to the pathogenesis of tendon inflammation -10, we het al. [et al. [Milosavljevic et al.  measured [et al.  and obtaThe comparison of tendinous and extratendinous enhancement describes the density of the capillaries in the inflamed area as a parameter of the inflammation intensity. Because capillary flow is not detectable in healthy adjacent tissue by using PDUS, only CEUS examination videos were graded by using this scoring. Further follow-up studies should focus on the clinical and prognostic value of this scoring.Extensive tenosynovial invasion can complicate the assessment of altered tendons so that even a complete tendon rupture can become a diagnostic challenge, because tendon edema and inhomogeneous echo texture make difficult the evaluation of tendon continuity and tenosynovitis. Furthermore, inflammatory adhesions may cause limitations in the dynamic examination. Contrast-enhanced detection of vascularity may provide additional information for a better characterization of continuity and the amount of synovial proliferation.Moreover, new therapeutic strategies like biologics attack at different points in the signal cascade that induces angiogenesis as part of the immune reaction. This leads to a further demand for sensitive detection and quantification of vascularization at the angiogenic level for therapy follow-up.We must admit several limitations of the study: CEUS is considered to be costly and time consuming, although both factors are much less than those of contrast-enhanced MRI. Ultrasound contrast agents have some advantages over MRI contrast agents, because they are less likely to leak into the synovial fluid and to diffuse into the tissue; therefore, they can accurately demonstrate changes of the intravascular compartment.Objective quantification of contrast enhancement seems promising for longitudinal assessment and comparison between studies. Standardization of measurements and interpretation of the characteristics of time/intensity curves suggest further investigation.Furthermore, we did not include intraobserver reliability because the application of contrast media is already invasive when compared with PDUS, and is more intensive in cost and time required.et al. [MRI would have been a nice gold standard, but because of the fact that MRI contrast agents diffuse into the extravascular compartment, it will not represent the true vascular compartment in hypervascularized synovium ,35. Theret al.  reportedOur sample size enabled us to identify significant findings and differences. Nevertheless, we believe that the significance of our data would have been greater with a larger cohort and additional observers to analyze the video sequences. Furthermore, comparing subjective and objective assessment by using brightness-quantification software might provide further information. We believe that computerized evaluation of intratendinous vascularization might be artefact prone because of slight changes in transducer tilt and the high baseline brightness of tendons itself that makes detection of faint enhancement insignificant.Our preliminary results show that CEUS is a promising tool to detect tendon vascularity with high sensitivity and excellent interobserver reliability when assessing intra- and peritendinous vascularity.CCP: cyclic citrullinated peptide; CDUS: color Doppler ultrasound; CE-MRI: contrast-enhanced magnetic resonance imaging; CEUS: contrast-enhanced grey-scale ultrasound; ECU: extensor carpi ulnaris; ESR: erythrocyte sedimentation rate; FCR: flexor carpi radialis; MI: mechanical index; MRI: magnetic resonance imaging; OMERACT: outcome measures in rheumatology clinical trials; PDUS: power Doppler ultrasound; RA: rheumatoid arthritis; RF: rheumatoid factor; ROI: region of interest; SI: signal intensity; US: ultrasound.The authors declare that they have no competing interests.ASK designed the study, carried out the ultrasonographic examinations, helped to configure the scoring system, was one of the subjective observers, and helped to draft the manuscript and revised it critically. MF carried out the objective quantification, helped to configure the scoring system, was one of the subjective observers, and drafted and wrote the manuscript. RA, JG, MS, WJ, and MG participated in the design and coordination of the study and helped to draft the manuscript. GMF made substantial contributions to analysis and interpretation of data and performed the statistical analysis. All authors read and approved the final manuscript.


The information provided in patient-centered care and shared decision-making influences patients’ concerns and adherence to treatment. In the decision-making process, patients experience decisional conflict. The Decisional Conflict Scale (DCS) is a 16-item, self-administered questionnaire consisting of 5 subscales developed to assess patients’ decisional conflict. This study aimed to develop the Japanese version of the DCS and to clarify the influence of the information provided by pharmacists’ on decisional conflict among patients with cancer.We developed the Japanese version of the DCS by using the forward-backward translation method. One hundred patients who were recommended a new chemotherapy regimen were recruited. The psychometric properties of the Japanese DCS, including internal consistency, convergent validity, discriminant validity, and construct validity, were examined. We assessed the decisional conflict of patients before and after the pharmacists’ provision of information.Ninety-four patients, predominately female, with an average age of 58.1 years were sampled. The scores on the 5 subscales of the DCS showed high internal consistency . Multi-trait scaling analysis and cluster analysis showed strong validity. The mean total DCS score decreased significantly from 40.2 to 31.7 after patients received information from the pharmacists . Scores on all 5 subscales, namely, uncertainty, informed, values clarity, support, and effective decision, also significantly improved .The psychometric properties of the Japanese version of the DCS are considered appropriate for it to be administered to patients with cancer. Pharmacists’ provision of information was able to decrease decisional conflict among patients with cancer who were recommended a new chemotherapy regimen. In recent years, patient-centered care and shared decision-making have been recognized as essential factors in oncology practice ,2. BecauThe DCS is divided into five subscales of uncertainty, informed, values clarity, support, and effective decision-making, and is composed of 16 items that use a 5-point Likert-type response . Decisional conflict was calculated from calculating the total scores obtained on these 16 items. The uncertainty subscale estimates the degree of uncertainty a patient faces in decision-making. Informed, values clarity, and support subscales are considered modifiable factors that contribute to uncertainty and represent feelings of being uninformed, the clarity of personal values, and feelings of being unsupported, respectively. The effective decision subscale measures the combination of informed choice, patient response value, and satisfaction. The total score and the score on each subscale are calculated according to the DCS user’s manual and both can range from 0 to 100, with 100 indicating extremely high decisional conflict. An effect size of 0.3 to 0.4 is assumed to be a meaningful difference [omakase” (entrusting) model in Japan, has existed in the Japanese physician-patient communication for many years [Understanding the information that a patient requires, particularly regarding the knowledge of treatment options, is essential in the decision-making process -13. Duriny years . This mony years . In respny years ,19. In any years -22. A reny years . A proviThe aim of the present study was two-fold. First, we aimed to develop the Japanese version of the DCS and to examine the internal consistency, as well as the construct, criterion, and factorial validity in patients with cancer who were recommended a new chemotherapy regimen. Second, we aimed to analyze the influence of pharmacists’ provision of information on decisional conflict in patients with cancer.The DCS has three versions, namely, statement format, question format, and low literacy. The statement format (based on responses on statements with responses ranging from strongly agree to strongly disagree.), which is the one used in this study, has 16 items  and five response categories. The statement format of the DCS was translated into Japanese through the forward-backward translation method . Two natEach participant completed the Japanese version of the DCS before and after pharmacists’ provision of information. The repeated measurements result in random errors, which caused regression to the mean (RTM) . TherefoThis study included patients with various types of cancer and settings. Thus, participants may have various dysfunction and symptoms. Baseline quality of life (QOL) score, including assessment of function and symptoms, is known as a prognostic factor for survival in patients with cancer . To asseWe obtained demographic information, including age, gender, marital status, level of education, and employment status, from the patients through the questionnaire. The level of education was classified into three levels, namely, low (elementary: grades 1–6 and junior high school: grades 7–9), middle (high school: grades 10–12), and high (university or graduate school: grade 13 or above). Clinical information, such as cancer type, prior chemotherapy, and chemotherapy type, was obtained from the patients’ medical records.This study was conducted on patients with cancer at Tokyo Medical University Hospital from June 2011 to April 2012. The criteria for eligibility were as follows: 20 to 75 years of age, diagnosed with any type of cancer, scheduled for receiving information from a pharmacist, and recommended for a new chemotherapy regimen. Patients who were not Japanese or had a serious psychiatric disease were excluded. Sample size was calculated to detect a meaningful difference of decisional conflict before and after the pharmacists’ provision of information. We estimated that 88 patients would be needed for an effect size of 0.3, a power of 80%, and a significance level of 0.05 (with a two-sided paired t-test). A target number of 100 registered patients was thus set to account for patients who may not complete the study.Data were collected through self-administered questionnaires before and after pharmacists’ provision of information. At Tokyo Medical University hospital, the therapeutic strategy was determined by physicians or a team conference that includes pharmacists. First, treating physicians met with patients and recommended the therapeutic strategy. Next, pharmacists met with patients and asked to complete the DCS and then left patients. At least one hour later, pharmacists returned and asked patients to complete the DCS a second time to address the RTM. After patients completed the survey for a second time, pharmacists provided information to patients for all treatment options. This information mainly consisted of the aim of treatment, side effects, and supportive care for the most highly recommended treatment option, and was relayed without a specific protocol. After the pharmacist has provided the necessary information, patients then completed the DCS a third time, the EORTC QLQ-C30, and the questionnaire regarding socio-demographics. Nine pharmacists (3 men and 6 women) were involved in this study. The mean (S.D.) age and work experience of these pharmacists were 30.8 (2.4) years and 7.6 (2.1) years, respectively. The mean length of discussion was 30 ± 11.8 min. After receiving information from the pharmacists’, the patients then decided about treatment with their physicians.Reliability and validity were investigated by using the average score on the first two DCSs to address RTM. The reliability of the five subscales was estimated by calculating Cronbach’s alpha. A Cronbach’s alpha value of >0.7 was considered acceptable. Construct validity, which refers to the ability of a measurement tool to actually measure the psychological concept being studied, was assessed through item-domain correlation and multi-trait scaling analysis for convergent validity and discriminant validity. Convergent validity tests whether constructs that should be related are related and discriminant validity tests whether believed unrelated constructs are, in fact, unrelated. Both are considered subcategories or subtypes of construct validity. A correlation of 0.4 or greater between an item and its domain, which must also be significantly higher than the correlation of the same item with a different domain, is required for convergent validity. Pearson correlation coefficient was calculated for the item-domain correlation to check the correlation of each item in a given scale for convergent validity and discriminant validity and for correlation between the score on each scale of the DCS and the scores on the EORTC QLQ-C30. Cluster analysis was conducted to examine the factorial structure of the DCS. We hypothesized that the optimal number of clusters was five, based on the DCS subscale number, and used SAS  VARCLUS procedure, which is a method for clustering variables. While the conventional clustering method divides observation into clusters, the VARCLUS produces readily interpretable disjoint clusters . A paireThis study was conducted in accordance with the Japanese Ethical Guidelines for Epidemiological Research and World Medical Association Declaration of Helsinki. All patients gave written informed consent. The protocol was approved by the institutional review board of Tokyo Medical University.One hundred inpatients participated between June 2011 and April 2012. We excluded the data of six patients from analysis due to deviation from protocol; two were not administered the second DCS and four completed only one side of a double-sided questionnaire. Thus, 94 patients (94%) were ultimately included in the analysis. Participants’ basic characteristics are shown in Table To assess internal consistency, Cronbach’s alpha coefficient was calculated. Internal consistency was high for all domains of the DCS  and satisfactory for all evaluated items Table .Item-domain correlation was nearly equal for each item in the four subscales of uncertainty, informed, values clarity, and effective decision. The coefficient of item-domain correlation for item 8 and the support subscale 0.63) was relatively lower than that for items 7 (0.70) and 9 (0.80). The criterion of convergent validity and discriminant validity were met in all domains. The results of the cluster analysis are presented in Table  was relaWith respect to baseline QOL, the mean (SD) of global health status (GHS)/QOL was 55.1 (23.2). All Spearman correlation coefficients between each DCS score and the EORTC QLQ-C30, including GHS/QOL, function scores, and symptom scores, were not above 0.4; therefore, no correlations were observed between decisional conflict and QOL.The mean (SD) of the total score at baseline, 40.2 (21.1), was significantly reduced to 31.7 (20.5) after factoring in pharmacists’ provision of information  -certified Oncology Pharmacist and JSPHCS-certified Senior Oncology Pharmacist. TY is a professor at Tohoku University Graduate School of Medicine, as well as a biostatistician and methodologist in clinical oncology research.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6947/13/50/prepub


Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. A number of studies have conducted on the association of TP53 codon 72 polymorphisms with susceptibility to breast carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship.We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Jan 2009. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications.A total of seventeen case-control studies, including 12226 cases and 10782 controls, met the included criteria and thus were selected. Ultimately, the relevant data were extracted and further analyzed using systematic meta-analyses. Overall, no associations of TP53 codon 72 polymorphisms with breast carcinoma were observed . In the subgroup analysis by ethnicity, statistically similar results were obtained when the data were stratified as Asians, Caucasians and Africans.TP53 codon 72 polymorphisms might not be a low-penetrant risk factor for developing breast carcinoma.Collectively, the results of the present study suggest that  Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer in the world . It is bPreviously, a number of studies indicate that family history is a risk factor for breast cancer , indicatRecently, a growing body of research has conducted on the association of breast cancer risk with tumour suppressors. TP53, one of the most extensive studied genes as a tumor suppressor, has been thought to have a critical function in cell cycle regulation. In case of its mutation, this regulation could be lost, resulting in cell proliferation without control and development of cancer. Previously, TP53 mutation has been indicated to associate with risks of a number of cancers such as lung cancer, breast Recently, much attention has been focused on possible associations of TP53 polymorphisms and cancer risks. The most informative polymorphism in TP53 gene is located in exon 4 at codon 72, which encodes two distinct functional allelic forms arginine (Arg) and proline (Pro) because of a transversion G to C , resultiIn recent literature, inconclusive data regarding TP53 codon 72 were found in some cancers, such as gastric cancer in which controversial conclusions were obtained in Asians  and in iAs a single study may have been underpowered in clarifying the relationship of TP53 codon 72 polymorphisms with breast carcinoma susceptibility, in the present study we performed evidence-based quantitative meta-analyses that can increase statistical power to address the association.TP53, P53, codon 72, breast, carcinoma, neoplasm, tumor, cancer and polymorphism. The keywords were paired each time in order to get more relevant information. For example, the word "breast" was always kept and others were substituted in different moments.We carried out a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Jan 2009, with a combination of the following keywords: We evaluated potentially associated publications by checking their titles and abstracts and then procured the most relevant publications for a closer examination. Moreover, the reference lists of the selected papers were also screened for other potential articles that possibly have been missed in the initial search. The following criteria were used for the literature selection for the further meta-analysis:1. Studies concerning the association of TP53 codon 72 polymorphism with breast carcinoma;2. Case–control or cohort studies;3. Papers presenting the breast cancer diagnoses and the sources of cases and controls;4. Articles offering the size of the sample, odds ratios (ORs) and their 95% confidence intervals (CIs) or the information that can help infer the results;5. The number of individuals homozygous for arginine (Arg/Arg), proline (Pro/Pro) and heterozygous (Pro/Arg) in breast cancer cases and controls should be offered;6. The methods of data collection and analysis should be statistically acceptable.Accordingly, the following exclusion criteria were also used:1. The design and the definition of the experiments were obviously different from those of the selected papers.2. The source of cases and controls and other essential information were not offered;3. The genetic distribution of the control group was inconsistent with Hardy-Weinberg equilibrium (HWE).4. Reviews and duplicated publications.After searching, we reviewed all papers in accordance with the criteria defined above for further analysis.Data were carefully extracted from all eligible publications independently by two of the authors according to the inclusion criteria mentioned above. For conflicting evaluations, an agreement was reached following a discussion. If a consensus could not be reached, another author was consulted to resolve the dispute and then a final decision was made by the majority of the votes. The extracted information was entered into a database. For data not provided in the main text, the relevant information was obtained by contacting corresponding authors as possible as we could.P > 0.05, ORs were pooled according to the fixed-effect model (Mantel-Haenszel), Otherwise, the random-effect model (DerSimonian and laird) was used. The significance of the pooled ORs was determined by Z-test. The HWE was assessed via Fisher's exact test.The odds ratio (OR) of TP53 codon 72 polymorphisms and breast cancer risk was estimated for each study. The pooled ORs were performed for additive model (Arg/Arg vs Pro/Pro), dominant model (Arg/Arg+Arg/Pro versus Pro/Pro) and recessive model (Arg/Arg versus Arg/Pro+Pro/Pro), respectively. For detection of any possible sample size biases, the OR and its 95% confidence interval (CI) to each study was plotted against the number of participants respectively. A Chi-square based Q statistic test was performed to assess heterogeneity. If the result of the heterogeneity test was P = 0.05 (Nfs0.05) [Publication bias was assessed by visual inspection of funnel plots, in whicNfs0.05)  for the A total of 131 studies regarding TP53 codon 72 with respect to breast cancer were searched and screened for retrieval, of which 97 irrelevant studies were excluded. Then, 9 studies -34 were We established a database according to the extracted information from each article. The relevant information was listed in Table We analyzed the heterogeneity of Arg/Arg versus Pro/Pro and dominant model (Arg/Arg+Arg/Pro versus Pro/Pro) as well as recessive model (Arg/Arg versus Arg/Pro+Pro/Pro). As shown in Table Table In the present study, a total of 17 studies were included. Nevertheless, the study conducted by Weston et al.  concerneP > 0.05). For dominant model (Arg/Arg+Arg/Pro versus Pro/Pro), the data available for our meta-analysis were obtained from 18 case-control studies containing 12226 cases and 10782 controls, of which 11137 cases and 9444 controls had the combined genotypes of Arg/Arg and Arg/Pro, while 1089 cases and 1338 controls had the homozygote Pro/Pro genotype. The overall OR was 1.12 (95% CI = 0.96–1.32) and the test for overall effect Z value was 1.47 (P > 0.05). Similarly, for recessive model (Arg/Arg versus Arg/Pro+Pro/Pro), the data were extracted from the 18 case-control studies concerning 12226 cases and 10782 controls, of which 6288 cases and 5112 controls had the wild-type homozygote Arg/Arg genotype while 5938 cases and 5670 controls had the combined variant genotypes (Arg/Pro and Pro/Pro) of the TP53 codon 72. The overall OR was 1.13 (95% CI = 0.98–1.31) and the test for overall effect Z value was 1.65 (P > 0.05).As shown in Table Considering the possible impact of ethnic variation on the results, we conducted subgroup analysis concerning Asians, Caucasians and Africans, respectively. Likewise, the subgroup analyses failed to suggest marked association between TP53 codon 72 polymorphisms and breast cancer risk in Asians, Caucasians and Africans.In order to compare the difference and evaluate the sensitivity of the meta-analyses, we also presented the results of the fixed-effect models as listed in Table 0.05 for evaluation of the stability of the results. Consequently, the Nfs0.05 were 237, 143 and 271 for additive, dominant model and recessive model respectively, which were more than five times of the number of the included studies, suggesting that the results of these meta-analyses are relatively stable and the publication biases might not have an evident influence on the results of the meta-analyses.Funnel plots were created for assessment of possible publication biases. Then, Egger's linear regression tests were used to assess the symmetric of the plots. As shown in Table In the present study, the results of meta-analyses showed that individuals with TP53 codon 72 polymorphism might not have significant associations with increased or decreased susceptibility to breast carcinoma.A previous meta-analysis conducted by Koushik et al.  regardinThe underlying mechanisms by which TP53 polymorphism influences cancer risk are not fully understood. TP53 is the most frequently investigated gene that is often mutated in a variety of cancers. Nevertheless, several single-nucleotide polymorphisms have been studied and reported in TP53 gene . The polA well-known risk factor, HPV infection, is thought to have an association with increased susceptibility to some cancers such as cervical  and oralHeterogeneity is a potential problem when interpreting the results of meta-analysis . In the 0.05 showed no remarkable publication biases in the meta-analyses. Second, in the subgroup analysis, the number of studies regarding Africans was relatively limited. It may be underpowered to explore the real association. Thus, the results may be interpreted with caution. Third, whether the experimental and control groups were from the same socio-economic status or the same geographic area have not been clearly presented in some of the included original papers, leading to any possible biases. Furthermore, the sample sizes of some included studies are rather small, which might be one of the reasons contributing to the between-study heterogeneity. Therefore, a number of further studies with large sample sizes with well-matched controls are required. Besides, gene-gene and gene-environment interactions should also be considered in the further studies.Some limitations might be included in this study. First, in this meta-analysis, most published studies and papers written in English or Chinese were searched. Moreover, although papers written in some other languages, cited by PubMed, were also searched, it is possible that some related published or unpublished studies that might meet the inclusion criteria were missed. Hence, some inevitable publication biases might exist in the results, though the NfsIn summary, despite the limitations, the results of the present meta-analysis suggest that genetic variations of TP53 codon 72 may not have a marked association with breast cancer risk.The authors declare that they have no competing interests.WZ and YZ conceived of the study, and carried out the analysis of the literatures and drafted the manuscript. ZX carried out the collection of the literatures. LC helped with the statistical analysis and manuscript drafting. ZC and WZ conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


Intercellular communication is pivotal in optimizing and synchronizing cellular responses to keep homeostasis and to respond adequately to external stimuli. In the central nervous system (CNS), glutamatergic and GABAergic signals are postulated to be dependent on the glutamate/GABA-glutamine cycle for vesicular loading of neurotransmitters, for inactivating the signal and for the replenishment of the neurotransmitters. Islets of Langerhans release the hormones insulin and glucagon, but share similarities with CNS cells in for example transcriptional control of development and differentiation, and chromatin methylation. Interestingly, CNS proteins involved in secretion of the neurotransmitters and emitting their responses as well as the regulation of these processes, are also found in islet cells. Moreover, high levels of glutamate, GABA, and glutamine and their respective vesicular and plasma membrane transporters have been shown in the islet cells and there is emerging support for these amino acids and their transporters playing important roles in the maturation and secretion of insulin and glucagon. In this review, we will discuss the feasibility of recent data in the field in relation to the biophysical properties of the transporters  and physiology of hormone secretion in islets of Langerhans. The endocrine cells of the pancreas and the cells of nervous system have different functions but also reveal interesting similarities. Islet cells of Langerhans secrete insulin and glucagon and are considered to be necessary for maintaining glucose homeostasis. However, neurons may also release insulin, and compelling evidence have been provided for a brain-centered glucoregulatory system that work in concert with the islet cells to regulate plasma levels of glucose –3. InterClassical neuronal signaling is a form of paracrine signaling where a neurotransmitter is released at the synapse from a neuron and the message is conveyed by activation of specific receptors on the surface of an adjacent neuron. Several amino acids play fundamental roles in synaptic transmission. Glutamate and GABA are the main fast excitatory and inhibitory neurotransmitters, respectively. After their release, the signal is partly inactivated by transport of the released neurotransmitter into astroglial cells and conversion to glutamine catalyzed by glutamine synthetase (GS) , 10. GluThe endocrine cells of the pancreas share many characteristics with the cells of the central nervous system (CNS). The two tissues share a similar transcription program  and have2+ channels , islet cells contain synaptic-like microvesicles (SLMVs) resembling synaptic vesicles found in nerve terminals , 36. Thechannels , 38, andchannels . Furtherchannels . In addichannels .2+ influx and insulin secretion , the primary glucose transporter present on β-cells  of the Slc17 family , whereasIslet cells express both VGLUTs and VGAT Figure . In α-ce2+ secreted together with insulin . H. H43). H insulin . However insulin . β-cells insulin , 71, 72, insulin .Thus, both islet SGs and SLMVs have the machinery necessary to load them with glutamate and/or GABA and glycine, which can then be released in an exocytotic manner.+-dependent glutamate transport across the cell membrane in islet cells (Naet cells , probablet cells , can teret cells A. In facet cells .EAAT2 has also been shown to be strongly expressed on the membrane of SGs in β-cells , and co-+-ATPase which pumps protons into the SGs (Figure +-ATPase. If glutamate leaves the SGs through EAAT2, three positively charged sodium ions and a proton will be exported, while one potassium ion will enter the SG. Thus, there will be a net export of positive charge, further counteracting inhibition of the H+-ATPase, allowing for further acidification of the SG. Acidification is crucial for the conversion of pro-insulin to active insulin (Gammelsæter and co-workers postulated that glutamate transport might participate in the maturation of insulin in the SGs, and thus the regulation of insulin release . SGs cons Figure B. Uptake insulin , 79, and insulin B, also r insulin . Chlorid insulin , 82, andThe islets of Langerhans express transcripts for several members of the Slc38 gene family Figures A and 2 . Immunof+ (SN1 translocates glutamine coupled to a symport of Na+ . In addi+ , 84, 85.+ , 84–87. + , but at + , as discGlutamine has been shown to have a profound effect on insulin secretion –6. Incre glucose . This is glucose . Alterna glucose B. Glutam glucose , 21, 85.no acids . This efno acids , and theno acids . Thus, gLack of coupling to proton translocation enables the SATs to utilize both the electrical and the chemical gradients of sodium, creating higher glutamine concentration gradients compared to SN1 , 23, 90.All in all, as SN1 changes direction of transport at glutamine concentrations well within physiological fluctuations in amino acid content of the blood , SN1 migThe main components of synaptic transmission are present in the islet cells implicating similarities in signaling pathways. This notion is further reinforced by the fact that human neural progenitor cells may be differentiated to produce insulin . In the This review was written by Monica Jenstad and Farrukh Abbas Chaudhry in collaboration.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the present study, we used magnetic resonance imaging and voxel-based morphometry (VBM) to test three language tasks in Japanese Sign Language (JSL): word-level (Word), sentence-level (Sent), and discourse-level (Disc) decision tasks. We analyzed cortical activity and gray matter (GM) volumes of Deaf signers, and clarified three major points. First, we found that the activated regions in the frontal language areas gradually expanded in the dorso-ventral axis, corresponding to a difference in linguistic units for the three tasks. Moreover, the activations in each region of the frontal language areas were incrementally modulated with the level of linguistic integration. These dual mechanisms of the frontal language areas may reflect a basic organization principle of hierarchically integrating linguistic information. Secondly, activations in the lateral premotor cortex and inferior frontal gyrus were left-lateralized. Direct comparisons among the language tasks exhibited more focal activation in these regions, suggesting their functional localization. Thirdly, we found significantly positive correlations between individual task performances and GM volumes in localized regions, even when the ages of acquisition (AOAs) of JSL and Japanese were factored out. More specifically, correlations with the performances of the Word and Sent tasks were found in the left precentral/postcentral gyrus and insula, respectively, while correlations with those of the Disc task were found in the left ventral inferior frontal gyrus and precuneus. The unification of functional and anatomical studies would thus be fruitful for understanding human language systems from the aspects of both universality and individuality.In both vocal and sign languages, we can distinguish word-, sentence-, and discourse-level integration in terms of  It might be thought that a sign language is a unique or atypical language, because it is used only in a visual mode without auditory representations for most words. It is true that Deaf  participants almost exclusively rely on visual information for language processing throughout their lives, which is not the case for individuals with normal hearing. However, sign languages share the same basic properties of word-, sentence-, and discourse-level processes with vocal languages  study of Deaf adults reported that activations in the left frontal and some other regions during a grammatical judgment task were negatively correlated with the ages of acquisition (AOAs) of American Sign Language (ASL) , and/or poor task performances (null hit rates). Table A dialog between two Deaf signers (a woman and a man) was prepared in JSL . It should be noted that there was only one type of probes  included in each task block. The purpose of including probes was to ensure the participants' full attention to lexical information, sentence expressions, or discourse flows, thereby allowing assessment of their linguistic proficiency for each task. A number of linguistic studies with lexical, syntactic, or contextual decision tasks inherently involved anomaly detection in the tasks, and we have already established that activations of the frontal language areas depend on the type of decisions, but not on the anomaly of stimuli themselves , sentence-level (Sent), and discourse-level (Disc) decision tasks. In the Word and Sent tasks, each dialog sentence was presented in a random order; in the Disc task, the dialog sentences were presented in the original order, and completed in seven separate blocks. Therefore, the overall stimuli were physically equated among the language tasks. On the other hand, individual tasks imposed different “task sets”  as explained below, while these tasks basically included probe detection in common in that anomalous probes kotoba” (“word”) for the Word, “hyougen” (“expression”) for the Sent, and “kaiwa” (“conversation”) for the Disc task. In the Word task, probes were pseudo-signs freely devised by the native signers, and the participants were asked to detect the probes by focusing on word-level information among the disconnected dialog sentences. Lexical decision critically involves word-level integration; for sign languages, elements of handshape, location, and movement are combined into real words. In the Sent task, probes were syntactically anomalous JSL expressions, and the participants were asked to detect the probes by focusing on sentence expressions  among the disconnected dialog sentences. These syntactic errors included violations of tense , was visually presented for 1.3 s. In the R task, normal sentences used in the three language tasks were played backward and presented in a randomized order, and a probe was a successively repeated “backward sentence.” During each R block, video images of only one signer  were presented, since successive presentation of different signers could not become a probe. The participants reported that it was impossible to comprehend sentences composed of backward signs, although some of the signs were recognizable as meaningful. Here, it should be noted that the stimuli used in the language and R tasks were physically equivalent, i.e., in terms of the visual stimuli themselves, which included hand shapes, facial expressions, and body movements. Activation by the contrasts between the language and R tasks  thus reflected the processes of individual words (in common for the language tasks) and associated linguistic integration (different among the language tasks), while general cognitive factors such as lower-level visual perception, probe detection, short-term memory, response selection, and motor responses were fully controlled.As a baseline for the language tasks, a repetition (R) task was tested with the same probe detection. At the initiation of each R block, the task type, “Every participant underwent a total of eight scanning sessions, each of which had seven blocks and lasted for 220.7–221.1 s. In the first seven sessions, four blocks of the baseline R task were alternately presented with a block of the Word, Sent, or Disc task (appearing once in a pseudo-random order). In the last session, four blocks of the R and three blocks of the Disc task were alternately presented, with a part of the original dialog being repeated once more with new probes in the Disc task. In each block of the Disc and R tasks, there was always a single probe, and in each block of the Word and Sent tasks, there were either one or two probes. There were a total of ten different probes for each of the Word, Sent, and Disc tasks, whereas there were 32 probes for the R task. In each language task, no sentence appeared more than twice. The use of more blocks for the Disc task might have increased the brain activations, but the number of blocks was largest for the R task Figure . Since td′, which was computed from the Z-scores of hit rates and correct rejection rates. If these rates were 1.00, the formula of 1 – 1/(2N) was used  for hit rates, and that of other stimuli in each task  for correct rejection rates. Reaction times (RTs) were calculated from the onset of each dialog sentence containing a probe.The stimulus presentation and button-press signal acquisition were controlled using the Lab-VIEW software package and interface . The accuracy of each task was evaluated with 2, resolution = 3 × 3 mm2]. In a single scanning run, we obtained 77 volumes following three dummy images, which allowed for the rise of the MR signals. High-resolution T1-weighted images of the whole brain  were acquired with a three-dimensional fast spoiled gradient-echo (3D FSPGR) sequence . These structural images were used for normalizing fMRI and VBM data.The participants were in a supine position, and their heads were immobilized inside the radio-frequency coil with straps. The MRI scans were conducted on a 3.0 T MRI system . We scanned 32 axial slices that were 3-mm thick with a 0.3-mm gap, covering from −42.9 to 62.7 mm from the anterior to posterior commissure (AC-PC) line in the vertical direction, using a gradient-echo echo-planar imaging (EPI) sequence . Paired t-tests showed that the R task was significantly easier than the other three tasks (Bonferroni corrected p < 0.05). Based on a comparison of the d′ values for the three language tasks, the Word task was the easiest, whereas the Sent task was the most difficult (corrected p < 0.05).The task performances were well above the chance level, as indicated by the fact that the value of 1) Table . These hd′ among the participants showed that the performance of the Word task was significantly correlated with that of the Sent task   Table . If somer = 0.91, p < 0.0001); the ages and DOE of JPN were also correlated . The AOAs and DOE of JSL were negatively correlated with each other , while the AOAs and DOE of JPN were not correlated , probably due to the smaller variances for the AOAs of JPN. The correlation between the AOAs of JSL and JPN was not significant , indicating that these AOAs were independent of each other for the participants.On the other hand, the ages of the participants were strongly correlated with the DOE of JSL  = 165, p < 0.0001]. Paired t-tests showed that the RTs for the R task were significantly shorter than those for the other three tasks (corrected p < 0.05). Among the RTs for the three language tasks, the RTs for the Word task were the longest, whereas those for the Disc task were the shortest (corrected p < 0.05). In the VBM analyses, we used the d′ of each task to represent the linguistic proficiency of individuals, because d′ controls for any response bias the participants may have, and thus is more reliable than RTs in this context.According to a One-Way rANOVA on the RTs, there was a significant main effect of the task  and task  with no significant interaction . Paired t-tests showed that the signal changes for Disc − R were significantly higher than those for Word − R in all three regions (Bonferroni corrected p < 0.05). Task difficulty cannot explain these modulation patterns, as the Sent task was the hardest among the three language tasks; the patterns were also independent of general short-term memory, because we subtracted responses in the R task. Therefore, not only the dorso-ventral expansion of activated regions in the frontal language areas, but also overactivation in each of these regions was primarily influenced by the level of linguistic integration.We focused on the frontal language areas with clear hierarchical integration, and chose three regions of interest (ROIs). The local maximum of each region of the L. LPMC, L. F3op/F3t, and L. F3O was taken serially from significant activation in Word − R, Sent − R, and Disc − R, respectively Table , to ensup < 0.05). In Sent − R, we observed clear left-lateralized activations in the L. F3op/F3t and L. LPMC, as well as right-lateralized activations in the MTG/STG , we examined overactivation during sentence-level processes when compared with lower levels. This contrast exhibited more focal activation in the L. LPMC and L. F3op/F3t Figure , Table 5d′ of each language task and GM volumes in localized regions (FDR-corrected p < 0.05). Between the d′ of the Word task and GM volumes, we found a prominent correlation in the dorsolateral surface of the left precentral gyrus and postcentral gyrus   , Z(19) = 4.9, p < 0.001, 1440 voxels]  = 3.9, p < 0.001, 449 voxels], which was just below the threshold of FDR-corrected p < 0.05. Finally, we also found a strong correlation between the d′ of the Disc task and GM volumes in the L. F3O  and in the left precuneus   reading of English texts has reported that activations in the bilateral frontal and temporal regions increased in magnitude and spatial extent for each of these regions, with the greatest increase being induced by narratives, followed in order by unconnected sentences and word lists  (Hasson et al., Lesion studies have shown that, as in vocal languages, damage in the left hemisphere caused aphasia in sign languages, while body movements or production of non-linguistic gestures were relatively spared (Corina et al., In addition to the lateral frontal cortex, we observed consistent activation in the pre-SMA in the language tasks Table . The prebilateral primary motor and somatosensory cortices were larger in professional keyboard players than non-musicians (Gaser and Schlaug, left PreCG/PostCG. Indeed, even two-hand signs have certain phonological constraints, such that the handshapes and movements must be either more complex in the dominant hand or symmetric in both hands (Sandler and Lillo-Martin, d′ of the Sent task, previous voxel-based lesion symptom mapping and fMRI studies have shown that the anterior insula is critical for coordinating speech articulation (Dronkers, d′ of the Disc task, has been shown to be involved in the shifting attention between different locations in space necessary for the coordination of motor control (Wenderoth et al., d′ of the Disc task, would also be functionally specialized in discourse-level integration, further supporting its pivotal role in sentence comprehension.Previous VBM studies have shown that increased GM volumes in distinct regions were associated with proficiencies in different aspects of vocal languages, including vocabulary, literacy, or syntactic abilities (Mechelli et al., consistently left-lateralized activation in the frontal language areas among the participants we tested (Figures universality of linguistic processing beyond modality differences and human diversities, which would also be generalizable to other individuals in any natural languages that are based on universal grammar (Chomsky, In spite of the fact that we utilized JSL and examined Deaf signers, which included some children and disproportionate numbers of females, we found  Figures , 3. MoreChomsky, . In concConceived and designed the experiments: Tomoo Inubushi and Kuniyoshi L. Sakai. Performed the experiments: Tomoo Inubushi and Kuniyoshi L. Sakai. Analyzed the data: Tomoo Inubushi and Kuniyoshi L. Sakai. Wrote the paper: Tomoo Inubushi and Kuniyoshi L. Sakai.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Enalapril maleate, the oldest and most widely distributed ACEI, and alacepril, the newest and antioxidant ACEI, were compared in the point of cardioprotective effect for Dahl salt-sensitive rat. In order to evaluate the correlation between the three factors, cardiac fibrosis and blood pressure/oxidative-stress marker (tissue TBARS), index of correlation was calculated. The results showed a significant difference in cardiac fibrosis between high-dose alacepril  and enalapril maleate . There was significant correlation between cardiac fibrosis and oxidative-stress marker, although there was no correlation between cardiac fibrosis and blood pressure. Fibrosis was more influenced by oxidative stress not by blood pressure, we should not select ACEI only by blood pressure-lowering effect and should more consider cardioprotective effects of ACEI. Heart failure is defined as a syndrome that demonstrates a systolic dysfunction, diastolic dysfunction, or both. There are many mechanisms by which heart failure can be induced. However, cardiac remodeling and sequential fibrosis of cardiac muscle seems to contribute equally to cardiac failure. Although many factors are referred to as causative agents in cardiac remodeling, the renin-angiotensin system (RAS), sympathetic nerve system, and reactive oxygen species (ROS) are considered the major factors that intricately interact with each another. Because angiotensin II (Ang II) is generated by the RAS and induces the activation of sympathetic nerve system and augmentation of ROS, regulation of the RAS is recognized as an important measure for preventing fibrosis of cardiac muscle. Two types of RAS, circulating RAS and cardiac RAS, which act in different ways have been reported –6. Circu Various types of ACEIs with very similar basic vasodepressive effects are available; however, they differ slightly in their pharmacokinetics. To stabilize the therapeutic effect and minimize the adverse effects, the currently available ACEIs are in the form of prodrugs and need to be converted into an active form in the body before they take effect. In addition, some ACEIs may act more directly on ACE in tissues than on ACE in the circulating blood . CurrentThe experimental procedures were approved by the Institutional Animal Care and Use Committee of the Tokyo University of Agriculture and Technology. Three-week-old Dahl salt-sensitive rats  were fed a low-salt (0.3% NaCl) diet (BP 168.8 ± 52 mmHg), and by 7 weeks of age, they were switched to a high-salt (8% NaCl) diet. They were then divided into four subgroups that received a low dose of alacepril , a high dose of alacepril , enalapril , and placebo . From 7 weeks of age, noninvasive blood pressure measurements were obtained every 2 weeks using a tail-cuff method . Echocardiographic studies were performed using a phased array sector scanner . Under general anesthesia with intraperitoneal administration of ketamine hydrochloride (60 mg/kg) and xylazine hydrochloride (5 mg/kg), a right parasternal short-axis image was obtained. In the papillary muscles, the size of the diastolic thickness of the interventricular septum , the diastolic thickness of the interventricular septum ), the diastolic thickness of the left-ventricular posterior wall , the systolic thickness of the left-ventricular posterior wall , the left-ventricular internal dimension at end diastole , and the left-ventricular internal dimension at end systole  were measured with M-mode measurement, and the fractional shortening (%FS) was calculated from LVIDs and LVIDd. A left parasternal apical four-chamber view was then obtained to record mitral inflow. The E and A peaks were measured, and the A/E ratio was calculated. Each echocardiographic measurement was repeated three times, and their average value was used for assessment. At 19 weeks of age, the rats received a lethal injection of sodium pentobarbital. Blood samples were collected from the vena cava, after which a midline thoracotomy was performed and the heart was removed and cut cross-sectionally at the papillary muscle. The apical region of the heart was used for the assay of oxidative stress, and the basal region for the measurement of cardiac fibrosis. Both blood and cardiac samples were immediately frozen and stored at −80°C until the measurements were obtained.Urine 8-hydroxy-2′deoxyguanosine (8-OHdG) and plasma and tissue thiobarbituric acid reactive substances (TBARS) were used as indexes of lipid peroxidation and oxidative stress. 8-OHdG levels were determined by the method previously reported using commercial assay kit , applicable to samples from human, mouse, rat, rabbit, dog, cattle, and horse . After iμm) in the usual manner. They were then stained with hematoxylin-eosin and picrosirius red stain. The collagen density percentage was determined in the left ventricle. Each region was assessed following staining with picrosirius red in 10 random fields with a magnification of ×200. The collagen density percentage was calculated using a computerized morphometry system , and the sum of all the areas stained positive for sirius red was divided by the sum of all myocardial areas for each individual rat. Left ventricular histological examination was conducted to quantify the cardiac fibrosis. The ventricles were paraffin-embedded and cut into thin sections . Results are expressed as mean ± SD. Differences at specific stages between groups were assessed using one-way ANOVA and Bonferroni's multiple comparison test. A probability value of  A total of 40 DS rats (10 rats in each group) were used in the present study. The mean blood pressure before ACEI administration was 136.9 ± 4.2 mmHg, and a significant increase were observed in each group at 19 weeks of age . There were no significant differences between Group E and Group P. The detailed data relating to urine 8-OHdG, plasma, and tissue TBARS and fibrosis are summarized in P = 0.76 and P = 0.95, r = 0.01 and r = 0.001, resp., for cardiac fibrosis and P = 0.92 and P = 0.52, r = 0.001 and r = 0.07, resp., for blood pressure). Tissue TBARS in Groups H and E were significantly correlated with cardiac fibrosis in the left ventricle , whereas there was no significant correlation between cardiac fibrosis and blood pressure . The coefficient of correlation between cardiac fibrosis and blood pressure (mmHg)/tissue TBARS (nmol/mg protein) is shown in DS rat have been reported to show steep elevation in blood pressure depending on the amount of salt intake , 13. EleNo differences in blood pressure were observed between the groups. At 19 weeks of age, ACEI administration began to decrease the blood pressure, especially in Group H. The decrease in blood pressure observed in the high-dose alacepril group could have been due to the drug potency; alternately, an antiadrenergic or antioxidant effect, which only alacepril possesses, might have been acting synergistically to promote the hypotensive effect.To study the antiadrenergic effect of alacepril, cardiac rate was monitored. There were no significant differences between groups, and a direct antiadrenergic effect of alacepril was not confirmed. The cardiac rate of the conscious DS rats is about 500 beats/min, and this rate might have been elevated because of the stress of the blood pressure measurement in the present study. Assessment of cardiac rate therefore seems unsatisfactory as a method of estimating the antiadrenergic effect; another method, such as measurement of blood norepinephrine concentration, might provide a more accurate alternative.Antioxidant effect was estimated by three parameters: 8-OHdG in blood plasma and urine, and tissue TBARS in heart muscle. 8-OHdG is released into cytoplasm when deoxyguanine is attacked by oxidative damage. Released 8-OHdG is not metabolized; it circulates in the blood and is then excreted as a filtrate in the urine . Because Measurement of cardiac fibrosis in the left ventricle represents the amount of cardiac remodeling of the heart exposed to high blood pressure for 12 weeks. Although decreased ROS levels were observed in Group H, no significant decrease in cardiac fibrosis nor blood pressure was observed between Group P. One reason for this result was that Group P showed high dispersion of the drug, which might have been related to dispersion in salt-sensibility, pressure overload, and reactivity to the ROS. In addition, the rate of cardiac fibrosis was low in each group, and therefore it was not considered as a significant difference except for between Group H and Group E. From our previous study, we had thought that 12 weeks would be sufficient to induce cardiac failure; however, a longer observation period might be necessary . Cardiac Cardiac hyperplasia was observed at the posterior wall of the left ventricle and the interventricular septum on echocardiography at 19 weeks of age. Pressure overload was the main reason for the hyperplasia, and ACEIs showed a suppressive effect on its development. Significant differences were observed between Groups P and E, but not between the groups given ACEIs. It has been reported that the rennin system is not affected by salt-induced hypertension in the DS rat and the sympathetic nervous system is more involved in this model . Systoli The present study reported relatively low levels of cardiac fibrosis in DS rats used in the present study, and this study model seemed to be inappropriate for the evaluation of ACEI for suppression of fibrosis. However, individual analysis of the rate of fibrosis, ROS, and blood pressure enabled us to demonstrate the relationship between these factors. The results showed the importance of ROS in heart muscle, and suggest that we should pay more attention to this factor when we use ACEIs to treat patients with heart failure. In the present study, we used the pressure overload model to evaluate the direct sympathoinhibitory action and free radical scavenging effect more clearly; however, the general indication for use of alacepril in veterinary medicine is volume overload such as mitral regurgitation. We should also evaluate the effect of alacepril using a volume overload model from the perspective of its free radical scavenging effect.