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Rheumatoid vasculitis is a rare etiology for pulmonary hypertension (PH) in patients with connective tissue disease. We encountered a case of acute PH crisis in a case with rheumatoid vasculitis eight months after undergoing adalimumab reduction. Since no repetition of arthralgia occurred after the adalimumab reduction, we decided to not increase the dose of adalimumab. However, hemodynamic collapse thereafter developed and even though steroid pulse therapy was administered, the patient nevertheless died. The autopsy showed clusters of acute and chronic inflammation around the remodeled pulmonary arteries along with micro-thrombi in the vessel lumen. We should consider the possibility of critical worsening of PH as a phenotype of vasculitis related to immunosuppressive therapy reduction.

Background Plasmodium sp., which causes malaria, must first develop in mosquitoes before being transmitted. Upon ingesting infected blood, gametes form in the mosquito lumen, followed by fertilization and differentiation of the resulting zygotes into motile ookinetes. Within 24 h of blood ingestion, these ookinetes traverse mosquito epithelial cells and lodge below the midgut basal lamina, where they differentiate into sessile oocysts that are protected by a capsule. Methods We identified an ookinete surface and oocyst capsule protein (OSCP) that is involved in ookinete motility as well as oocyst capsule formation. Results We found that knockout of OSCP in parasite decreases ookinete gliding motility and gradually reduces the number of oocysts. On day 15 after blood ingestion, the oocyst wall was significantly thinner. Moreover, adding anti-OSCP antibodies decreased the gliding speed of wild-type ookinetes in vitro. Adding anti-OSCP antibodies to an infected blood meal also resulted in decreased oocyst formation. Conclusion These findings may be useful for the development of a transmission-blocking tool for malaria. Graphical abstract

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.

Functional tricuspid regurgitation (FTR) is associated with prognosis for various heart diseases, but its association with pulmonary hypertension (PH) remains unclear. We studied 111 PH patients. Mid-term follow-up echocardiography was performed 7.1 ± 4.1 months after PH-specific therapy. The severity of FTR was graded as none or trace, mild, moderate, or severe, while more than moderate TR was defined as significant. Moreover, mid-term improvement in FTR after therapy was defined as an improvement in severity of FTR by a grade of 1 or more. Long-term follow-up to determine the primary endpoint of death or hospitalization for heart failure lasted 39 ± 14 months. Mid-term improvement in FTR after PH-specific treatment was observed in 25 patients (23%), and the primary end points occurred in 27 patients (24%) during the long-term follow-up. The Kaplan–Meier curve indicated that the non-FTR group showed more favorable long-term outcomes than the FTR group (log-rank P = 0.008). It further indicated that patients with mid-term improvement in FTR also had more favorable long-term outcomes than those without such improvement (log-rank P = 0.03). When divided into four sub-groups based on combined assessment of baseline FTR and mid-term improvement in FTR, long-term outcomes for patients without mid-term improvement in their baseline FTR were worse than for the other sub-groups (log-rank P = 0.02). Multiple regression analysis showed that a relative change in tricuspid annular diameter at the mid-term follow-up after PH-specific therapy was the only independent determinant parameters for mid-term improvement in FTR. FTR appears to be a valuable factor for predicting long-term outcomes for PH patients, and combined assessment of baseline FTR and mid-term improvement in FTR after PH-specific therapy may have clinical implications for better management of such patients.

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line drug for the treatment of pulmonary arterial hypertension (PAH). In addition, bosentan is approved for patients with digital ulcers related to systemic sclerosis. Liver dysfunction is a major adverse effect of bosentan and may lead to discontinuation of therapy. The purpose of this study was to identify genomic biomarkers to predict bosentan-induced liver injury. A total of 69 PAH patients were recruited into the study. An exploratory analysis of 1936 single-nucleotide polymorphisms (SNPs) in 231 genes involved in absorption, distribution, metabolism, and elimination of multiple medications using Affimetrix DMET™ (Drug Metabolism Enzymes and Transporters) chips was performed. We extracted 16 SNPs (P 0.05) using the Jonckheere-Terpstra trend test and multiplex logistic analysis; we identified two SNPs in two genes, CHST3 and CHST13, which are responsible for proteoglycan sulfation and were significantly associated with bosentan-induced liver injury. We constructed a predictive model for bosentan-induced liver injury (area under the curve [AUC]: 0.89, sensitivity: 82.61%, specificity: 86.05%) via receiver operating curve (ROC) analysis using 2 SNPs and 2 non-genetic factors. Two SNPs were identified as potential predictive markers for bosentan-induced liver injury in Japanese patients with pulmonary arterial hypertension. This is the first pharmacogenomics study linking proteoglycan sulfating genes to drug-induced liver dysfunction, a frequently observed clinical adverse effect of bosentan therapy. These results may provide a way to personalize PAH medicine as well as provide novel mechanistic insights to drug-induced liver dysfunction.

Antiphospholipid syndrome (APS) is a cause of chronic thromboembolic pulmonary hypertension (CTEPH) and it is associated with an increased risk of postoperative neurological complications. We experienced a case of reversible parkinsonism after pulmonary endarterectomy (PEA) and subsequent multiple cerebral infarctions under standard anticoagulation therapy in a patient with CTEPH associated with APS. Strict management using a combination of antiplatelet and anticoagulation therapy should be considered in patients with a high titer of triple antiphospholipid antibodies in the perioperative period. We should be aware of the high risk of postoperative neurologic manifestations in patients with APS.

Objectives Our goal was to evaluate whether endothlin-1 (ET-1) plays an important role in the Fontan circulation. Methods Thirteen patients with single-ventricle physiology (Glenn circulation, n = 7; Fontan circulation, n = 6) were evaluated using lung histopathological and immunohistochemical studies and then compared with the normal autopsied controls without congenital heart disease (n = 13). We evaluated the medial thickness of the small pulmonary arteries. For 10 of these patients, quantitative real-time polymerase chain reaction analyses of ET-1, endothelin receptors Type A and Type B, endothelin-converting enzyme-1 and endothelial nitric oxide synthase were performed. Results The medial thickness of the small pulmonary arteries in patients with single-ventricle physiology was greater than that of those in the control group (P = 0.0341). Severe medial hypertrophy of the pulmonary arteries was observed in patients who had poor outcomes. Immunohistochemical studies revealed that the marked expression of ET-1 was observed in the endothelium and media of their pulmonary arteries. In these patients, the messenger RNA expression of ET-1 was also increased. Two patients showed high levels of expression of ETAR and ETBR, although these 2 cases maintain good Fontan circulation. Conclusions Medial hypertrophy and the overexpression of ET-1 in the pulmonary arteries were observed in some patients in whom the Fontan circulation failed. Our data suggest that ET-1 may play an important role in maintaining the Fontan circulation.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the main subgroups of pulmonary hypertension (PH). Despite differences in their etiologies, both diseases are characterized by vascular remodeling, resulting in progressive right heart failure. Noninvasive periodic evaluation of exercise tolerance has become increasingly important. Cardiopulmonary exercise testing (CPET) and a 6-minute walk test (6MWT) are now both recommended for evaluating exercise tolerance, but there is insufficient knowledge about possible differences in the associations of exercise tolerance with right heart catheterization (RHC) data for patients with PAH and CTEPH.A retrospective study was performed with 57 patients with PH (24 with PAH and 33 with CTEPH) all of whom underwent echocardiography, CPET, 6MWT, and RHC.For both patients with PAH and CTEPH, peak heart rate during CPET was significantly higher than that from 6MWT, whereas minimum peripheral oxygen saturation during CPET and 6MWT was similar. For patients with PAH, significant correlations were observed between peak (Equation is included in full-text article.)O2 and cardiac index (CI) (r = 0.59; P = .002) and between (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slopes and CI (r =-0.46, P = .02), as well as a nonsignificant correlation tendency for peak (Equation is included in full-text article.)O2 and pulmonary vascular resistance (PVR) and for (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 and PVR (r =-0.39; P = .05; and r = 0.39; P = .06, respectively). For patients with CTEPH, however, a significant correlation was observed only between (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slopes and CI (r =-0.38; P = .02).PH etiology should be considered when assessing exercise tolerance, whereas CPET can be effective in addition to hemodynamic assessment by means of RHC for periodic evaluation during followup.

It is well known that Down's syndrome is a strong risk factor for mortality after Fontan operations. We performed two lung biopsies in a Down's syndrome patient who underwent staged Fontan operations. The pathological findings revealed severe pulmonary arterial hypertrophy and a quantitative real-time polymerase chain reaction revealed the overexpression of endothelin and a decline in the eNOS level at the Fontan operation. Although the preoperative hemodynamic studies revealed that all of the criteria for Fontan had been fulfilled, the patient died of acute cardiac insufficiency, 35 days after the Fontan operation.

Although violations of laws, such as shoplifting, are considered to be common in frontotemporal dementia (FTD) patients, there have been few studies on this subject and the frequencies and types of such violations have not been clarified. The objective of this study was to conduct a retrospective investigation of FTD patients in the psychiatry departments of multiple institutions to determine the types and frequencies of any law violations and compare them with those of AD patients. All patients were examined between January 2011 and December 2015 at the specialized dementia outpatient clinics of 10 facilities (5 psychiatry departments of university hospitals, 5 psychiatric hospitals). According to diagnostic criteria, 73 behavior variant FTD (bvFTD) patients, 84 semantic variant of primary progressive aphasia (svPPA) patients, and 255 age- and sex-matched AD subjects as the control group were selected. The findings revealed a higher rate of law violations in the bvFTD and svPPA patients before the initial consultation as compared to the AD group (bvFTD: 33%, svPPA: 21%, AD: 6%) and that many patients had been referred due to such violations. Laws had been broken 4 times or 5 or more times in several cases in the FTD group before the initial consultation. Regarding rates for different types of violation, in bvFTD subjects, the highest rate was for theft, followed by nuisance acts and hit and run. In svPPA, theft had the highest rate, followed by ignoring road signs. There was no gender difference in law violations but they were more frequent when the disease was severe at the initial consultation in the FTD group. As the rates of law violations after the initial consultation were lower than before it, interventions were considered to have been effective. These findings may be useful for future prevention as well as to the legal system.

Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2 ± 9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p = 0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039–1.713; p = 0.03). Moreover, patients with RV-RWT ≥0.21 showed better long-term outcomes than did those without (log-rank p = 0.03), while those with RV-RWT ≥0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT

Pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) have showed beneficial effects on hemodynamics and exercise tolerance in patients with chronic thromboembolic pulmonary hypertension (CTEPH) [(1,2)][1]. Although several publications have demonstrated improvement in health

We conducted a study on "anger" seen in obsessive-compulsive disorder (OCD). Subjects were 40 men and women (age range: 20-58 years) admitted to the Jikei University Center for Morita Therapy who had been diagnosed with OCD (DSM-IV-TR) and undergone inpatient Morita therapy. The Japanese version of the Structured Clinical Interview for DSM-IV (SCID) (DSM-IV Axis I and Axis II diagnoses), the Yale-Brown Obsessive Compulsive Scale (Y- BOCS) (changes in OCD severity), the State-Trait Anger Expression Inventory (STAXI-2) using "anger" as the indicator, and the State-Trait Anxiety Inventory (STAI) using "anxiety" as the indicator were used, and the data were subjected to statistical analysis. Improvements were seen in the Y-BOCS for all of the following : total score, obsessional idea, compulsive act, insight, and avoidance. These results indicate that inpatient Morita ther- apy improves OCD. In the STAI, improvements were seen for both state anxiety and trait anxiety. Improvement of trait anxiety may be considered an indicator of the cultivation of a hypochondriacal temperament. In the STAXI-2, improvements were seen for anger reaction and anger expression-in, which are both aspects of the obsessive-compulsive style (Salzman, L.). Improvements in these items therefore indicate that inpatient Morita therapy improves aspects of the obsessive-compulsive style. A correlation with the degree of OCD improvement was observed for the insight level. Poor insight was a factor associated with poor outcomes of inpatient Morita therapy. Furthermore, two cases were presented, and the actual condition of treatment for OCD and "anger" in inpatient Morita therapy was elucidated.

Several studies have noted an effect of DNA methylation on the pathogenesis of Alzheimer's disease (AD). We have already reported that DNA methylation levels in the NCAPH2/LMF2 promoter region can be a useful biomarker for the diagnosis of AD and amnesic mild cognitive impairment (aMCI). However, there is still uncertainty about the mechanism by which NCAPH2/LMF2 methylation affects the pathogenesis of AD and aMCI. In this study, we investigated relationships between NCAPH2/LMF2 methylation and other factors. AD (n=30) and aMCI (n=28) subjects were included in this study. NCAPH2/LMF2 methylation levels were measured by pyrosequencing. Correlations between methylation levels and other factors including age at onset, sex, duration of disease, education, mini-mental state examination (MMSE) and frontal assessment battery (FAB) scores, APOE genotype, degree of hippocampal atrophy, and total brain atrophy were measured. Degrees of hippocampal atrophy and total brain atrophy were measured by VSRAD (Voxel-Based Specific Regional Analysis System for Alzheimer's Disease). Regression analysis revealed that only hippocampal atrophy according to VSRAD is a significant dependent variable correlated with NCAPH2/LMF2 methylation levels. Our results suggest that DNA methylation in the NCAPH2/LMF2 promoter region is associated with hippocampal atrophy through apoptosis.

Background Late-life somatoform disorders (SDs) are characterized by various aging-associated factors. Recently, cognitive decline, including executive dysfunction, has been reported as an etiological factor of late-life SDs. The response to treatment for late-life SDs varies from one patient to another. Treatment strategies for late-life SDs require these etiological factors to be considered. We hypothesized that the treatment response in patients with late-life SDs was associated with executive dysfunction. Objective The aim of the present study was to confirm the changes in disease severity over a 2-year follow-up period and to determine which etiological factors are related to the treatment response in patients with late-life SDs. Methods We examined 55 patients with late-life SDs who were treated with pharmacotherapy and supportive psychotherapy at baseline. The changes in the disease severity and cognitive profiles over a 2-year follow-up period were evaluated. Additionally, we investigated which etiological factors at baseline were related to treatment resistance. Results Of the 55 patients who were enrolled in the present study, 31 completed the 2-year follow-up period. Overall, the disease severity improved significantly in patients with late-life SDs. On the contrary, executive function decreased throughout the research period. Moreover, we found that executive dysfunction and the presence of hyperlipidemia at baseline were related to treatment resistance. Conclusions These results suggest that aging-associated etiological factors be considered for the treatment of late-life SDs.

Background The Neuropsychiatric Inventory (NPI) comprises 12 items, which were conventionally determined by psychopathological symptoms of patients with dementia. The clinical rating scales with structured questionnaires have been useful to evaluate neuropsychiatric symptoms (NPSs) of patients with dementia over the past twenty year. Objective The aim of this study was to classify the conventional NPSs in patients with Alzheimer's disease (AD) requiring antipsychotic treatment for their NPSs into distinct clusters to simplify assessment of these numerous symptoms. Methods Twelve items scores (product of severity and frequency of each symptom) in the NPI taken from the baseline visit were classified into subgroups by principle component analysis using data from 421 outpatients with AD enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Phase 1. Chi square tests were conducted to examine the co-occurrence of the subgroups. Results We found four distinct clusters: aggressiveness (agitation and irritabilities), apathy and eating problems (apathy and appetite/eating disturbance), psychosis (delusions and hallucinations), and emotion and disinhibition (depression, euphoria, and disinhibition). Anxiety, aberrant motor behavior, and sleep disturbance were not included by these clusters. Apathy and eating problems, and emotion and disinhibition co-occurred (p = 0.002), whereas aggressiveness and psychosis occurred independent of the other clusters. Conclusions Four distinct category clusters were identified from NPSs in patients with AD requiring antipsychotic treatment. Future studies should investigate psychosocial backgrounds or risk factors of each distinct cluster, in addition to their longitudinal course over treatment intervention.

Objectives: Pulmonary hypertension (PH ) is characterized by marked and sustained elevation of pulmonary vascular resistance and pulmonary artery pressure, and subsequent right‐sided heart failure. Right ventricular (RV ) function and exercise capacity have been recognized as important prognostic factors for PH . Our aim was to investigate RV contractile reserve and exercise capacity during a leg‐positive pressure (LPP ) maneuver. Methods: The study population comprised 43 PH patients and 17 normal controls. All patients underwent echocardiography at rest and during LPP stress. Exercise capacity was assessed by 6‐minute walk distance for PH patients. RV relative wall thickness was calculated from dividing by RV free wall thickness by basal RV linear dimensions at end‐diastole. RV function was calculated by averaging peak speckle‐tracking longitudinal strain from the RV free wall. RV contractile reserve was assessed as the difference in RV free wall strain at rest and during LPP stress. Changes in left ventricular stroke volume (ΔSV ) during LPP stress were also calculated. Results: ΔSV and RV contractile reserve of PH patients were significantly lower than of controls (3.6 ± 6.0 mL vs 8.5 ± 2.3 mL, and 8.2 ± 11.9% vs 14.5 ± 6.6%; both P < 0.01). RV contractile reserve of PH patients with ΔSV 3.3 mL (3.9 ± 13.2% vs 12.3 ± 8.9%; P = 0.02). ΔSV had also significant correlation with 6‐minute walk distance (r = 0.42, P = 0.006). Multivariate regression analysis showed that RV relative wall thickness was an independent determinant parameter of ΔSV during LPP stress for PH patients (β = 3.2, P = 0.003). Conclusions: Preload stress echocardiography in response to LPP maneuver, a noninvasive and easy‐to‐use procedure for routine clinical use, proved to be useful for the assessment of RV contractile reserve and exercise capacity of PH patients.

Background Residual symptoms after pulmonary endarterectomy ( PEA ) remain as the clinical issues to be solved. Additional balloon pulmonary angioplasty ( BPA ) after PEA showed its efficacy with symptoms in a case series, although long‐term spontaneous recovery of exercise ability after PEA was also reported. However, no studies have validated the clinical efficacy of additional BPA by directly comparing PEA with and without BPA . The aim of this study was to retrospectively evaluate the efficacy of additional BPA as a sequential hybrid therapy for chronic thromboembolic pulmonary hypertension after PEA . Methods and Results Among 44 patients with chronic thromboembolic pulmonary hypertension, 20 patients had residual symptoms after PEA. Of those, 10 patients underwent additional BPA (hybrid group) and were compared with the other 10 patients, who were followed up without BPA ( PEA group). The period from PEA to additional BPA was 7.3±2.3 months. In hybrid group, mean pulmonary arterial pressure was significantly improved by PEA (40.6±1.8 to 26.9±3.1 mm Hg, P =0.001) and improved further (to 16.7±1.8 mm Hg, P =0.002) with additional BPA , which resulted in remarkable improvement in World Health Organization ( WHO ) functional class (pre‐ to post‐BPA: class I/ II / III / IV , 0/5/4/1 to 7/3/0/0; P PEA group at follow‐up, the hybrid group achieved better mean pulmonary arterial pressure (18.7±1.7 versus 30.2±3.2 mm Hg, P =0.008), WHO functional class (class I/ II / III / IV , 7/3/0/0 versus 0/8/2/0; P =0.001), and 6‐minute walking distance (429±38 versus 319±22 m, P =0.028). Conclusions A sequential hybrid strategy improved residual symptoms and exercise capacity compared with single‐ PEA therapy.

Background Late-life somatic symptom disorder (SSD) is characterized by various aging-associated factors, such as a functional decline, psychosocial problems, and cognitive dysfunction. However, the details of the cognitive dysfunction that occur in late-life SSD are still unknown. Objective The aims of this study were to reveal the cognitive profile of patients with late-life SSD and to evaluate how cognitive dysfunction affects disease severity. Methods We compared the cognitive profiles of patients with late-life SSD ( n = 40) with those of normal control subjects ( n = 21). In addition, we divided the patients with late-life SSD into mild-to-moderate ( n = 24) and severe ( n = 16) groups and compared the cognitive profiles of the 3 groups. Results Patients with late-life SSD exhibited a lower Mini-Mental State Examination total score and attention decline. In the 3-group comparison, the severe group had a lower Mini-Mental State Examination score and Frontal Assessment Battery score than the normal control group, whereas no significant difference was seen between the mild-to-moderate and the normal control groups. Conclusions Our data suggest that different cognitive patterns may exist depending on disease severity, possibly indicating differences in pathogenesis.

Objective This study aimed to investigate the structural changes in the slit diaphragm, caused by early diabetes, and the nephroprotective effect of C-peptide. Methods Streptozotocin-induced type 1 diabetic Wistar rats were divided into control, control plus C-peptide, early diabetes, and early diabetes plus C-peptide groups. C-peptide was infused into rats for one day. The slit diaphragm component proteins podocin, CD2AP, and nephrin, were stained immunofluorescently and their distribution quantitatively analyzed by determining the overlapping area ratio. The interfoot process gap length was measured from electron microscopic images. Results Diabetic duration correlated best with the area ratio of podocin and CD2AP (r = 0.626), followed by other protein combinations, showing progressive change in the slit diaphragm structure. C-peptide-treatment did not alter area ratios. The interfoot process gap length was wider in diabetic rats (p

Background/objective The aim of the present study was to investigate predictors of atypical antipsychotic (AAP) treatment continuation and response by week 8 in patients with Alzheimer's disease (AD) who have psychotic/aggressive symptoms using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) dataset. Methods Clinical data was utilized from 421 AD outpatients with psychotic/aggressive symptoms who needed interventional treatment. Logistic regression analyses were performed to examine which baseline sociodemographic and clinical characteristics contributed to treatment 'continuation' and 'response', the latter of which was evaluated by the Clinical Global Impression of Change (CGI-C), Neuropsychiatric Inventory (NPI), and Brief Psychiatric Scale (BPRS). Results The treatment continuation rate was 48.7%, and CGI-C, NPI, and BPRS response rate by the last observation carried forward method were 42.7%, 48.6%, and 37.5%, respectively. No significant predictor was identified for treatment continuation in the Caucasian patients (n = 331), while better treatment response was predicted by a lower Mini-Mental State Examination score, treatment with risperidone (versus olanzapine and quetiapine), history of diabetes mellitus, healthier physical status, and more severe initial psychotic symptoms. Conclusions Comparatively high intolerability from AAPs in the short term was confirmed. We found that baseline clinical predictors to treatment response in Caucasian AD patients with psychotic/aggressive symptoms include treatment with risperidone (versus quetiapine and olanzapine), diabetes mellitus, global physical status, cognitive impairment, and psychotic symptoms. Going forward, these findings may help to determine treatment strategies or care plans.

Preprocedural recognition of the segment of latest mechanical contraction along with the anatomy of the coronary venous system is important for successful and effective cardiac resynchronization therapy. We present a case of ischemic cardiomyopathy who underwent implantation of a cardiac resynchronization therapy device with a defibrillator, which was facilitated by preprocedural computed tomographic images reconstructed to visualize the left ventricular slab and the coronary venous system simultaneously on the cardiac contour. The present reconstruction method using computed tomography is optimal and feasible method to incorporate the echocardiographic findings into the procedure performed under fluoroscopy appropriately.

Anosognosia in Alzheimer's disease (AD) is a complicated, non-unitary phenomenon. In a clinical setting, patients with mild AD often preserve their awareness partially. We hypothesized that compensation, as well as neural dysfunction, could be correlated with anosognosia in mild AD.The severity of anosognosia was evaluated using the Anosognosia Questionnaire for Dementia in 37 subjects with mild AD or mild cognitive impairment due to AD. The subjects also underwent single-photon emission computed tomography with N-isopropyl-p-[The severity of anosognosia was relatively mild; the mean Anosognosia Questionnaire for Dementia score was 6.76 ± 14.16. Subjects were divided into two groups: anosognosia (+) (n = 11) and anosognosia (-) (n = 26). In the single-photon emission computed tomography data analysis, the severity of anosognosia was correlated with both lower regional cerebral blood flows of the right prefrontal cortex and higher regional cerebral blood flows of the parietal cortex, especially the left temporo-parietal junction.Our results suggest that anosognosia in mild AD could be correlated with compensation as well as neural dysfunction. We speculate that this compensation may be related to the retrieval of outdated autobiographical memory.

Aims To evaluate the efficacy and safety of balloon pulmonary angioplasty (BPA) in patients with non-operable chronic thromboembolic pulmonary hypertension (CTEPH) using the results of pulmonary endarterectomy (PEA) for operable patients as a reference, and annotate the role of BPA in the management of CTEPH. Methods and results Data from 53 CTEPH patients were collected retrospectively. Twenty-four operable patients underwent PEA, and 29 non-operable patients underwent BPA. Patients who underwent BPA showed improved mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output (39.4±6.9 to 21.3±5.6 mmHg, 763±308 to 284±128 dyn·s-1·cm-5, 3.47±0.80 to 4.26±1.15 L/min, respectively); patients who received PEA showed similar efficacy (44.4±11.0 to 21.6±6.7 mmHg, 781±278 to 258±125 dyn·s-1·cm-5, 3.35±1.11 to 4.44±1.58 L/min, respectively). The mortality rates of BPA and PEA patients were 3.4% and 8.3%, respectively. Conclusions The efficacy and safety of BPA for non-operable cases were similar to those achieved using PEA for operable cases. BPA could be an additional treatment option for non-operable CTEPH patients, and most CTEPH patients can be satisfactorily treated by BPA or PEA.

Various aging associated factors, such as functional decline, psychosocial problems, and cognitive dysfunction, are risk factors for somatoform disorders (SDs) in the elderly. The aim of the present study was to evaluate how cognition is correlated with the severity of late-life SDs from a neuropsychological viewpoint.Fifty-three patients over 60 years of age who had been diagnosed as having SDs were examined in this study. The severity of the somatic symptoms was assessed using the Hamilton Anxiety Rating Scales (HAMA). Cognitive functions were assessed using the Mini-Mental State Examination (MMSE), the Frontal Assessment Battery (FAB), and the Japanese version of the Neurobehavioral Cognitive Examination (J-COGNISTAT).The J-COGNISTAT subtest score for attention was below the cutoff point (8 points) but was not correlated with the severity of the somatic symptoms in the patients with late-life SDs. The severity of anxiety as assessed using the HAMA was significantly correlated with the calculation scores (P0.005) among the J-COGNISTAT subtests, the FAB total (P0.05), and the FAB subtest scores (similarities and motor series) (P0.01). Other factors, including the benzodiazepine dosage, antidepressant dosage, the duration of illness, and the onset age, were not significantly correlated with the symptomatic severities.Patients with late-life SDs showed attention deficits, but no correlation was seen between the attention deficits and symptomatic severities. Attention deficits might be associated with the appearance of symptoms. Executive dysfunction and working memory might be associated with the severity of symptoms.

Introduction: Although anxiety symptoms are often observed in Alzheimer's disease (AD), little attention has been paid to this symptom compared with other neuropsychiatric symptoms. Methods: Twenty-six patients with mild AD underwent both magnetic resonance imaging and single photon emission tomography with technetium-99m ethyl cysteinate dimer. Neuropsychiatric symptoms were evaluated using the Behavioral Pathology in Alzheimer's Disease Scale (Behave-AD). We investigated the relationship between anxiety and neuroimaging using Statistical Parametric Mapping 8 software. Results: The Behave-AD anxiety score was correlated with hyperperfusion in the bilateral anterior cingulate cortices and a reduction in the gray matter volume in the right precuneus and inferior parietal lobule. Conclusion: Our results suggest that anxiety in AD could overlap with the neural correlates of anxiety disorders, and that the specific degeneration associated with AD might be associated with anxiety.

Dopamine D2/3 receptors (D2/3Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D2/3 HIGH), which has a high affinity for endogenous dopamine, and low-affinity state (D2/3 LOW). The density of D2/3 HIGH can be measured with (R)-2-11CH3O-N-n-propylnorapomorphine ([11C]MNPA), while total density of D2/3 HIGH and D2/3 LOW (D2/3Rs) can be measured with [11C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [11C]MNPA to that of [11C]raclopride ([11C]MNPA/[11C]raclopride) may reflect the proportion of the density of D2/3 HIGH to that of D2/3Rs. In the caudate and putamen, [11C]MNPA/[11C]raclopride reflects the proportion of the density of D2 HIGH to that of D2Rs. To evaluate the reliability of the PET paradigm with [11C]MNPA and [11C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP ND) measured with [11C]MNPA and of [11C]MNPA/[11C]raclopride in healthy humans. Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [11C]MNPA and [11C]raclopride scans. BP ND values in the caudate and putamen were calculated. Test-retest reproducibility of BP ND of [11C]MNPA and [11C]MNPA/[11C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). The absolute variability of [11C]MNPA BP ND was 5.30 ± 3.96 % and 12.3 ± 7.95 % and the ICC values of [11C]MNPA BP ND were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [11C]MNPA/[11C]raclopride was 6.11 ± 3.68 % and 11.60 ± 5.70 % and the ICC values of [11C]MNPA/[11C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively. In the present preliminary study, the test-retest reproducibility of BP ND of [11C]MNPA and of [11C]MNPA/[11C]raclopride was reliable in the caudate and putamen.

Background: Right heart catheterization (RHC) is the gold standard for the diagnosis of pu lmonary hypertension (PH) and a useful tool for monitoring PH . However, there are some disadvantages in the regular use of RHC because it is invasive . Noninvasive methods for monitoring hemodynamics are needed to manage patients with PH. In this study, we aimed to evaluate the reliability of noninvasive hemodynamic assessment with whole-body impedance cardiography (Non-Invasive Cardiac System [NICaS]) for PH. Methods and Results: We investigated 55 consecutive patients undergoing RHC. Two- thirds of them had pulmo­ nary arterial hypertension and one-third had chronic thromboembolic PH ; 25% of the patients were receiving medi­ cal therapy. Cardiac output (CO) was estimated by NICaS (NI-CO), thermodilution (TO-CO), and the Fick method (Fick-CO). There was a strong correlation between NI-CO and TO-CO (r=O.715. P

Interaction of receptor for advanced glycation end products (RAGE) with amyloid-β increases amplification of oxidative stress and plays pathological roles in Alzheimer's disease (AD). Oxidative stress leads to α-synuclein aggregation and is also a major contributing factor in the pathogenesis of Lewy body dementias (LBDs). Therefore, we aimed to investigate whether RAGE gene polymorphisms were associated with AD and LBDs.Four single nucleotide polymorphisms (SNPs)-rs1800624, rs1800625, rs184003, and rs2070600-of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBDs patients, and 105 age-matched controls.Linkage disequilibrium (LD) examination showed strong LD from rs1800624 to rs2070600 on the gene (1.1 kb) in our cases in Japan. Rs184003 was associated with an increased risk of AD. Although there were no statistical associations for the other three SNPs, haplotypic analyses detected genetic associations between AD and the RAGE gene. Although relatively few cases were studied, results from the SNPs showed that they did not modify the risk of developing LBDs in the Japanese population.Our findings suggested that polymorphisms in the RAGE gene are involved in genetic susceptibility to AD. Copyright © 2016 John WileySons, Ltd.

From the standpoint of early interventions for dementia, a convenient method of diagnosis using biomarkers is required for Alzheimer’s disease (AD) in the early stage as well as amnesic mild cognitive impairment (aMCI). Focusing on differences in DNA methylation due to AD and aMCI, in the present study, we first conducted genome-wide screening, measuring blood DNA methylation levels by the Illumina Infinium HD Methylation Assay in 3 small age-and gender-matched groups consisting of 4 subjects each: normal controls (NC), aMCI and AD. The genome-wide analysis produced 11 DNA methylation loci that distinguished the 3 groups. For confirmation, we increased group sizes and examined samples by pyrosequencing which revealed that DNA methylation in the NCAPH2/LMF2 promoter region was significantly decreased in the AD (n = 30) and aMCI (n = 28) groups as compared to the NC group (n = 30) (P < 0.0001, ANCOVA). No association was found between methylation levels and APOE genotype. NCAPH2/LMF2 methylation levels were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.

Aims Hypertensive patients develop cardiac hypertrophy and fibrosis with increased stiffness, contractile deficit and altered perfusion. Angiotensin II (AngII) is an important factor in the promotion of this pathology. The effects of AngII are partly mediated by endothelin-1 (ET-1) and transforming growth factor-β. The exact feature of these pathways and the intercellular communications involved remain unclear. In this study, we explored the role of endothelial cell-derived ET-1 in the development of AngII-induced cardiac fibrosis and hypertrophy. Main methods We used mice with vascular endothelial cell specific ET-1 deficiency (VEETKO) and their wild type littermates (WT). Mice were infused for one week with AngII (3.2 mg/kg/day, n = 12) or vehicle (0.15 mol/L NaCl and 1 mmol/L acetic acid, n = 5), using subcutaneous mini-pumps. Hearts were stained with hematoxylin–eosin and masson's trichrome for histology. Cardiac gene expression and protein abundance were measured by Northern Blot, real time PCR and Western Blot. Key findings AngII-induced cardiac hypertrophy, interstitial and perivascular fibrosis were less pronounced in VEETKO mice compared to WT. Blood pressure increased similarly in both genotypes. Expression of connective tissue growth factor, tumor growth factor-β, collagen I and III in response to AngII required endothelial ET-1. Endothelial ET-1 was also necessary to the elevation in protein kinase C δ abundance and ERK1/2 activation. AngII-induced elevation in PKCe abundance was however ET-1 independent. Significance This study underscores the significance of ET-1 from the vasculature in the process of AngII-induced cardiac hypertrophy and fibrosis, independently from blood pressure. Endothelial ET-1 represents therefore a possible pharmacological target.

We investigated whether neurotrophin (NT)-3 polymorphisms influenced the executive function of patients with 2 separate disease stages with similar dementia conditions: amnestic mild cognitive impairment (A-MCI) or mild Alzheimer disease (AD).Among 215 outpatients with dementia and MCI, 155 with mild AD (n = 108) or A-MCI (n = 47) were recruited and divided into three genotypic groups based on the representative NT-3 functional polymorphisms rs6332 and rs6489630. Next, we compared the frontal assessment battery (FAB) total and subtest scores between the three genotypic groups.The total FAB score was not significantly associated with the rs6332 and rs6489630 genotypes; however, the conflicting instructions score among the 6 subtests was significantly associated with the rs6332 genotype (p0.05). Moreover, in patients with mild AD, the conflicting instructions score differed significantly among the three genotypic groups of rs6332 (p0.05) (G/GA/A: p = 0.042 and G/AA/A: p = 0.041). No significant differences in any other demographic variables were observed among the three genotypes of rs6332 and rs6489630.These results suggested that an NT-3 polymorphism, rs6332, may significantly influence executive function, reflecting interference performances among patients with mild-stage AD.

Aim: Twenty patients (14 of them women) suffering from psychophysiological insomnia (PPI) were enrolled for cognitive behavior therapy (CBT). The mean age of the patients was 56.9 years, and the mean duration of insomnia morbidity was 8.9 years. Each received individual combined CBT treatments consisting of stimulus control, sleep reduction, cognitive therapy and sleep hygiene education over a period of 1 month. Methods: Just before the CBT and after its completion, sleep measurements were conducted that involved (i) sleep logs, Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS), and the Pittsburgh Sleep Quality Index (PSQI); (ii) actigraphy measurement; (iii) dissociation between subjective and objective evaluation of sleep calculated from sleep logs and actigraphy results; and (iv) correlation between DBAS and the aforementioned sleep parameters. Because the intention was to focus on patients' incorrect cognition about sleep, the definition ‘changes in dissociation between the sleep log and actigraphically measured sleep’ was used as the primary outcome and ‘changes in DBAS score’ as the secondary outcome. Results: After the CBT the following was found: (i) underestimation by PPI patients of the objective evaluation of sleep; (ii) a decrease in the dissociation between the subjective and objective evaluation of sleep; (iii) improvement of the DBAS; and (iv) improvement of sleep logs and actigraphy measurements. Moreover, there was a correlation between the improvement of PSQI, sleep logs and DBAS. Conclusion: CBT for insomnia is able to redress incorrect cognition about sleep, leading to improvement of the disorder.

The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [(123)I]beta-CIT or positron emission tomography (PET) with [(11)C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [(11)C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [(11)C]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean+/-SD: 22+/-7.6, range: 7-32). The binding potential (BP(ND)) of [(11)C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BP(ND) were analyzed using a statistical parametric mapping system. Significant reductions of BP(ND) were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BP(ND) in the insular cortex. Although significantly reduced BP(ND) in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BP(ND). The change in [(11)C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

Aims Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1f/f; Tie2-Cre (+)] mice. Methods and results Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1f/f;Tie2-Cre (+) mice ( n = 35) and the wild-type (WT) littermates ( n = 34). Following this intervention, neointima formation was reduced in ET-1f/f;Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation. Conclusion The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.

Gene delivery to the lung has rapidly progressed as an important method for studying various chronic lung diseases. Viral vectors, albeit highly efficient, are limited by the host immune response. Electroporation, a well-known non-viral method, can efficiently deliver genes to the lung, but is unable to induce stable gene expression. The Tol2 transposon is another non-viral method that can induce stable gene expression by reinserting its genes into the host genome. In this study, we combined electroporation and Tol2 transposons to obtain stable, high-level gene expression in the mouse lung. Tol2 transposon plasmids (pT2A-EGFP; Tol2, pCAGGS-TP; transposase) were optimized in vitro, and the electroporation procedure (pCAG-EGFP) was optimized in mouse lungs. After optimization, a combination of electroporation plus the Tol2 transposon was used in a comparative analysis with electroporation plus pCAG-EGFP. GFP expression levels were quantified and visualized on days 4 and 7 post-electroporation. We successfully reproduced the Tol2 transposon system in vitro and the electroporation procedure in vivo. We observed sustainable GFP expression using electroporation plus the Tol2 transposon on days 4 and 7, while electroporation plus pCAG-EGFP resulted in decreased GFP expression on day 7. We were able to induce high-level, stable gene expression in mouse lungs using a combination of electroporation and the Tol2 transposon. This represents a safer method for lung gene delivery that can be used as an alternative to viral vectors.

Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved.

The cerebral monoaminergic nervous system was monitored for its diurnal changes to find whether these can be used as neurochemical indices for emotional states. Freely moving rats that were not anesthetized were used: by employing an in vivo microdialysis technique, the levels of extracellular monoamine metabolites were measured. Under an alternating 12 h light and dark (LD) cycle and subsequent constant light (LL) condition, the extracellular 5-hydroxyindoleacetic acid (5-HIAA) level was significantly higher in the dark phase than in the light phase in the medial prefrontal cortex (mPFC). However, the 5-HIAA levels in the light and dark phases in the striatum or hippocampus did not significantly differ. The homovanillic acid (HVA) level was significantly higher in the dark phase than in the light phase in the mPFC and striatum. These findings indicate that the extracellular 5-HIAA level in the mPFC has site-specific circadian rhythmicity. Furthermore, considering the relationship among diurnal rhythm, emotional disturbance and the mPFC, the site-specific diurnal rhythmicity of 5-HIAA in the mPFC may be a useful index in neurochemical studies on emotional states, such as seen in affective disorders and psychiatric diseases.

Background: Several lines of studies have suggested the involvement of serotonin transporter (5-HTT) in the pathophysiology of mood disorders. The aim of this study was to examine whether 5-HTT binding was altered in patients with mood disorders using positron emission tomography (PET). Methods: Thirteen antidepressant-naive or -free patients with mood disorders and 21 age-matched healthy control subjects participated in this study. The patients consisted of 7 with major depressive disorder (MDD) and 6 with bipolar disorder (BD). Positron emission tomography scans were performed using a selective ligand for 5-HTT, [ 11 C](+)McN5652. The uptake was quantified in the thalamus and midbrain by graphical method with reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. Results: Binding potential in the thalamus was significantly increased in patients with mood disorders as compared to control subjects, whereas BP in the midbrain did not differ between the groups. Subgroup comparison showed that MDD patients had significantly higher BP in the thalamus compared to control subjects. Binding potential of the thalamus was higher by approximately 22% in the combined patients and 23% in MDD patients relative to control subjects. Conclusions: These findings may suggest the possibility of altered 5-HTT in patients with mood disorders. Functional abnormality in the thalamus may be involved in the pathophysiology of mood disorders.

Paroxetine, a selective serotonin (5-HT) reuptake inhibitor, increased extracellular 5-HT and dopamine levels, as determined by microdialysis, in the medial prefrontal cortex (mPFC) of freely moving rats. There was a difference in the time course of the maximum response between the 5-HT and dopamine levels after paroxetine administration. The extracellular dopamine concentration reached its maximum 20 min after the peak effect of 5-HT had appeared. The paroxetine-induced increase in extracellular dopamine concentration, but not 5-HT concentration, was inhibited by the 5-HT(3)-receptor antagonist granisetron. These results suggest that the increase in extracellular dopamine concentration in the mPFC elicited by paroxetine is the result of stimulation of 5-HT(3) receptors by the extracellular accumulation of 5-HT in the mPFC.

KIBRA plays an important role in synaptic plasticity in human hippocampus related to cognitive function. Functional studies suggest that KIBRA is a potential candidate gene for memory and Alzheimer's disease (AD) risk. A single nucleotide polymorphism, Rs17070145 C allele affects the onset of AD in an age-dependent manner comparing with T/T genotypes and is also associated with risk of substance abuse and relapse. The aim of this case-control study was to investigate whether the rs17070145 polymorphism affected the onset of AD in an age-dependent manner in a Japanese population. We analysed KIBRA and APOE genotypes in 237 young AD cases, 154 age-matched control cases and 160 old AD cases. The analyses were performed by stratifying alcohol consumption and the APOE status. We used single photon emission computed tomography (SPECT) to analyse patients with AD with the rs17070145 polymorphism. The genotypic and allelic frequencies of the young AD group differed significantly from those of control and old AD groups. There was a significant association among high alcohol consumption (HAC-AD group) and the genotypic and allelic frequencies of the rs17070145 polymorphism. Logistic regression analyses demonstrate synergism between the APOE genotype and the rs17070145 C allele to increase the risk of AD in the young group; this was confirmed in the HAC-AD group. The SPECT study revealed hyperperfusion in the C allele carrier group was detected in the right inferior frontal gyrus compared with the T/T group. KIBRA rs17070145 affects specific phenotypes of patients with AD.

Catechol-O-methyltransferase (COMT) plays an important role in dopamine degradation, which is associated with the pathophysiology of Alzheimer's disease (AD) and alcoholism. A functional COMT polymorphism, Val158Met (rs4680 G A), affects the onset of AD and is associated with alcohol dependence through dopamine receptor sensitivity in the prefrontal cortex.The aim of this case-control study (398 cases and 149 controls) was to investigate whether Val158Met polymorphism influences the onset of AD stratified according to alcohol consumption and apolipoprotein E (APOE) status. We also used single photon-emission computed tomography (SPECT) to analyse 26 patients with AD with the polymorphism.As a function of APOE status, the genotypic frequencies of rs4680 in patients with AD did not differ from those in controls. We detected a significant association between high alcohol consumption in patients with AD (HAC-AD group) and the polymorphism in genotypic and allelic frequencies. Logistic regression analyses demonstrated that the presence of the APOE genotype with rs4680 increased the risk for HAC-AD synergistically. Hyperperfusion in the right sub-lobar insula of patients with the G/G genotype was found compared with that of patients with the G/A genotype. SPECT studies showed a relationship between the polymorphism and compensatory reactions for dysfunctions of dopaminergic neurotransmission in AD pathophysiology.Although genetic association between the polymorphism and the onset of AD in a Japanese population were not observed, the polymorphism affected the risk for HAC-AD.

Inhibition of atherosclerosis progression has long been the subject of intensive pathophysiologic investigations. The identification of a novel target molecule to redeem the cellular processes remains a major challenge in cardiology. Signal peptide CUB domain EGF-like repeat protein (SCUBE) family has been detected on human tissues and cultured cells. Two members of the SCUBE family, SCUBE1 and SCUBE3 are reported to play a role in cardiovascular diseases. The other member, SCUBE2 has been reported to mediate Hedgehog (Hh) protein signaling and is expressed in major blood vessels during mouse embryogenesis. However its involvement in cardiovascular diseases is not known yet. The aim of this study was to investigate SCUBE2 expression and localization in diffuse intimal thickening (DIT), an early event of atherosclerosis and in advanced lesion of atherosclerotic plaque. Carotid artery ligation in C57BL/6J mice was performed to induce intimal thickening, mimicking DIT in human. After 2 weeks of ligation, mRNA level of SCUBE2 increased significantly, while in LDLr-/- mice fed with high fat diet, a human atherosclerosis model, mRNA level of SCUBE2 expression markedly increased 8 weeks after start of the high fat diet. Our findings were confirmed by the observation of SCUBE2 expression in human coronary artery with DIT and advanced lesion of atherosclerotic plaque. Previous investigations described that SCUBE2 mediates Hh signaling pathway. We have observed that SCUBE2 expression is associated with Sonic Hedgehog (Shh) and its receptor, Patched (Ptc), both in DIT and advanced plaque lesion. Our results suggested that SCUBE2 is a new target molecule in atherosclerosis and might play an important role in atherosclerotic plaque progression via Hh signal transduction.

Background Vascular calcification accompanying chronic kidney disease increases the mortality and morbidity associated with cardiovascular disorders, but no effective therapy is available. We hypothesized that glycosaminoglycans may contribute to osteoblastic differentiation of vascular smooth muscle cells during vascular calcification. Methods and Results We used exostosin‐like glycosyltranferase 2–deficient ( EXTL 2 knockout) mice expressing high levels of glycosaminoglycans in several organs including the aorta. We performed 5/6 subtotal nephrectomy and fed the mice a high‐phosphate diet to induce chronic kidney disease. Overexpression of glycosaminoglycans in the aorta enhanced aortic calcification in chronic kidney disease in EXTL 2 knockout mice. Ex vivo and in vitro, matrix mineralization in aortic rings and vascular smooth muscle cells of EXTL 2 knockout mice was augmented. Furthermore, removal of glycosaminoglycans in EXTL 2 knockout and wild‐type mice‐derived vascular smooth muscle cells effectively suppressed calcium deposition in a high‐phosphate environment. Conclusions These results illustrate an important role for glycosaminoglycans in the development of vascular calcification. Manipulation of glycosaminoglycan expression may have beneficial effects on the progression of vascular calcification in chronic kidney disease patients.

Although aldosterone has an essential role in controlling electrolyte and body fluid homeostasis, aldosterone also exerts certain pathological effects on the kidney. Several previous studies have attempted to examine these deleterious effects. However, the majority of these studies were performed using various injury models, including high-salt treatment and/or mineralocorticoid administration, by which the kidney changes observed were not only due to aldosterone but also due to prior injury caused by salt and hypertension. In the present study, we investigated aldosterone's pathological effect on the kidney using a mouse model with a high level of endogenous aldosterone. We used cryptochrome-null (Cry 1, 2 DKO) mice characterized by high aldosterone levels and low plasma renin activity and observed that even under normal salt exposure conditions, these mice showed increased albumin excretion and kidney tubular injury, decreased nephrin expression and increased reactive oxygen species production in the absence of hypertension. Exposure to high salt levels exacerbated the kidney damage observed in these mice. Moreover, we noted that decreasing blood pressure without blocking aldosterone action did not provide beneficial effects to the kidney in high-salt-treated Cry 1, 2 DKO mice. Thus, our findings support the hypothesis that aldosterone has deleterious effects on the kidney independent of high-salt exposure and high blood pressure.

Modifications of proteoglycans, subendothelial retention of low-density lipoproteins (LDL) and their subsequent oxidation initiate the development of atherosclerosis. Therefore, detection of lipoprotein entrapment in the arterial wall is an important feature for the analysis of the mechanisms of atherosclerosis. The administration of fluorescent-labeled LDL in vivo is a breakthrough way to assess the traffic of LDL in the arterial wall. The present study demonstrated the feasibility of visualizing LDL in carotid ligation-induced intimal thickening of arterial wall after intravenous rhodamine-labeled LDL injection in mice. Kinetics of rhodamine-labeled LDL showed similar characteristics as native LDL and labeled-LDL could be detected both by spectrophotometric and microscopic analysis. Kinetics analysis of rhodamine-labeled LDL revealed that the labeled LDL was present in almost all tissue, predominantly in the liver, 6 hours after injection. Rhodamine-labeled LDL was visualized in intimal thickening of carotid 6 to 18 hours after injection, indicating that the LDL was actively trapped in the arterial wall. In conclusion, rhodamine-labeled LDL would be a useful tool to investigate the development of atherosclerosis.

Abnormal eating behaviours are specific to frontotemporal lobar degeneration and increase caregiver burden. Topiramate, an anticonvulsant, suppresses cravings for alcohol and other substances and is a potential treatment for binge eating. However, there are few reports on topiramate efficacy for abnormal eating behaviours in frontotemporal lobar degeneration patients. We present three Japanese frontotemporal lobar degeneration patients with abnormal eating behaviours. Topiramate was effective, especially for compulsive eating, in cases with distinct lobar atrophy, but not for all abnormal eating behaviours.

Alterations in lipoproteins are involved in the pathophysiology of Alzheimer’s disease (AD). For sporadic AD, the Apolipoprotein E (APOE) is recognized as a sole genetic risk factor. Apolipoprotein A1 (APOA1) has been suggested to bind amyloid β and promoter polymorphisms of the APOA1 gene were likely to affect the onset of the disease. Apolipoprotein D (APOD) expression is upregulating in AD brain and evidences showed APOD polymorphisms affect the risk for AD. The aim of this study was to investigate whether polymorphisms of both APOA1 and APOD genes are associated with early-onset AD (EOAD) and late-onset AD (LOAD). Common single nucleotide polymorphisms (SNPs) of the two genes were analyzed using a case–control study design. There were no associations between the two SNPs of the APOA1 gene and the onset of AD. No synergetic associations were found among the APOA1 SNPs, APOE and the risk for AD. Rs7659, 3′ UTR polymorphism of the APOD gene was associated with EOAD in APOEe4 (−) subgroup. We were unable to show any impact of the other two SNPs of the APOD gene on the risk for AD. Our results suggest that the variation of the APOD gene modifies the risk for AD. Further association studies for APOD 3′ UTR polymorphisms with other ethnic groups would be needed.

In order to conduct early therapeutic interventions for Alzheimer's disease (AD), convenient, early diagnosis markers are required. We previously reported that changes in DNA methylation levels were associated with amnestic mild cognitive impairment (aMCI) and AD. As the results suggested changes in DNA methylation levels in the COASY and SPINT1 gene promoter regions, in the present study we examined DNA methylation in these regions in normal controls (NCs, n = 30), aMCI subjects (n = 28) and AD subjects (n = 30) using methylation-sensitive high resolution melting (MS-HRM) analysis. The results indicated that DNA methylation in the two regions was significantly increased in AD and aMCI as compared to NCs (P < 0.0001, P < 0.0001, ANOVA). Further analysis suggested that DNA methylation in the COASY gene promoter region in particular could be a high sensitivity, high specificity diagnosis biomarker (COASY: sensitivity 96.6%, specificity 96.7%; SPINT1: sensitivity 63.8%, specificity 83.3%). DNA methylation in the COASY promoter region was associated with CDR Scale Sum of Boxes (CDR-SB), an indicator of dementia severity. In the SPINT1 promoter region, DNA methylation was negatively associated with age in NCs and elevated in aMCI and AD subjects positive for antibodies to Herpes simplex virus type 1 (HSV-1). These findings suggested that changes in DNA methylation in the COASY and SPINT1 promoter regions are influenced by various factors. In conclusion, DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.

Secundum atrial septal defect (ASD) is the most common form of congenital heart disease in adults. Surgical and transcatheter closures of ASD are widely accepted therapeutic approaches. In patients with severe pulmonary arterial hypertension (PAH), however, the closure of the defect is still controversial. We report two cases of ASD patients with severe PAH successfully repaired subsequent to effective medical therapy. Subsequent shunt closure after targeted medical therapy can be an effective strategy in selected ASD patients with severe PAH.