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Advance care planning (ACP) is essential in managing serious and chronic illnesses to ensure that patients receive care aligned with their personal values, goals, and preferences. This review focuses on integrating ACP in the treatment of patients receiving implantable left ventricular assist devices (VADs). The heart failure palliative care team developed a unique advance directive form and pamphlet to facilitate ACP discussions, emphasizing not only medical treatment preferences but also patients' values and life goals.The study highlights the distinction between bridge to transplantation (BTT) and destination therapy (DT) in VAD patients, with different goals and considerations for ACP. The use of decision aids developed especially for DT candidates as a communication tool helps in sharing patients' wishes and facilitates shared decision-making, particularly in the complex decisions surrounding DT therapy.Challenges in implementing ACP, such as time constraints due to urgent medical conditions, difficulties in patient communication, and the recent COVID-19 pandemic, are addressed. The need for a comprehensive healthcare system capable of supporting patients' ACP wishes, especially in the community setting, is also pointed out.Future directions include not only developing materials to ease ACP discussions and ensuring that ACP content is shared among healthcare providers to foster collaborative and detailed planning, but also a call for widespread adoption of ACP in Japan.This is a translation of a paper written in Japanese Journal of Artificial Organs (Vol. 52, No. 1, pp. 89-92) with additions and corrections., (© 2024. The Japanese Society for Artificial Organs.)

Aims: The ALIMENT-HF trial aims to determine whether high-calorie and high-protein oral nutritional supplements (ONS) are safe and beneficial for older adult outpatients with heart failure (HF)., Methods and Results: This multicentre, single-arm, interventional pilot trial is designed to evaluate the tolerance, efficacy, and safety of ONS in older adult outpatients with chronic HF, malnutrition, and anorexia. In total, 80 outpatients with HF regardless of their left ventricular ejection fraction will be treated with ONS, including high-energy (900 kcal/day) and high protein (36 g/day) supplementation, at eight sites in Japan. Inclusion criteria are as follows: age, ≥65 years; outpatients receiving maximally tolerated guideline-directed medical therapy for HF and without change in their diuretic dosage during the last 3 months; outpatients at risk of malnutrition, defined as a Malnutrition Universal Screening Tool score ≥1 point, and anorexia, defined using a Simplified Nutritional Appetite Questionnaire for the Japanese Elderly (SNAQ-JE) score of ≤14 points. Nutritional intervention will continue for up to 120 days, with an observational period lasting for a further 60 days. The primary outcome is a change in body weight between baseline and day 120., Conclusions: The ALIMENT-HF trial will evaluate the tolerance, efficacy, and safety of high-calorie and high-protein-rich ONS in older outpatients with HF co-morbid with malnutrition and anorexia and will provide insightful information for future randomized controlled trials., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective General fatigue is one of the most frequent chief complaints in primary care, and an accurate assessment of fatigue has a direct impact on a patient's quality of life and treatment decisions. The Fatigue Assessment Scale (FAS), a measure of general fatigue, is useful for assessing fatigue in diverse cultures and diseases. However, there has been no study showing the reliability and validity of the scale in the Japanese context. The present study assessed the reliability and validity of the Japanese version of the FAS. Methods This study was conducted on 649 patients with long COVID who had a high frequency of general fatigue. To test the structural validity of the FAS, the patients were randomly divided into two groups: one in which an exploratory factor analysis (EFA) was conducted and one in which a confirmatory factor analysis (CFA) was conducted. Cronbach's alpha was calculated to assess internal consistency reliability. Results As 58 patients had missing values, we analyzed the data of 591 patients. The EFA led to an FAS comprising two factors. The CFA showed an acceptable fit for this two-factor model. The internal consistency was found to be good (Cronbach's alpha =0.89). Conclusion This study verified the structural validity and internal consistency and reliability of the Japanese version of the FAS. The results indicate that the Japanese version of the FAS is useful for assessing general fatigue in patients with long COVID in Japan.

Background: Although percutaneous endoscopic gastrostomy (PEG) placement is still widely practiced in Japan, studies from Western countries report that it is less beneficial for patients in end-of-life care with cognitive decline. Decisions regarding PEG placement are largely influenced by physician judgment., Objectives: The aim of this study was to investigate the background and perceptions of Japanese physicians regarding PEG for older adults in end-of-life care and to identify the factors associated with differences in physician judgment regarding PEG., Design: The study employed a cross-sectional design., Setting/subjects: A questionnaire on PEG for older adults in end-of-life care was sent to Japanese physicians. Logistic regression analysis was used to calculate the odds ratios (ORs) and confidence intervals (CIs) of the association between PEG recommendations and each factor., Results: PEG placement was advised for bedridden patients and older adults with cognitive decline by 26% of the physicians who responded to the survey. Differences in physician perceptions of PEG feeding were associated with the recommendation for PEG, benefits of preventing aspiration pneumonia (OR: 4.9; 95% CI: 3.1-8.2), impact on post-discharge accommodation decisions (OR: 6.1; 95% CI: 1.9-30.9), and hesitancy to recommend a PEG placement (OR: 1.9; 95% CI: 1.3-4.5). Working in a facility with PEG placement (OR: 2.0; 95% CI: 1.2-3.5) was an associated background factor., Conclusions: Differences in Japanese physicians' attitudes toward using PEG feeding for older adults in end-of-life care were significantly associated with differences in their perceptions of the impact of PEG feeding and working in a facility with PEG placement., (© Yoko Sakamoto et al., 2024; Published by Mary Ann Liebert, Inc.)

Background: Knee osteoarthritis (KOA) is highly prevalent in older women, and previous studies suggest the involvement of hormonal factors play a role in the pathogenesis of osteoarthritis. KOA causes musculoskeletal impairment, resulting in decreased physical activity, muscle mass, and strength, which leads to sarcopenia and further increases the burden on healthcare systems. Oestrogen replacement therapy (ERT) improves joint pain and muscle performance in early menopausal women. Muscle resistance exercise (MRE) is a non-pharmacological method that preserves the physical functions of patients with KOA. However, data on short-term oestrogen administration combined with MRE in postmenopausal women, especially in those aged > 65 years, are limited. Therefore, this study presents a protocol of a trial aimed to examine the synergistic effect of ERT and MRE on lower-limb physical performance in older women with KOA., Methods: We will conduct a double-blinded, randomised placebo-controlled trial in 80 Japanese women aged > 65 years living independently with knee pain. The participants will be randomly categorised into two groups: (1) 12-week MRE programme with transdermal oestrogen gel containing 0.54 mg oestradiol per push and (2) 12-week MRE programme with placebo gel. The primary outcome measured using the 30-s chair stand test, and secondary outcomes (body composition, lower-limb muscle strength, physical performance, self-reported measure of knee pain, and quality of life) will be measured at baseline, 3 months, and 12 months, and these outcomes will be analysed based on the intention-to-treat., Discussion: The EPOK trial is the first study to focus on the efficacy of ERT on MRE among women aged > 65 years with KOA. This trial will provide an effective MRE to prevent KOA-induced lower-limb muscle weakness, confirming the benefit of short-term oestrogen administration., Trial Registration: Japan Registry of Clinical Trials: jRCTs061210062. Registered 17th December 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs061210062 ., (© 2023. The Author(s).)

Background: Excessive psychological stress in medical students affects their mental health and causes problems such as burnout and depression. Furthermore, changes in the learning environment to online learning due to the COVID-19 pandemic have had a psychological effect on medical students. However, the relationships between medical students' perceived stress and different methods of communication, including in-person and online communication, remain unclear. The purpose of this study was to investigate the differences in stress perception of medical students depending on in-person communication and online communication during the COVID-19 pandemic., Methods: This study was a cross-sectional study conducted from September to October in 2020. All of the students of Okayama University School of Medicine were asked to participate in a questionnaire survey. The explanatory variables were the frequency and length of communications with others (by in-person or online communication), empathy, and lifestyle. The main outcome measure was perceived stress. Subgroup analysis was conducted for students who preferred to be by themselves and students who preferred to study together and interact with other people. Univariate analysis and multivariate multiple regression analysis were conducted. Gender and grade, which have been shown to be associated with stress in previous studies, were used as covariates for multiple regression analysis., Results: Valid responses to the questionnaire survey were received from 211 (29.4%) of the 717 students. There was no significant association between perceived stress and online communication, but the number of people with which students had in-person communication (1-2 people compared to 0 as a control, regression coefficient [B] = -4.4, 95% confidence interval [CI]; -7.8, -1.1, more than 10 people, B = -12, 95% CI: -18, -5.8) and the length of communication (more than 120 min, B = -4.5, 95% CI: -8.1, -0.92) were associated with a reduction in perceived stress. In subgroup analysis, the number of people with in-person communication and the length of communication had significant associations with stress reduction even in the group of students who had a preference for being by themselves., Conclusion: In-person communications rather than online communications were associated with a lower level of perceived stress. In subgroup analysis, this trend was statistically significant in the group of students who had a preference for being by themselves.

Purpose: To investigate if early exercise can help prevent skeletal muscle loss and improve the clinical outcomes of esophageal cancer patients receiving preoperative neoadjuvant chemotherapy (NAC)., Methods: This was a single-center, retrospective observational cohort study of 110 patients with advanced esophageal cancer. We analyzed the effect of early exercise on the risk of skeletal muscle loss (defined as > 2.98%) during NAC and the subsequent clinical outcomes. Patients in the early exercise group (n = 71) started exercise therapy 8 days earlier than those the late exercise group (n = 39)., Results: The median age of the patients was 65.4 years, the mean BMI was 21.1 kg/m 2 , and 92 (84%) of the 110 patients were men. Skeletal muscle loss occurred in 34% and 67% of the early and late exercise groups, respectively (p < 0.001). There was a lower risk of surgical site infection in the early exercise group (1% vs 16%, p = 0.021). Multivariate analysis revealed that early exercise reduced the risk of skeletal muscle loss (OR = 0.25, 95% CI 0.09-0.65, p = 0.006)., Conclusions: Our results suggest that early exercise reduces the risk of both skeletal muscle loss during NAC and subsequent surgical site infection in patients with esophageal cancer., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Hairs are often used for DNA analysis in criminal investigations. DNA analysis of hairs with root sheaths is easy in many cases, but analyses using only the shaft or tip of the hair are often difficult. Here we describe a suspected case of child abuse in which we were commissioned to perform DNA analysis. Among 100 hairs, PCR amplification was succeeded in 99 samples, and as a result of direct sequencing, mitochondrial DNA (mtDNA) of the 99 hairs were classified into 6 types. The most common type was the 8-base substitution type of 16,168T-16,172C-16,183C-16,189C-16,217C-16,249C-16,325C-16,390A, which was observed in 86 hairs. This corresponded to the type of the victim. Total 736 STRs (75.5%) in 975 loci of 65 hairs could be typed, and only an amelogenin locus was typed in another hair. All 15 loci were typed in 10 hairs. STR types of 65 (98.5%) in 66 hairs were consistent with that of the victim. From 10 naturally-shed hair of a person, only 37 STRs (30.8%) in 120 loci of 8 hairs were typed, and all 15 loci could not be typed in these hairs. This difference in success rates of STR analysis suggested strongly that the hairs in this case were not shed naturally but forcibly, and the relevance to child abuse was suspected., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Refeeding syndrome occurs when reinstating nutrition to severely malnourished patients. It can sometimes be fatal, particularly as a result of cardiac involvement such as congestive heart failure and arrhythmias. The aim of this study was to report a case of cardiogenic shock that occurred during refeeding in a patient with anorexia nervosa (AN). The cardiogenic shock was due to a previously unrecognized mechanism, namely a transient left midventricular obstruction that completely disappeared after treatment., Methods: A 46-y-old woman with AN who had followed a carbohydrate- and a fat-deficient diet for >10 y was hospitalized for dyspnea on exertion. She had severely impaired cardiac systolic function on admission and was considered high risk for refeeding syndrome. During a stepwise increase of calories, she showed no electrolyte or mineral abnormalities characteristic of refeeding syndrome., Results: After intravenous administration of a fat emulsion, the patient suffered from cardiogenic shock due to an unexpected mechanism, namely a left midventricular obstruction caused by cardiac hypercontraction, a thickened left ventricular wall, and intravascular volume depletion. With cessation of the fat emulsion and initiation of volume repletion she recovered from shock immediately and her echocardiogram returned to normal by discharge., Conclusions: This case illustrated a novel cause of cardiogenic shock during refeeding and the need for caution during the intravenous administration of a fat emulsion in patients with initial left ventricular systolic dysfunction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We propose a new oral immunotherapy (OIT) method that includes a small amount of a food allergen in the diet. However, it is not clear whether this method will induce oral desensitization and immune tolerance. Therefore, we investigated the therapeutic effectiveness using a 1% food allergen diet in an allergic mouse model. C3H/HeJ mice were sensitized to ovomucoid (OM) in alum four times at 12-d intervals. Sensitized mice were divided into two groups: the OIT group (19% casein diet with 1% OM) and the non-treated group (20% casein diet without OM). The non-sensitized mice served as the non-allergy group. The OIT treatment was performed for 4 wk. To assess desensitization and immune tolerance, we performed oral and intraperitoneal OM challenges, assessed vascular permeability of the dorsal skin, and measured allergic biomarkers. The OIT group exhibited significantly lower oral symptom scores and vascular permeability than the non-treated group, but the two groups did not differ in intraperitoneal allergy symptom scores. Furthermore, the OIT group had significantly higher OM-specific IgA levels in their plasma than the non-treated group. However, the plasma levels of OM-specific IgE, IgG1, and IgG2a were not significantly different between the OIT and the non-treated groups. These results suggest that the proposed OIT using an OM-supplemented diet may induce desensitization, but not immune tolerance, in an OM allergic mouse model.

In various pathological events, particularly in oxygen radical-mediated cell injury, both apoptosis and necrosis play essential roles. Apoptosis and some types of necrosis are induced via increases in mitochondrial membrane permeability, called mitochondrial outer membrane permeabilization (MOMP) and permeability transition pore (PTP) opening, respectively. To search for small compounds that inhibit both MOMP-mediated apoptosis and PTP-mediated necrosis, we performed a mitochondria-based high-throughput screening of a chemical library. We identified TMD#7538, a small compound that inhibits both MOMP and PTP opening. Consistent with the fact that this compound inhibited both apoptosis and necrosis, it efficiently suppressed H2O2-induced cell death in mouse embryonic fibroblasts and rat neonatal cardiomyocytes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in the salvage pathway for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and thereby regulates the deacetylase activity of sirtuins. Here we show accommodative regulation of myocardial NAD(+) by monocyte-derived extracellular Nampt (eNampt), which is essential for hemodynamic compensation to pressure overload. Although intracellular Nampt (iNampt) expression was decreased in pressure-overloaded hearts, myocardial NAD(+) concentration and Sirt1 activity were preserved. In contrast, iNampt was up-regulated in spleen and monocytes, and circulating eNampt protein and nicotinamide mononucleotide (NMN), a key precursor of NAD(+), were significantly increased. Pharmacological inhibition of Nampt by FK866 or depletion of monocytes/macrophages by clodronate liposomes disrupted the homeostatic mechanism of myocardial NAD(+) levels and NAD(+)-dependent Sirt1 activity, leading to susceptibility to cardiomyocyte apoptosis and cardiac decompensation in pressure-overloaded mice. These biochemical and hemodynamic defects were prevented by systemic administration of NMN. Our studies uncover a crucial role of monocyte-derived eNampt in myocardial adaptation to pressure overload, and highlight a potential intervention controlling myocardial NAD(+) against heart failure.

Disruption of angiotensin II type 1 (AT1) receptor prolonged life span in mice. Since aging-related decline in skeletal muscle function was retarded in Atgr1a(-/-) mice, we examined the role of AT1 receptor in muscle regeneration after injury. Administration of AT1 receptor blocker irbesartan increased the size of regenerating myofibers, decreased fibrosis, and enhanced functional muscle recovery after cryoinjury. We recently reported that complement C1q, secreted by macrophages, activated Wnt/β-catenin signaling and promoted aging-related decline in regenerative capacity of skeletal muscle. Notably, irbesartan induced M2 polarization of macrophages, but reduced C1q expression in cryoinjured muscles and in cultured macrophage cells. Irbesartan inhibited up-regulation of Axin2, a downstream gene of Wnt/β-catenin pathway, in cryoinjured muscles. In addition, topical administration of C1q reversed beneficial effects of irbesartan on skeletal muscle regeneration after injury. These results suggest that AT1 receptor blockade improves muscle repair and regeneration through down-regulation of the aging-promoting C1q-Wnt/β-catenin signaling pathway.

Enzymatic proteolysis by calpains, Ca(2+)-dependent intracellular cysteine proteases, has been implicated in pathological processes such as cellular degeneration or death. Here, we investigated the role of calpain activation in the hearts subjected to myocardial infarction. We produced myocardial infarction in Cast(-/-) mice deficient for calpastatin, the specific endogenous inhibitory protein for calpains, and Cast(+/+) mice. The activity of cardiac calpains in Cast(+/+) mice was not elevated within 1 day but showed a gradual elevation after 7 days following myocardial infarction, which was further pronounced in Cast(-/-) mice. Although the prevalence of cardiomyocyte death was indistinguishable between Cast(-/-) and Cast(+/+) mice, Cast(-/-) mice exhibited profound contractile dysfunction and chamber dilatation and showed a significant reduction in survival rate after myocardial infarction as compared with Cast(+/+) mice. Notably, immunofluorescence revealed that at 28 days after myocardial infarction, calpains were activated in cardiomyocytes exclusively at the border zone and that Cast(-/-) mice showed higher intensity and a broader extent of calpain activation at the border zone than Cast(+/+) mice. In the border zone of Cast(-/-) mice, pronounced activation of calpains was associated with a decrease in N-cadherin expression and up-regulation of molecular markers for cardiac hypertrophy and fibrosis. In cultured rat neonatal cardiomyocytes, calpain activation by treatment with ionomycin induced cleavage of N-cadherin and decreased expression levels of β-catenin and connexin 43, which was attenuated by calpain inhibitor. These results thus demonstrate that activation of calpains disassembles cell-cell adhesion at intercalated discs by degrading N-cadherin and thereby promotes left ventricular remodeling after myocardial infarction., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.

Perioperative management of a spinocerebellar ataxia patient by epidural anesthesia is reported. A 67-year-old woman with left femur neck fracture underwent femoral head replacement. An epidural catheter was placed without difficulty at the L3-4 interspace using the loss of resistance technique. A total of 1% mepivacaine 13 ml was administered in divided doses to obtain bilateral T5 analgesic level. Hypotension (79 mmHg systolic) was observed transiently, and ephedrine 8 mg was administered which successfully elevated blood pressure. Overall, hemodynamics and respiratory status were stable. Postoperative analgesia was maintained by infusion of 0.2% ropivacaine at 2 ml x hr(-1). The patient's postoperative course was uneventful, and her neurologic conditions remained unchanged.

Background: To prospectively determine the safety and effectiveness of continuous infusion of low-dose remifentanil for the reduction of pain in patients for epidural catheterization., Methods: This study was approved by the institutional review board. Written informed consent was obtained. Fifty two patients (27 men, 25 women, age range 16-96 years, mean age 68 years) were given continuous infusion of various rates of application (none, 0.02, 0.05, and 0.07 microg x kg -1 x hr-1) of remifentanil. Blood pressure, heart rate, pulse oximetry oxygen saturation and respiratory rate were recorded during the procedure of epidural catheterization. Pain score was measured with the visual analogue scale (VAS), and complications including muscle stiffness, nausea and vomiting, and depressed level of consciousness were monitored., Results: Every rate of application, pulse oximetry oxygen saturation and systemic blood pressure were decreased but the reduction was not marked. The muscle stiffness, nausea and vomiting, and depressed level of consciousness were not observed in all the cases. No other serious complications were observed., Conclusions: Continuous infusion of low-dose remifentanil is a safe and effective method for palliation of pain in epidural catheterization.

A growing body of evidence has suggested that the use of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) leads to a significant decrease in mortality and morbidity in patients with congestive heart failure. The AT1 receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated Ang II has agonistic action on AT1 receptor. However, recent in vitro studies have demonstrated that AT1 receptor is structurally flexible and instable, and has significant and varying levels of spontaneous activity in an Ang II-independent manner. Furthermore, mechanical stress activates AT1 receptor by inducing conformational switch without the involvement of Ang II. Experimental studies have demonstrated that Ang II-independent activation of AT1 receptor is profoundly relevant to the pathogenesis of cardiac remodeling in vivo, and that these agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonist activity emerges as an important pharmacological parameter that contributes to cardioprotective effects of ARBs through inhibiting both Ang II-dependent and -independent activation of AT1 receptor.

Calpains are Ca(2 +) -dependent cysteine proteases. Fifteen gene products of calpains are expressed in mammals. Among them, Calpain 1 and Calpain 2 are ubiquitously expressed and have been investigated extensively. Under the physiological conditions, calpain activity is strictly regulated by endogenous inhibitory protein, Calpastatin. Calpains are activated in the various cardiovascular diseases and implicated in their pathogenesis by degrading numerous target proteins. Here we briefly summarize the physiological and pathological role of calpains in the cardiovascular diseases.

The octapeptide angiotensin II (Ang II) plays a homeostatic role in the regulation of blood pressure and water and electrolyte balance, and also contributes to the progression of cardiovascular remodeling. Ang II activates Ang II type 1 (AT1) receptor and type 2 (AT2) receptor, both of which belong to the seven-transmembrane, G protein-coupled receptor family. Most of the actions of Ang II such as promotion of cellular prolifaration, hypertrophy, and fibrosis are mediated by AT1 receptor. However, in some pathological situations, AT2 receptor shows an increase in tissue expression and functions to antagonize the actions induced by AT1 receptor. Recent studies have advanced our understanding of the molecular mechanisms underlying receptor activation and signal transduction of AT1 and AT2 receptor in the cardiovascular system.

The angiotensin II (Ang II) type 1 (AT(1)) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT(1) receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT(1) receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT(1) receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the Gα(q11) subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT(1) receptor is constitutively activated independent of Ang II. As a consequence, AT(1)Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT(1)Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart.

The aim of this study was to examine the relationship between menses-associated health problems of women, such as premenstrual symptoms, menstrual pain and irregular menstrual cycles, and psychosocial stress. A cross-sectional study was conducted among Japanese college students, measuring psychosocial stress levels by means of IMPS (The Inventory to Measure Psychosocial Stress). A total of 264 female students (mean age 19.4 years), who were invited to participate in the study in October 2007, completed the questionnaire, which dealt with anthropometric data, lifestyle, menstrual history, and menstrual health status. Forty-three students were excluded due to missing data, and the remaining 221 were analyzed. The proportions of students who reported premenstrual symptoms, menstrual pain, and the experience of irregular menstrual cycles were 79%, 79%, and 63%, respectively. Students who reported premenstrual symptoms, menstrual pain, and the experience of irregular menstrual cycles had higher stress scores than those who did not. Multiple logistic regression analyses were used to identify independent factors associated with having premenstrual symptoms, menstrual pain, and the experience of irregular menstrual cycles. Stress score, heavy menstrual flow, and menstrual pain were significant predictors for premenstrual symptoms, while age at menarche and having premenstrual symptoms were significant predictors for menstrual pain. Both stress score and body mass index were found to be significant predictors for having experienced irregular menstrual cycles. The results suggest that psychosocial stress is independently associated with premenstrual symptoms and the experience of irregular menstrual cycles among college students, implying that changes in the functional potentiality of women as a result of stress are related with changes in their menstrual function.

The aim of this study was to examine the relationship between psychosocial stress and intraocular pressure among apparently healthy subjects. Psychosocial stress among 1,461 public school workers (883 men and 578 women) was measured using the inventory to measure psychosocial stress (IMPS) and intraocular pressure was measured using a non-contact tonometer (Topcon CT-90). After controlling for the effects of likely confounding variables such as age, body mass index (BMI), glycosylated hemoglobin, systolic blood pressure, alcohol consumption, smoking status, and exercise, partial correlations and hierarchical multiple regression analysis were performed in order to test the hypothesis that IMPS-measured stress score was associated with intraocular pressure. IMPS-measured stress score was found to correlate positively with intraocular pressure in women after controlling for the effects of confounding variables, whereas this relationship was not found in men. Hierarchical multiple regression analysis indicated that IMPS-measured stress score was positively associated with intraocular pressure in women independent of confounding variables, but not in men. Perturbations of the hypothalamic-pituitary-adrenal (HPA) axis associated with stress are considered to be partly responsible for an increase in intraocular pressure among people suffering from psychosocial stress. Further research is needed to elucidate the relationship between this stress-associated increase in intraocular pressure and open-angle glaucoma.

In order to study the phosphorylated proteins in the resting Xenopus laevis oocytes, the proteins detected by Western blotting using phospho-(Ser/Thr) PKA substrate antibody (PKA substrate antibody) in forskolin-stimulated oocytes were purified and identified by mass spectrometry. Several proteins (ribosomal S6 protein, elongation factor-2 (EF-2), poly A binding protein, releasing factor 1) were identified, and the phosphorylation of EF-2 was further studied. Partially purified Xenopus EF-2 (xEF-2) was phosphorylated by PKA in vitro and this phosphorylation was detected by Western blotting using PKA substrate antibody. The phosphorylation of Thr-57 in xEF-2 (corresponding to Thr-56 of the mammalian enzyme) was detected in the partially purified xEF-2 from the resting oocytes, but this xEF-2 did not react with the PKA substrate antibody. These results suggest that Thr-57 in xEF-2 was phosphorylated, but xEF-2 does not seem to be phosphorylated by PKA in resting oocytes although PKA can phosphorylate xEF-2 in vitro and probably in forskolin-treated oocytes.

The aim of this study was to examine the relationship between the stress score measured using the Inventory to Measure Psychosocial Stress (IMPS) and biomedical parameters regarding health status among apparently healthy subjects in order to evaluate the validity of the IMPS. Out of the 1,941 public school workers in Kyushu and Okinawa, Japan, who were admitted to a hospital for medical check-ups, 1,499 workers responded to questionnaires which assessed the degree of stress response (i.e., stress score) measured using the IMPS, and the degree of stress tolerance capacity (i.e., stress intolerance score) measured using the Inventory to Measure Stress Tolerance Capacity (IMST). One thousand two-hundred and one workers (684 men and 517 women) were analyzed, excluding 298 subjects who were taking medication for hypertension, hyperuricemia, hyperlipidemia and diabetes, or had a value for glycosylated hemoglobin (HbA1c)>or=6.0 percent. An increase in the stress score was positively associated with an increase in both body fat percentage and glycosylated hemoglobin values among men, while it was positively associated with an increase in plasma triglyceride concentrations among women. The stress score significantly correlated with the value for glycosylated hemoglobin even after controlling for age, body mass index, alcohol consumption, smoking, and exercise among men. An increase in the stress intolerance score was positively associated with an increase in body fat percentage among men, while it was positively associated with an increase in body weight, body mass index, and body fat percentage among women. Our result that the stress score measured using the IMPS was associated with obesity and unfavorable glycemic changes is in congruency with the model that psychosocial stress has a detrimental effect on humans by inducing obesity and insulin resistance, suggesting that the IMPS is a valid means to evaluate psychosocial stress levels among an otherwise healthy population.

2-(p-amylcinnamoyl)amino-4-chlorobenzoic acid (PACA), pharmacological inhibitor of phospholipase A(2) (PLA(2)), inhibits epinephrine-stimulated thromboxane production in human platelets. In this study, we investigated the effect of PACA on meiotic maturation individually in stages V and VI oocytes. PACA prevented the maturation in stage V but merely delayed the process in stage VI oocytes. This was associated with the strong inhibition of Mos synthesis at both stages. Besides, PACA-induced inhibition of MAPK activation was evident in stage V but not in stage VI oocytes. PACA also inhibited the activation of Cdc2 kinase (Cdc2) in stage V but merely delayed the process in stage VI oocytes. Furthermore, 5 microM and higher concentrations of PACA completely inhibited the activation of MAPK and Cdc2 only in stage V, not in stage VI, oocytes. Moreover, we propose PACA as a new tool for the study of Xenopus oocyte maturation, which can also play a unique role for the studies of the stage-specific activation of MAPK and Cdc2.

A sensitive enzyme immunoassay (EIA) specific for hepatitis B virus core antigen (HBcAg) and hepatitis B e antigen (HBeAg) was developed. We designated the precore/core gene products as hepatitis B virus (HBV) core-related antigens (HBcrAg). In order to detect HBcrAg even in anti-HBc/e antibody-positive specimens, the specimens were pretreated in detergents. The antibodies are inactivated by this pretreatment and, simultaneously, the antigens are released and the epitopes are exposed. The assay demonstrated 71 to 112% recovery using HBcrAg-positive sera. We observed no interference from the tested anticoagulants or blood components. When the cutoff value was tentatively set at 10(3) U/ml, all healthy control (HBsAg/HBV-DNA negative; n = 108) and anti-HCV antibody-positive (n = 59) sera were identified as negative. The assay showed a detection limit of 4 x 10(2) U/ml using recombinant antigen. Detection limits were compared in four serially diluted HBV high-titer sera. The HBcrAg assay demonstrated higher sensitivity than HBV-DNA transcription-mediated amplification (TMA) or HBeAg radio immunoassay (RIA) in the dilution test. HBcrAg concentrations correlated well with HBV-DNA TMA (r = 0.91, n = 29) and in-house real-time detection-PCR (r = 0.93, n = 47) in hepatitis B patients. On HBeAg/anti-HBe antibody seroconversion panels, the HBcrAg concentration changed in accordance with HBV-DNA levels. HBcrAg concentration provides a reflection of HBV virus load equivalent to HBV-DNA level, and the assay therefore offers a simple method for monitoring hepatitis B patients.