Efficacy and safety of remote cardiac rehabilitation in the recovery phase of cardiovascular diseases (RecRCR study): A multicenter, nonrandomized, and interventional trial in Japan.

Backgrounds: Remote cardiac rehabilitation has proven useful in patients with cardiovascular disease; however, the methodology had not been fully validated. This study aimed to investigate the efficacy and safety of remote cardiac rehabilitation (RCR) with real-time monitoring and an ergometer using a bidirectional communication tool during the recovery phase of cardiovascular diseases. Methods: This multicenter, nonrandomized, interventional study was conducted at 29 institutions across Japan and enrolled patients with cardiovascular diseases who met indications for cardiac rehabilitation (CR) after receiving in-hospital treatment. The RCR group exercised at home using an ergometer and was monitored in real-time using interactive video and monitoring tools for 2-3 months. Educational instructions were provided concurrently through e-learning approaches. The safety of the RCR protocol and the improvement in peak oxygen consumption (VO2) were compared with those of the historical control group that participated in center-based CR. Results: Fifty-three patients from the RCR group were compared with 103 historical controls having similar background characteristics. No patients in RCR experienced significant cardiovascular complications while engaging in exercise sessions. After 2-3 months of RCR, the peak VO2 improved significantly, and the increases in the RCR group did not exhibit any significant differences compared to those in the historical controls. During follow-up, the proportion of patients whose exercise capacity increased by 10% or more was also evaluated; this finding did not indicate a statistically significant distinction between the groups. Conclusions: RCR during the recovery phase of cardiovascular diseases proved equally efficient and safe as center-based CR.

Evaluation of the antiplasmodial efficacy of synthetic 2,5-diphenyloxazole analogs of compounds naturally derived from Oxytropis lanata.

The persistent prevalence and dissemination of drug-resistant malaria parasites continue to challenge the progress of malaria eradication efforts. As a result, there is an urgent need to search for and develop innovative therapies. In this study, we screened synthetic 2,5-diphenyloxazole analogs from Oxytropis lanata. Among 48 compounds, 14 potently inhibited the proliferation of P. falciparum strains 3D7 (chloroquine-sensitive) and K1 (multidrug-resistant) in vitro, exhibited IC50 values from 3.38 to 12.65 µM and 1.27-6.19 µM, respectively, and were toxic to human foreskin fibroblasts at 39.53-336.35 µM. Notably, Compounds 31 (2-(2',3'-dimethoxyphenyl)-5-(2″-hydroxyphenyl)oxazole) and 32 (2-(2',3'-dimethoxyphenyl)-5-(2″-benzyloxyphenyl)oxazole) exhibited the highest selectivity indices (SIs) against both P. falciparum strains (3D7/K1), with values > 40.20/>126.58 and > 41.27/> 59.06, respectively. In the IC50 speed and stage-specific assays, Compounds 31 and 32 showed slow action, along with distinct effects on the ring and trophozoite stages. Microscopy observations further revealed that both compounds impact the development and delay the progression of the trophozoite and schizont stages in P. falciparum 3D7, especially at concentrations 100 times their IC50 values. In a 72-h in vitro exposure experiment at their respective IC80 in P. falciparum 3D7, significant alterations in parasitemia levels were observed compared to the untreated group. In Compound 31-treated cultures, parasites shrank and were unable to reinvade red blood cells (RBCs) during an extended 144-h incubation period, even after compound removal from the culture. In vivo assessments were conducted on P. yoelii 17XNL-infected mice treated with Compounds 31 and 32 at 20 mg/kg administered once daily for ten days. The treated groups showed statistically significant lower peaks of parasitemia (Compound 31-treated: trial 1 12.7%, trial 2 15.8%; Compound 32-treated: trial 1 12.7%, trial 2 14.0%) compared to the untreated group (trial 1 21.7%, trial 2 28.3%). These results emphasize the potential of further developing 2,5-diphenyloxazoles as promising antimalarial agents.

A new assessment method for right ventricular diastolic function using right heart catheterization by pressure-volume loop.

Diastolic stiffness coefficient (ß) and end-diastolic elastance (Eed) are ventricular-specific diastolic parameters. However, the diastolic function of right ventricle had not been investigated sufficiently due to the lack of established evaluation method. We evaluated the validity of these parameters calculated using only data of right heart catheterization (RHC) and assessed it in patients with restrictive cardiomyopathy (RCM) and cardiac amyloidosis. We retrospectively analyzed 46 patients with heart failure who underwent RHC within 10 days of cardiac magnetic resonance (CMR). Right ventricular end-diastolic volume and end-systolic volume were calculated using only RHC data, which were found to be finely correlated with those obtained from CMR. ß and Eed calculated by this method were also significantly correlated with those derived from conventional method using CMR. By this method, ß and Eed were significantly higher in RCM with amyloidosis group than dilated cardiomyopathy group. In addition, the ß and Eed calculated by our method were finely correlated with E/A ratio on echocardiography. We established an easy method to estimate ß and Eed of right ventricle from only RHC. The method finely demonstrated right ventricular diastolic dysfunction in patients with RCM and amyloidosis.

[Synthetic Study on Bicyclic Depsipeptides Containing an Intramolecular Disulfide Bond].

Bicyclic depsipeptide natural products containing an intramolecular disulfide bond are potent histone deacetylase (HDAC) inhibitors. Among them, FK228 (romidepsin) is approved for treating cutaneous T-cell lymphoma and peripheral T-cell lymphoma. This study focused on developing a new synthesis method for producing this class of natural products for use as HDAC inhibitors with high efficacy and low toxicity. In this paper, the total syntheses of FK228 as well as spiruchostatins A and B are described. The synthesis routes include a convergent way to assemble seco-acids via the amide condensation of amine segments with carboxylic acid segments. The syntheses of C4- and C7-modified FK228 analogs (FK-A1 to FK-A8) are also described. The evaluation of HDAC and cell growth inhibitory activities of the synthesized analogs revealed novel aspects of their structure-activity relationship. Potent and highly isoform-selective HDAC1 inhibitors were identified. Furthermore, the analogs showed phosphatidylinositol 3-kinase (PI3K) inhibitory activity. Structural optimization of the analogs as HDAC/PI3K dual inhibitors led to the identification of FK-A11 as the most potent analog.

Residual Pulmonary Vascular Resistance Increase Under Left Ventricular Assist Device Support Predicts Long-Term Cardiac Function After Heart Transplantation.

Aims: We compared hemodynamics and clinical events after heart transplantation (HTx) in patients stratified by the severity of residual pulmonary vascular resistance (PVR) after left ventricular assist device (LVAD) implantation for bridge to transplantation. Methods: We retrospectively analyzed patients who had undergone HTx at the University of Tokyo Hospital. We defined the high PVR group as patients with PVR of >3 Wood Units (WU) as measured by right heart catheterization performed 1 month after LVAD implantation. Results: We included 85 consecutive HTx recipients, 20 of whom were classified in the high PVR group and 65 in the low PVR group. The difference in PVR between the two groups became apparent at 2 years after HTx (the high PVR group: 1.77 ± 0.41 WU, the low PVR group: 1.24 ± 0.59 WU, p = 0.0009). The differences in mean pulmonary artery pressure (mPAP), mean right arterial pressure (mRAP), and mean pulmonary capillary wedge pressure (mPCWP) tended to increase from the first year after HTx, and were all significantly higher in the high PVR group at 3 years after HTx (mPAP: 22.7 ± 9.0 mm Hg vs. 15.4 ± 4.3 mm Hg, p = 0.0009, mRAP: 7.2 ± 3.6 mm Hg vs. 4.1 ± 2.1 mm Hg, p = 0.0042, and mPCWP: 13.4 ± 4.5 mm Hg, 8.8 ± 3.3 mm Hg, p = 0.0040). In addition, pulmonary artery pulsatility index was significantly lower in the high PVR group than in the low PVR group at 3 years after HTx (2.51 ± 1.00 vs. 5.21 ± 3.23, p = 0.0033). The composite event including hospitalization for heart failure, diuretic use, and elevated intracardiac pressure (mRAP ≥ 12 mm Hg or mPCWP ≥ 18 mm Hg) between the two groups was significantly more common in the high PVR group. Residual high PVR was still an important predictor (hazard ratio 6.5, 95% confidence interval 2.0-21.6, and p = 0.0023) after multivariate Cox regression analysis. Conclusion: Our study demonstrates that patients with residual high PVR under LVAD implantation showed the increase of right and left atrial pressure in the chronic phase after HTx.

Determining the factors for interhospital transfer in advanced heart failure cases.

Background: There are some patients with advanced heart failure (HF), for whom implantable left ventricular assist device (LVAD) or heart transplantation (HTx) should be considered. Some of them need to be transferred between hospitals. There are few reports on the interhospital transfer of patients with advanced HF and their subsequent clinical course.In this study, we investigated the characteristics and clinical course of patients transferred to a LVAD/HTx center, focusing on the distance between hospitals. Methods: We retrospectively examined 141 patients who were transferred to our hospital, considering the indications of LVAD implantation or HTx. We divided the patients into two groups: those referred <33 km (short-distance) and those referred more than 33 km (long-distance). The primary outcome was the composite outcome of increased catecholamine dose, mechanical support, or renal dysfunction within 1 week of transfer. Results: Continuous catecholamine infusion was significantly more common in patients in the long-distance group, whereas extracorporeal membrane oxygenation (ECMO) placement was significantly more common in short-distance group.Patients transferred via long distance had significantly higher rates of increased catecholamine doses, mechanical support including intra-aortic balloon pumping (IABP) and ECMO, and renal dysfunction within 1 week of transfer than patients transferred via short distance. Multivariate analysis showed that low body mass index (BMI) and long distance were independent predictive factors for the primary outcome. Conclusions: When patients with advanced HF are transferred from far distant hospitals or with low BMI, it may be necessary to devise various measures for interhospital transport.

Total synthesis and antimicrobial evaluation of (+)-hygrophorone B12 and its analogues.

This paper describes the synthesis and evaluation of lead compounds with a new chemical skeleton that is not found in conventional antimicrobial agents. The biologically attractive cyclopentenoid (+)-hygrophorone B12, isolated from the fruiting bodies of Hygrophorus abieticola, and its analogues were synthesized in a longer linear sequence of twelve steps, starting from a cyclopentenone derivative. This synthesis involved the following crucial steps: (i) oximation of a ketone to stabilize the requisite aldehyde to install a side chain and (ii) coupling of an aldehyde with a side chain to assemble the desired hygrophorone. Then, the antimicrobial activity of these hygrophorones towards clinically relevant bacterial pathogens was evaluated. The results showed that hygrophorone B12 and its analogues are especially effective in preventing the proliferation of gram-positive bacteria. In addition, it was found that some structural features such as the presence of the enone moiety as well as the carbon-carbon triple bond on the hydrocarbon chain were pivotal to increase the antimicrobial activity of hygrophorone B. This study is expected to support the development of novel antimicrobial agents by flexibly synthesizing hygrophorone B analogues with a carbon five-membered ring skeleton from the common intermediate.

Social and environmental risks as contributors to the clinical course of heart failure.

Heart failure is a major contributor to healthcare expenditures. Many clinical risk factors for the development and exacerbation of heart failure had been reported, including diabetes, renal dysfunction, and respiratory disease. In addition to these clinical parameters, the effects of social factors, such as occupation or lifestyle, and environmental factors may have a great impact on disease development and progression of heart failure. However, the current understanding of social and environmental factors as contributors to the clinical course of heart failure is insufficient. To present the knowledge of these factors to date, this comprehensive review of the literature sought to identify the major contributors to heart failure within this context. Social factors for the risk of heart failure included occupation and lifestyle, specifically in terms of the effects of specific occupations, occupational exposure to toxicities, work style, and sleep deprivation. Socioeconomic factors focused on income and education level, social status, the neighborhood environment, and marital status. Environmental factors included traffic and noise, air pollution, and other climate factors. In addition, psychological stress and behavior traits were investigated. The development of heart failure may be closely related to these factors; therefore, these data should be summarized for the context to improve their effects on patients with heart failure. The present study reviews the literature to summarize these influences.

Long-Term renal function after implantation of continuous-flow left ventricular assist devices: A single center study.

BACKGROUND: Implantable continuous-flow left ventricular assist device (LVAD) improve renal function in advanced heart failure. However, the long-term effects of LVAD on renal function have not been investigated thoroughly. We aimed to assess long-term renal function in patients with LVAD support and to identify predictors for late deterioration in renal function (LDRF). METHODS: One hundred patients underwent LVAD implantation as a bridge to transplant at the University of Tokyo Hospital between May 2011 and December 2018. We assessed renal function at intervals (preoperative, 1, 6, 12, 18, 24 and 30 months after LVAD implantation). We divided patients into two groups: "with LDRF," whose renal function at 30 months had decreased by >25% compared with preoperatively (n = 14), and "without LDRF" (n = 55). RESULTS: Renal function improved at 1 month, returned to preoperative levels at 6 months, and remained there up to 30 months after LVAD implantation. However, renal function impairment became evident in patients with LDRF 18 months after LVAD implantation. A ratio of right atrial pressure/pulmonary artery wedge pressure > 0.57 and left ventricular dimension diastole ≤ 67 mm were preoperative independent risk factors for LDRF. In addition, the incidence of perioperative acute kidney injury, ventricular arrhythmia, aortic insufficiency, and late right ventricular failure was significantly higher in patients with LDRF. CONCLUSION: LDRF after LVAD implantation corresponded to several risk factors, including a small left ventricle and LVAD-related complications, such as right ventricular failure.

Efficacy and Safety of Remote Cardiac Rehabilitation in the Recovery Phase of Cardiovascular Diseases: Protocol for a Multicenter, Nonrandomized, Single-Arm, Interventional Trial.

BACKGROUND: Conventional group-based outpatient cardiac rehabilitation through monitoring and center-based approaches for patients in the recovery phase has shown strong evidence for the prevention of cardiovascular diseases. However, there are some cases in which maintaining attendance of center-based cardiac rehabilitation is difficult. OBJECTIVE: This study aims to ascertain the safety and efficacy of remote cardiac rehabilitation (RCR) in the recovery phase in patients with cardiovascular disease. METHODS: Patients satisfying the study criteria will be recruited from multiple institutions (approximately 30) across Japan. In total, 75 patients (approximately 2 or 3 patients from each institution) are proposed to be recruited. Patients enrolled in the RCR group will be lent devices necessary for RCR (including calibrated ergometers and tablets). Patients will perform anaerobic exercise at home using ergometer for 30-40 minutes at least 3 times weekly. During exercise, an instructor will monitor the patient in real time (using interactive video tools and monitoring tools for various vital data). Moreover, educational instructions will be given 3 times weekly using e-learning methods. RESULTS: The primary endpoint is the peak oxygen uptake 2-3 months from the start of exercise or 6-min walk test. The extracted data will be compared between RCR patients and controls without RCR. CONCLUSIONS: The establishment of the system of RCR proposed in this study will lead to the development of more extensive applications, which have been insufficient through conventional interventions. TRIAL REGISTRATION: University Hospital Medical Information Network-Clinical Trials Registry UMIN-CTR UMIN000042942; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000048983. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30725.

Is branched-chain amino acid nutritional supplementation beneficial or detrimental in heart failure?

Sarcopenia or cachexia is often complicated in heart failure. Nutritional support, particularly branched-chain amino acid (BCAA) supplementation, is a candidate treatment for improving sarcopenia or cachexia in elderly patients. However, the efficacy of BCAA supplementation in patients with heart failure has not been established, and the issue is comparatively more complex. Indeed, there are conflicting reports on the efficacy of BCAA supplementation. The evidence for including BCAA supplementation in treating patients with heart failure was reviewed, and the complexity of the issue was discussed.

Synthesis and evaluation of trypanocidal activity of derivatives of naturally occurring 2,5-diphenyloxazoles.

African trypanosomiasis is a zoonotic protozoan disease affecting the nervous system. Various natural products reportedly exhibit trypanocidal activity. Naturally occurring 2,5-diphenyloxazoles present in Oxytropis lanata, and their derivatives, were synthesized. The trypanocidal activities of the synthesized compounds were evaluated against Trypanosoma brucei brucei, T. b. gambiense, T. b. rhodesiense, T. congolense, and T. evansi. Natural product 1 exhibited trypanocidal activity against all the species/subspecies of trypanosomes, exhibiting half-maximal inhibitory concentrations (IC50) of 1.1-13.5 µM. Modification of the oxazole core improved the trypanocidal activity. The 1,3,4-oxadiazole (7) and 2,4-diphenyloxazole (9) analogs exhibited potency superior to that of 1. However, these compounds exhibited cytotoxicity in Madin-Darby bovine kidney cells. The O-methylated analog of 1 (12) was non-cytotoxic and exhibited selective trypanocidal activity against T. congolense (IC50 = 0.78 µM). Structure-activity relationship studies of the 2,5-diphenyloxazole analogs revealed aspects of the molecular structure critical for maintaining selective trypanocidal activity against T. congolense.

Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation.

Background: Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease. Case Summary: A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection. Discussion: This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher's exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.

Association between infectious event and de novo malignancy after heart transplantation.

The aim of the study was to investigate the incidence of and risk factors for de novo malignancy after heart transplantation (HTx) in a single center. We assessed 102 consecutive patients who received HTx and were followed-up in our center regularly for > 1 year from June 2006 to May 2018. We investigated the incidence of and risk factors for de novo malignancy. The cumulative incidence of each malignancy type during the follow-up period was one (0.98%) for skin cancer, four (3.92%) for nonskin solid organ cancer, and six (5.88%) for posttransplant lymphoproliferative disorder (PTLD). The percentage of patients with more than one infectious event ≤ 1 year after HTx was higher in the malignancy group than in the non-malignancy group. Furthermore, Kaplan-Meier analysis revealed that the incidence rate of infectious events was higher in patients with malignancies than in those without (log-rank P < 0.001). After dividing malignancies into a PTLD group and a solid organ malignancy group, we found that negative Epstein-Barr virus serostatus, cytomegalovirus-positive antigenemia, and the occurrence of any viral or gastrointestinal infectious event at ≤ 1 year were more frequent in patients with PTLD than in patients without it. The survival rate was significantly lower for patients with solid organ malignancy than for patients without malignancy. In conclusion, there was a correlation between infectious events and de novo malignancy, particularly in patients with PTLD. We should confirm this finding by conducting a larger cohort study.

Concise Syntheses of Violaceoids A and C.

The concise syntheses of two alkylated hydroquinone natural products, violaceoids A and C, were accomplished by a protecting-group-free method employing the commercially available 2,5-dihydroxybenzaldehyde as the starting material. The key strategy of the syntheses is the utilization of alkenylboronic acid as both the coupling and temporary protective reagents to efficiently introduce the requisite alkenyl side chain of violaceoid A. Moreover, the synthesis of violaceoid C is reported here for the first time.

Differences in the prognoses of patients referred to an advanced heart failure center from hospitals with different bed volumes.

Few reports have discussed appropriate strategies for patient referrals to advanced heart failure (HF) centers with available left ventricular assist devices (LVADs). We examined the association between the characteristics and prognoses of referred patients with advanced HF and the bed volume of the referring hospitals. This retrospective analysis evaluated 186 patients with advanced HF referred to our center for consultation about the indication of LVAD between January 1, 2015, and August 31, 2018. We divided the patients into two groups according to the bed volume of their referring hospital (high bed volume hospitals (HBHs): ≥ 500 beds in the hospital; low bed volume hospitals (LBHs): < 500 beds). We compared the primary outcome measure, a composite of LVAD implantation and all-cause death, between the patients referred from HBHs and patients referred from LBHs. The 186 patients with advanced HF referred to our hospital, who were referred from 130 hospitals (87 from LBHs and 99 from HBHs), had a mean age of 43.0 ± 12.6 years and a median left ventricular ejection fraction of 22% [15-33%]. The median follow-up duration of the patients was 583 days (119-965 days), and the primary outcome occurred during follow-up in 42 patients (43%) in the HBH group and 20 patients (23%) in the LBH group. Patients referred from HBHs tended to require catecholamine infusion on transfer more often than those referred from LBLs (36.5% (HBH), 20.2% (LBL), P = 0.021). Kaplan-Meier analysis indicates that the occurrence of the primary outcome was significantly higher in the HBH patients than in the LBH patients (log-rank P = 0.0022). Multivariate Cox proportional hazards analysis revealed that catecholamine support on transfer and long disease duration were statistically significant predictors of the primary outcome. Patients from HBHs had a greater risk of the primary outcome. However, the multivariate analysis did not indicate an association between referral from an HBH and the primary outcome. In contrast, catecholamine support on transfer, long duration of disease, and low blood pressure were independent predictors of the primary outcome. Therefore, these should be considered when determining the timing of a referral to an advanced HF center, irrespective of the bed volume of the referring hospital.

Efficacy and Safety of Direct Oral Anticoagulant for Treatment of Atrial Fibrillation in Cerebral Amyloid Angiopathy.

A 75-year-old man with a history of atrial fibrillation (AF) and anticoagulant therapy presented with a headache. Cerebral amyloid angiopathy (CAA) was diagnosed after MRI of the brain revealed cortical superficial siderosis, lobar intracerebral hemorrhage, and lobar microbleeds. Anticoagulant therapy was carefully discontinued. Several years later, he was admitted with sudden onset left upper-extremity weakness. In addition to CAA bleeding lesions, a diffusion-weighted brain MRI showed multiple infarct lesions of high signal intensity. The administration of edoxaban 7.5 mg/day (later increased up to 30 mg/day) prevented ischemic stroke recurrence without exacerbation of cerebral bleeding. This could indicate that CAA patients with AF who had previous adverse effects from warfarin can safely use newer direct oral anticoagulants, such as edoxaban, to prevent ischemic stroke without danger of cerebral hemorrhage. The superiority of edoxaban as compared with warfarin might be due to its antioxidant effect because vascular oxidative stress plays a causal role in CAA-induced cerebrovascular dysfunction, CAA-induced cerebral hemorrhage, and CAA formation itself. We explained the beneficial effect of edoxaban for CAA by the mechanism of oxidative stress in the paper.

Clinical importance of respiratory muscle fatigue in patients with cardiovascular disease.

Patients with cardiovascular diseases frequently experience exertional dyspnea. However, the relationship between respiratory muscle strength including its fatigue and cardiovascular dysfunctions remains to be clarified.The maximal inspiratory pressure/maximal expiratory pressure (MIP/MEP) before and after cardiopulmonary exercise testing (CPX) in 44 patients with heart failure and ischemic heart disease were measured. Respiratory muscle fatigue was evaluated by calculating MIP (MIPpost/MIPpre) and MEP (MEPpost/MEPpre) changes.The mean MIPpre and MEPpre values were 67.5 ±â€Š29.0 and 61.6 ±â€Š23.8 cm H2O, respectively. After CPX, MIP decreased in 25 patients, and MEP decreased in 22 patients. We evaluated the correlation relationship between respiratory muscle function including respiratory muscle fatigue and exercise capacity evaluated by CPX such as peak VO2 and VE/VCO2 slope. Among MIP, MEP, change in MIP, and change in MEP, only the value of change in MIP had an association with the value of VE/VCO2 slope (R = -0.36, P = .017). In addition, multivariate analysis for determining factor of change in MIP revealed that the association between the change in MIP and eGFR was independent from other confounding parameters (beta, 0.40, P = .017). The patients were divided into 2 groups, with (MIP change < 0.9) and without respiratory muscle fatigue (MIP change > 0.9), and a significant difference in peak VO2 (14.2 ±â€Š3.4 [with fatigue] vs 17.4 ±â€Š4.7 [without fatigue] mL/kg/min; P = .020) was observed between the groups.Respiratory muscle fatigue demonstrated by the change of MIP before and after CPX significantly correlated with exercise capacity and renal function in patients with cardiovascular disease.

The Efficacy of Lactulose for the Treatment of Hyperammonemic Encephalopathy Due to Severe Heart Failure.

Hyperammonemic encephalopathy secondary to heart failure is rare and there had been little reports about effective treatment. Organ hypoperfusion or congestion by heart failure may lead to various organ dysfunctions, and liver and intestinal circulatory impairment might cause ammonia metabolic failure. Here, we report on the case of a patient with hyperammonemic encephalopathy that was secondary to heart failure, which was effectively treated by lactulose.

In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells.

Liphagal, isolated from the marine sponge Aka coralliphaga, exhibits phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitory activity and cytotoxic effects in human cancer cells. Siphonodictyal B, the biogenetic precursor of liphagal, also has PI3K inhibitory activity. However, its cytotoxic or antitumor activities have not been evaluated. In this study, we demonstrated that siphonodictyal B inhibits several kinases such as CDK4/6, CDK7, and PIM2 in addition to PI3K in vitro and that siphonodictyal B exhibits more potent cytotoxic effects than liphagal against human colon cancer cell lines. Furthermore, treatment with siphonodictyal B resulted in increased PARP cleavage, a larger sub-G1 fraction, and a larger annexin V-positive cell population, all of which are indicative of apoptosis induction. As a mechanism of apoptosis induction, we found that siphonodictyal B activates the p38 MAPK pathway, leading the upregulation of proapoptotic factors. Moreover, siphonodictyal B increased ROS levels, thus promoting p38 MAPK pathway activation. NAC, an ROS scavenger, almost completely reversed both the cytotoxic and p38 MAPK pathway-activating effects of siphonodictyal B. These results indicate that the p38 MAPK pathway might be involved downstream of ROS signaling as part of the mechanism of siphonodictyal B-induced apoptosis. Finally, siphonodictyal B displayed antitumor effects in a human colon cancer xenograft mouse model and increased p38 phosphorylation in tumor tissue. These results suggest that siphonodictyal B could serve as the basis of a novel anticancer drug.