A retrospective database analysis of erythropoiesis-stimulating agent treatment patterns and associated healthcare resource use in patients with non-dialysis-dependent chronic kidney disease-related anaemia in Japan.

AIM: This study was conducted to evaluate clinical characteristics, treatment patterns, and healthcare resource use (HCRU) for patients in Japan with non-dialysis-dependent chronic kidney disease (CKD) and anaemia. METHODS: This retrospective, longitudinal, epidemiological database extraction study used the JMDC Claims Database, comprising ~9.4 million unique beneficiaries. The observation period for anaemia and erythropoiesis-stimulating agent (ESA)/iron treatment was 1 January 2015 to 31 December 2018, and for HCRU and costs was 1 April 2016 to 31 March 2018. The non-dialysis-dependent CKD anaemia population, and the ESA treatment, iron treatment, and no-treatment cohorts were evaluated. Patient characteristics, treatment patterns, and outcomes were summarised descriptively. RESULTS: The non-dialysis-dependent CKD anaemia population included 5908 patients (7.9%), with 464 patients in the ESA treatment cohort, 809 patients (13.7%) in the iron treatment cohort (13.7%), and 4405 (74.6%) patients in the no-treatment cohort. The prevalence of patients prescribed an antihypertensive, antidiabetic, and/or antihyperlipidaemic medication generally increased with increasing baseline CKD stage. Proportions of no treatment for anaemia decreased while ESA treatment increased with increasing CKD stage; ESA treatment increased with decreasing baseline haemoglobin levels. Patients in the ESA treatment cohort generally had more frequent events associated with HCRU and higher costs from HCRU-associated activities (e.g., inpatient and outpatient care, pharmacy). CONCLUSION: As CKD severity increased, anaemia management changed from iron use or no treatment to ESA use; however, anaemia may be undertreated across all CKD stages. ESA-treated patients incurred greater HCRU-associated costs relative to other patients with non-dialysis-dependent CKD anaemia in Japan.

Cost-effectiveness analysis of enzalutamide for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer in Japan.

BACKGROUND: We aimed to evaluate cost-effectiveness of enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer patients in Japan. METHODS: A Markov model was developed to capture time spent by patients in various health states: stable, progression and death. Abiraterone acetate and docetaxel were set as active comparators. Clinical outcomes were obtained from the PREVAIL, COU-AA-302 and TAX327 trials. Treatment sequence, concomitant drugs and therapies for adverse events were estimated from responses to a survey by 14 Japanese prostate cancer experts. The analytic perspective was public healthcare payer, with a 10-year time horizon. The incremental cost-effectiveness ratio was estimated from quality-adjusted life-years and Japanese public healthcare costs. Probabilistic sensitivity analysis was performed to assess the robustness of the findings. RESULTS: According to the survey, the most common treatment sequences were (i) enzalutamide â†’ docetaxel â†’ cabazitaxel (enzalutamide-first sequencing), (ii) abiraterone â†’ enzalutamide â†’ docetaxel (abiraterone-first sequencing) and (iii) docetaxel→ enzalutamide â†’ cabazitaxel (docetaxel-first sequencing). In the base-case analysis, enzalutamide-first sequencing saved 1.74 million Japanese Yen versus abiraterone-first sequencing, with a 0.129 quality-adjusted life-year gain (dominant). Enzalutamide-first sequencing had a cost increase of 4.44 million Japanese Yen over docetaxel-first sequencing, with a 0.371 quality-adjusted life-years gain. The incremental cost-effectiveness ratio of enzalutamide-first sequencing versus docetaxel-first sequencing was estimated as 11.94 million Japanese Yen/quality-adjusted life-years. Probabilistic sensitivity analyses demonstrated that, compared with abiraterone-first sequencing, enzalutamide-first sequencing had an 87.4% probability of being dominant. CONCLUSIONS: Results modeled herein suggest that the enzalutamide-first sequencing is more cost-effective than the abiraterone-first sequencing, but less cost-effective than docetaxel-first sequencing for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

Cost-effectiveness analysis of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in Japan.

BACKGROUND: The cost of treating Clostridioides difficile infection (CDI), particularly recurrent disease, is high. In clinical trials, fidaxomicin has been associated with significantly lower recurrence rates and higher sustained cure rates versus vancomycin. The high acquisition cost of fidaxomicin has limited its acceptance into clinical practice. OBJECTIVE: To evaluate the cost-effectiveness of fidaxomicin versus vancomycin in patients with CDI after failure of metronidazole in the Japanese healthcare setting. METHODS: Clinical results from three phase III trials and inputs based on assumptions validated by clinical experts in Japan were used in a semi-Markov model with 1-year time horizon. Incremental cost-effectiveness ratios (ICERs) for fidaxomicin versus vancomycin were expressed as cost per quality-adjusted life year (QALY) and interpreted using willingness-to-pay thresholds of JPY 5,000,000 (primary) and JPY 7,500,000 (secondary) per QALY gained in Japan. Probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Higher drug acquisition costs for fidaxomicin were partially offset by lower hospitalization costs driven by fewer recurrences, lower costs of complications, and fewer general practitioner visits versus vancomycin. The ICER for fidaxomicin versus vancomycin was estimated at JPY 5,715,183 per QALY gained. Sensitivity analyses showed a 46% probability of fidaxomicin being cost-effective versus vancomycin at a willingness-to-pay threshold of JPY 5,000,000 per QALY gained. At a threshold of JPY 7,500,000, there was a 54% probability of fidaxomicin being cost-effective. CONCLUSIONS: Fidaxomicin treatment in patients with CDI following failure of metronidazole improves health outcomes with partial offset of higher drug acquisition costs versus vancomycin.

Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis.

We conducted a systematic review of the literature and network meta-analysis (NMA) to compare the relative effectiveness of antibiotic treatments for Clostridioides (Clostridium) difficile infection (CDI) including vancomycin (VCM), metronidazole (MTZ) and fidaxomicin (FDX). Eligible studies were randomised controlled trials (RCTs) including adults with any severity of CDI that was treated with VCM, MTZ or FDX. The NMA was performed using a Bayesian framework, using a fixed-effects model. The searches identified seven publications for inclusion, which provided five RCTs for VCM versus MTZ, and three RCTs for FDX versus VCM. The NMA showed that for clinical cure rate, there was no difference for FDX versus VCM, and there was a significant difference in favour of FDX versus MTZ (odds ratio [OR]: 1.77; 95% credible interval [CrI] 1.11, 2.83]). For recurrence rate, there was a significant difference in favour of FDX versus both VCM (OR: 0.50; 95% CrI: 0.37, 0.68) and MTZ (OR: 0.44; 95% CrI: 0.27, 0.72). For sustained cure (clinical cure without recurrence), there was a significant difference in favour of FDX versus VCM (OR: 1.61; 95% CrI: 1.27, 2.05) and MTZ (OR: 2.39; 95% CrI: 1.65, 3.47). These findings suggest that FDX and VCM are effective first-line treatments for mild or moderate CDI, whereas MTZ is not, and FDX may be more effective at preventing CDI recurrence than VCM.

[A cross-sectional analysis of the health-related quality of life and work productivity in Japanese subjects with self-reported chronic constipation using the National Health and Wellness Survey 2017].

BACKGROUND: Chronic constipation (CC) is associated with lower health-related quality of life (HR-QoL) and work productivity in Western countries;however, limited data in Japanese subjects are available. METHODS: This retrospective, cross-sectional analysis used the data from the National Health and Wellness Survey (NHWS), a web-based questionnaire survey conducted in 2017 for the Japanese general population. Subjects were allocated to the self-reported CC group when they answered "yes" to the question "Did you have chronic constipation in the past 12 months?". Other subjects were allocated to the non-CC group. Self-reported CC population was sub-categorized as per the abdominal symptoms. The HR-QoL was assessed using the Medical Outcomes Study 12-Item Short-Form Health Survey version 2 using the Mental Component Summary (MCS), Physical Component Summary (PCS), and Role/Social Component Summary (RCS) scores (3-component method). Work productivity was assessed using the Work Productivity and Activity Impairment:General Health version 2.0 for absenteeism, presenteeism, work productivity loss, and activity impairment. RESULTS: Of the 30001 respondents, 3373 had self-reported CC (895 with abdominal symptoms, 2478 without abdominal symptoms) and 26628 did not report CC. The differences in the summary scores [95% confidence interval (CI) ] adjusted for potential confounders between self-reported CC and non-CC (self-reported CC - non-CC) were -1.60 (-1.98, -1.22) in MCS, -0.78 (-1.19, -0.37) in PCS, and -2.09 (-2.57, -1.61) in RCS;the differences in the adjusted summary scores (95% CI) between self-reported CC with and without abdominal symptoms (self-reported CC with abdominal symptoms - without abdominal symptoms) were -0.95 (-1.77, -0.14) in MCS, -1.67 (-2.66, -0.68) in PCS, and -2.05 (-3.55, -0.55) in RCS. All the summary scores were lower in those with self-reported CC and abdominal symptoms than in those with self-reported CC without abdominal symptoms;all the adjusted differences between the summary scores were statistically significant. The adjusted risk ratio (95% CI) of each outcome of self-reported CC relative to non-CC was 1.34 (1.04, 1.73) in absenteeism, 1.21 (1.12, 1.31) in presenteeism, 1.20 (1.11, 1.29) in work productivity loss, and 1.21 (1.15, 1.27) in activity impairment. In terms of statistics, the risk of decreased work productivity for all the outcomes was significantly higher in those with than in those without self-reported CC, indicating decreased work productivity in those with self-reported CC. CONCLUSION: HR-QoL and work productivity were lower in those with self-reported CC than in those who did not report CC, suggesting that CC negatively affects the HR-QoL and work productivity.

Retrograde percutaneous coronary intervention for acute myocardial infarction following blunt chest trauma.

A 78-year-old man was admitted to the emergency department because of chest pain following blunt chest trauma. Chest X-ray revealed multiple rib fractures. However, electrocardiogram showed ST elevation in inferior leads suggesting acute myocardial infarction (AMI). Emergency coronary angiography revealed normal left coronary artery and occluded proximal right coronary artery. Thus, percutaneous coronary intervention (PCI) was performed immediately. Antegrade PCI was unsuccessful due to a very large false lumen, which was caused by a blunt trauma. However, retrograde guidewire (GW) manipulation was relatively easy to negotiate the occluded lesion. After GW externalization, we deployed two drug eluting stents for this lesion. To our knowledge, this is the first case of retrograde PCI that led to a successful reperfusion therapy for AMI following blunt chest trauma.

Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.

Comparative Efficacy and Safety of Peficitinib Versus Tofacitinib and Baricitinib for Treatment of Rheumatoid Arthritis: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity. RESULTS: The network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes. CONCLUSIONS: Peficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors.

Assessment of microbial adherent carriers for possible application in nitrogen removal: a fundamental study.

Microbes have been used for cleaning polluted environments and degrading unwanted compounds. This study assessed the feasibility of using three microbial adherent carriers, Isolite, activated carbon fiber (ACF), and a marine sediment solidified carrier, MSSC, which was newly developed from dredged waste marine sediment, to remove nitrogen in sediment. The properties of three carriers were investigated, and the extent of microbe adhesion to the carriers was observed by using scanning electron microscopy. The amount of nitrogen removed by MSSC was higher than that removed by Isolite and ACF. We concluded that MSSC may be useful as a microbial adherent carrier.

Construction of a consortium comprising ammonia-oxidizing bacteria and denitrifying bacteria isolated from marine sediment.

A unique consortium of ammonia-oxidizing bacteria (AOB) and denitrifying bacteria was obtained via a long-term, 3-step cultivation of isolates from organically-enriched marine sediment. We developed this microbial consortium for possible applications in the remediation of degraded habitats in closed aquaculture or other aquatic environments via microbial degradation. Analysis of media components found definitive evidence of nitrogen removal via the coupling of ammonia-oxidation and denitrification. The phylogenetic diversity of the consortium was investigated by performing polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) that targeted the 16S rRNA gene, and the functional genes involved in ammonia-oxidation (amoA) and denitrification (nirS, nirK, norB and nosZ). Consequently, no significant divergence was observed, and thus it is suggested microbial populations were selected via a long-term, 3-step incubation process. All of the 16S rRNA clones fell into three phylogenetic groups, namely, gamma-proteobacteria, Actinobacteria and Flavobacteria. For almost half of the clones, the closest relatives in the database were identified as Alcanivorax spp. and these clones were present at all cultivation stages. The presence of these species as the dominant clones is significant since these bacterial species are known to reduce nitrate to nitrite. Accordingly, their abundance in our microbial consortium may have been responsible for the observed stepwise denitrification. All sequences of the amoA gene were identified to be Nitrosomonas lineage. Half of the nirS clones were identified to be from one major group of well-known denitrifying bacteria, Pseudomonas sp. Furthermore, 70% of the nirK clones were closely related to the nirK sequences of uncultured bacterial clones isolated from arable soil. The qnorB clones consisted of clusters exclusively, and formed a distinct cluster from the novel sequences of cultivated species. The nosZ clones also were not found in any of the closest relatives in the database including the uncultured bacterium from marine sediment. The unique clones obtained from the functional genes were related to each denitrification step.

Burden of Anemia in Chronic Kidney Disease Patients in Japan: A Literature Review.

Anemia is a common complication for patients with chronic kidney disease (CKD) and is associated with cardiovascular comorbidities and reduced quality of life. The incidence of anemia increases as kidney function declines and affects approximately 32% of Japanese patients with stage 3-5 CKD. This review examined the current literature on anemia in CKD patients in Japan to provide an overview of the burden of anemia in CKD. Medline, Embase, and Igaku Chuo Zasshi databases were searched to identify relevant manuscripts and abstracts published from 2004 onward. The population included CKD patients with anemia, and the outcomes of interest were epidemiology, economic, humanistic, and treatment patterns. Observational studies, database analysis, and economic evaluation studies were included in the analysis. A total of 1151 references were identified, and 50 were eligible for final review. Economic burden was reported in most studies (n = 37) followed by treatment patterns (n = 26), and epidemiological (n = 25) and humanistic (n = 1) burdens. Prevalence of anemia varied largely (0-95%) based on the different definitions of anemia, and increased with CKD severity. Higher mortality was associated with erythropoiesis-stimulating agent (ESA) resistance and lower hemoglobin levels among patients treated with ESA. Drug dosage was the most reported economic burden (n = 33), followed by medical, and non-medical outcomes. Costs associated with anemia were considerable and depended on dialysis status and ESA treatment. Only one study reported data on quality of life, suggesting that further investigation on the humanistic burden of anemia in CKD is needed.

Rheumatoid Meningitis Occurring during Etanercept Treatment.

We report a 65-year-old man who had repetitive seizures 6 months after receiving etanercept, methotrexate, and prednisolone for rheumatoid arthritis. Mononuclear cells were mildly increased in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) showed high intensity along sulci of the frontal and parietal lobes. Brain biopsy revealed lymphocyte and plasma cell infiltration in the meninges, confirming the diagnosis of rheumatoid meningitis. After steroid pulse therapy, seizures resolved and clinical findings improved. When etanercept was replaced by tocilizumab, rheumatoid meningitis did not recur. Although TNF-α inhibitors can control joint symptoms of rheumatoid arthritis, they may induce rheumatoid meningitis.

C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction.

OBJECTIVES: We assessed the hypothesis that in vivo administration of C-type natriuretic peptide (CNP) might attenuate cardiac remodeling after myocardial infarction (MI) through its antifibrotic and antihypertrophic action. BACKGROUND: Recently, we have shown that CNP has more potent antifibrotic and antihypertrophic effects than atrial natriuretic peptide (ANP) in cultured cardiac fibroblasts and cardiomyocytes. METHODS: Experimental MI was induced by coronary ligation in male Sprague-Dawley rats; CNP at 0.1 mug/kg/min (n = 34) or vehicle (n = 35) was intravenously infused by osmotic mini-pump starting four days after MI. Sham-operated rats (n = 34) served as controls. After two weeks of infusion, the effects of CNP on cardiac remodeling were evaluated by echocardiograpic, hemodynamic, histopathologic, and gene analysis. RESULTS: C-type natriuretic peptide markedly attenuated the left ventricular (LV) enlargement caused by MI (LV end-diastolic dimension, sham: 6.7 +/- 0.1 mm; MI+vehicle; 8.3 +/- 0.1 mm; MI+CNP: 7.7 +/- 0.1 mm, p < 0.01) without affecting arterial pressure. Moreover, there was a substantial decrease in LV end-diastolic pressure, and increases in dP/dt(max), dP/dt(min), and cardiac output in CNP-treated MI rats compared with vehicle-treated MI rats. Importantly, CNP infusion markedly attenuated an increase in morphometrical collagen volume fraction in the noninfarct region (sham: 3.1 +/- 0.2%; MI+vehicle: 5.7 +/- 0.5%; MI+CNP: 3.9 +/- 0.3%, p < 0.01). In addition, CNP significantly reduced an increase in cross-sectional area of the cardiomyocytes. These effects of CNP were accompanied by suppression of MI-induced increases in collagen I, collagen III, ANP, and beta-myosin heavy chain messenger ribonucleic acid levels in the noninfarct region. CONCLUSIONS: These data suggest that CNP may be useful as a novel antiremodeling agent.

Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway.

BACKGROUND: Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. METHODS AND RESULTS: Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28+/-4% to 16+/-1%, P<0.01), left ventricular end-diastolic pressure (19+/-2 to 8+/-2 mm Hg, P<0.05), and myocardial apoptotic death (19+/-2% to 9+/-4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion. CONCLUSIONS: Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.

Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) migrate to injured vascular endothelium and differentiate into mature endothelial cells. We investigated whether transplantation of vasodilator gene-transduced EPCs ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. METHODS AND RESULTS: We obtained EPCs from cultured human umbilical cord blood mononuclear cells and constructed plasmid DNA of adrenomedullin (AM), a potent vasodilator peptide. We used cationic gelatin to produce ionically linked DNA-gelatin complexes. Interestingly, EPCs phagocytosed plasmid DNA-gelatin complexes, which allowed nonviral, highly efficient gene transfer into EPCs. Intravenously administered EPCs were incorporated into the pulmonary vasculature of immunodeficient nude rats given MCT. Transplantation of EPCs alone modestly attenuated MCT-induced pulmonary hypertension (16% decrease in pulmonary vascular resistance). Furthermore, transplantation of AM DNA-transduced EPCs markedly ameliorated pulmonary hypertension in MCT rats (39% decrease in pulmonary vascular resistance). MCT rats transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone. CONCLUSIONS: Umbilical cord blood-derived EPCs had a phagocytosing action that allowed nonviral, highly efficient gene transfer into EPCs. Transplantation of AM gene-transduced EPCs caused significantly greater improvement in pulmonary hypertension in MCT rats than transplantation of EPCs alone. Thus, a novel hybrid cell-gene therapy based on the phagocytosing action of EPCs may be a new therapeutic strategy for the treatment of pulmonary hypertension.

Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts.

Insulin-like growth factor (IGF)-1 appears to play an important role in cardiac hypertrophy or remodeling. However, the role of endogenous IGF-1 in the growth of cardiac myocytes and fibroblasts remains unclear. This study investigated the major site of the production of cardiac IGF-1 and the local effects of endogenous IGF-1 secreted from cardiac cells. A significant expression of IGF-1 mRNA was found in cultured neonatal and adult rat cardiac fibroblasts, but not in myocytes. In addition, an in vivo examination by in situ hybridization histochemical analyses demonstrated the IGF-1 transcripts in the interstitial fibrotic tissue of the ventricle. Time-dependent secretion of IGF-1 protein was also observed in cultured cardiac fibroblasts. An antibody against IGF-1 decreased collagen synthesis in cardiac fibroblasts under basal conditions. Fibroblast-conditioned medium, as well as exogenous IGF-1, increased protein synthesis in cardiac myocytes, and this increase was inhibited by antibodies against IGF-1 and IGF-1 receptor, IGF binding protein-3, and IGF-1 receptor antagonist. These observations suggest that IGF-1 is produced and released mainly from cardiac fibroblasts and that endogenous IGF-1 promotes collagen synthesis by cardiac fibroblasts and hypertrophy of myocytes as an autocrine and a paracrine factor. Cardiac IGF-1 may function as an endogenous modulator of cardiac hypertrophy or remodeling.

Increased plasma ghrelin level in lung cancer cachexia.

PURPOSE: Ghrelin, a novel growth hormone-releasing peptide,has been shown to cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in cachexia associated with lung cancer. EXPERIMENTAL DESIGN: Plasma ghrelin level was measured in 43 patients with lung cancer and 21 control subjects. Patients with lung cancer were divided into two groups: patients with cachexia (n = 21) and those without cachexia (n = 22). RESULTS: Plasma ghrelin level did not significantly differ between all patients with lung cancer and controls (157 +/- 10 versus 132 +/- 8 fmol/ml, P = 0.1). However, plasma ghrelin level was significantly higher in patients with cachexia than in those without cachexia (180 +/- 17 versus 135 +/- 10 fmol/ml, P = 0.011). Furthermore, plasma ghrelin level increased significantly in patients with decreased food intake after chemotherapy (from 136 +/- 11 fmol/ml to 170 +/- 16 fmol/ml on day 8, 179 +/- 20 fmol/ml on day 21 after start of chemotherapy), although plasma ghrelin level did not significantly change in those without decreased food intake. CONCLUSIONS: Baseline plasma ghrelin level was elevated in cachectic patients with lung cancer, and follow-up plasma ghrelin level increased in patients with anorexia after chemotherapy. Considering the positive energy effects induced by ghrelin, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with lung cancer.

Chest pain and ST elevation associated with fever in patients with asymptomatic Brugada syndrome: fever and chest pain in Brugada syndrome.

Brugada syndrome is a disease with a high risk of sudden cardiac death. Genetic mutations of the cardiac sodium channel are linked to the characteristic electrocardiogram abnormality of Brugada syndrome. Dysfunction of the mutated sodium channel is reported to be temperature-sensitive. We experienced two patients with asymptomatic Brugada syndrome who showed significant ST elevation in precordial leads while they were in a febrile state. Moreover, these patients had chest pain during precordial ST elevation. From these cases, asymptomatic Brugada syndrome should be considered as one of differential diagnoses when we examine the patients who complained of fever and chest pain. Furthermore, we should lower the elevated body temperature in patients with Brugada syndrome, because fever caused spontaneous ST elevation leading to fatal ventricular arrhythmias.

Ventricular nonmyocytes inhibit doxorubicin-induced myocyte apoptosis: involvement of endogenous endothelin-1 as a paracrine factor.

A cross-talk between cardiac myocytes and nonmyocytes via humoral factors plays an important role in the development of cardiac growth. However, it remains to be elucidated whether humoral factors produced from nonmyocytes have a protective effect on acute myocardial injury. The present in vitro study investigated the antiapoptotic effect of nonmyocytes on doxorubicin (DOX)-induced myocyte apoptosis and its molecular mechanism. Myocyte-nonmyocyte coculture and treatment with nonmyocyte-conditioned media significantly attenuated DOX-induced myocyte apoptosis. Treatment with nonmyocyte-conditioned media stimulated the phosphorylation of ERK, Akt, and cAMP response element-binding protein (CREB) in myocytes. Nonmyocyte-conditioned media also increased protein levels of Bcl-2 but not Bcl-xL and decreased caspase-3 activation induced by DOX. MAPK kinase-specific inhibitor PD98059, phosphatidylinositol-3 kinase-Akt inhibitor LY294002, and CREB antisense oligonucleotide significantly blocked the antiapoptotic effect of nonmyocyte-conditioned media. A considerable amount of endothelin (ET)-1 production was detected in nonmyocytes but not in myocytes. Exogenous ET-1 mimicked nonmyocyte-conditioned media-mediated ERK and CREB phosphorylation and Bcl-2 protein increase but not Akt phosphorylation. In addition, ET-A receptor antagonists BQ123 and BQ485 partially blocked nonmyocyte-conditioned media-mediated antiapoptotic effect, ERK and CREB phosphorylation, and Bcl-2 protein increase. Nonmyocyte-conditioned media and exogenous ET-1 unchanged protein levels of manganese superoxide dismutase and oxidative stress-related product levels augmented by DOX. The present findings demonstrate that cardiac nonmyocytes inhibit DOX-induced myocyte apoptosis, at least in part, via ET-1 secretion-mediated CREB activation independent of the decrease in oxidative stress.

Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.

We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered two inhibitors with improved oral bioavailability [6 (K(i) = 13 nM, BA = 44%) and 7 (K(i) = 9.8 nM, BA = 42%)]. 6 demonstrated in vivo efficacy in models of inflammation and lymphoma.