First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Long-term effect of pulmonary rehabilitation in idiopathic pulmonary fibrosis: a randomised controlled trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time. TRIAL REGISTRATION NUMBER: UMIN000026376.

Mean pulmonary artery pressure estimated by echocardiogram rapidly exceeds 20 mmHg from the normal range in patients with connective tissue disease.

Earlier intervention for pulmonary hypertension (PH) has been reported to improve the prognosis of patients with connective tissue disease (CTD). However, it is not fully elucidated how rapidly PH develops in patients showing normal mean pulmonary arterial pressure (mPAP) at the index investigation. We evaluated 191 CTD patients with normal mPAP retrospectively. The mPAP was estimated by the formerly defined method employing echocardiography (mPAPecho). We investigated predictive factors that predict increasing mPAPecho at follow-up transthoracic echocardiography (TTE) using uni- and multi variable analysis. The mean age was 61.5 years old, and 160 patients were female. The percentage of patients in whom mPAPecho exceeded 20 mmHg at follow-up TTE was 38%. Multivariable analysis revealed that acceleration time/ejection time (AcT/ET) measured at the right ventricular outflow tract at initial TTE was independently associated with the consequent increase of mPAPecho at the follow-up TTE. When using 0.43 of best cutoff value in AcT/ET calculated by receiver operating characteristic analysis, the change in mPAPecho in patients with low AcT/ET was significantly higher than in those with high AcT/ET (3.05 mmHg in patients with AcT/ET < 0.43 and 1.00 mmHg in patients with AcT/ET ≥ 0.43, p < 0.001). Thirty-eight percent of CTD patients who show the normal estimated mPAP by TTE develop gradual elevation of mPAP to the level to consider early intervention within 2 years. AcT/ET at initial TTE can predict increasing mPAP at follow-up TTE.

Identification of cell cycle-associated and -unassociated regulators for expression of a hepatocellular carcinoma oncogene cyclin-dependent kinase inhibitor 3.

Human cyclin-dependent kinase inhibitor 3 (CDKN3) is a known oncogene in hepatocellular carcinoma (HCC) and its expression is promoted during tumor development. CDKN3 serves as a cell cycle regulator and its dysregulation is considered to be a causal factor for tumor progression. However, the molecular basis of the regulation of CDKN3 expression remains largely elusive. Using in silico approach, we identified CDKN3SE, a super enhancer (SE), and enhancer RNA (eRNA) candidates transcribed from this SE. Among the eRNA candidates, the expression of CDKN3eRNA was detected in the human HCC model cell line HepG2, and was found to facilitate the expression of CDKN3 without affecting the cell proliferation rate. In silico screening revealed two DNA-binding transcription factors, upstream stimulatory factor (USF) 1 and 2, involved in the regulation of CDKN3eRNA expression on CDKN3SE. A knock-down of USF1/USF2 expression in the HepG2 cells did not affect CDKN3eRNA expression, while the expression of CDKN3 was down-regulated. In a USF2 dominant negative HepG2 cell line generated by genome editing, a drastically altered cell shape and lowered cell proliferation rate were found; however, the expression of CDKN3eRNA appeared unaffected. Thus, the present study illustrated two regulators for CDKN3 expression: USF2, as a cell cycle-associated protein regulator, and CDKN3eRNA, as a cell cycle-unassociated RNA regulator.

Cicatricial organising pneumonia associated with fibrosing interstitial pneumonia - a clinicopathological study.

AIMS: The recent recognition of cicatricial organising pneumonia (ciOP) indicates that the ciOP may resemble or simulate fibrotic interstitial pneumonia; however, there has been great uncertainty regarding the affected populations, pathogenesis, clinical relevance and characteristics. In this study, we compared the characteristics of fibrotic interstitial pneumonia with and without ciOP. METHODS AND RESULTS: We enrolled 121 patients from the consultation archive whose pathological findings were fibrotic interstitial pneumonia and for whom follow-up clinical data were available. We reviewed these cases histopathologically and classified them according to whether or not they showed ciOP. We compared the clinicopathological features between the two groups. CiOP, histopathologically characterised by deposition of dense collagenous fibres within the alveolar space without destruction of the lung structure, was found in 48 patients (39.7%). None of the cases with ciOP experienced acute exacerbation during 12 months' follow-up. The group with ciOP had more severe diffusion impairment but this, together with restrictive ventilatory impairment, improved significantly compared to the group without ciOP. CONCLUSION: CiOP is a histopathological finding commonly found in fibrotic interstitial pneumonia. It does not relate to acute exacerbation or decrease in pulmonary function.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Urine albumin-to-creatinine ratio on admission predicts early rehospitalization in patients with acute decompensated heart failure.

Detecting high-risk patients for early rehospitalization is crucial in heart failure patient care. An association of albuminuria with cardiovascular events is well known. However, its predictive impact on rehospitalization for acute decompensated heart failure (ADHF) remains unknown. In this study, 190 consecutive patients admitted due to ADHF between 2017 and April 2019 who underwent urinalysis were enrolled. Among them, 140 patients from whom urine albumin-to-creatinine ratio (UACR) was measured with spot urine samples on admission were further analyzed. The association between UACR and rehospitalization due to HF during 1 year after discharge was evaluated. The mean age of 140 participants was 77.6 years and 55% were men. Only 18% (n = 25) of patients presented with normoalbuminuria (UACR < 30 mg/g∙creatinine), whereas 59% (n = 83) and 23% (n = 32) showed microalbuminuria (UACR 30-300 mg/g·creatinine) and macroalbuminuria (UACR > 300 mg/g·creatinine), respectively. The level of UACR on admission was correlated with the risk of subsequent rehospitalization due to HF (p = 0.017). The receiver operating characteristic analysis indicated that the best cut-off values for the UACR and B-type natriuretic peptide (BNP) levels to predict ADHF rehospitalization were 50 mg/g·creatinine and 824 pg/ml, respectively. When the patients were divided into four groups using both cut-off values, the individual predictive impacts of UACR and BNP on rehospitalization were comparable. Patients with both elevated UACR and BNP levels had a higher rate of HF rehospitalization than those with elevated BNP levels alone (p < 0.05). The combination of both values enabled more accurate prediction of HF rehospitalization than BNP levels alone. In conclusion, UACR could be a new useful biomarker to predict HF rehospitalization in patients with ADHF, especially in combination with the levels of BNP, and should be further evaluated in a prospective study.

Androgen-dependent and DNA-binding-independent association of androgen receptor with chromatic regions coding androgen-induced noncoding RNAs.

Androgen induces the binding of its receptor (AR) to androgen-responsive elements (AREs), while genome-wide studies showed that most androgen-induced AR binding sites on chromatin were unrelated to AREs. Enhancer RNAs (eRNAs), a class of noncoding RNAs (ncRNAs), are transcribed from superenhancers (SEs) and trigger the formation of large ribonucleoprotein condensates of transcription factors. By in silico search, an SE is found to be located on the locus of KLK3 that encodes prostate specific antigen. On the KLK3 SE, androgen-induced expression of ncRNAs was detected and designated as KLK3eRNAs in LNCaP cells, and androgen-induced association of AR and FOXA1 on the KLK3eRNA coding regions was detected. Such androgen-induced association of an AR mutant lacking DNA binding activity on the KLK3eRNA coding regions was undetectable on an exogenous ARE. Thus, the present findings suggest a molecular basis of androgen-induced association of AR with chromatin on ARE-unrelated sequences.

Mechanisms of increased vascular stiffness down the aortic tree in aging, premenopausal female monkeys.

Protection against increased vascular stiffness in young women is lost after menopause. However, little is known about vascular stiffness in older, premenopausal females, because most of the prior work has been conducted in rodents, which live for only 1-3 yr and do not go through menopause. The goal of the current investigation was to quantitate differences in stiffness down the aortic tree and the mechanisms mediating those differences in older, premenopausal (24 ± 0.7 yr) versus young adult (7 ± 0.7 yr) female nonhuman primates. Aortic stiffness (ß), calculated from direct and continuous measurements of aortic diameter and pressure in chronically instrumented, conscious macaque monkeys, increased 2.5-fold in the thoracic aorta and fivefold in the abdominal aorta in old premenopausal monkeys. The aortic histological mechanisms mediating increased vascular stiffness, i.e., collagen/elastin ratio, elastin, and collagen disarray, and the number of breaks in elastin and collagen fibers were greater in the old premenopausal versus young monkeys and greater in the abdominal versus the thoracic aorta and greatest in the iliac artery. In addition, more immature and less cross-linked fibers of collagen were found in the aortas of young females. Aortic stiffness increased in old premenopausal female monkeys, more so in the abdominal aorta than in the thoracic aorta. Histological mechanisms mediating the increased aortic stiffness were augmented in the old premenopausal females, greater in the abdominal versus the thoracic aorta, and greatest in the iliac artery.NEW & NOTEWORTHY This is the first study to examine vascular stiffness down the aortic tree in aging premenopausal females (24 ± 0.7 yr old), whereas prior work studied mainly rodents, which are short-lived and do not undergo menopause. Histological mechanisms mediating vascular stiffness in older premenopausal females increased progressively down the aortic tree, with greater increases in the abdominal aorta compared with the thoracic aorta and with the greatest increases and differences observed in the iliac artery.

Manipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling.

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.

Rats are protected from the stress of chronic pressure overload compared with mice.

The goal of this investigation was to compare the effects of chronic (4 wk) transverse aortic constriction (TAC) in Sprague-Dawley rats and C57BL/6J mice. TAC, after 1 day, induced similar left ventricular (LV) pressure gradients in both rats (n = 7) and mice (n = 7) (113 ± 5.4 vs. 103 ± 11.5 mmHg), and after 4 wk, the percent increase in LV hypertrophy, as reflected by LV/tibial length (51% vs 49%), was similar in rats (n = 12) and mice (n = 12). After 4 wk of TAC, LV systolic and diastolic function were preserved in TAC rats. In contrast, in TAC mice, LV ejection fraction decreased by 31% compared with sham, along with increases in LV end-diastolic pressure (153%) and LV systolic wall stress (86%). Angiogenesis, as reflected by Ki67 staining of capillaries, increased more in rats (n = 6) than in mice (n = 6; 10 ± 2 vs. 6 ± 1 Ki67-positive cells/field). Myocardial blood flow fell by 55% and coronary reserve by 28% in mice with TAC (n = 4), but they were preserved in rats (n = 4). Myogenesis, as reflected by c-kit-positive myocytes staining positively for troponin I, is another mechanism that can confer protection after TAC. However, the c-kit-positive cells in rats with TAC were all negative for troponin I, indicating the absence of myogenesis. Thus, rats showed relative tolerance to severe pressure overload compared with mice, with mechanisms involving angiogenesis but not myogenesis.

Effect of Oral Qing-Dai Medication on Pulmonary Arterial Pressure Levels in Patients With Ulcerative Colitis.

BACKGROUND: Qing-Dai (QD) treatment of patients with ulcerative colitis (UC) sometimes causes pulmonary arterial hypertension (PAH). However, the relationship of QD treatment to pulmonary arterial systolic pressure (PASP) in patients with UC has not been clarified.Methods and Results:The 27 patients with UC who were screened for PAH by transthoracic echocardiography (TTE) and underwent repeat TTE at 1 year were analyzed in this prospective observational study. Mean age was 44.0 years old, and median follow-up duration was 392. During the follow-up, 21 patients continued QD treatment (continuous group) and 6 patients discontinued the treatment (discontinuous group). In all patients, no significant difference in PASP levels between baseline and at follow-up was observed (21.4 vs. 21.3 mmHg, P=0.802). Furthermore, the mean PASP of patients in the continuous group did not differ from baseline to follow-up (21.4 mmHg to 22.6 mmHg, P=0.212); however, in the discontinuous group mean PASP was significantly decreased (21.5 mmHg to 16.8 mmHg, P=0.005). Moreover, changes in PASP from baseline to follow-up differed between the continuous and discontinuous groups (+1.1 mmHg vs. -4.7 mmHg, P=0.004). In addition, multivariable analyses revealed that only the duration of oral QD at baseline affected the increase of PASP. CONCLUSIONS: In patients with UC, QD treatment may have an undesirable association with an increase in PASP.

Urinary composition predicts diuretic efficiency of hypertonic saline solution with furosemide therapy and heart failure prognosis.

Recently, we and other group have reported that furosemide administration along with hypertonic saline solution enhanced diuretic efficiency of furosemide. However, little is known about factors which associated with high diuretic efficiency by hypertonic saline solution with furosemide therapy. To identify predictors of diuretic efficiency in the hypertonic saline solution with furosemide therapy, we recruited 30 consecutive hospitalized heart failure (HF) patients with volume overload (77 ± 10 years, systolic blood pressure > 90 mmHg, and estimated glomerular filtration rate > 15 ml/min/1.73 m2). Hypertonic saline with furosemide solution, consisting of 500 ml of 1.7% hypertonic saline solution with 40 mg of furosemide, was administered continuously over 24 h. The patients were divided into two groups on the basis of 24-h urine volume (UV) after initiation of diuretic treatment ≥ 2000 ml (high urine volume: HUV) and < 2000 ml (low urine volume: LUV). The basal clinical characteristics of both groups were analyzed and the predictors of HUV after receiving the treatment were identified. There were not significant differences between two groups in baseline clinical characteristics and medication. Univariate logistic analysis revealed that blood urea nitrogen/creatinine ratio, urine urea nitrogen/creatinine ratio (UUN/UCre), fractional excretion of sodium, and tricuspid annular plane systolic excursion positively associated with HUV. Multivariate logistic regression analysis revealed that UUN/UCre at baseline was independently associated with HUV, and UUN/UCre best predicts HUV by the therapy with a cut-off value of 6.16 g/dl/g Cre (AUC 0.910, 95% CI 0.696-0.999, sensitivity 80%, specificity 87%). The Kaplan-Meier curves revealed significant difference for HF rehospitalization and death rate at 180 days between patients with UUN/UCre ≥ 6.16 g/dl/g Cre and those with UUN/UCre < 6.16 g/dl/g Cre (log-rank P = 0.0489). UUN/UCre at baseline strongly predicted of diuretic efficiency in the hypertonic saline solution with furosemide therapy, and was associated with HF prognosis.

Influence of dietary iron intake restriction on the development of hypertension in weanling prehypertensive rats.

Hypertension is a major public health problem leading to death. To reduce the morbidity and mortality in patients with hypertension, it is crucial to develop a novel strategy for prevention of hypertension. We have currently reported an attempt at dietary iron intake restriction as non-pharmacological treatment of hypertension in patients with hypertension. However, it remains fully unknown whether dietary iron restriction prevents the development of hypertension. We investigated the influence of dietary iron restriction on the development of hypertension in weanling pre-hypertensive model rats. 3-week-old male stroke-prone spontaneously hypertensive rats (SHR-SP) were randomly divided into two groups and were given an ad libitum normal diet or an iron-restricted diet for 12 weeks. Blood pressure was progressively increased in SHR-SP according to growth, while dietary iron restriction attenuated the development of hypertension. Proteinuria was also increased in SHR-SP according to growth, whereas dietary iron restriction suppressed the increment of proteinuria. SHR-SP exhibited glomerulosclerosis and exacerbated renal interstitial fibrosis at 15 weeks old, indicating that SHR-SP developed hypertensive nephropathy in the adult stage; however, these changes were attenuated by dietary iron restriction. Gelatin zymography showed dietary iron restriction decreased both renal MMP-2 and MMP-9 activities in SHR-SP at 15 weeks old. Of interest, dietary iron restriction suppressed renal TGFß-RI expression and Smad2 phosphorylation in SHR-SP. Furthermore, dietary iron restriction decreased renal fibrosis, renal MMP-2 and MMP-9 activities, renal TGFß-RI expression, and Smad2 phosphorylation in rats with unilateral ureteral obstruction. Dietary iron restriction prevented the development of hypertension in weanling pre-hypertensive rats.

Exercise hypoxaemia as a predictor of pulmonary hypertension in COPD patients without severe resting hypoxaemia.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) in COPD is associated with morbidity and mortality. Previous studies showed a relationship between resting hypoxaemia and PH, but little is known about the relationship between exercise hypoxaemia and PH in COPD without resting hypoxaemia. METHODS: A retrospective observational study of COPD patients without resting hypoxaemia was conducted to evaluate the relationships between exercise hypoxaemia and pulmonary haemodynamics. Clinical characteristics, pulmonary function, blood gas analysis, 6-min walk distance (6MWD) and oxygen saturation of peripheral artery (SpO2 ) at the end of the 6-min walk test (6MWT) were reviewed. Correlation analysis and stepwise regression analysis were performed to identify the predictor of mean pulmonary artery pressure (mPAP). RESULTS: Eighty-four consecutive patients with a mean predicted forced expiratory volume in 1 s (FEV1 ) of 47 ± 21% were evaluated. In univariate analysis, mPAP had negative correlations with age (r = -0.27, P < 0.05), arterial partial pressure of oxygen (PaO2 , r = -0.24, P < 0.05), % predicted forced vital capacity (FVC, r = -0.28, P < 0.05), % predicted FEV1 (r = -0.40, P < 0.001), FEV1 /FVC ratio (r = -0.33, P < 0.005), % predicted diffusion capacity for carbon monoxide (DLCO , r = -0.40, P < 0.001), 6MWD (r = -0.40, P < 0.001) and SpO2 at the end of the 6MWT (r = -0.74, P < 0.001). In stepwise regression analysis, SpO2 at the end of the 6MWT and 6MWD remained as independent predictors of mPAP (R2 = 0.60). In receiver operating characteristic (ROC) analysis, SpO2 at the end of the 6MWT presented an area under the curve of 0.896 for the prediction of PH, with a sensitivity of 0.86 and specificity of 0.84 for the cut-off point of 81%. CONCLUSION: In addition to 6MWD, exercise hypoxaemia indicates PH in patients with COPD without resting hypoxaemia.

Comparison of salt with low-dose furosemide and carperitide for treating acute decompensated heart failure: a single-center retrospective cohort study.

Hypertonic saline with furosemide has been proposed for a long time as an effective therapeutic option for the treatment of acute decompensated heart failure (ADHF). We previously reported the efficacy of continuous infusion of 1.7 % hypertonic saline plus low-dose furosemide in treatment for ADHF. Although this therapeutic strategy can be a useful option for effective decongestion in treatment for ADHF, there is no study that assesses the effect and safety of saline supplementation compared with standard therapy in Japan. The aim of this study was to investigate the efficacy, safety, and cost-effectiveness of 1.7 % hypertonic saline plus low-dose furosemide infusion compared with carperitide. We compared clinical outcomes, adverse events, and cost for patients receiving carperitide (carperitide group) with those for patients receiving 1.7 % hypertonic saline plus low-dose furosemide (salt group) during the initial hospitalization for ADHF. The cost analysis was performed on the basis of the previous report about cost-effectiveness of acute heart failure. A total of 175 ADHF patients received either carperitide (n = 111) or 1.7 % hypertonic saline plus low-dose furosemide infusion (n = 64) as initial treatment. There were no differences in length of hospital stay (27 ± 19 vs. 25 ± 16 day, p = 0.170) and infusion period (7.2 ± 6.1 vs. 8.4 ± 7.5 day, p = 0.474) between the two groups. The incidence of rehospitalization did not differ at 1 month (7.6 vs. 6.6 %, p = 1.000) and 1 year (36.8 vs. 37.7 %, p = 0.907) between the two groups. The Kaplan-Meier curves revealed no significant difference for 1 year all-cause mortality between the two groups (log-rank, p = 0.724). The single hospitalization cost was 95,314 yen lower and the yearly hospitalization cost 125,628 yen lower in the salt group compared with the carperitide group. Thus, intravenous 1.7 % hypertonic saline plus low-dose furosemide infusion is as effective as carperitide in terms of clinical outcome and is a cost-effective therapeutic strategy for the treatment of ADHF.

Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome.

The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

Iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice.

Several recent observations provide the association of iron deficiency with pulmonary hypertension (PH) in human and animal studies. However, it remains completely unknown whether PH leads to iron deficiency or iron deficiency enhances the development of PH. In addition, it is obscure whether iron is associated with the development of pulmonary vascular remodeling in PH. In this study, we investigate the impacts of dietary iron restriction on the development of hypoxia-induced pulmonary vascular remodeling in mice. Eight- to ten-week-old male C57BL/6J mice were exposed to chronic hypoxia for 4 weeks. Mice exposed to hypoxia were randomly divided into two groups and were given a normal diet or an iron-restricted diet. Mice maintained in room air served as normoxic controls. Chronic hypoxia induced pulmonary vascular remodeling, while iron restriction led a modest attenuation of this change. In addition, chronic hypoxia exhibited increased RV systolic pressure, which was attenuated by iron restriction. Moreover, the increase in RV cardiomyocyte cross-sectional area and RV interstitial fibrosis was observed in mice exposed to chronic hypoxia. In contrast, iron restriction suppressed these changes. Consistent with these changes, RV weight to left ventricular + interventricular septum weight ratio was increased in mice exposed to chronic hypoxia, while this increment was inhibited by iron restriction. Taken together, these results suggest that iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice.

Association of dietary iron restriction with left ventricular remodeling after myocardial infarction in mice.

Several epidemiologic studies have reported that body iron status and dietary iron intake are related to an increased risk of acute myocardial infarction (MI). However, it is completely unknown whether dietary iron reduction impacts the development of left ventricular (LV) remodeling after MI. Here, we investigate the effect of dietary iron restriction on the development of LV remodeling after MI in an experimental model. MI was induced in C57BL/6 J mice (9-11 weeks of age) by the permanent ligation of the left anterior descending coronary artery (LAD). At 2 weeks after LAD ligation, mice were randomly divided into two groups and were given a normal diet or an iron-restricted diet for 4 weeks. Sham operation without LAD ligation was also performed as controls. MI mice exhibited increased LV dilatation and impaired LV systolic function that was associated with cardiomyocyte hypertrophy and interstitial fibrosis in the remote area, as compared with the controls at 6 weeks after MI. In contrast, dietary iron restriction attenuated LV dilatation and impaired LV systolic function coupled to cardiomyocyte hypertrophy and interstitial fibrosis in the remote area. Importantly, cardiac expression of cellular iron transport proteins, transferrin receptor 1 and divalent metal transporter 1 was increased in the remote area of MI mice compared with the controls. Dietary iron restriction attenuated the development of LV remodeling after MI in mice. Cellular iron transport might play a role in the pathophysiological mechanism of LV remodeling after MI.

Japan PGx Data Science Consortium Database: SNPs and HLA genotype data from 2994 Japanese healthy individuals for pharmacogenomics studies.

Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing.