Associations of time-dependent changes in phosphorus levels with cardiovascular diseases in patients undergoing hemodialysis: results from the Japan Dialysis Active Vitamin D (J-DAVID) randomized clinical trial.

Background: While the risk of exceeding the standard range of phosphorus levels has been investigated, the impact of the degree of fluctuations has not been investigated. Methods: Data were derived from the Japan Dialysis Active Vitamin D trial, a 4-year prospective, randomized study involving 976 patients without secondary hyperparathyroidism undergoing hemodialysis in Japan. Laboratory data were collected every 6 months and the primary outcome was the time to the occurrence of cardiovascular events. The effect of time-dependent changes in phosphorus levels was assessed using a time-varying Cox proportional hazards regression model. Results: The median serum phosphorus levels at baseline and at the final observation were 4.70 mg/dl [interquartile range (IQR) 3.90-5.30] and 5.00 mg/dl (IQR 4.20-5.80), respectively. Over each 6-month period, phosphorus changes ranged from -7.1 to +6.7 mg/dl, with a median value of -0.1 to +0.3 mg/dl. During follow-up, composite cardiovascular events occurred in 103 of 964 patients. Although the P-value for the interaction between serum phosphorus level fluctuations and baseline phosphorus levels was insignificant, the following trends were observed. First, patients with relatively high initial phosphorus levels over a 6-month period showed a trend towards a higher hazard, with greater changes in the phosphorus level over the 6-month period. Second, it was suggested that oral vitamin D receptor activators could contribute to the relationship between fluctuating phosphorus levels and cardiovascular events. Conclusions: Our results suggest the importance of maintaining stable phosphorus levels, not only in the normal range, but also without fluctuations, in the risk of cardiovascular events among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis.

Effects of alfacalcidol on cardiovascular outcomes according to alkaline phosphatase levels in the J-DAVID trial.

In the Japan Dialysis Active Vitamin D (J-DAVID) trial, oral alfacalcidol numerically, but not significantly, increased the risk of cardiovascular events among patients undergoing hemodialysis. Because the cardiovascular effect of alfacalcidol could be modulated by bone turnover status, this post-hoc analysis of the J-DAVID examined how alkaline phosphatase (ALP), a more precise marker of bone turnover than parathyroid hormone (PTH), modifies the impact of alfacalcidol. The J-DAVID was a 48-month, open-label, randomized controlled trial comparing oral alfacalcidol with no vitamin D receptor activators use in terms of cardiovascular events among 976 hemodialysis patients without secondary hyperparathyroidism. This post-hoc analysis included 959 patients with available data on baseline ALP. The median [25-75th percentile] baseline ALP level was 234 [183-296] U/L. In a Cox proportional hazards model, ALP did not significantly modify the effect of alfacalcidol on the rate of cardiovascular events or all-cause death (P for effect modification = 0.54 and 0.74, respectively). The effect of alfacalcidol on time-series changes in calcium, phosphate, and intact PTH were similar across ALP subgroups. In conclusion, oral alfacalcidol did not significantly affect cardiovascular outcomes irrespective of bone turnover status.

Effects of Polymorphisms in the Serotonin Transporter Promoter-Linked Polymorphic Region on Postthoracotomy Pain Severity.

PURPOSE: Serotonin (5-HT) is highly associated with pain modulation. The human 5-HT transporter (5-HTT) gene (SLC6A4) features several polymorphisms in its promoter region (5-HTTLPR) that affect the 5-HTT expression. The S allele of 5-HTTLPR induces low 5-HT tone, and it may influence the modulation of chronic pain. Meanwhile, pain occurs in 40-50% of patients after thoracic surgery, and its mechanism remains under investigation. This study assessed the role of 5-HTTLPR polymorphisms in postthoracotomy pain severity. PATIENTS AND METHODS: A total of 178 patients undergoing pneumonectomy were enrolled. The genotypes of 5-HTTLPR were divided into two groups: S/S group and S/L or L/L group. Linear mixed-effects models were used to assess the association between 5-HTTLPR genotypes and the numerical rating scale (NRS) score change over time. RESULTS: Among the participants, data were obtained for 162 patients. The genotype distribution was as follows: S/S, 67.3%; S/L or L/L, 32.7%. No significant difference in patient characteristics was found between the genotype groups. There was no significant interaction between the 5-HTTLPR genotypes and the NRS score change over time (p = 0.842). CONCLUSION: Polymorphisms in 5-HTTLPR were not associated with postthoracotomy pain severity.

Uric acid shown to contribute to increased oxidative stress level independent of xanthine oxidoreductase activity in MedCity21 health examination registry.

Uric acid has both antioxidant and pro-oxidant properties in vitro by scavenging and production of reactive oxygen species (ROS). This cross-sectional study examined whether uric acid possesses effects on oxidative stress under physiological conditions independent of xanthine oxidoreductase (XOR), which is involved in uric acid and ROS production. Serum uric acid level was measured, while plasma XOR activity was determined using our high-sensitive assay in 192 participants (91 males, 101 females) who underwent health examinations and were not taking an antihyperuricemic agent. For antioxidant potential and oxidative stress level, biological antioxidant potential (BAP) and derivative of reactive oxygen metabolites (d-ROMs) in serum, respectively, were measured. Median uric acid level and plasma XOR activity were 5.6 mg/dL and 26.1 pmol/h/mL, respectively, and BAP and d-ROMs levels were 2112.8 µmol/L and 305.5 Carr U, respectively. Multivariable regression analyses revealed no significant association of serum uric acid level with BAP level, whereas serum uric acid level showed a significant association with d-ROMs level independent of plasma XOR activity (p = 0.045), which was prominent in females (p = 0.036; p for interaction = 0.148). Uric acid might contribute to increased oxidative stress independent of XOR activity by increasing ROS production, without affecting ROS scavenging, especially in females.

Effectiveness of rotavirus vaccines against hospitalisations in Japan.

BACKGROUND: In Japan, rotavirus hospitalisation occurs at a rate from 2.8 to 13.7 per 1000 child-years among children age less than 5 years, and it imposes a substantial burden to the healthcare system in the country. While both monovalent (RV1) and pentavalent (RV5) rotavirus vaccines are licensed in Japan, neither has been incorporated in the national infant immunization programme. In this study, we estimated vaccine effectiveness (VE) in Japan. METHODS: This study was conducted in Yuri-Kumiai General Hospital located in a city in the north-western part of Japan. Age-eligible children for rotavirus vaccination were enrolled if they were hospitalized for rotavirus gastroenteritis between September 2013 and August 2016. Rotavirus gastroenteritis was defined by the detection of rotavirus antigen by immunochromatography. "Vaccinated" was defined as infant inoculated with at least one dose of either RV1 or RV5. A conditional logistic regression analysis was performed by modelling the year of birth, year of admission, residence of the children and vaccination status, and by matching the age of cases with that of test-negative controls. The adjusted odds ratio of the vaccinated over unvaccinated was then used to calculate VE in the formula of (1 - adjusted odds ratio) × 100. RESULTS: Out of the 244 patients enrolled, rotavirus antigen was detected in 55 (22.5%) of whom 10 (18.2%) were vaccinated, whereas 94 (49.7%) of 189 test-negative controls were vaccinated. During the study period, the vaccine uptake rate in the controls increased from 36.2% to 61.8%. On the other hand, the vaccination coverage over the three years was 64.2% in Yuri-Honjo city (three quarters of the catchment), and 91.4% in Nikaho city (one quarter of the catchment). The VE was calculated to be 70.4% (95% confidence interval: 36.0-86.4%, P = 0.002). The point estimate of the VE was lower but its 95% confidence interval overlaps those of the efficacies obtained from clinical trials in Japan. CONCLUSION: The rotavirus vaccine was effective in the real-world setting in Japan as in the clinical trials, and the introduction of rotavirus vaccine in the national infant immunization schedule will substantially reduce the number of rotavirus gastroenteritis hospitalisation in Japan.

Common reed accumulates starch in its stem by metabolic adaptation under Cd stress conditions.

In a previous study, we reported that the common reed accumulates water-soluble Cd complexed with an α-glucan-like molecule, and that the synthesis of this molecule is induced in the stem of the common reed under Cd stress. We studied the metabolic background to ensure α-glucan accumulation under the Cd stress conditions that generally inhibit photosynthesis. We found that the common reed maintained an adequate CO2 assimilation rate, tended to allocate more assimilated (11)C to the stem, and accumulated starch granules in its stem under Cd stress conditions. AGPase activity, which is the rate-limiting enzyme for starch synthesis, increased in the stem of common reed grown in the presence of Cd. Starch accumulation in the stem of common reed was not obvious under other excess metal conditions. Common reed may preferentially allocate assimilated carbon as the carbon source for the formation of Cd and α-glucan complexes in its stem followed by prevention of Cd transfer to leaves acting as the photosynthetic organ. These responses may allow the common reed to grow even under severe Cd stress conditions.

Long-term prognosis of patients with Kawasaki disease complicated by giant coronary aneurysms: a single-institution experience.

BACKGROUND: Some patients with Kawasaki disease develop giant coronary aneurysms and coronary stenosis, leading to ischemic heart disease. The aim of this study was to determine the long-term prognosis of patients with Kawasaki disease with giant aneurysms. METHODS AND RESULTS: From our institutional database, 76 patients (57 men and 19 women) who developed giant aneurysms after January 1, 1972, were identified. Information on patient demographics, catheter and surgical interventions, and most recent status was collected from medical charts and patients' contacts. From these data, we calculated the survival rate and cumulative coronary intervention rate. The average age at onset was 2.9±2.9 years, and the median observational period was 19 years. During this period, 7 patients died and 1 patient underwent a heart transplantation, resulting in 95%, 88%, and 88% survival rates at 10, 20, and 30 years after the onset of KD, respectively. On the other hand, catheter and surgical coronary interventions (median, 1 intervention; range, 1 to 7 interventions) were performed to alleviate coronary ischemia in 46 patients (61%) at 1 month to 21 years (mode at 1 month) after onset, resulting in 28%, 43%, and 59% cumulative coronary intervention rates at 5, 15, and 25 years after onset, respectively. CONCLUSIONS: The long-term survival of patients with Kawasaki disease complicated by giant coronary aneurysms is moderately good with multiple catheter and surgical interventions. Further research should focus on the prevention of coronary vascular remodeling and on the indications for and effectiveness of percutaneous and surgical coronary interventions.

Increased plasma type B natriuretic peptide in the acute phase of Kawasaki disease.

BACKGROUND: The aim of this study was to identify possible factors associated with type-B natriuretic peptide (BNP) production in the acute phase of Kawasaki disease (KD). METHODS: Subjects were 54 patients with KD (KD group [KDG]) and 18 age-matched controls (control group [CG]). We evaluated left ventricular function using multi-modal echocardiography and determined blood chemistry including BNP, white blood cell count, C-reactive protein (CRP), and interleukin (IL)-6 in the KDG. We compared echocardiographic parameters between the KDG and the CG and determined the correlation between log (BNP) and echocardiographic parameters, white blood cell count, CRP, and IL-6 in the KDG. RESULTS: The KDG showed high BNP (169.6 ± 529.6 pg/ml) despite preserved left ventricular function indicated by no significant difference in left ventricular ejection fraction (72.2 ± 9.2 vs 71.2 ± 7.8 %), z-score of left ventricular diastolic dimension (0.8 ± 1.3 vs 0.9 ± 0.8 SD), and Tei index (0.29 ± 0.09 vs 0.30 ± 0.06) between the KDG and the CG. However, left ventricular ejection fraction (r =-0.44, P= .001) and left ventricular end-diastolic dimension (r = 0.30, P < .05) significantly correlated with log (BNP). On the other hand, the KDG showed high CRP (89.7 ± 55.6 mg/l) and high IL-6 (242.2 ± 243.5 pg/ml), and CRP (r = 0.60, P < 0.0001) and IL-6 (r = 0.78, P < 0.0001) significantly correlated with log (BNP). Multiple stepwise regression analysis identified IL-6 (r = 0.77, P < 0.0001) most significantly correlated with log (BNP). CONCLUSIONS: In acute KD, BNP significantly increases, despite well-preserved global left ventricular function, and inflammation might be associated with this increased BNP.

Stanford type B aortic dissection associated with pregnancy in patients with Marfan syndrome-A case report and review of the literature.

A 36-year-old female patient known to have Marfan syndrome (MFS) presented with Stanford type B aortic dissection (type B-AD) 3 days after delivery although she had taken oral ß-blocker and underwent prophylactic cesarean section at 34 weeks when she showed 42 mm of the ascending aorta. She was successfully treated medically without further progression of the dissection. A review of the literature revealed an additional 19 patients with MFS who suffered from type B-AD associated with pregnancy. Of 20 patients, 1 (5%) died but the remaining 19 patients were successfully treated either medically (n = 9) or surgically (n = 10). Of 13 patients whose aortic diameter was known, 5 showed <40 mm of the ascending aorta. Pregnancy in MFS can be complicated by type B-AD with a peak around term delivery irrespective of the size of ascending aorta and even with ß-blocker.

Impact of intravenous immunoglobulin infusion on longitudinal left ventricular performance in patients with acute Kawasaki disease of usual course.

PURPOSE: To determine the acute change in cardiac performance after intravenous immunoglobulin infusion (IVIG) in patients with acute Kawasaki disease (KD). MATERIALS AND METHODS: Subjects were 33 patients with KD who were treated with IVIG 2 g/kg and recovered without coronary artery lesion and 27 controls. Subjects underwent combined two-dimensional, Doppler, and tissue Doppler echocardiographic (TDI) studies. In KD, these echocardiographic studies were performed before IVIG, 48 h after IVIG, and in convalescence. Echocardiographic variables were compared between KD and controls as well as among 3 time points in KD. RESULTS: Before IVIG, KD showed significantly higher peak aortic velocity and shorter aortic ejection time as results of tachycardia and significantly lower E' (p<0.04) but significantly higher E/E' (p<0.02). After IVIG, patients with KD became afebrile and showed significantly lower TDI indices such as S', E', and, A' and isovolumic acceleration (IVA) (163+/-56 vs. 208+/-70 cm/s(2), p<0.01) with higher TDI-derived Tei index (0.50+/-0.10 vs. 0.44+/-0.06, p<0.02) than controls. These differences tended to disappear in convalescence. In analysis of repeated measurements, except for hemodynamic changes associated with tachycardia, S' (7.9+/-1.3 vs. 7.0+/-1.1 vs. 7.4+/-0.9 cm/s, p<0.001), IVA (227+/-72 vs. 163+/-56 vs. 180+/-63, p<0.05), and A' (7.7+/-3.0 vs. 5.6+/-1.3 vs. 6.7+/-2.3 cm/s, p<0.001) were significantly different among these time points. CONCLUSIONS: In patients with acute KD with usual course, IVIG induced transient sub-clinical longitudinal left ventricular dysfunction.

Correlation between right ventricular Tei index by tissue Doppler imaging and pulsed Doppler imaging in fetuses.

The aim was to compare the right ventricular (RV) Tei index obtained by the tissue Doppler imaging (TDI) method with that obtained by the pulsed Doppler method in 29 fetuses aged 24-39 weeks (29.9 +/- 4.0 weeks). From pulsed Doppler recordings, the tricuspid closing-to-opening time (a) and RV ejection time (b) were measured. The Tei index determined by the pulsed Doppler method was calculated as (a - b)/b. From TDI recordings, the time interval during diastole (a') and the duration of the systole S-wave (b') were measured. The modified Tei index obtained by TDI was calculated as (a' - b')/b'. The time a' correlated strongly with a (r = 0.90, p < 0.0001). The mean difference between a' and a was 0.3 +/- 5.0 ms. There was also a strong correlation between b' and b (r = 0.94, p < 0.0001). The mean difference between b' and b was 0.5 +/- 3.3 ms. The TDI-Tei index correlated with the pulsed Doppler-Tei index (r = 0.83, p < 0.0001). The mean difference between the TDI-Tei index and the pulsed Doppler-Tei index was -0.003 +/- 0.04. This study demonstrated that the TDI-Tei index correlates well with the Tei index determined by pulsed Doppler in fetuses, suggesting that the TDI-Tei index is a feasible approach to assess global RV function in fetuses.

Usefulness of exercise-induced changes in plasma levels of brain natriuretic peptide in predicting right ventricular contractile reserve after repair of tetralogy of Fallot.

Elevated levels of brain natriuretic peptide (BNP) have been associated with ventricular dysfunction, and exercise tests have been used for assessing cardiac contractile reserve. We examined the relation between BNP and right ventricular (RV) contractile reserve during exercise in patients after repair of tetralogy of Fallot (TOF). A total of 45 patients, 26 of whom underwent repair of TOF at 2 to 3 years of age and 19 age-matched healthy children, were studied. Plasma levels of BNP were measured at baseline and at maximal exercise. Echocardiography combined with tissue Doppler imaging (TDI) was performed at rest and during supine bicycle submaximal exercise. The peak value of the first derivation of RV pressure (peak dP/dt) was measured by the continuous-wave Doppler method. The severity of pulmonary regurgitation (PR) (mild, moderate, or severe) was based on color Doppler findings. Plasma BNP levels were significantly higher in patients with TOF than in controls (44 +/- 34 vs 6 +/- 4 pg/ml, p <0.01). Exercise was associated with increased plasma BNP levels in both groups. A larger increment in BNP was noted in patients with TOF than in normal subjects (15 +/- 12 vs 2 +/- 2 pg/ml, p <0.01). The peak systolic myocardial velocity (Sa) and peak dP/dt values increased significantly in both groups during exercise; however, the magnitude of increase in both of these values was significantly less in patients with TOF than in controls (36 +/- 19% vs 70 +/- 19% and 42 +/- 11% vs 81 +/- 12%, respectively; p <0.01). There were significant correlations between the increment in BNP and changes in Sa and peak dP/dt values (r = -0.67 and -0.53, p <0.01, respectively), and the severity of PR (r = 0.74, p <0.01). Thus, exercise increases plasma levels of BNP, and greater increases are associated with impaired RV contractile reserve in patients with TOF with various degrees of PR.