Association between reduced left ventricular ejection fraction and peritoneal dialysis related peritonitis: a single center retrospective cohort study in Japan.

We present a single-center retrospective analysis of 228 Japanese patients with peritoneal dialysis, in which we examined whether reduced left ventricular ejection fraction (LVEF) is a risk factor for peritonitis development. Time-dependent multivariable-adjusted Cox proportional hazards models revealed that reduced LVEF (LVEF < 50% vs. preserved LVEF ≥ 50%, hazard ratio (HR) 2.10; 95% confidence interval (CI) 1.16-3.82) was associated with peritonitis. Qualitatively, similar associations with reduced LVEF (< 50%) were observed for enteric peritonitis (adjusted HR 7.68; 95% CI 2.51-23.5) but not for non-enteric peritonitis (adjusted HR 1.15; 95% CI 0.54-2.44). Reduced LVEF is associated with a significantly higher risk of subsequent peritonitis, particularly enteric peritonitis. These results indicate that patients with reduced LVEF may be at risk of enteric peritonitis from bowel sources caused by intestinal involvement due to cardiac dysfunction.

Pre-treatment hematuria and crescents predict estimated glomerular filtration rate trajectory after methylprednisolone pulse therapy with tonsillectomy for IgA nephropathy.

BACKGROUND: Glomerular hematuria and proteinuria are typical manifestations of IgA nephropathy (IgAN). However, hematuria severity is not considered a useful marker of the potential benefits of corticosteroid administration as proteinuria severity only is included in the current guidelines. METHODS: In this retrospective cohort study, we enrolled 133 patients diagnosed with IgAN through biopsy. We calculated the 2-year estimated glomerular filtration rate (eGFR) slope (mL/min/1.73m2/year) and eGFR trajectory after methylprednisolone pulse therapy using mixed effects models stratified by the Oxford classification and three categories of pre-treatment hematuria: mild [urinary red blood cells (URBCs) < 10/high-power field (HPF)], moderate (URBCs 10-30/HPF), and severe (URBCs ≥ 30/HPF). RESULTS: The severe pre-treatment hematuria group showed a significantly higher likelihood of having crescents (odds ratio (OR), 4.3; 95% confidence interval (CI), 1.7-10.9). In the longitudinal analysis of 103 patients, most of whom underwent tonsillectomy, the severe pre-treatment hematuria group had a significantly higher 2-year eGFR slope after methylprednisolone pulse therapy than the mild and moderate hematuria groups (mild, -0.52 ± 1.97; moderate, -0.32 ± 1.99; severe, 1.44 ± 3.20 mL/min/1.73m2/year). Patients with C2 scores showed a significantly higher 2-year eGFR slope after methylprednisolone pulse therapy than those with C0 and C1 scores (C0, -0.38 ± 1.74; C1, 0.81 ± 3.02; C2, 3.29 ± 3.68 mL/min/1.73m2/year). Analyses of eGFR trajectory after methylprednisolone pulse therapy revealed that the eGFR improved only in patients with severe pre-treatment hematuria or C2 score (Pinteraction with time < 0.001). CONCLUSIONS: The eGFR is likely to improve after methylprednisolone pulse therapy with tonsillectomy in IgAN patients with severe pre-treatment hematuria or a high percentage of crescents.

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients.

Peritonitis is a major and the most significant complication of peritoneal dialysis (PD). Although some predictors of peritonitis in PD patients are known, the association between proton pump inhibitor (PPI) use and peritonitis has not been characterized. Here, we examined whether PPI use is a risk factor for the development of peritonitis, based on a single-center retrospective analysis of 230 consecutive Japanese PD patients at Narita Memorial Hospital. We assessed the association between PPI use and subsequent first episode of peritonitis using multivariate Cox proportional hazards models, following adjustment for clinically relevant factors. The median follow-up period was 36 months (interquartile range, 19-57 months). In total, 86 patients (37.4%) developed peritonitis. Analysis with multivariate Cox proportional hazards models revealed the following significant predictors of peritonitis: PPI use (adjusted hazard ratio [HR] = 1.72, 95% confidence interval [CI]: 1.11-2.66; P = 0.016) and low serum albumin level (per g/dl adjusted HR = 0.59, 95% CI: 0.39-0.90; P = 0.014). Thus, PPI use was independently associated with PD-related peritonitis. The results suggest that nephrology physicians should exercise caution when prescribing PPIs for PD patients.

Optimal Experimental Condition of IR pMAIRS Calibrated by Using an Optically Isotropic Thin Film Exhibiting the Berreman Effect.

Infrared (IR) p-polarized multiple-angle incidence resolution spectrometry (pMAIRS) is a useful spectroscopic tool for revealing the molecular anisotropic structure in a thin film, which is used for the molecular orientation analysis of many functionalized organic thin films. Infrared pMAIRS provides both in-plane (IP) and out-of-plane (OP) vibrational mode spectra, which are influenced by the choice of the angles of incidence, i.e., angle set. To obtain quantitatively reliable pMAIRS spectra, therefore, the optimal angle set must be revealed. In a former study, an optimization study was carried out on a silicon substrate by using the band intensity ratio of the IP and OP spectra of highly oriented molecules in a thin film, which has a problem that the optimized results cannot be used for another substrate. In the present study, a totally new idea using an optically isotropic thin film as a standard sample is proposed to comprehensively explore the optimal angle set on various substrates: the band shift due to the Berreman effect of a strongly absorbing compound is used, instead of the band intensity. This new approach makes the pMAIRS calibration for various substrates a much easier task. With the optimal angle set, the molecular orientation angle in the film calculated by the pMAIRS spectra is also found to be reliable quantitatively. This technique opens a user-friendly way to a reliable molecular orientation analysis in an ultrathin film using IR pMAIRS.

Postcardiac injury syndrome following vascular interventional radiofrequency ablation for paroxysmal atrial fibrillation.

Postcardiac injury syndrome (PCIS) occurs following a pericardial or myocardial injury. On the other hand, PCIS following cardiac catheter intervention is rare and can be difficult to diagnose because of its delayed onset. A 24-year-old man underwent radiofrequency ablation (RFA) for paroxysmal atrial fibrillation and suffered from general fatigue and left-sided pleural effusion three months after the procedure. His symptoms and effusion were effectively treated within a month by administrating nonsteroidal anti-inflammatory drugs. However, seven months later, he developed left-sided chest pain and low-grade fever. Computed tomography showed a thickening of the parietal pleura and reccurence of the pleural effusion. Pleural biopsy by video-assisted thoracoscopy demonstrated chronic pleuritis with a non-necrotizing granulomatous reaction. Given the previous RFA, and in the absence of infection or malignant disease, he was diagnosed with PCIS and treated with colchicine.

Effect of zinc supplementation on bone formation in hemodialysis patients with normal or low turnover bone.

Zinc (Zn) is an essential trace element, which has been shown to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption in vitro. In thalassemia, major patients Zn supplementation was reported to increase whole-body bone mineral content and areal bone mineral density. Therefore, we investigated the effect of Zn supplementation on bone formation in hemodialysis (HD) patients. Nine male patients with age of 66 (35-78) years indicated by median (range), HD vintage of 57 (4-97) months and serum intact parathyroid hormone (PTH) of 113 (6-310) pg/mL were supplemented with polaprezinc containing 34 mg Zn/day for 18 months. Doses of vitamin D were not changed during supplementation. Blood was collected at baseline, 3, 6, 12 and 18 months. Serum Zn increased significantly from 58 (52-65) µg/dL to 71 (57-93) µg/dL at three months and remained unchanged until 18 months. No changes were observed in serum intact PTH during supplementation. Although we found no changes in serum bone alkaline phosphatase (BAP) during Zn supplementation analyzed by Friedman test and Scheffe post hoc test, a significant trend of increase in serum BAP was verified by Jonckheere-Terpstra test (p = 0.0409). On the contrary, there was no trend in serum TRACP5b by Jonckheere-Terpstra test. Therefore, we suggested the effect of Zn supplementation on promoting bone formation, not affected by the status of PTH and vitamin D, in HD patients with normal or low turnover bone.

Strategies for the creation and maintenance of reconstructed arteriovenous fistulas using the forearm basilic vein.

Reconstruction of an arteriovenous fistula (AVF) after an initial failure to provide long-term patency has been desired in the era when hemodialysis patients' prognosis is improving. The forearm basilic vein AVF should be considered, before an artificial graft shunt or an AVF in the cubital region. The present study was designed to establish a strategy for the creation and maintenance of AVFs using the forearm basilic vein. This study reviewed 76 cases of reconstructed AVF including 18 cases using the basilic vein (23.7% of total cases). The following four points were considered: arm positioning of the cubital flexion position combined with the forearm supinated position; several small skin incisions with a subcutaneous tunnel; sufficient venous dilatation using Fogarty balloon catheter; and early percutaneous angioplasty introduction for immature AVF. The primary and secondary patency rates were examined. A radiobasilic AVF was created through a subcutaneous tunnel in two cases. The primary and secondary patency rates of AVF with the basilic vein were 54.7% and 76.7% respectively, whereas those of AVF with the cephalic vein were 49.3% and 71.3%. The basilic was not inferior to the cephalic vein (P-value of the log-rank test for primary and secondary patency rates were 0.927 and 0.811, respectively). Early stage percutaneous angioplasty was effective in five cases with immature AVF. The forearm basilic vein was useful in AVF reconstruction and equivalent to radiocephalic reconstruction. Careful observation and percutaneous angioplasty during the early period after the surgery were essential for long-term patency.

Impact of culprit plaque volume and composition on myocardial microcirculation following primary angioplasty in patients with ST-segment elevation myocardial infarction: virtual histology intravascular ultrasound analysis.

BACKGROUND: An impaired myocardial perfusion state after primary angioplasty is a strong predictor of long-term adverse outcomes in patients with STEMI. We assessed the relationship between culprit plaque characteristics and myocardial perfusion state after primary angioplasty in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 101 consecutive patients with de novo STEMI were divided into 3 groups according to the state of myocardial perfusion assessed by ST-segment elevation resolution (STR): Group A (complete: STR ≥ 70%, n=26), Group B (partial: STR<70% but ≥ 30%, n=55) and Group C (none: STR<30%, n=20). We analyzed plaque features by virtual histology intravascular ultrasound (VH-IVUS) and assessed the relationship between culprit plaque characteristics and STR after primary angioplasty. RESULTS: Total plaque volume was significantly higher in Group C than in Groups A and B (146.4 ± 38.0 mm(3)vs. 93.3 ± 29.1 mm(3) and 105.8 ± 31.5 mm(3), p<0.001, respectively). Necrotic core (NC) volume was also significantly higher in Group C than in Groups A and B (25.4 ± 8.0m m(3), vs. 11.9 ± 6.3 mm(3) and 17.3 ± 9.7 mm(3), p<0.001, respectively). Analysis of receiver-operating characteristic curves revealed that total plaque volume and NC volume had the best diagnostic accuracy of all the VH-IVUS parameters to predict STR<30%. The optimal cutoff values (sensitivity/specificity) were 123.4 mm(3) (75.0%/75.3%) for total plaque volume and 20.3mm(3) (75.0%/74.1%) for NC volume. CONCLUSIONS: Culprit plaque with large plaque burden and high NC volume is closely associated with poor STR after revascularization.

A case of idiopathic ventricular fibrillation in which implanted loop recorder was useful in application decision for implantation of implantable cardioverter-defibrillator.

Establishing a symptom-rhythm correlation in patients with unexplained syncope is complicated because of its sporadic, infrequent, and unpredictable nature. Recently, an implantable loop recorder (ILR) has become available to evaluate undiagnosed recurrent arrhythmic episodes particularly in unexplained syncopes, and its usefulness has been reported in patients with recurrent syncopes that remain unexplained after conventional work-up. A 65-year-old man was referred to our hospital for loss of consciousness with nocturnal paroxysmal seizures. He had experienced several similar episodes. No family history of sudden death was evident, and apparent structural heart disease was absent. Coronary angiography with intracoronary ergonovine provocation showed vasospasm in left coronary artery without organic stenosis. Ventricular tachyarrhythmias were not induced by programmed electrical stimuli. According to the guideline, he was at once categorized as having class IIb indication for implantable cardioverter defibrillator implantation. However, his symptoms were not relieved despite administration of anti-anginal medications including nitrates and calcium antagonist. Implantation of an ILR was performed and revealed an episode of ventricular fibrillation during generalized-convulsion attack during sleep. ILR is useful in determining the presence of fatal arrhythmias during syncope, although conventional diagnostic testing, such as electrocardiogram, Holter monitoring, and external loop recording, is inconclusive.

Etv2/ER71 induces vascular mesoderm from Flk1+PDGFRα+ primitive mesoderm.

Etv2 (Ets Variant 2) has been shown to be an indispensable gene for the development of hematopoietic cells (HPCs)/endothelial cells (ECs). However, how Etv2 specifies the mesoderm-generating HPCs/ECs remains incompletely understood. In embryonic stem cell (ESC) differentiation culture and Etv2-null embryos, we show that Etv2 is dispensable for generating primitive Flk-1(+)/PDGFRα(+) mesoderm but is required for the progression of Flk-1(+)/PDGFRα(+) cells into vascular/hematopoietic mesoderm. Etv2-null ESCs and embryonic cells were arrested as Flk-1(+)/PDGFRα(+) and failed to generate Flk-1(+)/PDGFRα(-) mesoderm. Flk-1(+)/Etv2(+) early embryonic cells showed significantly higher hemato-endothelial potential than the Flk-1(+)/Etv2(-) population, suggesting that Etv2 specifies a hemato-endothelial subset of Flk-1(+) mesoderm. Critical hemato-endothelial genes were severely down-regulated in Etv2-null Flk-1(+) cells. Among those genes Scl, Fli1, and GATA2 were expressed simultaneously with Etv2 in early embryos and seemed to be critical targets. Etv2 reexpression in Etv2-null cells restored the development of CD41(+), CD45(+), and VE-cadherin(+) cells. Expression of Scl or Fli1 alone could also restore HPCs/ECs in the Etv2-null background, indicating that these 2 genes are critical downstream targets. Furthermore, VEGF induced Etv2 potently and rapidly in Flk-1(+) mesoderm. We propose that Flk-1(+)/PDGFRα(+) primitive mesoderm is committed into Flk-1(+)/PDGFRα(-) vascular mesoderm through Etv2 and that up-regulation of Etv2 by VEGF promotes this commitment.

Cavity volume of ruptured plaque is an independent predictor for angiographic no-reflow phenomenon during primary angioplasty in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Plaque rupture plays a critical role for the development of acute myocardial infarction. However, whether quantitative parameters with regard to the cavity size of ruptured plaque are associated with no-reflow (NR) phenomenon following primary angioplasty remains to be elucidated. METHODS AND RESULTS: A total of 53 patients with de novo ST-elevation myocardial infarction (STEMI) who had plaque rupture at the culprit lesion defined by pre-intervention virtual histology intravascular ultrasound (VH-IVUS) were enrolled. Patients were divided into two groups according to the presence of NR phenomenon: NR group (n=19) and non-NR group (n = 34). By VH-IVUS, we evaluated cavity length, maximum area, and volume of ruptured plaque in culprit lesions. The cavity length, maximum area, and volume were significantly higher in the NR group than those of the non-NR group (4.8 ± 2.1 mm vs. 2.9 ± 4.8 mm, p < 0.001; 3.6 ± 1.4 mm² vs. 1.9 ± 0.5 mm², p < 0.001; 11.5 ± 6.3 mm³ vs. 3.7 ± 2.2 cm³, p < 0.001). A multiple logistic regression analysis revealed that the cavity volume was an independent risk for NR phenomenon. Receiver-operating characteristic analysis revealed that the cavity volume could predict NR phenomenon. CONCLUSIONS: The cavity size of ruptured plaque is closely associated with NR phenomenon in patients with STEMI. Evaluation of the cavity volume by VH-IVUS may provide useful information for the prediction of NR phenomenon.

[Relationship between coronary and abdominal calcification score, serum osteoprotegerin (OPG), and serum tartrate-resistant acid phosphatase (TRACP) -5b in pre-dialysis CKD patients].

Osteoprotegerin (OPG) inhibits interaction of the receptor-activator of nuclear factor-kappaB (RANK) ligand (RANKL) with its receptor RANK, which is expressed on osteoclasts. OPG appeared to accelerate vascular calcification in vitro by the inhibition of vascular osteoclast-like cells. On the contrary, early-onset arterial calcification was observed in OPG-deficient mice. We measured the coronary artery calcification score (CACS) and abdominal aortic calcification score (AAoCS) by multi-detector computed tomography in 30 pre-dialysis CKD patients (eGFR 20 mL/min on average). Biomarkers were measured, including serum OPG, soluble RANKL (sRANKL) and tartrate-resistant acid phosphatase (TRACP) -5b (the biomarker of osteoclasts independent of renal function). The median values of CACS and AAoCS were 54.4 and 1,088 Agatston units (AU), respectively. Serum OPG was increased and serum sRANKL was decreased. In a multivariate logistic regression analysis using CACS > or = 100 AU as the outcome variable, CACS was found to be positively correlated with serum corrected Ca x iP product and serum OPG, though it was not correlated with serum TRACP-5b. ROC curve analysis showed that the serum OPG cutoff value predicting CACS > or = 100 AU was 5.2 pmol/L (624 pg/mL). In a stepwise regression analysis, log (AAoCS + 1) was positively correlated with serum OPG alone, but it was not correlated with age, eGFR, serum albumin and bone alkaline phosphatase (BAP). No correlation was found between serum OPG and serum TRACP-5b. In conclusion, vascular calcification in pre-dialysis CKD patients was correlated with an increase in OPG, but was independent of serum TRACP-5b. The decrease in serum sRANKL may have been caused by the increase in OPG production.

Relationship between plaque composition and no-reflow phenomenon following primary angioplasty in patients with ST-segment elevation myocardial infarction--analysis with virtual histology intravascular ultrasound.

BACKGROUND: The angiographic no-reflow phenomenon after primary percutaneous coronary intervention (PCI) carries a poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). However, the type of plaque composition that associates with the angiographic no-reflow phenomenon remains unclear. METHODS: A total of 44 patients with STEMI were enrolled in this study. After thrombectomy with an aspiration catheter, virtual histology intravascular ultrasound (VH-IVUS) of the infarct-related vessel was performed. Patients were divided into two groups according to final thrombolysis in myocardial infarction (TIMI) flow grade at the completion of PCI procedure. Complete reperfusion group (CR-group) was defined as final TIMI flow grade 3, and no-reflow group (NR-group) was defined as final TIMI flow < or = 2. The relationship between plaque composition and angiographic no-reflow phenomenon was analyzed. RESULTS: The angiographic no-reflow phenomenon was observed in 20 individuals. The summation of the percentage of fibrofatty+necrotic core and fibrofatty+dense calcium was significantly higher in the NR-group. Receiver-operating characteristics analysis revealed that the summation of the volume and percentage of fibrofatty+necrotic core (> 20.1 mm(3), 26.2%) and fibrofatty+dense calcium (> 20.0 mm(3), 22.6%) predict the angiographic no-flow phenomenon. CONCLUSION: The fibrofatty-rich component with necrotic core or dense calcium derived from VH-IVUS is closely related to the angiographic no-reflow phenomenon observed in primary PCI.

[A 78-year-old man with unruptured aneurysm of Valsalva found accidentally by syncope during straining].

A 78-year-old man who suffered from syncope and light-headedness during straining. The patient visited to our department for evaluation of his symptom. Cardiac auscultation revealed a grade II/IV systolic murmur along the left parasternal border. Electrocardiography showed T wave inversion at the right precordial leads. Echocardiography demonstrated an unruptured aneurysm originating at the sinus of Valsalva protruding into the right ventricular outflow tract. Cardiac cathtererization demonstrated a pressure gradient of 34 mmHg between the right ventricular cavity and pulmonary artery with a large aneurysm originating from the right coronary cusp. Because of his low activity of daily living owing to old cerebral infarction, we managed the patient conservatively.

Multiple mesoderm subsets give rise to endothelial cells, whereas hematopoietic cells are differentiated only from a restricted subset in embryonic stem cell differentiation culture.

In the developing mouse, vascular endothelial cell (EC) and hematopoietic cell (HPC) lineages are two initial cell lineages that diverge from mesodermal cells, which have been roughly subdivided into three subtypes according to their geographical location: the organizer, embryonic mesoderm in the primitive streak, and extraembryonic mesoderm during gastrulation. Although the initial progenitors that become the two lineages appear in both vascular endothelial growth factor receptor 2(+) (VEGFR2(+)) lateral and extraembryonic mesoderm, little is known about the underlying molecular events that regulate the derivation of ECs and HPCs. Here, we describe an experimental system consisting of two types of embryonic stem cell lines capable of distinguishing between organizer and the middle section of the primitive streak region. Using this system, we were able to establish a defined culture condition that can separately induce distinct types of mesoderm. Although we were able to differentiate ECs from all mesoderm subsets, however, the potential of HPCs was restricted to the VEGFR2(+) cells derived from primitive streak-type mesodermal cells. We also show that the culture condition for the progenitors of primitive erythrocytes is separated from that for the progenitors of definitive erythrocytes. These results suggest the dominant role of extrinsic regulation during diversification of mesoderm.

Dissecting the molecular hierarchy for mesendoderm differentiation through a combination of embryonic stem cell culture and RNA interference.

Although there is a criticism that embryonic stem (ES) cell differentiation does not always reflect the differentiation process involved in mouse development, it is a suitable model system to dissect the specific differentiation pathway. We established the culture conditions that selectively differentiated mouse ES cells into three germ layers containing mesendoderm, definitive endoderm (DE), visceral endoderm (VE), mesoderm, and neuroectoderm. However, the molecular mechanisms of differentiation under each specific condition still remain unclear. Here, in combination with the RNA interference-mediated gene knockdown (KD) method, we show that Eomesodermin (Eomes), Mixl1, Brachyury (T), and GATA6 are major molecular determinants in the differentiation of mesendoderm, DE, VE, and mesoderm. Eomes plays a pivotal role in an early stage of mesendoderm differentiation, whereas Mixl1 does the same in the later stage where mesendoderm differentiates into DE. Further analyses of quantitative reverse transcription polymerase chain reaction and overexpression of Mixl1 demonstrated that Mixl1 is genetically a downstream molecule of Eomes. In addition, both Eomes and Mixl1 act as negative regulators of T expression. This strategy also reveals that Eomes and T play cell-autonomous roles in platelet-derived growth factor receptor alpha (PDGFRalpha)+ vascular endothelial growth factor receptor 2 (VEGFR2)+ and PDGFRalpha+ mesoderm generations, respectively. Our results obtained from this study are fully consistent with previous knockout studies of those genes. The present study, therefore, demonstrates that the major molecular mechanism underlying in vitro ES cell differentiation largely recapitulates that in actual embryogenesis, and the combination of our culture system and RNAi-mediated gene KD is an useful tool to elucidate the molecular hierarchy in in vitro ES cell differentiation. Disclosure of potential conflicts of interest is found at the end of this article.