Functional analysis of Samd11, a retinal photoreceptor PRC1 component, in establishing rod photoreceptor identity.

Establishing correct neuronal cell identity is essential to build intricate neural tissue architecture and acquire precise neural function during vertebrate development. While it is known that transcription factors play important roles in retinal cell differentiation, the contribution of epigenetic factors to establishing cell identity during retinal development remains unclear. We previously reported that Samd7, a rod photoreceptor cell-specific sterile alpha motif (SAM) domain protein, functions as a Polycomb repressive complex 1 component (PRC1) that is essential for establishing rod identity. In the current study, we analyzed a functional role of Samd11, another photoreceptor-enriched SAM-domain protein, in photoreceptor differentiation and maturation. We observed that Samd11 interacts with Phc2 and Samd7, suggesting that Samd11 is a component of PRC1 in photoreceptor cells. We generated Samd11-null allele and established Samd7/11 double knock-out (DKO) mouse. The Samd7/11 DKO retina exhibits shortened photoreceptor outer segments by electron microscopy analysis. Microarray analysis revealed that Samd7/11 DKO up-regulated more retinal genes than Samd7-/- alone, partial functional redundancy of Samd7 and Samd11. Taken together, the current results suggest that Samd7 and Samd11 are PRC1 components and that Samd7 is the major regulator while Samd11 is an accessory factor used for the establishment of precise rod photoreceptor identity.

Resistance to Erythropoiesis-Stimulating Agents in Pre-Dialysis and Post-Dialysis Mortality in Japanese Incident Hemodialysis Patients.

BACKGROUND/AIMS: There is lack of definitive evidence about the association between erythropoiesis-stimulating agent (ESA) responsiveness in the pre-dialysis phase and mortality. Therefore, we conducted a hospital-based, retrospective, cohort study to assess the predictive value of ESA response for prognosis in incident hemodialysis patients. METHODS: A total of 108 patients without preexisting cardiovascular disease who had been started on maintenance hemodialysis were studied. ESA responsiveness just before starting dialysis was estimated using an erythropoietin resistance index (ERI). The endpoint was defined as all-cause death. RESULTS: During a mean follow-up period of 3.1 ± 1.6 years, 18 (17%) patients died. Overall, the multivariate Cox regression analysis revealed that the log-transformed ERI remained an independent predictor of all-cause death after adjustment using a propensity score (hazard ratio 2.25, 95% CI 1.25-4.06). CONCLUSIONS: Among incident hemodialysis patients, hyporesponsiveness to ESA may be associated with mortality.

Biological variation of procalcitonin levels in hemodialysis patients.

BACKGROUND: There is no obvious evidence regarding biological variation of procalcitonin (PCT) levels in hemodialysis (HD) patients without infections. The aim of this study was to determine the within- and between-person biological variation of PCT levels in HD patients without infections. METHODS: A multicenter, prospective, cohort study enrolled 123 HD patients without any signs of infectious disease. Baseline PCT levels were determined pre- and post-HD, and then repeated pre-HD PCT measurements were performed at 2, 4, 8, 12, 16, 20, and 24 weeks after baseline blood-sampling, regardless of the presence or absence of infectious disease. Analytical variation (CVa), the within-person biological variation (CVi), between-person biological variation (CVb), individual index (II), and the reference change value (RCV) were calculated. RESULTS: The mean age was 62.4 years, 76.4% were male, and 32.5% had diabetes. The mean duration of HD was 87 months. The median value for baseline pre-HD PCT was 0.23 ng/mL, which is much higher than the reference level for healthy individuals. PCT levels decreased of 46.6% after a single HD session. CVi was 24.9%, CVb was 54.2%, II was 0.46, and RCV was calculated as 96.4% with 99% probability. CONCLUSIONS: The PCT level was significantly higher in stable HD patients without manifest bacterial infection. CVb was more variable than CVi in HD patients, which indicates that relative change is more important than absolute PCT levels for diagnosing bacterial infection, and doubling or more of the baseline PCT level may imply the presence of a bacterial infection in HD patients.

Usefulness of multidisciplinary care to prevent worsening renal function in chronic kidney disease.

BACKGROUND: Comprehensive education about lifestyle, nutrition, medications and other types of treatment is important to prevent renal dysfunction in patients with chronic kidney disease (CKD). However, the effectiveness of multidisciplinary care on CKD progression has not been evaluated in detail. We aimed to determine whether multidisciplinary care at our hospital could help prevent worsening renal function associated with CKD. METHODS: A total of 150 pre-dialysis CKD outpatients accompanied (n = 68) or not (n = 82) with diabetes mellitus (DM) were enrolled into this study. We assessed annual decreases in estimated glomerular filtration rates (ΔeGFR), and measured systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin (Hb), uric acid (UA), low-density lipoprotein cholesterol (LDL), hemoglobin A1c (HbA1c) values and urinary protein to creatinine ratios (UPCR) 12 months before and after multidisciplinary care. In addition, changes in the number of medications and prescription ratio before and after multidisciplinary care were assessed in 90 patients with CKD who could confirm their prescribed medications. RESULTS: The ΔeGFR significantly improved between before and after multidisciplinary care from - 5.46 to - 0.56 mL/min/1.73 m2/year, respectively. The number of medications and prescription ratio showed no significant changes before and after multidisciplinary care. The ratios of improved ΔeGFR were found in 66.7% of all patients, comprising 63.1% of males and 76.9% of females, 64.8% without DM and 69.4% with DM. Values for UA, LDL, and HbA1c were significantly reduced among patients with improved ΔeGFR. CONCLUSION: Comprehensive multidisciplinary care of outpatients might help prevent worsening renal function among patients with CKD.

Thallium-201 washout rate of stress myocardial perfusion imaging as a predictor of mortality in diabetic kidney disease patients initiating hemodialysis: an observational, follow-up study.

BACKGROUND: Thallium-201 washout rate of stress myocardial perfusion imaging (MPI) has been reported to correlate with coronary flow reserve which is a parameter of myocardial microcirculation. However, the evidence for its use in diabetic kidney disease (DKD) has been lacking, and the association between thallium-201 washout rate and adverse outcomes including death is unknown. Therefore, the present study was conducted to evaluate the predictive ability of thallium-201 washout rate for mortality in DKD patients initiating hemodialysis. METHODS: A total of 96 patients with type 2 diabetes who had been started on maintenance hemodialysis undergoing stress MPI with thallium-201 within 1 year, 72 men and 24 women, with a median age of 67 years, were studied. The endpoint was defined as all-cause death. The Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During the mean follow-up period of 3.4 ± 2.1 years, 18 (18.8%) deaths occurred. Cumulative survival rates during the follow-up period, with thallium-201 washout rate levels in the lowest tertile (3.1-36.2%), the middle tertile (36.5-46.3%), and the highest tertile (46.4-66.2%), were 51.0, 86.5, and 85.3%, respectively. Overall, the multivariate Cox regression analysis revealed that thallium-201 washout rate remained an independent predictor of death after adjusting by confounding variables (HR 0.91, 95% CI 0.85-0.97). CONCLUSIONS: Among DKD patients initiating hemodialysis, thallium-201 washout rate seems to be useful for predicting death.

Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity.

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7-null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7-deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity.

Ick Ciliary Kinase Is Essential for Planar Cell Polarity Formation in Inner Ear Hair Cells and Hearing Function.

Cellular asymmetries play crucial roles in development and organ function. The planar cell polarity (PCP) signaling pathway is involved in the establishment of cellular asymmetry within the plane of a cell sheet. Inner ear sensory hair cells (HCs), which have several rows of staircase-like stereocilia and one kinocilium located at the vertex of the stereocilia protruding from the apical surface of each HC, exhibit a typical form of PCP. Although connections between cilia and PCP signaling in vertebrate development have been reported, their precise nature is not well understood. During inner ear development, several ciliary proteins are known to play a role in PCP formation. In the current study, we investigated a functional role for intestinal cell kinase (Ick), which regulates intraflagellar transport (IFT) at the tip of cilia, in the mouse inner ear. A lack of Ick in the developing inner ear resulted in PCP defects in the cochlea, including misorientation or misshaping of stereocilia and aberrant localization of the kinocilium and basal body in the apical and middle turns, leading to auditory dysfunction. We also observed abnormal ciliary localization of Ift88 in both HCs and supporting cells. Together, our results show that Ick ciliary kinase is essential for PCP formation in inner ear HCs, suggesting that ciliary transport regulation is important for PCP signaling.SIGNIFICANCE STATEMENT The cochlea in the inner ear is the hearing organ. Planar cell polarity (PCP) in hair cells (HCs) in the cochlea is essential for mechanotransduction and refers to the asymmetric structure consisting of stereociliary bundles and the kinocilium on the apical surface of the cell body. We reported previously that a ciliary kinase, Ick, regulates intraflagellar transport (IFT). Here, we found that loss of Ick leads to abnormal localization of the IFT component in kinocilia, PCP defects in HCs, and hearing dysfunction. Our study defines the association of ciliary transport regulation with PCP formation in HCs and hearing function.

Point of care assessment of cardiac troponin T level in CKD patients with chest symptom.

We challenged to identify the cutoff value of cTnT in chronic kidney disease (CKD) patients by point of care assessment way. A single center, prospective cross-sectional study was planned and performed. 201 consecutive patients who were visited emergency room for chest symptoms were enrolled in this study. All patients were performed routine practice for differential diagnosis of chest symptom by cardiologist. Simultaneously, semiquantitative measurement of cTnT was performed using same blood sampling on the blind condition to cardiologists for this study. Study patients were divided into four groups according to the estimated glomerular filtration rate (eGFR), CKD1-2, CKD3, CKD4-5, and CKD5D. Usefulness of semiquantitative measurement for diagnosing ACEs was investigated in each group. 77 (38%) of total patient was diagnosed as acute coronary events (ACEs). About 50% of patients were showing cTnT level less than 0.03 ng/mL. The cTnT level over 0.1 ng/mL was found in 30% of total subjects. Mean quantitative value of cTnT was 0.29 ± 0.57 ng/mL in total subjects. Estimated cutoff value in CKD3 patients was 0.088 ng/mL with a sensitivity of 59.3% and specificity of 80.0%. Interestingly, the cutoff values of CKD1-2, CKD4-5, and CKD5D were 0.047, 0.18, and 0.27 respectively, which are half, two times, and three times of CKD3 cutoff value 0.088. The specificities of four cutoff values in each CKD group were showing over 80%, which is higher than sensitivity, respectively. In CKD patients, semiquantitative, point of care assessment of cTnT could be a useful tool for screening for ACEs.

Usefulness of an Upright T-Wave in Lead aVR for Predicting the Short-Term Prognosis of Incident Hemodialysis Patients: A Potential Tool for Screening High-Risk Hemodialysis Patients.

BACKGROUND/AIMS: An upright T-wave in lead aVR (aVRT) has recently been reported to be associated with cardiovascular death and mortality among the general population and patients with prior cardiovascular disease (CVD). However, evidence for the predictive ability of aVRT in patients with chronic kidney disease is lacking. Therefore, a hospital-based, prospective, cohort study was conducted to evaluate the predictive ability of an upright aVRT for the short-term prognosis in incident hemodialysis patients. METHODS: Among 208 patients who started maintenance hemodialysis, 79 with preexisting CVD (CVD cohort) and 129 with no history of CVD (non-CVD cohort), were studied. An upright and non-upright aVRT were defined as a wave with a positive deflection in amplitude of ≥0 mV and a negative deflection in amplitude of <0 mV, respectively. The endpoint was all-cause death. RESULTS: Overall, the prevalence of an upright aVRT was 22.6% at baseline. During the mean follow-up period of 2.1 ± 1.0 years, 33 deaths occurred. Cumulative survival rates at 3 years after starting dialysis in patients with an upright and non-upright aVRT were 50.0 and 80.7%, respectively, in the CVD cohort and 92.0 and 91.3%, respectively, in the non-CVD cohort. In the CVD cohort, multivariate Cox regression analysis showed that an upright aVRT was an independent predictor of death after adjusting for confounding variables. CONCLUSION: Among Japanese hemodialysis patients at high risk for CVD, an upright aVRT seems to be useful for predicting death.

The FRAX ® as a predictor of mortality in Japanese incident hemodialysis patients: an observational, follow-up study.

The World Health Organization Fracture Risk Assessment Tool (FRAX(®)) was recently developed to estimate the 10-year absolute risk of osteoporotic fracture among the general population. However, the evidence for its use in chronic kidney disease patients has been lacking, and the association between the FRAX(®) and mortality is unknown. Therefore, a hospital-based, prospective, cohort study was conducted to evaluate the predictive ability of the FRAX(®) for mortality in hemodialysis patients. A total of 252 patients who had been started on maintenance hemodialysis, 171 men and 81 women, with a mean age of 67 ± 14 years, was studied. The endpoint was defined as all-cause death. The Cox proportional hazards model was used to calculate hazard ratios and 95 % confidence intervals. During the mean follow-up period of 3.4 ± 2.7 years, 61 deaths occurred. The median (interquartile range) of the FRAX(®) for major osteoporotic fracture was 6.9 (4.6-12.0) % in men and 19.0 (7.6-33.0) % in women. Cumulative survival rates at 5 years after starting dialysis, with the FRAX(®) levels above and below the median, were 51.9 and 87.9 %, respectively, in men and 67.4 and 83.7 %, respectively, in women. Overall, in men, the multivariate Cox regression analyses revealed that the log-transformed FRAX(®) remained an independent predictor of death after adjusting by confounding variables. However, in women, the significant association between the FRAX(®) value and the outcome was eliminated if age was put into these models. Among Japanese hemodialysis patients, the FRAX(®) seems to be useful for predicting death, especially in men.

Declining prevalence of coronary artery disease in incident dialysis patients over the past two decades.

AIM: The medical management of patients with chronic kidney disease(CKD) has changed within the past 20 years. We speculate that this change has resulted in a decrease in the prevalence of atherosclerotic cardiovascular disease in patients with CKD. The aim of the present study was to analyze changes in the prevalence of coronary artery disease(CAD) in patients newly started on hemodialysis, as well as trends in clinical factors and medications over the past two decades. METHODS: This single-center cross-sectional study examined data for 315 consecutive patients starting hemodialysis(age, 64±12 years; men, 73%; diabetic nephropathy, 57%) between January 1993 and December 2010. All patients were routinely screened for CAD within three months of starting hemodialysis, regardless of whether ischemic heart disease was suspected. The patients were categorized into six groups based on the date of the initial dialysis session in order to compare the historical prevalence of unidentified CAD(uCAD) in association with the clinical factors. In addition, we performed a subgroup analysis among 222 patients without known cardiac disease. RESULTS: The prevalence of uCAD gradually declined from 69% to 25% over 18 years(p＜0.001 for trend). The mean high-density lipoprotein cholesterol(HDL-C) concentration increased(p＜0.001 for trend), while the median C-reactive protein(CRP) level decreased over time. In parallel with these trends, the proportion of statin users significantly increased over time(p＜0.001 for trend). The use of erythropoiesis-stimulating agents(ESAs) and renin angiotensin aldosterone system inhibitors(RAS-Is) also increased during the same period(both p＜0.001 for trend). A univariate logistic regression analysis identified a significant association between the prevalence of uCAD and the use of ESAs(OR: 0.565, p=0.016) or RAS-Is(OR: 0.501, p=0.004). In addition, a lower BMI, lower HDL-Clevel and higher CRP level were found to be closely associated with uCAD, independent of confounding variables. The findings for the new dialysis patients without cardiac disease were similar. CONCLUSIONS: The prevalence of uCAD in patients with end-stage kidney disease has remarkably decreased over the past two decades. Major improvements in the medical management of CKD may modify the prevalence of coronary atherosclerosis.

Efficacy of N-terminal pro-brain natriuretic peptide digit number for screening of cardiac disease in new haemodialysis patients.

AIM: The usefulness of the absolute N-terminal pro-brain natriuretic peptide (NT-ProBNP) concentration and its digit number for screening for cardiac disease was explored in new haemodialysis patients. METHODS: A cross-sectional study involving 71 (68 ± 14 years, 83% male) new dialysis patients was conducted. Receiver operator characteristic curve analysis was performed to identify the cutoff level of NT-proBNP for identifying cardiac disease at the start of dialysis. RESULTS: The median NT-proBNP concentration was 6576 pg/mL just before the first dialysis session and its mean digit number was 4.3 ± 0.6. Overall, 67%, 52%, 9% and 35% of patients had left ventricular (LV) hypertrophy, LV dilatation, systolic dysfunction and significant coronary artery disease, respectively. NT-proBNP levels of about 6000, 10,000 and 14,000 pg/mL were the best cutoff levels for the diagnosis of coronary artery disease (AUC, 0.754; P < 0.001), LV systolic dysfunction (area under the curve (AUC), 0.765, P = 0.001) and LV dilatation (AUC, 0.685, P = 0.008), respectively. Interestingly, 4.5 was the best digit number cutoff for all cardiac abnormalities. These findings suggest that a digit number of 5 or more means a potentially high risk for cardiovascular disease and a digit number of 3 or less means a relatively low risk. CONCLUSIONS: The NT-proBNP concentration just before the first dialysis session is a useful tool for screening for cardiac abnormalities. Considering the wide variation of the NT-proBNP cutoff levels depending on each cardiac abnormality, the digit number could be potentially easier to use for initial risk stratification for cardiac disease in new dialysis patients.

[Clinical application of PGA-tube for regeneration of intrapelvic nerves during extended surgery for intrapelvic recurrent rectal cancer].

For the regeneration of injured peripheral nerves, we have devised a PGA-tube that is composed of a tube of polyglycolic acid containing collagen sponge. This PGA-tube was applied clinically to reconstruct a peripheral nerve that had been resected during extended surgical resection of for intrapelvic recurrent rectal cancer. Four months after the surgical resection, the function of the left hip joint has improved remarkably, whereas the function had been lost just after the operation. It is suggested that the PGA-tube will be useful for regeneration of peripheral nerves that are resected during operation for intrapelvic malignancy.