Pressure induces peritoneal fibrosis and inflammation through CD44 signaling.

Peritoneal dialysis (PD) is a widely used sustainable kidney replacement therapy. Prolonged use of PD fluids is associated with mesothelial-mesenchymal transition, peritoneal fibrosis, and eventual ultrafiltration (UF) failure. However, the impact of pressure on the peritoneum remains unclear. In the present study, we hypothesized increased pressure is a potential contributing factor to peritoneal fibrosis and investigated the possible mechanisms. In vitro experiments found that pressurization led to a mesenchymal phenotype, the expression of fibrotic markers and inflammatory factors in human mesothelial MeT-5A cells. Pressure also increased cell proliferation and augmented cell migration potential in MeT-5A cells. The mouse PD model and human peritoneum equilibrium test (PET) data both showed a positive association between higher pressure and increased small solute transport, along with decreased net UF. Mechanistically, we found that significant upregulation of CD44 in mesothelial cells upon pressurization. Notably, the treatment of CD44 neutralizing antibodies prevented pressure-induced phenotypic changes in mesothelial cells, while a CD44 inhibitor oligo-fucoidan ameliorated pressure-induced peritoneal thickening, fibrosis, and inflammation in PD mice. To conclude, intraperitoneal pressure results in peritoneal fibrosis in PD via CD44-mediated mesothelial changes and inflammation. CD44 blockage can be utilized as a novel preventive approach for PD-related peritoneal fibrosis and UF failure.

Prevention and management of cytomegalovirus infection and disease in kidney transplant: A consensus statement of the Transplantation Society of Taiwan.

Kidney transplant recipients have an increased risk of cytomegalovirus (CMV) infection and disease. A strategy for mitigating the risk of CMV infection in kidney transplant recipients has not yet been established in Taiwan. The Transplantation Society of Taiwan aimed to develop a consensus by expert opinion on the prevention and management of CMV infection. Based on the results of Consensus Conference, we suggested low-dose valganciclovir prophylaxis (450 mg once daily) for kidney transplant recipients. The prophylaxis duration was ≥6 months for high-risk (D+/R-) patients and 3 months for moderate-risk (R+) patients. Even for low-risk (D-/R-) patients, prophylaxis for at least 3 months is recommended because of the high seroprevalence of CMV in Taiwan. CMV prophylaxis was suggested after anti-thymocyte globulin treatment but not after methylprednisolone pulse therapy. Routine surveillance after prophylaxis, secondary prophylaxis after CMV disease treatment, and mTOR inhibitors for primary CMV prophylaxis were not recommended. Letermovir and marabavir are emerging CMV agents used for prophylaxis and refractory CMV disease. CMV immunoglobulins have been used to treat refractory CMV disease in Taiwan. We hope this consensus will help professionals manage patients with CMV in Taiwan to improve the quality of care.

Prevention and management of tuberculosis in solid organ transplantation: A consensus statement of the transplantation society of Taiwan.

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug-drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients.

Allogeneic adipose tissue-derived stem cells ELIXCYTE® in chronic kidney disease: A phase I study assessing safety and clinical feasibility.

The purpose of this phase I clinical trial is to assess the safety and tolerability of allogeneic adipose tissue-derived stem cells (ADSCs) among chronic kidney disease (CKD) patients. 12 eligible CKD patients with an estimated glomerular filtration rate (eGFR) of 15-44 ml/min/1.73 m2 received one dose of intravenous allogeneic ADSCs (ELIXCYTE® ), as 3 groups: 3 low dose (6.4 × 107 cells in total of 8 ml), 3 middle dose (19.2 × 107 cells in total of 24 ml) and 6 high dose (32.0 × 107 cells in total of 40 ml) of ELIXCYTE® and evaluated after 48 weeks. Primary endpoint was the safety profiles in terms of incidence of adverse events (AEs) and serious adverse event (SAE). Two subjects in high dose group experienced a total of 2 treatment-related AEs which are Grade 1 slow speech and Grade 1 bradyphrenia after the infusion. One subject in middle dose group experienced an SAE unlikely related to treatment, grade 2 proteinuria. No fatal AE was reported in this study. An increase in eGFR was observed in 7 out of 12 subjects (58%) at Week 24 and in 6 of 12 subjects (50%) by Week 48. By Week 24, an increase in eGFR by more than 20% among all CKD patients with baseline eGFR â‰§ 30 ml/min/1.73 m2 as compared to only 2 subjects in baseline eGFR < 30 ml/min/1.73 m2  group. No significant reduction in proteinuria was noted among all subjects. This phase I trial demonstrated single-dose intravenous ELIXCYTE was well tolerated in moderate-to-severe CKD patients and its preliminary efficacy warrants future studies.

The Influence of Diabetes Mellitus on the Risks of End-Stage Kidney Disease and Mortality After Liver Transplantation.

This retrospective study aimed to investigate the effect of diabetes mellitus (DM) on the risks of end-stage kidney disease (ESKD) and post-liver transplantation (post-LT) mortality. Using data from the National Health Insurance Research Database, Taiwan, 3,489 patients who received a LT between 1 January 2005, and 31 December 2015, were enrolled in this study and divided into the pre-existing DM, post-LT DM (PLTDM), and without DM groups. All subjects were followed up from 1 year after LT to the index date for ESKD, and the occurrence of death, or until 31 December 2016. Of the 3,489 patients with LT, 1,016 had pre-existing DM, 215 had PLTDM, and 2,258 had no DM pre- or post-LT. The adjusted HRs of ESKD were 1.77 (95% Confidence Interval [CI], .78-3.99) and 2.61 (95% CI, 1.63-4.18) for PLTDM group and pre-existing DM group compared to without DM group, respectively. For the risk of death, the adjusted HRs were 1.05 (95% CI, .72-1.55) and 1.28 (95% CI, 1.04-1.59) for PLTDM group and pre-existing DM group compared to those without DM group, respectively. The sensitivity analysis for the risk of ESKD and death also revealed the consistent result. Pre-existing DM has significant increase the risk of post-LT ESKD and mortality. The role of PLTDM should be explored to explain postoperative morbidity and mortality.

Genetic insight into primary glomerulonephritis.

Primary glomerulonephritis is a major global health concern and a disorder with significant heritable components. Rapid advances in sequencing technologies have led to genome-wide, high-throughput investigations of the genetic basis of complex human traits. Genetic studies have successfully mapped several susceptibility loci and disease-causing genes for different subtypes of primary glomerulonephritis. These studies have revealed that IgA nephropathy-associated genes have a highly complex, polygenic and pleiotropic genetic architecture and that genetic susceptibility to membranous nephropathy may be driven by a few large-effect loci. Furthermore, both susceptibility genes and high-penetrant gene mutations reportedly contribute to the development of the most heterogeneous phenotype of focal segmental glomerulosclerosis. The genetic heterogeneity between each glomerular disease type and within different populations has indicated disease-specific and ethnicity-specific underlying molecular mechanisms for the disorders. The findings from genome-wide association studies (GWAS) have mainly included variants on or near the major histocompatibility (MHC) loci, highlighting the molecular basis for the shared pathogenesis of the immune-mediated disease. Recent studies with increased sample sizes and higher resolutions of genome-wide imputation have provided novel insights into the pathogenesis of glomerular disorders. Further integration of results from genomic studies with functional genomics datasets can indicate novel targets for drug discovery as well as potential tools for patient diagnosis and stratification. However, larger GWASs and sequencing studies in independent cohorts and more standardized inclusion of phenotypes across studies are required for each subtype of glomerular disease.

Impact of dialysis modality on major adverse cardiovascular events and all-cause mortality: a national population-based study.

BACKGROUND: Only few studies with inconsistent results comparing the relative risk of cardiac mortality between peritoneal dialysis (PD) and hemodialysis (HD). Switches between renal replacement therapy (RRT) modalities render objective assessment of survival benefits a greater challenge. METHODS: Data were retrieved from Taiwan's National Health Insurance Database from 1 January 2006 to 31 December 2015. We included 13 662 and 41 047 long-term dialysis patients in a propensity score matching study design and a time-varying study design, respectively, to compare major adverse cardiovascular events (MACEs) between patients receiving PD and HD. We also included 109 256 dialysis patients to compare the all-cause mortality among different RRT modalities. RESULTS: For MACE, the hazard ratio (HR) for PD patients compared to HD patients was 0.95 [95% confidence interval (CI) 0.89-1.02] in the propensity score study design and 1.06 (95% CI 1.01-1.12) in the time-varying study design. For all-cause mortality, the HR for PD patients compared to HD patients was 1.09 (95% CI 1.05-1.13) in the propensity score study design and 1.13 (95% CI 1.09-1.17) in the time-varying study design. The HR for death was higher at a level of statistical significance for females (1.21, 95% CI 1.15-1.28), patients ≥65 years old (1.30, 95% CI 1.24-1.36) and diabetes mellitus (DM; 1.28, 95% CI 1.22-1.34). CONCLUSIONS: The HR for MACE is significantly higher among PD patients in time-varying design analysis. In addition, all-cause mortality was higher in PD patients compared to patients with HD, especially in those who were aged ≥65 years, female or DM.

Periodontal disease and risk of mortality and kidney function decline in advanced chronic kidney disease: a nationwide population-based cohort study.

OBJECTIVES: Periodontal disease is prevalent in patients with chronic kidney disease (CKD) and potentially associated with kidney function decline. However, it is uncertain whether periodontal disease affects the risk of mortality and morbidity in patients with advanced CKD. MATERIALS AND METHODS: Taiwan's National Health Insurance Research Database was used to conduct a nationwide population-based cohort study. Propensity score matching procedures were performed to select people with stage 5 CKD and to compare the long-term risk of mortality, end-stage renal disease, and major adverse cardiovascular events (MACE) between people with and without periodontal disease. Multivariable Cox regression analyses were conducted to calculate the adjusted hazard ratio (aHR) with 95% confidence interval (CI) for the outcome of interest. RESULTS: A total of 8119 subjects with stage 5 CKD were initially included. After matching to demographic and clinical covariates, 1254 subjects with 7099 person-years of follow-up were selected for analyses. Periodontal disease was not associated with long-term risks of all-cause mortality (aHR: 0.77, 95% CI: 0.49-1.22), progression to end-stage renal disease (aHR: 0.91, 95% CI: 0.75-1.10), or MACE (aHR: 1.18, 95% CI: 0.91-1.53). These findings were generally consistent across subgroups of age, sex, comorbid diabetes, uses of systemic antibiotic, and different dental procedures. CONCLUSIONS: Periodontal disease is not a predictor for long-term mortality or morbidity in patients with advanced CKD. CLINICAL RELEVANCE: These results provide important evidence to elucidate the relationship between periodontitis and critical clinical outcomes of advanced CKD.

A Framework of Visual Checkout System Using Convolutional Neural Networks for Bento Buffet.

In recent years, the technology of artificial intelligence (AI) and robots is rapidly spreading to countries around the world. More and more scholars and industry experts have proposed AI deep learning models and methods to solve human life problems and improve work efficiency. Modern people's lives are very busy, which led us to investigate whether the demand for Bento buffet cafeterias has gradually increased in Taiwan. However, when eating at a buffet in a cafeteria, people often encounter two problems. The first problem is that customers need to queue up to check out after they have selected and filled their dishes from the buffet. However, it always takes too much time waiting, especially at lunch or dinner time. The second problem is sometimes customers question the charges calculated by cafeteria staff, claiming they are too expensive at the checkout counter. Therefore, it is necessary to develop an AI-enabled checkout system. The AI-enabled self-checkout system will help the Bento buffet cafeterias reduce long lineups without the need to add additional workers. In this paper, we used computer vision and deep-learning technology to design and implement an AI-enabled checkout system for Bento buffet cafeterias. The prototype contains an angle steel shelf, a Kinect camera, a light source, and a desktop computer. Six baseline convolutional neural networks were applied for comparison on food recognition. In our experiments, there were 22 different food categories in a Bento buffet cafeteria employed. Experimental results show that the inception_v4 model can achieve the highest average validation accuracy of 99.11% on food recognition, but it requires the most training and recognition time. AlexNet model achieves a 94.5% accuracy and requires the least training time and recognition time. We propose a hierarchical approach with two stages to achieve good performance in both the recognition accuracy rate and the required training and recognition time. The approach is designed to perform the first step of identification and the second step of recognizing similar food images, respectively. Experimental results show that the proposed approach can achieve a 96.3% accuracy rate on our test dataset and required very little recognition time for input images. In addition, food volumes could be estimated using the depth images captured by the Kinect camera, and a framework of visual checkout system was successfully built.

Quantitative determination of human IgA subclasses and their Fc-glycosylation patterns in plasma by using a peptide analogue internal standard and ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry.

RATIONALE: Glycosylation on immunoglobulins is important for the immune function. In this study, we developed and validated a method for the absolute quantification of IgA subclasses and relative quantification of IgA-Fc glycopeptides by using affinity purification and ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS). Only micro-volumes of plasma were required from each sample and we also applied the method to discover IgA and IgA-glycopeptide profiles in patients with chronic kidney diseases and IgA nephropathy. METHODS: Peptide M affinity beads were used to purify IgA, and a cost-effective peptide analogue was added as internal standard. With an efficient on-bead digestion process, purified samples were analyzed by UHPLC/MS/MS in multiple reaction monitoring mode. RESULTS: Correlation coefficients were greater than 0.999 for the IgA1 and IgA2 calibration curves and greater than 0.994 for glycopeptide regression curves. Intraday and interday precisions for IgA1 and IgA2 were <1.6% and <5.1% RSD, respectively. Intraday and interday accuracies ranged from 102.6 to 114.9% and 103.5 to 113.5% for IgA1 and IgA2, respectively. Stabilities of IgA1 and IgA2 at -80°C for 7 to 15 days ranged from 96.0 to 109.4%, respectively. The Pearson's correlation coefficient was 0.916 when comparing the IgA quantification results of the 30 clinical samples by using ELISAs and the developed UHPLC/MS/MS method. Compared with healthy controls, IgA and IgA-glycopeptides showed different profiles in patients with chronic kidney diseases and IgA nephropathy. CONCLUSIONS: The developed method showed good validation results, and the absolute quantification results of IgA correlated with those from ELISA. The pilot application study showed that IgA and IgA-glycopeptides can be potential biomarker candidates for kidney diseases, and more clinical sample applications are worth investigating.

Resuscitation fluid types in sepsis, surgical, and trauma patients: a systematic review and sequential network meta-analyses.

BACKGROUND: Crystalloids and different component colloids, used for volume resuscitation, are sometimes associated with various adverse effects. Clinical trial findings for such fluid types in different patients' conditions are conflicting. Whether the mortality benefit of balanced crystalloid than saline can be inferred from sepsis to other patient group is uncertain, and adverse effect profile is not comprehensive. This study aims to compare the survival benefits and adverse effects of seven fluid types with network meta-analysis in sepsis, surgical, trauma, and traumatic brain injury patients. METHODS: Searched databases (PubMed, EMBASE, and Cochrane CENTRAL) and reference lists of relevant articles occurred from inception until January 2020. Studies on critically ill adults requiring fluid resuscitation were included. Intervention studies reported on balanced crystalloid, saline, iso-oncotic albumin, hyperoncotic albumin, low molecular weight hydroxyethyl starch (L-HES), high molecular weight HES, and gelatin. Network meta-analyses were conducted using random-effects model to calculate odds ratio (OR) and mean difference. Risk of Bias tool 2.0 was used to assess bias. Confidence in Network Meta-Analysis (CINeMA) web application was used to rate confidence in synthetic evidence. RESULTS: Fifty-eight trials (n = 26,351 patients) were identified. Seven fluid types were evaluated. Among patients with sepsis and surgery, balanced crystalloids and albumin achieved better survival, fewer acute kidney injury, and smaller blood transfusion volumes than saline and L-HES. In those with sepsis, balanced crystalloids significantly reduced mortality more than saline (OR 0.84; 95% CI 0.74-0.95) and L-HES (OR 0.81; 95% CI 0.69-0.95) and reduced acute kidney injury more than L-HES (OR 0.80; 95% CI 0.65-0.99). However, they required the greatest resuscitation volume among all fluid types, especially in trauma patients. In patients with traumatic brain injury, saline and L-HES achieved lower mortality than albumin and balanced crystalloids; especially saline was significantly superior to iso-oncotic albumin (OR 0.55; 95% CI 0.35-0.87). CONCLUSIONS: Our network meta-analysis found that balanced crystalloids and albumin decreased mortality more than L-HES and saline in sepsis patients; however, saline or L-HES was better than iso-oncotic albumin or balanced crystalloids in traumatic brain injury patients. TRIAL REGISTRATION: PROSPERO website, registration number: CRD42018115641).

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast-osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast-osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = -0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/ß-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid-bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast-osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Progressive multifocal leukoencephalopathy in a renal transplant patient.

End-stage renal disease (ESRD) has a major impact on health and affects more than 600,000 people in the USA. The current mainstay treatments include dialysis and kidney transplantation (KT), and patients who have received KT have a higher quality of life and a lower mortality risk than those on chronic dialysis. Therefore, KT is considered the more preferred treatment modality for patients with ESRD. However, even though KT results in a higher long-term survival rate, the use of immunosuppressants is associated with various complications, including opportunistic infections and malignancies, which may lead to a higher risk of death in the first year after transplantation. Progressive multifocal leukoencephalopathy (PML) is a rare complication following KT, with an incidence of 0.027% in KT recipients. We present a case of PML following immunosuppressant therapy in a patient who received KT.

A systematic review and meta-analysis of the comparison of performance among step-tip, split-tip, and symmetrical-tip hemodialysis catheters.

OBJECTIVE: Patients with end-stage renal disease need vascular access to ensure sufficient blood flow during hemodialysis (HD). Patients who are poor candidates for arteriovenous access creation require long-term catheter placement. Problems such as dialysate recirculation, thrombosis, catheter-related infections, and malfunction can occur with HD catheters. Different tip designs (step, split, and symmetrical) have been developed to ameliorate the catheter-related problems. The aim of the study was to compare the efficacy and safety of split-tip, step-tip, and symmetrical-tip HD catheters. METHODS: The PubMed, Embase, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were searched for studies published before November 2017. Studies comparing the clinical and rheologic outcomes of step-, split-, or symmetrical-tip catheters in patients undergoing HD were included in this meta-analysis. We conducted meta-analyses using random-effects models. The primary outcomes were catheter survival time and incidence of functioning catheters. The secondary outcomes were delivered blood flow rate, blood recirculation rate, and incidence of catheter-related complications. RESULTS: Seven randomized controlled trials and one retrospective study with a total of 988 patients were included. No significant differences were observed in the delivered blood flow rate (weighted mean difference, -5.37 mL/min; 95% confidence interval [CI], -23.75 to 13.02), incidence of catheter-related infections (risk ratio [RR], 1.18; 95% CI, 0.63-2.22), or incidence of catheter-related thrombosis (RR, 1.29; 95% CI, 0.64-2.59) between step-tip catheters and advanced (both split-tip and symmetrical-tip) catheters. Moreover, a meta-analysis of the incidence of functioning catheters at 1 month, 6 months, and 12 months revealed that the outcome of step-tip catheter use was better than that of split-tip catheter use, but with a significant difference only at 6 months (RR, 1.22; 95% CI, 1.02-1.46). CONCLUSIONS: None of the catheter types exhibited unique features that can enhance their suitability for application. Hence, catheters can be selected by also considering different factors, including costs, ease of procedures, expertise of the clinician, and education and preference of the patient.

Association of plasma folate, vitamin B12 levels, and arsenic methylation capacity with developmental delay in preschool children in Taiwan.

Developmental delay has been associated with inefficient arsenic methylation capacity in preschool children. Folate and vitamin B12 are important nutrients that produce s-adenosylmethionine during single-carbon metabolism and provide methyl groups for arsenic methylation. The aim of the present study was to explore whether plasma folate and vitamin B12 levels influence arsenic methylation capacity and in turn are related to developmental delay in preschool children. A case-control study was conducted in 178 children with developmental delay and 88 normal children, who were recruited from Shin Kong Wu Ho-Su Memorial Teaching Hospital from August 2010 to March 2014. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in the urine was determined by high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Plasma folate and vitamin B12 levels were measured using a SimulTRAC-SNB radioassay. The results show that the combination of high plasma folate and high vitamin B12 levels were correlated with efficient arsenic methylation capacity (low MMAV %, low InAs %, and high DMAV %). High MMAV % significantly increased and high DMAV % and secondary methylation index decreased the odds ratio (OR) of developmental delay in a dose-dependent manner in both low plasma folate and low vitamin B12 (low/low) groups; the multivariate OR and 95% confidence interval were 5.01 (0.83-30.06), 0.21 (0.04-1.23), and 0.20 (0.03-1.20), respectively. This is the first study to show that the combination of high plasma folate and high vitamin B12 levels increases arsenic methylation capacity and indirectly decreases the OR of developmental delay in preschool children.

Association of endothelin genetic variants and hospitalized infection complications in end-stage renal disease (ESRD) patients.

BACKGROUND: Infection is the second most common cause of mortality for patients with end-stage renal disease (ESRD), accompanying with immune dysfunction. Endothelin (EDN) is known to be related to inflammation; however, it is unknown whether genetic variants of the EDN gene family are associated with increased risk of hospitalized infection events. METHODS: Nineteen tagging single-nucleotide polymorphisms (tSNPs) of the EDN gene family were selected for genotyping a cohort of 190 ESRD patients. Patient demographics were recorded, the subtypes of infection events were identified, and association analysis between the EDN genetic variants and hospitalized infection events was performed. RESULTS: In this study, 106 patients were hospitalized for infection events. The leading events were pneumonia, bacteremia, and cellulitis. The minor allele of rs260741, rs197173, and rs926632 SNPs of EDN3 were found to be associated with reduced risk of hospitalized bacteremia events. CONCLUSIONS: The minor allele of rs260741, rs197173, and rs926632 in EDN3 were associated with reduced risk of hospitalized bacteremia events in ESRD patients.

The Kidney Clock Contributes to Timekeeping by the Master Circadian Clock.

The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.

Temporal-Spatial Establishment of Initial Niche for the Primary Spermatogonial Stem Cell Formation Is Determined by an ARID4B Regulatory Network.

During neonatal testis development, centrally located gonocytes migrate to basement membrane of the seminiferous cords, where physical contact with a niche established by Sertoli cells is essential for transition of gonocytes into spermatogonial stem cells (SSCs). To provide structural support and signaling stimuli for the gonocyte-to-SSC transition that occurs at a specific location during a finite phase, temporal-spatial establishment of the niche is critical. To date, the factors that guide Sertoli cells to establish the initial stem cell niche remain largely unknown. Using the Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice, we demonstrated that ablation of AT-rich interaction domain 4B (ARID4B) resulted in abnormal detachment of Sertoli cells from the basement membrane of seminiferous cords during the gonocyte-to-SSC transition phase, suggesting failure to establish a niche for the SSC formation. Without support by a niche environment, gonocytes showed disarranged cell distribution in the Arid4bSCKO testes and underwent apoptosis. The commitment of gonocytes to differentiate into the spermatogonial lineage was broken and the capability of SSCs to self-renew and differentiate was also impaired. Gene expression profiling revealed the molecular mechanisms responsible for the phenotypic changes in the Arid4bSCKO testes, by identifying genes important for stem cell niche function as downstream effectors of ARID4B, including genes that encode gap junction protein alpha-1, KIT ligand, anti-Müllerian hormone, Glial cell-line derived neurotrophic factor, inhibin alpha, inhibin beta, and cytochrome P450 family 26 subfamily b polypeptide 1. Our results identified ARID4B as a master regulator of a signaling network that governs the establishment of a niche during the critical gonocyte-to-SSC transition phase to control the fate of gonocytes and SSCs. Stem Cells 2017;35:1554-1565.

Omega-3 fatty acids for dialysis vascular access outcomes in patients with chronic kidney disease.

BACKGROUND: Maintaining long-term vascular access patency is necessary for high quality haemodialysis (HD) treatment of patients with the terminal and most serious stage of chronic kidney disease (CKD) - end-stage kidney disease (ESKD). Oral supplementation with omega-3 fatty acids (ω-3FA) may help to prevent blockage of the vascular access by reducing the risk of thrombosis and stenosis. OBJECTIVES: To evaluate the efficacy and safety of ω-3FA supplementation versus placebo or no treatment for maintaining vascular access patency in ESKD patients undergoing HD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 23 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) of omega-3 fatty acids versus placebo that assessed the patency of arteriovenous fistula (AVF) or arteriovenous graft (AVG) types of vascular access in ESKD patients. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of each eligible study using the Cochrane Risk of Bias tool and made separate overall risk of bias judgments for the efficacy and safety outcomes. The certainty of evidence was assessed using the GRADE approach. The primary efficacy outcome was loss of vascular patency and the primary safety outcomes were occurrences of serious adverse events (e.g. death, hospitalisation, cardiovascular events, major bleeding). Secondary outcomes were the occurrence of non-serious adverse events (e.g. minor bleeding, gastrointestinal events and other adverse events). Efficacy effects were reported as risk ratios (RR) and safety effects as risk differences (RD) with 95% confidence intervals (CI). Studies were pooled separately by type of vascular access using a random-effects model. MAIN RESULTS: Five studies (833 participants) were included; one was a very small pilot study of 7 participants. All studies compared oral ω-3FA supplements against placebo. Four studies enrolled participants with arteriovenous grafts (AVGs), and the other had participants with arteriovenous fistulas (AVFs). The risk of bias for both efficacy and safety outcomes was unclear for all studies, due mainly to incomplete reporting for allocation concealment and incompleteness of study follow-up.In AVF patients, ω-3FA supplementation probably makes little or no difference to the 12-month risk of patency loss (1 study, 536 participants: RR 1.01, 95% CI 0.84 to 1.21; moderate certainty evidence), risk of death (1 study, 567 participants: RD 0.00, 95% CI -0.03 to 0.02; moderate certainty evidence) and risk of hospitalisation (1 study, 567 participants: RD 0.00, 95% CI -0.08 to 0.08; low certainty evidence). There was no information on cardiovascular events and major bleeding.In AVG patients, it is very uncertain whether ω-3FA supplementation reduces the risk of patency loss within 6 months (2 studies, 41 participants: RR 0.91, 95% CI 0.36 to 2.28; very low certainty evidence) or 12 months (2 studies, 220 participants: RR 0.59, 95% CI 0.27 to 1.31; very low certainty evidence). ω-3FA supplementation may make little or no difference to the risk of death within 6 to 12 months in AVG patients (4 studies, 261 participants: RD 0.01, 95% CI -0.05 to 0.07; low certainty evidence). It is very uncertain if ω-3FA supplementation increases the risk of hospitalisation (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence), changes the risk of cardiovascular events (4 studies, 261 participants: RD -0.02, 95% CI -0.11 to 0.07; very low certainty evidence), or increases the risk of major bleeding (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence) within 6 to 12 months in AVG patients. There may be an increase in the risk of mild gastrointestinal adverse reactions (3 studies, 65 participants: RD 0.25, 95% CI 0.07 to 0.43; low certainty evidence) such as a sensation of bloatedness, gas or a fishy aftertaste. AUTHORS' CONCLUSIONS: In CKD patients with an AVF, there is moderate certainty that ω-3FA supplementation makes little or no difference to preventing patency loss; and in patients with an AVG, it is very uncertain that ω-3FA supplementation prevents patency loss within 12 months.