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The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)–induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis. Sprague–Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, H&E staining, TUNEL staining, and Western blotting were measured in the left ventricle. Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G. Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea–enhanced cardiac apoptosis via enhancing survival pathways.

Imperforate anus (IA) is associated with several urological anomalies, including vesicoureteral reflux (VUR), a major contributor to high morbidity in patients with anorectal malformations. This retrospective study was performed to elucidate the risk factors of vesicoureteral reflux (VUR) and UTI in children with IA. We used the National Health Insurance Research Database (NHIRD) to estimate the frequency of congenital anomalies of the kidney and urinary tract (CAKUT) in children with IA. We also investigated the frequencies of VUR, UTI, and CAKUT in children with IA along with the risk factors of VUR. We enrolled 613 children between 2000 and 2008 (367 males and 246 females; 489 low-position IA and 124 high-position IA). High-position IA was associated with a significantly increased risk of VUR compared with low-position IA (OR: 2.68, 95% CI: 1.61, 4.45). In addition, children with IA along with CAKUT, hydronephrosis, or UTI had a higher risk of VUR (OR: 8.57, 95% CI: 3.75, 19.6; OR: 7.65, 95% CI: 4.48, 13.1; and OR: 31.8, 95% CI: 11.5, 88.3, respectively). UTI, as well as chromosomal anomalies, were more frequent in children with high-position IA. Patients with a high-position IA had a greater risk of VUR, particularly those with CAKUT, hydronephrosis, or UTI. Such patients must periodically undergo urinalysis to screen for UTI and early voiding cystourethrogram to rule out VUR and prevent consequent renal damage. Chromosomal analysis is suggested to rule out Down syndrome.

The purpose of this study was to investigate whether or not angiotensin II type 1 receptor blocker irbesartan (ARB) with a partial agonist of PPAR-γ could protect against chronic nocturnal intermittent hypoxia (CIH)-induced cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis.Sprague-Dawley rats were in a normoxic control group (CON-G), or rats were in a chronic nocturnal intermittent hypoxia group (HP-G, from 3 to 7% oxygen versus 21% oxygen per forty seconds cycle, nocturnally 8 h per day for 1 month), or rats were in a chronic nocturnal intermittent hypoxia group pretreated with ARB (50 mg/kg/day, S.C.) (ARB-HP-G). Echocardiography, HE staining, TUNEL staining, and Western blotting were measured in the left ventricle.Hypoxia-induced SIRT1 degradation, Fas receptors, FADD, active caspase-8 and caspase-3 (Fas/FasL apoptotic pathway) and Bax, tBid, active caspase-9 and -3 (mitochondrial apoptotic pathway) and TUNEL-positive apoptosis were reduced in ARB-HP-G when compared with HP-G. IGF-I, IGF1 receptor, p-PI3k, p-Akt, Bcl2, and Bcl-XL (IGF1/PI3K/AKT pro-survival pathway) were increased in ARB-HP-G compared to HP-G.Our findings suggest that the ARB may prevent cardiac Fas/FasL to mitochondrial apoptotic pathways and enhance cardiac IGF1/PI3K/AKT pro-survival pathway in the sleep apnea model associated with JNK de-activation and SIRT1 upregulation. ARB prevents chronic sleep apnea-enhanced cardiac apoptosis via enhancing survival pathways.

The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy.We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients.We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells.Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN.In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.

Background: Heat shock protein-70 (Hsp-70) exhibits cytoprotective effects against oxidative stress-induced airway injury. This study aimed to examine Hsp-70 and 8-hydroxy-2′-deoxyguanosine (8-OHdG) from tracheal aspirates (TA) in very low-birth weight (VLBW) preterm infants to predict the development of bronchopulmonary dysplasia (BPD).Methods: This birth cohort study enrolled 109 VLBW preterm infants, including 32 infants who developed BPD. Hsp-70 and 8-OHdG concentrations from TA were measured by immunoassay. The apoptosis of TA epithelial cells obtained on Day 28 after birth was measured using annexin-V staining assay.Results: Hsp-70 and 8-OHdG levels in TA fluid were persistently increased from Day 1 to Day 28 of life in the BPD group. Multiple linear regression analysis demonstrated that BPD was significantly associated with gestational age, respiratory distress syndrome, and TA Hsp-70 and 8-OHdG levels on post-natal Day 28. The TA Hsp-70 level positively correlated with TA 8-OHdG level on the Day 1 (r = 0.47) and Day 28 of life (r = 0.68). Incubation of recombinant Hsp-70 with primary epithelial cells derived from TA of patients decreased hydrogen peroxide-induced epithelial cell death.Conclusions: Hsp-70 levels are associated with a state of oxidative injury in the development of BPD.

Autophagy plays a major role in defending against oxidative stress in respiratory epithelial cells. The complement regulatory protein CD46 can enhance autophagy and decrease local complement activation at sites of inflammation. This study investigated the mechanism by which CD46 protects against oxidative stress-mediated apoptosis in respiratory epithelium in asthmatic patients. Nasal mucosa samples were obtained from 60 adults with mild asthma who received turbinectomy and 30 controls. A decreased expression of CD46 and increased apoptosis were noted in the damaged nasal epithelium from the asthmatic patients. Primary epithelial cells cultured with Dermatophagoides pteronyssinus 2 showed decreased CD46 and increased cleaved CASPASE-3A expressions. Crosslinking CD46 mAb could induce the formation of autophagosomes and LC3-II expression in primary epithelial cells. CD46 engagement could induce autophagy against hydrogen peroxide-induced epithelial cell death, whereas the autophagy inhibitor 3-methyladenine decreased this effect. In addition, CD46 engagement decreased the expressions of PRO-IL-1β and NLRP3, enhanced the expression of scaffold protein GOPC, and diminished hydrogen peroxide-induced 8-OHdG, IL-1β and IL-6 production. Silencing ATG5 in human lung epithelial A549 cells decreased CD46-activated autophagy with LC3-II. CD46 induced autophagy and decreased the oxidative stress-mediated apoptosis of respiratory epithelium, and this may offer a new therapeutic strategy to treat asthma.

The insulin-like growth factor type 2 receptor (IGF2R) overexpression has been implicated in heart disease progression. Unregulated IGF2R signaling triggers cardiac hypertrophy, apoptosis, and cardiomyopathies. The present study investigated the role of IGF2R in cardiomyocyte apoptosis under high glucose (HG) levels and in streptozotocin (STZ) induced diabetic rat hearts. We found that IGF2 and IGF2R protein expression were highly upregulated under high glucose condition in H9c2 cells as well as in STZ induced diabetic rat hearts. Using immunoblotting and TUNEL assay, we found that elevated glucose condition induced IGF2R expression leads to activation of Gαq mediated calcineurin-dependent signaling pathway, which further leads to downstream activation and expression of cardiac hypertrophy related proteins, ANP and BNP. Further, we found that glucose-induced IGF2R expression downregulated survival protein p-Akt, p-Bad (Ser 155) and enhanced the expression of apoptosis-inducing proteins cytochrome c and cleaved Caspase-3. Our results suggested that hyperglycemic condition leads to cellular cardiomyocyte apoptosis both in vitro and in vivo models, via abnormally increased activation of the IGF2R signaling pathway.

Background Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN. Methods The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis. Results CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes. Conclusions IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.

Background Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement. Objectives The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD. Methods To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults. Results LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes. Conclusions Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD.

BACKGROUND This study aimed to investigate the relationship between CD4+ regulatory T cells (Tregs) and innate lymphoid cells (ILCs) in children with primary immune thrombocytopenia (ITP) undergoing high-dose intravenous immunoglobulin (IVIG) therapy. METHODS We enrolled a cohort of 30 children with newly diagnosed ITP and 30 healthy controls and collected blood samples for levels of Tregs, ILCs, relevant cytokines, and Treg suppression assay at the diagnosis, two days, four weeks, and one year (only platelet count) after high-dose IVIG treatment. IVIG partial responders was defined by a platelet count less than 100 × 109 /L at 12 months after IVIG treatment. RESULTS Children with newly diagnosed ITP exhibited elevated levels of ILC1, ILC2, ILC3, Th17, myeloid dendritic cells (DCs), plasmacytoid DCs, and serum IFN-γ and IL-17A levels, accompanied by a decrease in IL-10-producing Tregs. High-dose IVIG therapy reversed these aberrations. Platelet counts positively correlated with Tregs (rho = 0.72) and negatively correlated with both ILC1 (rho = -0.49) and ILC3 (rho = -0.60) (P

BACKGROUND 4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8+ Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8+ CD25+ CD137+ Treg suppressive function to decrease nasal nitric oxide (nNO) levels. METHODS Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8+ CD25+ T cells and suppressive function of CD8+ CD25+ CD137+ Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8+ CD25+ CD137+ T cells was analyzed by Western blotting. RESULTS Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8+ T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8+ CD25+ CD137+ population in PBMCs. Pam3CSK4-stimulated CD8+ CD25+ CD137+ Tregs induced IL-10 and TGF-β and suppressed CD4+ CD25- T-cell proliferation mainly by cell contact inhibition. CD8+ CD25+ CD137+ Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8+ CD25+ T cells decreased Pam3CSK4-activated Foxp3 expression. CONCLUSION Der p IT expanded CD8+ CD25+ CD137+ Tregs and decreased nNO levels. Induced CD137 expression on CD8+ CD25+ Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.

Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis. A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006–2010) and 1352 patients with TMA in the 2011 cohort (2011–2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment. The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort). This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.

Background/purpose This study aims to examine the characteristics of Taiwanese children with chronic kidney disease (CKD) and delineate the factors that lead to disease progression in this population. Methods We reviewed the records of the Taiwan Pediatric Renal Collaborative Study, a multicenter database of Taiwanese children with CKD. Multivariate regression analysis was used to identify the main factors associated with disease progression. Results A total of 382 children aged 1-18 years were included in the study (median age was 10.6 years; interquartile range: 6.4-13.8). There were 197 males (51.6%) and 185 females. CKD Stage 1 was diagnosed in 159 children (41.6%), Stage 2 in 160 (41.9%), Stage 3 in 51 (13.4%), and Stage 4 in 12 (3.1%). Fifty-six children (14.7%) experienced CKD progression. A multivariate analysis for all patients indicated that the risk for disease progression was increased in children with CKD secondary to a structural abnormality, genetic disease, anemia, elevated diastolic blood pressure, or elevated blood urea nitrogen. Compared with children with Stage 1 CKD, those with Stage 2 and Stage 4 CKD had decreased risk for CKD progression in this short-term cohort follow-up. Conclusion CKD etiology affects disease progression. Careful monitoring and treatment of anemia and elevated blood pressure in children with CKD may slow disease progression.

There is little information available on the association between primary renal disease (PRD) and long-term mortality in the pediatric dialysis population. The objective of this study was to explore mortality risks in children and adolescents on chronic dialysis, specifically focused on the risk of various PRDs. The study cohort included children and adolescents with end-stage renal disease (ESRD) (aged &lt, 20 years) who had received dialysis for at least 90 days between 2000 and 2014 and were identified from Taiwan&rsquo, s National Health Insurance medical claims. A total of 530 children and adolescents were included in the study. The median age of the included patients was 13.6 years and 305 (57.5%) patients were males. One hundred and seven patients died during the follow-up period and the median survival time was 6.0 years. Mortality was highest in the youngest patients. For patients with the following PRDs, mortality was significantly higher than that in patients with primary glomerulonephritis: secondary glomerulonephritis (adjusted hazard ratio (aHR): 2.50, 95% confidence interval (CI): 1.03&ndash, 6.08), urologic disorder (aHR: 4.77, 95% CI: 1.69&ndash, 13.46), and metabolic diseases (aHR: 5.57, 95% CI: 1.84&ndash, 16.85). Several kinds of PRDs appear to have high mortality risks in the pediatric dialysis population. These differences in mortality risk highlight the importance of the focused clinical management of these high-risk subgroups.

4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8Der p IT expanded CD8

Cardiac rhabdomyoma (CR) is the most common cardiac tumor in newborns. Approximately 75% of cases are associated with tuberous sclerosis complex. Although these tumors usually spontaneously regress after 2 years of age, they can be life-threatening when they obstruct major cardiac inflow or outflow pathways. Everolimus is an inhibitor of the mammalian target of rapamycin, reducing its production of the proteins harmartin and tuberin. Everolimus has demonstrated a remarkable suppression effect in children with tuberous sclerosis complex at doses of 4.7–5.6 mg/M2/day and serum trough levels of 5–15 ng/mL. Since 2012, five case reports of neonates with CR have also reported the tumor-regressing effect of everolimus. However, the optimal dosage for neonates is still unknown. Over the past 2 years, we have deliberately used a low dose everolimus regimen (0.3–0.67 mg/M2/day) in three neonates with large CRs, in an effort to maintain serum trough levels at 3–7 ng/mL. In all three cases, the tumors regressed smoothly within 2 months. Regarding the drug’s side effect of predisposing patients to infection, we observed that adenovirus pneumonia occurred in one case at 3 months of age, and chicken pox occurred in another case at 9 months of age; both recovered smoothly. Our three cases of neonatal CR demonstrate that a low-dose everolimus regimen is an effective treatment for tumor regression.

Aims Fibroblast growth factor 23 (FGF23) and Klotho are associated with vascular calcification and cardiovascular disease in dialysis patients. Sevelamer has been shown to reduce progression of vascular calcification. This study aimed to determine the long-term effect of sevelamer treatment on serum FGF23 and Klotho levels in chronic haemodialysis (HD) patients. Methods In the post-hoc analysis, we measured serum FGF23, Klotho and other biochemical factors (Ca, P, i-PTH, hsCRP, LDL-C) in 50 haemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. Twenty-three patients received sevelamer and 27 patients received calcium carbonate. Results After 48-week sevelamer treatment, there were significant changes with lower LDL-C (from 2.82 ± 0.78 to 1.65 ± 0.53 mmol/L, P = 0.000), lower FGF23 (from 2465.97 (2568.88) to 795.61 (1098.39), P = 0.000) and higher s-Klotho levels (from 189.35 (161.88) to 252.94 (517.80) pg/mL, P = 0.000). In calcium carbonate group, there were no significant changes of LDL-C and FGF23, but with a borderline significant increase of s-Klotho level (from 142.34 (265.24) to 188.57 (252.38) pg/mL, P = 0.054). Multivariate analysis showed that FGF23 decrement was associated with sevelamer treatment (β = −0.277, P = 0.005), change of serum phosphate (β = 0.609, P = 0.000) and calcium levels (β = 0.635, P = 0.000). The increase of serum Klotho was associated with the decrease of serum phosphate (β = 0.490, P = 0.019). Conclusion Maintenance HD patients had lower serum FGF23 levels, accompanied with significantly increased serum Klotho levels, after 48-week sevelamer treatment. The FGF23 decrement was associated with sevelamer use, the change of serum phosphate and calcium levels. The serum Klotho increment was proportional to the phosphate-lowering power of the binders.

Aim Multidisciplinary care (MDC) for patients with chronic kidney disease (CKD) may help to optimize disease care and improve clinical outcomes. Our study aimed to evaluate the effectiveness of pre-end-stage renal disease (ESRD) patients under MDC and usual care in Taiwan. Method In this 3-year retrospective observational study, we recruited 822 ESRD subjects, aged 18 years and older, initiating maintenance dialysis more than 3 months from five cooperating hospitals. The MDC (n = 391) group was cared for by a nephrologists-based team and the usual care group (n = 431) was cared for by sub-specialists or nephrologists alone more than 90 days before dialysis initiation. Patient characteristics, dialysis modality, hospital utilization, hospitalization at dialysis initiation, mortality and medical cost were evaluated. Medical costs were further divided into in-hospital, emergency services and outpatient visits. Results The MDC group had a better prevalence in peritoneal dialysis (PD) selection, less temporary catheter use, a lower hospitalization rate at dialysis initiation and 15% reduction in the risk of hospitalization (P

Regulatory T (Treg) cells play a central role in protecting against the development of allergic asthma and interleukin-10 (IL-10) producing T regulatory type 1 (Tr1) cells contribute to the regulation of asthma. Complement regulatory protein CD46 was shown to stimulate the development of IL-10 producing Tr1 cells. Crosslinking of CD46 during CD4+ T cell priming induces production of large amount of IL-10 and granzyme B. These CD46-induced regulatory T cells (Tr1) does not require pre-existing basal expression of FoxP3. Through local IL-10 and granzyme B secretion, such Tr1 cell could control T-cell-mediated inflammation. In asthmatic patients, we found that diminished IL-10, granzyme B, and CCR 4 expression from CD3/CD46-activated Tr1 cells. CD3/CD46-activated Tr1 cells from asthma patients co-cultured with BEAS-2B cells suppressed dermatophagoides pteronyssinus 2 (Der p 2)-induced nuclear factor-κB/p65 by cell contact inhibition. Decreased interaction of CD3/CD46-activated Tr1 and BEAS-2B cells from asthmatics was associated with downregulation of phosphorylation of protein kinase B expression. Decreased interaction between CD46-mediated Tr1 and lung epithelial cells with less IL-10 and granzyme B production may contribute to airway inflammation in allergic asthma. Der p specific immunotherapy enhances the suppressive function of IL-10 in CD46-mediated Tr1 cell from asthmatic patients and suppresses airway inflammation in these patients. Based on these results, it might be possible to design therapeutic strategies to manipulate complement activated Tr1 cells to achieve allergen tolerance and suppress airway inflammation in patients with allergic asthma.

The aim of this study was to: (a) analyze the results of a large-scale newborn screening program for Pompe disease, and (b) establish an effective diagnostic protocol to obtain immediate, valid diagnosis of infantile-onset Pompe disease (IOPD) to promote earlier treatment and better outcomes. In this study, 402,281 newborns were screened for Pompe disease from January 1, 2008 to May 1, 2012. Infants with low acid α-glucosidase (GAA) activity were referred to Taipei Veterans General Hospital for diagnostic confirmation. Physical examination, biochemical parameter (creatine kinase [CK], alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase), and echocardiogram assessments were performed immediately to effectively differentiate IOPD from suspected late-onset Pompe disease (LOPD) or false-positive cases with pseudodeficiency mutation. Six infants with IOPD all presented with hypotonia, extremely low GAA enzyme activity (≤0.5 µmol/L/hr) in initial dried blood spot analysis, high CK (≥250 U/L), and high left ventricular mass index (LVMI, ≥80 g/m(2)). By analyzing these parameters, IOPD was distinguished effectively and immediately from suspected LOPD and false-positive cases. Except for the first referred case, five of the infants with IOPD received first-time enzyme replacement therapy (ERT) within 4 hr of admission and exhibited marked improvement. Our findings indicate that certain clinical manifestations (hypotonia, high CK, enlarged LVMI, and extremely low GAA enzyme activity in initial dried blood spot analysis) can help in the rapid and effective differentiation of patients with IOPD from other patient with low GAA activity. Such differentiation allows for the early application of first-time ERT and leads to better outcomes.

Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement.The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD.To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919GA (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults.LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes.Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD.

Defective recruitment of regulatory T cells (Treg) function to the airway is important in the pathogenesis of allergic asthma. Complement regulatory protein (CD46) is a newly defined costimulatory molecule for Treg activation, which together with IL-10/granzyme B production may aid in suppressing asthmatic inflammation. This study examines chemotaxis and adhesion molecule expression on CD3/CD46-activated CD4(+) T cells (Tregs) from patients with and without asthma to suppress mite allergen-induced respiratory epithelial cells inflammation and to elucidate the mechanism of CD46-mediated Treg activation. Diminished IL-10/granzyme B and CCR4 expression from CD3/CD46-activated Tregs appeared in asthmatic subjects. CD3/CD46-activated Tregs from asthma patients co-cultured with BEAS-2B cells suppressed Dermatophagoides pteronyssinus 2 induced nuclear factor-κB/p65 by cell contact inhibition. Decreased interaction of CD3/CD46-mediated Tregs and BEAS-2B cells from asthmatics was associated with downregulated phosphorylation of protein kinase B (AKT) expression. Results provide the first evidence that decreased interaction between CD46-mediated Tregs and lung epithelial cells with less IL-10/granzyme B production may cause airway inflammation in allergic asthma.

Aim: The long-term survival of Taiwanese children with end-stage renal disease (ESRD) has not been reported before. This study aimed to determine the long-term survival, mortality hazards and causes of death in paediatric patients receiving dialysis. Methods: Paediatric patients (aged 19 years and younger) with incident ESRD who were reported to the Taiwan Renal Registry from 1995 to 2004 were included. A total of 319 haemodialysis (HD) and 156 peritoneal dialysis (PD) patients formed the database. After stratification by dialysis modality, multivariate Cox proportional-hazards model was constructed with age, sex and co-morbidity as predictive variables. Results: The annual paediatric ESRD incidence rate was 8.12 per million of age-related populations. The overall 1-, 5-, and 10-year survival rates for PD patients were 98.1%, 88.0% and 68.4%, respectively, and were 96.9%, 87.3% and 78.5% for HD patients. The survival analysis showed no significant difference between HD and PD (P = 0.4878). Using ‘15–19 years’ as a reference group, the relative risk (RR) of the youngest group (0–4 years) was 6.60 (95% CI: 2.50–17.38) for HD, and 5.03 (95% CI: 1.23–20.67) for PD. The death rate was 24.66 per 1000 dialysis patient-years. The three major causes of death were infection (23.4%), cardiovascular disease (13.0%) and cerebrovascular disease (10.4%). Hemorrhagic stroke (87.5%) was the main type of foetal cerebrovascular accident. Conclusion: We conclude that there was no significant difference of paediatric ESRD patient survival between HD and PD treatment in Taiwan. The older paediatric ESRD patients had better survival than younger patients.

The pathogenesis of renal involvement in Wiskott-Aldrich syndrome (WAS) is unclear and renal outcome is generally poor in such situations. Here we present the case of an 8-year-old boy with WAS who developed hematuria, proteinuria, and declining renal function that did not improve with the combined use of immunosuppressive agents and angiotensin-converting-enzyme inhibitor. Renal pathology revealed IgA nephropathy (IgAN). The patient underwent splenectomy for refractory thrombocytopenia. The proteinuria remitted and renal function improved after splenectomy, long-term antibiotic prophylaxis, and tapering of immunosuppressive agents.

BACKGROUND The question of which modality, either peritoneal dialysis (PD) or hemodialysis (HD), confers the survival advantage for incident ESRD patients with pre-existing cardiovascular disease (CVD) remains unanswered. METHODS Data used in this study were extracted from the National Health Insurance Research Database in Taiwan. From 1997 to 2007, incident ESRD patients who underwent dialysis longer than three months were selected. The established dialysis modality at day 90 was used to analyze the impact of dialysis modality on survival. For each PD patient indentified, five HD patients matched for age, sex, and year in which the patients received their first dialysis treatment were randomly selected. Finally, a total of 35 664 patients including 29 720 HD patients and 5944 PD patients were selected. The primary outcome was death after commencing dialysis. RESULTS For diabetic ESRD patients with or without coronary artery disease (CAD) or congestive heart failure (CHF), patients receiving PD had inferior survival compared with those receiving HD (P

Hypertension and hypertensive end-organ damage have been associated with decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) both can inhibit NO availability by competition with L-arginine (L-Arg). However, whether a combined analysis of these 3 parameters can serve as an ideal biomarker of hypertension remains unclear. We measured the plasma and renal levels of L-Arg, ADMA, and SDMA in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) control rats at 3 stages: 4 weeks old (prehypertensive), 12 weeks old (hypertensive), and 24 weeks old (end-organ damage). The plasma and renal L-Arg/ADMA ratio (AAR) and the ADMA/SDMA ratio (ASR) were computed for all 3 age stages. Our results revealed an ADMA level increase, and an AAR decrease in plasma and kidneys may develop early on, even before the onset of hypertension in 4-week-old SHRs. The renal ADMA level and AAR were restored in SHRs at 24 weeks of age, which might protect SHRs against kidney injury. We found that the plasma AAR is superior to the levels of L-Arg and ADMA in plasma, and it predicted blood pressure and urinary NOx levels. Renal AAR is a strong independent marker of renal dimethylarginine dimethylaminohydrolase (DDAH) activity. The plasma ASR was correlated strongly to blood pressure. However, renal DDAH activity was related to the renal ASR but not the plasma ASR. In conclusion, the AAR and ASR may serve as better markers for disease activity and progression than each individual parameter. Clinical use of these ratios to elucidate the role of ADMA in hypertension awaits further validation.

Aiming the extract of Cordyceps sinensis significantly inhibits airway inflammation, airway hyperresponsiveness, and the infiltration of eosinophils in the airway of rats and may be related to the modulation of T helper (Th)1 and Th2 cells functions. The mechanisms of C. sinensis involved in modulation of suppression inflammation are not yet determined. In this study, the mechanism involved in the extract of C. sinensis-C.S.3-modulated suppression of inflammation was investigated in vivo and in vitro systems. The results showed that C.S.3 reduced airway inflammation in ovalbumin-induced allergic mice. Furthermore, we found C.S.3 could decrease extracellular signal-regulated kinase 1/2 signaling pathway to suppress activity of nuclear factor-κB in lung cells and cultured airway smooth muscle cells. Conclusion C.S.3 may provide clinical applications for asthma in the future.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, decreases NO synthesis. Plasma ADMA concentrations increase markedly in hypertension. We tested whether the development of hypertension and the increases in ADMA in spontaneously hypertensive rats (SHR) are prevented by aliskiren, a renin inhibitor. Male SHRs and normotensive Wistar Kyoto (WKY) control rats, aged 4 weeks (pre-hypertensive stage), were assigned to 4 groups: untreated SHRs and WKY rats, and SHRs that received oral aliskiren 10 and 30 mg/kg/day for 6 weeks. All rats were sacrificed at age 10 weeks. Blood pressure decreased at age 6, 8, and 10 weeks in SHRs that received high-dose aliskiren. Aliskiren mitigated the increases in plasma ADMA in SHRs. Renal ADMA levels were lower in SHRs that received high-dose aliskiren versus SHRs. SHRs experienced decreased plasma and kidney l -Arg-to-ADMA ratios versus control rats, which were reverted by 30 mg/kg aliskiren. Renal cortical neuronal NOS-α and -β levels increased in SHRs fed with high-dose aliskiren. Early aliskiren treatment mitigates increases in ADMA, restores l -Arg-to-ADMA ratios, enhances neuronal NOS-α, prevents decreased nNOS-β levels in the kidney—which might restore NO bioavailability and contribute to the decrease of blood pressure in young SHRs. Our findings suggest that aliskiren is a therapeutic agent for prehypertension that regulates the ADMA/NO pathway.

Background. In dialysis patients, protein-energy wasting (PEW) is associated with high mortality, and some indicators of PEW, such as serum albumin value, subjective global assessment (SGA) score and handgrip strength (HGS), may predict mortality. However, whether PEW is associated with poor renal outcomes and whether the indicators of PEW can predict renal outcomes in patients with non-dialysis-dependent chronic kidney disease (CKD-ND) is still unclear.Methods. We enrolled 128 clinically stable patients with CKD-ND and followed up for 33.8 +/- 9.2 months. Baseline characteristics, echocardiographic information, laboratory data, HGS, SGA scores, anthropometric parameters, bio-impedance analyses and other indicators of PEW were examined in relation to the risk of reaching renal composite end points of pre-dialysis mortality or dialysis-dependent end-stage renal disease.Results. Twenty-six patients reached composite renal end points. Multivariate Cox regression analyses showed that HGS was an independent predictor of renal outcome in patients with CKD-ND of Stages 1-5 [CKD(1-5), hazard ratio (HR) = 0.90, P = 0.004] or advanced CKD-ND of Stages 3b [defined as estimated glomerular filtration rate (eGFR) of 30-44 mL/min/1.73m(2)] to 5 (CKD(3b-5), HR 0.91, P = 0.031), but not serum albumin, SGA score or other indicators of PEW. When the cutoffs were set at 24.65 kg in men with CKD(1-5), 20.15 kg in men with CKD(3b-5) and 10.15 kg in women with CKD(1-5) or CKD(3b-5), which were deduced from receiver-operating characteristics analyses, patients with lower HGS had significantly poor renal outcomes in Kaplan-Meier survival analyses in all subgroups and higher HR for reaching renal end points in multivariate Cox regression analyses in all subgroups except for women with CKD(3b-5), whose HR had marginal significance (HR = 3.78, P = 0.068) after adjusting for age and eGFR.Conclusions. This is the first study demonstrating that HGS is an independent predictor of composite renal outcomes in CKD-ND patients. HGS can be incorporated to clinical practice for assessing nutrition status and renal prognosis in patients with CKD-ND.