Asthma control associated with anxiety and depression in asthmatic children following post-acute COVID-19.

BACKGROUND: Poor asthma control may adversely affect mental health. Our study investigates the correlation between inadequate asthma control, exhaled nitric oxide (FENO) levels, and anxiety and depression among pediatric asthma patients with COVID-19. METHODS: This prospective case-control study enrolled 520 asthmatic children (8-15 years), including 336 patients diagnosed with COVID-19 after rapid antigen testing at home and 184 age-matched asthmatic patients without COVID-19 infection. FENO and spirometry were performed 1 month after COVID-19 infection. Scores for Child Anxiety-Related Disorders (SCARED) and depression screen derived from Patient Health Questionnaire-9 (PHQ-9) to assess their mental health status. Childhood asthma control test (C-ACT), FENO levels, and spirometry were correlated with the SCARED and PHQ-9 questionnaires. RESULTS: SCARED subscales, including generalized anxiety disorder, social anxiety disorder, school avoidance, and depression scores from PHQ-9, exhibited a significant increase in asthmatic patients diagnosed with COVID-19 (p < .05). Among asthmatic children with SARS-CoV-2 infection, the poor asthma control group exhibited the highest SCARED and PHQ-9 measurements (p < .01). Multiple linear regression analysis indicated that reduced C-ACT scores and elevated FENO levels in asthmatic children with COVID-19 were significant risk factors for both anxiety and depression scores (p < .05). Lower C-ACT scales were associated with high scores of SCARED (r = -0.471) and PHQ-9 (r = -0.329) in asthmatic children (p < .001). CONCLUSIONS: The current study emphasizes the need for healthcare professionals to closely monitor asthma control in asthmatic children to prevent heightened risks of depression and anxiety during the ongoing COVID-19 pandemic.

Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: 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.

Angiotensin II receptor blocker irbesartan attenuates sleep apnea-induced cardiac apoptosis and enhances cardiac survival and Sirtuin 1 upregulation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Intravenous immunoglobulin therapy enhances suppressive regulatory T cells and decreases innate lymphoid cells in children with immune thrombocytopenia.

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 < 0.05). Significantly lower Tregs and higher ILC1, ILC3, DCs, and serum IL-17A levels were noted in the partial responders (n = 8) versus responders (n = 22; P < 0.05). We found that Tregs suppressed proliferation of ILCs and CD4+ T cells in CD25-depleted peripheral PBMCs and enhanced the apoptosis of CD4+ CD45RO+ T cells in vitro following IVIG therapy. CONCLUSIONS: Effective high-dose IVIG therapy for children with newly diagnosed ITP appears to result in the induction of Tregs, which suppresses ILC proliferation in vitro and is associated with platelet response.

Allergen-specific immunotherapy enhances CD8+ CD25+ CD137+ regulatory T cells and decreases nasal nitric oxide.

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-ß 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.

IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy.

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-ß1) 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-ß1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-ß1, 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.

The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3+IL-17+ T cells.

BACKGROUND: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4+ forkhead box P3 (FOXP3)+ T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3+IL-17+ T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear. METHODS: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. The study groups included control and UUO mice that were monitored for 7, 14 or 21 days. RESULTS: Juxtaglomerular (JG) hyperplasia, angiotensin II type 1 receptor (AT1R) expression and lymphocyte infiltration were observed in renal tissues after UUO but were decreased after trichostatin A (TSA) treatment, a HDAC inhibitor. The number of CD4+FOXP3+ T cells increased progressively, along with the number of FOXP3+interleukin (IL)-17+ T cells, after 14 days, and their numbers then progressively decreased with increasing CD4+IL-17+ T cell numbers, as demonstrated by double immunohistochemistry. Progressive renal fibrosis was associated with the loss of CD4+FOXP3+IL-17+ T cells in splenic single-cell suspensions. FOXP3+IL-17+ T cells expressed TGF-ß1 both in vitro and in vivo, and TGF-ß1 expression was significantly knockdown by IL-17 siRNA in vitro. These cells were found to play a role in converting Tregs into IL-17- and TGF-ß1-producing cells. CONCLUSIONS: TSA treatment decreased JG hyperplasia, the percentage of FOXP3+IL-17+ cells and the degree of fibrosis, suggesting that therapeutic benefits may result from epigenetic modifications.

Regression of Neonatal Cardiac Rhabdomyoma in Two Months Through Low-Dose Everolimus Therapy: A Report of Three Cases.

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.

Clinical characteristics and prevalence of complications of chronic kidney disease in children: the Taiwan Pediatric Renal Collaborative study.

BACKGROUND: Little information is available regarding the clinical characteristics and prevalence of complications in children with chronic kidney disease (CKD), especially in early disease stages. The objective of this study was to determine the clinical characteristics and prevalence of complications in children with predialytic CKD. METHODS: This multicenter, cross-sectional study enrolled children at all stages of predialytic CKD. Children who were between the ages of 1 year and 18 years and who fulfilled the clinical criteria of CKD were included in the study. Baseline demographic data, previous history, clinical characteristics, and laboratory data were collected. RESULTS: A total of 757 children were included in the study. The median age at the time of enrollment was 10.6 years; 397 patients (52.4 %) were males. A total of 39.0 % of the patients were in CKD stage 1, 37.6 % were in stage 2, 14.8 % were in stage 3, 3.0 % were in stage 4, and 5.5 % were in stage 5. Nonglomerular renal diseases were the primary cause of CKD, comprising 51.9 % of the patients with CKD. The age at disease onset, gender, CKD stage distribution, and proportion of co-morbidities varied between the glomerular and nonglomerular CKD cases. Anemia, hyperlipidemia, hypocalcemia, and hyperphosphatemia were more prevalent in patients with glomerular CKD. The overall prevalence of complications was as follows: uncontrolled blood pressure, 44.1 %; anemia, 34.2 %; hyperlipidemia, 44.9 %; short stature, 10.3 %; and failure to thrive, 8.2 %. Uncontrolled blood pressure (BP), anemia, and hyperlipidemia were common, even in the early CKD stages. The prevalence of CKD complications generally increased with the worsening stage of CKD. CONCLUSIONS: This study reveals differences in CKD etiology and prevalence of specific complications according to the stage of CKD. Early recognition and awareness of complications are mandatory for clinicians during the follow-up visits of children with CKD.

Etiology and pediatric chronic kidney disease progression: Taiwan Pediatric Renal Collaborative Study.

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.

A large-scale nationwide newborn screening program for Pompe disease in Taiwan: towards effective diagnosis and treatment.

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.

Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients.

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 (ß = -0.277, P = 0.005), change of serum phosphate (ß = 0.609, P = 0.000) and calcium levels (ß = 0.635, P = 0.000). The increase of serum Klotho was associated with the decrease of serum phosphate (ß = 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.

Multidisciplinary care improves clinical outcome and reduces medical costs for pre-end-stage renal disease in Taiwan.

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 < 0.05). After adjusting for gender, age and Charlson Comorbidity Index score, there were lower in-hospital and higher outpatient costs in the MDC group during 3 months before dialysis initiation (P < 0.05). In contrast, medical costs (NT$ 146,038 vs 79,022) and hospitalization days (22.4 vs 15.5 days) at dialysis initiation were higher in the usual care group. Estimated medical costs during 3 months before dialysis till dialysis initiation, the MDC group yielded a reduction of NT$ 59,251 for each patient (P < 0.001). Patient mortality was not significantly different. CONCLUSION: Multidisciplinary care intervention for pre-ESRD patients could not only significantly improve the quality of disease care and clinical outcome, but also reduce medical costs.

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

IMPORTANCE: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Spectrum of PHEX Mutations and FGF23 Profiles in a Taiwanese Cohort With X-Linked Hypophosphatemia Including 102 Patients.

BACKGROUND/AIM: X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. PATIENTS AND METHODS: We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. RESULTS: The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. CONCLUSION: Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.

Analysis of androgen receptor and anti-Müllerian hormone pathways in human granulosa cells under luteinizing hormone treatment.

BACKGROUND: The objective of this study was to determine the gene expression profiles of the androgen/androgen receptor (AR) and anti-Müllerian hormone (AMH)/ Sry-related high-mobility group box 9 (SOX9) pathways in granulosa-luteal cells from patients undergoing standard in vitro fertilization (IVF) with or without recombinant luteinizing hormone (rLH) therapy. METHODS: Levels of reproductive hormones in the pre-ovulatory follicular fluid and the expression levels of LHR (luteinizing hormone receptor), AR, SOX9, AMH, AR-associated protein 54(ARA54)and ARA70 were determined in granulosa-luteal cells by real-time reverse-transcription PCR. The effects of androgen and rLH treatments on AR and AMH expression levels were also tested in vitro using HO23 cells. RESULTS: We collected 35 an 70 granulosa cell samples from patients cycled with and without rLH supplementation, respectively. The clinical outcomes were similar in patients who received rLH therapy and those who did not, though the pre-ovulatory follicular fluid levels of androstenedione, testosterone, and estradiol were significantly higher and progesterone was lower in the rLH supplementation group. Moreover, granulosa-luteal cell mRNA levels of LHR, AR, AMH, and SOX9 were significantly higher in the rLH supplementation group relative to the group that did not receive rLH supplementation. In addition, we observed significant correlations between LHR and AR mRNA expression and among AR, AMH, and SOX9 mRNA expression in granulosa-luteal cells from patients undergoing standard IVF treatment. CONCLUSIONS: Increased expression of LHR, AR, AMH, and SOX9 is characteristic of granulosa-luteal cells from IVF/ intracytoplasmic sperm injection (ICSI) patients receiving rLH supplementation.

Effectiveness of multidisciplinary care for chronic kidney disease in Taiwan: a 3-year prospective cohort study.

BACKGROUND: Previous studies have demonstrated that multidisciplinary pre-dialysis education and team care may slow the decline in renal function for chronic kidney disease (CKD). Our study compared clinical outcomes of CKD patients between multidisciplinary care (MDC) and usual care in Taiwan. METHODS: In this 3-year prospective cohort study from 2008 to 2010, we recruited 1056 CKD subjects, aged 20-80 years, from five hospitals, who received either MDC or usual care, had an estimated glomerular filtration rate (eGFR) <60 mL/min, were matched one to one with the propensity score including gender, age, eGFR and co-morbidity diseases. The MDC team was under-cared based on NKF K/DOQI clinical practice guidelines and the Taiwanese pre-end-stage renal disease (ESRD) care program. The incidence of progression to ESRD (initiation of dialysis) and mortality was compared between two groups. We also monitored blood pressure control, the rate of renal function decline, lipid profile, hematocrit and mineral bone disease control. RESULTS: Participants were prone to be male (64.8%) with a mean age of 65.1 years and 33.1 months of mean follow-up. The MDC group had higher prescription rates of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), phosphate binder, vitamin D3, uric acid lower agents and erythropoietin-stimulating therapy and better control in secondary hyperparathyroidism. The decline of renal function in advanced stage CKD IV and V was also slower in the MDC group (-5.1 versus -7.3 mL/min, P = 0.01). The use of temporary dialysis catheter was higher in the usual care group, and CKD patients under MDC intervention exhibited a greater willingness to choose peritoneal dialysis modality. A Cox regression revealed that the MDC group was associated with a 40% reduction in the risk of hospitalization due to infection, and a 51% reduction in patient mortality, but a 68% increase in the risk of initiation dialysis when compared with the usual care group. CONCLUSIONS: MDC patients were found to have more effective medication prescription according to K/DOQI guidelines and slower renal function declines in advanced/late-stage CKD. After MDC intervention, CKD patients had a better survival rate and were more likely to initiate renal replacement therapy (RRT) instead of mortality.

Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous multisystem inflammatory disease with wide variability in clinical manifestations. Natural arising CD4+ regulatory T cells (Tregs) play a critical role in maintaining peripheral tolerance by suppressing inflammation and preventing autoimmune responses in SLE. Additionally, CD8+ regulatory T cells, type 1 regulatory T cells (Tr1), and B regulatory cells also have a less well-defined role in the pathogenesis of SLE. Elucidation of the roles of various Treg subsets dedicated to immune homeostasis will provide a novel therapeutic approach that governs immune tolerance for the remission of active lupus. Diminished interleukin (IL)-2 production is associated with a depleted Treg cell population, and its reversibility by IL-2 therapy provides important reasons for the treatment of lupus. This review focuses on the pathogenesis and new therapeutics of human Treg subsets and low-dose IL-2 therapy in clinical benefits with SLE.

Macrophage migration inhibitory factor increases cell motility and up-regulates αvß3 integrin in human chondrosarcoma cells.

The macrophage migration-inhibitory factor (MIF) is a pro-inflammatory cytokine first known for its effect on macrophage migration and activation. Recent studies have shown that MIP plays a critical role in tumor growth, angiogenesis, and metastasis. Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effects of MIF on human chondrosarcoma cells are largely unknown. In the present study, MIF was found to increase the migration and the expression of αvß3 integrin in human chondrosarcoma cells. The phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB pathways were activated by MIF treatment, and the MIF-induced expression of integrin and migration activity were inhibited by the specific inhibitors and mutant forms of PI3K, Akt, and NF-κB cascades. In addition, migration-prone sublines demonstrated that increased cell migration ability was correlated with increased expression of MIF and αvß3 integrin. Taken together, our results indicate that MIF enhanced the migration of the chondrosarcoma cells by increasing αvß3 integrin expression through the PI3K/Akt/NF-κB signal transduction pathway.

Functional defects of CD46-induced regulatory T cells to suppress airway inflammation in mite allergic asthma.

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.