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.

High serum anti-Müllerian hormone concentrations have a negative impact on fertilization and embryo development rates.

RESEARCH QUESTION: What is the impact of high serum anti-Müllerian hormone (AMH) concentrations on fertilization and embryo development among infertile women undergoing treatment with assisted reproductive technology (ART)? DESIGN: Retrospective study of 1036 infertile women undergoing ART; women were divided into three groups according to serum AMH concentrations: AMH <1.1 ng/ml, 1.1-5.0 ng/ml and >5.0 ng/ml. The fertilization and embryo development rates of patients with different AMH concentrations and after stratification according to age were compared. RESULTS: Women with high AMH concentrations were younger and had higher testosterone concentrations (0.4 ± 0.13 versus 0.3 ± 0.12 versus 0.3 ± 0.08 µg/dl, P < 0.001) than women with low AMH concentrations. However, analysis of the embryo development rate showed negative outcomes for women with high AMH concentrations, including a poor fertilization rate (76.3 ± 17.36 versus 82.1 ± 19.15 versus 82.4 ± 25.38, P = 0.003), and poor day 3 embryo development rate (55.6 ± 23.88 versus 62.6 ± 26.52 versus 62.8 ± 32.65, P = 0.014). Multivariate linear regression analysis showed significantly negative correlations of the AMH concentrations with the fertilization rate (P < 0.001) and day 3 embryo development rate (P = 0.006). Subgroup analysis showed that age 30 years or younger had a significant negative correlation with AMH and the embryo development rate, including the fertilization rate (P < 0.001) and day 3 embryo development rate (P = 0.037). CONCLUSION: These results suggest that high serum AMH concentrations, contributing to a hyperandrogenic environment and leading to decreased oocyte developmental competence, may have a negative impact on fertilization and the early stage of embryo development in women undergoing treatment with ART.

Children with allergic rhinitis and a risk of epilepsy: A nationwide cohort study.

PURPOSE: Little is known about whether allergic disease is associated with a subsequent increased risk of childhood-onset epilepsy. We used a large, population-based cohort study to examine whether children with antecedent allergic rhinitis (AR) were associated with a subsequent increased risk of epilepsy. METHODS: This retrospective population-based cohort study was conducted by using data from the 2000-2012 Taiwan's National Health Insurance Research Database. We enrolled 67,537 children aged 0-18 years diagnosed with AR and 67,537 age- and gender-matched children without the diagnosis of AR. The incidence rate (per 10,000 person-years) of epilepsy was calculated. We used Cox proportional hazards regression analysis to estimate hazard ratios (HRs) and 95 % confident interval (CI). RESULTS: Of the 135,074 children included in the analyses, those with AR had a higher incidence rate of epilepsy (6.84 versus 3.95 per 10,000 person-years, p < 0.001) and an earlier age at diagnosis of epilepsy than those without AR [8.54 (4.90) versus 9.33 (5.40) years, p = 0.03)]. The Kaplan-Meier survival analysis demonstrated that the children with AR had a higher likelihood of developing epilepsy than those without AR (p < 0.001). After adjusting for confounding factors in multivariate model, children with AR had a 76 % increased risk of epilepsy (HR 1.76, 95 % CI 1.51-2.04) than those without AR. Boys had a 21 % increased risk of epilepsy (HR 1.21, 95 % CI 1.05-1.40) than girls. CONCLUSIONS: These results suggest that children with AR were associated with an increased subsequent risk of epilepsy.

Neonatal hyperbilirubinaemia is associated with a subsequent increased risk of childhood-onset type 1 diabetes.

Background: Type 1 diabetes (T1D) is one of the most common chronic diseases of childhood. Whether neonatal hyperbilirubinaemia increases the risk of T1D remains unclear.Aim: To estimate the association between neonatal hyperbilirubinaemia and phototherapy and the risk of T1D using a large nationwide population-based cohort.Methods: This retrospective study was conducted using data from the National Health Insurance Research Database in Taiwan from 2001 until 2005. Altogether, 23,784 neonates aged <30 days diagnosed with hyperbilirubinaemia and 47,568 neonates without hyperbilirubinaemia were enrolled and frequency-matched to the hyperbilirubinaemia group by gender, age, parental occupation and urbanisation. Cox regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI).Results: Of the 71,352 neonates included, those with hyperbilirubinaemia had a higher incidence of T1D (4.76 vs 2.68 per 10,000 person-years, p < 0.001) and an earlier mean age at onset of T1D [4.13 (2.80) vs 5.80 (2.67) years, p < 0.001] than those without hyperbilirubinaemia. After adjusting for confounding factors in multivariable analysis, the neonates with hyperbilirubinaemia had a 66% increased risk of developing T1D (HR 1.66, 95% CI 1.26-2.18). Girls had a 1.41-fold (HR 1.41, 95% CI 1.10-1.82) greater risk of T1D than boys. Additionally, neonates with a history of perinatal complications (HR 1.66, 95% CI 0.99-2.80) and neonatal infections (HR 2.13, 95% CI 1.45-3.15) had an increased subsequent risk of T1D.Conclusions: The results suggest that neonatal hyperbilirubinaemia is associated with a subsequently increased risk of childhood-onset T1D.Abbreviations: T1D, type 1 diabetes; CI, confidence interval; NHI, national health insurance; NHIA, National Health Insurance Administration; NHIRD, National Health Insurance Research Database; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; G6PD, glucose-6-phosphate dehydrogenase; LBW, low birthweight; HRs, hazard ratios.

Evaluation of efficacy and safety of Lactobacillus rhamnosus in children aged 4-48 months with atopic dermatitis: An 8-week, double-blind, randomized, placebo-controlled study.

OBJECTIVE: The main objective of this study was to evaluate the efficacy and safety of Lactobacillus rhamnosus in children aged 4-48 months with atopic dermatitis. METHODS: The design of this study was a two-center, double-blind, randomized, and placebo-controlled study with two parallel groups to evaluate the efficacy and safety profile of L. rhamnosus in children aged 4-48 months with atopic dermatitis diagnosed using Hanifin and Rajka criteria and with a Scoring of Atopic Dermatitis (SCORAD) ≥ 15 at enrollment. The duration of this study was 8 weeks with a total of five visits. The enrolled patients were allocated into either a treatment group (one ComProbi capsule containing L. rhamnosus a day) or a control group (one capsule of placebo a day) at a ratio of 1:1. The primary endpoint was to compare the mean change from baseline in SCORAD after 8 weeks of treatment. The other secondary end points were to compare the following: the mean changes from baseline in SCORAD at postbaseline visits, the frequency and total amount of the use of corticosteroids during the 8-week treatment, the frequency of atopic dermatitis and the symptom-free duration, the mean changes from baseline in Infant Dermatitis Quality of Life Questionnaire at Week 4 and Week 8, and the mean changes from baseline in the Dermatitis Family Impact Questionnaire at Week 4 and Week 8. RESULTS: The mean changes in SCORAD from baseline at Week 8 was -21.69 ± 16.56 in the L. rhamnosus group and -12.35 ± 12.82 in the placebo group for the intent-to-treat population (p = 0.014). For the per-protocol population, the mean change of SCORAD from baseline was -23.20 ± 15.24 in the L. rhamnosus group and -12.35 ± 12.82 in the placebo group (p = 0.003). Significant differences were demonstrated between groups at Week 8 in intensity in the intent-to-treat population and per-protocol population. Throughout the period, the amount of topical corticosteroids used showed no difference between groups. No significant difference was noted in the overall symptom-free durations compared with the placebo group. Infant Dermatitis Quality of Life Questionnaires and Dermatitis Family Impact Questionnaires scores improved significantly at Week 4 and Week 8 but did not reach statistical significance. Adverse events were documented in 14/33 patients in the L. rhamnosus group (42.42%, 35 events) and in 15/33 placebo patients (45.45%, 37 events). CONCLUSIONS: The results of this study indicated that L. rhamnosus was effective in decreasing symptoms of atopic dermatitis after an 8-week treatment by comparing the mean change of SCORAD from baseline with a placebo (p < 0.05). The reduction in SCORAD resulted from a consistent decrease in all components of SCORAD. Patients who took L. rhamnosus for 8 weeks expressed less SCORAD in the three components: area of affected skin, intensity of atopic dermatitis, and patient symptoms, with a significant decrease in the mean change of intensity from baseline compared with placebo.

Oral fungal immunomodulatory protein-Flammulina velutipes has influence on pulmonary inflammatory process and potential treatment for allergic airway disease: A mouse model.

BACKGROUND/PURPOSE: House dust mite (HDM) is well known as one of the major indoor allergens that trigger allergic inflammation, especially asthma, and accounts for 85% of all cases. So far, asthma has been thought of as a condition of imbalance between T helper (Th)1 and Th2. Fungal immunomodulatory protein-Flammulina velutipes (FIP-fve) has been seemingly demonstrated to modulate the response to Th1 cytokine production. The aim of this study was to investigate if the oral administration of FIP-fve can inhibit HDM-induced asthma inflammation in the mouse model. METHODS: We divided the mice (female BALB/c, 4-6 weeks) into four groups: the prevention group, which consisted of mice sensitized by HDM (intraperitoneally on Day 1, Day 7, and Day 14, and intranasally on Day 14, Day 17, Day 21, Day 24, and Day 27) fed with FIP-fve from Day 1 to Day 14; the treatment group, which comprised mice that received treatment from Day 14 to Day 28; the positive control (PC, sensitized by HDM fed without FIP-fve) group; and the negative control group (NC, nonsensitized). Airway hyperresponsiveness induced by methacholine challenge was determined using whole-body barometric plethysmography. In addition, cytokines were analyzed from bronchoalveolar lavage fluid and serum. Histopathological studies and Liu's staining method in mice lungs were also performed. RESULTS: The results showed that both pre- and posttreated FIP-fve groups had significantly reduced airway hyperresponsiveness compared with the PC group after methacholine challenge. In addition, a significantly decreased level of HDM-specific immunoglobulin E in serum and decreased production of Th2 cytokines in bronchoalveolar lavage fluid and serum were observed in these two FIP-fve fed groups. Moreover, more decreased amounts of infiltrating inflammatory cells were present in the lungs of FIP-fve fed groups than those of the PC group. CONCLUSION: Oral FIP-fve had an anti-inflammatory effect on the acute phase of the airway inflammatory process induced by HDM in the mouse model and might have a potentially therapeutic role for allergic airway diseases.

Antimicrobial Resistance and Diagnostic Imaging in Infants Younger Than 2 Months Old Hospitalized With a First Febrile Urinary Tract Infection: A Population-based Comparative Study.

BACKGROUND: Data on urinary tract infection (UTI) in infants ≤2 months of age are limited. We examined clinical characteristics, antimicrobial resistance, imaging findings and clinical outcomes in infants ≤2 months of age and children 2-24 months of age hospitalized with the first febrile UTI. METHODS: Children ≤24 months of age hospitalized with their first-diagnosed febrile UTI were prospectively studied. Renal ultrasonography, Tc-dimercaptosuccinic acid scanning and voiding cystourethrography were performed in all children. RESULTS: Of the 388 children analyzed (255 boys and 133 girls), 61 patients were ≤2 months of age, representing 15.7% of the whole population, whereas 327 patients were 2-24 months of age. Escherichia coli was the predominant bacterium, with similar antimicrobial resistance in the 2 groups, and associated E. coli bacteremia occurred in 9 patients (2.3%). Renal ultrasonography showed abnormal findings in 130 patients (33.5%), but there was no difference in the rate of abnormal findings between the groups. Vesicoureteral reflux (VUR) was present in 130 children (33.5%), including 93 (24%) with grades III-V VUR. VUR was more prevalent in the infants ≤2 months of age (P = 0.007), but there was no difference in the prevalence of grades III-V VUR between the groups. The incidence of renal scarring was 28.6% (111/388), and it did not differ between the groups. CONCLUSIONS: There are similarities in clinical characteristics, antimicrobial resistance, imaging findings and clinical outcomes after a first UTI between the young infants ≤2 months and children 2-24 months of age. The same guidelines for the diagnosis and management after the first febrile UTI can be applied to children who are ≤24 months of age.

Role of Renal Ultrasonography in Predicting Vesicoureteral Reflux and Renal Scarring in Children Hospitalized with a First Febrile Urinary Tract Infection.

BACKGROUND: This study was designed to examine the capability of renal ultrasonography (US) for predicting vesicoureteral reflux (VUR) and renal scarring (RS), and to assess, using initial US, the significant urologic abnormalities that impact on management of children hospitalized with a first febrile urinary tract infection (UTI). METHODS: Hospitalized children aged ≤ 2 years with a first febrile UTI were prospectively evaluated using imaging studies, including (99m)Tc dimercaptosuccinic acid (DMSA) scan, US, and voiding cystourethrography. RESULTS: Of the 310 children analyzed (195 boys and 115 girls), 105 (33.9%) had abnormal US. Acute DMSA scans were abnormal in 194 children (62.6%), including 89 (45.9%) with concomitant abnormal US. There was VUR in 107 children (34.5%), including 79 (25.5%) with Grades III-V VUR. The sensitivity and negative predictive values of US were 52.3% and 75.1%, respectively, for Grades I-V VUR and 68.4% and 87.8%, respectively, for Grades III-V VUR. Eighty-five children (27.4%) had RS, including 55 (64.7%) with abnormal US. Of the 105 children with abnormal US, 33 (31.4%) needed subsequent management (surgical intervention, parental counseling, or follow up of renal function). Nephromegaly on initial US and Grades III-V VUR were risk factors of RS. CONCLUSION: Abnormal US may carry a higher probability of Grades III-V VUR and RS, and can affect subsequent management in a significant number of children. Nephromegaly on initial US and Grades III-V VUR are strongly associated with an increased risk for RS. Thus, US should be performed on children after a first febrile UTI and children with normal US may not require voiding cystourethrography.

Necrotizing pneumonia and acute purulent pericarditis caused by Streptococcus pneumoniae serotype 19A in a healthy 4-year-old girl after one catch-up dose of 13-valent pneumococcal conjugate vaccine.

Streptococcus pneumoniae is a common cause of infectious diseases in children that may lead to life-threatening complications. Acute purulent pericarditis is an uncommon complication of S. pneumoniae in the antibiotic era. A healthy 4-year-old girl was admitted with pneumonia and pleural effusion. She had received one catch-up dose of 13-valent pneumococcal conjugate vaccine at 2 years of age. She rapidly developed necrotizing pneumonia, complicated by bronchopleural fistula presenting as subcutaneous emphysema and pneumothorax and acute purulent pericarditis. S. pneumoniae serotype 19A was subsequently identified from blood, empyema and pericardial fluid cultures. After appropriate antibiotic therapy and a right lower lobectomy, her condition stabilized and she promptly recovered. This case highlights two rare potential clinical complications of pneumococcal disease in a child: necrotizing pneumonia and acute purulent pericarditis. This is the first report of a child who received just one catch-up dose of 13-valent pneumococcal conjugate vaccine at 2 years of age, as per the United States' Advisory Committee on Immunization Practice's recommendations, but who still developed severe invasive pneumococcal disease with life-threatening complications caused by S. pneumoniae serotype 19A.

Extra-adrenal paraganglioma presenting as acute chest pain mimicking acute myocardial infarction in a 10-year-old boy.

Extraadrenal paragangliomas are rare pediatric tumors with variable symptoms that cause difficultly in diagnosis and delayed treatment. We report the case of a 10-year-old boy who presented to the pediatric emergency department with acute chest pain and dyspnea mimicking a non-ST-segment elevation acute myocardial infarction. He was subsequently found to have an extraadrenal paraganglioma after a series of imaging and laboratory examinations. The mass was subsequently removed, and the diagnosis of extraadrenal paraganglioma was confirmed histologically. Acute coronary syndrome as the presenting feature of extraadrenal paragangliomas in pediatric population is an even rarer clinical entity.

Comparison of the effects of air pollution on outpatient and inpatient visits for asthma: a population-based study in Taiwan.

BACKGROUND: A nationwide asthma survey on the effects of air pollution is lacking in Taiwan. The purpose of this study was to evaluate the time trend and the relationship between air pollution and health care services for asthma in Taiwan. METHODS: Health care services for asthma and ambient air pollution data were obtained from the National Health Insurance Research database and Environmental Protection Administration from 2000 through 2009, respectively. Health care services, including those related to the outpatient and inpatient visits were compared according to the concentration of air pollutants. RESULTS: The number of asthma-patient visits to health-care facilities continue to increase in Taiwan. Relative to the respective lowest quartile of air pollutants, the adjusted relative risks (RRs) of the outpatient visits in the highest quartile were 1.10 (P-trend  = 0.013) for carbon monoxide (CO), 1.10 (P-trend  = 0.015) for nitrogen dioxide (NO2), and 1.20 (P-trend <0.0001) for particulate matter with an aerodynamic diameter ≦ 10 µm (PM10) in the child group (aged 0-18). For adults aged 19-44, the RRs of outpatient visits were 1.13 (P-trend = 0.078) for CO, 1.17 (P-trend = 0.002) for NO2, and 1.13 (P-trend <0.0001) for PM10. For adults aged 45-64, the RRs of outpatient visits were 1.15 (P-trend = 0.003) for CO, 1.19 (P-trend = 0.0002) for NO2, and 1.10 (P-trend = 0.001) for PM10. For the elderly (aged ≥ 65), the RRs of outpatient visits in were 1.12 (P-trend  = 0.003) for NO2 and 1.10 (P-trend  = 0.006) for PM10. For inpatient visits, the RRs across quartiles of CO level were 1.00, 1.70, 1.92, and 1.86 (P-trend  = 0.0001) in the child group. There were no significant linear associations between inpatient visits and air pollutants in other groups. CONCLUSIONS: There were positive associations between CO levels and childhood inpatient visits as well as NO2, CO and PM10 and outpatient visits.

Comparison of procalcitonin and different guidelines for first febrile urinary tract infection in children by imaging.

BACKGROUND: We examined the ability of a procalcitonin (PCT) protocol to detect vesicoureteral reflux (VUR) and renal scarring (RS), evaluated procedural costs and radiation burden, and compared four representative guidelines for children with their first febrile urinary tract infection (UTI). METHODS: Children aged ≤2 years with their first febrile UTI who underwent renal ultrasonography (US), acute and late technetium-99m ((99m)Tc)-dimercaptosuccinic acid scan, and voiding cystourethrography were prospectively studied. The representative guidelines applied in a retrospective simulation included the American Academy of Pediatrics (AAP), National Institute of Clinical Excellence, top-down approach (TDA), and Italian Society of Pediatric Nephrology (ISPN). These were compared in terms of ability to detect abnormalities, procedural costs and radiation. RESULTS: Of 278 children analyzed, 172 (61.9%) had acute pyelonephritis. There was VUR in 101 (36.3%) children, including 73 (26.3%) with grades III-V VUR. RS was identified in 75 (27.0%) children. To detect VUR, TDA and PCT had the highest sensitivity for grades I-V VUR (80.2%) and III-V VUR (94.5%), respectively, whereas AAP had the highest specificity for I-V VUR (77.4%) and III-V VUR (78.0%), respectively. TDA and PCT had the highest sensitivity (100%) for detecting RS. The highest cost and radiation dose was associated with TDA, whereas AAP had the least expenditure and radiation exposure. By multivariate analysis, PCT and VUR, especially grades III-V, were independent predictors of RS. CONCLUSIONS: There is no perfect guideline for first febrile UTI children. The PCT protocol has good ability for detecting high-grade VUR and RS. If based on available imaging modalities and reducing cost and radiation burden, clinical suggestions in the AAP guidelines represent a considerable protocol.

Prevalence of childhood allergic diseases in central Taiwan over the past 15 years.

BACKGROUND: The prevalence of asthma, allergic rhinitis and atopic eczema in children from the developed and developing countries has been increasing. METHODS: Three epidemiological surveys of the prevalence of bronchial asthma, allergic rhinitis and atopic eczema in schoolchildren in Taichung, located in central Taiwan, were conducted in 1987, 1994, and 2002. The first questionnaire was used before the International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire was developed; the last two surveys were modified using ISAAC questionnaires. RESULTS: A total of 37,801, 75,960, and 11,580 children were studied in 1987, 1994 and 2002, respectively. The prevalence of allergic diseases had increased in the past two decades. Results indicate that the prevalence of bronchial asthma had risen, from 2.19% in 1987, and 3.54% in 1994, to 6.99% in 2002. Regardless of sex, the prevalence of bronchial asthma decreased with increasing age. The prevalence of allergic rhinitis was 5.1% in 1987, 12.46% in 1987, and 27.59% in 2002, and the prevalence of atopic eczema was 1.10% in 1987, 1.88% in 1994, and 3.35% in 2002. CONCLUSION: There has been a significant increase in the prevalence of bronchial asthma, allergic rhinitis and atopic dermatitis in Taichung schoolchildren from 1987 to 2002.

Association of a lymphotoxin-alpha gene polymorphism and atopic asthma in Taiwanese children.

BACKGROUND: The lymphotoxin-alpha (LT-alpha) gene is located on chromosome 6 (6p21.1-6p21.3) and it may regulate tumor necrosis factor (TNF) production. TNF is a potent cytokine in the airway inflammatory response. Polymorphisms of TNF-associated genes have been related to asthma. This study investigated an LT-alpha-Ncol polymorphism in the first intron of the LT-alpha gene (LT-alpha-Ncol*1 allele, as a variant type; and LT-alpha-Ncol*2 allele), which may predispose individuals to asthma and atopy. METHODS: Polymerase chain reaction-based assays were performed to determine LT-alpha-Ncol genotypes among our subjects. A genetic case control analysis was then performed on 114 atopic asthmatic and 155 non-asthmatic unrelated children. RESULTS: There was a statistically higher frequency of LT-alpha-Ncol*1 allele carriers (1/1+1/2) in the subjects with atopic asthma than in controls (OR=1.923; 95% CI = 1.061-3.484; p = 0.031). CONCLUSION: The results indicate that LT-alpha-Ncol*1 may be a risk factor for atopic asthma in Taiwanese children.

Anterior mediastinal immature teratoma with precocious puberty in a child with Klinefelter syndrome.

Klinefelter syndrome occurs in approximately 1 in 1000 males. A 4-year-old boy presented with precocious puberty and an anterior mediastinal mass. Serum alpha-fetoprotein and human chorionic gonadotropin levels were mildly increased. Computed tomography revealed a germ cell tumor (GCT) of the mediastinum. Complete resection of the tumor was performed. Histologic analysis revealed an immature teratoma. Males with Klinefelter syndrome develop GCTs at a rate 50 times higher than unaffected males. This case report calls attention to the need to rule out Klinefelter syndrome in boys who present with precocious puberty and a mediastinal GCT.