Antenatal Corticosteroid Exposure is Associated with Childhood Mental Disorders in Late Preterm and Term Infants.

OBJECTIVES: To study the association between antenatal corticosteroids treatment and childhood mental disorders in infants born at different gestational ages, and to investigate the effect of different administration timing. STUDY DESIGN: This population-based cohort study used data from the Taiwan National Health Insurance Research Database. All singleton live births born between 2004 and 2010 were enrolled and followed up for at least 6 years. The primary outcome was any childhood mental disorder. Secondary outcomes included 7 specific subgroups of mental disorders. RESULTS: A total of 1 163 443 singleton infants were included in the analysis, and 16 847 (1.45%) infants were exposed to antenatal corticosteroid treatment. Children exposed to antenatal corticosteroids were found to have a higher risk of developing childhood mental disorders in the entire cohort (hazard ratio [HR], 1.13; 95% CI, 1.08-1.18), the term group (HR, 1.11; 95% CI, 1.05-1.16), and the late-preterm group (HR, 1.15; 95% CI, 1.06-1.25). The administration of corticosteroids in the early stage of pregnancy (<28 weeks of gestation) significantly increased the risk of childhood mental disorders (HR, 1.22; 95% CI, 1.14-1.31). CONCLUSIONS: Exposure to antenatal corticosteroid treatment increases the cumulative risk of childhood mental disorders and attention deficit hyperactivity disorders, both in term and late preterm infants. The administration of corticosteroids in the early stage of pregnancy tends to increase the risk of mental disorders.

Efficacy of a Novel Palivizumab Prophylaxis Protocol for Respiratory Syncytial Virus Infection in Congenital Heart Disease: A Multicenter Study.

OBJECTIVE: To analyze the efficacy of a novel palivizumab protocol for hemodynamically significant congenital heart disease (hsCHD) in subtropical areas without clear respiratory syncytial virus seasonality. STUDY DESIGN: Since July 2013, the National Health Insurance program has provided reimbursement for palivizumab prophylaxis with a novel monthly protocol in selected patients with hsCHD under 1 year of age. We performed a multicenter study to assess the trend of respiratory syncytial virus hospitalizations in patients with hsCHD from 2010 to 2016 during the prepalivizumab, transition, and postpalivizumab periods, and compared treatment and propensity-matched control groups. RESULTS: A total of 747 patients were enrolled in the study group and 809 in the control group. The male:female was 836:720. Cyanotic CHD was observed in 42.9% of patients. The mean age at diagnosis of CHD was 32.9 days. After 516 685 patient-days of follow-up and a mean of 3.9 doses of palivizumab in the treatment group, respiratory syncytial virus hospitalization rates decreased by 53% and 49% before and after match compared with the control group (P = .009 and .029, respectively). Hospitalization days and intensive care unit admission rate also decreased similarly in the treatment group. The efficacy of this protocol was more prominent in patients with cyanotic hsCHD. The annual respiratory syncytial virus-associated hospitalization rates also decreased significantly from the prepalivizumab to the palivizumab period (from 4.8% to 2.0%; P = .038). CONCLUSION: Palivizumab prophylaxis through the novel monthly protocol for patients with hsCHD is effective in reducing respiratory syncytial virus-related hospitalizations.

Three-dimensional structure and cytokine distribution of platelet-rich fibrin.

OBJECTIVES:: Previous reports have revealed that several cytokines (including platelet-derived growth factor-BB, transforming growth factors-ß1 and insulin-like growth factor-1) can enhance the rate of bone formation and synthesis of extracellular matrix in orthopaedics or periodontology. This study aimed to determine the concentration of cytokines within platelet-rich fibrin microstructures and investigate whether there are differences in the different portions of platelet-rich fibrin, which has implications for proper clinical use of platelet-rich fibrin gel. METHODS:: Whole blood was obtained from six New Zealand rabbits (male, 7 to 39 weeks old, weight 2.7-4 kg); it was then centrifuged for preparation of platelet-rich fibrin gels and harvest of plasma. The resultant platelet-rich fibrin gels were used for cytokine determination, histological analyses and scanning electron microscopy. All plasmas obtained were subject to the same cytokine determination assays for the purpose of comparison. RESULTS:: Cytokines platelet-derived growth factor-BB and transforming growth factor-ß1 formed concentration gradients from high at the red blood cell end of the platelet-rich fibrin gel (p=1.88×10-5) to low at the plasma end (p=0.19). Insulin-like growth factor-1 concentrations were similar at the red blood cell and plasma ends. The porosities of the platelet-rich fibrin samples taken in sequence from the red blood cell end to the plasma end were 6.5% ± 4.9%, 24.8% ± 7.5%, 30.3% ± 8.5%, 41.4% ± 12.3%, and 40.3% ± 11.7%, respectively, showing a gradual decrease in the compactness of the platelet-rich fibrin network. CONCLUSION:: Cytokine concentrations are positively associated with platelet-rich fibrin microstructure and portion in a rabbit model. As platelet-rich fibrin is the main entity currently used in regenerative medicine, assessing cytokine concentration and the most valuable portion of PRF gels is essential and recommended to all physicians.

Three-dimensional structure and cytokine distribution of platelet-rich fibrin

OBJECTIVES: Previous reports have revealed that several cytokines (including platelet-derived growth factor-BB, transforming growth factors-β1 and insulin-like growth factor-1) can enhance the rate of bone formation and synthesis of extracellular matrix in orthopaedics or periodontology. This study aimed to determine the concentration of cytokines within platelet-rich fibrin microstructures and investigate whether there are differences in the different portions of platelet-rich fibrin, which has implications for proper clinical use of platelet-rich fibrin gel. METHODS: Whole blood was obtained from six New Zealand rabbits (male, 7 to 39 weeks old, weight 2.7-4 kg); it was then centrifuged for preparation of platelet-rich fibrin gels and harvest of plasma. The resultant platelet-rich fibrin gels were used for cytokine determination, histological analyses and scanning electron microscopy. All plasmas obtained were subject to the same cytokine determination assays for the purpose of comparison. RESULTS: Cytokines platelet-derived growth factor-BB and transforming growth factor-β1 formed concentration gradients from high at the red blood cell end of the platelet-rich fibrin gel (p=1.88×10-5) to low at the plasma end (p=0.19). Insulin-like growth factor-1 concentrations were similar at the red blood cell and plasma ends. The porosities of the platelet-rich fibrin samples taken in sequence from the red blood cell end to the plasma end were 6.5% ± 4.9%, 24.8% ± 7.5%, 30.3% ± 8.5%, 41.4% ± 12.3%, and 40.3% ± 11.7%, respectively, showing a gradual decrease in the compactness of the platelet-rich fibrin network. CONCLUSION: Cytokine concentrations are positively associated with platelet-rich fibrin microstructure and portion in a rabbit model. As platelet-rich fibrin is the main entity currently used in regenerative medicine, assessing cytokine concentration and the most valuable portion of PRF gels is essential and recommended to all physicians.

Progressive Coronary Dilatation Predicts Worse Outcome in Kawasaki Disease.

OBJECTIVE: To explore the implication of serial coronary changes on the late coronary outcomes in patients with Kawasaki disease (KD) with coronary aneurysms ≧ 4 mm. STUDY DESIGN: We performed a retrospective review of 78 patients with KD with large coronary aneurysms (1980-2013, male: 76.9%; 792 patient-years). Progressive coronary dilatation was defined for those with progressive enlargement of coronary arteries in 3 consecutive echocardiograms. RESULTS: We studied 27 patients with KD with giant aneurysms (≧ 8 mm) and 51 patients with KD with medium aneurysms (4-8 mm). All the giant and 43.1% of medium aneurysms persisted during the study period. For the patients with giant aneurysms, their 10-year freedom from acute myocardial infarction/cardiovascular death and all ischemia was 66% and 52%, respectively. The median intervals for the aneurysm diameters reaching their peak were 3.3 months (giant) and 0.25 months (medium), respectively. In patients with giant aneurysms, the 10-year freedom from ischemia was much lower in those with progressive coronary dilatation (28% vs 59%, P = .021). In patients with medium aneurysms, the probability of 5-year persistence of aneurysm was much greater (67.2% vs 14.8%, P < 10(-3)) in those with progressive coronary dilatation. Male sex and intravenous immunoglobulin therapy were not associated with the late outcomes in the patients with KD who had aneurysms larger than 4 mm. CONCLUSIONS: In addition to coronary diameters 1 month after the onset of KD, progressive coronary dilatation at 2 or more months after diagnosis may be an indicator of duration, and the severity of vasculitis and adverse dilative remodeling were associated with worse late coronary outcomes.

Risk of Respiratory Syncytial Virus Infection in Cyanotic Congenital Heart Disease in a Subtropical Area.

OBJECTIVE: To compare the risk of respiratory syncytial virus (RSV)-associated hospitalization and analyze the epidemiology of RSV infection in patients with cyanotic and acyanotic congenital heart disease (CHD), we analyzed the nationwide health insurance database from 2005-2010. STUDY DESIGN: This study included 1050 patients with cyanotic CHD and 7077 patients with acyanotic CHD. Patients with acyanotic CHD were further classified into hemodynamically significant (hs)-acyanotic and non-hs-acyanotic groups according to whether they underwent surgery or took at least 2 anticongestive medications. RESULTS: RSV-associated hospitalization was higher in the cyanotic group than in hs-acyanotic and non-hs-acyanotic groups both before 1 year of age (4.8% vs 2.1% vs 1.5%, P < .001) and between 1 and 2 years of age (0.9% vs 0.56% vs 0.14%, P = .003). The hospitalization duration, intensive care, ventilator support prevalence, hospitalization cost, and mortality rate were significantly higher in the cyanotic group than in the other 2 groups. Logistic regression revealed that cyanotic CHD was the most significant risk factor for the ventilator support and RSV-associated mortality. In both patients with cyanotic and acyanotic CHD, RSV-associated hospitalization rate was higher in patients aged younger than 1 year and in spring and autumn in Taiwan, a subtropical country. CONCLUSIONS: The results show that patients with cyanotic CHD have a higher risk of severe RSV infection than do those with acyanotic CHD. RSV prophylaxis is more important and may reduce costs more for patients with cyanotic CHD.

Severe bacterial infection in patients with heterotaxy syndrome.

OBJECTIVE: To determine the incidence of sepsis in patients with heterotaxy syndrome. STUDY DESIGN: From our institutional database, we identified patients with heterotaxy syndrome and other complex congenital heart disease (CHD) born between 2001 and 2011. Severe bacterial infection was defined as sepsis with positive culture result or infection with abscess formation. RESULTS: We enrolled 95 patients with heterotaxy syndrome (88 with right atrial isomerism and 7 with left atrial isomerism) and 142 patients with complex CHD. With 1026 person-years follow-up, the 5-year survival was 52% and 65.7% in heterotaxy and complex CHD groups, respectively (P = .239). Community-acquired severe bacterial infection occurred only in heterotaxy syndrome (13 episodes in 10 patients, 3 of whom had spleen noted at imaging study) with 2- and 5 years cumulative severe bacterial infection rate of 9.6% and 14.5%, respectively. The overall mortality rate of those with community-acquired severe bacterial infection was 31%. Pneumococcus and Citrobacter freundii were the most common pathogens. Nosocomial severe bacterial infection occurred in 33.3% of all patients and 12.5% of all procedures. The rates (0.59 and 0.52/100 hospitalization days in heterotaxy and complex CHD group) and the pathogens of nosocomial severe bacterial infection were similar between heterotaxy and complex CHD groups. CONCLUSIONS: Patients with heterotaxy syndrome are at high risk for community-acquired severe bacterial infection and also have high mortality rate whether the spleen is present or not. The risk of nosocomial severe bacterial infection seems similar to that of patients with other complex CHD.

Atopic diathesis in patients with Kawasaki disease.

OBJECTIVE: To determine the association between Kawasaki disease (KD) and atopic diathesis (atopic dermatitis [AD], allergic rhinitis, and asthma) in children younger than 5 years of age. STUDY DESIGN: In this nationwide study, we aimed to analyze the association and temporal relationship between KD and atopic diathesis. Data were obtained from the National Health Insurance Research Database of Taiwan from 1997 to 2010. In total, 200 patients with KD younger than 5 years of age and 800 age- and sex-matched control subjects were enrolled. RESULTS: In the whole study population, an increased risk of any concomitant atopic diseases was observed in patients with KD (OR 1.61, 95% CI 1.15-2.26). The risk of AD was increased in male patients between 1 and 5 years of age (OR 3.02, 95% CI 1.22-7.50). More than 60% of the patients developed atopic diseases after the diagnosis of KD. CONCLUSION: There appears to be an association between KD and risk of AD. Most of the atopic diseases occurred after the episode of KD.

Long-term outcomes of pediatric sinus bradycardia.

OBJECTIVES: To delineate the long-term outcomes and mechanisms of pediatric sinus bradycardia. STUDY DESIGN: Participants with sinus bradycardia who were identified from a survey of 432,166 elementary and high school students, were enrolled 10 years after the survey. The clinical course, heart rate variability, and hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene were assessed. RESULTS: A total of 104 (male:female was 60:44; prevalence, 0.025%) participants were observed to have sinus bradycardia at age 15.5 ± 0.2 years with a mean heart rate of 48.4 ± 0.4 beats per minute; 86 study participants (83%) responded to clinical assessment and 37 (36%) underwent laboratory assessment. Athletes composed 37.8% of the study participants. During the extended 10-year follow-up, 15 (17%) of the participants had self-limited syncopal episodes, but none had experienced life-threatening events. According to Holter recordings, none of the participants had heart rate <30 beats per minute or a pause longer than 3 seconds. Compared with 67 age- and sex-matched controls, the variables of heart rate based on the spectral and time domain analysis of the participants with sinus bradycardia were all significantly higher, indicating higher parasympathetic activity. The results of mutation analysis were negative in the HCN4 gene in all of our participants. CONCLUSIONS: The long-term outcomes of the children and adolescents with sinus bradycardia identified using school electrocardiographic survey are favorable. Parasympathetic hyperactivity, instead of HCN4 gene mutation, is responsible for the occurrence of sinus bradycardia.

Detection of flaviviruses and orthobunyaviruses in mosquitoes in the Yucatan Peninsula of Mexico in 2008.

A total of 191,244 mosquitoes from 24 species were collected in the Yucatan Peninsula of Mexico from January to December 2008, and tested for the presence of cytopathic virus by virus isolation in Vero cells. Eighteen virus isolates were obtained, all of which were orthobunyaviruses. These were identified by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing as Cache Valley virus (n=17) and South River virus (n=1). A subset (n=20,124) of Culex quinquefasciatus collected throughout the year was further tested by RT-PCR using flavivirus-specific primers. Flavivirus RNA was present in this mosquito species year-round. The overall flavivirus minimal infection rate, expressed as the number of positive mosquito pools per 1000 mosquitoes tested, was 7.7 and the monthly flavivirus minimal infection rates ranged from 4.3 to 16.6. Approximately one-third of the RT-PCR products were sequenced and all corresponded to Culex flavivirus, a recently discovered insect-specific flavivirus.

Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis.

Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1-q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRbeta), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRbeta through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology.

Reversal of cardiac dysfunction after enzyme replacement in patients with infantile-onset Pompe disease.

OBJECTIVE: To compare the effects of enzyme replacement therapy (ERT) on cardiac performance in symptomatic and symptom-free infants with Pompe disease. STUDY DESIGN: Patients diagnosed between 1983 and 2008 were identified. Before the initiation of ERT, systolic dysfunction appeared only in patients > or = 5 months; thus we used this cut-point in age to divide clinically symptomatic patients into early and late treatment groups (Clin-E and Clin-L). Newborn screening (NBS) identified symptom-free patients. RESULTS: Among a total of 40 patients, 14 received ERT: 5 in the Clin-L, 4 in the Clin-E, and 5 in the NBS groups. All patients showed cardiomegaly, hypertrophic myocardium, and elevated B-type natriuretic peptide (measured in the Clin-E and NBS groups). ERT improved the survival and outcomes. Regressed myocardial hypertrophy and lowered B-type natriuretic peptide level occurred after 1 to 6 months of ERT. Nonetheless, there were 2 deaths and 2 survivors requiring ventilator support in the Clin-L group. Despite the regressed QRS voltage and shortened QT dispersion, life-threatening arrhythmias were still observed in 3, but none in the NBS group. CONCLUSION: ERT may restore the cardiac function in both symptomatic and symptom-free patients, but the beneficial effect may be unpredictable if given after the age of 5 months.

Detection of RNA from a novel West Nile-like virus and high prevalence of an insect-specific flavivirus in mosquitoes in the Yucatan Peninsula of Mexico.

As part of our ongoing surveillance efforts for West Nile virus (WNV) in the Yucatan Peninsula of Mexico, 96,687 mosquitoes collected from January through December 2007 were assayed by virus isolation in mammalian cells. Three mosquito pools caused cytopathic effect. Two isolates were orthobunyaviruses (Cache Valley virus and Kairi virus) and the identity of the third infectious agent was not determined. A subset of mosquitoes was also tested by reverse transcription-polymerase chain reaction (RT-PCR) using WNV-, flavivirus-, alphavirus-, and orthobunyavirus-specific primers. A total of 7,009 Culex quinquefasciatus in 210 pools were analyzed. Flavivirus RNA was detected in 146 (70%) pools, and all PCR products were sequenced. The nucleotide sequence of one PCR product was most closely related (71-73% identity) with homologous regions of several other flaviviruses, including WNV, St. Louis encephalitis virus, and Ilheus virus. These data suggest that a novel flavivirus (tentatively named T'Ho virus) is present in Mexico. The other 145 PCR products correspond to Culex flavivirus, an insect-specific flavivirus first isolated in Japan in 2003. Culex flavivirus was isolated in mosquito cells from approximately one in four homogenates tested. The genomic sequence of one isolate was determined. Surprisingly, heterogeneous sequences were identified at the distal end of the 5' untranslated region.

Cardiac conduction disturbance detected in a pediatric population.

OBJECTIVE: To delineate the prevalence and clinical implications of cardiac conduction disturbance (CCD) in school-age children. STUDY DESIGN: Between 1999 and 2001, a citywide survey of 432,166 elementary and high school students had been performed in Taipei by questionnaire, electrocardiography, phonocardiography, and physical examination. Patients with any abnormalities on this survey were referred for final diagnosis. RESULTS: After excluding those with congenital heart disease (CHD), the prevalence of CCD was 0.75%, higher in males than in females (0.78% vs 0.71%). Incomplete right bundle branch block (IRBBB; 0.32%), complete right bundle branch block (CRBBB; 0.11%), ventricular premature contraction (0.11%), and Wolff-Parkinson-White syndrome (0.067 %) were the most common diagnoses. Second-degree atrioventricular block, IRBBB, CRBBB, and intraventricular conduction delay were more common in males; and atrial premature contraction was more common in females. The prevalence of CCD increased with age, from 0.48% in elementary school students to 0.97% in high school students. After detection of CCD, 39 patients with previously undiagnosed atrial septal defect (ASD) and 15 high-risk patients were found. The sensitivity of IRBBB in screening for ASD was 34.67%. CONCLUSIONS: The prevalence of CCD in children without CHD was 0.75%. Detection of CCD helped identify patients with unrecognized ASD and high-risk cardiac patients.

Noninvasive diagnosis of aortic coarctation in neonates with patent ductus arteriosus.

OBJECTIVES: To find a noninvasive method to detect coarctation of the aorta (CoA) in the presence of a patent ductus arteriosus (PDA) in neonates. STUDY DESIGN: From 1994 to 1998, 36 neonates with CoA and PDA confirmed by surgery or cardiac catheterization were studied; another 19 neonates with isolated PDA served as control patients. The prospective study was conducted from 2001 to 2002 on 162 neonates. RESULTS: Among the 36 neonates in the CoA group, 14 patients (39%) had blood pressure discrepancy, 26 patients (72%) had a visualized posterior shelf by echocardiogram, and the ratio of isthmus/descending aorta diameters (I/D ratio) was below 0.64 in 32 patients (89%). None of the control patients had these features. A diagnostic approach was subsequently proposed, according to which a neonate with PDA who fulfilled any of the above features was diagnosed as CoA plus PDA. In the prospective study, the sensitivity and positive predictive values of this method were both 91.7%, whereas the specificity and negative predictive values were both 99.3%. CONCLUSIONS: Echocardiographic measurements of I/D ratio along with the delineation of posterior shelf and a BP discrepancy can satisfactorily identify CoA in the presence of PDA in neonates.

Cytokine gene polymorphisms in endemic pemphigus foliaceus: a possible role for IL6 variants.

Endemic pemphigus foliaceus (EPF) is a complex autoimmune disease characterized by the presence of antibodies against desmoglein 1, which lead to the loss of adhesion among keratinocytes (acantholysis). Variants of HLA class II genes have been the only genetic factors found to modulate susceptibility to EPF. This study aims at investigating the influence of cytokine genetic variants in the pathogenesis of EPF, since they may affect the expression levels of these immunomodulatory molecules. The sample included 168 patients and 189 controls and was comprised of mostly Caucasoids and Mulattos. The approach consisted of a case-control association study and the alleles were identified by mismatched PCR-RFLP. No associations were found with variants of IL1A, IL1B, IL1RN, IL4R and IL10. There was a weak negative association with the haplotype -1082G -592C (OR=0.49) of the IL10 gene in Mulattos. In regard to polymorphism -590 of the IL4 gene, a positive association with the T/T genotype (OR=2.71) and a negative association with the C variant (OR=0.37) were found. Associations with IL6 -174 variants suggest that the C/C genotype has a protective effect (OR=0.13) while carriers of the G allele are more susceptible (OR=7.66) to EPF.