Single-Cell Meta-Analysis of Neutrophil Activation in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Reveals Potential Shared Immunological Drivers.

BACKGROUND: Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share similar clinical manifestations, including cardiovascular complications, suggesting similar underlying immunopathogenic processes. Aberrant neutrophil activation may play a crucial role in the shared pathologies of KD and MIS-C; however, the associated pathogenic mechanisms and molecular drivers remain unknown. METHODS: We performed a single-cell meta-analysis of neutrophil activation with 103 pediatric single-cell transcriptomic peripheral blood mononuclear cell data across 9 cohorts, including healthy controls, KD, MIS-C, compared with dengue virus infection, juvenile idiopathic arthritis, and pediatric celiac disease. We used a series of computational analyses to investigate the shared neutrophil transcriptional programs of KD and MIS-C that are linked to systemic damage and cardiac pathologies, and suggested Food and Drug Administration-approved drugs to consider as KD and MIS-C treatment. RESULTS: We meta-analyzed 521 950 high-quality cells. We found that blood signatures associated with risks of cardiovascular events are enriched in neutrophils of KD and MIS-C. We revealed the expansion of CD177+ neutrophils harboring hyperactivated effector functions in both KD and MIS-C, but not in healthy controls or in other viral-, inflammatory-, or immune-related pediatric diseases. KD and MIS-C CD177+ neutrophils had highly similar transcriptomes, marked by conserved signatures and pathways related to molecular damage. We found the induction of a shared neutrophil expression program, potentially regulated by SPI1 (Spi-1 proto-oncogene), which confers enhanced effector functions, especially neutrophil degranulation. CD177 and shared neutrophil expression program expressions were associated with acute stages and attenuated during KD intravenous immunoglobulin treatment and MIS-C recovery. Network analysis identified hub genes that correlated with the high activation of CD177+ neutrophils. Disease-gene association analysis revealed that the KD and MIS-C CD177+ neutrophils' shared expression program was associated with the development of coronary and myocardial disorders. Last, we identified and validated TSPO (translocator protein) and S100A12 (S100 calcium-binding protein A12) as main molecular targets, for which the Food and Drug Administration-approved drugs methotrexate, zaleplon, metronidazole, lorazepam, clonazepam, temazepam, and zolpidem, among others, are primary candidates for drug repurposing. CONCLUSIONS: Our findings indicate that CD177+ neutrophils may exert systemic pathological damage contributing to the shared morbidities in KD and MIS-C. We uncovered potential regulatory drivers of CD177+ neutrophil hyperactivation and pathogenicity that may be targeted as a single therapeutic strategy for either KD or MIS-C.

Normal Development of the Corpus Callosum and Evolution of Corpus Callosum Sexual Dimorphism in Infancy.

OBJECTIVES: The aim of this study was to establish reference ranges for the corpus callosum in infancy and to clarify how sexual dimorphism evolves between the fetal stage and infancy. METHODS: Normal sonograms from cerebral ultrasonographic examinations of 1- to 6-month-old healthy full-term infants were selected. The length and thickness of the corpus callosum were determined, and the effect of sex on these values was analyzed. Studies on corpus callosum sexual dimorphism were reviewed. RESULTS: In total, sonograms from 236 1- to 6-month-old infants (120 male and 116 female) were collected, and the typical values (5th-95th percentiles) of the corpus callosum were determined for each group. During the first 2 months, with and without brain size adjustment, the corpus callosum in female infants was significantly thicker than that in male infants (mean thickness ± SD: 1 month, male infant, 1.8 ± 0.3 mm; female infant, 2.1 ± 0.3 mm; P = .005; 2 months, male infant, 1.8 ± 0.2 mm; female infant, 2.0 ± 0.3 mm; P = .002). The corpus callosum thickness of male and female infants had no significant differences after 2 months of age. Sexual dimorphism was not detected in corpus callosum length. CONCLUSIONS: Our study provides reference data on typical corpus callosum development in infants. In the fetal period and early infancy, the corpus callosum in female infants is thicker than that in male infants. From 3 months onward, the corpus callosum sexual dimorphism becomes insignificant throughout childhood. The evolvement of corpus callosum sexual dimorphism suggests that maternal factors may influence brain development.

Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences.

OBJECTIVE: Enzyme replacement therapy (ERT), the only approved therapy for infantile-onset Pompe disease (IOPD), had heterogeneous clinical effects due to factors such as severity, age at first treatment, dosage, and dosing regimens. We report the clinical and biochemical outcomes of a cohort of IOPD patients identified through newborn screening, and evaluating the dosage effect. STUDY DESIGN: A retrospective observational study was designed to describe the long-term clinical and biochemical outcomes of a uniform cohort of IOPD patients who have been treated with high-dosage of ERT. RESULTS: Twenty-eight patients received alglucosidase alpha at either the labeled dosage followed by a high dosage (n = 23) or a high dosage exclusively (n = 5). At a median age of 8.3 years (0.8-17.3), 15 patients were walkers, 8 were weak walkers, and 5 were nonwalkers. The three groups exhibited a significant difference in the age of gross motor decline (p < .001). In patients with classical IOPD diagnosed through newborn screening, those late in ERT initiation (p = .006) or late in high-dosage ERT initiation (p = .044) had a higher risk of motor decline. At the latest assessment, both serum creatine kinase (CK) and urinary glucose tetrasaccharide (uGlc4) levels were lowest in the walkers. During follow up, the biomarker levels, once rose, never returned to normal. CONCLUSION: Low CK and uGlc4 levels were correlated with favorable response to ERT in IOPD patients, although CK may be more fluctuated than uGlc4. High-dose ERT instituted immediately at newborn screening seems to give the best outcome, and a dosage increase is necessary upon - or, even better, before - a rise in biomarker levels.

Influence of Latitude on the Prevalence of Kawasaki Disease: A Retrospective Cohort Study from the Taiwan National Health Insurance Database and Review of the Literature.

Background: Countries at higher latitudes have higher incidence rates of Kawasaki disease (KD) than do countries at lower latitudes in the Asian and West Pacific area. However, the precise influence of latitude on KD incidence rates requires further clarification. Methods: We searched the Longitudinal Health Insurance Database 2005 to retrieve patients’ medical records from 1996 to 2009. The patients with KD were categorized as living in northern, middle, and southern Taiwan; the period prevalence of KD for each area was determined. Climate variables, including temperature, sunshine duration, precipitation, and relative humidity, were collected from the Taiwan Central Weather Bureau. The effect of latitude on the period KD prevalence and the correlation between climate variables and KD prevalence were calculated. Results: After patients without complete data excluded, a total of 61,830 children up to 10 years old were retrieved, from which 404 patients with KD were recognized. The period prevalence of KD increased significantly with latitude (p = 0.0004). Climate variables associated with high temperature demonstrated a connection with KD prevalence; however, this correlation was not statistically significant. Conclusions: Our study demonstrated that higher latitude is associated with a higher KD prevalence in Taiwan.

Early-life arsenic exposure promotes atherogenic lipid metabolism in adolescence: A 15-year birth cohort follow-up study in central Taiwan.

BACKGROUND: Inorganic arsenic (iAs) exposure potentially causes diabetes and cardiovascular diseases in adults. However, its effect on glucose and lipid metabolism in early life remains unknown. OBJECTIVE: We evaluated the associations between early-life arsenic exposure and profiles of glucose and lipids in a 15-year birth cohort in central Taiwan. METHODS: We studied 237 adolescents through 5 waves of follow-up interviews and examinations at ages of approximately 2, 5, 8, 11, and 14 y. We obtained at least one follow-up urine measurement for arsenic species and blood sample collection up to 14 y of age and identified group-based trajectories of serial iAs by semiparametric mixture modeling. Multiple linear and logistic regressions were performed to assess the effect of the arsenic exposure trajectory on serum fasting glucose, total cholesterol (TCHO), triglycerides (TGs), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL). RESULTS: Three trajectories of postnatal arsenic exposure were identified, namely stable-low (31.4%), stable-high (48.2%), and rising-high (20.4%) groups. Compared with the stable-low trajectory group, the percent changes in TCHO and LDL was 14% (95% confidence interval 4-24%) and 23% (9-38%) for the group with "rising-high" trajectory and was 8% (-1-16%) and 16% (4-29%) for the group with "stable-high" trajectory. The rising-high group was also associated with an increase in the TCHO/HDL ratio by 14% (95% CI 3%-25%). The adjusted odds ratios of high developmental trajectories of TCHO, TG, LDL, and non-HDL levels were 4.0 (95% CI 1.2-13.7), 12.2 (2.2-67), 7.3 (1.8-30), and 3.6 (0.9-14.6), respectively, in the rising-high group (reference: stable-low group). CONCLUSION: Our findings suggest that conversion to an atherogenic lipid profile in adolescents may be associated with early-life exposure to environmental arsenic, particularly during the pre-adolescent period. An environmental modification approach for preventing As-related cardiovascular disease is recommended to begin early in life.

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease.

BACKGROUND: Early initiation of enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is an effective treatment for patients with infantile-onset Pompe disease (IOPD) but cannot prevent a slow progression of myopathy. Albuterol has been shown to be helpful in adult patients with Pompe disease, and therefore, we administered an open-label adjunctive therapy with albuterol in IOPD patients undergoing ERT. METHODS: Fourteen patients, aged 2 to 12 years, were enrolled in this study; all of them had a disease onset before 12 months of life, and 13 of them were ambulatory because of early initiation of ERT. All patients received albuterol (also referred to as salbutamol) 12 mg daily for 26 weeks. The outcome measurements included a 6-minute walk test, four-stair climb test (SCT), the standing/walking/running/jumping domains of Gross Motor Function Measure-88, speech quality, serum creatine kinase, and urinary glucose tetrasaccharide. Outcome and safety measurements were evaluated at baseline, and at 1, 3, and 6 months (26 weeks) after entering the trial. RESULTS: After a period of 26 weeks, among the 12 patients who were able to complete the SCT, the median time needed decreased by 22% (p = 0.034). Other parameters inconsistently improved in a variety of individuals. Eleven adverse events, including nausea, urinary frequency, and tachycardia, were potentially related to the study drug, but all were mild and disappeared after a brief drug withdrawal. One patient was actively withdrawn from the trial because of poor compliance. CONCLUSIONS: The results of our study suggest that albuterol showed a good safety profile as an adjunctive treatment in our IOPD cohort, although the benefits are limited.

Frontal horn cysts in normal neonates.

Frontal horn cysts (FHCs) are elliptical, smooth, thin-walled cysts adjacent to the tip of the anterior horns of the lateral ventricles. Among 3,545 terms or near term healthy babies who underwent cranial ultrasound examination in our hospital over a 2-year 5-month period, 18 were found to have FHCs (17 typical and one atypical; seven bilateral and 11 unilateral, of which seven were on the left and four on the right). The female to male ratio was 2:1. The incidence of FHCs in normal term babies was thus 0.5%. Six children had resolution of the cyst within 1 month, and 6 more had resolution on repeat scan from 2 to 11 months of age. Four children did not have subsequent ultrasonography to document resolution, but they had normal growth and development. Two were lost to follow up. The infant with an atypical FHC had an enlarged left frontal horn cyst with a midline shift on follow up, but he had normal development. Our study suggests that FHC may be a normal physiologic variant or a benign pathologic condition that can be expected to resolve spontaneously within a few months. It is reasonable to follow typical FHC by cranial ultrasound examinations at 1 or 2 and 6 months of age. In the case of an atypical cyst, more frequent follow up and further image studies like CT or MRI are necessary.

Corpus callosum and motor development in healthy term infants.

BACKGROUND: Corpus callosum atrophy has been associated with cognitive and motor deficits in elderly people. However, the role of the corpus callosum in infant development is unclear. The aim of this study was to assess the impact of corpus callosum size on motor development in infants. METHODS: We investigated cerebral ultrasonograms performed on healthy infants aged 4 to 6 months. The correlation between the development of rolling over and corpus callosum size was calculated for determining odds ratios. Covariates, including gestational age, sex, age in months, and head circumference were tested using logistic regression. RESULTS: We investigated 244 cerebral ultrasonograms performed on term infants from 2009 to 2011. The percentage of rolling over development in the examined infants increased with age (47.8%, 78.4%, and 97.5% at ages 4, 5, and 6 months, respectively). There was no significant difference in the development of rolling over between male (67.9%) and female (73.6%) children or among different gestational age groups. After the other covariates in the logistic model were adjusted, only age and corpus callosum size (length and thickness) were significantly associated with the development of rolling over: 3.86 times the odds (confidence interval, 2.1 to 7.0) for age in months, 1.14 times the odds (confidence interval, 1.0 to 1.3) for corpus callosum length, and 3.92 times the odds (confidence interval, 1.6 to 9.6) for corpus callosum thickness. CONCLUSIONS: Corpus callosum size is positively associated with the development of rolling over in healthy term infants, independent of the gestational age, sex, age, and head circumference.

Eye-of-the-Tiger sign is not Pathognomonic of Pantothenate Kinase-Associated Neurodegeneration in Adult Cases.

An eye-of-the-tiger sign is previously known to have one-to-one correlation with pantothenate kinase-associated neurodegeneration (PKAN). Reviewing the literature on this subject, the correlation between eye-of-the-tiger sign and PKAN seems to show an interesting hypothesis that differs from conventional conclusion. We analyze the published papers in an attempt to reflect this trend and illustrate our points with findings in a 39-year-old man. His brain magnetic resonance imaging study shows typical eye-of-the-tiger sign suggestive of PKAN. Genetic analyses revealed no mutations in pantothenate kinase 2.