Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

Association between children's sleep patterns and problematic behaviors at age 5.

BACKGROUND: Night-shift lifestyles affect children as well as adults, and are associated with sleep and behavioral problems among children. This study aimed to investigate associations among sleep patterns, individual/environmental factors, and problematic behaviors in children at age 5 years. METHODS: Data for sleep patterns, individual / environmental factors, and problematic behaviors for 8,689 5-year-old children were collected from health-checkup records. Problematic behaviors investigated were anxious behavior (being afraid, difficulty being separated from the mother), developmental behavior (violence, restlessness, rebellious behavior, restrictive diet, stereotypic play), personal habits (thumb-sucking, nail-biting, tic, masturbation), and excretory problems. The relationships between sleep patterns (bedtime, sleep duration) and the presence of these behaviors were analyzed. Individual / environmental factors that affected problematic behaviors were statistically identified using a tree-form model. RESULTS: Late bedtime and short sleep duration showed significant adverse effects on children's problematic behaviors - odds ratio (OR): 1.07, 95% confidence interval (CI): 1.03-1.11 and OR: 0.92, 95% CI: 0.87-0.97, respectively. Long television watching time, abnormality at birth, and lack of father's support also showed significant adverse effects on problematic behaviors (OR: 2.34, 95% CI: 1.87-2.94), and significantly affected late bedtime and short sleep duration. CONCLUSIONS: There were significant associations among sleep patterns, individual / environmental factors, and problematic behaviors in 5-year-old children. Improving children's sleep patterns, reducing the duration of television watching, and improving support from fathers may reduce problematic behaviors.

Reliability and validity of the Children's Depression Inventory-Japanese version.

BACKGROUND: Depression has major negative consequences for individuals and society, and psychological assessment tools for early disease detection are needed. The aim of this study was to investigate the reliability and validity of an updated Japanese version of the Children's Depression Inventory (CDI-J) and set a cut-off score for the detection of depression. METHODS: The participants consisted of 465 children and adolescents aged 7-17 years. The control (CON) groups consisted of students recruited from elementary and junior-high school (CONEJ) and children recruited from among hospital staff members (CONRE), while the outpatient clinical (OPC) groups consisted of pediatric psychosomatic outpatients (OPCPD) and adolescent psychiatric outpatients (OPCPS). The CON and OPC CDI-J scores underwent factor analysis using varimax rotation, followed by measurement invariance analysis. The Youth Self-Report (YSR) was administered to assess concurrent validity. The Mini-International Neuropsychiatric Interview was administered to the OPC group to diagnose current depressive symptoms. Receiver operating characteristics (ROC) analysis was conducted to evaluate case-finding performance and to set cut-off points for the detection of depression. RESULTS: The CDI-J was reliable in terms of internal consistency (Cronbach α = 0.86; mean inter-item correlation, 0.16). Re-test reliability was substantial (mean interval 18 days: γ = 0.59, P < 0.05). The four-factor solution exhibited adequate internal consistency (range, 0.52-0.73) and correspondence (Pearson correlation of 0.65 with the YSR) for both the CON and OPC groups. On ROC analysis the optimal cut-off score was 23/24. CONCLUSION: The CDI-J can be used as a reliable and well-validated instrument alongside standard diagnostic procedures.

Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse.

Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice. We successfully generated both male and female Mecp2-deficient mice on the wild-type C57BL/6 background and PER2(Luciferase) (PER2(Luc)) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Generated Mecp2-deficient mice recapitulated reduced activity in mouse models of RTT, and their activity rhythms were diminished in constant dark conditions. Furthermore, real-time bioluminescence imaging showed that the amplitude of PER2(Luc)-driven circadian oscillation was significantly attenuated in Mecp2-deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes of PER2(Luc) bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.

Distinguishing primary from secondary Δ(4) -3-oxosteroid 5ß-reductase (SRD5B1, AKR1D1) deficiency by urinary steroid analysis.

OBJECTIVE: Deficiency of Δ(4) -3-oxosteroid 5ß-reductase (5ß-reductase), a bile acid synthesis disorder, presents findings of neonatal cholestasis and hyper-3-oxo-Δ(4) bile aciduria. The 5ß-reductase enzyme participates in not only bile acid synthesis but also hepatic steroid metabolism. Deficiency of 5ß-reductase includes 2 types: primary deficiency, with an SRD5B1 gene mutation; and secondary deficiency, lacking a mutation. Secondary deficiency is caused by fulminant liver failure from various aetiologies including neonatal hemochromatosis (NH). Distinguishing primary from secondary deficiency based on γ-glutamyltransferase (GGT), serum total bile acids (TBA), and urinary bile acid analysis using gas chromatography-mass spectroscopy (GC-MS) is very difficult. SRD5B1 gene analysis is the only reliable method. We examined urinary steroid analysis as a way to distinguish primary from secondary 5ß-reductase deficiency. DESIGN, PATIENTS AND MEASUREMENTS: We examined 12 patients with cholestatic jaundice, normal or slightly elevated GGT, and hyper-3-oxo-Δ(4) bile aciduria using urinary steroid analysis by GC-MS of both cortisol and cortisone compounds, such as 5ß-tetrahydrocortisol (5ß-THF) and 5ß-tetrahydrocortisone (5ß-THE). Patients previously were diagnosed with primary 5ß-reductase deficiency (n = 3), deficiency secondary to NH (n = 3) and deficiency secondary to other liver disorders (n = 6). RESULTS: Urinary steroid analysis in 3 primary deficiency and 3 NH patients showed low 5ß-THE and elevated 5α/5ß-THE ratios, making distinction difficult without also considering the clinical course and abdominal magnetic resonance imaging (MRI) findings, such as a very low signal intensity in liver and/or pancreas, especially in T2 -weighted images. In the six patients with other secondary deficiencies, urinary 5ß-THF and 5α/5ß-THF differed from those in primary deficiency (P < 0·05). CONCLUSIONS: Urinary steroid analysis can distinguish primary and NH-related deficiencies from other secondary deficiencies.

De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.

Trans-pulmonary echocardiography as a guide for device closure of patent ductus arteriosus.

OBJECTIVES: The aim of this study was to develop trans-pulmonary echocardiography (TPE) to guide device closure of patent ductus arteriosus (DC-PDA). BACKGROUND: Aortography requires a large amount of contrast yet may give us an inadequate image to evaluate anatomy or residual shunt in patients with large PDA or dilated vessels and is precluded in patients with renal dysfunction. Practically, there is no imaging modality to monitor the entire procedure except for trans-esophageal echocardiography that requires general anesthesia. METHODS: Subjects were seven patients with ages ranged from 6- to 77-years old and body weight > 15 kg. The size of the PDA ranged from 1.8 to 6.3 mm with pulmonary to systemic flow ratios from 1.2 to 2.2. During DC-PDA using Ampaltzer Duct Occluder or coil, an intra-cardiac echocardiographic (ICE) catheter was advanced into pulmonary arteries and standard views were developed to guide DC-PDA. RESULTS: We have developed two standard views; the main pulmonary artery view (MPA view) and the left pulmonary artery view (LPA view). The MPA view provided aortic short axis view equivalent to that seen by trans-thoracic echocardiography in children. The LPA view, obtained by the echo probe in the LPA and turned it up upside down, provided long axis view of the PDA allowing more precise anatomical evaluation. TPE allowed us to monitor the entire procedure and determine residual shunts. CONCLUSIONS: TPE in the MPA and LPA view can be an effective guide for DC-PDA. This report leads to new application of this imaging device.

Successful diuretics treatment of protein-losing enteropathy in Noonan syndrome.

There are few reports on successful high-dose spironolactone treatment of refractory protein-losing enteropathy (PLE) caused by Fontan procedure. We report successful diuretics treatment with spironolactone and furosemide at standard dose, of refractory PLE in a patient with Noonan syndrome and repaired congenital heart disease. This is the first successful application of diuretics treatment in a patient with refractory PLE without Fontan procedure. This case illustrates that diuretics treatment can be the first-line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome.

Molecular pathology of MELAS and L-arginine effects.

BACKGROUND: The pathogenic mechanism of stroke-like episodes seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) has not been clarified yet. About 80% of MELAS patients have an A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is the base change at position 14 in the consensus structure of tRNA(Leu(UUR)) gene. SCOPE OF REVIEW: This review aims to give an overview on the actual knowledge about the pathogenic mechanism of mitochondrial cytopathy at the molecular levels, the possible pathogenic mechanism of mitochondrial angiopathy to cause stroke-like episodes at the clinical and pathophysiological levels, and the proposed site of action of l-arginine therapy on MELAS. MAJOR CONCLUSIONS: Molecular pathogenesis is mainly demonstrated using ρ(0) cybrid system. The mutation creates the protein synthesis defects caused by 1) decreased life span of steady state amount of tRNA(Leu(UUR)) molecules; 2) decreased ratio of aminoacyl-tRNA(Leu(UUR)) versus uncharged tRNA(Leu(UUR)) molecules; 3) the accumulation of aminoacylation with leucine without any misacylation; 4) accumulation of processing intermediates such as RNA 19, 5) wobble modification defects. All of these loss of function abnormalities are created by the threshold effects of cell or organ to the mitochondrial energy requirement when they establish the phenotype. Mitochondrial angiopathy demonstrated by muscle or brain pathology, as SSV (SDH strongly stained vessels), and by vascular physiology using FMD (flow mediated dilation). MELAS patients show decreased capacity of NO dependent vasodilation because of the low plasma levels of l-arginine and/or of respiratory chain dysfunction. Although the underlying mechanisms are not completely understood in stroke-like episodes in MELAS, l-arginine therapy improved endothelial dysfunction. GENERAL SIGNIFICANCE: Though the molecular pathogenesis of an A3243G or T3271C mutation of mitochondrial tRNA(Leu(UUR)) gene has been clarified as a mitochondrial cytopathy, the underlying mechanisms of stroke-like episodes in MELAS are not completely understood. At this point, l-arginine therapy showed promise in treating of the stroke-like episodes in MELAS. This article is part of a Special Issue entitled Biochemistry of Mitochondria.

MELAS: a nationwide prospective cohort study of 96 patients in Japan.

BACKGROUND: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (OMIM 540000) is the most dominant subtype of mitochondrial myopathy. The aim of this study was to determine the prevalence, natural course, and severity of MELAS. METHODS: A prospective cohort study of 96 Japanese patients with MELAS was followed between June 2003 and April 2008. Patients with MELAS were identified and enrolled based on questionnaires administered to neurologists in Japan. MELAS was defined using the Japanese diagnostic criteria for MELAS. Two follow-up questionnaires were administered to neurologists managing MELAS patients at an interval of 5years. RESULTS: A prevalence of at least 0.58 (95% confidential interval (CI), 0.54-0.62)/100,000 was calculated for mitochondrial myopathy, whereas the prevalence of MELAS was 0.18 (95%CI, 0.02-0.34)/100,000 in the total population. MELAS patients were divided into two sub-groups: juvenile form and adult form. Stroke-like episodes, seizure and headache were the most frequent symptoms seen in both forms of MELAS. Short stature was significantly more frequent in the juvenile form, whereas hearing loss, cortical blindness and diabetes mellitus were significantly more frequent in the adult form. According to the Japanese mitochondrial disease rating scale, MELAS patients showed rapidly increasing scores (mean±standard deviation, 12.8±8.7) within 5years from onset of the disease. According to a Kaplan-Meier analysis, the juvenile form was associated with a higher risk of death than the adult form (hazard ratio, 3.29; 95%CI, 1.32-8.20; p=0.0105). CONCLUSIONS AND GENERAL SIGNIFICANCE: We confirmed that MELAS shows a rapid degenerative progression within a 5-year interval and that this occurs in both the juvenile and the adult forms of MELAS and follows different natural courses. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.

Infection surveillance after a natural disaster: lessons learnt from the Great East Japan Earthquake of 2011.

PROBLEM: On 11 March 2011, the Great East Japan Earthquake produced a catastrophic tsunami that devastated the city of Rikuzen-Takata and left it without an effective health infrastructure and at increased risk of outbreaks of disease. APPROACH: On 2 May 2011, a disease-surveillance team was formed of volunteers who were clinicians or members of Rikuzen-Takata's municipal government. The team's main goal was to detect the early signs of disease outbreaks. LOCAL SETTING: Seven weeks after the tsunami, 16 support teams were providing primary health care in Rikuzen-Takata but the chain of command between them was poor and 70% of the city's surviving citizens remained in evacuation centres. The communication tools that were available were generally inadequate. RELEVANT CHANGES: The surveillance team collected data from the city's clinics by using a simple reporting form that could be completed without adding greatly to the workloads of clinicians. The summary findings were reported daily to clinics. The team also collaborated with public health nurses in rebuilding communication networks. Public health nurses alerted evacuation centres to epidemics of communicable disease. LESSONS LEARNT: Modern health-care systems are highly vulnerable to the loss of advanced technological tools. The initiation--or re-establishment--of disease surveillance following a natural disaster can therefore prove challenging even in a developed country. Surveillance should be promptly initiated after a disaster by (i) developing a surveillance system that is tailored to the local setting, (ii) establishing a support team network, and (iii) integrating the resources that remain--or soon become--locally available.

MLL2 and KDM6A mutations in patients with Kabuki syndrome.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.

Two neonatal cholestasis patients with mutations in the SRD5B1 (AKR1D1) gene: diagnosis and bile acid profiles during chenodeoxycholic acid treatment.

BACKGROUND AND AIMS: In two Japanese infants with neonatal cholestasis, 3-oxo-Δ(4)-steroid 5ß-reductase deficiency was diagnosed based on mutations of the SRD5B1 gene. Unusual bile acids such as elevated 3-oxo-Δ(4) bile acids were detected in their serum and urine by gas chromatography-mass spectrometry. We studied effects of oral chenodeoxycholic acid treatment. PATIENTS AND METHODS: SRD5B1 gene analysis used peripheral lymphocyte genomic DNA. Diagnosis and treatment of these two patients were investigated retrospectively and prospectively investigated. RESULTS: With respect to SRD5B1, one patient was heterozygous (R266Q, a novel mutation) while the other was a compound heterozygote (G223E/R261C). Chenodeoxycholic acid treatment was effective in improving liver function and decreasing unusual bile acids such as 7α-hydroxy- and 7α,12α-dihydroxy-3-oxo-4-cholen-24-oic acids in serum and urine. CONCLUSION: Primary bile acid treatment using chenodeoxycholic acid was effective for these patients treated in early infancy before the late stage of chronic cholestatic liver dysfunction.

Sleep patterns of Japanese preschool children and their parents: implications for co-sleeping.

AIM: The aim of this study was to investigate the direct relationship of sleep schedule and sleep quality variables between healthy preschool children and their parents, focusing on the influence of the difference in bedtime between each other. METHODS: Forty-seven Japanese 5-year-old children and their primary parent were studied. The parents completed questionnaires including the Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index. The children wore an actigraph for one week. RESULTS: Although sleep patterns of children were generally independent of their parents, late sleep end time and bedtime of children were associated with parents' late sleep end time on weekends. For 87% of children and parents who shared a bedroom, sleep quality was negatively affected by a shorter difference in bedtimes between child and parent, but not by co-sleeping. CONCLUSION: Sleep behaviours of parents can influence those of their children. For parents and children who share a bedroom, the timing of bedtime rather than co-sleeping may be a key factor in modulating sleep patterns. Trying to get children asleep and subsequently falling asleep at a similar time may disturb parents' sleep quality, which may subsequently affect that of their children.

[Rett syndrome: the state of research, and future perspectives].

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by normal early psychomotor development followed by the loss of psychomotor and acquired purposeful hand skills and the onset of stereotyped movement of the hands and gait disturbance. The causative gene was discovered, and the disease was found to be caused by a mutation of methyl-CpG-binding protein 2. However, in many ways this clinically peculiar condition remains a mystery. I review the current status of clinical and basic research on RTT including data on the neurophysiology of the disease, neurotransmitter involvement, neuroimaging and neuropathology findings, molecular biology, animal models, regenerative medicine including ES cells and iPS cells, and other interventions and therapeutic trials.

Arterial spin labeling image findings in the acute phase in paediatric patients with acute encephalopathy with biphasic seizures and late reduced diffusion.

Introduction: Diagnosing acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) after the first seizure (early seizure/seizures, ES/ESs) is challenging because a reduced apparent diffusion coefficient (ADC) in the cortical or subcortical white matter, often described as having a "bright-tree appearance (BTA)," is usually not observed until secondary seizures (late seizures, LSs) occur. Previous studies have reported hypoperfusion on arterial spin labeling (ASL) within 24 h after ES/ESs in patients with AESD and hyperperfusion within 24 h after LS onset. This study aimed to investigate cerebral blood flow in the hyperacute phase (between ES/ESs and LSs) using ASL in patients with AESD. Methods: Eight ASL images were acquired in six patients with AESD admitted to our hospital from October 2021 to October 2022. ASL findings in the hyperacute phase were investigated and video-electroencephalogram findings obtained around ASL image acquisition in the hyperacute phase were evaluated. Results: Four ASL images were obtained for three patients before LS onset, with three images showing hyperperfusion areas and one image showing hypoperfusion areas. These hyperperfuion regions coincided with BTA on subsequent images of these patients.In one patient, the first ASL image was obtained in the late hyperacute phase and revealed hyperperfusion areas with a slightly abnormal change on diffusion-weighted image (DWI), which were not accompanied by ADC abnormalities. The second ASL image obtained 51 h after the first ASL, and before LS onset revealed more prominent hyperperfusion areas than the first ASL image, which were accompanied by BTA. In another patient, the ASL image obtained 82 h after ES revealed hyperperfusion areas without abnormal change on DWI or ADC. Conclusion: This study revealed that two patients exhibited hyperperfusion regions and another patient exhibited hypoperfusion regions among three patients who underwent ASL imaging during the period from 24 h after ES/ESs to LSs in patients with LSs or cooling initiation in patients without LSs due to early anaesthesia induction (late hyperacute phase). Further prospective studies on cerebral blood flow are required to explore the relationship among the timing of image acquisition, the presence of electrographic seizures, and ASL findings in patients with AESD.

Molecular diagnosis of 405 individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

Long-term prognosis of patients with Kawasaki disease complicated by giant coronary aneurysms: a single-institution experience.

BACKGROUND: Some patients with Kawasaki disease develop giant coronary aneurysms and coronary stenosis, leading to ischemic heart disease. The aim of this study was to determine the long-term prognosis of patients with Kawasaki disease with giant aneurysms. METHODS AND RESULTS: From our institutional database, 76 patients (57 men and 19 women) who developed giant aneurysms after January 1, 1972, were identified. Information on patient demographics, catheter and surgical interventions, and most recent status was collected from medical charts and patients' contacts. From these data, we calculated the survival rate and cumulative coronary intervention rate. The average age at onset was 2.9±2.9 years, and the median observational period was 19 years. During this period, 7 patients died and 1 patient underwent a heart transplantation, resulting in 95%, 88%, and 88% survival rates at 10, 20, and 30 years after the onset of KD, respectively. On the other hand, catheter and surgical coronary interventions (median, 1 intervention; range, 1 to 7 interventions) were performed to alleviate coronary ischemia in 46 patients (61%) at 1 month to 21 years (mode at 1 month) after onset, resulting in 28%, 43%, and 59% cumulative coronary intervention rates at 5, 15, and 25 years after onset, respectively. CONCLUSIONS: The long-term survival of patients with Kawasaki disease complicated by giant coronary aneurysms is moderately good with multiple catheter and surgical interventions. Further research should focus on the prevention of coronary vascular remodeling and on the indications for and effectiveness of percutaneous and surgical coronary interventions.

Sleep architecture in healthy 5-year-old preschool children: associations between sleep schedule and quality variables.

AIM: Although disturbed sleep quality such as night awakenings and difficulties in falling asleep are common symptoms during sleep in preschool children, relationships between sleep quality and sleep schedule are mostly unknown. This study aimed to evaluate the relationships between sleep schedule and quality variables in preschool children. METHODS: Sleep-wake patterns of 48 healthy 5-year-old children were assessed over 7 consecutive days using actigraphy. RESULTS: Children with longer sleep latency had a lower sleep quality, a later bedtime, a later sleep onset time, a shorter nocturnal sleep period and a longer daytime nap. Children with a longer nocturnal sleep period on weekends compared with weekdays had longer sleep latency and a later sleep onset time on weekdays, resulting in a lower sleep quality on weekends. An irregular bedtime on weekdays was associated with a later sleep onset time and a shorter sleep period on weekends. CONCLUSION: Sleep quality and schedule were linked with each other, which may explain why sleep problems tend to aggregate and form a wider syndrome of disturbed sleep even in young children. Strategies solely targeting the improvement of sleep quantity may not promote ideal sleep; simultaneous considerations for the sleep rhythm and quality may be required.

Kana reading disability and Das-Naglieri Cognitive Assessment System findings in children with attention deficit hyperactivity disorder.

BACKGROUND: Epidemiological and clinical studies suggest that attention deficit hyperactivity disorder (ADHD) and reading disability co-occur more frequently than would be expected by chance. The purposes of this study were to (i) assess the frequency of Japanese syllabary (Kana) reading disability (RD) and (ii) measure the psychometric properties of the Das-Naglieri Cognitive Assessment System (DN-CAS) in a clinic-referred sample of Japanese children with ADHD. METHODS: Twenty children with ADHD aged 8-13 years were evaluated using both Kana reading tasks and the DN-CAS. RESULTS: Seven children (35%) showed excessive reading time in at least two of four Kana reading tasks and were diagnosed as ADHD plus RD. The children with ADHD plus RD took significantly longer to read a single mora, four-syllable words, and short sentences. There was no significant difference in the time it took the children with ADHD plus RD to read four-syllable non-words compared to the children with ADHD only. The children with ADHD plus RD had significantly lower simultaneous-processing scores in the DN-CAS compared to children with ADHD but not RD. CONCLUSION: Children with ADHD should be given Kana reading tasks because RD is highly comorbid with ADHD. DN-CAS is a useful method for evaluating cognitive processing in children with ADHD with or without RD.