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1.  Altered SPECT 123I-iomazenil Binding in the Cingulate Cortex of Children with Anorexia Nervosa 
Several lines of evidence suggest that anxiety plays a key role in the development and maintenance of anorexia nervosa (AN) in children. The purpose of this study was to examine cortical GABA(A)-benzodiazepine receptor binding before and after treatment in children beginning intensive AN treatment. Brain single-photon emission computed tomography (SPECT) measurements using 123I-iomazenil, which binds to GABA(A)-benzodiazepine receptors, was performed in 26 participants with AN who were enrolled in a multimodal treatment program. Sixteen of the 26 participants underwent a repeat SPECT scan immediately before discharge at conclusion of the intensive treatment program. Eating behavior and mood disturbances were assessed using Eating Attitudes Test with 26 items (EAT-26) and the short form of the Profile of Mood States (POMS). Clinical outcome scores were evaluated after a 1-year period. We examined association between relative iomazenil-binding activity in cortical regions of interest and psychometric profiles and determined which psychometric profiles show interaction effects with brain regions. Further, we determined if binding activity could predict clinical outcome and treatment changes. Higher EAT-26 scores were significantly associated with lower iomazenil-binding activity in the anterior and posterior cingulate cortex. Higher POMS subscale scores were significantly associated with lower iomazenil-binding activity in the left frontal, parietal cortex, and posterior cingulate cortex (PCC). “Depression–Dejection” and “Confusion” POMS subscale scores, and total POMS score showed interaction effects with brain regions in iomazenil-binding activity. Decreased binding in the anterior cingulate cortex and left parietal cortex was associated with poor clinical outcomes. Relative binding increases throughout the PCC and occipital gyrus were observed after weight gain in children with AN. These findings suggest that cortical GABAergic receptor binding is altered in children with AN. This may be a state-related change, which could be used to monitor and guide the treatment of eating disorders.
PMCID: PMC4754452  PMID: 26909048
anorexia nervosa; cingulate cortex; GABA; children; iomazenil SPECT
2.  Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias 
Scientific Reports  2015;5:11204.
Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.
PMCID: PMC4466896  PMID: 26073556
3.  Upregulated GABA Inhibitory Function in ADHD Children with Child Behavior Checklist–Dysregulation Profile: 123I-Iomazenil SPECT Study 
The child behavior checklist–dysregulation profile (CBCL–DP) refers to a pattern of elevated scores on the attention problems, aggression, and anxiety/depression subscales of the child behavior checklist. The aim of the present study was to investigate the potential role of GABA inhibitory neurons in children with attention deficit/hyperactivity disorder (ADHD) and dysregulation assessed with a dimensional measure. Brain single photon emission computed tomography (SPECT) was performed in 35 children with ADHD using 123I-iomazenil, which binds with high affinity to benzodiazepine receptors. Iomazenil binding activities were assessed with respect to the presence or absence of a threshold CBCL–DP (a score ≥210 for the sum of the three subscales: Attention Problems, Aggression, and Anxiety/Depression). We then attempted to identify which CBCL–DP subscale explained the most variance with respect to SPECT data, using “age,” “sex,” and “history of maltreatment” as covariates. Significantly higher iomazenil binding activity was seen in the posterior cingulate cortex (PCC) of ADHD children with a significant CBCL–DP. The Anxiety/Depression subscale on the CBCL had significant effects on higher iomazenil binding activity in the left superior frontal, middle frontal, and temporal regions, as well as in the PCC. The present brain SPECT findings suggest that GABAergic inhibitory neurons may play an important role in the neurobiology of the CBCL–DP, in children with ADHD.
PMCID: PMC4451796  PMID: 26082729
CBCL-dysregulation profile; iomazenil; GABA; ADHD
4.  High correlation between salivary cortisol awakening response and the psychometric profiles of healthy children 
Cortisol awakening response (CAR) as an indicator of psychological stress and related physical and psychiatric diseases has attracted growing attention from researchers. Although CAR changes have been investigated extensively in children with behavioral and psychiatric disorders, the association between CAR and conventional psychometric scales for healthy children has not been reported. The aim of this study was to investigate the association between salivary CAR and subscales of Profiles of Mood States (POMS), a self-assessment questionnaire widely used to evaluate the temporal emotional states of healthy children.
This study included 18 healthy girls aged 13–16 years. Saliva was collected immediately on awakening, 30 min and 60 min after waking, and then at 2-hour intervals from 9 am to 5 pm. The current mood state, including depression, anxiety, fatigue, and other psychometric profiles were assessed using POMS. The magnitude of salivary CAR and the area under the concentration-time curve (AUC) for diurnal salivary cortisol were compared with the profiles. There were significant positive correlations between the magnitude of CAR and the POMS subscales for "Depression-Dejection", "Tension-Anxiety", "Fatigue", and "Confusion". No correlation was found between the AUC salivary cortisol level and the psychometric profiles.
Salivary CAR was associated with various mood states of healthy female children but diurnal salivary cortisol AUC was not. Salivary CAR may be a biomarker of the physical and mental condition of healthy female children.
PMCID: PMC3995602  PMID: 24625309
Cortisol awakening response; Hypothalamus-pituitary-adrenal axis; Saliva; Children
5.  Correction: Age-Specific Sex-Related Differences in Infections: A Statistical Analysis of National Surveillance Data in Japan 
PLoS ONE  2012;7(10):10.1371/annotation/e63213bd-8e30-4b2d-a37f-bcd1409f26ae.
PMCID: PMC3484160
6.  Age-Specific Sex-Related Differences in Infections: A Statistical Analysis of National Surveillance Data in Japan 
PLoS ONE  2012;7(7):e42261.
To prevent and control infectious diseases, it is important to understand how sex and age influence morbidity rates, but consistent clear descriptions of differences in the reported incidence of infectious diseases in terms of sex and age are sparse.
Methods and Findings
Data from the Japanese surveillance system for infectious diseases from 2000 to 2009 were used in the analysis of seven viral and four bacterial infectious diseases with relatively large impact on the Japanese community. The male-to-female morbidity (MFM) ratios in different age groups were estimated to compare incidence rates of symptomatic reported infection between the sexes at different ages. MFM ratios were >1 for five viral infections out of seven in childhood, i.e. male children were more frequently reported as infected than females with pharyngoconjunctival fever, herpangina, hand-foot-and-mouth disease, mumps, and varicella. More males were also reported to be infected with erythema infectiosum and exanthema subitum, but only in children 1 year of age. By contrast, in adulthood the MFM ratios decreased to <1 for all of the viral infections above except varicella, i.e. adult women were more frequently reported to be infected than men. Sex- and age-related differences in reported morbidity were also documented for bacterial infections. Reported morbidity for enterohemorrhagic Escherichia coli infection was higher in adult females and females were reportedly more infected with mycoplasma pneumonia than males in all age groups up to 70 years.
Sex-related differences in reported morbidity for viral and bacterial infections were documented among different age groups. Changes in MFM ratios with age may reflect differences between the sexes in underlying development processes, including those affecting the immune, endocrine, and reproductive systems, or differences in reporting rates.
PMCID: PMC3407080  PMID: 22848753
7.  Alterations of Gene Expression and Glutamate Clearance in Astrocytes Derived from an MeCP2-Null Mouse Model of Rett Syndrome 
PLoS ONE  2012;7(4):e35354.
Rett syndrome (RTT) is a neurodevelopmetal disorder associated with mutations in the methyl-CpG–binding protein 2 (MeCP2) gene. MeCP2-deficient mice recapitulate the neurological degeneration observed in RTT patients. Recent studies indicated a role of not only neurons but also glial cells in neuronal dysfunction in RTT. We cultured astrocytes from MeCP2-null mouse brain and examined astroglial gene expression, growth rate, cytotoxic effects, and glutamate (Glu) clearance. Semi-quantitative RT-PCR analysis revealed that expression of astroglial marker genes, including GFAP and S100β, was significantly higher in MeCP2-null astrocytes than in control astrocytes. Loss of MeCP2 did not affect astroglial cell morphology, growth, or cytotoxic effects, but did alter Glu clearance in astrocytes. When high extracellular Glu was added to the astrocyte cultures and incubated, a time-dependent decrease of extracellular Glu concentration occurred due to Glu clearance by astrocytes. Although the shapes of the profiles of Glu concentration versus time for each strain of astrocytes were grossly similar, Glu concentration in the medium of MeCP2-null astrocytes were lower than those of control astrocytes at 12 and 18 h. In addition, MeCP2 deficiency impaired downregulation of excitatory amino acid transporter 1 and 2 (EAAT1/2) transcripts, but not induction of glutamine synthetase (GS) transcripts, upon high Glu exposure. In contrast, GS protein was significantly higher in MeCP2-null astrocytes than in control astrocytes. These findings suggest that MeCP2 affects astroglial genes expression in cultured astrocytes, and that abnormal Glu clearance in MeCP2-deficient astrocytes may influence the onset and progression of RTT.
PMCID: PMC3332111  PMID: 22532851
8.  Functional near-infrared spectroscopy studies in children 
Psychosomatic and developmental behavioral medicine in pediatrics has been the subject of significant recent attention, with infants, school-age children, and adolescents frequently presenting with psychosomatic, behavioral, and psychiatric symptoms. These may be a consequence of insecurity of attachment, reduced self-confidence, and peer -relationship conflicts during their developmental stages. Developmental cognitive neuroscience has revealed significant associations between specific brain lesions and particular cognitive dysfunctions. Thus, identifying the biological deficits underlying such cognitive dysfunction may provide new insights into therapeutic prospects for the management of those symptoms in children. Recent advances in noninvasive neuroimaging techniques, and especially functional near-infrared spectroscopy (NIRS), have contributed significant findings to the field of developmental cognitive neuroscience in pediatrics. We present here a comprehensive review of functional NIRS studies of children who have developed normally and of children with psychosomatic and behavioral disorders.
PMCID: PMC3337812  PMID: 22433235
Development; Children; Cognitive neuroscience; Near-infrared spectroscopy
9.  Sex- and Age-Related Differences in Morbidity Rates of 2009 Pandemic Influenza A H1N1 Virus of Swine Origin in Japan 
PLoS ONE  2011;6(4):e19409.
The objective of the present study was to determine whether the morbidity rates of the 2009 pandemic influenza A H1N1 virus (pdmH1N1) varied by age and/or sex.
Methods and Findings
Retrospective analysis of 2,024,367 cases of pdmH1N1 was performed using the national surveillance data from influenza sentinel points in Japan. The male-to-female morbidity ratios (M/F ratios) in nineteen age groups were estimated as the primary outcome. The M/F ratios for pdmH1N1 influenza were: >1 in age groups <20 years and ≥80 years (p<0.001); <1 in age groups 20–79 years (p<0.001). This data suggests that males <20 years of age may be more likely to suffer from pdmH1N1 influenza than females in the same age categories. When the infection pattern for pdmH1N1was compared with that of seasonal influenza outbreaks between 2000 and 2008, the M/F ratio for pdmH1N1 influenza was higher in ages 3–29 years and lower in ages 40–79 years. Because the present study was based on the national surveillance, it was impossible to estimate the morbidity rate for the Japanese population. It is also likely that the data did not capture asymptomatic or mild infections.
Although exposure to the pdmH1N1 virus is assumed to be similar in both boys and girls, M/F ratios were >1 in those younger than 20 years. The subsequent reversal of the M/F ratio in the adult generation could be due to several possibilities, including: greater immunity among adult males, more asymptomatic infections among males, less reporting of illness by males, or differences in exposure to the virus and probability of visiting a clinic. These results suggest that the infection and virulence patterns of pdmH1N1 are more complex than previously considered.
PMCID: PMC3084848  PMID: 21559366
10.  Utility of Subjective Sleep Assessment Tools for Healthy Preschool Children: A Comparative Study Between Sleep Logs, Questionnaires, and Actigraphy 
Journal of Epidemiology  2010;20(2):143-149.
Sleep pattern is an important factor in a child’s mental, behavioural and physical status. To evaluate the sleep patterns of children, subjective tools such as sleep logs and questionnaires are still widely used in addition to objective methods of sleep assessment. Despite the established correlation between subjective and objective sleep variables, the characteristic features of subjective assessment have not been elucidated.
To investigate the characteristics of parental sleep assessment (daily sleep log and brief questionnaire) in preschool children, a 7-day actigraphic sleep study was conducted in 48 healthy 5-year-old children.
Sleep schedule variables in the parental reports generally correlated well with actigraphic assessment of sleep patterns; however, sleep periods were longer in parental reports than in actigraphic recordings. Although the daily sleep log was better correlated with actigraphy, the brief questionnaire showed a good correlation with sleep pattern on weekday actigraphic assessments. Parental reports recorded fewer than 10% of the night wakings recorded by actigraphy.
Subjective sleep assessments remain useful, although their utility depends on the purpose and size of the study in question. However, knowledge of the potential biases and characteristics of such assessments is essential for correct interpretation of the data.
PMCID: PMC3900813  PMID: 20139658
actigraphy; sleep log; questionnaire; preschool child; sleep pattern; subjective sleep assessment; parental report
11.  A Novel Subjective Sleep Assessment Tool for Healthy Elementary School Children in Japan 
Journal of Epidemiology  2010;20(Suppl 2):S476-S481.
A child’s sleep pattern is important in defining his or her mental and physical well-being. Although we have reported previously on the utility of collecting 2 weeks of daily sleep logs, this type of record keeping is often onerous for the parents. Therefore, we established a new questionnaire, called the Japan Children’s Study Sleep Questionnaire (JCSSQ), which is used to collect sleep pattern data over 4 weeks, including weekdays, Saturdays, Sundays, and holidays.
Two parent-administered sleep assessment tools, the JCSSQ and a daily sleep log, were used to examine the sleeping patterns of 105 school children (58 boys and 47 girls; age range, 6–12 years) in Fukuoka, Japan. Parents were requested to record sleep logs for 14 days after the JCSSQ. Sleep/wake status was recorded on the sleep log, from which data on the parameters of “sleep onset time”, “waking time”, “sleep period”, and “number of nights waking” were extracted.
There were no significant differences between the JCSSQ and the logs for waking time data collected on weekdays, Saturdays, and Sundays. However, there was a significant difference (P = 0.03) between the JCSSQ and the sleep logs with respect to the sleep onset time data collected on Saturdays.
The JCSSQ was easy to fill out, and the data collected using the JCSSQ on weekdays were both valid and generally consistent with those collected using sleep logs. However, for sampling on Saturdays and Sundays, the JCSSQ data did not correlate with the sleep log data.
PMCID: PMC3920410  PMID: 20179368
Japan Children’s Study Sleep Questionnaire; sleep log; school-child; sleep pattern; parental report
12.  Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth 
Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor–deficient (AT1a–/–) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a–/– mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the β-galactosidase gene was inserted into the AT1a gene locus in AT1a–/– mice, the site of β-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a–/– mice, the major site of the β-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a–/– mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.
PMCID: PMC162282  PMID: 12840060

Results 1-12 (12)