Repression of anti-apoptotic genes via AP-1 as a mechanism of apoptosis induction in ventricular cardiomyocytes.

Nitric oxide (NO) is increased under several pathophysiological, mainly inflammatory processes in the heart and has been characterized as an inducer of apoptosis in cardiomyocytes. The transcription factor activating protein-1 (AP-1) has been identified as a mediator of NO-induced apoptosis. Genes that are regulated by AP-1 under apoptotic conditions have not been identified yet. Therefore, we performed a microarray analysis with subsequent real-time polymerase chain reaction (PCR) to identify genes regulated by AP-1 in NO-induced ventricular cardiomyocytes of rats and tested the functional role of these genes in apoptosis. Cardiomyocytes were transformed with AP-1 decoy oligonucleotides for inhibition of AP-1 activity. These, as well as non-transformed control cells, were stimulated with the NO donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP, 100 microM) for 2 h. Some of the genes with differential gene expression on microarrays were further analysed by real-time PCR. Genes that are induced by SNAP were not identified. However, four genes, pyridoxal kinase, heat shock protein 10 (Hsp10), antigen identified by monoclonal antibodies 4F2 (4F2) and myosin light chain 2, were downregulated by SNAP in presence of AP-1. Pyridoxal kinase, Hsp10 and 4F2 have anti-apoptotic effects in unstimulated cells because downregulation of their expression by antisense oligos induced apoptosis in cardiomyocytes. An involvement of these genes in NO-induced apoptosis could only be proven for pyridoxal kinase. In conclusion, using microarray technology, we identified three anti-apoptotic genes (Hsp10, 4F2 and pyridoxal kinase) in ventricular cardiomyocytes, which may help the cells to resist some apoptotic stimuli. The downregulation of these genes results in cardiomyocyte apoptosis. Prevention of their downregulation may protect cardiomyocytes against apoptotic stimuli, and this may be of therapeutic benefit.

The effect of Kawasaki disease on cognition and behavior.

OBJECTIVE: To determine whether there are associated long-term deficits in the cognitive, academic, or behavioral outcomes of children with a previous episode of Kawasaki disease. DESIGN: Cohort analytic study. SETTING: A tertiary care pediatric hospital in Ottawa, Ontario. PARTICIPANTS: Thirty-two patients with a past diagnosis of Kawasaki disease. Siblings of the patients with Kawasaki disease were eligible to be controls. MEASURES: A blinded psychometrist (Y.K.) assessed cognition by the appropriate Wechsler Intelligence scale, academic achievement by the Wechsler Individual Achievement Test, and behavior by the Achenbach Child Behavior Checklist. RESULTS: No differences were found in cognitive or academic measures and the mean scores corresponded closely to national norms. Parents rated their children who had Kawasaki disease as having significantly more internalizing (P<.03) and attentional (P<.02) behavior problems than controls; the risk of a clinically significant behavioral score was 3.3 times greater (P<.03; 95% confidence interval, 1.1-9.9) than for sibling controls. CONCLUSIONS: While no effect on cognitive development or academic performance was demonstrated, these results provide preliminary indication of a post-Kawasaki disease deficit in internalizing and attentional behavior.

Neuropsychological sequelae of haemolytic uraemic syndrome. Investigators of the HUS Cognitive Study.

BACKGROUND: Severe haemolytic uraemic syndrome (HUS) in childhood can cause stroke, hemiplegia, cortical blindness, and psychomotor retardation. These outcomes are evident at the time of discharge immediately after the acute illness. Less is known about the neuropsychological outcomes of less severely affected children who recover from acute HUS. AIMS: This multicentre case control study investigated the hypothesis that children who survive an acute episode of HUS without recognizable neurological injuries have greater impairment of cognitive, academic, and behavioural functions than controls. DESIGN: Children with HUS were eligible if they had no evidence of severe neurological dysfunction when discharged from one of six Canadian hospitals. Controls had been admitted to hospital for a non-HUS illness and were matched by age, sex, first language, and socioeconomic status. All subjects underwent evaluation of behaviour, academic achievement, cognitive function, and verbal abilities using standardised tests administered by a psychometrist blinded to the case or control status. RESULTS: Ninety-one case control pairs were enrolled. No important differences between patients with HUS and paired controls were evident on tests of IQ, behaviour, verbal abilities, or academic achievement. There was no increased risk of attention deficit disorder among patients with HUS. There was no correlation between the severity of acute renal failure and neuropsychological measures, although scores on some verbal ability tests were lower in those with the highest serum creatinine concentrations during illness. CONCLUSIONS: Children discharged from hospital without apparent neurological injury after an episode of acute HUS do not have an increased risk of subclinical problems with learning, behaviour, or attention.

Sequelae of haemolytic uraemic syndrome.

Twenty two patients with previous episodes of haemolytic uraemic syndrome (HUS) were investigated for evidence of deficits in cognitive, behavioural, and academic function. Patients were pair matched with 22 controls for age (+/- 1 year), gender, and socioeconomic status. HUS patients had numerically lower cognitive and achievement scores and higher behavioural problem ratings than their controls on every measure. None of the group differences was significant at the 0.01 level. Significance values between 0.10 and 0.01 were obtained for the Wechsler full scale and verbal intelligence quotient scores and for several of the achievement measures and behaviour ratings. These results were conservatively interpreted as trends and are considered to provide preliminary indications of a post-HUS deficit in behaviour, verbal intelligence, and the verbally based skills of reading comprehension and vocabulary. The findings provide interim guidelines for follow up care but require confirmation and elaboration in a larger study.

Effect of therapeutic plasma concentrations of theophylline on behavior, cognitive processing, and affect in children with asthma.

A double-blind, randomized, crossover study assessed the effects of theophylline on behavior, mood, and efficiency of cognitive processing. Thirty-one children aged 8 to 12 years with moderate asthma were randomly assigned to 10-day theophylline followed by placebo or to placebo followed by theophylline experimental conditions separated by 2-day washout periods. Theophylline plasma concentrations and pulmonary function tests were performed throughout the study. Cognitive functioning tests and self-report measures were administered at baseline and after each medication phase. Behavior ratings were obtained from parents and teachers. Parents' and teachers' ratings did not reflect a theophylline effect on attention or activity level; children's self-reports showed no changes in mood, and no statistically significant differences were found on measures of cognitive processing. Large individual differences in sensitivity to theophylline effects were present. Although most of the children tolerated theophylline well, those already having attentional or achievement problems appeared vulnerable to adverse effects. Individual response differences should be a focus of future studies.

Cognitive function in long survivors of childhood acute lymphoblastic leukemia.

Thirty long survivors of childhood acute lymphoblastic leukemia were compared with their healthy siblings on cognitive and neuropsychological measures. The subjects were comparable in treatment variables except for type of central nervous system prophylaxis received. Thirteen were given radiotherapy with intrathecal medication, and seventeen received only intrathecal treatment. Patients receiving only intrathecal medication did not differ from controls. Patients receiving radiotherapy scored lower on several measures including Wechsler Full Scale and Performance IQ. Irradiated girls scored lower than boys on most measures. Children whose clinical management has included radiation therapy appear to be at risk for later mild cognitive deficits. No consistent pattern of neuropsychological deficits has emerged and observed deficit patterns may reflect individual vulnerabilities.

Mild conductive hearing loss and language development: a one year follow-up study.

Thirteen children aged 3 to 5 years with mild conductive hearing losses and histories of otitis media were pair-matched with audiologically normal children on age, sex, socioeconomic status, family intactness, and first language (English). The Test for Auditory Comprehension of Language, the Northwestern Syntax Screening Test, and the Developmental Sentence Scoring Procedure were administered. Phonology errors were tabulated from the spontaneous language sample. The language evaluation was repeated after a 1-year interval. All measures differentiated the groups at highly significant levels on the initial assessment. All tests except the Test for Auditory Comprehension of Language continued to show significant differences a year later. The results support the hypothesis that children who experience recurrent middle ear problems are at risk for persistent language delay.

Mother-child interaction observed at home.

Lower-class and middle-class mother-child pairs were observed in their homes. In contrast to other studies, very few class differences were found in maternal behavior. These results are discussed in terms of the contexts in which observations are made.