Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post‐translational modification caused by Ca+2‐regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue‐specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan‐PAD inhibitor Cl‐amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS‐treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl‐amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug‐directed intervention in neurotrauma.
To determine whether standard-length computerized training enhances working memory (WM), transfers to other cognitive domains and shows sustained effects, when controlling for motivation, engagement, and expectancy.
Methods
97 post-secondary students (59.8% female) aged 18–35 years with Attention-Deficit/Hyperactivity Disorder, were randomized into standard-length adaptive Cogmed WM training (CWMT; 45-min/session), a shortened-length adaptive version of CWMT (15 min/session) that controlled for motivation, engagement and expectancy of change, or into a no training group (waitlist-control group). All three groups received weekly telephone calls from trained coaches, who supervised the CWMT and were independent from the research team. All were evaluated before and 3 weeks post-training; those in the two CWMT groups were also assessed 3 months post-training. Untrained outcome measures of WM included the WAIS-IV Digit Span (auditory-verbal WM), CANTAB Spatial Span (visual-spatial WM) and WRAML Finger Windows (visual-spatial WM). Transfer-of-training effects included measures of short-term memory, cognitive speed, math and reading fluency, complex reasoning, and ADHD symptoms.
Results
Performance on 5/7 criterion measures indicated that shortened-length CWMT conferred as much benefit on WM performance as did standard-length training, with both CWMT groups improving more than the waitlist-control group. Only 2 of these findings remained robust after correcting for multiple comparisons. Follow-up analyses revealed that post-training improvements on WM performance were maintained for at least three months. There was no evidence of any transfer effects but the standard-length group showed improvement in task-specific strategy use.
Conclusions
This study failed to find robust evidence of benefits of standard-length CWMT for improving WM in college students with ADHD and the overall pattern of findings raise questions about the specificity of training effects.
