Intracranial pressure monitors in traumatic brain injury: a systematic review

We conducted a systematic review to examine the relationship between intracranial pressure monitors (ICP) monitors and mortality in traumatic brain injury (TBI). We systematically searched for articles that met the following criteria: (1) adults patients, (2) TBI, (3) use of an ICP monitor, (4) point estimate for mortality with ICP monitoring (5) adjustment for potential confounders. Six observational studies were identified with 11,371 patients. There was marked between-study heterogeneity that precluded a pooled analysis. Patients with ICP monitors had different clinical characteristics and received more ICP targeted therapy in the ICU. Four studies found no significant relationship between ICP monitoring and survival, while the other two studies demonstrated conflicting results. Significant confounding by indication in observational studies limits the examination of isolated TBI interventions. More research should focus on interventions that affect TBI careplan systems. Further research is needed to identify which subset of severe TBI patients may benefit from ICP monitoring.     

Functional adaptive changes within the hippocampal memory system of patients with multiple sclerosis

Memory deficits are highly prevalent in multiple sclerosis (MS). As the hippocampus is crucial to memory processing, a functional magnetic resonance imaging (fMRI) task was used to investigate changes in hippocampal function in MS patients with and without cognitive decline. Fifty patients with MS, (34 cognitively preserved (CP) and 16 cognitively impaired (CI)) and 30 healthy controls completed an episodic memory fMRI task (encoding and retrieval) that was used to specifically activate the hippocampus. During encoding of correctly remembered items, increased brain activation was seen in the parahippocampal areas bilaterally and in the left anterior cingulate gyrus in the CP patients compared to the controls (unclustered, Z ≥ 3.1, P ≤ 0.001). No brain areas showed less activation. In CI patients the right (para)hippocampal areas and the prefrontal cortex showed less brain activation compared to controls (cluster-corrected, P < 0.05). The posterior cingulate gyrus and the left precuneus showed increased activation in CI patients when compared to controls (unclustered Z ≥ 3.1, P ≤ 0.001). No significant differences were found on structural MRI measures between the CP and CI patients. These results suggest the presence of functional adaptation in the memory network before cognitive decline becomes evident in MS, as displayed by the increased brain activation in the hippocampal-cingulate memory system in CP patients. Interestingly, CI patients showed less activation in the hippocampal network during correct encoding. These findings are important for future cognitive therapeutic studies, since cognitive intervention might be most effective before cognitive impairment is present and when adaptive changes of the brain are most prominent.     

SK2 channels are neuroprotective for ischemia-induced neuronal cell death

In mouse hippocampal CA1 pyramidal neurons, the activity of synaptic small-conductance Ca²⁺-activated K⁺ channels type 2 (SK2 channels) provides a negative feedback on N-methyl--aspartate receptors (NMDARs), reestablishing Mg²⁺ block that reduces Ca²⁺ influx. The well-established role of NMDARs in ischemia-induced excitotoxicity led us to test the neuroprotective effect of modulating SK2 channel activity following cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Administration of the SK channel positive modulator, 1-ethyl-benzimidazolinone (1-EBIO), significantly reduced CA1 neuron cell death and improved CA/CPR-induced cognitive outcome. Electrophysiological recordings showed that CA/CPR-induced ischemia caused delayed and sustained reduction of synaptic SK channel activity, and immunoelectron microscopy showed that this is associated with internalization of synaptic SK2 channels, which was prevented by 1-EBIO treatment. These results suggest that increasing SK2 channel activity, or preventing ischemia-induced loss of synaptic SK2 channels, are promising and novel approaches to neuroprotection following cerebral ischemia.     

The risk of reduced physical activity in children with probable Developmental Coordination Disorder: a prospective longitudinal study

The aim of the current study was to test the hypothesis that children with probable Developmental Coordination Disorder have an increased risk of reduced moderate to vigorous physical activity (MVPA), using data from a large population based study. Prospectively collected data from 4331 children (boys = 2065, girls = 2266) who had completed motor coordination testing at 7 years and accelerometry at 12 years were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC). Probable DCD (p-DCD) was defined, using criteria based on the DSM IV classification, as those children below the 15th centile of the ALSPAC Coordination Test at seven years who had a functional impairment in activities of daily living or handwriting, excluding children with a known neurological diagnosis or IQ < 70. Secondary exposure variables consisted of subtests from the ALSPAC Coordination test (manual dexterity, ball skills and balance). Objective measurement of the average daily minutes of MVPA was recorded as ≥3600 counts per minute (cpm) using actigraph accelerometry. Boys with p-DCD were less physically active than boys without DCD (mean difference in MVPA 4.36 cpm, t = 2.69; p = 0.007). For boys, targeting skill (bean bag toss) was related to increased MVPA, after adjustment for confounding factors including neonatal, family and environmental factors as well as Body Mass Index at age seven and 12 years (β = 0.76, t = 3.37, p < 0.001, CI 0.32-1.20). There was no difference in level of MVPA in girls with and without p-DCD (mean difference 1.35 min, t = 0.97, p = 0.31), which may reflect the low levels of MVPA of girls in this cohort. Our findings suggest that the presence of movement difficulties, particularly poor targeting (bean bag toss/ball skills), at a young age is a potential risk factor for reduced MVPA in boys.     

Sodium-23 magnetic resonance imaging has potential for improving penumbra detection but not for estimating stroke onset time

Tissue sodium concentration increases in irreversibly damaged (core) tissue following ischemic stroke and can potentially help to differentiate the core from the adjacent hypoperfused but viable penumbra. To test this, multinuclear hydrogen-1/sodium-23 magnetic resonance imaging (MRI) was used to measure the changing sodium signal and hydrogen-apparent diffusion coefficient (ADC) in the ischemic core and penumbra after rat middle cerebral artery occlusion (MCAO). Penumbra and core were defined from perfusion imaging and histologically defined irreversibly damaged tissue. The sodium signal in the core increased linearly with time, whereas the ADC rapidly decreased by >30% within 20 minutes of stroke onset, with very little change thereafter (0.5–6 hours after MCAO). Previous reports suggest that the time point at which tissue sodium signal starts to rise above normal (onset of elevated tissue sodium, OETS) represents stroke onset time (SOT). However, extrapolating core data back in time resulted in a delay of 72±24 minutes in OETS compared with actual SOT. At the OETS in the core, penumbra sodium signal was significantly decreased (88±6%, P=0.0008), whereas penumbra ADC was not significantly different (92±18%, P=0.2) from contralateral tissue. In conclusion, reduced sodium-MRI signal may serve as a viability marker for penumbra detection and can complement hydrogen ADC and perfusion MRI in the time-independent assessment of tissue fate in acute stroke patients.     

Testing the specificity of executive functioning impairments in adolescents with ADHD,ODD/CD and ASD

Current diagnostic systems conceptualise attention deficit hyperactivity disorder (ADHD), oppositional defiant/conduct disorder (ODD/CD) and autism spectrum disorder (ASD) as separate diagnoses. However, all three demonstrate executive functioning (EF) impairments. Whether these impairments are trans-diagnostic or disorder-specific remains relatively unexplored. Four groups of 10–16 year-olds [typically developing (TD; N = 43), individuals clinically diagnosed with ADHD (N = 21), ODD/CD (N = 26) and ASD (N = 41)] completed Go/NoGo and Switch tasks. Group differences were tested using analysis of co-variance (ANCOVA) including age, IQ, sex, conduct problems and ADHD symptoms as co-variates. Results indicated some disorder-specificity as only the ASD group demonstrated decreased probability of inhibition in the Go/NoGo task compared to all other groups. However, shared impairments were also found; all three diagnostic groups demonstrated increased reaction time variability (RTV) compared to the TD group, and both the ODD/CD and the ASD group demonstrated increased premature responses. When controlling for ADHD symptoms and conduct problems, group differences in RTV were no longer significant; however, the ASD group continued to demonstrate increased premature responses. No group differences were found in cognitive flexibility in the Switch task. A more varied response style was present across all clinical groups, although this appeared to be accounted for by sub-threshold ODD/CD and ADHD symptoms. Only the ASD group was impaired in response inhibition and premature responsiveness relative to TD adolescents. The findings suggest that some EF impairments typically associated with ADHD may also be found in individuals with ASD.     

μ‐Opioid receptor knockout mice are insensitive to methamphetamine‐induced behavioral sensitization

Repeated administration of psychostimulants to rodents can lead to behavioral sensitization. Previous studies, using nonspecific opioid receptor (OR) antagonists, revealed that ORs were involved in modulation of behavioral sensitization to methamphetamine (METH). However, the contribution of OR subtypes remains unclear. In the present study, using μ‐OR knockout mice, we examined the role of μ‐OR in the development of METH sensitization. Mice received daily intraperitoneal injection of drug or saline for 7 consecutive days to initiate sensitization. To express sensitization, animals received one injection of drug (the same as for initiation) or saline on day 11. Animal locomotor activity and stereotypy were monitored during the periods of initiation and expression of sensitization. Also, the concentrations of METH and its active metabolite amphetamine in the blood were measured after single and repeated administrations of METH. METH promoted significant locomotor hyperactivity at low doses and stereotyped behaviors at relative high doses (2.5 mg/kg and above). Repeated administration of METH led to the initiation and expression of behavioral sensitization in wild‐type mice. METH‐induced behavioral responses were attenuated in the μ‐OR knockout mice. Haloperidol (a dopamine receptor antagonist) showed a more potent effect in counteracting METH‐induced stereotypy in the μ‐OR knockout mice. Saline did not induce behavioral sensitization in either genotype. No significant difference was observed in disposition of METH and amphetamine between the two genotypes. Our study indicated that the μ‐opioid system is involved in modulating the development of behavioral sensitization to METH. © 2010 Wiley‐Liss, Inc.     

Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams

Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2–24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.     

推动医疗改革应制定分区医疗系统战略

医疗改革是一个世界性难题,各国在医疗改革中都会遇到各自相关的问题。改革艰巨,但并不是不可能完成,本文作者认为,通过关注以分区的方式提供医疗服务可以让医疗改革取得实效。本文从划定分区边界的方式出发,介绍了制定分区医疗战略的五个步骤,并讨论了各医疗系统成功实施各自战略所需采取的措施,这也可以为我国正在推行的医疗改革提供一定的借鉴和参考。