Cerebral Palsy

Lead, a systemic toxicant affecting virtually every organ system, primarily affects the central nervous system, particularly the developing brain. Consequently, children are at a greater risk than adults of suffering from the neurotoxic effects of lead. To date, no safe lead-exposure threshold has been identified. The ability of lead to pass through the blood-brain barrier is due in large part to its ability to substitute for calcium ions. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurologic disorders. At the molecular level, lead interferes with the regulatory action of calcium on cell functions and disrupts many intracellular biological activities. Experimental studies have also shown that lead exposure may have genotoxic effects, especially in the brain, bone marrow, liver, and lung cells. Knowledge of the neurotoxicology of lead has advanced in recent decades due to new information on its toxic mechanisms and cellular specificity. This paper presents an overview, updated to January 2009, of the neurotoxic effects of lead with regard to children, adults, and experimental animals at both cellular and molecular levels, and discusses the biomarkers of lead exposure that are useful for risk assessment in the field of environmental health.

OBJECTIVE: T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-beta in MS patients. METHODS: In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17-producing myelin basic protein-stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-alphaR1) expression, IFN-beta-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody-stimulated PB lymphocytes. RESULTS: Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-alphaR1 expression, IFN-beta-induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-alphaR1 expression and IFN-beta-dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells. INTERPRETATION: Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-alphaR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-beta therapy. Ann Neurol 2009;65:499-509.

The (pro)renin receptor [(P)RR] plays pivotal role in the renin angiotensin system and although experimental models emphasize the role of (P)RR in fibrosis , in organ damage associated with hypertension and diabetes, a mutation of the (P)RR gene resulting in a truncated Delta4-(P)RR is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. Our aims were to study (P)RR expression in mouse brain and the effect of transfection of Delta4-(P)RR on neuronal differentiation of PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed the expression of (P)RR in cortical neurons, pyramidal cells and thalamic relay nuclei. In mouse neurons the receptor is found on plasma membrane and in synaptic vesicles and stimulation by renin provoked ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the endoplasmic reticulum and redistributed to neurite projections when cells were induced to differentiate by NGF. In contrast, Delta4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Co-transfection of PC-12 with (P)RR and Delta4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with Delta4-(P)RR suggesting that the XLMR and epilepsy phenotype resulted from a dominant negative effect of Delta4-(P)RR. In conclusion, our results show that (P)RR is expressed in mouse brain where it may have a role in neuronal cell differentiation and suggest that the XLMR and epilepsy phenotype resulted from a dominant negative effect of the Delta4-(P)RR protein. Key words: (pro)renin receptor, neuronal cell differentiation.

ABSTRACT: BACKGROUND: S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium. METHODS: The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay. RESULTS: Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p<0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 ug/L, p=<0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p=0.97). Delirious state (before, during, after) (p<0.001), day of blood withdrawal (p<0.001), pre- or postoperative status (p=0.001) and type of fracture (p=0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p=0.43) or NSE levels (p=0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium. CONCLUSIONS: Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for delirium.

AIMS: Most brain diseases are complex entities. Although animal models or cell culture experiments mimic some disease aspects, human post mortem brain tissue remains essential to advance our understanding of brain diseases using biochemical and molecular techniques. Post mortem artefacts must be properly understood, standardized, and either eliminated or factored into such experiments. Here we examine the influence of several premortem and post mortem factors on pH, and discuss the role of pH as a biochemical marker for brain tissue quality. METHODS: We assessed brain tissue pH in 339 samples from 116 brains provided by 8 different European and 2 Australian brain bank centres. We correlated brain pH with tissue source, post mortem delay, age, gender, freezing method, storage duration, agonal state and brain ischaemia. RESULTS: Our results revealed that only prolonged agonal state and ischaemic brain damage influenced brain tissue pH next to repeated freeze/thaw cycles. CONCLUSIONS: pH measurement in brain tissue is a good indicator of premortem events in brain tissue and it signals limitations for post mortem investigations.

Abstract Aging may be an important factor affecting brain injury by intracerebral hemorrhage (ICH). In the present study, we investigated the responses of glial cells and monocytes to intracerebral hemorrhage in normal and aged rats. ICH was induced by microinjecting autologous whole blood (15 muL) into the striatum of young (4 month old) and aged (24 month old) Sprague-Dawley rats. Age-dependent relations of brain tissue damage with glial and macrophageal responses were evaluated. Three days after ICH, activated microglia/macrophages with OX42-positive processes and swollen cytoplasm were more abundantly distributed around and inside the hemorrhagic lesions. These were more dramatic in aged versus the young rats. Western blot and immunohistochemistry analyses showed that the expression of interleukin-1beta protein after ICH was greater in aged rats, whereas the expression of GFAP and ciliary neurotrophic factor protein after ICH was significantly lower in aged rats. These results suggest that ICH causes more severe brain injury in aged rats most likely due to overactivation of microglia/macrophages and concomitant repression of reactive astrocytes.

Recent studies have reported that the majority of patients with multiple system atrophy (MSA) had hypertensive heart disease. However, the effect of autonomic failure on the brain in MSA has not been studied. We consecutively enrolled 63 patients with MSA and selected 63 age- and sex-matched healthy subjects. We performed a comparative analysis of cerebrovascular lesions between the patients with MSA and the control subjects and analyzed predisposing factors for cerebrovascular lesions in the patients with MSA. There was no significant difference in lacune and territorial infarcts between the patients with MSA and the control subjects. The median grading score of white matter hyperintensity (WMH) was significantly higher in the patients with MSA (1.0, interquartile range 0.5-2.0) than the control subjects (0.0, interquartile range 0.0-1.0; P < 0.01). In the patients with MSA, there was strong correlation between the grading score of WMH and supine systolic blood pressure (r = 0.529, P < 0.001) after adjusting for age. Multiple linear regression analysis showed that age and supine systolic blood pressure was significantly and independently correlated with the grading score of WMH. The present study demonstrates that patients with MSA had more severe WMH and that supine systolic pressure is a major contributing factor for the severity of WMH, suggesting that patients with MSA have target-organ damage of the brain.

Objectives: Recovery from stroke is dependent on the survival of neurons in the dynamic peri-infarcted region. Although several markers of neuronal injury and apoptotic cell death have been described, administration of neuroprotective drugs directed at specific molecules has had limited success. A complete understanding of deregulated genes associated with neuronal death would be beneficial. Our previous microarray studies identified increased expression of a novel protein, the B-cell translocation gene 2 (BTG2), in infarcted regions. Methods: We have used immunohistochemistry and Western blotting to examine the expression and localization of BTG2 in stroked brain tissue and immunofluorescent staining of human fetal brain neurons to determine if oxygen-glucose deprivation affected its expression. Results: We show that BTG2 is strongly expressed in peri-infarcted and infarcted regions of brain tissue, localizing in neuronal nuclei and cytoplasm, whilst being absent or very weakly expressed in normal looking contralateral tissue. Exposure of human fetal brain neurons to oxygen-glucose deprivation also induced BTG2 expression in the cytoplasm and perinuclear regions of cells staining positive for propidium iodide (a marker of nuclear damage). Conclusions: BTG2 may be a modulator of cell survival and differentiation and could help to protect against cell death by inhibition of necrosis and/or apoptotic signalling pathways. Copyright © 2009 S. Karger AG, Basel.

Background: Patients with internal carotid artery (ICA) stenosis have an increased incidence of coronary heart disease. Evidence about the incidence of clinically silent myocardial infarction (MI) in these patients is limited. Contrast-enhanced cardiac magnetic resonance (CMR) imaging allows for the detection of minor myocardial damage. Objective: We tested whether patients with ICA stenosis exhibit a relevant incidence of silent MI when assessed by CMR. Methods: In a single-center study, 77 consecutive patients (age 68 +/- 7 years) with suspected ICA stenosis were imaged prospectively with a combined MRI protocol including T(1), T(2), diffusion-weighted imaging, fluid-attenuated inversion recovery, and contrast-enhanced MR angiography (CEMRA) imaging of the brain and a short (11 min) CMR protocol with left ventricular function and late gadolinium enhancement imaging. Blinded to any clinical information, two readers evaluated the cardiac and neuroradiologic examinations. Results: Of 154 imaged ICA, 85 presented with stenosis and 17 were occluded. In 7 patients, the suspected ICA stenosis could not be confirmed by CEMRA. In the remaining 70 patients with ICA stenosis, 34.3% had cerebral lesions (15.7% with a homodynamic pattern,18.6% with territorial infarction). CMR detected MI in 29 (41%) patients, whereas ECG and medical history enabled diagnosis in only 7 (10%) patients. Conclusions: ICA stenosis patients have a higher incidence of myocardial scars proving silent MI when detected by contrast-enhanced CMR than clinically expected. Whether the presence and extent of silent MIs detected by CMR affect peri-interventional risk and prognosis of ICA stenosis patients remains to be evaluated in a large patient cohort with long-term follow-up. Copyright © 2009 S. Karger AG, Basel.

Introduction: Ambulance personnel use wheeled stretchers for moving patients in the out-of-hospital setting. The nature of adverse events and associated injuries occurring during ambulance stretcher operation was characterised. METHODS: Data from the United States Food and Drug Administration’s Manufacturer and User Facility Device Experience Database (MAUDE) were used. All adverse events involving ambulance stretchers during the years 1996-2005 were identified. The nature of the event, the method of stretcher handling, the individuals injured and the nature of the resulting injuries were identified. RESULTS: There were 671 reported adverse events. The most common adverse events were stretcher collapse (54%; 95% CI 50 to 57%), broken, missing or malfunctioning part (28%; 95% CI 25 to 32%) and dropped stretcher (7%; 95% CI 5 to 9%). Adverse events most commonly occurred during unloading of the stretcher from the ambulance (16%; 13 to 19%). Injuries occurred in 121 events (18%; 95% CI 15 to 21%), most often involving sprains/strains (29%), fractures (16%) and lacerations/avulsions (13%). There were three traumatic brain injuries and three deaths. Patients sustained injuries in 52 events (43%), and ambulance personnel sustained injuries in 64 events (53%). More than one individual sustained injuries in 12 events. CONCLUSION: Adverse events may occur during ambulance stretcher operation and can result in significant injury to patients and ambulance personnel.