Cerebral Palsy

Streptozotocin (STZ) is a nitrosamine-related compound that causes Alzheimer’s disease (AD)-type neurodegeneration with cognitive impairment, brain insulin resistance, and brain insulin deficiency. Nitrosamines and STZ mediate their adverse effects by causing DNA damage, oxidative stress, lipid peroxidation, pro-inflammatory cytokine activation, and cell death, all of which occur in AD. We tested the hypothesis that exposure to N-nitrosodiethylamine (NDEA), which is widely present in processed/preserved foods, causes AD-type molecular and biochemical abnormalities in central nervous system (CNS) neurons. NDEA treatment of cultured post-mitotic rat CNS neurons (48 h) produced dose-dependent impairments in ATP production and mitochondrial function, and increased levels of 8-hydroxy-2′-deoxyguanosine, 4-hydroxy-2-nonenal, phospho-tau, amyloid-beta protein precursor-amyloid-beta (AbetaPP-Abeta), and ubiquitin immunoreactivity. These effects were associated with decreased expression of insulin, insulin-like growth factor (IGF)-I, and IGF-II receptors, and choline acetyltransferase. Nitrosamine exposure causes neurodegeneration with a number of molecular and biochemical features of AD including impairments in energy metabolism, insulin/IGF signaling mechanisms, and acetylcholine homeostasis, together with increased levels of oxidative stress, DNA damage, and AbetaPP-Abeta immunoreactivity. These results suggest that environmental exposures and food contaminants may play critical roles in the pathogenesis of sporadic AD.

Male sex is a well-established risk factor for poor neurodevelopmental outcome following premature birth. The mechanisms behind this sex-related difference are unknown. The damage associated with prematurity can be mimicked in rodents by prolonged exposure to sublethal postnatal hypoxia. This chronic hypoxia leads to anatomical changes in mice that strongly resemble the loss of volume, decreased myelination and ventriculomegaly seen in preterm newborns. However, no sex differences have been previously noted in this rodent model. We hypothesized that sex comparisons in hypoxic mice would show sex related differences in brain volume and white matter loss in response to the same degree of hypoxic insult. Mice were placed in chronic sublethal hypoxia from postnatal day 3-11. Cortical, hippocampal, and cerebellar volumes and myelination indices were measured. We found that the male hippocampus, normally larger than the female, undergoes a greater volume loss compared to females (p<0.05). Myelination, generally greater in males, was significantly disrupted by hypoxia in neonatal male forebrain. These results support the use of this rodent model to investigate the basis of sex related susceptibility to brain damage and develop new sex based neuroprotective strategies.

This study investigated the neuropsychological hallmarks of posterior cortical atrophy (PCA). Seventeen patients with PCA, 17 patients with probable Alzheimer’s disease (PAD), and 17 healthy age-matched subjects underwent neuropsychological testing for abstract reasoning, visuospatial abilities, memory, language, executive functions, praxes, and attention. The PCA patients were significantly more impaired in visual perception, spatial memory, visual attention, and visuospatial reasoning compared to the PAD patients who were relatively more impaired in episodic memory. In the PCA group, no test score correlated with disease duration or age of clinical onset, whereas, in the PAD group, several scores correlated with disease duration. Compared to the healthy subjects, both patient groups showed multiple cognitive deficits. Thus, PCA is characterised by distinctive visuospatial deficits that reflect the distribution of brain damage and contrast with the memory impairment of PAD patients. Specific neuropsychological tests may contribute to early identification of cortical dementia for diagnostic and research purposes.

Volumetric abnormalities in the subcortical structures have been described in schizophrenia. However, it still has to be clarified if subtle microstructural damage is also present. Thus, we aimed to detect subcortical volume and mean diffusivity (MD) alterations in 45 patients with diagnosis of schizophrenia compared with 45 age-, gender-, and educational attainment-matched healthy comparison (HC) participants, by using a combined volumetry and diffusion tensor imaging (DTI) method. A secondary aim was to identify the neuropsychological correlates of subcortical abnormalities in the schizophrenic group. We found thalami and hippocampi bilaterally and left accumbens to show MD increase in the schizophrenic group. No volumetric decrease was found. Moreover, significant correlations between the MD values in subcortical structures (right thalamus and hippocampus and left accumbens) and working memory performance were found. Thus, subcortical microstructural alterations are present in schizophrenia even in absence of volumetric abnormalities. Furthermore, microstructural damage in subcortical areas is linked to working memory, suggesting the presence of a subtle microstructural subcortical dysfunction in the pathoetiological mechanism underlying high cognitive load performances in schizophrenia. Finally, our findings indicate that MD is a more sensitive marker of brain tissue deficits than signal intensity variations measured in T1-weighted imaging data, consistently with previous reports. Thus, DTI appears to be an invaluable tool to investigate subcortical pathology in schizophrenia, greatly enhancing the ability to detect subtle brain changes in this complex disorder.

Background Interdisciplinary care for patients with traumatic brain injury focuses on treating the primary brain injury and limiting further brain damage from secondary injury. Intensive care unit nurses have an integral role in preventing secondary brain injury; however, little is known about factors that influence nurses’ judgments about risk for secondary brain injury. Objective To investigate which physiological and situational variables influence judgments of intensive care unit nurses about patients’ risk for secondary brain injury, management solely with nursing interventions, and management by consulting another member of the health care team. Methods A multiple segment factorial survey design was used. Vignettes reflecting the complexity of real-life scenarios were randomly generated by using different values of each independent variable. Surveys containing the vignettes were sent to nurses at 2 level I trauma centers. Multiple regression was used to determine which variables influenced judgments about secondary brain injury. Results Judgments about risk for secondary brain injury were influenced by a patient’s oxygen saturation, intracranial pressure, cerebral perfusion pressure, mechanism of injury, and primary diagnosis, as well as by nursing shift. Judgments about interventions were influenced by a patient’s oxygen saturation, intracranial pressure, and cerebral perfusion pressure and by nursing shift. The initial judgments made by nurses were the most significant variable predictive of follow-up judgments. Conclusions Nurses need standardized, evidence-based content for management of secondary brain injury in critically ill patients with traumatic brain injury.

Electrical stimulation (ES) can dramatically enhance neurite outgrowth through conductive polymers and accelerate peripheral nerve regeneration in animal models of nerve injury. Therefore, conductive tissue engineering graft in combination with ES is a potential treatment for neural injuries. Conductive tissue engineering graft can be obtained by seeding Schwann cells on conductive scaffold. However, when ES is applied through the conductive scaffold, the impact of ES on Schwann cells has never been investigated. In this study, a biodegradable conductive composite made of conductive polypyrrole (PPy, 2.5%) and biodegradable chitosan (97.5%) was prepared in order to electrically stimulate Schwann cells. The tolerance of Schwann cells to ES was examined by a cell apoptosis assay. The growth of the cells was characterized using DAPI staining and a MTT assay. mRNA and protein levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in Schwann cells were assayed by RT-PCR and Western blotting, and the amount of NGF and BDNF secreted was determined by an ELISA assay. The results showed that the PPy/chitosan membranes supported cell adhesion, spreading, and proliferation with or without ES. Interestingly, ES applied through the PPy/chitosan composite dramatically enhanced the expression and secretion of NGF and BDNF when compared with control cells without ES. These findings highlight for the first time the possibility of enhancing nerve regeneration in conductive scaffolds through ES-increased neurotrophin secretion. (c) 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2009.

Multiple sclerosis (MS), which results in damage of the white matter at multiple foci, poses a far-reaching public health problem in view of the burden it imposes on the affected young and middle-aged. Some previous data suggested that roles could be played in the demyelinization of the white matter of the brain by the malfunctioning of the mitochondria and mitochondria-associated reactive oxygen species. In this context, we hypothesized that the finely tuned dynamic stability of the mitochondrial membrane potential (MMP), which is the main mirror of the functional state of the mitochondria, is essential for the intact nature of the glia cells in the brain. Setting out from this, our aim in this study was to examine how the rs10807344 and rs2270450 genetic variants of mitochondrial uncoupling protein 4 (mUCP4) can give rise to the development of MS, since mUCP4 is presumed to be of great importance in the regulation of the MMP and cellular energy metabolism. The clinical and genetic data on 120 relapsing-remitting MS patients and 250 neuroimaging alteration-free subjects were analyzed. The rs10807344 CC genotype proved to exert a protective effect against the occurrence of MS (neuroimaging alteration-free controls, 58%; MS group, 33%; P < 0.0000089; OR, 0.32; 95% CI: 0.2-0.56, P < 0.005). The present findings indirectly raise the possibility that a shift or imbalance in the finally regulated MMP plays a role in the development of MS.

The purpose of this study is to measure the effects of a tomographic synchrotron irradiation on healthy mouse brain. The cerebral cortexes of healthy nude mice were irradiated with a monochromatic synchrotron beam of 79 keV at a dose of 15 Gy in accordance with a protocol of photoactivation of cisplatin previously tested in our laboratory. Forty-eight hours, one week and one month after irradiation, the blood brain barrier (BBB) permeability was measured in the irradiated area with intravital multiphoton microscopy using fluorescent dyes with molecular weights of 4 and 70 kDa. Vascular parameters and gliosis were also assessed using quantitative immunohistochemistry. No extravasation of the fluorescent dyes was observed in the irradiated area at any measurement time (48 h, 1 week, 1 month). It appears that the BBB remains impermeable to molecules with a molecular weight of 4 kDa and above. The vascular density and vascular surface were unaffected by irradiation and no gliosis was induced. These findings suggest that a 15 Gy/79 keV synchrotron irradiation does not induce important damage on brain vasculature and tissue on the short term following irradiation.

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT(1))-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs’ protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT(1)-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats. The antioxidative and antiinflammatory properties were also investigated. R-147176 significantly reduced infarct volume, without influence on blood pressure, in both models. R-147176 significantly reduced the numbers of ED-1-positive cells and of TUNEL-positive cells, and protein carbonyl formation in the damaged brain. This ARB derivative, despite its significantly lower AT1 affinity and virtually no antihypertensive effect, ameliorated ischemic cerebral damage through antioxidative and antiinflammatory properties. These findings suggest potential usefulness of R-147176 as a pharmacological tool to investigate the ARBs’ protective effect in experimental stroke and open new therapeutic avenues.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 June 2009; doi:10.1038/jcbfm.2009.82.

Neurons are highly dependent on astrocyte survival during brain damage. To identify genes involved in astrocyte function during ischemia, we performed mRNA differential display in astrocytes after oxygen and glucose deprivation (OGD). We detected a robust downregulation of S6 kinase 1 (S6K1) mRNA that was accompanied by a sharp decrease in protein levels and activity. OGD-induced apoptosis was increased by the combined deletion of S6K1 and S6K2 genes, as well as by treatment with rapamycin that inhibits S6K1 activity by acting on the upstream regulator mTOR. Astrocytes lacking S6K1 and S6K2 (S6K1; S6K2-/-) displayed a defect in BAD phosphorylation and in the expression of the anti-apoptotic factors Bcl-2 and Bcl-xL. Furthermore reactive oxygen species (ROS) were increased while translation recovery was impaired in S6K deficient astrocytes following OGD. Rescue of either S6K1 or S6K2 expression by adenoviral infection revealed that protective functions were specifically mediated by S6K1, as this isoform selectively promoted resistance to OGD and reduction of ROS levels. Finally, in vivo effects of S6K suppression were analyzed in the permanent middle cerebral artery occlusion (MCAO) model of ischemia, in which absence of S6K expression increased mortality and infarct volume. In summary, this article uncovers a protective role for astrocyte S6K1 against brain ischemia, indicating a functional pathway that senses nutrient and oxygen levels and may be beneficial for neuronal survival.