Cerebral Palsy

AIM. To evaluate the usefulness of positron emission tomography (PET) as a predictor of long-term disability after a severe traumatic brain injury (TBI). PATIENTS AND METHODS. Fifty-six patients who had sustained a severe TBI were assessed with a broad battery of cognitive and functional scales at baseline and 6-months after inclusion in a multidisciplinary rehabilitation program. All patients underwent a FDG-PET at baseline. A physician blind to clinical data performed a semiquantitative analysis (normal vs altered) of functional neuroimaging (PET), including four cortical and three subcortical areas. The total number of lesions (cortical, subcortical and total) was correlated to the intensity of the TBI and to clinical data at admission and at follow-up. RESULTS. All patients showed changes in cerebral metabolism, being the thalamus the area most frequently affected. The degree of cerebral hypometabolism showed a significant correlation with TBI severity, functional disability, global outcome and cognitive impairment not only at baseline but also at follow-up. CONCLUSIONS. According to our results, FDG-PET may be a useful tool when studying brain dysfunction after severe TBI. FDG-PET findings correlate with the TBI severity, and with the level of patients’ disability, as well as with the degree of memory and intelligence impairment. However, clinical variables related to the severity of the TBI, still are the best predictors of functional outcome after TBI.

Sesame ( SESAMUM INDICUM L.) is an important oilseed crop that possesses a wide spectrum of pharmacological activities. Many studies have been conducted to investigate its health-promoting effects. Compared to other plant oils, sesame seed oil is highly stable to oxidation and has been demonstrated to have protective effects against ischemia-reperfusion injury in the rat brain. However; the effects of defatted sesame seeds extract (DSE) have not been studied yet. The purpose of this study was to evaluate the protective effect of DSE against ischemia models. For IN VITRO ischemia, oxygen-glucose deprivation followed by reoxygenation (OGD-R, 4 h OGD followed by 24 h reoxygenation) in HT22 cells was used to investigate the protective effects on cell death and the inhibitory effects on lipid peroxidation. For IN VIVO ischemia, the middle cerebral artery occlusion (MCAo, 2 h of MCAo followed by 22 h of reperfusion) rat model was used. Twenty-two h after occlusion the rats were assessed for neurobehavioral deficit and infarct volume. DSE (0.1-10 microg/mL) significantly reduced the cell death and inhibited lipid peroxidation induced by OGD-R. DSE (30, 100 and 300 mg/kg, P. O.) given twice at 0 h and 2 h after onset of ischemia reduced brain infarct volume dose-dependently and improved sensory-motor function. The therapeutic time window of DSE (300 mg/kg, P. O.) was 2 h after MCAo in rats. In conclusion, our results show that DSE may be effective in ischemia models by an antioxidative mechanism.

Insights into the molecular basis and the temporal evolution of neurotoxicity in prion disease are increasing, and recent work in mice leads to new avenues for targeting treatment of these disorders. Using lentivirally mediated RNA interference (RNAi) against native prion protein (PrP), White et al. report the first therapeutic intervention that results in neuronal rescue, prevents symptoms and increases survival in mice with established prion disease.(1) Both the target and the timing of treatment here are crucial to the effectiveness of this strategy: the formation of the neurotoxic prion agent is prevented at a point when diseased neurons can still be saved from death. But the data also give new insights into the timing of treatment in the context of the pattern of spread of prion infection throughout the brain, with implications for developing the most effective treatments. This perspective considers developments in the field that led to the rationale for targeting endogenous prion protein (PrP) in prion therapeutics and to the discovery of a window of reversibility of early neuronal damage in prion disease. It introduces RNA interference (RNAi) and its therapeutic use in this context and discusses insights into prion pathogenesis and future treatment strategies and goals. A key concept is targeting the critical brain regions for the spread of prion replication. This may have relevance in other neurodegenerative diseases due to protein misfolding, which recent literature suggests may also propagate throughout the brain in disease-specific patterns.

We studied effects of tetrac (tetraiodothyroacetic acid) on survival of GL261, a murine brain tumor cell line, following single doses of 250 kVp x-rays and on repair of damage (sublethal and potentially lethal damage repair; SLDR, PLDR) in both exponential and plateau phase cells. Cells were exposed to 2 muM tetrac (1 h at 37 degrees C) prior to x-irradiation. At varying times after irradiation, cells were re-plated in medium without tetrac. Two weeks later, colonies were counted and results analyzed using either the linear-quadratic (LQ) or single-hit, multitarget (SHMT) formalisms. Tetrac sensitized both exponential and plateau phase cells to x-irradiation, as shown by a decrease in the quasi-threshold dose (Dq), leading to an average tetrac enhancement factor (ratio of SF(2) values) of 2.5. Tetrac reduced SLDR in exponential cells by a factor of 1.8. In plateau phase cells there was little expression of SLDR, but tetrac produced additional cell killing at 1-4 h after the first dose. For PLDR expression in exponential cells, tetrac inhibited PLDR by a factor of 1.9, and in plateau phase cells, tetrac decreased PLDR expression by a factor of 3.4. These data show that the decreased Dq value seen after single doses of x-rays with tetrac treatment is also accompanied by a significant decrease in recovery from sublethal and potentially lethal damage.

IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-gamma and TNF-alpha mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte “sink” that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.

Microglia do not constitute a single, uniform cell population, but rather comprise cells with varied phenotypes, some which are beneficial and others that may require active regulatory control. Thus, gaining a better understanding of the heterogeneity of resident microglia responses will contribute to any interpretation regarding the impact of any such response in the brain. Microglia are the primary source of the pro-inflammatory cytokine, tumor necrosis factor (TNF) that can initiate various effects through the activation of membrane receptors. The TNF p55 receptor contains a death domain and activation normally leads to cellular apoptosis; however, under specific conditions, receptor activation can also lead to the activation of NFkappaB and contribute to cell survival. These divergent outcomes have been linked to receptor localization with receptor internalization leading to cell death and membrane localization supporting cell survival. A second TNF receptor, TNF p75 receptor, is normally linked to cell growth and survival, however, it can cooperate with the p55 receptor and contribute to cell death. Thus, while an elevation in TNFalpha in the brain is often considered an indicator of microglia activation and neuroinflammation, a number of factors come into play to determine the final outcome. Data is reviewed demonstrating that heterogeneity in morphological response of microglia and the expression of TNFalpha and TNF receptors are critical in identifying and characterizing neurotoxic events as they relate to neuroinflammation, neuronal damage and in stimulating neuroprotection.

Recent literature indicates that low-dose methylene blue (MB), an autoxidizable dye with powerful antioxidant and metabolic enhancing properties, might prevent neurotoxin-induced neural damage and associated functional deficits. This study evaluated whether local MB may counteract the anatomical and functional effects of the intrastriatal infusion of the neurotoxin rotenone in the rat. To this end, stereological analyses of striatal lesion volumes were performed and changes in oxidative energy metabolism in the striatum and related motor regions were mapped using cytochrome oxidase histochemistry. The influence of MB on striatal levels of oxidative stress induced by rotenone was determined, and behavioral tests were used to investigate the effect of unilateral MB co-administration on motor asymmetry. Rotenone induced large anatomical lesions resembling “metabolic strokes”, whose size was greatly reduced in MB-treated rats. Moreover, MB prevented the decrease in cytochrome oxidase activity and the perilesional increase in oxidative stress associated with rotenone infusion in the striatum. MB also prevented the indirect effects of the rotenone-induced lesion on cytochrome oxidase activity in related motor regions, such as the striatal regions rostral and caudal to the lesion, the substantia nigra compacta and reticulata, and the pedunculopontine nucleus. At a network level, MB maintained a global strengthening of functional connectivity in basal ganglia-thalamocortical motor circuits, as opposed to the functional decoupling observed in rotenone-alone subjects. Finally, MB partially prevented the behavioral sensorimotor asymmetries elicited by rotenone. These results are consistent with protective effects of MB against neurotoxic damage in the brain parenchyma. This study provides the first demonstration of the anatomical, metabolic and behavioral neuroprotective effects of MB in the striatum in vivo, and supports the notion that MB could be a valuable intervention against neural damage associated with oxidative stress and energy hypometabolism.

OBJECTIVE: To investigate the spatial nature of mental number line. METHODS: Number bisection test was conducted on 8 right-brain-damaged patients with persistent left neglect, 8 right-brain-damaged patients without spatial neglect, and 8 healthy control subjects, all aged- and education-level-matched and right-handed. RESULTS: The error rate in subjective midpoint of the 8 neglect patients was (44.63+/-12.49)% (forward direction) and (46.00+/-12.10)% (reverse direction), both significantly higher than those of the right brain damage control group [(3.34+/-4.32)% and (5.21+/-5.21)% respectively] and healthy control group [(0.00+/-0.00)% and (0.00+/-0.00)% respectively] (all P<0.01). The longer the interval between the numbers, the higher right-shift error rate: corresponding to the interval sizes as 3, 5, 7, and 9, the mean deviation rates of antrorse presentation were (-4.25+/-7.87)%, (12.63+/-19.06)%, (58.38+/-24.30)%, and (111.50+/-53.54)% respectively, and the mean deviation rates of reverse presentation were (-18.40+/-25.35)%, (-1.60+/-21.4)%, (56.80+/-27.04)%, and (108.20+/-55.10)% respectively. Analysis of variance of the antrorse presentation and reverse presentation showed the result: F=1.705 and P=0.262. Correlation analysis of the mental number bisection task and line bisection task showed the result: r=0.887 and P=0.045. The control subjects made very few errors in subjective midpoint and their performance was not affected by interval sizes. The magnitude of numbers used did not influence the performance in any group. CONCLUSION: The performance of neglect patients in bisecting mental number line closely mirrors their difficulty in bisecting physical lines. This demonstrates the spatial nature of the mental number line isomorphism to physical lines. The mental number line is orientated in a left-to-right manner. Disorder exists at the characterization level in neglect patients.

OBJECTIVE: To investigate the effects of Shenmai injection containing active principles of Ginseng and ophiopogon root on the expression of hypoxia-inducible factor 1-alpha (HIF-1alpha) in brain after hypoxic-ischemic brain damage (HIBD). METHODS: 108 neonatal SD rats were randomly divided into 2 equal groups: (1) Shenmai group (Group SM), undergoing ligation of the right common carotid artery to establish HIBD models, breathing immediately a mixed gas with 8% oxygen and 92% nitrogen for 2 hours to cause HI insult, and then injected intraperitoneally with Shenmai injection 10 mg/kg once a day for 7 days, and (2) normal saline (NS) group (Group NS) undergoing ligation of the right common carotid artery to establish HIBD models, breathing immediately a mixed gas with 8% oxygen and 92% nitrogen for 2 h, and then injected intraperitoneally with NS 10 mg/kg once a day for 7 days. Another 54 neonatal rats underwent sham operation but did not undergo hypoxia as control group (Group C), 2, 12, and 24 hours, and 3, 7, and 14 days after HI insult 9 rats from each group were killed with their right hippocampal tissues taken out. Flow cytometry was used to examine the apoptotic rate of the hippocampal neurons. RT-PCR was used to detect the mRNA expression of HIF-1alpha. RESULTS: (1) The apoptosis rate of the right hippocampal tissues began increase 2 h after Hi insult, peaked 24 h after HI, then gradually decreased, and almost returned to the original levels 14 d after HI. There was no significant differences in apoptosis rates 14d after HI among the 3 groups (all P > 0.05). The neuron apoptosis rates 12 h, 24 h, 3 d, and 7 d after HI of Group SM were all significantly lower than those of Group NS (e.g 24 h: (11.95 +/- 1.13)% vs (16.80 +/- 1.44)%, all P < 0.05). (2) The HIF-1alpha mRNA expression level in right brain began to increase 2 h after HI, peaked 24 h after HI, then gradually decreases, and returned to the original level 14 d after Hi in both Group SM and Group NS; The HIF-1alpha mRNA expression in right brain 12 h, 24 h, 3 d, and 7 d after HI of Group SM were all significantly higher than those of Group NS (e.g 24 h: (44.32 +/- 4.03)% vs (35.63 +/- 3.73)%, all P < 0.05). CONCLUSION: The HIF-1alpha mRNA expression in brain tissue is up-regulated after HI insult. Shenmai injection helps increase the mRNA expression of HIF-1alpha in brain and reduces the apoptosis of hippocampus neurons after HI insult.

OBJECTIVE: To determine the underlying etiology, associated malformations, clinical course, and prognostic significance of congenital chylothorax. STUDY DESIGN: A retrospective analysis of 11 neonates admitted to our neonatal intensive care unit with congenital chylothorax between January 2000 and June 2008. The post-discharge clinical and developmental course was evaluated by a telephone survey performed in July 2008. RESULTS: Antenatal diagnosis was established in 9 out of 11 infants by ultrasound examination; 5 had intrauterine pleural drainage. Eight infants had either structural or chromosomal abnormalities. The postnatal treatment included mechanical ventilation, drainage of pleural fluid and feeding with enriched medium chain triglyceride formula. Somatostatin was administered in one case. Six patients developed nosocomial infections. Two patients died after resolution of the chylothorax from deteriorating renal failure. Seven patients were traced for follow up and six of them achieved age appropriate developmental milestones. CONCLUSION: The recovery from chylothorax and future prognosis were dependent on the underlying etiology. Chylothorax was often a secondary event, with apparently favorable clinical and developmental prognosis when the underlying or/and associated condition was treatable. Pediatr Pulmonol. (c) 2009 Wiley-Liss, Inc.