Cerebral Palsy

Genetic damage in multiple organs of acutely exercised rats.

admin — Mon, 22 Nov 2010 08:51:29 +0000

The aim of this study was to investigate the effects of acute exercise on genomic damage in an animal model. Male adult Wistar rats were divided into the following groups: control and acute exercised (experimental). For this purpose, 15 animals were accustomed to running on a rodent treadmill for 15?min per day for 5 days (10-20?m?min(-1); 08 grade). After 4 days at rest, active animals ran on the treadmill (22?m?min(-1), 58 grade) till exhaustion. Cells from peripheral blood, liver, heart, and brain were collected after 0, 2, and 6?h after exercise. The results showed that acute exercise was able to induce genetic damage in peripheral blood cells after 2 and 6?h of exercise, whereas liver pointed out genetic damage for all periods evaluated. No genetic damage was induced either in brain or in heart cells. In conclusion, our results suggest that acute exercise could contribute to the genetic damage in peripheral blood and liver cells. It seems that liver is a sensitive organ to the genotoxic insult after acute exercise. Copyright © 2010 John Wiley & Sons, Ltd.

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion.

admin — Mon, 22 Nov 2010 08:51:27 +0000

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3-4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents.

Insights into a mummy: a paleoradiological analysis.

admin — Mon, 22 Nov 2010 08:51:24 +0000

The aim of the study was to analyze possible human skeletal remains within the wrappings of a mummy from the Archaeological Museum, Zagreb, Croatia through the use of the multidetector CT (MDCT) technology. Plain X-ray films and MDCT images of the mummy were taken in both frontal and lateral views. In a single volumetric acquisition of the whole body by MDCT 0.75 mm axial slices were obtained and combined with sagittal and coronal reformatting and three-dimensional (3D) reconstruction. Sex and age was assessed visually using standard anthropological methods. The results suggest that the mummy was of an adult female, most likely over 40 years of age at death. Pathologies observed included degenerative changes on the vertebral column and healed fractures of the lower right arm. Damage of the ethmoid bone at the roof of the nasal cavity was most likely caused by mortuary brain removal practice. Remnants of a resin and an unusual object were found inside the cranial cavity. An elongated metal object and additional three metal “belts” can be seen on the lower portion of the body. All internal organs were removed and thoracic and abdominal cavities were filled with various substances, most likely mud and pieces of linen cloth. Our results show that the MDCT is a very useful technique for assessing the human remains in archeological samples, especially in comparison to the use of plain film (X-ray), where important details are obscured and 3D imaging impossible.

Neurochemical Evidence that Lysine Inhibits Synaptic Na(+),K (+)-ATPase Activity and Provokes Oxidative Damage in Striatum of Young Rats In vivo.

admin — Mon, 22 Nov 2010 08:51:23 +0000

Lysine (Lys) accumulation in tissues and biological fluids is the biochemical hallmark of patients affected by familial hyperlysinemia (FH) and other inherited metabolic disorders. In the present study we investigated the effects of acute administration of Lys on relevant parameters of energy metabolism and oxidative stress in striatum of young rats. We verified that Lys in vivo intrastriatal injection did not change the citric acid cycle function and creatine kinase activity, but, in contrast, significantly inhibited synaptic Na(+),K(+)-ATPase activity in striatum prepared 2 and 12 h after injection. Moreover, Lys induced lipid peroxidation and diminished the concentrations of glutathione 2 h after injection. These effects were prevented by the antioxidant scavengers melatonin and the combination of ?-tocopherol and ascorbic acid. Lys also inhibited glutathione peroxidase activity 12 h after injection. Therefore it is assumed that inhibition of synaptic Na(+),K(+)-ATPase and oxidative damage caused by brain Lys accumulation may possibly contribute to the neurological manifestations of FH and other neurometabolic conditions with high concentrations of this amino acid.

A Systematic Molecular Pathology Study of a Laboratory Confirmed H5N1 Human Case.

admin — Mon, 22 Nov 2010 08:51:21 +0000

Autopsy studies have shown that human highly pathogenic avian influenza virus (H5N1) can infect multiple human organs other than just the lungs, and that possible causes of organ damage are either viral replication and/or dysregulation of cytokines and chemokines. Uncertainty still exists, partly because of the limited number of cases analysed. In this study, a full autopsy including 5 organ systems was conducted on a confirmed H5N1 human fatal case (male, 42 years old) within 18 hours of death. In addition to the respiratory system (lungs, bronchus and trachea), virus was isolated from cerebral cortex, cerebral medullary substance, cerebellum, brain stem, hippocampus ileum, colon, rectum, ureter, aortopulmonary vessel and lymph-node. Real time RT-PCR evidence showed that matrix and hemagglutinin genes were positive in liver and spleen in addition to positive tissues with virus isolation. Immunohistochemistry and in-situ hybridization stains showed accordant evidence of viral infection with real time RT-PCR except bronchus. Quantitative RT-PCR suggested that a high viral load was associated with increased host responses, though the viral load was significantly different in various organs. Cells of the immunologic system could also be a target for virus infection. Overall, the pathogenesis of HPAI H5N1 virus was associated both with virus replication and with immunopathologic lesions. In addition, immune cells cannot be excluded from playing a role in dissemination of the virus in vivo.

Inhibition of the Striatal Specific Phosphodiesterase PDE10A Ameliorates Striatal and Cortical Pathology in R6/2 Mouse Model of Huntington’s Disease.

admin — Mon, 22 Nov 2010 08:51:18 +0000

BACKGROUND: Huntington’s disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington’s pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse.

METHODOLOGY/PRINCIPAL FINDINGS: R6/2 mice were treated with the highly selective PDE10A inhibitor TP-10 from 4 weeks of age until euthanasia. TP-10 treatment significantly reduced and delayed the development of the hind paw clasping response during tail suspension, deficits in rotarod performance, and decrease in locomotor activity in an open field. Treatment prolonged time to loss of righting reflex. These effects of PDE10A inhibition on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal and cortical cell loss, the formation of striatal neuronal intranuclear inclusions, and the degree of microglial activation that occurs in response to the mutant huntingtin-induced brain damage. Striatal and cortical levels of phosphorylated CREB and BDNF were significantly elevated.

CONCLUSIONS/SIGNIFICANCE: Our findings provide experimental support for targeting the cAMP and CREB signaling pathways and more broadly transcriptional dysregulation as a therapeutic approach to Huntington’s disease. It is noteworthy that PDE10A inhibition in the R6/2 mice reduces striatal pathology, consistent with the localization of the enzyme in medium spiny neurons, and also cortical pathology and the formation of neuronal nuclear inclusions. These latter findings suggest that striatal pathology may be a primary driver of these secondary pathological events. More significantly, our studies point directly to an accessible new therapeutic approach to slow Huntington’s disease progression, namely, PDE10A inhibition. There is considerable activity throughout the pharmaceutical industry to develop PDE10A inhibitors for the treatment of basal ganglia disorders. The present results strongly support the investigation of PDE10A inhibitors as a much needed new treatment approach to Huntington’s disease.

Central auditory disorders: toward a neuropsychology of auditory objects.

admin — Mon, 22 Nov 2010 08:51:16 +0000

PURPOSE OF REVIEW: Analysis of the auditory environment, source identification and vocal communication all require efficient brain mechanisms for disambiguating, representing and understanding complex natural sounds as ‘auditory objects’. Failure of these mechanisms leads to a diverse spectrum of clinical deficits. Here we review current evidence concerning the phenomenology, mechanisms and brain substrates of auditory agnosias and related disorders of auditory object processing.

RECENT FINDINGS: Analysis of lesions causing auditory object deficits has revealed certain broad anatomical correlations: deficient parsing of the auditory scene is associated with lesions involving the parieto-temporal junction, while selective disorders of sound recognition occur with more anterior temporal lobe or extra-temporal damage. Distributed neural networks have been increasingly implicated in the pathogenesis of such disorders as developmental dyslexia, congenital amusia and tinnitus. Auditory category deficits may arise from defective interaction of spectrotemporal encoding and executive and mnestic processes. Dedicated brain mechanisms are likely to process specialized sound objects such as voices and melodies.

SUMMARY: Emerging empirical evidence suggests a clinically relevant, hierarchical and modular neuropsychological model of auditory object processing that provides a framework for understanding auditory agnosias and makes specific predictions to direct future work.

Complementary roles of grey matter MTR and T2 lesions in predicting progression in early PPMS.

admin — Mon, 22 Nov 2010 08:51:14 +0000

Objective To investigate whether T2 lesion load and magnetisation transfer ratio (MTR) in the normal-appearing white matter (NAWM) and grey matter (GM) at study entry are independent predictors of progression and whether their changes correlate with the accrual of disability, over 5 years in early primary progressive multiple sclerosis (PPMS). Methods Forty-seven patients with early PPMS and 18 healthy controls were recruited at baseline and invited to attend clinical 6-monthly assessments for 3 years, and after 5 years. Patients were scored on the Expanded Disability Status Scale and multiple sclerosis functional composite subtests (25-foot timed walk test (TWT), nine-hole peg test and paced auditory serial addition test). At each time point, all subjects underwent brain MRI including T2-weighted, magnetisation transfer and volumetric sequences. T2 lesion load (T2LL), MTR histogram parameters and volumes for NAWM and GM were calculated. Statistical analyses identified predictors of progression and correlations between MRI changes and clinical changes over time. Results Baseline T2LL and GM peak location and peak height MTR were independent predictors of progression, as measured by TWT; a model including these three predictors explained 91% of the variance of the progression on TWT, a significantly higher percentage than that obtained when the predictors were modelled individually (80%, 74% and 68%, respectively). A greater progression rate correlated with a steeper increase in T2LL and a faster decline in GM mean and peak location MTR. Conclusions The combined assessment of both visible white matter damage and GM involvement is useful in predicting progression in PPMS.

Both MHC and non-MHC genes regulate inflammation and T-cell response after traumatic brain injury.

admin — Mon, 22 Nov 2010 08:51:13 +0000

Genetic regulation of autoimmune neuroinflammation is a well known phenomenon, but genetic influences on inflammation following traumatic nerve injuries have received little attention. In this study we examined the inflammatory response in a rat traumatic brain injury (TBI) model, with a particular focus on major histocompatibility class II (MHC II) presentation, in two inbred rat strains that have been extensively characterized in experimental autoimmune encephalomyelitis (EAE); DA and PVG. In addition, MHC and Vra4 congenic strains on these backgrounds were studied to give information on MHC and non-MHC gene contribution. Thus, allelic differences in Vra4, harboring the Ciita gene, was found to regulate expression of the invariant chain at the mRNA level, with a much smaller effect exerted by the MHC locus itself. Notably, however, at the protein level the MHC congenic PVG-RT1(av1) strain displayed much stronger MHCII (+) presentation, as shown both by immunolabeling and flow cytometry, than the PVG strain, dwarfing the effect of Ciita. The PVG-RT1(av1) strain had significantly more T cell influx than both DA and PVG, suggesting regulation both by MHC and non-MHC genes. Finally, in terms of outcome, the EAE susceptible DA strain displayed a significantly smaller resulting lesion volume than the resistant PVG-RT1(av1) strain. These results provide additional support for a role of adaptive immune response after neurotrauma and demonstrate that outcome is significantly affected by host genetic factors.

Genomic damage in the progression of chronic kidney disease in rats.

admin — Mon, 22 Nov 2010 08:51:12 +0000

Patients with chronic renal failure exhibit massive oxidative genome damage and an elevated risk of cancer. Previous studies have demonstrated the relationship between DNA damage and carcinogenesis. The current study aimed to investigate whether the progression of chronic kidney disease induces genomic damage in an animal model. Adult Wistar rats were assigned to either the control or chronic kidney disease groups. The chronic kidney disease group was subdistributed into five groups with progressively longer durations of disease (30, 60, 90, 120 and 150 days). The results showed that chronic kidney disease induced genomic damage in the blood, liver and kidney cells during all periods evaluated, as indicated by the mean tail moment measured in the comet assay. In brain cells, no genetic damage was induced at early/intermediate disease durations; however, positive genotoxicity was found at 120 and 150 days. Blood pressure and pro-inflammatory cytokine levels (IL-1?, IL-1?, IL-6 and TNF?) were increased after chronic kidney disease induction, while blood iron concentration was significantly reduced in these animals. The results suggest that chronic kidney disease progression contributes to DNA damage in blood, liver, kidney and brain and that such damage can be mediated by hypertension, an inflammatory status and iron deficiency. Additionally, the brain was sensitive to genotoxic insult after extended chronic kidney disease, suggesting a potentially important role of genetic damage in the neurological disorders of end-stage renal patients.