Cerebral Palsy

Non-neonatal hypoxic-ischemic encephalopathy is a clinical condition often related to cardiopulmonary arrest that demands critical management and treatment decisions. Management depends mainly on the degree of neurological impairment and prognostic considerations. Computed tomography (CT) is often used to exclude associated or mimicking pathology. If any, only nonspecific signs such as cerebral edema, sulci effacement, and decreased gray matter (GM)/white matter (WM) differentiation are evident. Pseudosubarachnoid hemorrhage, a GM/WM attenuation ratio <1.18, and inverted GM attenuation are associated with a poor prognosis. Magnetic resonance (MR) imaging is more sensitive than CT in assessing brain damage in hypoxic-ischemic encephalopathy. Some MR findings have similarities to those seen pathologically, based on spatial distribution and time scale, such as lesions distributed in watershed regions and selective injury to GM structures. In the acute phase, lesions are better depicted using diffusion-weighted imaging (DWI) because of the presence of cytotoxic edema, which, on T2-weighted images, only become apparent later in the early subacute phase. In the late subacute phase, postanoxic leukoencephalopathy and contrast enhancement could be observed. In the chronic phase, atrophic changes predominate over tissue signal changes. MR can be useful for estimating prognosis when other tests are inconclusive. Some findings, such as the extent of lesions on DWI and presence of a lactate peak and depleted N-acetyl aspartate peak on MR spectroscopy, seem to have prognostic value.

OBJECTIVE:: The current study investigates activation of the nutritional anti-inflammatory pathway by lipid-rich nutrition. BACKGROUND:: Enteral nutrition activates humoral and neural pathways to regulate food intake and sustain energy balance. Recently, we demonstrated that enteral nutrition and in particular lipid-rich nutrition modulates inflammation and prevents organ damage. METHODS:: Male rats were fasted or fed lipid-rich nutrition before hemorrhagic shock. Disruption of afferent vagal fibers with capsaicin (deafferentation) was used to investigate involvement of afferent fibers. Peripheral activation of afferent vagal fibers via cholecystokinin (CCK)-mediated activation of CCK-1 receptors was investigated using administration of the selectively peripheral acting CCK-1 receptor antagonist, A70104 and PEGylated-CCK9. Tissue and blood were collected 90 minutes after shock to assess systemic inflammation and intestinal integrity. RESULTS:: Deafferentation reversed the inhibitory effect of lipid-rich nutrition on systemic levels of tumor necrosis factor-alpha and interleukin-6, and on intestinal leakage of horseradish peroxidase and bacterial translocation. Furthermore, the protective effects of lipid-rich nutrition were negated by A70104, indicating that lipid-rich nutrition triggers peripheral CCK-1 receptors on vagal afferents to modulate inflammation. These findings were substantiated by the fact that pretreatment of fasted rats with PEGylated-CCK9, which acts on peripheral CCK-1 receptors, attenuated systemic inflammation, and loss of intestinal integrity. CONCLUSION:: These data demonstrate that enteral lipid-rich nutrition modulates inflammation and preserves intestinal integrity via CCK release which activates CCK-1 receptors located on afferent vagal fibers. Taken together, the current study reveals a novel gut-brain-immune axis and provides new insight into the applicability of enteral nutrition to treat inflammatory conditions.

Background A haemodynamically important patent ductus arteriosus (PDA) is a risk factor for brain damage in preterm infants. The authors previously reported lower regional cerebral oxygen saturation (rScO(2)) in infants with PDA, which recovered after administration of indomethacin. However, PDA ligation has been reported to pose an even higher risk of neurodevelopmental impairment. Objective To investigate the impact of surgical closure of PDA on rScO(2) and cerebral fractional tissue oxygen extraction (cFTOE), measured by near-infrared spectroscopy, and on amplitude-integrated electro-encephalography (aEEG) measured brain activity. Design/methods In 20 preterm infants (gestational age 24.7-30.4 weeks; birth weight 630-1540 g), blood pressure, arterial saturation, rScO(2), cFTOE and aEEG were monitored before, during and up to 24 h after surgery. Results Before surgery, median (range) rScO(2) was 53% (41-68%), and during surgery, but before ductal clipping, it was 46% (31-89%). Eleven infants showed a drop in blood pressure and 13 infants a drop in rScO(2) during surgery (range 2-21%), accompanied by a decrease in aEEG amplitude. Twelve infants had rScO(2) values below 50% during surgery, with five being below 40%. Only at 24 h after surgery was rScO(2) higher (61% (36-85%), p<0.05) and cFTOE values lower (0.38 (0.09-0.61); p<0.05) compared with preclipping values. Conclusion Ductal ligation poses a risk for a further decrease in already compromised cerebral oxygenation in preterm infants.

The association between anti-triosephosphate isomerase (TPI) antibodies and MRL/MpJ-Fas(lpr) (MRL/lpr) mice was examined. We found that serum anti-TPI antibody levels in MRL/lpr mice, measured by enzyme-linked immunosorbent assay, were significantly higher than that of age-matched Balb/c mice and NZB/WF1 mice. Anti-TPI antibodies were detected in serum and cerebrospinal fluid in MRL/lpr mice by Western blotting. Inoculation of anti-TPI monoclonal antibody-producing hybridoma into the brain of Balb/c mice resulted in immunoglobulin deposition in the regions near the ventricles, hippocampus, and choroid plexus. Anti-TPI antibodies may play a role in the etiology of brain damage and behavioral deficits in MRL/lpr mice. Copyright © 2010 Elsevier B.V. All rights reserved.

ABSTRACT: BACKGROUND: Using a murine model of herpes simplex virus (HSV)-1 encephalitis, our laboratory has determined that induction of proinflammatory mediators in response to viral infection is largely mediated through a Toll-like receptor-2 (TLR2)-dependent mechanism. Published studies have shown that, like other inflammatory mediators, reactive oxygen species (ROS) are generated during viral brain infection. It is increasingly clear that ROS are responsible for facilitating secondary tissue damage during central nervous system infection and may contribute to neurotoxicity associated with herpes encephalitis. METHODS: Purified microglial cell and mixed neural cell cultures were prepared from C57B/6 and TLR2-/- mice. Intracellular ROS production in cultured murine microglia was measured via 2′ ,7′-Dichlorofluorescin diacetate (DCFH-DA) oxidation. An assay for 8-isoprostane, a marker of lipid peroxidation, was utilized to measure free radical-associated cellular damage. Mixed neural cultures obtained from beta-actin promoter-luciferase transgenic mice were used to detect neurotoxicity induced by HSV-infected microglia. RESULTS: Stimulation with HSV-1 elevated intracellular ROS in wild-type microglial cell cultures, while TLR2-/- microglia displayed delayed and attenuated ROS production following viral infection. HSV-infected TLR2-/- microglia produced less neuronal oxidative damage to mixed neural cell cultures in comparison to HSV-infected wild-type microglia. Further, HSV-infected TLR2-/- microglia were found to be less cytotoxic to cultured neurons compared to HSV-infected wild-type microglia. These effects were associated with decreased activation of p38 MAPK and p42/p44 ERK in TLR2-/- mice. CONCLUSIONS: These studies demonstrate the importance of microglial cell TLR2 in inducing oxidative stress and neuronal damage in response to viral infection.

ABSTRACT Peripheral inflammation could play a role in the origin and development of certain neurodegenerative disorders. To ascertain this possibility, a model of dopaminergic neurodegeneration based on the injection of the inflammatory agent lipopolysaccharide (LPS) within the substantia nigra (SN) was assayed in rats with ulcerative colitis (UC) induced by the ingestion of dextran sulphate sodium. We found an increase in the levels of inflammatory markers from serum (TNF-alpha, IL-1beta, IL-6 and the acute phase protein C-reactive protein) and SN (TNF-alpha, IL-1beta, IL-6, iNOS, ICAM-1, microglial and astroglial populations) of rats with UC, as well as an alteration of the blood-brain barrier permeability and the loss of dopaminergic neurons. UC reinforced the inflammatory and deleterious effects of LPS. On the contrary, clodronate encapsulated in liposomes (ClodLip), which depletes peripheral macrophages, ameliorated the effect of LPS and UC. Peripheral inflammation might represent a risk factor in the development of Parkinson’s disease.

OBJECTIVE: Spinal cord injury (SCI) leads to permanent motor and sensory deficits due to the damage of ascending and descending fiber tracts. In addition, malfunctions such as neuropathic pain or muscle spasms develop in many patients, possibly caused by injury-induced plastic changes of neuronal circuits above and below the lesion. New treatment strategies for spinal cord injury aim at enhancing plasticity and neurite growth, for example, by blocking the key neurite growth inhibitor Nogo-A or its downstream effectors. It is therefore crucial to investigate potential effects of such treatments on malfunctions such as muscle spasms. In addition, locomotor training, now a standard therapeutic tool to improve walking ability in incomplete SCI subjects, can be expected to influence the rearrangement of spinal cord circuits and the development of muscle spasms and other malfunctions. METHODS AND RESULTS: Here we present and validate a new rat model for muscle spasms after incomplete SCI and show that both intrathecal anti-Nogo-A antibody treatment and locomotor training, started early after injury, permanently reduce the development of muscle spasms. INTERPRETATION: The results show that an antibody-mediated suppression of the growth inhibitory protein Nogo-A leads to functional recovery and a lower level of malfunctions, suggesting the formation of functionally meaningful connections in the damaged spinal cord. Treadmill training early after SCI also has a beneficial effect. ANN NEUROL 2010;68:48-57.

Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.Oncogene advance online publication, 28 June 2010; doi:10.1038/onc.2010.249.

BACKGROUND: Cigarette smoke (CS) is associated with oxidative stress in several organs because it contains high concentrations of free radicals and reactive oxygen species. Experimental models, using different strains, provide important insights into the genetic basis of diseases. This study sought to identify, in different mouse strains, the organ that is most-susceptible to CS-induced oxidative stress to obtain an optimized experimental animal model of oxidative injury induced by CS. MATERIAL/METHODS: Male Swiss, DBA/2, C3H, BALB/c, and C57BL/6 mice were exposed to CS 3 times a day (4 cigarettes per session) for 60 consecutive days. Control groups from the same strains were sham-treated. Protein content, malondialdehyde level, myeloperoxidase activity, and nitrite level were assayed in lung, liver, kidney, and brain from all strains. Catalase and glutathione peroxidase activities were measured. Analyses of data were done by using a 1-way ANOVA with Bonferroni's post-test (P<.05). RESULTS: Cigarette smoke exposure resulted in distinct, organ-specific responses among strains. The survival rate of DBA/2 mice was lowest. BALB/c and C57BL/6 strains were more-susceptible to oxidative damage in the lung and liver. C3H and C57BL/6 mice were more-susceptible to oxidative damage in the brain. No renal oxidative damage was seen. CONCLUSIONS: Mouse strains and individual organs display a range of susceptibilities to CS-induced oxidative stress. BALB/c and C57BL/6 strains appear to be the best choices as experimental models for studying CS effects on liver and lung, and C3H and C57BL/6 strains for CS-effects on the brain.

STUDY DESIGN.: An in vitro cadaveric biomechanical study. OBJECTIVE.: To determine the stability of translaminar screws compared to pedicle screws at T1-T2 for constructs bridging the cervicothoracic junction. SUMMARY OF BACKGROUND DATA.: Instrumented fixation of the cervicothoracic junction is challenging both biomechanically, due to the transition from the mobile cervical to the rigid thoracic spine, and technically, due to the anatomic constraints of the T1-T2 pedicles. For these reasons, an alternate fixation technique at T1-T2 that combines ease of screw insertion and a favorable safety profile with biomechanical stability would be clinically beneficial. METHODS.: A 6-degree of freedom spine simulator was used to test multidirectional flexibility in 8 human cadaveric specimens. Flexion, extension, lateral bending, and axial rotation were tested in the intact condition, followed by destabilization via a simulated 2-column injury at C7-T1. Specimens were reconstructed using C5-C6 lateral mass screws and either translaminar or pedicle screws placed at T1, followed by caudal extension to T2. A 3-column injury at C7-T1 was then performed and specimens were tested using a posterior only approach with either translaminar or pedicle screws placed at T1 and T1-T2. Finally, anterior fixation at C7-T1 was added and multidirectional flexibility testing performed as previously described. RESULTS.: Following a 2-column injury at C7-T1, there were no significant differences in segmental flexibility at C7-T1 between translaminar and pedicle screw fixation when placed at T1-T2 (P > 0.05). For a 3-column injury treated posteriorly, translaminar screws at T1-T2 provided increased flexibility compared to pedicle screws in flexion/extension (P < 0.05). There were no differencesin segmental flexibility at C7-T1 between the 2 techniques following the addition of anterior fixation (P > 0.05). CONCLUSION.: Translaminar screws in the upper thoracic spine offer similar stability to pedicle screw fixation for constructs bridging the cervicothoracic junction. Small differences in range of motion must be weighed clinically against the potential benefits of translaminar screw insertion at T1-T2.