Cerebral Palsy

Disorders affecting the central nervous system frequently involve programmed neuronal loss. There are well-established changes in gene expression that occur in neurodegenerative diseases, and traumatic and ischemic injuries. Yet, we currently lack sufficient knowledge of the underlying mechanisms leading to the altered gene expression profiles affecting cell survival in the brain and spinal cord. The cell loss is accelerated by the induction of pro-cell death gene expression profiles through an altered balance of pro- and anti-apoptotic transcription factors. Dysregulation of these transcription factors constitutes one of the earliest events in these disorders and may offer a therapeutic window of opportunity for intervention across a narrow time period prior to irreversible neuronal death. There has been increasing interest in the modulation of these cell death factors to prevent or mitigate damage to neurons, with the goal of improving the lives of affected individuals. Here we review some of the recent patents that have been developed in the course of this research in the context of five different transcription factors.

Numerous studies in animals and humans have shown that damage to the vestibular system in the inner ear results in spatial memory deficits, presumably because areas of the brain such as the hippocampus require vestibular input to accurately represent the spatial environment. Consistent with this hypothesis, studies in animals have demonstrated that complete bilateral vestibular deafferentation (BVD) causes a disruption of place cell firing as well as theta activity. The aim of this study was to investigate whether BVD in rats affects baseline field potentials (field excitatory postsynaptic potentials and population spikes) and long-term potentiation (LTP) in CA1 and the dentate gyrus (DG) of awake freely moving rats up to 43 days post-BVD and of anesthetized rats at 7 months post-BVD. Compared to sham controls, BVD had no significant effect on either baseline field potentials or LTP in either condition. These results suggest that although BVD interferes with the encoding, consolidation, and/or retrieval of spatial memories and the function of place cells, these changes are not related to detectable in vivo decrements in basal synaptic transmission or LTP, at least in the investigated pathways. (c) 2009 Wiley-Liss, Inc.

‘Binomial’ cell proliferation and cell death have been studied in only a few non-mammalian vertebrates, such as fish. We thought it of interest to map cell proliferation/apoptosis in the brain of the frog (Rana esculenta L.) as this animal species undergoes, during the annual cycle, physiological events that could be associated with central nervous system damage. Therefore, we compared the active period and the deep underground hibernation of the frog. Using western blot analysis for proliferating cell nuclear antigen (PCNA), we revealed a positive 36 kDa band in all samples and found higher optical density values in the hibernating frogs than in active frogs. In both active and hibernating frogs, we found regional differences in PCNA-immunoreactive cells and terminal transferase dUTP nick-end labelling apoptotic cells in the ventricular zones and parenchyma areas of the main encephalon subdivisions. During the active period of the frogs, the highest concentration of PCNA-immunoreactive cells was found in the ventricle dorsal zone of the cerebral hemispheres but only some of the cells were apoptotic. By contrast, the tectal and cerebellar ventricular zones had a small or medium amount of PCNA-immunoreactive cells, respectively, and a higher number of apoptotic cells. During hibernation, an increased PCNA-immunoreactive cell number was observed in both the brain ventricles and parenchyma compared with active frogs. This increase was primarily evident in the lateral ventricles, a region known to be a proliferation ‘hot spot’. Although differences existed among the brain areas, a general increase of apoptotic cell death was found in hibernating frogs, with the highest number of apoptotic cells being detected in the parenchyma of the cerebral hemispheres and optic tectum. In particular, the increased number of apoptotic cells in the hibernating frogs compared with active frogs in the parenchyma of these brain areas occurred when cell proliferation was higher in the corresponding ventricular zones. We suggest that the high number of dying cells found in the parenchymal regions of hibernating frogs might provide the stimulus for the ventricular zones to proliferate. Hibernating frogs could utilize an increased cell proliferation in the brain areas as a neuroprotective strategy to face cell death and the onset of neurological damages. Therefore, the hibernator promises to be a valuable model for studying the mechanisms naturally carried out by the central nervous system in order to adapt itself or survive adverse conditions.

Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta stimulate glucuronosyltransferase genes (S and P) in endothelial cells (ECs) and up-regulate sulfoglucuronosyl paragloboside (SGPG) expression, which serves as a ligand for T cell adhesion. However, the mechanism of cytokine-mediated gene up-regulation has not been elucidated. To evaluate the precise mechanism of SGPG up-regulation, we have specifically inhibited the SGPG synthesis in the cerebromicrovascular EC line (SV-HCECs), a transformed brain ECs of human origin. SV-HCECs were transfected with small interfering RNA designed to mimic the human natural killer epitope-1 sulfotransferase (HNK-1ST), the ultimate enzyme that transfers the sulfate group to glucuronic acid for SGPG synthesis. An inhibition of SGPG expression along with a reduction of human CD4(+) cell adhesion was observed in siRNA HNK-1ST (siHNK-1)-transfected cells after TNFalpha stimulation. A thorough screening of the signaling system confirmed that TNFalpha/IL-1beta stimulation up-regulated nuclear factor kappaB (NFkappaB) signaling in SV-HCECs. siHNK-1 transfection interfered with the SGPG up-regulation after TNFalpha/IL-1beta stimulation in transfected cells and reduced the T cell adhesion. Hence, our study indicates that T cell-SGPG adhesion in SV-HCECs may proceed through NFkappaB activation. In addition, siHNK-1 transfection reduced the NFkappaB activity compared with cells that were transfected with scrambled siRNA, before and after TNFalpha/IL-1beta stimulation. This is the first report indicating that NFkappaB signaling is involved in SGPG gene expression in brain ECs by an unknown mechanism. Its down-regulation by inhibiting HNK-1ST expression may have a potential use in preventing the T cell invasion and consequently nerve damage during inflammation. (c) 2009 Wiley-Liss, Inc.

INTRODUCTION: The aim of this study was to evaluate the patterns of hypoglycemic encephalopathy on diffusion-weighted imaging (DWI) and the relationship between the imaging patterns and clinical outcomes. METHODS: This retrospective study included 17 consecutive patients that had hypoglycemic encephalopathy with DWI abnormalities. The topographic distributions of the DWI abnormalities of the cortex, deep gray matter, and white matter structures were assessed. In addition, possible correlation between the patterns of brain injury on DWI and clinical outcomes was investigated. RESULTS: There were three patterns of DWI abnormalities: involvement of both gray and white matter (n = 8), selective involvement of gray matter (n = 4), and selective involvement of white matter (n = 5). There was no significant difference in the initial blood glucose levels among patients for each of the imaging patterns. Most patients (16/17) had bilateral symmetrical abnormalities. Among patients with bilateral symmetrical gray and/or white matter injuries, one had moderate to severe disability and 14 remained in a persistent vegetative state. The two patients with a focal unilateral white matter abnormality and a localized splenial abnormality recovered without neurological deficits. CONCLUSION: The results of this study showed that white matter was more sensitive to hypoglycemia than previously thought and there was no specific association between the patterns of injury and clinical outcomes whether the cerebral cortex, deep gray matter, and/or white matter were affected. Diffuse and extensive injury observed on the DWI predicts a poor neurologic outcome in patients with hypoglycemic injuries.

Hypoxic ischemia (HI) in newborns causes long-term neurological abnormalities. Systemic lipopolysaccharide (LPS) is neuroprotective in neonatal rats when injected 24 hours before HI. However, the effect on HI-induced neuroinflammation and the long-term outcome of LPS preconditioning in neonatal rats have not been examined. In a rat-pup HI model, compared with normal saline (NS), 0.3 mg/kg of LPS injected 24 hours before HI greatly increased microglial cell and macrophage activation and upregulated TNF-alpha and iNOS expression 12 hours post-injection, and resulted in high mortality during HI. In contrast, 0.05 mg/kg of LPS elicited very little microglia and macrophage activation and TNF-alpha and iNOS expression, and resulted in low mortality. Given 24 hours before HI, low-dose (0.05 mg/kg) LPS greatly reduced microglia and macrophage activation, TNF-alpha expression, and reactive oxygen species production 24 hours post-HI compared with NS-treated rats. Rats in the low-dose LPS group also showed significantly better learning and memory and less brain damage in adulthood. Learning and memory performance between the LPS-HI, LPS, and NS groups was not significantly different. We conclude that low-dose LPS preconditioning in neonatal rats greatly reduces HI-induced neuroinflammation, and provides long-term neuroprotection against behavioral and pathological abnormalities.

Transient myeloproliferative disorder (TMD) is a hematologic abnormality usually associated with Down syndrome that may present with a skin eruption in addition to typical systemic findings. We report a case of a patient with TMD and a vesiculopustular eruption without the phenotypic characteristics of Down syndrome who was found to have mosaic trisomy 21. Mutations of the globin transcription factor 1 gene, GATA1, are associated with both TMD and acute megakaryocytic leukemia. Transient myeloproliferative disorder typically presents with pancytopenia, hepatosplenomegaly, and immature circulating white blood cells, and affects approximately 10% of neonates with Down syndrome. These abnormalities rapidly regress within the first few months of life. However, 20% to 30% of neonates with Down syndrome and TMD later develop leukemia. The tumor antigen PRAME (preferentially expressed antigen in melanoma) may serve as a marker for leukemic transformation. We report an illustrative case to alert clinicians about this uncommon cause of vesiculopustular eruption in a neonate without the phenotypic characteristics of Down syndrome and review the clinical findings and laboratory studies that aid in accurate diagnosis.

A black and white female German Holstein calf showed a highly deformed cranium. The animal was not able to stand. Further findings were bilateral strabismus divergens and negative pupillary light reflexes. Magnetic resonance imaging and pathological-anatomical examination showed that the cerebrum was replaced to a high degree by the ventricle system filled with 1.5 liters of cerebrospinal fluid. The hemispheres of the cerebellum were ruptured by the dilated fourth ventricle. In addition, the vermis and pons were missing and fluid accumulation in the subarachnoidal space extending up to the first spinal cord segments was visible. Inbreeding was not detected in the 3-generation-pedigree. No other affected calves from the same parents were known at the farm. Chromosomal abnormalities could not be detected after examination of 30 metaphase spreads using a light microscope. Infections and parasitic diseases could be ruled out for this anomaly. Very rare defect alleles might have been involved in the development of these inborn defects.

The aim of this study was to investigate the ultrasonographic venous anatomy at the popliteal fossa in relation to tibial nerve course in normal and varicose limbs in order to detect anatomical abnormalities suggesting the potential risk of tibial nerve damage during surgery. Ninety-seven consecutive patients (194 limbs) were investigated by duplex ultrasound examination of the popliteal fossa. Forty-seven patients (48%) were candidates for surgery due to small saphenous vein (SSV) reflux. The tibial nerve course and its relation to the SSV were investigated in healthy and diseased patients. The tibial nerve ran along the medial edge of the SSV in 171 (88%) of the examined limbs. It ran behind the vein in 7 limbs (4%) and laterally in 16 limbs (8%). In this particular anatomical arrangement the SSV ends in the popliteal vein, running horizontally behind or wrapped around the tibial nerve for a distance of several centimetres. The median distance of the tibial nerve from the SSV was 0.2 cm (range: 0.1-0.3) in healthy limbs and 0.1 cm (range: 0.1-0.2) in varicose limbs, progressively diminishing as it proceeds upward. A posterior and lateral course of the tibial nerve (12%) would expose the nerve to potential damage during surgical procedures. Patient eligibility for treatment for SSV incompetence should always be based on a detailed ultrasonographic assessment of the course of the tibial nerve at the popliteal fossa in order to avoid the slightly higher risk of nerve damage due to particular anatomical abnormalities.

(1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of “stimulus control”. This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness and altered vigilance, and atropinic effects; (9) Case-control studies showed a statistical link between benzodiazepine use in early pregnancy and birth defects such as cleft lip. In contrast, data on the use of doxylamine during pregnancy are reassuring; (10) Other sedative psychotropics have not been adequately tested in this setting or have been shown to have a negative risk-benefit balance; (11) In practice, patients who complain of poor-quality sleep should be given appropriate information on the mechanisms of normal sleep and related misconceptions, on the best methods for getting to sleep, and on the dangers of sedative psychotropics (dependence, withdrawal syndrome). When prescribing or dispensing a benzodiazepine to a woman of child-bearing age, the risk of birth defects, although not clearly demonstrated, must be mentioned.