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Abstract: Purpose: Human WWOX gene encoding WW domain-containing oxidoreductase, named WWOX, FOR, or WOX1, has been studied in various types of cancer cells and shown to be a tumor suppressor with pro-apoptotic properties. Mutation or gain-of-function of p53 in glioma cells is associated with resistance to radiation therapy and poor prognosis. In this study, we overexpressed WOX1 to examine the pro-apoptotic activity against human glioblastoma cells harboring mutant p53. Methods: Overexpression of WOX1 in glioblastoma cell lines and apoptosis-related assays were performed. Results: Our results showed that overexpressed WOX1 induced apoptosis of glioblastoma U373MG harboring mutant p53 by causing hypoploidy and DNA fragmentation. However, ectopic WOX1 had no effect with U87MG possessing wild type p53. Unlike temozolomide, WOX1 induced apoptosis of U373MG cells via a mitochondria-independent and caspase-3-independent pathway. Conclusions: Overexpression of WOX1 preferentially inhibited viability and induced apoptosis in human glioblastoma cells expressing mutant p53 via a mechanism independent of the intrinsic apoptotic pathway. Conceivably, the survival of human glioblastoma cells depends upon interactions between the gain-of-function of p53 and WOX1. This suggests that modulation of WOX1 expression may be a novel strategy for treating human glioblastoma cells with mutant p53. [Copyright &y& Elsevier]

Abstract: Background: Data pertaining to head injuries in adolescents in Taiwan are scarce. The purpose of this study was to investigate the trend and pattern of head injuries in adolescents in both urban and rural areas in Taiwan. Methods: We collected data from major hospitals in the urban (20) and fsin the rural (4) areas of Taiwan for a period of 3 years. Data were obtained from the Head Injury Registry, a 10-year electronic database of head injury in Taiwan. The inpatient medical records of adolescents with head injury were thoroughly reviewed. Severity of head injury was classified by the GCS score, and patient outcome at discharge from hospital was measured by the Glasgow Outcome Scale. Differences and correlation between study groups (13-15 and 16-18 years old) in the urban and rural areas were examined using 2-tailed t and χ 2 tests. Results: A total of 469 head injury cases in the urban area and 131 in the rural area were identified. Traffic accidents were the major cause of head injury, and motorcycles were the most predominant vehicles causing traffic accidents in both urban and rural areas. Intracranial hemorrhages were the most prevalent injury pattern in the study population. In both urban and rural areas, the severities of injury were not significantly different (P = .184), but the outcomes at discharge were significantly better in urban areas (P = .032). The correlation between the initial GCS and outcomes in both areas was significant (P < .001). Craniotomy was performed more frequently in the rural area than in the urban area (15.3% vs 7.2%). The mean hospital stay was shorter in the latter than in the former (P < .001). Education on helmet use, input of neurosurgical staff, and facility and emergency medical transportation service of head-injured patients following guidelines proposed by the WFNS are crucial for head injury and better control in rural areas. Conclusions: The causes, patterns, and outcomes of head injury were statistically different between the 2 age groups of adolescents in urban and rural areas. Further studies on adolescent head injury are necessary. [Copyright &y& Elsevier]

Abstract: Xq28 duplications encompassing the methyl CpG binding protein 2 (MECP2) in males exhibit a distinct phenotype, including developmental delay, facial dysmorphism, muscular hypotonia, intellectual disability, poor or absent speech, recurrent infections and early death. The vast majority of affected males inherit the MECP2 duplication from their usually asymptomatic carrier mothers. Only a few cases with Xq28 duplication originating from de novo unbalanced X/Y translocation have been reported and the paternal origin of the aberration has only been validated in three males in the related literature. Here we present a karyotypically normal male with features characteristic of the MECP2 duplication syndrome. The genome-wide SNP genotyping shows a de novo 2.26-Mb duplication from Xq28 to the terminus. The genotypes of the SNPs within the duplicated region indicated a paternal origin. Furthermore, the results of fluorescence in situ hybridization (FISH) indicated a novel Xq:Yp translocation, characterized as der(Y)t(Y;X)(p11.32;q28), which suggests an aberrant that occurred during spermatogenesis. The phenotype is compared to the previously reported cases with Xq28 duplication originated from an unbalanced X/Y translocation, and there was no specific part of the phenotype that could be contributed to the origin of parental imbalances. This report further highlights the capacity of high-molecular cytogenetic methods, such as SNP array and FISH, in the identification of submicroscopic rearrangement, structural configuration and parental origin of aberrant while in the evaluation of children with idiopathic developmental delay and intellectual disability. [Copyright &y& Elsevier]

Abstract: Early Onset Parkinson''s Disease (EOPD) is characterized by selective degeneration of nigrostriatal dopaminergic neurons and a marked response to levodopa. However, at present, few methods are available as diagnostic tools for EOPD except for 18F-DOPA PET. In addition, little is known about the correlation between clinical severity, neuroimaging grading and genetic susceptibility. In the present study, 99mTc-TRODAT-1 SPECT and brain MRI were used to identify 30 cases of non-familial EOPD from a Chinese cohort of 230. All 30 PD patients had an age of onset of less than 55 years (mean age at onset, 41.5±9.3 years). Each of the 30 EOPD cases was sub-classified into one of five stages based on the 99mTc-TRODAT-1 SPECT findings. In the early stages of PD (stages 1 and 2), a lower uptake of 99mTc-TRODAT-1 in the putamen was found, while uptake in the caudate nucleus was normal. In the latter stages (stages 3, 4, 5), 24 patients revealed a diffuse and uniform loss of 99mTc-TRODAT-1 uptake in the putamen and the caudate nucleus. Further, in conventional genetic studies of the 30 patients, six novel mutations were found in the Parkin gene, and these included five heterozygous point mutations (C441R, Q311H, V258M, C212G, and S193I) and one homozygous deletion (exon 10-12). Known polymorphisms (Ser167Asn, Val380Leu) were also found in a number of patients. However, gene dosage analysis did not reveal any compound heterozygous mutations in these 30 patients using quantitative duplex PCR. This is the first study to examine EOPD patients of Chinese ethnic background (not exhibiting a definite familial trait), to offer a complete genetic analysis of the Parkin gene, and to correlate clinical stages of the disease with dopamine re-uptake. [Copyright &y& Elsevier]

Neuregulin-1 (NRG-1) is expressed throughout the immature and adult central nervous system and it has been demonstrated to influence the migration of a variety of cell types in developing brain. Elevated levels of NRG-1 transcript are found in the adult brain after injury, leading to the suggestion that NRG-1 is involved in the physiological response to neuronal injury. Here, we report our findings that rats pre-treated with NRG-1 protein, undergoing cerebral ischemia 30 min later, had increased motor performance and less cerebral infarction than untreated rats. In the cortex of NRG-1 treated rats, ischemia induced a decrease in caspase-3 immunoreactivity and a reduction in the density of cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end-labeling. Improvement in behavioral assays was also found in animals treated with NRG-1. Pre-treatment with NRG-1 did not alter cerebral blood flow or other physiological parameters. NRG-1 reduced ischemia/reperfusion injury, indicating that it may act as an endogenous neuroprotective factor against stroke. Therefore, NRG-1 may represent a target for the development of new treatments for stroke. [Copyright &y& Elsevier]

In order to identify novel homeobox-containing genes involved in early embryonic development, we conducted a degenerate oligonucleotide polymerase chain reaction (PCR) screening of a murine embryonic stem (ES) cell cDNA library. ENK (early embryo specific expression NK family) was one of several genes isolated that was found to exhibit early embryo stage-specific expression. The full-length ENK cDNA was cloned and its genomic organization was characterized. Murine ENK spans 7.1 kb, encodes four exons and maps to mouse chromosome 6F2. Reverse transcriptase–PCR and Northern blot analyses show that ENK is preferentially expressed in pre-implantation mouse embryos and a higher level in blastocysts. Whole-mount in situ hybridization analysis further demonstrates that ENK mRNA is present predominantly in the inner cell mass of blastocysts. The expression of ENK is markedly higher in undifferentiated ES cells than in retinoic acid differentiated ES cells and embryonic bodies. ENK expression slightly decreased in early primitive ectoderm-like (EPL) cells and was absent after the 9.5-day embryo stages. ENK is one of the few homeobox-encoding genes preferentially expressed in ES cells during mammalian embryogenesis. [Copyright &y& Elsevier]

Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up-regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the treated twitcher mice was significantly prolonged and their neurobehavioral performance was improved. Taken together, our findings underscore the complexity of cerebellar neurodegeneration in GLD and highlight the potential effectiveness of gene therapy in mitigating neuropathological deficits in GLD and other neurodegenerative disorders in which Purkinje cells are involved. [ABSTRACT FROM AUTHOR]

The cavum septum pellucidum is not a part of the brain’s ventricular system and does not communicate with the lateral ventricles. However, under conditions of increased intraventricular pressure, cerebrospinal fluid may penetrate the septum and cause formation of a cavity. We report a neonate with pus accumulation in the cavum septum pellucidum after an episode of ventriculitis. The cavum septum pellucidum disappeared after medical and surgical management of the infection and increased intracranial pressure. [Copyright &y& Elsevier]

Abstract: Background: Patients suffering head injury in remote islands of Taiwan, which have a shortage of manpower and facilities, depend on EAMS for prompt and definitive treatment. Emergency air medical services are becoming an increasingly important issue in improving the quality of primary care and avoiding medicolegal problems. The purpose of this study was to investigate the characteristics of patients with head injury and use of EAMS. Methods: We reviewed all patients, especially head injury transported by air ambulance from a remote island, Kinmen (400 km from Taiwan Main Island), from January 2001 to December 2003. Data were collected with regard to demographics, disease classification, mechanism of injury, severity of head injury, ventilator use, and mortality rate. Results: A total of 215 patients were transferred, of whom 57 (27%) had head injury. The mean age of patients was 48.6 ± 23.8 years. Males accounted for 72% of the cases (male/female ratio, 2.6:1). Motor-vehicle accidents were the most common mechanism of injury (68%). There were 21 (37%), 20 (35%), and 16 (28%) patients in the minor, moderate, and severe head-injury groups, respectively. Nineteen patients (33%) received mechanical ventilation. The overall mortality rate was 14 % (8/57). In the severe head-injury group, the mortality rate was 44% (7/16). Conclusions: The higher incidence of head injury (26.5%) in EAMS than in ground transportation (19.8%) suggests that preflight assessment and in-flight management of patients conducted by an experienced escort team following guidelines for head injury in EAMS are a very important issue. [Copyright &y& Elsevier]