Is CSF cytology a useful diagnostic procedure in staging paediatric CNS tumours?

OBJECTIVES: To evaluate whether there are any factors that predict malignant cells being found in paediatric cerebrospinal fluid (CSF) samples. To determine whether CSF provides useful staging information not provided by magnetic resonance imaging (MRI) in paediatric patients with primary central nervous system (CNS) malignancy. METHODS: We compared the CSF cytology and spinal MRI staging results in paediatric patients with primary CNS malignancy at a UK tertiary referral centre, over a decade. RESULTS: Of 159 CSF samples, 72 samples were from 72 patients with primary CNS malignancy with spinal MRI available for comparison. Eight of these 72 had positive cytology (seven malignant and one suspicious). All had a high clinical suspicion of tumour at the time of sampling. Of the 72 patients, only two had evidence of CSF spread on MRI spinal staging and CSF cytology; ten had MRI without cytological evidence and six had cytological without MRI evidence. CONCLUSIONS: In paediatric patients with primary CNS tumours, CSF cytology provides useful staging information. Spinal MRI alone may miss some patients with CSF spread who would be identified with CSF cytology.

Cerebrovascular disease and the pathophysiology of Alzheimer's disease. Implications for therapy.

Dementia is a disease of the elderly, and although there are many causes of dementia, Alzheimer's disease (AD) and vascular dementia (VaD) account for the majority of cases world- wide. Many patients with dementia have radiological and neuropathological features of AD and VaD, with the classical neurofibrillary tangles and senile amyloid-beta (Abeta) plaques of AD together with the cerebral infarcts of VaD. In this review we examine the close relationship between AD and VaD and suggest that the age changes in cerebral blood vessels that are the basis of cerebrovascular disease and VaD may also be responsible for the failure of elimination of Abeta from the brain in AD. Abeta appears to be eliminated along the perivascular pathways by which interstitial fluid (ISF) drains from the brain (effectively the lymphatics of the brain). In aged individuals, insoluble Abeta amyloid fibrils are deposited in the ISF drainage pathways resulting in cerebral amyloid angiopathy (CAA). We review the evidence that age changes in cerebral arteries and cerebrovascular disease inhibit the perivascular drainage of ISF and Abeta along the walls of cerebral arteries resulting in the accumulation of insoluble and soluble Abeta in the brain in AD. Therapies for AD are reviewed, especially those involving immunotherapy for the removal of insoluble Abeta from the cerebral cortex and the facilitation of drainage of ISF and soluble Abeta from the brain.

Monosomy 16 as the sole abnormality in myeloid malignancies.

The majority of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients reported with chromosome 16 abnormalities had the inv(16)(p13q22) or t(16;16)(p13;q22) rearrangements, which were associated with a favorable prognosis. In contrast, del(16)(q22) was reported less commonly but was associated with a less favorable prognosis. We describe an 80-year-old woman who presented with MDS (refractory anemia). Chromosome analysis from bone marrow aspirate cultures showed monosomy 16 as the sole cytogenetic abnormality. Comparison of this patient with previously reported cases of monosomy 16 showed that this uncommon abnormality was associated with myeloid disorders. Monosomy 16 patients, similar to del(16)(q22) patients, tended to be elderly, presented with MDS or AML, and had a poor prognosis. The similarity in clinical course for del(16)(q22) and monosomy 16 patients suggests that the phenotype in both groups resulted from loss of important gene(s) on 16q, as distinct from the fusion gene product identified in the inv(16) and t(16;16) rearrangements.

Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1.

BACKGROUND: Neural cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been implicated in both the fasciculation and guidance of axons, but direct genetic evidence of a role for neural IgCAMs in axon guidance in vertebrates is lacking. The L1 subfamily of vertebrate neural IgCAMs function as both homophilic and heterophilic receptors for a variety of cell-surface and extracellular ligands and may signal through intracellular kinases or by recruitment of the fibroblast growth factor receptor. L1 itself has been implicated in many neural processes and is expressed widely in the embryonic and adult nervous systems. In humans, mutations in the L1 gene are linked with a spectrum of brain disorders, including loss of the corticospinal tract, but the mechanistic basis for these disorders is unknown. RESULTS: We show that mice that do not express L1 have defects in the guidance of axons of the corticospinal tract, a major motor control pathway projecting from the cortex to the spinal cord. Although the pathway to the caudal medulla appears normal, a substantial proportion of axons fail to cross the midline to the opposite dorsal column as normal. In adults, this results in a reduced decussation and in large numbers of axons projecting ipsilaterally. There is also a varying, but reduced, number of corticospinal axons in the dorsal columns of the spinal cord. These do not project beyond cervical levels. We show that these are defects in axon guidance, because they arise during the early stages of the development of the decussation. The presence of a ligand for L1, CD24, specifically at the point of decussation suggests a mechanism in which L1 functions to guide corticospinal axons across the midline. CONCLUSIONS: L1 function is necessary for the guidance of corticospinal axons across the pyramidal decussation in mice. Some of the defects in the corticospinal tract of humans with mutations in L1 could be due to errors in axon guidance at the pyramidal decussation.

Functional expression of rat GLUT 1 glucose transporter in Dictyostelium discoideum.

To facilitate expression of the rat GLUT 1 glucose transporter cDNA in Dictyostelium discoideum, we mutated the 5' end of the coding sequence such that the codons for the first ten amino acids conformed to preferred Dictyostelium codon usage. As determined by Western-blot analysis, a population of Dictyostelium transformed with the mutated cDNA expressed nonglycosylated GLUT 1 protein. Cell lines expressing GLUT 1 transport radiolabelled 2-deoxy-D-glucose at a rate 6-10 times that of cell lines transformed with vector alone. The initial rate of inward transport of 2-deoxy-D-glucose was stimulated several-fold by the presence of unlabelled glucose in the Dictyostelium cytoplasm, exemplifying the trans-activation of GLUT 1 transport characteristic of GLUT 1 present in erythrocyte membranes. The K(m) and Ki values for 2-deoxy-D-glucose, D-glucose, D-mannose and D-galactose were 3.7 mM, 2.6 mM, 11 mM and 30 mM respectively, similar to the values for GLUT 1 expressed in mammalian cells. L-Glucose and L-galactose, which are not transported by GLUT 1, do not inhibit uptake of 2-deoxy-D-glucose in Dictyostelium expressing GLUT 1. Thus, even though GLUT 1 expressed in Dictyostelium is not N-glycosylated, it transports hexoses normally; this is the first example of functional expression of a mammalian transport protein in this lower eukaryote.

Effect of age on oxygen consumption, superoxide dismutase, catalase, glutathione, inorganic peroxides and chloroform-soluble antioxidants in the adult male housefly, Musca domestica.

The objective of this study was to determine whether aging in the housefly is associated with a general decline in the efficiency of the mechanisms protective against the intermediates of oxygen metabolism. The rate of oxygen consumption, activities of superoxide dismutase (total and cyanide-insensitive) and catalase, and levels of inorganic peroxides, glutathione (GSH and GSSG) and chloroform-soluble antioxidants were measured in adult male houseflies at different ages. Rate of oxygen consumption declined in flies approaching the average life span of the population. Activity of total and cyanide-insensitive superoxide dismutase decreased during the last trimester of life. Catalase activity steadily declined with age while the concentration of inorganic peroxides gradually increased during the later two-thirds of the average life span. Levels of total glutathione and GSH decreased during later half of life whereas the relative concentration of GSSG increased during this period. The concentration of chloroform-soluble antioxidants sharply declined during the first half of life. These results are interpreted to suggest that the enzymatic and non-enzymatic defenses against oxygen free radicals and hydroperoxides tend to deteriorate with age in the adult housefly.