Sporadic encephalitis lethargica.

Three women (aged 21-36 years) developed acute illnesses that were similar to epidemic encephalitis lethargica. Each presented with a neuropsychiatric disturbance that was succeeded by pyrexia, a fluctuating conscious state and involuntary movements including oculogyria. Cerebrospinal fluid examination showed a predominantly lymphocytic pleocytosis (64-120x10(6) cells/L) and oligoclonal bands were detected in two cases. Two patients died, while the third made a gradual recovery. Post-mortem examination in the two fatal cases showed changes of lymphocytic meningitis and focal diencephalic lymphocytic infiltration, although these changes were mild relative to the effects of the clinical illness. The diagnosis of sporadic encephalitis lethargica relies on identifying shared clinical features with the past epidemic disease plus circumstantial evidence of immunological activity from laboratory investigations and some tests of exclusion of other disorders.

Lineage specification of neuronal precursors in the mouse spinal cord.

We have investigated the differentiation potential of precursor cells within the developing spinal cord of mice and have shown that spinal cord cells from embryonic day 10 specifically give rise to neurons when plated onto an astrocytic monolayer, Ast-1. These neurons had the morphology of motor neurons and > 83% expressed the motor neuron markers choline acetyltransferase, peripherin, calcitonin gene-related peptide, and L-14. By comparison, < 10% of the neurons arising on monolayers of other neural cell lines or 3T3 fibroblasts had motor neuron characteristics. Cells derived from dorsal, intermediate, and ventral regions of the spinal cord all behaved similarly and gave rise to motor neuron-like cells when plated onto Ast-1. By using cells that expressed the lacZ reporter gene, it was shown that > 93% of cells present on the Ast-1 monolayers were motor neuron-like. Time-lapse analysis revealed that the precursors on the Ast-1 monolayers gave rise to neurons either directly or following a single cell division. Together, these results indicate that precursors in the murine spinal cord can be induced to differentiate into the motor neuron phenotype by factors produced by Ast-1 cells, suggesting that a similar factor(s) produced by cells akin to Ast-1 may regulate motor neuron differentiation in vivo.

Regulation of neural precursor differentiation in the embryonic and adult forebrain.

1. Precursors form the neuroepithelium of the developing cortex and also from the adult sub-ventricular zone, can be cloned in vitro after stimulation with fibroblast growth factor (FGF)-2 and have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyteprecursor line, Ast-1, or FGF-1. 2. Neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol-lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the PCL gamma pathway. 3. The sequential expression of FGF-2 and FGF-1 within the developing forebrain neuroepithelium fits with the different functions the two FGF play in precursor regulation. 4. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan (HSPG) expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2; however, the differentiation into GFAP positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor beta receptor.

Regulation of the early development of the nervous system by growth factors.

Development of the nervous system, although patterned by intrinsic genetic expression, appears to be dependent on growth factors for many of the differentiation steps that generate the wide variety of neurons and glia found in the both the central and peripheral nervous system. By using in vitro assays, including clonal analysis, the precise function of the various growth factors and the differentiation potential of the various neural populations has begun to be described. This review discusses some of the recent findings and examines how neuronal differentiation may result from the interaction of several growth factors.

The differentiation and survival of murine neurons in vitro is promoted by soluble factors produced by an astrocytic cell line.

The influence of accessory cells on the generation of neurons and neuronal survival has been studied in vitro using an immortalised, cloned cell line, Ast-1, which has many of the functional and phenotypic characteristics of cells of the astrocytic lineage. It was found that monolayers of Ast-1 cells were equivalent to monolayers of primary astrocytes in their ability to promote the generation of neurofilament positive neurons from neuroepithelial cells obtained from embryonic day 10 (E10) mice; and both were superior to NIH 3T3 cells. Ast-1 cell monolayers were also found to provide a suitable substrate for the prolonged survival (at least 3 days in vitro) of neurofilament positive neurons obtained from E17 mice, whereas neurons plated onto NIH 3T3 cells were all dead after 2 days. Medium conditioned by Ast-1 cells displayed similar biological activities to that of the monolayers: it increased the number of neurons generated from the E10 neuroepithelial cells, whether they were plated directly onto glass coverslips or onto monolayers of NIH 3T3 cells; and it increased the survival of E17 neurons plated directly onto glass coverslips. In addition, the Ast-1 conditioned medium was shown to promote the survival of the neuroepithelial cells. These results confirm that one of the mechanisms by which astrocytes or their precursors may regulate neuronal development is by secreting soluble growth factors, as has been previously documented in the case of fibroblast growth factor (FGF) (Hatten et al., 1988; Drago et al., 1991a). However, it appears in this system that FGF is not responsible for the demonstrated biological activities, and the Ast-1 action appears to be mediated by putatively novel factor(s).