Developmental regulation of homeobox gene expression in dorsal root ganglion neurons is not recapitulated during regeneration of the crushed sciatic nerve.

The adult peripheral nervous system is able to regenerate after injury. Regeneration is associated with the expression of new genes and proteins. Proteins abundant in developing axons increase in expression after injury, whereas proteins involved in neurotransmission are downregulated. It has been hypothesized that molecular mechanisms underlying regeneration-associated alterations in gene expression may be a recapitulation of developmental processes. These gene expression changes are likely to be regulated by changes in the gene expression of transcription factors. As homeobox genes play important roles in embryonic development of the nervous system, it makes them candidates for a regulatory role in the process of regeneration. Here we show that the relative mRNA expression levels of Isl1 decreased shortly after crush, but those of DRG11, Lmx1b, and Pax3 did not change after crush. These data indicate that the developmental expression patterns of the homeobox genes studied here are not recapitulated during regeneration of the dorsal root ganglia neurons. We conclude that developmental gene expression programs controlled by these homeobox genes are not directly involved in sciatic nerve regeneration.

Distribution of cellular prion protein in normal human cerebral cortex--does it have relevance to Creutzfeldt-Jakob disease?

Creutzfeldt-Jakob disease and bovine spongiform encephalopathy are the best known forms of prion diseases. A basis for their pathogenesis is the transformation of normal prion protein to abnormal prion protein. This would mean that either loss of normal function or a gain of a toxic function of the prion protein would play a major role. Since the prime target for Creutzfeldt-Jakob disease in humans is the neocortex, and the intracortical distribution of the destructive process in prion diseases appears not to be haphazard, it may be that a clear cortical study of normal prion protein production in the premorbid human neocortex might contribute to insight in the pathogenesis of prion diseases. As no such study is available, we performed a detailed study in normal human cortex using immunohistochemistry for prion protein, in both frozen and vibratomised tissue, and in situ hybridisation for prion protein mRNA. We have found normal prion protein production mainly in the upper cortical neurons in neocortex and Purkinje cells in the cerebellum. This finding implicates that normal prion protein is more important as an anti-apoptotic signal in disease than abnormal prion protein is as a toxic substance.

Complement (C3) metabolism in systemic lupus erythematosus in relation to the disease course.

Metabolic turnover studies of complement components (C3) provide a direct insight into the dynamics of the complement regulation (synthesis and catabolism). To obtain information about the role of the complement system in relation to the disease course in patients with systemic lupus erythematosus (SLE), a prospective study was performed. The results of the C3 turnover studies were also correlated to the complement levels (C3) and to the presence of C3 conversion products (C3d) in circulation. In nearly all SLE patients (in 21 of the 26 metabolic turnover studies) a C3 hypercatabolism was found, with a quantitative difference depending on the disease phase. In the period preceding an exacerbation an impaired C3 synthesis was observed (in three of the four studies), in contrast to SLE patients in stable disease phase where in one case only a decrease C3 synthesis was calculated (1 out of 15 observations). A linear correlation was found between the serum C3-levels and the ratio of C3d/C3, suggesting that both serologic parameters are quantitatively indicative for C3 hypercatabolism. The study shows that in all SLE patients, irrespective of the disease stage, an increased C3 consumption is found, which supports the concept that a chronic inflammatory process is constantly present.

Determination of the half-life of C3 in patients and its relation to the presence of C3-breakdown products and/or circulating immune complexes.

Measurement of complement components in serum may not accurately assess the degree of activation of the complement system. An alternative approach is the measurement of conversion products of the complement components. The relation between the presence of an increased concentration of C3-conversion products and the metabolism of C3 was investigated. In a group of patients, circulating immune complexes were also measured (Clq-binding test) to see whether the combination of those markers yielded information on the C3 metabolism. In this study it is shown that static measurements of serum C3 levels is of no value for the degree of complement activation. Measurement of C3-conversion products may indicate C3 hypercatabolism (in 8 of the 11 patients with C3-conversion products), but it does not imply depressed C3 synthesis. Detection of circulating immune complexes by the C1q-binding assay did not always indicate a C3 hypercatabolism. Of 12 SLE patients studied, in 9 of them, a C3 hypercatabolism was detected, and 5 of these patients were clinically characterized by the presence of minor disease symptoms. Overall, the results indicated that detection of circulating immune complexes and/or C3-conversion products could not be used as an absolute measure for insight into the C3 metabolism.