Autoimmune encephalitis.

Over the past decade, the clinical spectrum of autoimmune encephalitis has expanded with the emergence of several new clinicopathological entities. In particular, autoimmune encephalitis has recently been described in association with antibodies to surface receptors and ion channels on neurological tissues. Greater clinician awareness has resulted in autoimmune encephalitis being increasingly recognised in patients with unexplained neurological and psychiatric symptoms and signs. The clinical spectrum of presentations, as well as our understanding of disease mechanisms and treatment regimens, is rapidly developing. An understanding of these conditions is important to all subspecialties of Internal Medicine, including neurology and clinical immunology, psychiatry, intensive care and rehabilitation medicine. This review provides a contemporary overview of the aetiology, investigations and treatment of the most recently described autoimmune encephalitides.

The three-dimensional structure at 2.4 A resolution of glycosylated proteinase A from the lysosome-like vacuole of Saccharomyces cerevisiae.

The crystal structures of glycosylated native proteinase A, an aspartic proteinase found in the vacuole of Saccharomyces cerevisiae, and its complex with a difluorostatone-containing tripeptide have been determined by molecular replacement to 3.5 A and 2.4 A resolutions, respectively. Superposition of the bound and native forms gave an r.m.s. difference of 0.6 A largely reflecting the poor resolution of the native crystal structure. The secondary and tertiary structures are highly similar to those found in porcine pepsin and lysosomal cathepsin D; superposition of the structure of proteinase A bound to the difluorostatone inhibitor on those of pepsin and cathepsin D gave pairwise r.m.s. differences for C(alpha) atoms of 1.36 A and 0.88 A. Most differences occur in loop regions. Comparison of the structure of the proteinase A-difluorostatone complex with that of endothiapepsin bound with the same inhibitor shows that the conformation and hydrogen bond interactions of the inhibitor in the active site are very similar, even though the enzymes have only 27% sequence identity. Electron density for the crystal structure of the proteinase A complex reveals five residues of the oligosaccharide structure attached to Asn67: Man-(1 --> 2)-alpha-Man-(1 --> 3)-beta-Man-(1 --> 4)-beta-GlcNAc-(1 --> 4)-beta-GlcNAc-Asn-67. The first three residues of the oligosaccharide cover the same region of the protein surface as those of the oligosaccharide attached to the equivalent position in cathepsin D. The second carbohydrate attachment site is disordered beyond the first carbohydrate residue in both enzymes.

Growth factor regulation of neurogenesis in adult olfactory epithelium.

Neurogenesis continues throughout adult life in the mammalian olfactory epithelium. This process is a dynamic state of proliferation, differentiation and cell death, probably regulated by autocrine and paracrine signals such as peptide growth factors. Previous investigations have demonstrated roles for some growth factors in olfactory neurogenesis in vitro, but the assay systems used make it difficult to be certain of their effects (proliferation, differentiation, enhanced survival) or their target cells. The present study investigated the effects of growth factors in cultures of purified olfactory epithelium comprising only basal cells and supporting cells in serum-free media. The advantage of this culture system is that proliferation, differentiation and survival of the basal cells and neurons can be examined separately. Under these conditions, three growth factors exerted well-defined effects: (i) fibroblast growth factor-2 stimulated proliferation of the globose basal cells; (ii) transforming growth factor-beta2 induced these cells to differentiate into neurons; and (iii) platelet-derived growth factor promoted survival of the differentiated neurons. We conclude that fibroblast growth factor-2, transforming growth factor-beta2 and platelet-derived growth factor act sequentially on precursor cells and immature neurons during neurogenesis in the adult olfactory epithelium.

The use of protein homologues in the rotation function.

The success of molecular replacement depends, in part, on the degree of similarity of the target and search molecules. We have systematically investigated this effect in cross-rotation functions for members of the aspartic proteinase family of enzymes. The influence of various parameters on peak heights was investigated for six search models using magnitude of F(obs) data for two target enzymes. The beneficial effects of high-resolution data and a large radius of integration are most pronounced when target and search molecules have high-percentage identities. Correction for small differences in domain-domain orientation (typically 4-8 degrees) between search and target structures leads to only a marginal improvement in the rotation-function peak height. There is an almost linear relationship between the structural distance, D, a parameter used in cluster analysis to define differences between three-dimensional protein structures, and the height of the cross-rotation-function peaks.

What white blood cell count should prompt antibiotic treatment in a febrile child? Tutorial on the importance of disease likelihood to the interpretation of diagnostic tests.

Most diagnostic tests are not dichotomous (negative or positive) but, rather, have a range of possible results (very negative to very positive). If the pretest probability of disease is high, the test result that prompts treatment should be any value that is even mildly positive. If the pretest probability of disease is low, the test result needed to justify treatment should be very positive. Simple decision rules that fix the cutpoint separating positive from negative test results do not take into account the individual patient's pretest probability of disease. Allowing the cutpoint to change with the pretest probability of disease increases the value of the test. This is primarily an issue when the pretest probability of disease varies widely between patients and depends on characteristics that are not measured by the test. It remains an issue for decision rules based on multiple test results if these rules fail to account for important determinants of patient-specific risk. This tutorial demonstrates how the value of a diagnostic test depends on the ability to vary the cutpoint, using as an example the white blood cell count in febrile children at risk for bacteremia.