These findings are consistent with a cumulative beneficial effect of pregnancy. Temporal changes toward an older maternal age of parturition and reduced offspring number may partly underlie the increasing female excess among MS cases over time.

The weakly electric fish Eigenmannia is able to detect temporal disparities as small as 400 nsec between two signals from different parts of the body surface (Carr et al., 1986). The elements of this time-comparison circuit have been identified by EM reconstruction of its component cells. Information about the timing of the zero-crossing of signals on each area of the body surface is coded in phase-coder receptors, a subset of tuberous electroreceptors. Electroreceptors on the body surface are innervated by primary afferents with their central termination on the spherical cells of the medullary electrosensory lateral line lobe. These cells project to lamina VI of the midbrain torus, a structure similar to the inferior colliculus. Afferents entering lamina VI form a very restricted terminal arbor in which they synapse on the three cell types of this lamina. Each afferent makes gap-junction synapses on one or two giant cell somata and morphologically mixed synapses on the distal dendrites of two types of small cell. The afferent terminals thus encode the timing of the electric signal on a local patch of the body surface, forming a somatotopic map of the body surface in lamina VI. The giant cells are adendritic and their axonal arbor is such as to distribute timing information originating from one part of the body surface throughout lamina VI, so that each region of lamina VI receives information about the timing of zero-crossings from the entire body surface from giant cells, as well as information from a local portion of the body surface from the afferent terminals. The giant cells terminate exclusively on the cell bodies of the small cells of lamina VI, shown to be sensitive to small temporal disparities by Heiligenberg and Rose (1985). Thus, each small cell receives a single synapse on its soma from a giant cell that conveys phase-coding information from some portion of the body surface and receives local phase-coding input onto its dendrites from spherical cell afferents. The sensitivity of the small cells to temporal disparities appears to be conferred by their segregation of inputs from two different parts of the body surface onto dendrites and soma, respectively. We propose that the dendritic input acts as a delay line, and the small cell fires maximally when the inputs from the dendrites and the giant cell input onto the soma coincide.

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n ¼ 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P ¼ 7 Â 10 245 ), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P ¼ 5 Â 10 27 ). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.

No abstract