Cerebral cavernous malformation (CCM) is a Mendelian model of stroke, characterized by focal abnormalities in small intracranial blood vessels leading to hemorrhage and consequent strokes and/or seizures. A significant fraction of cases is inherited as an autosomal dominant trait with incomplete penetrance. Among Hispanic Americans, virtually all CCM is attributable to a founder mutation localized to 7q ( CCM1 ). Recent analysis of non-Hispanic Caucasian kindreds, however, has excluded linkage to 7q in some, indicating at least one additional CCM locus. We now report analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. In addition to linkage to CCM1, analysis of linkage demonstrates linkage to two new loci, CCM2 at 7p13-15 and CCM3 at 3q25.2-27. Multilocus analysis yields a maximum lod score of 14.11, with 40% of kindreds linked to CCM1, 20% linked to CCM2 and 40% linked to CCM3, with highly significant evidence for linkage to three loci (linkage to three loci supported with an odds ratio of 2.6 x 10(5):1 over linkage to two loci and 1.6 x 10(9):1 over linkage to one locus). Multipoint analysis among families with high posterior probabilities of linkage to each locus refines the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these three loci can account for inheritance of CCM in all kindreds studied. Significant locus-specific differences in penetrance are identified. These findings have implications for genetic testing of this disorder and represent an important step toward identification of the molecular basis of this disease.
We studied seasonal, interannual, and both small- and large-scale spatial variation in the abundance of blacklegged ticks, Ixodes scapularis Say, in a semirural landscape in southeastern New York. Using transect drag sampling, we found that ticks were approximately twice as abundant in 1994 as in the preceding 2 yr. In 1994, larval ticks showed a strong peak in activity in late spring, coincident with the nymphal peak that year. All post-egg life stages were more abundant in forested than in shrubby or herbaceous habitat types, but peak abundance of larvae shifted from oak-dominated forest in 1992 to maple-dominated forest in 1993 and 1994. All life stages were highly clumped at small spatial scales, but larvae were the most aggregated. Within the forested habitat types, we observed an initial increase followed by a decrease in small-scale clumping during seasonal activity for each life stage. We discuss potential effects of the observed temporal and spatial variation on risk of Lyme disease. Because of pronounced variation in abundance and activity patterns among years and habitat types, we caution against generalizing from short-term or spatially limited studies.
Human activities often result in the creation of patchy landscapes, which may influence distribution and abundance of some wildlife species and their ectoparasites. Risk of exposure to Lyme disease is a function of the abundance of ticks (Ixodes scapularis, formerly I. dammini), which in turn may be determined by the distribution of key vertebrate hosts within landscapes. We used transect drag sampling and small‐mammal trapping to estimate, respectively, the abundance of host‐seeking and attached ticks in a rural landscape (southeastern New York) consisting of a mosaic of several discrete habitat types. Forested habitat types supported higher densities of host‐seeking ticks than herbaceous or shrub‐dominated habitats. However, in patches of little bluestem grass and gray dogwood shrubs, small mammals had high tick burdens despite low densities of host‐seeking ticks. There was an outbreak of larval ticks limited to oak‐dominated habitats in summer, 1992, which we postulate was related to unusually heavy acorn (mast) production attracting white‐tailed deer and attached adult deer ticks, in autumn 1991. This hypothesis was supported by low densities of larval ticks in oak patches in summer, 1993, following poor mast production the previous autumn. Instead, the 1993 larval peak shifted to maple‐dominated habitats, which may result from intensive use of these patches by deer in nonmast years. The abundance of host‐seeking nymphs was strongly correlated with the abundance of white‐footed mice the prior summer. Both the high tick burdens in little bluestem and dogwood patches, and shifting locations of larval outbreaks, appear to be functions of landscape configuration, especially patch size and juxtaposition.
These findings demonstrate that inherited CCM is not always caused by a mutant gene on 7q, indicating the presence of at least a second gene in which mutation can cause CCM. These results have implications for genetic testing and the pathogenesis of this disorder.
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