Williams-Beuren syndrome (WBS) is a developmental disorder caused by haploinsufficiency for genes in a 2-cM region of chromosome band 7q11.23. With the exception of vascular stenoses due to deletion of the elastin gene, the various features of WBS have not yet been attributed to specific genes. Although >/=16 genes have been identified within the WBS deletion, completion of a physical map of the region has been difficult because of the large duplicated regions flanking the deletion. We present a physical map of the WBS deletion and flanking regions, based on assembly of a bacterial artificial chromosome/P1-derived artificial chromosome contig, analysis of high-throughput genome-sequence data, and long-range restriction mapping of genomic and cloned DNA by pulsed-field gel electrophoresis. Our map encompasses 3 Mb, including 1.6 Mb within the deletion. Two large duplicons, flanking the deletion, of >/=320 kb contain unique sequence elements from the internal border regions of the deletion, such as sequences from GTF2I (telomeric) and FKBP6 (centromeric). A third copy of this duplicon exists in inverted orientation distal to the telomeric flanking one. These duplicons show stronger sequence conservation with regard to each other than to the presumptive ancestral loci within the common deletion region. Sequence elements originating from beyond 7q11.23 are also present in these duplicons. Although the duplicons are not present in mice, the order of the single-copy genes in the conserved syntenic region of mouse chromosome 5 is inverted relative to the human map. A model is presented for a mechanism of WBS-deletion formation, based on the orientation of duplicons' components relative to each other and to the ancestral elements within the deletion region.

BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and͞or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5 untranslated region of RAD51 (135C͞G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and͞or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) ‫؍‬ 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P ‫؍‬ 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and͞or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6 -9.8, P ‫؍‬ 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P ‫؍‬ 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. G erm-line mutations in the BRCA1 and BRCA2 genes increase susceptibility for both breast and ovarian cancer. Penetrance of these mutations is incomplete and age-dependent, thus cancer risk in carriers continues to increase with age even though the mean age of cancer diagnosis is younger in BRCA1͞ BRCA2 carriers compared with noncarriers (1). Estimates of penetrance have varied widely, perhaps as a result of different ascertainment schemes and͞or allelic effects. In families ascertained for multiple affected individuals suitable for linkage analysis, lifetime cancer risk (by age 70) was 85% for breast cancer in both BRCA1 and BRCA2 carriers (2, 3), 63% for ovarian cancer in BRCA1 carriers (2), and 27% for ovarian cancer in BRCA2 carriers (3). Significantly lower risk estimates were obtained in studies performed in less selected families or at the population level, with a 36-56% lifetime risk for breast cancer (4-7) and a 16% lifetime risk for ovarian cancer (5). These studies were performed in specific ethnic groups (Ashkenazi Jewish and the Iceland population) that harbor a limited number of specific mutations and could therefore be representative of these alleles, rather than reflect the general penetrance of BRCA1͞BRCA2 mutations. Such differences suggest that penetrance of BRCA1...

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Patterns of connections underlying cross-modality integration were studied by injecting distinguishable, retrograde tracers (Fluoro-Gold and diamidino yellow) in pairwise manner into different sensory representations (visual, somatosensory, and auditory) in the cerebral cortex of the rat. In agreement with previous single tracer studies, our results indicate that the central core of sensory areas receives projections mainly from a set of association areas located in a ringlike fashion along the margin of the cortical mantle. The visual cortex received projections from areas 48/49, area 29d, posterior agranular medial cortex (AGm), area 11, area 13, and area 35. All these areas were also connected to the auditory cortex with the exception of areas 29d and AGm. However, lateral to area 29d and posterior AGm, a band of neurons projecting to the auditory cortex was present. Somatosensory cortex was connected mainly with the more anterior aspect of the hemisphere, which included primary motor area, area 11, and area 13. The patterns of intermodality relationships revealed in the present study were of two main categories. In the anterior and lateral areas, an intermingling of cells projecting to different sensory modalities was observed. In contrast, in areas located along the medial aspect of the hemisphere, cells connected to different sensory modality representations tended to be segregated from each other. Postsubicular cortex (areas 48/49) contained both intermingled and segregated groups of cells. The incidence of clearly identified double-labeled cells concurrently projecting to two different sensory representations was extremely rare. These patterns may form a substrate for different levels of cross-modal sensory integration in the rat cortex.

Online health information and services for patients were suggested to improve symptom management and treatment adherence, thereby contributing to healthcare optimization. This paper aimed to characterize multiple sclerosis (MS) patients Internet usage. Information regarding browsing habits, Internet reliability, and the medical team's attitude to information collected online was obtained by questionnaires from MS patients. Data was compared between nonbrowsers, browsers on MS topics, and browsers on non-MS topics only. From the 96 patients recruited, 61 (63.5%) performed MS-related searches. The most viewed topics were “understanding the disease” and “treatments”. Patients reported that the information helped coping with MS and assured them of the appropriateness of their therapy. Shorter disease duration was correlated with higher Internet activity. Disabled patients were more interested in online interaction with specialists and support groups. This paper suggests that MS patients benefit from online information, and it emphasizes the importance of resources tailored to patients needs.