Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1.6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor ␣-induced protein 6 gene in all probands and the integrin ␣6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor ␣-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P ‫؍‬ 0.04). This association was confirmed in an independent cohort of female hip cases (n ‫؍‬ 338; P ‫؍‬ 0.04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (P ‫؍‬ 0.004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.

To study the impact of residual pyrethroid insecticide on the abundance and distribution of peridomestic Lutzomyia longipalpis, the sandfly vector of visceral leishmaniasis in Brazil, lambda-cyhalothrin was applied at 20 mg a.i.m-2 in the following interventions: (i) spraying of all animal pens in a village (blanket coverage); (ii) treatment of a subset of animal pens, either by spraying, or by installation of insecticide-impregnated 1 m2 cotton sheets as 'targets' (focal coverage). By sampling with CDC light traps, and using a novel analytical approach, we detected a 90% reduction in Lu.longipalpis abundance in sprayed sheds of the focal intervention. However, there was no discernible effect on the abundance of other phlebotomines trapped in sheds, or on the abundance of Lu.longipalpis in untreated dining-huts and houses. This differential impact on Lu.longipalpis abundance is explained in terms of the disruption of male pheromone production. Treated targets were approximately half as effective as residual spraying in reducing the abundance of Lu.longipalpis in sheds. Following blanket intervention, the abundance of Lu.longipalpis in traps fell by only 45% (not significant): catches at untreated dining-huts actually increased, possibly because the blanket coverage diverted Lu.longipalpis away from major aggregation sites at animal pens. It is recommended that care be taken during vector control programmes to ensure that all potential aggregation sites are treated. The possible consequences of leaving some sites untreated include poor control of peridomestic sandfly abundance and an increase in the biting rate on dogs and humans.

We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P

Tumor necrosis factor-stimulated gene-6 (TSG-6) encodes a 35-kDa protein, which is comprised of contiguous Link and CUB modules. TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues. It interacts with components of cartilage matrix (e.g. hyaluronan and aggrecan) and thus may be involved in extracellular remodeling during joint disease. In addition, TSG-6 has been found to have anti-inflammatory properties in models of acute and chronic inflammation. Here we have mapped the human TSG-6 gene to 2q23.3, a region of chromosome 2 linked with OA. A single nucleotide polymorphism was identified that involves a non-synonymous G 3 A transition at nucleotide 431 of the TSG-6 coding sequence, resulting in an Arg to Gln alteration in the CUB module (at residue 144 in the preprotein). Molecular modeling of the CUB domain indicated that this amino acid change might lead to functional differences. Typing of 400 OA cases and 400 controls revealed that the A 431 variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A 431 homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg 144 and Gln 144 allotypes in Drosophila Schneider 2 cells, and functional characterization, showed that there were no significant differences in the ability of these full-length proteins to bind hyaluronan or form a stable complex with inter-␣-inhibitor.