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BACKGROUND: Prior research has established that falls are commonplace in adults with hemophilia, and advises that physical therapy and exercise are successful in fall prevention. Recognizing obstacles and catalysts to physical therapy and exercise in people with hemophilia may augment the efficacy of efforts to prevent falls in this population. OBJECTIVES: To learn about the experiences and ideas of patients with hemophilia, especially associated with balance, falls, and exercise. METHODS: Semi-structured interviews with 14 adult patients with hemophilia were performed. The interviews were coded for themes founded on the study aims. RESULTS: Most subjects described difficulty with balance, often ascribed to joint problems. They believed that staying strong and fit could positively influence balance, but expressed concerns and fear related to falling. Those who exercised regularly did not view exercise as hazardous, while those who did not dependably exercise articulated worry that dangers of exercise may offset the benefits. The most common obstacle to exercise was pain and having someone to exercise with was often described as an enabler. Barriers to partaking in physical therapy included weak proof of its success and distrust in the therapist. Positive physical therapy experiences in the past and the connection with the therapist were reported as facilitators. CONCLUSIONS: People with hemophilia describe some attitudes and experiences that are unique to hemophilia while others are found in the general population. Attending to fear, pain, and support for interventions, while encouraging a robust therapeutic alliance and a plan for routine exercise may aid fall prevention behaviors.

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By use of newly developed subcongenic strains of mice from a parental B6.129-Il10-/- knockout/congenic strain, we have narrowed the critical region for a new behavioral QTL, called Emo4, for open-field activity to a segment of Chromosome 1 between Erbb4 (68.4Mb) and B3gnt7 (86.2 Mb). We have also uncovered an additional QTL governing repetitive beam breaks in the open field. This QTL, called Reb1, maps to the interval between Asb1 (91.4 Mb) and NM_172851 (100.0 Mb) and is one of the first QTLs mapped for this type of behavior. Genome-wide microarray expression analyses were then undertaken to help to identify candidate genes that may be the cause of these genetic differences in open-field performance. In this effort, we analyzed global gene expression differences in the amygdalae by use of Affymetrix GeneChips between B6, B6.129-Il10-/-, and B6.129R4. Several probe sets representing target Chr 1 genes were found that showed significantly differential expression in the subcongenic and congenic strains. Several candidate genes have been identified. One of these regions coincides with an homologous region in humans that has been associated with autism, a disease whose symptoms include repetitive actions. This study illustrates that the use of congenic strains combined with global gene expression analyses can produce a list of viable candidates. It further shows that caution should be observed when analyzing the effects of knockout/congenic strains because many of the gene expression differences in these comparisons could not be attributable to the ablated Il10 gene but rather to passenger gene effects.

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Positional cloning of quantitative trait loci in rodents is a common approach to identify genes involved in complex phenotypes, including genes important to human disease. However, cloning the causative genes has proved to be more difficult than determining their positions. New tools such as genomic sequence, clone libraries, and new genomic-based methods offer new approaches to identify these genes. Here we review how these new tools and approaches will improve our ability to discover the genes important in complex traits.

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In food preference studies, mammals are often categorized as being either neophilic or neophobic, i.e., preferring or disliking a novel-tasting food. To date, the genetic factors influencing novel food preference have not been elucidated. To understand this phenomenon, we investigated the genetics of food preference in eight inbred strains of mice. We gave them plain-, cinnamon-, or cocoa-flavored powdered food on day 0 for 45 min and then a choice of cinnamon- or cocoa-flavored food 14 days later. We determined their preference for novel versus already-experienced flavored food and found that some inbred strains chose the food that they had been given previously, while others chose a different food. In particular, the DBA/2 strain chose more cinnamon-flavored food after it was pre-exposed to cinnamon, while the B6 strain chose less cinnamon-flavored food after this initial exposure. The BXD recombinant inbred (RI) strain set was then used to map quantitative trait loci (QTLs) that influence this novel food preference. One of these QTLs was found to map to the distal end of Chromosome (Chr) 8.

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This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

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Habituation to a novel environment, as measured by a change in exploratory activity over time, can be measured both within (intrasession) and across (intersession) sessions. The role of genetics in intrasession habituation has been investigated previously in quantitative trait loci studies, but little attention has been focused on the role of genetics on intersession habituation. We reported recently that inbred strains respond differently in an intersession habituation test. By testing a total of 25 BXD recombinant inbred lines, we were able to map a chromosomal region that strongly influences the way in which mice habituate. This region located on chromosome 15 appears to the major one affecting habituation and accounts for 80% of the genetic variance. We subsequently confirmed this map position by testing (C57BL/6J x DBA/2J) F2 mice.

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By positional cloning techniques, we have identified the gene that is disrupted in the jcpk and bpk mouse models for polycystic kidney disease. This gene is the mouse homolog of the Drosophila Bicaudal C gene. Both of these mutations have been mapped to a very short stretch of Chromosome (Chr) 10. By sequencing the bicaudal C gene, Bicc1, in these models, it was found that the jcpk mutation results in a shortened and abnormal transcript, whereas the bpk mutation results in an abnormal 3' coding region. In Drosophila, this gene encodes a protein known to influence developmental processes. The mammalian homolog contains three KH (K homology) domains and a SAM (sterile alpha motif) domain and is expressed in the developing embryo, indicating that it may be important in RNA-binding and/or protein interactions during embryogenesis.

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We have characterized the phenotype of a mouse with a t(2;13) reciprocal translocation induced by chlorambucil. It results in abnormal eyelid formation as well as a series of neurological, physiological, and immunological abnormalities. This mutant has been termed T(2;13)1Fla/+. T(2;13)1Fla/+ mice exhibit open eyelids at birth, a dilute coat color, hyperactivity, and occasional circling and stargazing activity. At 1-6 months, T(2;13)1Fla/+ mice show signs of immune complex-mediated glomerulonephritis and die prematurely. Additionally, double-stranded DNA autoantibodies have been found in sera of T(2;13)1Fla/+ mice. Cytogenetic analysis situated the translocation breakpoint at the proximal end of Chromosome (chr) 2 at band A2, and on Chr 13 at band A4. The mutant phenotype completely correlated with the presence of the translocation. Additional genetic studies have mapped the mutation and translocation breakpoint to Chr 13 between D13Mit16 and D13Mit64, and to Chr 2 proximal to D2Mit5. By fluorescent in situ hybridization (FISH), the position of this mutation/translocation on Chr 13 has been mapped to a region less than 1cM from D13Mit61.

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Most knockout (KO) mice are produced with embryonic stem cells derived from a 129 strain. Because most KO strains are backcrossed to B6 yet retain a portion of their genome from 129, especially around the ablated target locus, phenotypes previously attributed to the ablated locus may be due to passenger 129 genes. Thus, the authors decided to test several 129 substrains for their behavioral characteristics. Seven 129 substrains were put through a battery of tasks to determine their behavioral profiles. Differences were found in anxiety-related behaviors in the zero-maze, habituation to the open field, and cued fear conditioning. All strains successfully performed the rotorod task. The behavioral differences observed may have important implications for the interpretation of data and show divergence of behavioral performance in these 129 substrains.

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We recently tested three inbred mouse strains (C57BL/6J, DBA/2J, C3H/HeJ) and two F1 hybrids (B6C3F1/J, C3D2F1/J) in an elevated zero-maze for 3 consecutive days. As measured by the latency to enter an open quadrant and percentage of time spent in the open, anxiety increased over the three trials. Furthermore, we observed that some strains used visual cues to avoid the open arms of the zero-maze on the initial exposure, while other strains may have used other sensory cues. These results suggest that strains differentially use or retain information, gathered from the initial exposure, to avoid the open quadrants on subsequent exposure to the maze. Moreover, this repeated trial test may more accurately reflect anxiety in strains that are visually impaired.

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Ten patients with pain due to osteoarthritis of the knee were treated in a double-blind cross-over study with two weeks of transcutaneous electrical nerve stimulation (TENS) and placebo. There was statistically significant pain relief by TENS and half of the patients chose to continue using TENS for pain control after the test month. However, at one year's follow-up, only two patients had sufficient benefit to continue using the device.

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