Association between loss of dp140 and cognitive impairment in duchenne and becker dystrophies.

The presence of variable degrees of non progressive cognitive impairment is recognized as a clinical feature of patients with Duchenne and Becker muscular dystrophies (DMD and BMD), but its pathogenesis still remains a matter of debate. A number of findings have proved that rearrangements located in the second part of the dystrophin ( DMD ) gene seem to be preferentially associated with cognitive impairment. Dp140 is a distal dystrophin isoform, mainly expressed during fetal brain development, whose role for neuropsychological functioning was suggested. The aims of the current study were to explore the possible association between cognitive impairment and DNA mutations affecting the regulatory regions of Dp140, as well as to compare the neuropsychological functioning of patients affected with DMD and Intermediate muscular dystrophy (IMD) with those affected by Becker muscular dystrophy (BMD). Fiftythree patients genetically diagnosed with DMD, IMD and BMD, subdivided according to sites of mutations along the DMD gene, underwent a neuropsychological assessment, evaluating their general cognitive abilities, verbal memory, attention and executive functions. Twenty patients with mutations, terminating in exon 44 or starting at exon 45 were tested by polymerase chain reaction (PCR) amplification of microsatellites STR44, SK12, SK21 and P20 DXS269, in order to evaluate the integrity of the Dp140 promoter region. According to our statistical results, there was not a significant difference in terms of general intelligence between the allelic forms of the disease, a higher frequency of mental retardation was observed in DMD patients. The patients with BMD had better results on tests, measuring long-term verbal learning memory and executive functions. We found that patients lacking Dp140 performed more poorly on all neuropsychological tests compared to those with preserved Dp140. Overall, our findings suggest that the loss of Dp140 is associated with a higher risk of intellectual impairment among patients with dystrophinopathies and highlights the possible role of this distal isoform in normal cognitive development.

Effect of foot orthotics on calcaneal eversion during standing and treadmill walking for subjects with abnormal pronation.

STUDY DESIGN: Repeated measures analysis of intervention. OBJECTIVES: To determine the effects of foot orthotics and shoewear on calcaneal eversion for standing and treadmill walking. BACKGROUND: Foot orthotics are commonly used as an intervention for treating lower extremity musculoskeletal pathology. Qualitative research regarding the benefit of foot orthotics tends to be favorable, while the results of quantitative studies often conflict. METHODS AND MEASURES: Eight men (mean age = 35.8 +/- 12.7 years) and 5 women (mean age = 30.4 +/- 10.6 years), who demonstrated abnormal pronation, walked quickly (average velocity = 1.9 m/s) on a treadmill with and without foot orthotics. Subjects were filmed using a 2-dimensional video system and plastic molds designed to indicate calcaneal position inside the shoe during static standing and treadmill walking. RESULTS: Paired t tests indicated that foot orthotics significantly reduced the mean maximum calcaneal eversion angle by 2.2 degrees and the mean calcaneal eversion angle at heel rise by 2.1 degrees during fast walking. Orthotic and nonorthotic conditions did not differ significantly for the remaining kinematic variables. A one-way ANOVA indicated that calcaneal eversion in standing was significantly greater for barefoot standing compared with standing in shoes with or without orthotics. ANOVA also indicated that the plastic molds provided reliable measures of calcaneal position. CONCLUSIONS: Foot orthotics have a significant effect on calcaneal eversion and shoes also should be considered in conjunction with foot orthotic prescription.

Functional analysis of Cdc42 in actin filament assembly, epithelial morphogenesis, and cell signaling during Drosophila development.

Cdc42, a member of the Rho family of GTP binding proteins, functions in the formation of polarized actin structures, in elongation of cell shape, and in cell signaling. Although genetic mutations previously have not been available in multicellular organisms, studies have attempted to discern Cdc42 functions in organisms, including Drosophila, using dominant active or interfering alleles. Here, for the first time, we examine the functions of Cdc42 in developing tissues using loss-of-function mutations in the Drosophila Cdc42 gene. We find that Cdc42(-) epithelial cells fail to elongate into a columnar cell shape and cannot maintain a monolayered epithelial structure. In contrast to previous studies, we find no requirement for Cdc42 in cell division or in activation of the Jun N-terminal kinase pathway. In addition, Cdc42 function is not required for cytoplasmic actin filament assembly in the nurse cells during oogenesis, although it may facilitate this process. Furthermore, our results indicate that Cdc42 plays a role in intercellular interactions between the germ line and the somatic follicle cells. These results confirm the role of Cdc42 in actin filament assembly and provide new insights into its functions in epithelial morphogenesis and regulating intercellular signaling events.

Relative stabilities of dinucleotide and tetranucleotide repeats in cultured mammalian cells.

The differences in rates of frameshift mutations between a dinucleotide repeat sequence [(CA)(17)] and a tetranucleotide repeat sequence [(GAAA)(17)] have been determined in immortalized, non-tumorigenic, mismatch repair-proficient mouse cells and in mismatch repair-defective human colorectal cancer cells. Clones with mutations were selected on the basis of restoration of activity of a bacterial neomycin resistance gene whose reading frame was disrupted by insertion of the microsatellite upstream of the translation initiation codon. This gene was introduced into the cells on a plasmid, which integrated into the genome of the host cells. Mutation rates of the tetra-nucleotide repeat were much lower than those of the dinucleotide repeat in both cell types. In addition, independent subclones of the colorectal cancer cell line were assayed by PCR for instability of endo-gen-ous tetranucleotide and dinucleotide repeat sequen-ces. In all cases, the mutation frequencies of the dinucleotide repeats were higher than those of the tetranucleotide repeats.

Effects of sex, religion, and amount of alcohol consumption on self-reported drinking-related problem behaviors.

The effect of sex, religion, and amount of alcohol consumed on the number of self-reported alcohol-related problem behaviors was examined for 331 students who were approached on three Eastern United States campuses and asked to complete anonymously a questionnaire reporting the number of drinking-related problem behaviors. It was hypothesized that Catholics, men, and people who drank more would report more problem behaviors. A 2 x 3 x 4 factorial analysis of variance with unequal ns showed all three hypotheses were confirmed, but no significant interactions were found. Given the enormity of the problem of alcohol abuse in the United States, further research examining alcohol use and the associated problem behaviors is essential.