Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Contains fulltext : 88828.pdf (publisher's version ) (Open Access)BACKGROUND: A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. METHODS AND RESULTS: Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. SIGNIFICANCE: These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk

Menadione kills trophozoltes and cysts of Giardia intestinalis

Production of reactive oxygen species by redox cycling in the presence of low levels of oxygen has been studied as a possible approach to anti-protozoal chemotherapeutic strategy. Incubation of the diplomonad flagellate Giardia intestinalis with 2-methy-1,4-naphthoquinone (menadione), under anaerobic conditions, gave UV absorption changes characteristic of reduction to menadiol; partial reversal was observed on admitting O-2. Under microaerobic conditions, similar to those on the surface of the jejunal mucosa, trophozoites consumed O-2 rapidly in the presence of menadione; reaction products included singlet O-2 (monitored by single photon counting of O-2-dependent low-level chemiluminescence) and H2O2 (measured by the formation of Complex I of microperoxiclase). Trophozoites became swollen and incapable of regulatory volume control; these irreversible responses led to loss of motility, cessation of flagellar activity and cell death. Comparison of the sensitivities of trophozoites to metroniclazole and menadione gave LC50 values (pg ml(-1)) of 1(.)2 and 0(.)7, respectively; corresponding values for cysts (measured by in vitro excystation capacities) were >50 and 1(.)3. Menadione (LD50 in mice, 0(.)5 g kg(-1)) is therefore a potentially more useful and general anti-giardial agent than metronidazole, as it is active against cysts as well as trophozoites

The microaerophilic flagellate Giardia intestinalis: oxygen and its reaction products collapse membrane potential and cause cytotoxicity

Trophozoites of the microaerophilic flagellate parasitic protozoon Giardia intestinalis have only a limited capacity to detoxify O2. Thus, when exposed to controlled concentrations of dissolved O2 >8 μM, they gradually lose their ability to scavenge O2. In a washed cell suspension stirred under 10% air in N2 (equivalent to 25 μM O2), inactivation of the O2-consuming system was complete after 3·5 h; during this period accumulation of H2O2 (3 μmol per 106 organisms) and oxidation of cellular thiols to 16% of their initial level occurred. Under 20% air (50 μM O2), respiratory inactivation was complete after 1·5 h, and under air (258 μM O2), after 50 min. Loss of O2-consuming capacity was accompanied by loss of motility. Use of the fluorogen 2,7-dichlorodihydrofluorescein acetate indicated that intracellular H2O2 is produced at extranuclear sites. Flow cytometric estimation of the plasma membrane electrochemical potentials using bis(1,3-dibutylbarbituric acid) trimethine oxonol, DiBAC4(3), showed that values declined from −134 mV to −20 mV after 4·5 h aeration. Incubation of organisms with 60 μM H2O2 for 10 min gave partial collapse of plasma membrane potential and complete loss of O2 uptake capacity; motility and viability as assessed by DiBAC4(3) exclusion were completely lost after 1 h. Inactivation of the O2-consuming system and loss of viability were also observed on exposure to singlet oxygen photochemically generated from rose bengal or toluidine blue

Oxygen homeodynamics in Giardia

A survey is given on the present knowledge of the polarized parton distribution functions. We give an outlook for further developments desired both on the theoretical as well on the experimental side to complete the understanding of the spin--structure of nucleons in the future.Comment: Proceedings of 15th International Workshop on Deep-Inelastic Scattering and Related Subjects (DIS2007), Munich, Germany, 16-20 Apr 2007, 6 page

Effect of cumulative loss of dystrophin isoforms on FSIQ.

<p>A boxplot representation of patient FSIQ data classified by the most 3′ dystrophin isoform affected by a mutation. Open circles = patient data points; Vertical lines represent ±1 standard deviation of the mean; boxes = 95% confidence intervals of the mean; horizontal bar = median.</p

Measurement of the clinical utility of a combined mutation detection protocol in carriers of Duchenne and Becker muscular dystrophy

There are significant clinical benefits to be gained from a combined mutation detection protocol for carrier detection. It is recommended that mutation-specific carrier frequencies for the different classes of dystrophin mutations should be taken into account in genetic counselling practic