MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction.

Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism.

Mulibrey nanism is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms' tumor. Mulibrey nanism is prevalent in the Finnish population and appears extremely rare elsewhere. However, cases outside of Finland may be underdiagnosed or misdiagnosed as having the 3-M or Silver-Russell syndrome, two important differential diagnostic disorders. Here, we report the first Australian patient with mulibrey nanism, in whom the occurrence of Wilms' tumor suggested the correct diagnosis. This was confirmed by the identification of two novel mutations in tripartite motif protein 37 (TRIM37) encoding a RING finger ubiquitin E3 ligase. Both mutations, the p.Cys109Ser B-box missense mutation and the p.Glu271_Ser287del in-frame deletion in the tumor necrosis factor receptor associated factor (TRAF) domain alter the subcellular localization of TRIM37. As both the B-box and the TRAF domains are predicted to be important for mediating the protein-protein interactions, these mutations may help the understanding of the cellular interactions of TRIM37. Our findings imply the importance of early molecular diagnostics in cases of suspected mulibrey nanism and of identifying novel mutations with potential relevance for unraveling the underlying molecular pathology. Ultrasound surveillance for Wilms' tumor is recommended for children with mulibrey nanism.

Experiences in methods to involve key players in planning protective actions in the case of a nuclear accident.

A widely used method in the planning of protective actions is to establish a stakeholder network to generate a comprehensive set of generic protective actions. The aim is to increase competence and build links for communication and coordination. The approach of this work was to systematically evaluate protective action strategies in the case of a nuclear accident. This was done in a way that the concerns and issues of all key players could be transparently and equally included in the decision taken. An approach called Facilitated Decision Analysis Workshop has been developed and tested. The work builds on case studies in which it was assumed that a hypothetical accident had led to a release of considerable amounts of radionuclides and, therefore, various types of countermeasures had to be considered. Six workshops were organised in the Nordic countries where the key players were represented, i.e. authorities, expert organisations, industry and agricultural producers.

Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3.

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterized by progressive hearing loss, severe retinal degeneration, and variably present vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibrium analyses in Finnish carriers of a putative founder mutation, the critical region was narrowed to 250 kb, of which we sequenced, assembled, and annotated 207 kb. Two novel genes-NOPAR and UCRP-and one previously identified gene-H963-were excluded as USH3, on the basis of mutational analysis. USH3, the candidate gene that we identified, encodes a 120-amino-acid protein. Fifty-two Finnish patients were homozygous for a termination mutation, Y100X; patients in two Finnish families were compound heterozygous for Y100X and for a missense mutation, M44K, whereas patients in an Italian family were homozygous for a 3-bp deletion leading to an amino acid deletion and substitution. USH3 has two predicted transmembrane domains, and it shows no homology to known genes. As revealed by northern blotting and reverse-transcriptase PCR, it is expressed in many tissues, including the retina.

Multiattribute risk analysis in nuclear emergency management.

Radiation protection authorities have seen a potential for applying multiattribute risk analysis in nuclear emergency management and planning to deal with conflicting objectives, different parties involved, and uncertainties. This type of approach is expected to help in the following areas: to ensure that all relevant attributes are considered in decision making; to enhance communication between the concerned parties, including the public; and to provide a method for explicitly including risk analysis in the process. A multiattribute utility theory analysis was used to select a strategy for protecting the population after a simulated nuclear accident. The value-focused approach and the use of a neutral facilitator were identified as being useful.

A sequence-ready map of the Usher syndrome type III critical region on chromosome 3q.

Usher syndrome type 3 (USH3; MIM 276902) is an autosomal recessive disorder associated with progressive hearing loss and retinal degeneration. We recently refined the localization of USH3 to a 1-cM genetic interval between markers D3S1299 and D3S3625. We have now constructed a bacterial artificial chromosome contig over the region. Novel polymorphic markers were generated and physically fine-mapped, allowing further narrowing of the critical interval to a 250-kb genomic fragment. Of seven ESTs mapping to the initial critical region, WI-11588 and SHGC-133 represent the human SIAH2 gene, which was excluded as a candidate for USH3 by sequencing and subsequently, by its position. KIAA0001 and D3S3882 derive from the transcript of a putative G-protein-coupled receptor gene that was excluded as a candidate by sequencing of patient DNA. These data provide a basis for the sequencing and final characterization of the USH3 region and isolation of the disease gene.

Stability of Fourier coefficients in relation to changes in respiratory air flow patterns.

The characterization of respiratory air flow patterns is a subject of continuous interest. The pattern of the air flow curve is an individual characteristic which remains constant over long periods of time. Basically two different approaches have been proposed to determine the individual parameters of the respiratory flow, namely the graphical characterization, which originated from visual indices and subsequently led to harmonic analysis, and the optimal control modeling approach. It has been suggested that respiratory personality can be accurately characterized by the Fourier coefficients of the air flow curve. The first four Fourier sine components should reproduce the shape of the cycle and remain constant in different environmental conditions for one individual. This paper evaluates the possibilities of the Fourier approximation approach to characterize the respiratory personality. The Fourier sine coefficients which were assumed to be invariable were found to be very sensitive to changes in respiratory times. Both the amplitude and the angle of the Fourier sine transformation varied when duration of inspiration and expiration changed.

Modified Pereyra procedure for female stress incontinence.

28 patients were treated with the modified Pereyra procedure for female stress urinary incontinence. In 12 patients this was the primary operative correction of the complaints and resulted in total continence in 10 patients (83%). The other patients had a recurrent stress incontinence which might have contributed to lower success rate of 54% in the total series. Due to less extensive surgery than in suprapubic urethropexy and due to low complication rate we feel that the modified Pereyra procedure is a good alternative as a primary operation for stress urinary incontinence.

Energy cost minimization in left ventricular ejection: an optimal control model.

A new optimization model for explaining the observed left ventricular ejection patterns is presented. In the system model, arterial load is described by a modified windkessel load. The ejection pattern for a given cardiac output with fixed stroke volume and duration of ejection is predicted by minimizing a criterion that describes the total ventricular O2 consumption. The ejection patterns of the model closely resemble the observed ejection patterns. Also, the model predictions for changes in the values of the system parameters are qualitatively correct. The results strongly suggest that the control of ejection pattern satisfies the principle of energy cost minimization.