We analyzed tandem duplication in the juxtamembrane (JM) domain of the FLT3 (FMS-like tyrosine kinase 3/FLK2, CD135) gene in 94 children with acute myeloid leukemia (AML) and evaluated its correlation with clinical features. Longer polymerase chain reaction (PCR) products were observed in five patients; 1/3 of M0, 1/9 of M1, 1/39 of M2, 1/9 of M3 and 1/12 of M5. The sequence analyses of abnormal PCR products showed that all the abnormal products were derived from tandem duplications involving the JM domain and that all the lengthened sequences were in-frame as we previously reported. Statistical analyses revealed a significantly lower incidence of the tandem duplication in childhood AML patients than in adult patients (P Ͻ 0.05), and significantly shorter disease-free survival in patients with mutant FLT3 than in patients with wild-type FLT3 (P Ͻ 0.05). Our results suggest that the tandem duplication in the JM domain of the FLT3 gene is not a frequent phenomenon but might be a factor of poor prognosis in childhood patients with AML.

We constructed plasmids carrying heat-inducible pemI and pemK genes, which were fused with the collagen-acZ sequence in frame. The PemK-collagen-LacZ (PemK*) protein produced from the fusion gene upon heat induction inhibited the growth of cells and killed most of the cells in the absence of the PemI protein but did not do so in the presence of the PemI protein. This supports our previous assumption that the PemK protein inhibits cell division, leading to cell death, whereas the PemI protein suppresses the function of the PemK protein. We also constructed the plasmid carrying the heat-inducible pem operon which consists of the intact pemI gene and the pemK gene fused with collagen4acZ. The simultaneously induced PemI and PemK* proteins did not inhibit the growth of cells. However, the temperature shift to 30°C after induction of both proteins at 42°C caused inhibition of cell growth and death of most cells. This suggests that the PemI protein is somehow inactivated upon the arrest of de novo synthesis of the PemI and PemK* proteins, allowing the PemK* protein to function. We observed that the PemI-collagen-LacZ (PemI*) protein was degraded faster than the PemK* protein, perhaps by the action of a protease(s). In fact, the Ion mutation, which caused no apparent degradation of the PemI* protein, did not allow the PemK* protein to function, supporting the suggestion described above.

There are more than 6000 rare diseases (defined as affecting <5/10 000 individuals in Europe, <200 000 people in the United States). The rarity can create problems including: difficulties in obtaining timely, accurate diagnoses; lack of experienced healthcare providers; useful, reliable and timely information may be hard to find; research activities are less common; developing new medicines may not be economically feasible; treatments are sometimes very expensive; and in developing countries, the problems are compounded by other resource limitations. Emphasis is required to support appropriate research and development leading to better prevention, diagnosis and treatments of rare diseases. Notably, clinical trials using already existing drugs may result in new, affordable, treatment strategies. Moreover, rare diseases may teach us about common disorders.ConclusionsCountries are encouraged to implement specific research and development activities within their individual capabilities, so that patients worldwide have equal access to necessary interventions to maximize the potential of every individual.

Structural changes of argon hydrate were investigated in a pressure range of 0.2 to 6.5 GPa at room temperature using a diamond anvil cell. In-situ X-ray diffractometry and optical microscopy revealed a sequence of three different structures in this pressure-temperature range. Argon hydrate exhibited a well-known cubic structure II at the pressure range of 0.2 to 0.6 GPa. At 0.7 GPa the cubic structure II transformed into a tetragonal phase. At 1.1 GPa, the tetragonal phase further transformed into a body-centered orthorhombic phase, which survived pressures up to 6.0 GPa. At pressures higher than 6.1 GPa, the orthorhombic phase decomposed into solid argon and ice VII. Structural analysis showed that the tetragonal structure observed was composed of two 14-hedra occupying two argon atoms in a unit cell, which was very similar to the tetragonal structure reported in previous literature. The body-centered orthorhombic structure observed was explained as a "filledice" structure, a newly reported structure in a water-methane system at high pressure. These results showed that the cubic structure II of argon hydrate was transformed, by way of a tetragonal cage structure, into just such a "filled-ice" structure.

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