Paroxysmal nocturnal hemoglobinuria (PNH) may arise during long-term followup of aplastic anemia (AA), and many AA patients have minor glycosylphosphatidylinositol (GPI) anchor-deficient clones, even at presentation. PIG-A gene mutations in AA/PNH and hemolytic PNH are thought to be similar, but studies on AA/PNH have been limited to individual cases and a few small series. We have studied a large series of AA patients with a GPI anchor-deficient clone (AA/PNH), including patients with minor clones, to determine whether their pattern of PIG-A mutations was identical to the reported spectrum in hemolytic PNH. AA patients with GPI anchor-deficient clones were identified by flow cytometry and minor clones were enriched by immunomagnetic selection. A variety of methods was used to analyze PIG-A mutations, and 57 mutations were identified in 40 patients. The majority were similar to those commonly reported, but insertions in the range of 30 to 88 bp, due to tandem duplication of PIG-A sequences, and deletions of more than 10 bp were also seen. In 3 patients we identified identical 5-bp deletions by conventional methods. This prompted the design of mutation-specific polymerase chain reaction (PCR) primers, which were used to demonstrate the presence of the same mutation in an additional 12 patients, identifying this as a mutational hot spot in the PIG-A gene. Multiple PIG-A mutations have been reported in 10% to 20% of PNH patients. Our results suggest that the large majority of AA/PNH patients have multiple mutations. These data may suggest a process of hypermutation in the PIG-A gene in AA stem

The energy trilemma forms the key driver for the future of energy research. In nuclear technologies, molten salt reactors are an upcoming option which offers new approaches. However, the key would be closed fuel cycle operation which requires sufficient breeding for a self-sustained long term operation ideally based on spent fuel. To achieve these attractive goals two challenges have been identified: achieving of sufficient breeding and development of a demand driven salt clean up system. The aim is to follow up on previous work to create an initial approach to achieving sufficient breeding. Firstly, identification of a salt system with a high solubility for fertile material and sufficiently low melting point. Secondly, evaluation of the sensitivity of the breeding performance on the sort of fissile material, the fissile material loading, and the core dimension all based on a realistic salt system which provides the solubility for sufficient fertile material to achieve the required breeding in a homogeneous reactor without breeding blanket. Both points are essential to create an innovative solution to harvest the fruits of a closed fuel cycle without the penalty of the prohibitively huge investments. It is demonstrated that the identified and investigated NaCl-UCl based systems are feasible to deliver the requested in-core breeding within the given solubility limits of fertile material in the salt system using either uranium as start-up fissile component or plutonium. This result is enriched by the analysis of the achievable full power days per inserted mass of plutonium. These new insights support reactor optimization and lead to a first conclusion that systems with lower power density could be very attractive in the case of low fuel cost, like it would be given when operating on spent nuclear fuel.