History of hadron therapy accelerators

In the last 60 years, hadron therapy has made great advances passing from a stage of pure research to a well-established treatment modality for solid tumours. In this paper the history of hadron therapy accelerators is reviewed, starting from the first cyclotrons used in the thirties for neutron therapy and passing to more modern and flexible machines used nowadays. The technical developments have been accompanied by clinical studies that allowed the selection of the tumours which are more sensitive to this type of radiotherapy. This paper aims at giving a review of the origin and the present status of hadron therapy accelerators, describing the technological basis and the continuous development of this application to medicine of instruments developed for fundamental science. At the end the present challenges are reviewed.     

Obesity in Older Adults: Technical Review and Position Statement of the American Society for Nutrition and NAASO,The Obesity Society

Obesity causes serious medical complications and impairs quality of life. Moreover, in older persons, obesity can exacerbate the age‐related decline in physical function and lead to frailty. However, appropriate treatment for obesity in older persons is controversial because of the reduction in relative health risks associated with increasing body mass index and the concern that weight loss could have potential harmful effects in the older population. This joint position statement from the American Society for Nutrition and NAASO, The Obesity Society reviews the clinical issues related to obesity in older persons and provides health professionals with appropriate weight‐management guidelines for obese older patients. The current data show that weight‐loss therapy improves physical function, quality of life, and the medical complications associated with obesity in older persons. Therefore, weight‐loss therapy that minimizes muscle and bone losses is recommended for older persons who are obese and who have functional impairments or medical complications that can benefit from weight loss.     

Distribution and microhabitats of native and non-native gammarids (Amphipoda, Crustacea) in Brittany, with particular reference to the endangered endemic sub-species Gammarus duebeni celticus

Aim  To assess temporal changes in gammarid distribution in Brittany and microhabitat-use overlap between the endangered endemic Gammarus duebeni celticus Stock & Pinkster, 1970 , the expanding natives G. pulex (Linnaeus, 1758) and Echinogammarus berilloni (Catta, 1878), and the introduced G. tigrinus Sexton, 1939.
Location  Brittany and adjacent regions in western France.
Methods  The spatial and temporal patterns in distribution of gammarids at the scale of Brittany were studied using 351 sites. Longitudinal distributions (from the source to the estuary of the river) and microhabitat-use (substratum type and water velocity) were also considered in selected rivers.
Results  At the regional scale, all species occurred together less often than expected statistically, with significant deviations from expected for G. pulex vs. both G. duebeni celticus and G. tigrinus , and for E. berilloni vs. both G. duebeni celticus and G. tigrinus . However, at the microhabitat scale, E. berilloni occurred significantly more often than expected with the endemic G. duebeni celticus , and this appears to be due to similar substratum and water velocity preferences, although at both the regional and microhabitat scales E. berilloni prefers wider streams than G. duebeni celticus . This study reveals a decline in the endangered G. duebeni celticus since 1970.
Main conclusions  The longitudinal and local distributions of G. duebeni celticus , and the higher-than-expected co-occurrence of the species with G. pulex , suggest that the decline of the endemic species may be due to changes in the environment and/or interference from native G. pulex , which is expanding its range in Brittany. The results are discussed as regards to the consequences for regional biodiversity.     

Cotransformation of Aspergillus nidulans: a tool for replacing fungal genes

Summary When a non-selected DNA sequence was added during the transformation of amdS320 deletion strains of Aspergillus nidulans with a vector containing the wild-type amdS gene the AmdS⁺ transformants were cotransformed at a high frequency. Cotransformation of an amdS320, trpC801 double mutant strain showed that both the molar ratio of the two vectors and the concentration of the cotransforming vector affected the cotransformation frequency. The maximum frequency obtained was defined by the gene chosen as selection marker for transformation. Cotransformation was used to induce a gene replacement in A. nidulans. An amdS320 strain was transformed to AmdS⁺ and cotransformed with a DNA fragment containing a fusion between a non-functional A. nidulans trpC gene and the Escherichia coli lacZ gene. Ten AmdS⁺, LacZ⁺ transformants with a Trp^– mutant phenotype were selected. All of these strains could be transformed with a functional copy of the A. nidulans trpC gene, but only two strains yielded TrpC⁺ transformants which, with a low frequency, had a LacZ^– phenotype. These latter transformants had also lost the AmdS⁺ phenotype. Southern blotting analysis of DNA from these transformants confirmed the inactivation of the wild-type trpC gene, but revealed that amdS vector sequences were also involved in the gene replacement events.     

Maggot therapy: a review of the therapeutic applications of fly larvae in human medicine, especially for treating osteomyelitis

In traditional medical practice, the larvae of some Diptera: Calliphoridae, notably Lucilia illustris (Meigen), L.sericata (Meigen) and Phormia regina (Meigen), have been employed for maggot therapy, i.e. to help clean lesions antiseptically, especially for treatment of chronic osteomyelitis. This mode of treatment remains appropriate for cases where antibiotics are ineffective and surgery impracticable.     

One-step gene disruption by cotransformation to isolate double auxotrophs in Candida albicans

Summary The Candida albicans LEU2 gene was disrupted by substituting lambda DNA for a small deletion within the LEU2 gene. Cotransformation with a selectable URA3 ARS vector was used to introduce a linear fragment containing the disruption into the genome of a C. albicans ura3 deletion mutant. Cotransformants containing the lambda DNA were identified by colony hybridization and the URA3 plasmid was subsequently cured. Leu2 disrupted heterozygotes were detected by Southern hybridization and one disruptant was subsequently treated with UV irradiation. Only one leu2 ura3 mutant (SGY-484) was isolated out of 11,000 mutagenized cells. SGY-484 was transformed to Leu⁺ with either the C. albicans or Saccharomyces cerevisiae LEU2 gene. Southern hybridization analysis revealed that the mutant is not homozygous for the disruption; the leu2 mutation reverts and is most likely a point mutation. Unexpectedly, an ade2 ura3 mutant was isolated from the same mutagenesis.     

Spatial arrangement of tiller replacement in Agropyron desertorum following grazing

Summary The spatial arrangement of tiller replacement was assessed on grazed and ungrazed tussocks of Agropyron desertorum (Fisch. ex Link) Schult. for three annual cycles. Frequency distributions of the number of replacement tillers per single progenitor were also determined. Tiller replacement was usually greater on the perimeter of tussocks than within the core, with or without grazing. Replacement was inversely related to grazing intensity, both on the perimeter and within the core of tussocks. Heights of replacement tillers on the perimeter or within the core seldom differed. Furthermore, grazing seldom affected the number of replacement tillers per progenitor. Greater tillering on the perimeter than within the core indicates that the tussocks were expanding. Apparently, grazing neither enhances tussock expansion and subsequent disintegration, nor does it necessarily lead to patches of tillers (multiple tillering per progenitor) within tussocks of A. desertorum.     

Three-dimensional structure of the quinoprotein methylamine dehydrogenase from Paracoccus denitrificans determined by molecular replacement at 2.8 A resolution.

The three-dimensional structure of the quinoprotein methylamine dehydrogenase from Paracoccus dentrificans (PD-MADH) has been determined at 2.8 A resolution by the molecular replacement method combined with map averaging procedures, using data collected from an area detector. The structure of methylamine dehydrogenase from Thio-bacillus versutus, which contains an "X-ray" sequence, was used as the starting search model. MADH consists of 2 heavy (H) and 2 light (L) subunits related by a molecular 2-fold axis. The H subunit is folded into seven four-stranded beta segments, forming a disk-shaped structure, arranged with pseudo-7-fold symmetry. A 31-residue elongated tail exists at the N-terminus of the H subunit in MADH from T. versutus but is partially digested in this crystal form of MADH from P. denitrificans, leaving the H subunit about 18 residues shorter. Each L subunit contains 127 residues arranged into 10 beta-strands connected by turns. The active site of the enzyme is located in the L subunit and is accessible via a hydrophobic channel between the H and L subunits. The redox cofactor of MADH, tryptophan tryptophylquinone is highly unusual. It is formed from two covalently linked tryptophan side chains at positions 57 and 107 of the L subunit, one of which contains an orthoquinone.     

Redox cycling of potential antitumor aziridinyl quinones

The formation of reactive oxygen intermediates (ROI) during redox cycling of newly synthesized potential antitumor 2,5-bis (1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied by assaying the production of ROI (superoxide, hydroxyl radical, and hydrogen peroxide) by xanthine oxidase in the presence of BABQ derivatives. At low concentrations (< 10 microM) some BABQ derivatives turned out to inhibit the production of superoxide and hydroxyl radicals by xanthine oxidase, while the effect on the xanthine-oxidase-induced production of hydrogen peroxide was much less pronounced. Induction of DNA strand breaks by reactive oxygen species generated by xanthine oxidase was also inhibited by BABQ derivatives. The DNA damage was comparable to the amount of hydroxyl radicals produced. The inhibiting effect on hydroxyl radical production can be explained as a consequence of the lowered level of superoxide, which disrupts the Haber-Weiss reaction sequence. The inhibitory effect of BABQ derivatives on superoxide formation correlated with their one-electron reduction potentials: BABQ derivatives with a high reduction potential scavenge superoxide anion radicals produced by xanthine oxidase, leading to reduced BABQ species and production of hydrogen peroxide from reoxidation of reduced BABQ. This study, using a unique series of BABQ derivatives with an extended range of reduction potentials, demonstrates that the formation of superoxide and hydroxyl radicals by bioreductively activated antitumor quinones can in principle be uncoupled from alkylating activity.     

C1 metabolism inParacoccus denitrificans: Genetics ofParacoccus denitrificans

Paracoccus denitrificans is able to grow on the C₁ compounds methanol and methylamine. These compounds are oxidized to formaldehyde which is subsequently oxidized via formate to carbon dioxide. Biomass is produced by carbon dioxide fixation via the ribulose biphosphate pathway. The first oxidation reaction is catalyzed by the enzymes methanol dehydrogenase and methylamine dehydrogenase, respectively. Both enzymes contain two different subunits in an ₂₂ configuration. The genes encoding the subunits of methanol dehydrogenase (moxF andmoxI) have been isolated and sequenced. They are located in one operon together with two other genes (moxJ andmoxG) in the gene ordermoxFJGI. The function of themoxJ gene product is not yet known.MoxG codes for a cytochromec _551i , which functions as the electron acceptor of methanol dehydrogenase. Both methanol dehydrogenase and methylamine dehydrogenase contain PQQ as a cofactor. These so-called quinoproteins are able to catalyze redox reactions by one-electron steps. The reaction mechanism of this oxidation will be described. Electrons from the oxidation reaction are donated to the electron transport chain at the level of cytochromec. P. denitrificans is able to synthesize at least 10 differentc-type cytochromes. Five could be detected in the periplasm and five have been found in the cytoplasmic membrane. The membrane-bound cytochromec ₁ and cytochromec ₅₅₂ and the periplasmic-located cytochromec ₅₅₀ are present under all tested growth conditions. The cytochromesc _551i andc _553i , present in the periplasm, are only induced in cells grown on methanol, methylamine, or choline. The otherc-type cytochromes are mainly detected either under oxygen limited conditions or under anaerobic conditions with nitrate as electron acceptor or under both conditions. An overview including the induction pattern of allP. denitrificans c-type cytochromes will be given. The genes encoding cytochromec ₁, cytochromec ₅₅₀, cytochromec _551i , and cytochromec _553i have been isolated and sequenced. By using site-directed mutagenesis these genes were mutated in the genome. The mutants thus obtained were used to study electron transport during growth on C₁ compounds. This electron transport has also been studied by determining electron transfer rates inin vitro experiments. The exact pathways, however, are not yet fully understood. Electrons from methanol dehydrogenase are donated to cytochromec _551i . Further electron transport is either via cytochromec ₅₅₀ or cytochromec _553i to cytochromeaa ₃. However, direct electron transport from cytochromec _551i to the terminal oxidase might be possible as well. Electrons from methylamine dehydrogenase are donated to amicyanin and then via cytochromec ₅₅₀ to cytochromeaa ₃, but other routes are used also.P. denitrificans is studied by several groups by using a genetic approach. Several genes have already been cloned and sequenced and a lot of mutants have been isolated. The development of a host/vector system and several techniques for mutation induction that are used inP. denitrificans genetics will be described.