308 research outputs found
A One Health approach to tackle tick-borne diseases - analysis of surveillance initiatives in selected EU countries: The Netherlands, Spain and Italy
Vesiculation in magmas from Stromboli and implications for normal Strombolian activity and paroxysmal explosions in basaltic systems
We performed a series of X-ray tomographic experiments and lattice Boltzmann
permeability simulations on pyroclastic products from explosive activity at Stromboli
between December 2004 and May 2006. We reconstructed the 3-D textures of vesicles to
investigate the relationship between the nature of vesiculation in the erupted products and
the dynamics of gas transport in the shallow conduit in order to derive implications for
the eruptive behaviour of basaltic volcanoes. Scoriae from normal Strombolian
explosions display remarkably consistent vesicle volume distributions fit by power-laws
with an exponent of 1 (±0.2). We ascribe the origin of such distributions to the combined
effect of coalescence and continuous nucleation events in the steady-state, shallow
magma system that supplies normal Strombolian activity. Volume distributions and
textures of vesicles in pumice clasts from the 5 April 2003 and 15 March 2007
paroxysmal activity are markedly different from those in the scoriae. Besides a powerlaw
function with a higher exponent, portions of these distributions can be also fit by an
exponential function, suggesting the attempt of the system to reach near-equilibrium
conditions. The investigated pumice clasts also lack the large, connecting vesicles
responsible for the development of degassing pathways in the Stromboli magma that
erupts the scoriae. This testifies to a decreased degassing efficiency of the magma
associated with paroxysmal explosions and potential overpressure build-up at depth. By
comparison with degassing experiments on basaltic melts, we derive a time constraint on
the order of minutes to hours for the incubation of paroxysms at Stromboli
Catalysis of proline isomerization and molecular chaperone activity in a tug-of-war
Catalysis of cis/trans isomerization of prolines is important for the activity and misfolding of intrinsically disordered proteins. Catalysis is achieved by peptidylprolyl isomerases, a superfamily of molecular chaperones. Here, we provide atomic insight into a tug-of-war between cis/trans isomerization and molecular chaperone activity. Catalysis of proline isomerization by cyclophilin A lowers the energy barrier for \u3b1-synuclein misfolding, while isomerase-binding to a separate, disease-associated protein region opposes aggregation. We further show that cis/trans isomerization outpowers the holding activity of cyclophilin A. Removal of the proline isomerization barrier through posttranslational truncation of \u3b1-synuclein reverses the action of the proline isomerase and turns it into a potent molecular chaperone that inhibits protein misfolding. The data reveal a conserved mechanism of dual functionality in cis/trans isomerases and define its molecular determinants acting on intrinsically disordered proteins
Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease: effect of N-acetyl transferase polymorphisms
AIM:
To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate (5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase (NAT) 1 and 2.
METHODS:
Concentrations of thioguanine nucleotides (TGN) and methymercaptopurine nucleotides (MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients (3 females and 9 males, median age 16 years) with inflammatory bowel disease (6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines (7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase (ITPA) and thiopurine methyl transferase (TPMT) genes was performed using PCR assays.
RESULTS:
Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes (range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations (absolute mean reduction 109 pmol/8
7 108 erythrocytes) was observed (median 221 pmol/8
7 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration (P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study.
CONCLUSION:
NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study
Gleam: the GLAST Large Area Telescope Simulation Framework
This paper presents the simulation of the GLAST high energy gamma-ray
telescope. The simulation package, written in C++, is based on the Geant4
toolkit, and it is integrated into a general framework used to process events.
A detailed simulation of the electronic signals inside Silicon detectors has
been provided and it is used for the particle tracking, which is handled by a
dedicated software. A unique repository for the geometrical description of the
detector has been realized using the XML language and a C++ library to access
this information has been designed and implemented.Comment: 10 pages, Late
Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn's disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics
PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients
European Council of Legal Medicine (ECLM) on-site inspection forms for forensic pathology, anthropology, odontology, genetics, entomology and toxicology for forensic and medico-legal scene and corpse investigation: the Parma form
Further to a previous publication by the European Council of Legal Medicine (ECLM) concerning on-site forensic and
medico-legal scene and corpse investigation, this publication provides guidance for forensic medical specialists, pathologists
and, where present, coroners’ activity at a scene of death inspection and to harmonize the procedures for a correct search,
detection, collection, sampling and storage of all elements which may be useful as evidence, and ensure documentation of
all these steps. This ECLM’s inspection form provides a checklist to be used on-site for the investigation of a corpse present
at a crime or suspicious death scene. It permits the collection of all relevant data not only for the pathologist, but also for
forensic anthropologists, odontologists, geneticists, entomologists and toxicologists, thus supporting a collaborative work
approach. Detailed instructions for the completion of forms are provided
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