«Red flags» en pacientes con polineuropatía amiloidótica familiar relacionada con transtiretina (hATTR) en el momento del diagnóstico en un área no endémica de España / Red flags in patients with hereditary transthyretin amyloidosis at diagnosis in a non-endemic area of Spain

Introducción: La polineuropatía relacionada con el depósito de amiloide por transtiretina (hATTR, por sus siglas en inglés) es una enfermedad poco común, multisistémica, de inicio en la edad adulta con un pronóstico ominoso sin tratamiento. Para reconocer la enfermedad en la etapa más temprana posible, se ha propuesto un grupo de signos y síntomas, comúnmente conocidos como «red flags», y su presencia puede indicar la presencia de una hATTR subyacente en pacientes con polineuropatía sensitivo-motora progresiva.Materiales y métodosSe analizó la frecuencia de «red flags» en el momento del diagnóstico en 30 pacientes con hATTR de un área no endémica de España, con una mayoría de pacientes de inicio tardío.ResultadosLas frecuencias de «red flags» fueron las siguientes: síndrome del túnel carpiano bilateral 15/30 (50%); disautonomía temprana en 17/30 (56%); síntomas gastrointestinales en 14/30 (46,6%); pérdida inexplicable de peso en 8/30 (26,6%); enfermedad cardiaca en 12/30 (40%); hallazgos cardiacos asintomáticos en 13/30 (43,3%); enfermedad renal en 1/30 (3,3%); opacidades vítreas en 0/30 (0%); neuropatía familiar en 21/30 (70%); cardiopatía familiar en 15/30 (50%) y antecedentes familiares gastrointestinales en 3/30 (10%). Todos los pacientes presentaron al menos una «red flag» en el momento del diagnóstico, con una mediana de 4 «red flags».ConclusiónLas «red flags», incluso en los pacientes de inicio tardío, fueron hallazgos comunes en el momento del diagnóstico y su presencia en un paciente con polineuropatía sensitivo-motora simétrica debería alertarnos y conducir el diagnóstico a lo largo de la hATTR hasta excluirlo, independientemente de la edad de inicio o de la región endémica. (AU)

Introduction: Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as “red flags,” have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy.Material and methodsWe analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients.ResultsThe frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags.ConclusionRed flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset. (AU)

Red flags in patients with hereditary transthyretin amyloidosis at diagnosis in a non-endemic area of Spain.

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as "red flags," have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy. MATERIAL AND METHODS: We analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients. RESULTS: The frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags. CONCLUSION: Red flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset.

Red flags in patients with hereditary transthyretin amyloidosis at diagnosis in a non-endemic area of Spain. / «Red flags¼ en pacientes con polineuropatía amiloidótica familiar relacionada con transtiretina (hATTR) en el momento del diagnóstico en un área no endémica de España.

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as "red flags," have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy. MATERIAL AND METHODS: We analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients. RESULTS: The frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags. CONCLUSION: Red flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset.

TWO NEW SINGLE-EXPOSURE, MULTI-DETECTOR NEUTRON SPECTROMETERS FOR RADIATION PROTECTION APPLICATIONS IN WORKPLACE MONITORING.

This communication describes two new instruments, based on multiple active thermal neutron detectors arranged within a single moderator, that permit to unfold the neutron spectrum (from thermal to hundreds of MeV) and to determine the corresponding integral quantities with only one exposure. This makes them especially advantageous for neutron field characterisation and workplace monitoring in neutron-producing facilities. One of the devices has spherical geometry and nearly isotropic response, the other one has cylindrical symmetry and it is only sensitive to neutrons incident along the cylinder axis. In both cases, active detectors have been specifically developed looking for the criteria of miniaturisation, high sensitivity, linear response and good photon rejection. The calculated response matrix has been validated by experimental irradiations in neutron reference fields with a global uncertainty of 3%. The measurements performed in realistic neutron fields permitted to determine the neutron spectra and the integral quantities, in particular H*(10).

A SINGLE-EXPOSURE, MULTIDETECTOR NEUTRON SPECTROMETER FOR WORKPLACE MONITORING.

This communication describes a recently developed single-exposure neutron spectrometer, based on multiple active thermal neutron detectors located within a moderating sphere, which have been developed jointly by CIEMAT (Spain), INFN (Italy) and Politecnico di Milano (Italy) in the framework of Italian and Spanish collaboration projects. The fabricated prototypes permit to achieve spectrometric resolution with nearly isotropic response for neutron with energies from thermal to 100-200 MeV, thus being able to characterise the complete neutron spectrum in only one exposure by unfolding the measured responses of the detectors. This makes it especially advantageous for characterising neutron fields and workplace monitoring purposes in neutron-producing facilities.

NUMERICAL ASSESSMENT OF 131I DEPOSITED IN THYROID FOR NON-STANDARD SITUATIONS.

At the CIEMAT whole-body counter, a low-energy germanium detector is used for the in vivo assessment of (131)I activity in thyroid, mainly for the individual monitoring programmes of workers. The detector is calibrated with a cylindrical neck phantom made of polymethyl methacrylate that mimics the neck of an adult, containing a vial with a radioactive solution. For an accurate activity assessment, it is necessary to perform the calibration of the detector with phantoms that closely reproduce the anatomy of a real person. Nevertheless, it is not affordable to count on a variety of physical phantoms covering the different anatomical characteristics that could be found over the whole population, including children. An alternative approach to face this situation is offered by the numerical calibration procedure based on Monte Carlo calculations in conjunction with realistic voxel phantoms. A series of computational voxel phantoms of different ages and dimensions have been used in this work to simulate an internal contamination of the thyroid and to estimate the response of the detector for measurements involving individuals whose anatomical characteristics differ from the reference adult man.

Internal dosimetry: towards harmonisation and coordination of research.

The CONRAD Project is a Coordinated Network for Radiation Dosimetry funded by the European Commission 6th Framework Programme. The activities developed within CONRAD Work Package 5 ('Coordination of Research on Internal Dosimetry') have contributed to improve the harmonisation and reliability in the assessment of internal doses. The tasks carried out included a study of uncertainties and the refinement of the IDEAS Guidelines associated with the evaluation of doses after intakes of radionuclides. The implementation and quality assurance of new biokinetic models for dose assessment and the first attempt to develop a generic dosimetric model for DTPA therapy are important WP5 achievements. Applications of voxel phantoms and Monte Carlo simulations for the assessment of intakes from in vivo measurements were also considered. A Nuclear Emergency Monitoring Network (EUREMON) has been established for the interpretation of monitoring data after accidental or deliberate releases of radionuclides. Finally, WP5 group has worked on the update of the existing IDEAS bibliographic, internal contamination and case evaluation databases. A summary of CONRAD WP5 objectives and results is presented here.

Analysis of a computational problem involving complex voxel geometries.

This communication briefly summarises the results obtained from the 'International comparison on MC modeling for in vivo measurement of Americium in a knee phantom' organised within the EU Coordination Action CONRAD (Coordinated Network for Radiation Dosimetry) as a joint initiative of EURADOS working groups 6 (computational dosimetry) and 7 (internal dosimetry). Monte Carlo simulations using the knee voxel phantom proved to be a viable approach to provide the calibration factor needed for in vivo measurements.

Application of the Spanish methodological approach for biosphere assessment to a generic high-level waste disposal site.

A methodological approach which includes conceptual developments, methodological aspects and software tools have been developed in the Spanish context, based on the BIOMASS "Reference Biospheres Methodology". The biosphere assessments have to be undertaken with the aim of demonstrating compliance with principles and regulations established to limit the possible radiological impact of radioactive waste disposals on human health and on the environment, and to ensure that future generations will not be exposed to higher radiation levels than those that would be acceptable today. The biosphere in the context of high-level waste disposal is defined as the collection of various radionuclide transfer pathways that may result in releases into the surface environment, transport within and between the biosphere receptors, exposure of humans and biota, and the doses/risks associated with such exposures. The assessments need to take into account the complexity of the biosphere, the nature of the radionuclides released and the long timescales considered. It is also necessary to make assumptions related to the habits and lifestyle of the exposed population, human activities in the long term and possible modifications of the biosphere. A summary on the Spanish methodological approach for biosphere assessment are presented here as well as its application in a Spanish generic case study. A reference scenario has been developed based on current conditions at a site located in Central-West Spain, to indicate the potential impact to the actual population. In addition, environmental change has been considered qualitatively through the use of interaction matrices and transition diagrams. Unit source terms of (36)Cl, (79)Se, (99)Tc, (129)I, (135)Cs, (226)Ra, (231)Pa, (238)U, (237)Np and (239)Pu have been taken. Two exposure groups of infants and adults have been chosen for dose calculations. Results are presented and their robustness is evaluated through the use of uncertainty and sensitivity analyses.

Assessment of the internal dose of 241Am in bone by in vivo measurements of activity deposited in knee.

In case of chronic exposure or long time after an acute intake of (241)Am as a consequence of an incident, the assessment of internal dose might be realised by estimating the total activity content of this element in the skeleton. For this purpose, a new methodology has been developed at the Whole Body Counting Laboratory of CIEMAT. In vivo measurements of this bone-seeker radionuclide in the knee are performed using four low energy germanium detectors inside a shielded room. The sensitivity study of this technique resulted in a minimum detectable activity of 7 Bq, for a counting time of 1800 s. Extrapolation to the total activity in the bone has been carried out by taking into account that the bone content of the knee calibration phantom is equivalent to 10.7% of the whole skeleton mass. The results of in vivo measurements of population and the procedure for internal dose evaluation are presented here.

Monte Carlo modelling for in vivo measurements of Americium in a knee voxel phantom: general criteria for an international comparison.

The general criteria and the scientific approach adopted for an 'International comparison on Monte Carlo modelling for in vivo measurement of Americium in a knee phantom' that is being organised within the EU Coordination Action CONRAD (Coordinated Network for Radiation Dosimetry) are described her. Detection system and a knee voxel phantom based on a computerised axial tomography of the Spitz anthropometric knee phantom with a homogeneous distribution of 241Am in bone have been considered for the simulation of three specific situations: (a) a single Low Energy Germanium detector for a point 241Am source in air; (b) the calculation of photon fluence spectra in air around the voxel phantom; and (c) the calculation of the energy distribution of pulses and peak detection efficiency in the real detection system geometry.

Coordination of research on internal dosimetry in Europe: the CONRAD project.

The EUropean RAdiation DOSimetry Group (EURADOS) initiated in 2005 the CONRAD Project, a Coordinated Network for Radiation Dosimetry funded by the European Commission (EC), within the 6th Framework Programme (FP). The main purpose of CONRAD is to generate a European Network in the field of Radiation Dosimetry and to promote both research activities and dissemination of knowledge. The objective of CONRAD Work Package 5 (WP5) is the coordination of research on assessment and evaluation of internal exposures. Nineteen institutes from 14 countries participate in this action. Some of the activities to be developed are continuations of former European projects supported by the EC in the 5th FP (OMINEX and IDEAS). Other tasks are linked with ICRP activities, and there are new actions never considered before. A collaboration is established with CONRAD Work Package 4, dealing with Computational Dosimetry, to organise an intercomparison on Monte Carlo modelling for in vivo measurements of (241)Am deposited in a knee phantom. Preliminary results associated with CONRAD WP5 tasks are presented here.

Spanish methodological approach for biosphere assessment of radioactive waste disposal.

The development of radioactive waste disposal facilities requires implementation of measures that will afford protection of human health and the environment over a specific temporal frame that depends on the characteristics of the wastes. The repository design is based on a multi-barrier system: (i) the near-field or engineered barrier, (ii) far-field or geological barrier and (iii) the biosphere system. Here, the focus is on the analysis of this last system, the biosphere. A description is provided of conceptual developments, methodological aspects and software tools used to develop the Biosphere Assessment Methodology in the context of high-level waste (HLW) disposal facilities in Spain. This methodology is based on the BIOMASS "Reference Biospheres Methodology" and provides a logical and systematic approach with supplementary documentation that helps to support the decisions necessary for model development. It follows a five-stage approach, such that a coherent biosphere system description and the corresponding conceptual, mathematical and numerical models can be built. A discussion on the improvements implemented through application of the methodology to case studies in international and national projects is included. Some facets of this methodological approach still require further consideration, principally an enhanced integration of climatology, geography and ecology into models considering evolution of the environment, some aspects of the interface between the geosphere and biosphere, and an accurate quantification of environmental change processes and rates.

A specific voxel phantom for in vivo measurements of 241Am in the knee.

Calibration phantoms for in vivo measurements of low-energy photons should be anatomically realistic to minimise the uncertainties in the activity assessment. The calibration of the detection system can be performed using computational techniques based on numerical phantoms. The purpose of this work is to approach a numerical calibration by Monte Carlo (MC) technique of a Germanium detection system for the determination of 241Am in the knee. A specific voxel phantom was built from a computerised tomography of the calibration Spitz knee phantom. The phantom and the procedure to generate the associated input file for the MC code, namely MCNPX, have been described, as well as the characterisation of the detectors according to the manufacturer data and the energy calibration curves of the spectrometer. The detection efficiency and the pulse-height distribution have been determined for a homogeneous contamination of 241Am in bone.

Monte Carlo based voxel phantoms for in vivo internal dosimetry.

The purpose of this communication is to describe briefly the computer programs developed to generate the MCNP input file corresponding to any segmented tomographic data and its application to the calibration procedures for in vivo internal dosimetry. The method has been applied to the determination of 241Am in bone by measurement in skull and knee using MCNP voxel models of a real human head and knee based on the tomographic Voxelman and Arms Down phantoms developed by Zubal et al. at Yale University.

[Arteriosclerosis obliterans and ozone therapy. Its administration by different routes]. / Ateroesclerosis obliterante y ozonoterapia. Administración por diferentes vías.

We report 72 non-diabetic patients with obliterant atherosclerosis, stadium II, (intermittent claudication). The medium age of these patients was 62 +/- 4.5 years old. They were randomly included into four groups. Three were treated with Ozone: one of them by endovenous way, other intramuscular way, and the last one by rectal way; meanwhile, in the fourth group the patients were submitted to conventional medical treatment (control group). In the three ozone-groups there weren't differences when they were compared between then. But there was a significant improvement in comparison with the control group. The claudication distance in the treadmill increased to the 2.5 km/hour. Ankle/arm pressure rates hadn't significant differences, this corroborates the ozone action on the microcirculation. The least uncomfortable, the more harmless and the more economic way was the rectal way.

[Ozone therapy in the advanced stages of arteriosclerosis obliterans]. / La ozonoterapia en los estadíos avanzados de la aterosclerosis obliterante.

Fifteen patients with atherosclerosis obliterans at the lower limbs, no candidates to revascularizing surgery were submitted to ozone therapy. An improvement statistically significant was noticed in the treatment groups since amputation ratio decreased (26.7%) and the need of pain's surgery procedures (13.3%) in comparison with the control group (46.7 and 26.7% respectively). Ozone therapy is considered as a good way in the management of the atherosclerosis with obliteration in late period.