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• Population-based disease registries are key instruments for rare diseases (RD) research.

To assess the differences in the cost-effectiveness of oral triptan therapy for migraines among European countries. A cost-effectiveness analysis of triptan therapy for migraine was conducted from a health-care payer perspective in four European countries (France, Italy, Spain and the UK). The study included those orally administered triptans available in all of these countries (almotriptan, brand-name sumatriptan, generic sumatriptan, zolmitriptan), and it was performed using a decision-tree model that incorporated costs of the drugs and probabilities associated with the possible events and outcomes. Average cost-effectiveness ratios were calculated in two different scenarios. The average cost-effectiveness ratio showed wide variations across the different countries, these differences being up to 131 % (almotriptan), 77 % (brand-name sumatriptan), 153 % (generic sumatriptan) and 77 % (zolmitriptan). Generic sumatriptan was the most cost-effective drug analysed in the studied countries. Caution must be taken when trying to transfer conclusions of pharmacoeconomics studies on migraines even in neighbouring countries. This cross-country variability is a concern for decision-makers and also for the elaboration of international recommendations and clinical practice guidelines.

a Departamento de Dermatologia, Hospital Infantil del Nino Jesus, Madrid, Spain b Departamento de Dermatologia, Hospital La Paz, Madrid, Spain c Departamento de Dermatologia, Hospital Sant Joan de Deu, Barcelona, Spain d Departamento de Dermatologia, Hospital Santa Creu y Sant Pau, Barcelona, Spain e Director of DeBRA, Spain f Enfermera del Centro de Referencia Estatal de Atencion a personas con Enfermedades Raras y sus familias, Burgos, Spain g Instituto de Investigacion de Enfermedades Raras. Instituto de Salud Carlos III, Madrid, Spain loaded from http://www.actasdermo.org, day 10/05/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Hens MJ, Alonso-Ferreira V, Villaverde-Hueso A, Abaitua I, Posada de la Paz M. Cost-effectiveness analysis of burning mouth syndrome therapy. Community Dent Oral Epidemiol 2012; 40: 185–192. © 2011 John Wiley & Sons A/S Abstract – Objective: To study the cost-effectiveness of four alternative treatments for burning mouth syndrome (BMS). Methods: A cost-effectiveness analysis was conducted from a healthcare payer perspective of four therapy strategies (amisulpride, paroxetine, sertraline and topical clonazepam), using a decision-tree model that incorporated direct healthcare costs and probabilities associated with the possible events and outcomes. Average cost-effectiveness and incremental cost-effectiveness ratios were calculated. Sensitivity analyses included the costs of brand name and generic drugs in five European countries (France, Italy, the Netherlands, Spain and UK), as well as two scenarios with different treatment length. Results: Of the drugs analysed, topical clonazepam proved to be the most cost-effective therapy. Although generic proved more efficient than brand name drugs, they displayed no advantage over brand name topical clonazepam. The Netherlands was the country with the highest overall drug efficiency. Sensitivity analyses highlighted the robustness of the model, because topical clonazepam proved to be the most efficient therapy under all the different scenarios. Conclusions: Topical clonazepam, which previous analyses of clinical evidence have shown to be the drug of choice for BMS, also proved to be the most cost-effective of the drugs analysed for this condition.

Background Patient registries (PRs) are important tools for public-health surveillance and rare-disease research. The purpose of this study is to identify the most important criteria for the creation of a rare-disease PR that could be used by public-health authorities to develop health policies. Methods A consensus-development Delphi study was used, with participants selected for their expertize in rare diseases and registries. Participants were asked to complete a questionnaire on the most important criteria for creating PRs. Three rounds were performed. Results Agreement was reached on half the questions in the first round and on 89% of questions in the final round, with a total expert participation rate of around 60% by the final stage. This study made it possible to reach a broader consensus starting from experts' initial assessment of the features that should be considered for the creation of a rare-disease PR. Conclusion The consensus method used made it possible to define the characteristics of a PR based on expert opinion within a rare-disease framework. This study may serve as a guide for helping other researchers plan and build a rare-disease PR.

Background and Objective: In 1981, toxic oil syndrome (TOS) appeared in Spain, affecting more than 20,000 persons and causing over 2500 deaths to date. Previous studies have addressed mortality only by gender and age. We analyzed possible prognostic factors in the survival of the cohort. Methods: The study period was 1 May 1981 to 31 December 1995 (31 December 1995 was the cut-off date for survivors). The study population consisted of the entire cohort. Overall mortality and TOS-related deaths were studied. Kaplan-Meier method and Cox regression were used in the analyses. Results: Among the 20,084 subjects in the cohort, 12,164 (60.6%) were women, and 7917 (39.4%) were men. Of the 1799 deaths, 958 (53.3%) were women, and 841 (46.71%) were men; of the 356 TOS-related deaths, 234 (65.7%) were women, and 122 (34.3%) were men. TOS was the leading cause of death among subjects

The aim of this study is to describe the childhood vasculitis hospital burden in Spain (1997-2011), considering type of disease, hospitalization rates and time trends. Data were obtained from the National Discharges Basic Minimum Data Set (National Patient Data Base). Inpatient events of children younger than 15 years of age were analyzed. Principal diagnosis of vasculitis were selected according Ninth Revision of the International Classification of Diseases: Takayasu arteritis, Polyarteritis nodosa, Kawasaki disease, Wegener`s granulomatosis, Churg-Strauss syndrome, and Henoch-Schönlein purpura. A total of 14518 children hospitalizations related to vasculitis were identified in Spain from 1997 to 2011. The average hospitalization rate for children was 13.33±1.71 per 100,000. Henoch-Schönlein purpura and Kawasaki disease were the most common type of vasculitis, hospitalization rates were 11.00 and 3.97 per 100,000 children, respectively. Other vasculitis hospitalizations are much rare in childhood. Average length of stay was 6.04 days and estimated cost per inpatient hospital care was 2,847€. Hospital case fatality rate was 0.05% for overall vasculitis. In conclusion, epidemiological data of childhood vasculitis are useful both to health decision-making and to identify research priorities.

Supplement 7th European Conference on Rare Diseases and Orphan Products (ERCD 2014) Background The development of a national Rare Diseases (RD) registry in Spain was launched in 2012 with the project SpainRDR, supported by the International Rare Diseases Research Consortium (IRDiRC). SpainRDR includes two different strategies: patient registries addressed to patient outcome research and population-based registries addressed to epidemiologic research, health and social planning [1]. The pilot study aims to detect the difficulties of developing the national and population-based RD registry.

Rapeseed oil denatured with aniline was the vehicle of the causal agent of the toxic oil syndrome (TOS) epidemic that occurred in Spain in 1981. Although the precise aetiologic agent remains unknown, researchers established that increasing concentrations of oleyl anilide and other fatty acid anilides were associated with an increased risk for disease. To examine the hypothesis that 5-litre plastic containers of rapeseed oil associated with TOS, and which contained oleyl anilide had a characteristic shape, we measured fatty acid, sterol and fatty acid anilide levels in oil from containers of different shapes. We identified 1673 bottles of oil that had been collected during the Spanish Government's oil exchange programme and linked these bottles to people with TOS as reported in the official government census of patients with TOS. Although rapeseed oil (identified by the presence of brassicasterol) was found in 798 (47.7%) of the 1673 bottles examined, contamination with fatty acid anilide occurred in only 329 (19.6%) of the 1673 bottles and 319 (97%) of the 329 were oil containers of the shape sold by RAELCA, an oil company in Madrid. The first aniline-denatured oil that RAELCA had purchased to be refined specifically for distribution was refined at the ITH refinery of Seville, and this oil has been most directly associated with the epidemic. Previous work has shown that the only toxic oil linked to a specific refinery was that associated with rapeseed oil from the ITH refinery in Seville, and the epidemic began shortly after this oil was delivered to RAELCA for retail sale. On the basis of these findings, we conclude that oil refined by ITH and distributed by RAELCA was the principal, and probably the only, oil responsible for the TOS epidemic. Information about the history and treatment of this oil may yield important clues towards identifying the aetiologic agent of TOS.

The etiologic agent(s) that was responsible for the 1981 toxic oil syndrome [TOS] epidemic in Spain has not been identified. Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry was used for the analysis of oils associated with TOS. Analyses focused on measuring 3-(N-phenylamino)-1,2-propanediol [PAP], the 3-oleyl ester of PAP [MEPAP], and the 1,2-di-oleyl ester of PAP [DEPAP]. DEPAP and MEPAP were found more frequently and at higher concentrations in TOS case-associated oils than in control oils with odds ratios of 13.7 (95% CI 5.0-38) and 21.9 (95% 6.1-78), respectively. Other fatty acid esters of PAP are also likely to be present in the TOS case-associated oils. More significantly, DEPAP and MEPAP were found in aniline-denatured rapeseed oil refined at ITH, the oil refining company with the clearest link to TOS cases, yet these PAP esters were not detected in unrefined aniline-denatured samples of rapeseed oil delivered to ITH. These results show that the esters of PAP were products of the ITH refining process and were not formed spontaneously during storage. PAP esters were not detected in samples of other aniline-denatured rapeseed oils that were refined elsewhere, and which were not associated with illness. These findings provide strong support for the hypothesis that one or more of the fatty acid esters of PAP were the etiologic agents for TOS.

Dystrophic epidermolysis bullosa (DEB) is a rare disease that represents a heavy burden for both the patient and the health care system. There are currently no data on the prevalence of DEB in Spain.To determine the prevalence of DEB in Spain.We used data from 3 incomplete population-based sources (hospital dermatology departments, diagnostic laboratories performing antigenic mapping, genetic testing or both, and the Spanish Association of Epidermolysis Bullosa Patients [DEBRA]) and combined them using the 3-source capture-recapture methodology.We identified 152 living DEB patients. The estimated prevalence of DEB was 6.0 cases per million (95% CI, 4.2-11.8) in adults and 15.3 (95% CI, 10.4-40.8) in children under 18 years of age. The data indicated that 77% of the patients were not being followed up in specialized centers of reference; 65% had not had a genetic diagnosis, and 76% were not members of DEBRA.The prevalence of DEB in Spain is 6.0 patients per million (95% CI, 4.2-11.8), a figure higher than previous estimates in many areas, but similar to those found in other southern Europe countries. The north-south difference may represent real geographic differences in prevalence, but it might be due to the fact that most of the data come from registries with a lower than expected catchment. Many patients are not being followed up in centers of reference, do not have genetic diagnosis, and are not members of patients' associations, suggesting that there is room for considerable improvement in their care.

El principal objetivo de este trabajo es desarrollar y poner al servicios de las administraciones sanitarias y también de los ciudadanos, un informe sobre los centros y unidades asistenciales y de investigación existentes en la Comunidad de Madrid (CM), que pudieran ser de utilidad para la planifi cación de los recursos orientados al control y seguimiento de las personas con enfermedades raras en el ámbito de esta comunidad.

Background: Hereditary ataxias (HA) comprise a group of genetically heterogeneous rare diseases. As important public health problems to be monitored, this study analyses the morbimortality of HA in Spain. Methods: Data were extracted from the national death index (1981-2008), using the International Classification of Diseases (ICD) 9th revision code 334 until 1998, and 10th revision code G11 from 1999 onwards. ICD-9 codes were then selected from the national discharge dataset (1998-2007). Age-adjusted morbidity and mortality rates were obtained by gender and 5-year period. Results: Of the 610 HA deaths from 1981 to 2008, 277 corresponded to Friedreich's ataxia (45.4%) and 333 (54.6%) to other and unspecified ataxias (non-Friedreich group). Both groups showed an increase in mortality trend, which was more pronounced in males from 1985-1989 to 1990-1994. Geographical distribution of mortality revealed higher risk for males, mainly in the north of Spain. A total of 5,341 HA hospitalisations were identified from 1998 to 2007. The average annual age-adjusted hospitalisation rate was 1.19 per 100,000 population, with a rising trend. Conclusion: This increase in morbidity and mortality, coupled with the slight interprovincial differences, indicate that more attention should be paid to these rare diseases by public authorities and society alike.

The toxic oil syndrome (TOS), a multisystemic disease, that occurred in Spain in 1981, was caused by the ingestion of rapessed oil denatured with 2% aniline. Due to the clinical course of the disease, immunophatological mechanisms have been suspected but a direct connection was never demonstrated. To analyse this possibility, we determined several immunological parameters in the sera of patients with TOS and without the disease, using a case-control design: total immunoglobulins, IgG and IgE antibodies against different toxic agents (oleylanilide, aniline, linoleyl-anilide, and 3-phenylaminopropane-1-2-diol), autoantibodies, cytokines (IL-4, IL-6, TNF, GM-CSF) and soluble receptors (sCD23 and sIL-2R). We detected high levels of sIL-2R in TOS patients compared to controls (P < 0.0001). A higher levels of sCD23 and IgE were also found. In addition, the response to oleyl-anilide of peripheral blood lymphocytes from TOS patients was studied and a significant proliferative response in 30% of TOS patients versus 5% controls was observed. Our data support the implication of the immune system in the acute phase of TOS, with a possible activation of T-cells and release of cytokines, that could explain some of the clinical findings in this phase of the disease.

Despite the low prevalence of Rare Diseases (RD), over 30 million EU citizens suffer from these conditions. This paper summarizes some aspects of these life-threatening chronic and debilitating diseases that usually require long term specialist care and costly formal and informal surveillance. Epidemiology does have an important role to play in the field of RD, since it provides appropriate methods and tools for assessing exposures and health outcomes. In this regard, the utility of registries, biobanks and population-based surveillance systems are discussed. The lack of effective diagnoses and treatments in RD patients often underlies their shortened life expectancy and quality of life. Due to the limited number of patients and the scarcity of relevant knowledge and expertise, coordination at European level is probably the best way of pooling the very limited resources available and provides a very high added-value. RD require the combined efforts of health and social care professionals, politicians, managers and researchers to increase the availability of effective disease management tools to improve care and to extend both life expectancy and Health Related Quality of Life.

The aim of this study was to assess the trend of motor neuron disease mortality in Spain from 1990 to 2005, and to ascertain the existence of geographical differences in mortality rates. MND deaths are registered by the National Statistics Institute of Spain – International Classification of Diseases (ICD) codes ICD9 335.2 (1990-1998) and ICD10 G12.2 (1999-2005). Annual sex- and age-specific rates, as well as rates adjusted for the standard European population were obtained. Provincial standardized mortality ratios (SMRs) were calculated for the study period. Respective provincial SMRs were smoothed with data from adjacent provinces using a Poisson model. Results showed that MND mortality increased in Spain from 1990 to 2005. Geographical differences between provinces were evident throughout the study period. In general, risk of death due to MND was higher in regions lying to the north of Spain. In conclusion, the temporal and geographical variability observed might be explained by genetic factors, differences in environmental exposures and the possible influence of the type of medical care and treatment received. Mortality depends also on health service quality and diagnostic validity. All these factors may play a very important role in analysis of MND mortality in Spain, and the contribution of each of these will have to be examined in depth by ad hoc studies.

The toxic oil syndrome (TOS) epidemic that occurred in Spain in spring 1981 has been associated with the consumption of rapeseed oil that was denatured with aniline for industrial use but diverted for human consumption. The precise aetiologic agent in the oil responsible for the outbreak has not been identified. To learn more about possible contaminants and how the contamination might have occurred, we visited two French companies that process rapeseed oil and that were identified in Spanish administrative and judicial records as the ones exporting aniline-denatured rapeseed oil to Spain in 1981. With the apparently full and voluntary co-operation of personnel at both companies, we reviewed the processes involved in manufacturing, treating and transporting rapeseed oil, and we have summarized the information provided to us. Of particular importance is the finding that oil exported to Spain was taken from stock, the rest of which was sold for human consumption in the French domestic market, apparently without any adverse health effects. The differences between the oil exported to Spain and the oil sold as food in France were that aniline equivalent to 2% of the weight of the oil was added to most of the Spanish oil but not to that sold in France, and that contamination of the Spanish oil may have occurred in the tank trucks used for transportation to Spain, which had previously carried industrial chemicals. There is no assurance that the trucks were cleaned appropriately for transporting a food product before the oil was loaded for the journey to Spain. Since the clinical manifestations of TOS are not those of aniline toxicity, we conclude that the aetiological agent of TOS is likely to be one of the following: (1) a contaminant in the aniline, (2) a contaminant introduced during transportation, (3) a reaction product of normal oil components or materials used in refining with either aniline or the potential contaminants mentioned under (1) or (2) above.

[ES] Enfermedad rara es aquella cuya prevalencia es inferior a 5 casos por cada 10.000 personas en la Comunidad Europea. La mayoría de los casos aparecen en la edad pediátrica, dada la alta frecuencia de enfermedades de origen genético y de anomalías congénitas. No obstante, la prevalencia es mayor en los adultos que en los niños, debido a la excesiva mortalidad de algunas enfermedades infantiles graves y a la influencia de ciertas enfermedades que aparecen a edades más tardías. La Red Epidemiológica de Investigación en Enfermedades Raras (REpIER) desarrolló el primer atlas de distribución geográfica de las enfermedades raras en España, evaluó la existencia de registros de enfermedades raras existentes, facilitó el ulterior desarrollo de planes autonómicos y acciones sociosanitarias y planteó un marco de necesidades a desarrollar, que más tarde han llegado a ser reconocidos como necesidades a resolver en el marco del Comunicado de la Comisión Europea sobre Enfermedades Raras y en la propia Ponencia del Senado. [EN] Rare diseases are those whose prevalence is below 5 cases per 10,000 inhabitants in the European Community. Most cases are diagnosed during paediatric age due to their genetic origin, while some others are congenital malformations. Nevertheless, a higher prevalence is seen during adulthood as most of the former diseases are very severe and patients die during childhood. At the same time, higher survival rates are related to some chronic rare diseases in adults. The Spanish Network of Research Epidemiology for Rare Diseases (REpIER) developed the first atlas showing the geographical distribution of rare diseases in Spain, assessed the Spanish rare disease registries, contributed to the further development of regional plans on rare diseases, as well as to social and health actions, and established the real group of needs to be solved. These have been included in the Communication of the European Commission on Rare Diseases as well as in the Spanish Senate Presentation. Sí

SUMMARY The participation of eosinophils in the Spanish toxic oil syndrome (TOS) was investigated. Eosinophil infiltration and degranulation in tissues from 52 patients with the TOS were examined by immunofluorescence staining for the eosinophil granule major basic protein (MBP). Serum MBP levels were determined in sera from 323 patients. Eosinophil infiltration and degranulation were found in several tissues, especially during the acute phase of the TOS, and serum MBP was significantly elevated during all phases of the disease, suggesting that eosinophils play a role in the pathogenesis of the TOS.

[ES] El objetivo de este artículo es dar a conocer las decisiones tomadas por el Comité de Ética del Instituto de Salud Carlos III para el Síndrome del Aceite Tóxico en relación con el desarrollo de proyectos de investigación en los que se podían utilizar muestras recogidas con anterioridad y para cuyo uso no se disponía del consentimiento de los pacientes, sobre una situación muy común en el ámbito de la investigación biomédica. A partir del proceso de debate acerca de la idoneidad ética de la utilización secundaria de estas muestras, se llegó a la conclusión de que en los estudios prospectivos se debe solicitar expresamente y por escrito el consentimiento del participante en el estudio para conservar las muestras y que éstas puedan ser utilizadas en investigaciones futuras, estableciendo con el donante los límites de su utilización. [EN] This Field Note aims to make known the decisions taken by the Ethics Committee of the Instituto de Salud Carlos III for Toxic Oil Syndrome regarding the secondary use of research specimens in biological research when informed consent is lacking. This is a common concern in the field of biomedical research. After debating the ethical suitability of the secondary use of these samples, our main conclusion is that researchers conducting prospective studies should expressly solicit written informed consent from participants in the study about i) whether there will or could be any secondary use of the samples and, if so, ii) whether such secondary use would be conditional on the type of research. Sí

The Spanish Rare Diseases Registries Research Network (SpainRDR) is a project aimed to build the National Rare Diseases Registry in Spain based on the input of two different methods: patient outcome research registries and population-based registries. The project has been approved within the IRDiRC framework and is co-funded by the Institute of Health Carlos III (ISCIII), the Health Departments of the Autonomous Communities (regions) and the Spanish Ministry of Health, Social Services and Equity (MSSSI) of Spain. The project addresses one of the main recommendations of the National Rare Diseases Strategy and also collaborates with some other RD registering actions like GRDR-NIH, RD-CONNECT and EPIRARE. With the unprecedented collaboration and support of medical societies, researcher networks, patient organizations, pharma industry and health policy makers, SpainRDR is running an effective and necessary way to develop knowledge and raise awareness of the rare diseases burden, which will contribute to design the provision of health and social services as well as the improvement of diagnosis, prognosis, treatment and quality life of patients and families affected by RD. The project is leading by the Institute of Rare Diseases research (IIER, ISCIII) and it is organised in six work packages: WP1 Coordination and Management, WP2 Registering activity related methods, WP3 Data analysis and outcomes research, WP4 Quality Assessment and ELSI issues, WP5 Dissemination and impact, and WP6 Patient registries. A Manual of Procedures including a quality assurance plan, common data elements, coding and classifications criteria, standard operating procedures, ELSI rules, statistical analysis methods and the official website network are actions already carried out or being finalized. Specific CDE have been also consolidated for those patient registries already implemented at the central RDR repository (alpha-1 antitrypsin deficiency, pulmonary histiocytosis, lymphangiomyomatosis, alveolar proteinosis, sarcoidosis, thraqueal stenosis, Sexual Developmental Disorders, Bullous Epidermolysis, ataxias and familiar spastic paraparesis). At the same time, some other patient registries' CDE´s are currently being developed, such as Congenital Suprarenal Hyperplasia and Bradykinin linked angioedema. We are preparing also CDEs for cystinosis and congenital anaemia. After the necessary pilot study developed during 2013, we are now collecting prevalence cases from 2012-2012 and the first preliminary results are already available using specific applications designed by SpainRDR.

In spring 1981, the sudden and massive epidemic of the Toxic Oil Syndrome (TOS) struck Spain, mainly in the central and northwestern areas of the country. The majority of cases were diagnosed during May, June and July of that year, with only a few documented at later dates, including one as long as a year after the epidemic outbreak (Posada, 1989). Neither clinically nor pathologically had any such disease been previously recognized, nor had its characteristics been seen in animal models.

Toxic-oil syndrome (TOS), a new disease that occurred in epidemic form in Spain in 1981, has been associated with the ingestion of unlabelled oil bought principally from travelling salesmen. Chemical analysis of oils taken from ill families has shown them to consist of varying proportions of different vegetable oils and animal fats, often showing chemical evidence of prior treatment with aniline. We investigated the unusual circumstances surrounding the reported occurrence of three TOS cases in two families in Sevilla, a city located far away (approximately 300 km) from the group of 14 provinces in central and northwestern Spain where 99% of the TOS cases occurred. Each case we investigated fitted the clinical picture of TOS and was not consistent with any other diagnosis. Illness apparently occurred as a result of ingestion of oil taken from the ITH oil refinery in Sevilla, a plant in which rapeseed and grapeseed oils were refined for the distributing firm through which oil bearing the causative agent of TOS is thought to have entered the market. These data provide further strong support for the hypothesis that food oil was the vehicle by which the aetiological agent of TOS was transmitted. Because ingestion of refined denatured rapeseed oil was most closely associated with the illness in time, the TOS agent was probably contained initially in this type of oil. The agent very probably entered later oil mixtures through such contaminated rapeseed oil.

Excerpt To the editor: In his exhaustive review of the hypercoagulable states (1), Schafer makes no mention of the situation caused by those diseases having increased eosinophil counts, the most ev...

The authors studied the pattern of occurrence of toxic oil syndrome, a previously undescribed disease that occurred in Spain in epidemic form in 1981, in two convents in Madrid. In one convent, the disease affected 66% of 35 novices and nuns who ingested oil from a suspect source, but none of 56 laywomen who ate the same meals but used a different type of oil. In the second convent, in which nuns were also exposed but laywomen were not, 98% of 43 nuns developed toxic oil syndrome compared with none of 70 laywomen. These findings support the hypothesis that a food oil transmitted the etiologic agent of toxic oil syndrome.

Previous reports have implicated 1-phenyl-5-vinyl imidazolidine-2-thione (PVIZT), a cyclic reaction product of aniline and naturally occurring rapeseed oil isothiocyanates, as the potential causative agent of the Spanish toxic oil syndrome (TOS). This report describes the synthesis, preliminary characterization and analysis of that reaction product, which has been identified as N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine (5-VTPA) rather than PVIZT. Oil samples (n = 21) that contained fatty acid anilides and were epidemiologically linked to TOS were analysed for the presence of 5-VTPA by extraction of the oil with methanol and clean-up on an ion-exchange column, followed by capillary gas chromatography mass spectrometry using selected ion detection. A limit of detection of less than 500 ppb was established for these analyses. No 5-VTPA could be detected, however, in any of the TOS oils. As 5-VTPA was shown to be unstable in both heated and unheated food oils, it is possible that the compound had been lost from the oils since the time of the epidemic in 1981. However, no direct evidence for the involvement of 5-VTPA in TOS could be obtained in this study.

To the Editor. —The study by Gilsanz et al 1 on the evolution of 317 patients suffering from toxic oil syndrome (TOS) includes a number of data on which we would like to comment. First, we are surprised by the low incidence of eosinophilia (40%) in relation to other series, 2 which even reached 98%. In 1,500 patients followed up by us, eosinophilia appeared in 86.4% of the patients. Similarly, we noticed the lack of data on hepatopathy. In our series, during the first six months, 20.1% of the patients had hepatopathy, after one year 21.5%, and after two years 19%. The clinical data demonstrate cytolytic, cholestatic, and mixed patterns. This affection corresponds to histologic alterations, 3 with inflammatory, degenerative, and microscopic cholestatic changes. The incidence of mitral prolapse in the series referred to by Gilsanz et al was 21% (4/19) and not 31% which, because of the small number

The symptoms of toxic oil syndrome (TOS), an epidemic that occurred in central and north-western Spain, developed in the great majority of patients during May or June 1981. We now describe the clinical and epidemiological data of five patients with TOS whose onset of symptoms was considerably later than the great majority of cases. In June 1982, one person became symptomatic as a result of consuming a suspect oil two months earlier. Four members of a family that started consuming a suspect oil in November 1981 became ill in December 1981. These data indicate that the aetiological agent of TOS persisted in stored oil for periods as long as one year. The apparent stability of the TOS aetiological agent increases the likelihood of its continued presence in significant concentrations in oils that have been stored since 1981. Thus, the use of such oils in further in vivo and in vitro toxicological studies may yet lead to the isolation and identification of the causal agent of TOS.

Two patients with hereditary, clinical, electromyographical and histological data typical of myotonic dystrophy are discussed. In both there was a thyroid disorder. The first patient had primary hypothyroidism, and the second a non-toxic multinodular goiter which necessitated total thyroidectomy. The EMG findings and the muscle histopathology of both patients are commented on and compared with the changes described in hypothyroidism. The disease processes in both patients are also discussed in relation to the muscle and metabolic changes described in myotonic dystrophy. The coexistence of these two diseases is not explicable in the light of present knowledge on the basis of a known genetic predisposition. Only two similar cases of myotonic dystrophy and hypothyroidism have been reported.

1 Polychlorinated dioxins (PCDDs) and furans (PCDFs) are known to produce a wide range of toxic effects. 2 PCDDs and PCDFs are typical contaminants of chlorinated phenols, and pentachlorophenol and related compounds have been shown to be widely distributed among selected oil samples taken from the 1981 Spanish toxic oil epidemic. 3 Six control and eight case oil samples were analysed using GC/MS for PCDDs and PCDFs. Only small concentrations, normally below 1 ng g-1, of the higher chlorinated PCDDs and PCDFs were detected. There were no statistical differences between the case and control oils. 4 These levels seem to be too low to elicit toxic effects, although they could be enough to potentiate the toxicity of other xenobiotics present in the oils. However, it is uncertain whether the levels of these compounds measured in 1990 reflect the levels present when the oils were consumed in 1981, or whether or not the levels measured in crude oils are representative of fried oils.

Over the last decade the European Union has been coordinating actions addressing various aspects of rare diseases and has funded several cross-border research projects. Recently has initiated the biggest rare disease international collaborative effort by launching the International Rare Diseases Research Consortium (IRDiRC). RARE-Bestpractices is one of the more than 100 collaborative research projects on rare diseases funded under the Seventh Framework Programme for Research and Technological Development (FP7; 2007-2013) (1). As a wide, open and inclusive network, RARE-Bestpractices will build on the knowledge of the experts in rare disease research area and experts in guideline development and health technology assessment area, brought together, for the first time, from academic institutions, agencies, organizations, patient advocacy groups, governmental bodies. The project aims at building a platform to collect and exchange information on best practices for the management of rare diseases; to identify relevant research needs; to promote the development of high quality guidelines; and to contribute in making patients, health professionals and policy makers “informed guideline users”. Besides, RARE-Bestpractices will intend to define the extent to which conclusions from cost-effectiveness analyses for pharmaceuticals are accounted for and implemented in guidelines across a range of countries.