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Biomedical subjects

M Posada de la Paz

Publications and source records attributed to M Posada de la Paz.

At least 19 recordsLinked to original sources

[The choice of the type of design in the clinical investigation studies. Case and control studies].

Case-control studies are appropriate designs in neurology sciences to search for risk factors that have already occurred in a group of patients. In them, the subjects are selected on the basis of whether they have the disease or not and then they are compared in regards to the risk factor or prognosis investigated. These sorts of designs can be performed in a shorter and cheaper way than the regular cohort studies. They are appropriate for the evaluation of rare diseases and can examine multiple etiological factors for a single disease. On the contrary, they are not so efficient when rare exposures are involved. Incidence rates in exposed and non-exposed subjects cannot be calculated and on some occasions, the timing between exposure and outcome can be very difficult to establish. The Odds Ratio and its confident intervals is the measurement used for estimating the risk strength in this design. The clinical neurologist should be familiar with these terms, given the frequency of case-control studies described in neurology science literature, and should know their principal advantages and limitations.

Case-Control Studies↗

Toxic oil syndrome: survival in the whole cohort between 1981 and 1995.

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 <40 years of age. Among the TOS-related deaths, the shortest survival times were for women and subjects <40 years of age. The major disease manifestations had the highest relative risks (RR) (liver disease, RR 3.83; pulmonary infection, RR 1.54; motor neuropathy, RR 2.24; pulmonary hypertension, RR 3.19; and eosinophilia, RR 1.14.). CONCLUSIONS: The major clinical manifestations showed worse prognosis for overall and TOS-related mortality. Application of these results to the survivors will help clarify the validity of these conclusions.

Adult↗

Determination of aniline derivatives in oils related to the toxic oil syndrome by atmospheric pressure ionization-tandem mass spectrometry.

In 1981, an unknown disease appeared in Spain, the Spanish Toxic Oil Syndrome. Nowadays and despite all efforts, the etiological agent is still unknown. Early studies showed a link between this illness and the consumption of denatured rapeseed oil fraudulently processed and marketed as edible oil. Two families of aniline derivatives present in these oils (fatty acid anilides and acylated phenyl amino propanediol derivatives or PAPs) were found to be good chemical markers of toxic oils. In this work, a new method has been developed to analyze these aniline derivatives in oil samples by HPLC-MS and HPLC-MS/MS with an API source. For their quantification, three different internal standards were used, one for anilides and two for PAPs. Quantification limits were 8 ppm for anilides and 0.2 ppm for PAPs. Anilides and PAPs were found in marker-positive samples at levels up to 50,000 and 330 ppm, respectively. The relative abundance of the different fatty acid anilides and PAPs correlates with the fatty acid composition of the oils. More than 2,600 different samples were analyzed by this method in the most exhaustive screening of suspected toxic oils carried out to date.

Aniline Compounds↗

Storage time and deodorization temperature influence the formation of aniline-derived compounds in denatured rapeseed oils.

In 1981 an epidemic, named Toxic Oil Syndrome, occurred in Spain as a result of ingestion of rapeseed oil denatured with 2% aniline, which had been imported for industrial use but was fraudulently diverted and processed for human consumption. Two groups of chemical compounds have been identified in the ingested toxic oil: fatty acid anilides and amino-propanediol derivatives. The objective of this work was to assess the effect of several refining process variables on the formation of 3-(N-phenylamino)-1,2-propanediol (PAP) esters. The amount of PAP esters in aniline-denatured oil increased dramatically when oil was heated from 250 degrees C to 300 degrees C. However, the ones formed when 300 degrees C was reached were lost during processing at that temperature. The level maintained during the operation time at 300 degrees C was higher in denatured samples stored for 3 weeks before refining than in denatured samples stored only for 1 week. Anilides were also analyzed. We found that anilides decreased very little with distillation time. In this paper we discuss the influence of storage time prior to refining and of elevated refining temperature, such as temperatures that might occur in close proximity to a deodorizer coil.

Aniline Compounds↗

Toxic oil syndrome: the perspective after 20 years.

Toxic oil syndrome burst upon the scene in Spain in May of 1981, draining the resources of a newly evolving political and social medicine system. The vehicle of the causative toxic agent was identified as an illicit oil that had been diverted from industrial use and refined in order to remove the aniline denaturant, and that was sold in unlabeled 5-liter containers by itinerant salesmen. Over 20,000 people were ultimately affected, and over 1,200 deaths from all causes have been recorded in the affected cohort. The epidemiologic investigation of toxic oil syndrome involved all facets of investigative and analytical work; from visits to factories and interviewing workers, to sophisticated chemical and statistical analytical techniques. This investigation serves as a further illustration that data and information of all types, and from a wide range of fields, need to be systematically collected and evaluated in order to best resolve an epidemiologic mystery. Astute clinical observation of the patients, however, led to the hypothesis that toxic oil syndrome was a result of a toxic exposure. In this and other epidemics of unknown etiology, clinical observation and the intense scrutiny of patients' histories, signs, and symptoms by treating clinicians have often led to hypotheses that could be tested epidemiologically. When there are medical unknowns, the role of the astute clinician continues to be crucial. The toxic oil syndrome epidemic is an example of how even a developed country can be affected by a massive epidemic of environmental origin if failures occur in the systems that control and regulate the food supply or other consumer products. However, such failures could occur anywhere that large commercial networks operate on the regulatory edge, and if these business lack an in depth knowledge of the consequences of alterations in manufacturing conditions. Such was the case with eosinophilia-myalgia syndrome as well, when apparently minor alterations in manufacturing conditions of L-tryptophan led to an increase in impurities in the product that were later associated with the illness. These risks are even greater in countries with few or inconsistent control systems, making the food and drug supply potential portals of entry for serious health hazards, as is further exemplified by the tragic episode of pediatric renal failure in Haiti associated with a legitimate consumer product, paracetamol elixir, that had been manufactured using a fraudulently supplied toxic ingredient, diethylene glycol (81). The potential toxicants in the adulterated rapeseed oil were present in extremely small amounts. If fatty acid anilides or related compounds are indeed the etiologic agents in toxic oil syndrome, then these compounds must be extremely toxic at the parts per million concentrations at which they were found. Further, the roles of causative agents in the development of disorders such as scleroderma, eosinophilic fasciitis, eosinophilic perimyositis, and other similar diseases are unknown, but scientists can speculate that some sort of low level environmental agent may play a role if such extremely small quantities of contaminants are indeed capable of causing disease. Although the exact identity of the etiologic agent in toxic oil syndrome remains unknown, work on toxic oil syndrome continues. Follow-up clinical studies and long-term mortality studies are under way. Investigation of the mechanisms involved in toxic oil syndrome continues. The identification of suspect chemical compounds, their characterization, and effects will hopefully one day contribute to the prevention of other similar diseases.

Aniline Compounds↗

[Clinical and analytical findings in patients with toxic oil syndrome. Study of a cohort of 758 patients].

OBJECTIVE: To report the symptoms and analytical findings observed in the collective of patients affected with the toxic oil syndrome (TOS) 18 years after the poisoning. METHODS: At the Centro de Investigación sobre el Síndrome del Aceite Tóxico (CISAT) we followed the clinical and analytical course of 758 patients affected with the TOS since December 1997 up to May 1999. Patients were evaluated by means of a previously standardized questionnaire in which a clinical review and a battery of complementary tests (thyroid hormones, spirometry with diffusion test and arterial gasometry) were included. One hundred and sixty-two patients underwent also echocardiogram because of presumptive pulmonary hypertension and/or heart disease. RESULTS: Out of the 758 patients, 516 were females and 242 males (M:F ratio 2:1), with ages ranging from 17 to 84 years (mean age 47 years). One of the most remarkable findings was the increased prevalence of cardiovascular risk factors: arterial hypertension (34%), dyslipemias (44%), overweight (40%), obesity (27%), carbohydrate intolerance (9%) and diabetes mellitus (9.4%). The most common reported symptoms were: cramps (78%), arthralgias (78%), and paresthesias (70%). Only 2.8% of patients reported to be asymptomatic. The analytical results most commonly changed were: changes in lipidic and carbohydrate metabolism (already reported), overt or subclinical hypothyroidism (6.6%) and respiratory changes in patients with no previous pulmonary disease: changes in spirometry (6%), diffusion test (8%) and hypoxemia (18%). Echocardiographic findings suggestive of PHT were obtained in 3.1% of cases. CONCLUSIONS: Although TOS occurred in 1981, this syndrome still has a relevant morbidity in a portion of the spanish population. To remark the high prevalence of cardiovascular risk factors with changes in lipidic and carbohydrate metabolism and subclinical hypothyroidism observed in our series. Further studies are necessary to evaluate the actual dimension of this poisoning.

Adolescent↗

Epidemiologic evidence for a new class of compounds associated with toxic oil syndrome.

Toxic oil syndrome appeared in epidemic form in Spain in 1981. Epidemiologic studies have demonstrated that illness was caused by consumption of rapeseed oil that had been denatured with aniline. Chemical analyses of oil specimens conducted in conjunction with epidemiologic studies have established that consumption of specific oils containing fatty acid anilide contaminants was associated with increased risk for disease. New chemical analytic methods identified a family of compounds, the di-fatty acid esters of phenylamino propane-diol, and one of these compounds, the 1,2-di-oleyl ester of 3-(N-phenylamino)-1,2-propanediol (DPAP), has been found to be more strongly associated with disease status than the fatty acid anilides. We found the odds ratio for exposure to DPAP (OR = 26.4, 95% CI = 6.4-76.3) is much higher than the odds ratio for exposure to oleyl anilide (OR = 4.1, 95% CI = 2.2-7.8), implying that exposure to DPAP was a more relevant risk factor for development of toxic oil syndrome than exposure to oleyl anilide. In this paper, we review and present analyses of data from multiple studies of the possible etiologic role of DPAP in toxic oil syndrome. The presence of DPAP in oil collected from affected and unaffected households was a more specific correlate of case relatedness than was the presence of fatty acid anilides, and it was equally sensitive. Moreover, DPAP was found in oil from the only refinery whose oil was clearly associated with illness.

Anilides↗

Health status measurement in Toxic Oil Syndrome.

Toxic Oil Syndrome (TOS) is a previously unreported condition which affected more than 20,000 people in Spain in 1981 and whose natural history is unknown. In 1993-94, a stratified random sample of 1400 survivors was drawn to measure their health status through clinical examination and their self-perception of well-being through the Nottingham Health Profile Questionnaire (NHPQ). Two-thirds of the sample population responded; indirect estimates suggest that selection bias was limited. Clear and intermediate signs of neuropathy were found in one-fifth and one-half of the patients, respectively. One-fourth and one-sixth showed some degree of scleroderma and contractures. All conditions were more frequent in women than in men and in age >50 than in younger ages. Although no concurrent control group was included in the study, prevalences of these conditions are well above expectations and are largely attributable to TOS. NHPQ scores increased with age in both sexes up to age 50, after which they reached a plateau (with values around 48 in men and 62 in women). Scores were associated to the occurrence of peripheral neurological changes, contractures, and scleroderma-like conditions. A multivariate analysis indicated age, sex, and severity of neurological conditions as major determinants of the NHPQ scores. This overall pattern of findings is peculiar to TOS and differs from the typical post-disaster nonspecific syndrome.

Adult↗

Toxic oil syndrome mortality: the first 13 years.

BACKGROUND: The toxic oil syndrome (TOS) epidemic that occurred in Spain in the spring of 1981 caused approximately 20000 cases of a new illness. Overall mortality and mortality by cause in this cohort through 1994 are described for the first time in this report. METHODS: We contacted, via mail or telephone, almost every living member of the cohort and family members of those who were known to have died in order to identify all deaths from 1 May 1981 through 31 December 1994. Cause of death data were collected from death certificates and underlying causes of death were coded using the International Classification of Diseases, 9th Revision. RESULTS: We identified 1663 deaths between 1 May 1981 and 31 December 1994 among 19 754 TOS cohort members, for a crude mortality rate of 8.4%. Mortality was highest during 1981, with a standardized mortality ratio (SMR) of 4.92 (95% confidence interval [CI]: 4.39-5.50) compared with the Spanish population as a whole. The highest SMR, (20.41, 95% CI: 15.97-25.71) was seen among women aged 20-39 years during the period from 1 May 1981 through 31 December 1982. Women <40 years old, who were affected by TOS , were at greater risk for death in most time periods than their unaffected peers, while older women and men were not. Over the follow-up period, mortality of the cohort was less than expected when compared with mortality of the general Spanish population, or with mortality of the population of the 14 provinces where the epidemic occurred. We also found that, except for deaths attributed to external causes including TOS and deaths due to pulmonary hypertension, all causes of death were decreased in TOS patients compared to the Spanish population. The most frequent underlying causes of death were TOS, 350 (21.1%); circulatory disorders, 536 (32.3%); and malignancies, 310 (18.7%). CONCLUSIONS: We conclude that while on average people affected by toxic oil syndrome are not at greater risk for death over the 13-year study period than any of the comparison groups, women <40 years old were at greater risk of death.

Adult↗

Toxic oil syndrome: traceback of the toxic oil and evidence for a point source epidemic.

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.

Anilides↗

Products of aniline and triglycerides in oil samples associated with the toxic oil syndrome.

The toxic oil syndrome (TOS) was a devastating disease that occurred in Spain in 1981. The disease was associated with the consumption of aniline-denatured and refined rapeseed oil that had been illegally sold as olive oil. Many aniline-derived oil components have been identified in the oils; however, no etiological agent has ever been identified for this disease. We have continued the study of the TOS problem by applying new technology in the form of liquid chromatography interfaced via atmospheric pressure ionization with tandem mass spectrometry. Using liquid chromatography tandem mass spectrometry, we studied diluted TOS-associated oils by direct analysis without prior sample treatment. Using this technology, we found new classes of compounds that are associated with disease-related oils. The compounds that have been identified are esters and ester amides of 3-(N-phenylamino)-1,2-propanediol and are products of aniline and triglycerides. Because of the varied fatty acid (oleic acid, etc.) content of the oils, many variations of the above compounds are possible. We now report the identities of more than 20 compounds not previously identified. These compounds are strongly associated with oils that caused the toxic oil syndrome. We believe these compounds should be considered for future animal studies.

Anilides↗

Possible etiologic agents for toxic oil syndrome: fatty acid esters of 3-(N-phenylamino)-1,2-propanediol.

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.

Aniline Compounds↗