Los acúfenos de Miguel Ángel y su relación con la toxicología / Miguel Ángel's tinnitus and its relation to toxicology

Resumen El Plomo ha tenido una estrecha relación con el mundo artístico pictórico a través de los pigmentos utilizados por los artistas durante milenios. El íntimo contacto con sustancias químicas potencialmente peligrosas para la salud, casi siempre sin medidas de higiene y seguridad laboral, ha desarrollado en muchos casos, enfermedades laborales en estos artistas, a veces sospechadas y en otros casos, más que confirmadas. En el presente trabajo se analiza la historia de vida laboral de Miguel Angel Buonarroti, de quien se tiene registro suficiente como para establecer un nexo causal con exposición laboral al Plomo.

Abstract Lead has shown a close relationship with the fine arts'world through the pigments used by artists for thousand of years. Close contact with potentially dangerous chemical substances for health, almost always without occupational hygiene and safety measures, has produced, in many cases, occupational illnesses in these artists, sometimes suspected and in other cases, more than confirmed. In the present work, the history of Miguel Angel Buonarroti's working life is analyzed, since there is sufficient record to establish a causal link with occupational exposure to Lead.

Association between blood lead exposure and mental health in pregnant women: Results from the Japan environment and children's study.

OBJECTIVE: Although environmental lead exposure has decreased, several studies have shown that low-level lead exposure can result in adverse psychological symptoms. However, few studies have examined lead neurotoxicity in pregnant women. We investigated the association between lead exposure and psychological symptoms in pregnant women, and between socio-economic status and blood lead levels. METHODS: Blood lead levels were measured in 17,267 pregnant women in the Japan Environment and Children's Study. Odds ratios (ORs) for high blood lead levels were calculated using multinomial logistic regression. Psychological symptoms were assessed using the Kessler Psychological Distress Scale (K6). ORs for depression (K6 ≥ 13 or ≥5) were calculated using logistic regression with adjustment for potential confounders. RESULTS: The geometric mean of whole blood lead levels was 0.58 µg/dl (range 0.14-6.75 µg/dl). Higher blood lead levels were associated with older age (OR 1.79, 9 5% confidence interval [CI] 1.46-2.19), unmarried status (OR 1.75, 95 % CI 1.31-2.33), lower household income (OR 1.76, 95 % CI 1.38-2.24), and lower educational attainment (OR 1.34, 95 % CI 1.20-1.48). The percentage of women with K6 scores ≥13 and ≥5 was 3 % and 28.2 %, respectively. There was no significant association between lead exposure and K6 score (K6 ≥ 13: OR 1.00, 95 % CI 0.76-1.32; K6 ≥ 5: OR 0.98, 95 % CI 0.88-1.09). CONCLUSION: Our results indicate a small but significant association between higher blood lead levels and lower socio-economic status in a population with low blood lead levels, but no association between low-level lead exposure and psychological symptoms.

Neurotoxicity of low-level lead exposure: History, mechanisms of action, and behavioral effects in humans and preclinical models.

Lead is a neurotoxin that produces long-term, perhaps irreversible, effects on health and well-being. This article summarizes clinical and preclinical studies that have employed a variety of research techniques to examine the neurotoxic effects of low levels of lead exposure. A historical perspective is presented, followed by an overview of studies that examined behavioral and cognitive outcomes. In addition, a short summary of potential mechanisms of action is provided with a focus on calcium-dependent processes. The current level of concern, or reference level, set by the CDC is 5 µg/dL of lead in blood and a revision to 3.5 µg/dL has been suggested. However, levels of lead below 3 µg/dL have been shown to produce diminished cognitive function and maladaptive behavior in humans and animal models. Because much of the research has focused on higher concentrations of lead, work on low concentrations is needed to better understand the neurobehavioral effects and mechanisms of action of this neurotoxic metal.

Lead exposure-induced cognitive impairment through RyR-modulating intracellular calcium signaling in aged rats.

Lead is widely distributed in the environment and has become a global public health issue. It is well known that lead exposure induces not only neurodevelopmental toxicity but also neurodegenerative diseases, with learning and memory impairment in the later stage. However, the molecular mechanisms remain elusive. The present study investigated the effects of early life and lifetime lead exposure on cognition and identified the molecular mechanisms involved in aged rats. The results herein demonstrated that the lead concentration in peripheral blood and brain tissues in aged rats was significantly increased in a lead dose-dependent manner. High-dose lead exposure caused cognitive functional impairment in aged rats, concomitant with a longer escape latency and a lower frequency of crossing the platform via Morris water maze testing compared to those in the control and low-dose lead exposure groups. Importantly, neuron functional defects were still observed even in early life lead exposure during the prenatal and weaning periods in aged rats. The neurotoxicity induced by lead exposure was morphologically evidenced by a recessed nuclear membrane, a swollen endoplasmic reticulum, and mitochondria in the neurons. Mechanistically, the exposure of aged rats to lead resulted in increasing free calcium concentration, reactive oxygen species, and apoptosis in the hippocampal neurons. Lead exposure increased RyR3 expression and decreased the levels of p-CaMKIIα/CaMKIIα and p-CREB/CREB in the hippocampus of aged rats. These findings indicated that early life lead exposure-induced cognition disorder was irreversible in aged rats. Lead-induced neurotoxicity might be related to the upregulation of RyR3 expression and high levels of intracellular free calcium with increasing lead concentration in injured neurons.

Did poor eyesight influence Goya's late works? Medicine and art history in search for an interpretation of Goya's late paintings.

PURPOSE: The aim of this article is to 'determine' the scope of Goya's eyesight difficulties and assess the extent to which those difficulties might explain his style of painting in the last years of his life. METHODS: We analyse the correspondence and late works of the Aragonese painter Francisco de Goya y Lucientes (1746-1828), who has been admired for his use of colour, his energetic loose brushstrokes, his disregard for details and his bold compositions, as well as for his different artistic styles throughout his life. RESULTS: The evolution of Goya's style of painting in his later works seems to have been the consequence of an eyesight condition, probably age-related cataracts at an advanced stage. The faded dark backgrounds, which become blurred with the silhouette of the person portrayed, could indicate a certain degree of eye strain. This can be traced in all these works, but is especially evident in the unfinished portrait of Pío de Molina (1827-1828), as well as in the portraits of Mariano Goya, the artist's grandson (1827), and Jacques Galos (1826). CONCLUSION: It has been considered that the late and isolated Goya's sight problems were a belated consequence of his severe illness of 1792. Nevertheless, in our opinion, this is a simplistic explanation and, given the painter's age, it is logical to presume that their cause could be age-related lens opacities. This article argues that medicine may become a subsidiary science to art history, as it can provide empirical evidence of the way painters' illnesses may have a strong impact on their artworks.

'El hombre de la mano seca': ¿iconografía de la parálisis saturnínica? / 'The man with the withered hand': iconography of the saturnine palsy?

Introducción. Los evangelios sinópticos cuentan que un hombre tenía la mano seca y no podía extenderla, en lo que parece la descripción de una parálisis radial. Entre los siglos X y XVII, varios iconografistas cristianos ilustraron este cuadro y produjeron un rico material aún inexplorado desde el punto de vista médico. Objetivo. Analizar la iconografía en cuestión, verificando las lesiones que reproduce y sus posibles causas. Desarrollo. Se seleccionaron seis representaciones: cuatro pertenecen a evangelios iluminados, una es un mosaico y otra, un fresco. En tres, la mano está péndula, y en otra sólo los dedos se ven flexionados. En tres, el brazo afectado aparece sostenido por la mano contralateral. La descripción de signos y posturas propias de pacientes con distintos grados de parálisis extensoras revela que los iluminadores conocieron enfermos reales. El saturnismo, frecuente en Europa durante el período en que se produjeron estas obras, parece la causa más probable. La hipótesis de que los mismos artistas pudieron haberse intoxicado por manipular pinturas con plomo no pudo confirmarse. Conclusiones. Las representaciones de la perícopa el hombre de la mano seca retratan con realismo distintos grados de parálisis motora consistentes con saturnismo. Desde esta perspectiva, pueden considerarse como las primeras imágenes de dicha entidad, cuyas mejores descripciones médicas llegarían únicamente siglos más tarde (AU)

Introduction. The synoptic gospels tell about a man who cannot extend his hand, that appeared dried. The description is consistent with radial palsy. Christian artists depicted this gospel story producing a rich material, unexplored from the medical point of view. Aim. To analyze the mentioned iconography verifying the depicted lesions and their possible causes. Development. Six representations of the evangelical text pertaining to the period comprehended between 10th and 17th centuries were selected. Four belong to illuminated gospels, one is a mosaic and the other one is a fresco. In three of them the figure with the palsy hand appeared holding the affected member with the opposite hand; another one has a foot drop. The description of postures that are characteristic of extensor palsies points out that these artists must have known real patients. Saturnism, frequent in Europe during the period in which these works were created, was probably the cause of the paralysis in these cases. Another hypothesis was that the artists could have suffered themselves saturnism, caused by manipulating paints with high lead content; this could not be confirmed. Conclusions. The iconographies of 'the man with the withered hand' are realistic representations of motor paralysis consistent with saturnine neuropathy. These works preceded for a long time the best medical descriptions of such condition (AU)

Environmental and Occupational Lead Exposure Among Children in Cairo, Egypt: A Community-Based Cross-Sectional Study.

The aim of this study was to assess childhood lead exposure in a representative sample of Cairo, and to investigate the possible risk factors and sources of exposure. This cross-sectional study was conducted from November 2014 through April 2015. The target population was children aged 6 to 18 years, recruited into 4 groups, garbage city, moderate-living standard area, urban and suburban schools, and workshops in the city of Cairo. Blood lead levels (BLLs) and hemoglobin (Hb) concentrations were measured. Also, potential local environmental sources were assessed for hazardous lead contamination. Analysis on 400 participants has been carried out. A total of 113 children had BLLs in the range 10 to 20 µg/dL. Smoking fathers, housing conditions, playing outdoors, and exposure to lead in residential areas were significantly correlated with high BLLs. The mean values of hemoglobin were inversely correlated with BLLs. Children involved in pottery workshops had the highest BLLs and the lowest Hb values with a mean of (43.3 µg/dL and 8.6 g/dL, respectively). The mean value of environmental lead in workshop areas exceeded the recommended levels. Also, those values measured in dust and paint samples of garbage city were significantly high. Moreover, the mean lead levels in the soil samples were significantly higher in urban schools (P = 0.03) than the suburban ones. Childhood lead poisoning accounts for a substantial burden in Egypt, which could be preventable. Development of national prevention programs including universal screening program should be designed to reduce incidence of lead toxicity among children.

[Outbreak of lead poisoning associated with Ayurvedic medicine]. / Brote de saturnismo asociado a un tratamiento basado en la medicina ayurvédica.

BACKGROUND AND OBJECTIVE: Lead poisoning is normally caused by repeated occupational inhalation of lead. However, lead may also be absorbed through the digestive route. Some alternative medical treatments, such as Ayurvedic medicine, can also contain lead and may result in poisoning. PATIENTS AND METHOD: We collected cases of lead poisoning related to Ayurvedic treatments attended at the Hospital Clinic of Barcelona. RESULTS: Two female patients, aged 45 and 57 years, respectively, who initiated Ayurvedic treatments which involved the ingestion of various medicaments, were included. The first patient presented with anemia and abdominal pain. The lead level was 74µg/dL and free erythrocyte protoporphyrin was 163µg/dL. She was treated with intravenous calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) and later with oral dimercaptosuccinic acid (DMSA) with a good evolution. The second patient presented with abdominal pain and a Burton's line. The lead level was 52µg/dL and free erythrocyte protoporphyrin was 262µg/dL. She was treated with oral DMSA and evolved favorably. Lead concentrations in some of the tablets supplied to the patients reached 2,003 and 19,650µg/g of tablet. CONCLUSIONS: Lead poisoning may result from treatments based on Ayurvedic medicine and may reach epidemic proportions. Health control of alternative medicines is necessary.

[The role of toxininduced autoimmune activity in formation of the endotoxemia during the lead exposure].

Here presented the features of formation of endotoxemia at microsaturnism. Here are the results of the retrospective study of toxininduced autoimmune activity and their role in toxemia depending on the degree of exposure of lead. Investigated the mechanisms of production of toxins and damaging potentials activity, molecular size toxins and parameters of their distribution and accumulation in the blood stream, due to the strength of toxinbearing fractions depending on the degree of microsaturnism.

Lead-induced effects on learning/memory and fear/anxiety are correlated with disturbances in specific cholinesterase isoform activity and redox imbalance in adult brain.

The aim of the present study was to investigate whether the underlying mechanism of lead (Pb)-induced effects on learning/memory and fear/anxiety behavior involves changes either on AChE G4 (most abundant in brain) or on G1 isoform activity, and/or to a putative local disruption of oxidant/antioxidant balance. Adult male mice were randomly divided into two groups (18 animals/group): a vehicle group [500ppm (mg/L) CH3COONa/day for 4weeks in their drinking water] and a Pb-treated group [500ppm Pb(CH3COO)2/day for 4weeks in their drinking water]. At the end of the treatment period, mice were subjected to the behavioral tasks. Learning/memory was tested by step-through passive avoidance test, whereas fear/anxiety was studied using the elevated plus-maze and thigmotaxis tests. Pb levels in mice brain were determined using atomic absorption spectrometry. AChE activity was determined colorimetrically, and GSH and MDA levels fluorometrically in whole brain minus cerebellum, cerebral cortex, midbrain, hippocampus, striatum and cerebellum. The possible correlations between learning/memory or fear/anxiety behavior with the AChE activity and/or the lipid peroxidation levels and GSH content were also examined. Pb consumption caused significant deficits on mice learning/memory ability and increased anxiety. The consumption of the Pb solution inhibited the activity of the two AChE isoforms in all brain regions tested. Moreover, Pb exposure increased lipid peroxidation and decreased GSH levels in all brain regions examined. Spearman correlation analysis revealed that the coefficients between the particular behaviors, AChE activity and redox balance were brain region- and AChE isoform-specific.

The lead-poisoned genius: saturnism in famous artists across five centuries.

Lead poisoning (saturnism) has been present throughout the history of mankind. In addition to possible ingestion from contaminated food, one of the most important ways in which poisoning caused morbid processes was by occupational exposure. This exposition was pandemic in the Roman Empire, and it has been claimed that it contributed to its fall, but it also caused numerous epidemics in Western countries until the nineteenth century. In the case of artists, and since the Renaissance period, this toxicity has been called painter's colic or painter's madness. The latter term is partly due to the mental disorders displayed by some of the great masters, including Michelangelo and Caravaggio, although it was long recognized that even house and industrial painters were prone to the disorder. This chapter examines the historical evidence of recognition of such toxicity and discusses the controversies raised by the possibility of professional lead poisoning in great artists. In addition to those mentioned above, many other artists across several centuries will be discussed, some being Rubens, Goya, Fortuny, Van Gogh, Renoir, Dufy, Klee, Frida Kahlo, and Portinari. This chapter also briefly mentions the possibility of lead poisoning in two famous composers: Beethoven and Handel. Whether suffering from lead poisoning or not, about which we cannot always be sure, we should still highlight and admire such geniuses fighting their disorders to bequeath us their immortals works.

Cumulative lead exposure in community-dwelling adults and fine motor function: comparing standard and novel tasks in the VA normative aging study.

BACKGROUND AND AIMS: Lead exposure in children and occupationally exposed adults has been associated with reduced visuomotor and fine motor function. However, associations in environmentally exposed adults remain relatively unexplored. To address this, we examined the association between cumulative lead exposure-as measured by lead in bone-and performance on the grooved pegboard (GP) manual dexterity task, as well as on handwriting tasks using a novel assessment approach, among men in the VA Normative Aging Study (NAS). METHODS: GP testing was done with 362 NAS participants, and handwriting assessment with 328, who also had tibia and patella lead measurements made with K-X-Ray Fluorescence (KXRF). GP scores were time (s) to complete the task with the dominant hand. The handwriting assessment approach assessed the production of signature and cursive lowercase l and m letter samples. Signature and lm task scores reflect consistency in repeated trials. We used linear regression to estimate associations and 95% confidence intervals (CI) with adjustment for age, smoking, education, income and computer experience. A backward elimination algorithm was used in the subset with both GP and handwriting assessment to identify variables predictive of each outcome. RESULTS: The mean (SD) participant age was 69.1 (7.2) years; mean patella and tibia concentrations were 25.0 (20.7)µg/g and 19.2 (14.6)µg/g, respectively. In multivariable-adjusted analyses, GP performance was associated with tibia (ß per 15µg/g bone=4.66, 95% CI: 1.73, 7.58, p=0.002) and patella (ß per 20µg/g=3.93, 95% CI: 1.11, 6.76, p=0.006). In multivariable adjusted models of handwriting production, only the lm-pattern task showed a significant association with tibia (ß per 15µg/g bone=1.27, 95% CI: 0.24, 2.29, p=0.015), such that lm pattern production was more stable with increasing lead exposure. GP and handwriting scores were differentially sensitive to education, smoking, computer experience, financial stability, income and alcohol consumption. CONCLUSIONS: Long-term cumulative environmental lead exposure was associated with deficits in GP performance, but not handwriting production. Higher lead appeared to be associated with greater consistency on the lm task. Lead sensitivity differences could suggest that lead affects neural processing speed rather than motor function per se, or could result from distinct brain areas involved in the execution of different motor tasks.

Effects of exposure to lead on the peripheral motor system of the rat. An ultrastructural study.

OBJECTIVE: To investigate the morphological changes in the peripheral motor system of the rat induced by exposure to lead. METHODS: This study was conducted at the Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia from January 2011 to January 2012. Female adult albino rats (n=10) were given lead acetate in their drinking water (500mg/L) for a period of 30 days. Female adult albino rats (n=5) were used as control. The soleus and gastrocnemius muscles were dissected and processed for electron microscopy. RESULTS: Lead administration induced morphological changes in all constituents of the peripheral motor system of the rat, including; extension of long processes by Schwann cells, engorgement of nerve terminals, withdrawal of some terminals, and muscle fiber alterations. CONCLUSION: Lead toxicity is detrimental to all constituents of the peripheral motor system of the rat. The histopathological changes explain some of the clinical manifestations of lead toxicity.

Adult lead encephalopathy.

The neurotoxicity of lead to the adult brain is less well-known than that seen in children. It may present as acute severe encephalopathy or as chronic cognitive and behavioural symptoms, either in isolation or with systemic features of lead intoxication. Magnetic resonance imaging findings in lead encephalopathy vary. The pathogenesis of lead encephalopathy and its effects on cognition both during development and in the adult are discussed. That encephalopathic symptoms do not correlate with blood lead levels and that they may persist after chelation are highlighted. As an illustration, we describe a patient with chronic cumulative lead intoxication, who presented with peripheral neuropathy, anaemia, and a 'lead line' on the gingiva. She had cognitive dysfunction with extensive subcortical and cerebellar white matter lesions on magnetic resonance imaging. An area of restricted diffusion in both frontal regions is likely to be due to active ongoing demyelinating at the 'leading edge' of the lesion. Although systemic features and the peripheral neuropathy improved with chelation, the encephalopathy showed only marginal change, with later appearance of a symmetric akinetic-rigid state.

Developmental origins of adult diseases and neurotoxicity: epidemiological and experimental studies.

To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers at this symposium presented their research results on different neurotoxic chemicals relating to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to inorganic mercury and methylmercury, and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-dose human equivalent gestational lead exposure produces late-onset obesity only in male mice that is associated with neurodegeneration. Didima de Groot presented results on prenatal exposure of rats to methylazoxymethanol and discussed the results in light of the etiology of western Pacific amyotrophic lateral sclerosis and Parkinson-dementia complex. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following acute 24 h exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment. The results indicate that developmental neurotoxicity results in permanent changes, thus emphasizing the need to prevent such toxicity.

Association of maternal and child blood lead and hemoglobin levels with maternal perceptions of parenting their young children.

Biological and psychosocial factors affect child development and behavior. Whereas biological underpinnings behind the neurotoxic effects of lead are studied extensively, the effects of psychosocial factors contributing to poor behavioral outcomes in lead-exposed children are not well understood. Parental attributes and practices may moderate or mediate the effects of lead on children's behavioral outcomes. We investigated the hypothesis that maternal and child lead and hemoglobin levels are associated with maternal perceptions of their parenting. Specifically, we hypothesized that children with higher blood lead (BLL) and lower hemoglobin concentrations would be associated with poorer maternal self-assessments of their parenting skills or the mother-child relationship. Children aged 13-55 months and their mothers (n=109) were recruited from among the participants of a previous lead and anemia screening study and from preschools in Montevideo, Uruguay. The mother-child pair attended two study visits: one to collect biological samples and answer demographic and child questionnaires, including statements regarding parenting; and a second to evaluate maternal IQ, depression and stress, and child development. Of the children, 51.6% had blood lead concentrations (BLLs) ≥ 5 µg/dL, 18.0% had anemia, and 8% had both conditions. Among mothers, 48.4% had BLLs ≥ 5 µg/dL, 16.0% had anemia, and 11% had both. BLLs ≥ 5 µg/dL in mother or child were associated with lower maternal perceptions of being skilled at discipline (p<0.05). Maternal anemia was associated with lower likelihood that mothers would let their children explore and play (p<0.05), whereas child anemia was associated with maternal perception of lower emotional support (p<0.01). In addition to shared environmental exposures, parenting and family interactions need to be considered as potentially contributing factors to poorer outcomes in lead-exposed children.