A memetic dynamic coral reef optimisation algorithm for simultaneous training, design, and optimisation of artificial neural networks.

Artificial Neural Networks (ANNs) have been used in a multitude of real-world applications given their predictive capabilities, and algorithms based on gradient descent, such as Backpropagation (BP) and variants, are usually considered for their optimisation. However, these algorithms have been shown to get stuck at local optima, and they require a cautious design of the architecture of the model. This paper proposes a novel memetic training method for simultaneously learning the ANNs structure and weights based on the Coral Reef Optimisation algorithms (CROs), a global-search metaheuristic based on corals' biology and coral reef formation. Three versions based on the original CRO combined with a Local Search procedure are developed: (1) the basic one, called Memetic CRO; (2) a statistically guided version called Memetic SCRO (M-SCRO) that adjusts the algorithm parameters based on the population fitness; (3) and, finally, an improved Dynamic Statistically-driven version called Memetic Dynamic SCRO (M-DSCRO). M-DSCRO is designed with the idea of improving the M-SCRO version in the evolutionary process, evaluating whether the fitness distribution of the population of ANNs is normal to automatically decide the statistic to be used for assigning the algorithm parameters. Furthermore, all algorithms are adapted to the design of ANNs by means of the most suitable operators. The performance of the different algorithms is evaluated with 40 classification datasets, showing that the proposed M-DSCRO algorithm outperforms the other two versions on most of the datasets. In the final analysis, M-DSCRO is compared against four state-of-the-art methods, demonstrating its superior efficacy in terms of overall accuracy and minority class performance.

Conserved roles for the dynein intermediate chain and Ndel1 in assembly and activation of dynein.

Processive transport by the microtubule motor cytoplasmic dynein requires the regulated assembly of a dynein-dynactin-adapter complex. Interactions between dynein and dynactin were initially ascribed to the dynein intermediate chain N-terminus and the dynactin subunit p150Glued. However, recent cryo-EM structures have not resolved this interaction, questioning its importance. The intermediate chain also interacts with Nde1/Ndel1, which compete with p150Glued for binding. We reveal that the intermediate chain N-terminus is a critical evolutionarily conserved hub that interacts with dynactin and Ndel1, the latter of which recruits LIS1 to drive complex assembly. In additon to revealing that the intermediate chain N-terminus is likely bound to p150Glued in active transport complexes, our data support a model whereby Ndel1-LIS1 must dissociate prior to LIS1 being handed off to dynein in temporally discrete steps. Our work reveals previously unknown steps in the dynein activation pathway, and provide insight into the integrated activities of LIS1/Ndel1 and dynactin/cargo-adapters.

The diversification of Caribbean Buxus in time and space: elevated speciation rates in lineages that accumulate nickel and spreading to other islands from Cuba in non-obligate ultramafic species.

BACKGROUND AND AIMS: The genus Buxus has high levels of endemism in the Caribbean flora, with ~50 taxa. In Cuba, 82 % grow on ultramafic substrates and 59 % are nickel (Ni) accumulators or Ni hyperaccumulators. Hence it is an ideal model group to study if this diversification could be related to adaptation to ultramafic substrates and to Ni hyperaccumulation. METHODS: We generated a well-resolved molecular phylogeny, including nearly all of the Neotropical and Caribbean Buxus taxa. To obtain robust divergence times we tested for the effects of different calibration scenarios, and we reconstructed ancestral areas and ancestral character states. Phylogenetic trees were examined for trait-independent shifts in diversification rates and we used multi-state models to test for state-dependent speciation and extinction rates. Storms could have contributed to Cuba acting as a species pump and to Buxus reaching other Caribbean islands and northern South America'. KEY RESULTS: We found a Caribbean Buxus clade with Mexican ancestors, encompassing three major subclades, which started to radiate during the middle Miocene (13.25 Mya). Other Caribbean islands and northern South America were reached from ~3 Mya onwards. CONCLUSIONS: An evolutionary scenario is evident in which Buxus plants able to grow on ultramafic substrates by exaptation became ultramafic substrate endemics and evolved stepwise from Ni tolerance through Ni accumulation to Ni hyperaccumulation, which has triggered species diversification of Buxus in Cuba. Storms could have contributed to Cuba acting as a species pump and to Buxus reaching other Caribbean islands and northern South America'.

Molecular basis for the recognition of the AUUAAA polyadenylation signal by mPSF.

The polyadenylation signal (PAS) is a key sequence element for 3'-end cleavage and polyadenylation of messenger RNA precursors (pre-mRNAs). This hexanucleotide motif is recognized by the mammalian polyadenylation specificity factor (mPSF), consisting of CPSF160, WDR33, CPSF30, and Fip1 subunits. Recent studies have revealed how the AAUAAA PAS, the most frequently observed PAS, is recognized by mPSF. We report here the structure of human mPSF in complex with the AUUAAA PAS, the second most frequently identified PAS. Conformational differences are observed for the A1 and U2 nucleotides in AUUAAA compared to the A1 and A2 nucleotides in AAUAAA, while the binding modes of the remaining 4 nt are essentially identical. The 5' phosphate of U2 moves by 2.6 Å and the U2 base is placed near the six-membered ring of A2 in AAUAAA, where it makes two hydrogen bonds with zinc finger 2 (ZF2) of CPSF30, which undergoes conformational changes as well. We also attempted to determine the binding modes of two rare PAS hexamers, AAGAAA and GAUAAA, but did not observe the RNA in the cryo-electron microscopy density. The residues in CPSF30 (ZF2 and ZF3) and WDR33 that recognize PAS are disordered in these two structures.

A real-time fluorescence assay for CPSF73, the nuclease for pre-mRNA 3'-end processing.

CPSF73 is the endonuclease that catalyzes the cleavage reaction for 3'-end processing of mRNA precursors (pre-mRNAs) in two distinct machineries, a canonical machinery for the majority of pre-mRNAs and a U7 snRNP (U7 machinery) for replication-dependent histone pre-mRNAs in animal cells. CPSF73 also possesses 5'-3' exonuclease activity in the U7 machinery, degrading the downstream cleavage product after the endonucleolytic cleavage. Recent studies show that CPSF73 is a potential target for developing anticancer, antimalarial, and antiprotozoal drugs, spurring interest in identifying new small-molecule inhibitors against this enzyme. CPSF73 nuclease activity has so far been demonstrated using a gel-based end-point assay, using radiolabeled or fluorescently labeled RNA substrates. By taking advantage of unique properties of the U7 machinery, we have developed a novel, real-time fluorescence assay for the nuclease activity of CPSF73. This assay is facile and high-throughput, and should also be helpful for the discovery of new CPSF73 inhibitors.

Recombinant laccase rPOXA 1B real-time, accelerated and molecular dynamics stability study.

BACKGROUND: Laccases (EC 1.10.3.2) are multi-copper oxidoreductases with great biotechnological importance due to their high oxidative potential and utility for removing synthetic dyes, oxidizing phenolic compounds, and degrading pesticides, among others. METHODS: A real-time stability study (RTS) was conducted for a year, by using enzyme concentrates from 3 batches (L1, L3, and L4). For which, five temperatures 243.15, 277.15, 298.15, 303.15, 308.15, and 313.15 K were assayed. Using RTS data and the Arrhenius equation, we calculated the rPOXA 1B accelerated stability (AS). Molecular dynamics (MD) computational study results were very close to those obtained experimentally at four different temperatures 241, 278, 298, and 314 K. RESULTS: In the RTS, 101.16, 115.81, 75.23, 46.09, 5.81, and 4.83% of the relative enzyme activity were recovered, at respective assayed temperatures. AS study, showed that rPOXA 1B is stable at 240.98 ± 5.38, 277.40 ± 1.32 or 297.53 ± 3.88 K; with t1/2 values of 230.8, 46.2, and 12.6 months, respectively. Kinetic and thermodynamic parameters supported the high stability of rPOXA 1B, with an Ed value of 41.40 KJ mol- 1, a low variation of KM and Vmax, at 240.98 ± 5.38, and 297.53 ± 3.88 K, and ∆G values showing deactivation reaction does not occur. The MD indicates that fluctuations in loop, coils or loops with hydrophilic or intermediate polarity amino acids as well as in some residues of POXA 1B 3D structure, increases with temperature; changing from three fluctuating residues at 278 K to six residues at 298 K, and nine residues at 314 K. CONCLUSIONS: Laccase rPOXA 1B demonstrated experimentally and computationally to be a stable enzyme, with t1/2 of 230.8, 46.2 or 12.6 months, if it is preserved impure without preservatives at temperatures of 240.98 ± 5.38, 277.40 ± 1.32 or 297.53 ± 3.88 K respectively; this study could be of great utility for large scale producers.

Global distribution patterns and niche modelling of the invasive Kalanchoe × houghtonii (Crassulaceae).

Invasive alien species are currently considered one of the main threats to global biodiversity. One of the most rapidly expanding invasive plants in recent times is Kalanchoe × houghtonii (Crassulaceae), an artificial hybrid created in the 1930s in the United States by experimental crossings between K. daigremontiana and K. tubiflora, two species endemic to Madagascar. Thanks to its large colonizing capacity (mainly derived from the production of asexual plantlets), K. × houghtonii soon escaped from cultivation and quickly spread in many parts of the world. However, its actual range is not well known due to the lack of a formal description until recent times (2006) and its strong morphological resemblance with one of its parentals (K. daigremontiana). The present study was aimed, in the first instance, to delimit the present distribution area of K. × houghtonii at the global scale by gathering and validating all its occurrences and to track its colonization history. Currently, K. × houghtonii can be found on all continents except Antarctica, although it did not reach a global distribution until the 2000s. Its potential distribution, estimated with MaxEnt modelling software, is mainly centered in subtropical regions, from 20° to 40° of both northern and southern latitudes, mostly in areas with a high anthropogenic activity. Unexpectedly, concomitant to a poleward migration, future niche models suggest a considerable reduction of its range by up to one-third compared to the present, which might be related with the Crassulaceaean Acid Metabolism (CAM) of K. × houghtonii. Further research may shed light as to whether a decrease in potential habitats constitutes a general pattern for Crassulaceae and CAM plants.

Differential effects of the dynein-regulatory factor Lissencephaly-1 on processive dynein-dynactin motility.

Cytoplasmic dynein is the primary minus-end-directed microtubule motor protein in animal cells, performing a wide range of motile activities, including transport of vesicular cargos, mRNAs, viruses, and proteins. Lissencephaly-1 (LIS1) is a highly conserved dynein-regulatory factor that binds directly to the dynein motor domain, uncoupling the enzymatic and mechanical cycles of the motor and stalling dynein on the microtubule track. Dynactin, another ubiquitous dynein-regulatory factor, releases dynein from an autoinhibited state, leading to a dramatic increase in fast, processive dynein motility. How these opposing activities are integrated to control dynein motility is unknown. Here, we used fluorescence single-molecule microscopy to study the interaction of LIS1 with the processive dynein-dynactin-BicD2N (DDB) complex. Surprisingly, in contrast to the prevailing model for LIS1 function established in the context of dynein alone, we found that binding of LIS1 to DDB does not strongly disrupt processive motility. Motile DDB complexes bound up to two LIS1 dimers, and mutational analysis suggested that LIS1 binds directly to the dynein motor domains during DDB movement. Interestingly, LIS1 enhanced DDB velocity in a concentration-dependent manner, in contrast to observations of the effect of LIS1 on the motility of isolated dynein. Thus, LIS1 exerts concentration-dependent effects on dynein motility and can synergize with dynactin to enhance processive dynein movement. Our results suggest that the effect of LIS1 on dynein motility depends on both LIS1 concentration and the presence of other regulatory factors such as dynactin and may provide new insights into the mechanism of LIS1 haploinsufficiency in the neurodevelopmental disorder lissencephaly.

Hipoxia perinatal en el Hospital Mederi de Bogotá: comportamiento en los años 2007 a 2011 / Perinatal hypoxia at Hospital Mederi in Bogotá: behavior in the period 2007-2011

RESUMEN Objetivo Identificar los factores de riesgo maternos, fetales y neonatales asociados a la hipoxia perinatal en los recién nacidos del Hospital Universitario Mayor Mederi (HUM Mederi), período 2007 a 2011. Metodología Del total de recién nacidos (8 837) en los años 2007 a 2011, en el HUM Mederi, se tomaron los casos que presentaron asfixia perinatal (AP) según la ACOG u otro diagnóstico de Dificultad Respiratoria (DR). Fuente: Registros del sistema informático de Servicio de Neonatología del Hospital Universitario Mayor Mederi. Se analizaron los factores de riesgo materno, fetal y neonatal. Los datos se mostraron de acuerdo al número de recién nacidos en cada grupo y en forma porcentual. Resultados La tasa de mortalidad global fue de 10,7. Los valores más bajos fueron en los años 2010 y 2011: 3.3 y 1.8 respectivamente. Diabetes gestacional, hipertensión, corioamnionitis y placenta previa fueron más frecuentes en el grupo con DR, mientras que hipoglicemia y sepsis lo fueron en el grupo con AP así como hipotonía e hipoacti-vidad entre las alteraciones neurológicas. Fue baja la correspondencia entre las alteraciones neurológicas y el Test de Apgar en los casos diagnosticados con AP. Conclusiones La tasa de mortalidad fue muy baja comparada a nivel regional y local. Hubo mayor número de recién nacidos con asfixia perinatal moderada. Los resultados del estudio coinciden con lo reportado. El mayor número de pre-término en los recién nacidos con DR enfatiza la importancia de controlar el implemento de acciones para disminuir los factores de riesgo asociados a esta condición.

ABSTRACT Objective To identify maternal, fetal and neonatal risk factors associated with perinatal hypoxia in neonates at Hospital Universitario Mayor Mederi (HUM Mederi) from 2007 to 2011. Methodology In the period 2007-2011, 8 837 children were born in HUM Mederi. Only the cases that presented with perinatal asphyxia (PA), according to the American Congress of Obstetricians and Gynecologists (ACOG), or another respiratory distress (RD) diagnosis were considered for this analysis, based on the computer records of the Neonatology Service in HUM Mederi. Maternal, fetal and neonatal risk factors were analyzed. Data were shown according to the number of newborns in each group and their percentage. Results The overall mortality rate was 10.7. The lowest values were found in 2010 and 2011 (3.3 and 1.8, respectively). Gestational diabetes, hypertension, chorioamnionitis and placenta previa were more frequent in the RD group, whereas hypoglycemia, sepsis, hypotonia and hypoactivity among neurological alterations were more common in the PA group. Correspondence between neurological alterations and Apgar Test was low in the cases diagnosed with PA. Conclusions The mortality rate was very low compared to regional and local levels, and more infants presented with moderate perinatal asphyxia. These results coincide with literature reports. The high number of preterm births with DR emphasizes the importance of controlling the implementation of actions to reduce the risk factors associated with this condition.

Dynamically weighted evolutionary ordinal neural network for solving an imbalanced liver transplantation problem.

OBJECTIVE: Create an efficient decision-support model to assist medical experts in the process of organ allocation in liver transplantation. The mathematical model proposed here uses different sources of information to predict the probability of organ survival at different thresholds for each donor-recipient pair considered. Currently, this decision is mainly based on the Model for End-stage Liver Disease, which depends only on the severity of the recipient and obviates donor-recipient compatibility. We therefore propose to use information concerning the donor, the recipient and the surgery, with the objective of allocating the organ correctly. METHODS AND MATERIALS: The database consists of information concerning transplants conducted in 7 different Spanish hospitals and the King's College Hospital (United Kingdom). The state of the patients is followed up for 12 months. We propose to treat the problem as an ordinal classification one, where we predict the organ survival at different thresholds: less than 15 days, between 15 and 90 days, between 90 and 365 days and more than 365 days. This discretization is intended to produce finer-grain survival information (compared with the common binary approach). However, it results in a highly imbalanced dataset in which more than 85% of cases belong to the last class. To solve this, we combine two approaches, a cost-sensitive evolutionary ordinal artificial neural network (ANN) (in which we propose to incorporate dynamic weights to make more emphasis on the worst classified classes) and an ordinal over-sampling technique (which adds virtual patterns to the minority classes and thus alleviates the imbalanced nature of the dataset). RESULTS: The results obtained by our proposal are promising and satisfactory, considering the overall accuracy, the ordering of the classes and the sensitivity of minority classes. In this sense, both the dynamic costs and the over-sampling technique improve the base results of the considered ANN-based method. Comparing our model with other state-of-the-art techniques in ordinal classification, competitive results can also be appreciated. The results achieved with this proposal improve the ones obtained by other state-of-the-art models: we were able to correctly predict more than 73% of the transplantation results, with a geometric mean of the sensitivities of 31.46%, which is much higher than the one obtained by other models. CONCLUSIONS: The combination of the proposed cost-sensitive evolutionary algorithm together with the application of an over-sampling technique improves the predictive capability of our model in a significant way (especially for minority classes), which can help the surgeons make more informed decisions about the most appropriate recipient for an specific donor organ, in order to maximize the probability of survival after the transplantation and therefore the fairness principle.

[Perinatal hypoxia at Hospital Mederi in Bogotá: behavior in the period 2007-2011]. / Hipoxia perinatal en el Hospital Mederi de Bogotá: comportamiento en los años 2007 a 2011.

OBJECTIVE: To identify maternal, fetal and neonatal risk factors associated with perinatal hypoxia in neonates at Hospital Universitario Mayor Mederi (HUM Mederi) from 2007 to 2011. METHODOLOGY: In the period 2007-2011, 8 837 children were born in HUM Mederi. Only the cases that presented with perinatal asphyxia (PA), according to the American Congress of Obstetricians and Gynecologists (ACOG), or another respiratory distress (RD) diagnosis were considered for this analysis, based on the computer records of the Neonatology Service in HUM Mederi. Maternal, fetal and neonatal risk factors were analyzed. Data were shown according to the number of newborns in each group and their percentage. RESULTS: The overall mortality rate was 10.7. The lowest values were found in 2010 and 2011 (3.3 and 1.8, respectively). Gestational diabetes, hypertension, chorioamnionitis and placenta previa were more frequent in the RD group, whereas hypoglycemia, sepsis, hypotonia and hypoactivity among neurological alterations were more common in the PA group. Correspondence between neurological alterations and Apgar Test was low in the cases diagnosed with PA. CONCLUSIONS: The mortality rate was very low compared to regional and local levels, and more infants presented with moderate perinatal asphyxia. These results coincide with literature reports. The high number of preterm births with DR emphasizes the importance of controlling the implementation of actions to reduce the risk factors associated with this condition.

OBJETIVO: Identificar los factores de riesgo maternos, fetales y neonatales asociados a la hipoxia perinatal en los recién nacidos del Hospital Universitario Mayor Mederi (HUM Mederi), período 2007 a 2011. METODOLOGÍA: Del total de recién nacidos (8 837) en los años 2007 a 2011, en el HUM Mederi, se tomaron los casos que presentaron asfixia perinatal (AP) según la ACOG u otro diagnóstico de Dificultad Respiratoria (DR). Fuente: Registros del sistema informático de Servicio de Neonatología del Hospital Universitario Mayor Mederi. Se analizaron los factores de riesgo materno, fetal y neonatal. Los datos se mostraron de acuerdo al número de recién nacidos en cada grupo y en forma porcentual. RESULTADOS: La tasa de mortalidad global fue de 10,7. Los valores más bajos fueron en los años 2010 y 2011: 3.3 y 1.8 respectivamente. Diabetes gestacional, hipertensión, corioamnionitis y placenta previa fueron más frecuentes en el grupo con DR, mientras que hipoglicemia y sepsis lo fueron en el grupo con AP así como hipotonía e hipoacti-vidad entre las alteraciones neurológicas. Fue baja la correspondencia entre las alteraciones neurológicas y el Test de Apgar en los casos diagnosticados con AP. CONCLUSIONES: La tasa de mortalidad fue muy baja comparada a nivel regional y local. Hubo mayor número de recién nacidos con asfixia perinatal moderada. Los resultados del estudio coinciden con lo reportado. El mayor número de pre-término en los recién nacidos con DR enfatiza la importancia de controlar el implemento de acciones para disminuir los factores de riesgo asociados a esta condición.

Exploitation of pairwise class distances for ordinal classification.

Ordinal classification refers to classification problems in which the classes have a natural order imposed on them because of the nature of the concept studied. Some ordinal classification approaches perform a projection from the input space to one-dimensional (latent) space that is partitioned into a sequence of intervals (one for each class). Class identity of a novel input pattern is then decided based on the interval its projection falls into. This projection is trained only indirectly as part of the overall model fitting. As with any other latent model fitting, direct construction hints one may have about the desired form of the latent model can prove very useful for obtaining high-quality models. The key idea of this letter is to construct such a projection model directly, using insights about the class distribution obtained from pairwise distance calculations. The proposed approach is extensively evaluated with 8 nominal and ordinal classifiers methods, 10 real-world ordinal classification data sets, and 4 different performance measures. The new methodology obtained the best results in average ranking when considering three of the performance metrics, although significant differences are found for only some of the methods. Also, after observing other methods of internal behavior in the latent space, we conclude that the internal projections do not fully reflect the intraclass behavior of the patterns. Our method is intrinsically simple, intuitive, and easily understandable, yet highly competitive with state-of-the-art approaches to ordinal classification.

Development of a multi-classification neural network model to determine the microbial growth/no growth interface.

Boundary models have been recognized as useful tools to predict the ability of microorganisms to grow at limiting conditions. However, at these conditions, microbial behaviour can vary, being difficult to distinguish between growth or no growth. In this paper, the data from the study of Valero et al. [Valero, A., Pérez-Rodríguez, F., Carrasco, E., Fuentes-Alventosa, J.M., García-Gimeno, R.M., Zurera, G., 2009. Modelling the growth boundaries of Staphylococcus aureus: Effect of temperature, pH and water activity. International Journal of Food Microbiology 133 (1-2), 186-194] belonging to growth/no growth conditions of Staphylococcus aureus against temperature, pH and a(w) were divided into three categorical classes: growth (G), growth transition (GT) and no growth (NG). Subsequently, they were modelled by using a Radial Basis Function Neural Network (RBFNN) in order to create a multi-classification model that was able to predict the probability of belonging at one of the three mentioned classes. The model was developed through an over sampling procedure using a memetic algorithm (MA) in order to balance in part the size of the classes and to improve the accuracy of the classifier. The multi-classification model, named Smote Memetic Radial Basis Function (SMRBF) provided a quite good adjustment to data observed, being able to correctly classify the 86.30% of training data and the 82.26% of generalization data for the three observed classes in the best model. Besides, the high number of replicates per condition tested (n=30) produced a smooth transition between growth and no growth. At the most stringent conditions, the probability of belonging to class GT was higher, thus justifying the inclusion of the class in the new model. The SMRBF model presented in this study can be used to better define microbial growth/no growth interface and the variability associated to these conditions so as to apply this knowledge to a food safety in a decision-making process.

Documento complementario a consultoría de apoyo a la ley del diálogo

Este documento es la complementación a los documentos, ya presentados, que contienen los indicadores socioeconómicos y demográficos por municipios y el resumen con resultados conclusiones y recomendaciones. Presenta leves diferencias de enfoque en las conclusiones

Factores de riesgo en la neuropatía epidémica cubana

Objetivo: Estudio de casos y controles para investigar si la neuropatía epidémica cubana era resultado de un proceso infeccioso, exposición a uno o más agentes tóxicos, vinculada al déficit de uno o varios nutrientes o consecuencia de más de una de las causas anteriores y sus posibles interacciones. Material y métodos: Fueron 311 casos de neuropatía epidémica con manifestaciones ópticas y periféricas y 373 contrtoles, a los cuales se les aplicó una encuesta con 55 preguntas relativas a datos generales y exposición previa de los factores a investigar. La evaluación se realilzó por separado para las formas clínicas con afectación óptica o periférica. En ambas formas clínicas no se encontró asociación entre enfermedad y deficiencias del saneamiento básico de las viviendas. Los eventos vitales fuente de estrés, así como la magnitud de la pérdida de peso y demás indicadores de déficit nutricional se asociaron significativamente con ambas formas clínicas, aun cuando los controles también presentaron alta frecuencia de afectaciones nutricionales. En ambos tipos de enfermedad la frecuencia de convivientes enfermos fue baja. El sexo femenino presentó un riesgo significativamente mayor de enfermar en la neuropatía periférica y el único factor tóxico identificado fue el tabaquismo para la neuropatía óptica. Se postula que el déficit nutricional, unido a factores intrínsecos individuales no precisados son determinantes en el desarrollo de la enfermedad; la exposición de estos sujetos al tabaco incrementó significativamente el riesgo de presentar neuropatía óptica. Conclusiones: 1. La baja frecuencia de convivientes enfermos y antecedentes de fiebre entre los casos, así como la falta de asociación con las deficiencias del saneamiento básico, no apoyaron la posible etiología infecciosa. 2. El único factor de riesgo de tipo tóxico que se puso de manifiesto fue el tabaquismo para la forma clínica con afectación óptica. 3. Los eventos vitales fuentes de estrés se asociaron significativamente a la ocurrencia de la enfermedad. 4. Ambas formas clínicas se asociaron con la pérdida de peso y otros indicadores de déficit nutricional (AU)