Exact solution for the interaction of two decaying quantized fields.

We show that the Markovian dynamics of two coupled harmonic oscillators may be analyzed using a Schrödinger equation and an effective non-Hermitian Hamiltonian. This may be achieved by a non-unitary transformation that involves superoperators; such transformation enables the removal of quantum jump superoperators, which allows us to rewrite the Lindblad master equation in terms of a von Neumann-like equation with an effective non-Hermitian Hamiltonian. This may be generalized to an arbitrary number of interacting fields. Finally, by applying an extra non-unitary transformation, we may diagonalize the effective non-Hermitian Hamiltonian to obtain the evolution of any input state in a fully quantum domain.

A pilot randomised controlled trial on the effectiveness of infant massage on the acceptance, commitment and awareness of influence in parents of babies with Down syndrome.

BACKGROUND: The emotional state of parents of babies with Down syndrome affects their babies' development and their parent-child bonding. The aim for this study was to conduct a pilot randomised controlled evaluation of the effect of infant massage on parents of babies with Down syndrome. METHODS: This pilot study compared two groups (intervention and control), each with 16 parents of babies with Down syndrome. Indices of acceptance, engagement and awareness of influence were measured at two different time points (pre-test and after 5 weeks) using the 'This Is My Baby' Interview. The allocation of families to each group was randomised. The experimental group performed infant massage, applied by the parents, for 5 weeks, every day for at least 10 min. The massage protocol was based on the methodology created by Vimala McClure. Parents in the control group received the intervention after completion of the study. RESULTS: The indices of acceptance, commitment and awareness of influence improved in the experimental group and in the control group. The 2 × 2 mixed-model analysis of variance indicates a statistically significant group-by-time interaction for all indices (P < 0.001), which was significantly higher in the experimental group than in the control group. CONCLUSIONS: The application of infant massage, by parents to their babies, improves the rates of acceptance, commitment and awareness of influence of parents of babies with Down syndrome in the short term.

Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings.

. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found.  Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism  without the brain malformations typically reported in patients with Knobloch syndrome.

Ytrrium-90 transarterial radioembolization in patients with gastrointestinal malignancies.

Transarterial radioembolization (TARE) with yttrium-90 (Y90) is a promising alternative strategy to treat liver tumors and liver metastasis from colorectal cancer (CRC), as it selectively delivers radioactive isotopes to the tumor via the hepatic artery, sparring surrounding liver tissue. The landscape of TARE indications is constantly evolving. This strategy is considered for patients with hepatocellular carcinoma (HCC) with liver-confined disease and preserved liver function in whom neither TACE nor systemic therapy is possible. In patients with liver metastases from CRC, TARE is advised when other chemotherapeutic options have failed. Recent phase III trials have not succeeded to prove benefit in overall survival; however, it has helped to better understand the patients that may benefit from TARE based on subgroup analysis. New strategies and treatment combinations are being investigated in ongoing clinical trials. The aim of this review is to summarize the clinical applications of TARE in patients with gastrointestinal malignancies.

A novel mutation in the ZNF462 gene c.3306dup; p.(Gln1103Thrfs*10) is associated to Weiss-Kruszka syndrome. A case report.

BACKGROUND: Weiss-Kruszka syndrome (WSKA) is a rare disorder caused by mutations in the ZNF462 gene or deletion of 9p31.2 chromosome region, involving ZNF462. The prevalence of WSKA is unknown as only 24 affected individuals have been described. This syndrome should be suspected in individuals presenting mild global developmental delay and common craniofacial abnormalities. CASE PRESENTATION: We presented a case of an infant, 3 years and 4-month life who presented pondostatural and psychomotor retardation, generalized hypotonia with hypermobility, bilateral palpebral ptosis, epicanthal folds, and poorly expressive facies as the main clinical features. These characteristics lead to the realization of genetics studies that resulted in the identification of a novel mutation c.3306dup; p.(Gln1103Thrfs*10) in ZNF462. CONCLUSIONS: WSKA should be suspected in individuals presenting mild global developmental delay, ptosis, downslanting palpebral fissures, exaggerated Cupid's Bow, arched eyebrows, epicanthal folds and short upturned nose with a bulbous tip. Hypertrophy of the ventricular septum and severe OSA were described in our patient and should be considered in future reviews of the disease. This case is added to the reduced number of publications previously reported regarding WSKA and contributes to understanding the genetic characteristics, clinical features, and diagnosis of this syndrome.Abbreviations: WSKA: Weiss-Kruszka syndrome; CP: craniofacial perimeter; WES: whole-exome sequencing; RSV: respiratory syncytial virus; OSA: obstructive sleep apnoea; ACMG: American College of Medical Genetics and Genomics.

Kapitza-Dirac photonic lattices.

We show that the Kapitza-Dirac effect may be modeled by classical light propagation in photonic lattices having a square power law for the refraction index coefficient. The dynamics is shown to be fully soluble because both systems share the same time-independent Schrödinger equation: the angular Mathieu equation. We examine the trajectories of classical light propagating in such structures.

Enabling propagation of anisotropic polaritons along forbidden directions via a topological transition.

Polaritons with directional in-plane propagation and ultralow losses in van der Waals (vdW) crystals promise unprecedented manipulation of light at the nanoscale. However, these polaritons present a crucial limitation: their directional propagation is intrinsically determined by the crystal structure of the host material, imposing forbidden directions of propagation. Here, we demonstrate that directional polaritons (in-plane hyperbolic phonon polaritons) in a vdW crystal (α-phase molybdenum trioxide) can be directed along forbidden directions by inducing an optical topological transition, which emerges when the slab is placed on a substrate with a given negative permittivity (4H-silicon carbide). By visualizing the transition in real space, we observe exotic polaritonic states between mutually orthogonal hyperbolic regimes, which unveil the topological origin of the transition: a gap opening in the dispersion. This work provides insights into optical topological transitions in vdW crystals, which introduce a route to direct light at the nanoscale.

Evidence for cometabolic transformation of weathered toxaphene under aerobic conditions using camphor as a co-substrate.

AIMS: Toxaphene is a persistent organic pollutant, composed of approximately 1000 highly chlorinated bicyclic terpenes. The purpose of this study was to evaluate if camphor, a structural analogue of toxaphene, could stimulate aerobic biotransformation of weathered toxaphene. METHODS AND RESULTS: Two enrichment cultures that degrade camphor as the sole carbon source were established from contaminated soil and biosolids. These cultures were used to evaluate aerobic transformation of weathered toxaphene. Only the biosolids culture could transform compounds of technical toxaphene (CTTs) in the presence of camphor, while no transformation was observed in the presence of glucose or with toxaphene as a sole carbon source. The transformed toxaphene had lower concentration of CTTs with longer retention times, and higher concentration of compounds with lower retention times. Gas chromatography with electron capture negative ion mass spectrometry (GC/ECNI-MS) showed that aerobic biotransformation mainly occurred with Cl8 - and Cl9 -CTTs compounds. The patterns of Cl6 - and Cl7 -CTTs were also simplified albeit to a much lesser extent. Seven camphor-degrading bacteria were isolated from the enrichment culture but none of them could degrade toxaphene. CONCLUSION: Camphor degrading culture can aerobically transform CCTs via reductive pathway probably by co-metabolism using camphor as a co-substrate. SIGNIFICANCE AND IMPACT OF THE STUDY: Since camphor is naturally produced by different plants, this study suggests that stimulation of aerobic transformation of toxaphene may occur in nature. Moreover plants, which produce camphor or similar compounds, might be used in bioremediation of contaminated soils.

Is there a link between depression, neurochemical asymmetry and cardiovascular function?

Although at present depression is one of the most disabling disorders in our social environment, the understanding of its pathogenesis and the resources for its treatment are still unsatisfactory. The importance of brain asymmetry in the pathogenesis of disorders in brain function, including mood disorders such as depression, is a highly unexplored, sometimes underrated, and even ignored topic. It is important to note that the basal and pathological functional lateralization must have an underlying neurochemical substrate. It is also necessary to indicate that the brain asymmetry extends to a neurovisceral integration whose behavior may also be lateralized. One of the most studied axis from the functional point of view is the brain-heart connection, in whose operation there are observations that suggest an asymmetric behavior in basal conditions that is modified by central and peripheral changes, as well as by pharmacological treatments. There are evidences that connect cardiovascular function, neurochemical asymmetries, and depression. A deep understanding of the bilateral behavior of the brain following pathophysiological changes in blood pressure as well as pharmacologically induced, can provide us with therapeutic suggestions for the treatment of depression. In this article, we analyze remarkable results of some representative selected contributions, with which we discuss our proposal on the relationship between hypertension, depression and neurochemical asymmetry.

Asymmetrical influence of a standard light/dark cycle and constant light conditions on the alanyl-aminopeptidase activity of the left and right retinas in adult male rats.

The retina acts as an independent clock informing the central pacemaker, the suprachiasmatic nucleus, under environmental light conditions, with consequences of such inputs for the central and peripheral nervous system. Differences in the behavior of the left and right retinas depending on environmental light conditions may influence the information projected to the brain hemispheres. The retina possesses neuropeptides that act as neurotransmitters or neuromodulators. Alanyl-aminopeptidase (AlaAP, EC 3.4.11.2) activity regulates some of these neuropeptides and therefore reflects their function. We analyzed AlaAP activity in the left and right retinas of adult male rats at successive time points under standard (12/12 h light/dark cycle) and nonstandard (constant light) conditions. AlaAP activity was measured fluorometrically using alanyl-beta-naphthylamide as the substrate. Under standard conditions, there were no differences in the left or right retina between time points, with the left retina predominating, particularly in the light period. In contrast, under constant light, no left versus right differences were observed, but significant differences between time points appeared. In comparison with standard conditions, constant conditions led to significantly higher AlaAP activity. Considering all the left retina data in comparison with all the right retina data, no correlation was found between the left and right retinas under standard conditions, but a significant positive correlation was observed under constant light. These results demonstrate an asymmetrical response of retinal AlaAP activity to changes in environmental light conditions, which may affect the functions in which the substrates of AlaAP are involved and the information projected to the brain hemispheres.

Mesenchymal Stem Cells for Liver Regeneration in Liver Failure: From Experimental Models to Clinical Trials.

The liver centralizes the systemic metabolism and thus controls and modulates the functions of the central and peripheral nervous systems, the immune system, and the endocrine system. In addition, the liver intervenes between the splanchnic and systemic venous circulation, determining an abdominal portal circulatory system. The liver displays a powerful regenerative potential that rebuilds the parenchyma after an injury. This regenerative mission is mainly carried out by resident liver cells. However, in many cases this regenerative capacity is insufficient and organ failure occurs. In normal livers, if the size of the liver is at least 30% of the original volume, hepatectomy can be performed safely. In cirrhotic livers, the threshold is 50% based on current practice and available data. Typically, portal vein embolization of the part of the liver that is going to be resected is employed to allow liver regeneration in two-stage liver resection after portal vein occlusion (PVO). However, hepatic resection often cannot be performed due to advanced disease progression or because it is not indicated in patients with cirrhosis. In such cases, liver transplantation is the only treatment possibility, and the need for transplantation is the common outcome of progressive liver disease. It is the only effective treatment and has high survival rates of 83% after the first year. However, donated organs are becoming less available, and mortality and the waiting lists have increased, leading to the initiation of living donor liver transplantations. This type of transplant has overall complications of 38%. In order to improve the treatment of hepatic injury, much research has been devoted to stem cells, in particular mesenchymal stem cells (MSCs), to promote liver regeneration. In this review, we will focus on the advances made using MSCs in animal models, human patients, ongoing clinical trials, and new strategies using 3D organoids.

Angiotensin II, dopamine and nitric oxide. An asymmetrical neurovisceral interaction between brain and plasma to regulate blood pressure.

Vital functions, such as blood pressure, are regulated within a framework of neurovisceral integration in which various factors are involved under normal conditions maintaining a delicate balance. Imbalance of any of these factors can lead to various pathologies. Blood pressure control is the result of the balanced action of central and peripheral factors that increase or decrease. Special attention for blood pressure control was put on the neurovisceral interaction between Angiotensin II and the enzymes that regulate its activity as well as on nitric oxide and dopamine. Several studies have shown that such interaction is asymmetrically organized. These studies suggest that the neuronal activity related to the production of nitric oxide in plasma is also lateralized and, consequently, changes in plasma nitric oxide influence neuronal function. This observation provides a new aspect revealing the complexity of the blood pressure regulation and, undoubtedly, makes such study more motivating as it may affect the approach for treatment.

Cystinyl and pyroglutamyl-beta-naphthylamide hydrolyzing activities are modified coordinately between hypothalamus, liver and plasma depending on the thyroid status of adult male rats.

The hypothalamus determinates metabolic processes in liver through endocrine and autonomic control. Hypothalamic neuropeptides, such as thyrotropin releasing hormone or vasopressin, have been involved in liver metabolism. The thyroid status influences metabolic processes including liver metabolism in modulating those hypothalamic peptides whose functional status is regulated in part by aminopeptidase activities. In order to obtain data for a possible coordinated interaction between hypothalamus, plasma and liver, of some aminopeptidase activities that may partially reflect the hydrolysis of those peptides, pyroglutamyl- (pGluAP) and cystinyl- (CysAP) beta-naphthylamide hydrolyzing activities were determined fluorimetrically, both in their soluble and membrane-bound forms, in eu- hypo- and hyperthyroid adult male rats. Hyperthyroidism and hypothyroidism were induced with daily subcutaneous injections of tetraiodothyronine (300 µg/kg/day) or with 0.03% methimazole in drinking water for 6 weeks. Results demonstrated significant changes depending on the type of enzyme and the thyroid status. The most striking changes were observed for CysAP in liver where it was reduced in hypothyroidism and increased in hyperthyroidism. Significant intra- and inter-tissue correlations were observed. While there were positive inter-tissue correlations between liver, plasma and hypothalamus in eu-and hypothyroid rats, a negative correlation between hypothalamus and liver was observed in hyperthyroidism. These results suggest the influence of thyroid hormones and an interactive role for these activities in the control of liver metabolism. The present data also suggest a role for CysAP and pGluAP activities in liver function linked to their activities in hypothalamus.

Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights.

The cardiovascular control involves a bidirectional functional connection between the brain and heart. We hypothesize that this connection could be extended to other organs using endocrine and autonomic nervous systems (ANS) as communication pathways. This implies a neuroendocrine interaction controlling particularly the cardiovascular function where the enzymatic cascade of the renin-angiotensin system (RAS) plays an essential role. It acts not only through its classic endocrine connection but also the ANS. In addition, the brain is functionally, anatomically, and neurochemically asymmetric. Moreover, this asymmetry goes even beyond the brain and it includes both sides of the peripheral nervous and neuroendocrine systems. We revised the available information and analyze the asymmetrical neuroendocrine bidirectional interaction for the cardiovascular control. Negative and positive correlations involving the RAS have been observed between brain, heart, kidney, gut, and plasma in physiologic and pathologic conditions. The central role of the peptides and enzymes of the RAS within this neurovisceral communication, as well as the importance of the asymmetrical distribution of the various RAS components in the pathologies involving this connection, are particularly discussed. In conclusion, there are numerous evidences supporting the existence of a neurovisceral connection with multiorgan involvement that controls, among others, the cardiovascular function. This connection is asymmetrically organized.

Quantitative PCR: an alternative approach to detect common copy number alterations in multiple myeloma.

Chromosome 1q gains and 13q deletions are common cytogenetic aberrations in multiple myeloma (MM) that confer a poor prognosis. There are several techniques for the targeted study of these alterations, but interphase fluorescence in situ hybridization (FISH) is the current gold standard. The aim of the present study was to validate quantitative PCR (qPCR) as an alternative to FISH studies in CD138+-enriched plasma cells (PCs) from MM patients at diagnosis. We analyzed 1q gains and 13q deletions by qPCR in 57 and 60 MM patients, respectively. qPCR applicability was 84 and 88% for 1q and 13q, respectively. The qPCR and FISH methods had a sensitivity and specificity of 88 and 71% for 1q gains, and 79 and 100% for 13q deletions. A second qPCR assay for each region was carried out to confirm the previous results. Paired qPCR (two assays) and FISH results were available from 53 MM patients: 26 for 1q amplification and 27 for 13q deletion. qPCR assays gave concordant results (qPCR-consistent) in 20 of the 26 (77%) 1q gains and 25 of the 27 (93%) 13q deletions. Considering only the consistent data, the overall concordance among qPCR and FISH was 85 and 100% for 1q gains and 13q deletions, respectively. Our results show a substantial agreement between qPCR and the gold standard FISH technique, indicating the potential of qPCR as an alternative approach, particularly when the starting material is too scarce or cells are too damaged to obtain accurate results from FISH studies.

[Brain asymmetry and dopamine: beyond motor implications in Parkinson's disease and experimental hemiparkinsonism]. / Asimetria cerebral y dopamina: mas alla de las implicaciones motoras en la enfermedad de Parkinson y hemiparkinsonismo experimental.

INTRODUCTION: Brain asymmetry could be defined as the existence of functional, anatomic or neurochemical differences between both hemispheres. It is a dynamic phenomenon, regulated by endogenous and exogenous factors. Its functional significance is poorly clarified and is only partially understood in very specific cases such as the relationship between the lateralized brain content of dopamine and its motor effects which is specially patent in Parkinson's disease. DEVELOPMENT: The asymmetric brain content of dopamine not only displays lateralized motor effects but also behavioral and autonomic asymmetric consequences. In fact, Parkinson's disease is characterized not only by unilateral motor symptoms that arise at the early stages, but has other non-motor symptoms such as autonomic or cognitive alterations that are also revealed asymmetrically. CONCLUSIONS: Brain asymmetry has been underestimated when analyzing the pathogeny of brain diseases and it has been partially studied only in some specific cases, such as Parkinson's disease. However, in order to appropriately understand some brain diseases such as Parkinson's disease, the need to consider this phenomenon has been highlighted.

TITLE: Asimetria cerebral y dopamina: mas alla de las implicaciones motoras en la enfermedad de Parkinson y hemiparkinsonismo experimental.Introduccion. La asimetria cerebral se puede definir como la existencia de diferencias funcionales, anatomicas o neuroquimicas entre los dos hemisferios cerebrales. Se trata de un fenomeno dinamico modulable por factores endogenos y exogenos. Su significado funcional esta apenas aclarado y solo lo esta en algunos casos muy concretos como, por ejemplo, la relacion existente entre el contenido cerebral lateralizado de dopamina y sus efectos motores, que se manifiesta especialmente en la enfermedad de Parkinson. Desarrollo. El contenido asimetrico cerebral de dopamina no solo da lugar a efectos motores lateralizados, sino que se extiende a consecuencias autonomicas y de conducta igualmente lateralizadas. De hecho, la enfermedad de Parkinson se caracteriza por sintomas motores unilaterales, que surgen en las fases iniciales de la enfermedad, y por otros sintomas no motores, como alteraciones autonomicas o cognitivas, que tambien se manifiestan de forma lateralizada. Conclusiones. La asimetria cerebral ha sido un aspecto infravalorado a la hora de analizar la patogenia de las enfermedades cerebrales, y solo en determinados casos, como en la enfermedad de Parkinson, se ha profundizado parcialmente en su estudio. Sin embargo, se ha puesto en evidencia que es necesario considerar este fenomeno para la adecuada comprension de algunas patologias cerebrales, como es el caso de la enfermedad de Parkinson.

Pitch perception deficits in nonverbal learning disability.

The nonverbal learning disability (NLD) is a neurological dysfunction that affects cognitive functions predominantly related to the right hemisphere such as spatial and abstract reasoning. Previous evidence in healthy adults suggests that acoustic pitch (i.e., the relative difference in frequency between sounds) is, under certain conditions, encoded in specific areas of the right hemisphere that also encode the spatial elevation of external objects (e.g., high vs. low position). Taking this evidence into account, we explored the perception of pitch in preadolescents and adolescents with NLD and in a group of healthy participants matched by age, gender, musical knowledge and handedness. Participants performed four speeded tests: a stimulus detection test and three perceptual categorization tests based on colour, spatial position and pitch. Results revealed that both groups were equally fast at detecting visual targets and categorizing visual stimuli according to their colour. In contrast, the NLD group showed slower responses than the control group when categorizing space (direction of a visual object) and pitch (direction of a change in sound frequency). This pattern of results suggests the presence of a subtle deficit at judging pitch in NLD along with the traditionally-described difficulties in spatial processing.

Handedness and gender influence blood pressure in young healthy men and women: A pilot study.

OBJECTIVE: The type and level of sex steroids influence blood pressure (BP). It has been suggested that functional brain asymmetries may be influenced by sex hormones. In addition, there are inter-arm differences in BP not yet related with handedness. In this study, we hypothesize a possible association between sex hormones, handedness, and inter-arm differences in blood pressure. METHODS: To analyze this hypothesis, we measured BP in the left and right arm of the left and right handed adult young men and women in menstrual and ovulatory phase and calculated their mean arterial pressure (MAP). RESULTS: Significant differences depending on sex, arm, handedness or phase of the cycle were observed. MAP was mostly higher in men than in women. Remarkably, in women, the highest levels were observed in the left handed in menstrual phase. Interestingly, the level of handedness correlated negatively with MAP measured in the left arm of right-handed women in the ovulatory phase but positively with the MAP measured in the right arm of right-handed women in the menstrual phase. CONCLUSIONS: These results may reflect an asymmetrical modulatory influence of sex hormones in BP control.

[CITY VS. COUNTRYSIDE: WHERE DO YOU EAT BEST AND HEALTHIEST?]. / URBANO O RURAL: ¿DÓNDE SE COME MEJOR Y DE FORMA MÁS SALUDABLE?

INTRODUCTION: bearing in mind the influence of the environment on the individuals and their choices and behaviours in general and particularly with respect to food, it might be interesting to explore whether eating habits are better or healthier in rural areas than in urban ones. OBJECTIVE: to analyse the perception of the level in which eating habits could be considered better or worse, more or less healthy, in rural and urban areas. METHOD: 281 students (18.37 ± 6.28 years) volunteered participated in the study completing an ad hoc questionnaire designed to measure the characteristics attributed by the participants to the rural and urban eating habits. RESULTS: 49.50% of the participants considered that food is better in rural areas, 8.50% in urban contexts and 42% equally in both rural and urban areas; 80.42% responded that food is healthier in rural areas and 19.57% in urban areas. In addition, 85.10% of the participants coming from rural families considered that food is healthier in the country and the same applies to 75.80% coming from urban families. DISCUSSION AND CONCLUSIONS: the perception about what is healthy is not uniform. From a general point of view it seems that eating better is not the same than eating healthier. The idea of eating better not always is synonymous of eating healthy from a medical-nutritional point of view. This difference could make it difficult to spread the idea of a healthy way of eating to the general population.

Introducción: considerando la influencia del entorno sobre el individuo y sus elecciones y comportamientos en general, y con respecto a la alimentación en particular, cabe preguntarse si ésta es más o menos sana en el ámbito rural o en el urbano. Objetivos: analizar la percepción del grado en que la alimentación puede considerarse mejor o peor y más o menos saludable en el ámbito rural y urbano. Método: 281 estudiantes (18,37 ± 6,28 años) participaron voluntariamente en el estudio mediante la cumplimentación un cuestionario ad hoc a fin de recoger las características atribuidas a la alimentación rural y urbana. Resultados: el 49,50% consideró que se come mejor en el ámbito rural, frente al 8,50% que estimó que se come mejor en el medio urbano, y el 42% consideró que se come por igual en ambos, respectivamente. En cuanto a la opción rural-urbano respecto a dónde se come de modo más saludable, el 80,42% afirmó que se come de forma más saludable en el medio rural y el 19,57% en el medio urbano. El 85,10% de los participantes con un origen familiar rural consideró que en el medio rural se come más saludablemente, frente al 75,80% cuyo origen familiar era urbano. Discusión y conclusiones: la percepción de lo sano no resulta uniforme, ni comer mejor es equiparable a comer más sano desde el punto de vista de la población general. Lo que se considera comer mejor no siempre se acerca al criterio médico-nutricional de saludable, e incluso puede alejarse de ello. Este aspecto puede hacer más difícil llevar la idea de una alimentación saludable a la generalidad de la población.