Decision-making and frontoparietal resting-state functional connectivity among impulsive-compulsive diagnoses. Insights from a Bayesian approach.

The Iowa Gambling Task (IGT) is one of the most widely used paradigms for assessing decision-making. An impairment in this process may be linked to several psychopathological disorders, such as obsessive-compulsive disorder (OCD), substance abuse disorder (SUD) or attention-deficit/hyperactivity disorder (ADHD), which could make it a good candidate for being consider a transdiagnostic domain. Resting-state functional connectivity (rsFC) has been proposed as a promising biomarker of decision-making. In this study, we aimed to identify idiosyncratic decision-making profiles among healthy people and impulsive-compulsive spectrum patients during the IGT, and to investigate the role of frontoparietal network (FPN) rsFC as a possible biomarker of different decision-making patterns. Using functional near-infrared spectroscopy (fNIRS), rsFC of 114 adults (34 controls; 25 OCD; 41 SUD; 14 ADHD) was obtained. Then, they completed the IGT. Hybrid clustering methods based on individual deck choices yielded three decision-makers subgroups. Cluster 1 (n = 27) showed a long-term advantageous strategy. Cluster 2 (n = 25) presented a maladaptive decision-making strategy. Cluster 3 (n = 62) did not develop a preference for any deck during the task. Interestingly, the proportion of participants in each cluster was not different between diagnostic groups. A Bayesian general linear model showed no credible differences in the IGT performance between diagnostic groups nor credible evidence to support the role of FPN rsFC as a biomarker of decision-making under the IGT context. This study highlights the importance of exploring in depth the behavioral and neurophysiological variables that may drive decision-making in clinical and healthy populations.

Psychometric instruments for the assessment of depressive symptoms in patients with delusional disorder: A systematic review.

Patients with delusional disorder (DD) are at an increased risk for the development of depressive symptoms. We aimed to examine the literature dealing with assessment tools to assess depressive symptoms in DD. A systematic review was performed by searching PubMed, Scopus and clinicaltrials.gov databases from inception until June 2021 (PRISMA guidelines). From 1863 initial retrieved records, 11 studies were included (N = 715 DD patients). Depressive comorbidity ranged from 20.9% to 53.5%. Seven studies used semistructured/structured interviews: OPCRIT 4.0 (n = 1), Manual for Assessment and Documentation of Psychopathology in Psychiatry (AMDP System) (n = 2), the MINI interview (n = 1), DSM-IV (n = 1), ICD-10 (n = 1); and the Diagnostic Interview Schedule (DIS-R) (n = 1). Seven studies used at least one observer-rated scale: Positive and Negative Syndrome Scale (PANSS)-depressive component (n = 2), Hamilton Rating Scale for Depression (HRSD, n = 3), Montgomery-Asberg Depression Rating Scale (MADRS, n = 1), Clinical Global Impression Scale (CGI, n = 1) and the Bipolar Affective Disorder Dimension Scale (BADDS, n = 1). Assessment scales administered in depressive disorders and schizophrenia are applied to DD. This is the first systematic review exploring the use of assessment tools for depressive symptoms in DD. The use of the MADRS to assess depressive symptoms can be recommended in combination with other clinical scales, for instance, the CGI.

Is it Possible to Assess the Two-Domain Definition of the Broad Autism Phenotype Using the Available Measurement Tools?

Although, the operationalization of the autism spectrum disorder has been updated around two domains, the broad autism phenotype (BAP) one has not. Additionally, the items of the three common BAP measures, the Broad Autism Phenotype Questionnaire (BAPQ), the Autism Quotient, and the Social Responsiveness Scale (SRS), remain organized around a non-consensual number of factors. We explored whether the items of these measures matched with the two-domain operationalization through a parallel analysis, which has suggested two main components, and two expert judgments which have assessed item wording, relevance, and construct representativeness. A remaining pool of 48 BAP-relevant items suggested a possible under-representation of two subdomains. Despite the relevance of all the BAPQ items, only the SRS ones tapped in all subdomains.

The androgen receptor expression and its activity have different relationships with prognosis in hepatocellular carcinoma.

The role of the Androgen Receptor (AR) expression and its activity in the prognosis of hepatocellular carcinoma (HCC) remains inconclusive. The aim of this study is to analyze the role of the AR expression and its activity as prognostic biomarkers in HCC. Three-hundred and thirty-seven patients from The Cancer Genome Atlas (TCGA) (107 females; 59.42 years [SD = 13.0]) were included. To infer AR activity, the expression-profile of previously validated androgen responsive genes (ARGs) was included. AR activity was shown by the AR-Score-21 (21 ARGs) and AR-Score-13 (13 ARGs) that were computed based on the expression of the selected ARGs. Those ARGs whose expression was significantly different between histological grades were used for computing two new AR-Scores. HCC patients with higher AR expression showed a higher median overall survival (OS). AR-Score 21 and AR-Score-13 did not show any association with prognosis. Six of the 21 ARGs of the AR-Score-21 and 7 of the 13 ARGs of the AR-Score-13 showed a significant different expression profile among histological grades. Based on these differences, another two AR-Scores were computed (AR-Score-6 and AR-Score-7). They showed the relative increase of upregulated to downregulated ARGs in high-grade HCC. Higher AR activity inferred by these AR-Scores was associated with worse outcomes. The expression of AR is associated with a better prognosis in HCC. However, the activity of the AR seems to be qualitatively different among histological grades. The AR activity inferred by the shifted ARGs is associated with a worse prognosis in HCC patients.

Therapeutic drug monitoring is useful when pharmacogenetic assessment is unavailable: case report of delusional disorder / La monitorización terapéutica de fármacos es útil cuando la evaluación farmacogenética no está disponible: caso clínico de trastorno delirante

Antipsychotic plasma levels have been extensively used in the assessment of poor treatment response, lack of adherence and adverse events in delusional disorder. It has not been used as an indicator of metabolizer status, to determine whether a delusional disorder patient is a poor, intermediate, or ultra-rapid metabolizer of antipsychotics. Pharmacogenetic probes are, of course, the right method for the latter task, but they are not readily available for clinical use. We report the case of a 46-year-old woman with delusional disorder who developed unexpected adverse effects to treatment with relatively low dose risperidone and poor symptomatic response. Blood level monitoring indicated high levels of risperidone and a high concentration-to-dose ratio, which suggested accumulation of unmetabolized risperidone. Paradoxically, extrapyramidal side effects increased when, after reducing the risperidone dose, 5 mg/day of aripiprazole was added. Consequently, the patient was switched to olanzapine 5 mg/day. Sertraline 150 mg/day was later added for comorbid depression. A complete symptomatic response was achieved. Although other factors may well have been at play, this sequence of events suggests that the patient was a slow metabolizer of CYP2D6, which metabolizes both risperidone and aripiprazole. With pharmacogenetic assessment not available, therapeutic drug monitoring helped clinicians decide on appropriate management

Los niveles plasmáticos de antipsicóticos han sido extensamente utilizados para la evaluación de la pobre respuesta terapéutica, la falta de adherencia y los eventos adversos en pacientes con trastorno delirante. No han sido frecuentemente utilizados como indicadores del estado metabólico, para determinar si un paciente con trastorno delirante es metabolizador pobre, intermedio o metabolizador ultra-rápido de antipsicóticos. Los test de farmacogenética son, por supuesto, el método más idóneo para la última tarea, pero no son fáciles de obtener para su uso clínico. Reportamos el caso de una mujer de 46 años de edad con trastorno delirante que ha desarrollado efectos adversos inesperados con el tratamiento a dosis bajas de risperidona, y una pobre respuesta clínica. La monitorización de niveles plasmáticos indicó niveles elevados de risperidona y una ratio elevada concentración-dosis, que sugirió acumulación de risperidona no adecuadamente metabolizada. Paradójicamente, los efectos secundarios se incrementaron, cuando al reducir la dosis de risperidona, se añadió aripiprazol 5mg/día. Por ello, se realizó un cambio a olanzapina 5 mg/día. Se añadió sertralina 150 mg/día posteriormente para el tratamiento de síntomas depresivos comórbidos. Se alcanzó una respuesta clínica completa. A pesar de que otros factores pudieran haber contribuido a ello, la secuencia de eventos sugiere que la paciente pudiera ser metabolizadora lenta del CYP2D6, que metaboliza risperidona y aripiprazol. En caso de no disponibilidad de tests farmacogenéticos, la monitorización de niveles plasmáticos, ayudó a los clínicos a decidir el manejo apropiado del paciente

Evaluation of the potential use of a meta-population for genomic selection in autochthonous beef cattle populations.

This study investigated the potential application of genomic selection under a multi-breed scheme in the Spanish autochthonous beef cattle populations using a simulation study that replicates the structure of linkage disequilibrium obtained from a sample of 25 triplets of sire/dam/offspring per population and using the BovineHD Beadchip. Purebred and combined reference sets were used for the genomic evaluation and several scenarios of different genetic architecture of the trait were investigated. The single-breed evaluations yielded the highest within-breed accuracies. Across breed accuracies were found low but positive on average confirming the genetic connectedness between the populations. If the same genotyping effort is split in several populations, the accuracies were lower when compared with single-breed evaluation, but showed a small advantage over small-sized purebred reference sets over the accuracies of subsequent generations. Besides, the genetic architecture of the trait did not show any relevant effect on the accuracy with the exception of rare variants, which yielded slightly lower results and higher loss of predictive ability over the generations.

Genomic differentiation between Asturiana de los Valles, Avileña-Negra Ibérica, Bruna dels Pirineus, Morucha, Pirenaica, Retinta and Rubia Gallega cattle breeds.

The Spanish local beef cattle breeds have most likely common origin followed by a process of differentiation. This particular historical evolution has most probably left detectable signatures in the genome. The objective of this study was to identify genomic regions associated with differentiation processes in seven Spanish autochthonous populations (Asturiana de los Valles (AV), Avileña-Negra Ibérica (ANI), Bruna dels Pirineus (BP), Morucha (Mo), Pirenaica (Pi), Retinta (Re) and Rubia Gallega (RG)). The BovineHD 777K BeadChip was used on 342 individuals (AV, n=50; ANI, n=48; BP, n=50; Mo, n=50; Pi, n=48; Re, n=48; RG, n=48) chosen to be as unrelated as possible. We calculated the fixation index (F ST ) and performed a Bayesian analysis named SelEstim. The output of both procedures was very similar, although the Bayesian analysis provided a richer inference and allowed us to calculate significance thresholds by generating a pseudo-observed data set from the estimated posterior distributions. We identified a very large number of genomic regions, but when a very restrictive significance threshold was applied these regions were reduced to only 10. Among them, four regions can be highlighted because they comprised a large number of single nucleotide polymorphisms and showed extremely high signals (Kullback-Leiber divergence (KLD)>6). They are located in BTA 2 (5 575 950 to 10 152 228 base pairs (bp)), BTA 5 (17 596 734 to 18 850 702 bp), BTA 6 (37 853 912 to 39 441 548 bp) and BTA 18 (13 345 515 to 15 243 838 bp) and harbor, among others, the MSTN (Myostatin), KIT-LG (KIT Ligand), LAP3 (leucine aminopeptidase 3), NAPCG (non-SMC condensing I complex, subunit G), LCORL (ligand dependent nuclear receptor corepressor-like) and MC1R (Melanocortin 1 receptor) genes. Knowledge on these genomic regions allows to identify potential targets of recent selection and helps to define potential candidate genes associated with traits of interest, such as coat color, muscle development, fertility, growth, carcass and immunological response.

Performance of genomic selection under a single-step approach in autochthonous Spanish beef cattle populations.

This study evaluated different strategies for implementing a single-step genomic selection programme in two autochthonous Spanish beef cattle populations (Pirenaica-Pi and Rubia Gallega-RG). The strategies were compared in terms of accuracy attained under different scenarios by simulating genomic data over the known genealogy. Several genotyping approaches were tested, as well as, other factors like marker density, effective population size, mutation rate and heritability of the trait. The results obtained showed gains in accuracy with respect to pedigree BLUP evaluation in all cases. The greatest benefit was obtained when the candidates to selection had their genotypes included in the evaluation. Moreover, genotyping the individuals with the most accurate predictions maximized the gains but other suboptimal strategies also yielded satisfactory results. Furthermore, the gains in accuracy increased with the marker density reaching a plateau at around 50,000 markers. Likewise, the effective population size and the mutation rate have also shown an effect, both increasing the accuracy with decreasing values of these population parameters. Finally, the results obtained for the RG population showed greater gains compared to the Pi population, probably attributed to the wider implantation of artificial insemination.

Bayesian analysis of parent-specific transmission ratio distortion in seven Spanish beef cattle breeds.

Transmission ratio distortion (TRD) is the departure from the expected Mendelian ratio in offspring, a poorly investigated biological phenomenon in livestock species. Given the current availability of specific parametric methods for the analysis of segregation data, this study focused on the screening of TRD in 602 402 single nucleotide polymorphisms covering all autosomal chromosomes in seven Spanish beef cattle breeds. On average, 0.13% (n = 786) and 0.01% (n = 29) of genetic markers evidenced sire- or dam-specific TRD respectively. There were no single nucleotide polymorphisms accounting for both sire- and dam-specific TRD at the same time, and only one marker (rs43147474) accounted for (sire-specific) TRD in all seven breeds. It must be noted that rs43147474 is located in the fourth intronic region of the GTP-binding protein 10 gene, and this locus has been previously linked to the maintenance of mitochondria and nucleolar architectures. Alternatively, other candidate genes surround this hot-spot for sire-specific TRD in the cattle genome, and they are related to embryonic and postnatal lethality as well as prostate cancer, among others. This research characterized the distribution of TRD in the bovine genome, highlighting heterogeneous results when comparing across breeds.

La vena femoral como vía de acceso alternativa para la estimulación cardiaca definitiva: experiencia de un centro / The femoral vein alternate path as for cardiac pacing final: Experience center

No disponible

Reproductive biology and nectar production of the Mexican endemic Psittacanthus auriculatus (Loranthaceae), a hummingbird-pollinated mistletoe.

Many mistletoe species produce 'bird'-pollinated flowers; however, the reproductive biology of the majority of these species has not been studied. Psittacanthus auriculatus is a Mexican endemic mistletoe, most common in open, dry mesquite grassland. Knowledge of the reproductive biology of P. auriculatus is essential for understanding species formation and diversification of Psittacanthus mistletoes, but it is currently poorly understood. Thus, we studied floral biology and phenology, nectar production and breeding system and pollination of this species. The hermaphroditic red-pink flowers open from the middle to the tip and petals are curly, but remain partially fused forming a floral tube of ca. 20-mm long. Flowers are partially protandrous, produce large amounts of nectar, last 2 days, and stigma receptivity is highest during the second day. We recorded hummingbirds (Cynanthus latirostris, Hylocharis leucotis, Amazilia beryllina, A. violiceps, Calothorax lucifer, Archilochus colubris) and less commonly butterflies (Agraulis vanillae, Anteos clorinde, Papilio multicaudatus, Phocides urania, Phoebis sennae) as floral visitors. P. auriculatus flowers are self-compatible. However, this mistletoe is an obligate animal-pollinated species, as the sensitive stigma avoids self-pollination. Under natural conditions, reproductive success was higher than in manually selfed or cross-pollinated flowers, likely due to the traplining foraging behaviour of hummingbirds. We suggest that the apparent efficient foraging behaviour of hummingbirds maintains gene flow among P. auriculatus, promoting outcrossing.

Genetic diversity and divergence among Spanish beef cattle breeds assessed by a bovine high-density SNP chip.

The availability of SNP chips for massive genotyping has proven to be useful to genetically characterize populations of domestic cattle and to assess their degree of divergence. In this study, the Illumina BovineHD BeadChip genotyping array was used to describe the genetic variability and divergence among 7 important autochthonous Spanish beef cattle breeds. The within-breed genetic diversity, measured as the marker expected heterozygosity, was around 0.30, similar to other European cattle breeds. The analysis of molecular variance revealed that 94.22% of the total variance was explained by differences within individuals whereas only 4.46% was the result of differences among populations. The degree of genetic differentiation was small to moderate as the pairwise fixation index of genetic differentiation among breeds (F) estimates ranged from 0.026 to 0.068 and the Nei's D genetic distances ranged from 0.009 to 0.016. A neighbor joining (N-J) phylogenetic tree showed 2 main groups of breeds: Pirenaica, Bruna dels Pirineus, and Rubia Gallega on the one hand and Avileña-Negra Ibérica, Morucha, and Retinta on the other. In turn, Asturiana de los Valles occupied an independent and intermediate position. A principal component analysis (PCA) applied to a distance matrix based on marker identity by state, in which the first 2 axes explained up to 17.3% of the variance, showed a grouping of animals that was similar to the one observed in the N-J tree. Finally, a cluster analysis for ancestries allowed assigning all the individuals to the breed they belong to, although it revealed some degree of admixture among breeds. Our results indicate large within-breed diversity and a low degree of divergence among the autochthonous Spanish beef cattle breeds studied. Both N-J and PCA groupings fit quite well to the ancestral trunks from which the Spanish beef cattle breeds were supposed to derive.

On the prediction of Hodgkin lymphoma treatment response.

PURPOSE: The cure rate in Hodgkin lymphoma is high, but the response along with treatment is still unpredictable and highly variable among patients. Detecting those patients who do not respond to treatment at early stages could bring improvements in their treatment. This research tries to identify the main biological prognostic variables currently gathered at diagnosis and design a simple machine learning methodology to help physicians improve the treatment response assessment. METHODS: We carried out a retrospective analysis of the response to treatment of a cohort of 263 Caucasians who were diagnosed with Hodgkin lymphoma in Asturias (Spain). For that purpose, we used a list of 35 clinical and biological variables that are currently measured at diagnosis before any treatment begins. To establish the list of most discriminatory prognostic variables for treatment response, we designed a machine learning approach based on two different feature selection methods (Fisher's ratio and maximum percentile distance) and backwards recursive feature elimination using a nearest-neighbor classifier (k-NN). The weights of the k-NN classifier were optimized using different terms of the confusion matrix (true- and false-positive rates) to minimize risk in the decisions. RESULTS AND CONCLUSIONS: We found that the optimum strategy to predict treatment response in Hodgkin lymphoma consists in solving two different binary classification problems, discriminating first if the patient is in progressive disease; if not, then discerning among complete and partial remission. Serum ferritin turned to be the most discriminatory variable in predicting treatment response, followed by alanine aminotransferase and alkaline phosphatase. The importance of these prognostic variables suggests a close relationship between inflammation, iron overload, liver damage and the extension of the disease.

Current indications and new applications of intense pulsed light.

Intense pulsed light (IPL) systems have evolved since they were introduced into medical practice 20 years ago. Pulsed light is noncoherent, noncollimated, polychromatic light energy emitted at different wavelengths that target specific chromophores. This selective targeting capability makes IPL a versatile therapy with many applications, from the treatment of pigmented or vascular lesions to hair removal and skin rejuvenation. Its large spot size ensures a high skin coverage rate. The nonablative nature of IPL makes it an increasingly attractive alternative for patients unwilling to accept the adverse effects associated with other procedures, which additionally require prolonged absence from work and social activities. In many cases, IPL is similar to laser therapy in effectiveness, and its versatility, convenience, and safety will lead to an expanded range of applications and possibilities in coming years.

Idiopathic facial aseptic granuloma.

Idiopathic facial aseptic granuloma (IFAG) is a condition that is commonly encountered in clinical practice, but is rarely reported. It appears in childhood and its pathogenesis is still unknown. It has a benign course with resolution within a few months without aggressive treatment. Microbiological tests are negative and histological findings are nonspecific. It is possible that this condition is part of the spectrum of granulomatous rosacea in childhood. We present two cases in which diagnosis of IFAG was established and resolved without sequelae following topical antibiotic treatment.

Monitoring changes in the demographic and genealogical structure of the main Spanish local beef breeds.

Demographic and pedigree analyses describe the structure and dynamics of livestock populations. We studied information recorded in the herdbooks of Asturiana de los Valles (AV; N = 458,806), Avileña-Negra Ibérica (ANI; N = 204,623), Bruna dels Pirineus (BP; N = 62,138), Morucha (Mo; N = 65,350), Pirenaica (Pi; N = 217,428), Retinta (Re; N = 135,300), and Rubia Gallega (RG; N = 235,511) beef breeds from their creation until 2009. All breeds have increased in the number of registered cows in recent years. In all breeds, herds do not behave as isolated entities and a high rate of exchange of breeding males between herds exists. A percentage of herds (12-52%) make some type of selection and sell bulls to other herds. There were large differences in average number of progeny per bull, ranging from 15.6 (AV) to 373.7 animals (RG, with a high incidence of AI). Generation interval estimates ranged from 4.7 (AV) to 7.6 (RG) yr in the sire pathway and from 5.95 (AV) to 7.8 (Mo) yr in the dam pathway. Density of pedigrees varied among breeds, with Pi, ANI, and Re having the more dense pedigrees, with average completeness indexes of more than 96% in the first generation and 80% when 6 generations were considered. A general increase in average inbreeding was observed in all breeds in the years analyzed. For animals born in 2009, average inbreeding coefficients ranged from 0.6 (BP) to 7.2% (Re) when all animals were considered and from 3.6 (Pi) to 17.6% (BP) when only inbred animals were considered. Due to the lack of completeness of pedigrees in most populations, inbreeding coefficients may be considered as a lower bound of the true parameters. The proportion of inbred animals tended to increase in the periods analyzed in all breeds. Differences between inbreeding and coancestry rates (except in RG) suggest the presence of population structure. Effective population size (Ne) based on the inbreeding rate estimated by regression ranged from 43 to 378 for Re and BP, whereas Ne estimates based on coancestry were greater, with a range of 100 for RG to 9,985 for BP. These facts suggest that an adequate mating policy can help to monitor inbreeding so as not to lose genetic variability. Effective number of ancestors in 2009 for 6 of the breeds ranged from 42 (RG) to 220 (AV), with BP having much a greater value, and was lower than was the effective number of founders in all breeds, suggesting the existence of bottlenecks.

Patrones de microscopia confocal para el cáncer cutáneo no melanoma y aplicaciones clínicas / Confocal Microscopy Patterns in Nonmelanoma Skin Cancer and Clinical Applications

Actualmente la microscopia confocal reflectante es la técnica diagnóstica no invasiva más prometedora para el estudio de estructuras cutáneas situadas entre la capa córnea y la dermis reticular superficial, obteniendo imágenes paralelas a la superficie cutánea en tiempo real y con una resolución microscópica similar a la observada en la histología convencional. Numerosos estudios han señalado las principales características confocales que se observan en distintas enfermedades cutáneas, tanto tumorales como inflamatorias, demostrando una buena correlación con ciertos patrones dermatoscópicos, así como con el examen histológico. Además, se han descrito algoritmos diagnósticos y patrones confocales que han demostrado unas altas tasas de sensibilidad y especificidad para el diagnóstico de tumores cutáneos de tipo melanoma y no melanoma. Las posibles aplicaciones presentes y futuras de esta tecnología son muy amplias, no solo como herramienta diagnóstica no invasiva, sino también para la evaluación de distintos procesos dinámicos como aquellos que ocurren tras la exposición de la piel a la radiación ultravioleta, o la respuesta de los tumores a terapias no invasivas como la terapia fotodinámica. Explicamos con detalle los hallazgos confocales característicos de los principales tumores cutáneos de tipo no melanoma y discutimos las posibles aplicaciones de esta novedosa técnica diagnóstica en la práctica diaria de la consulta dermatológica

Reflectance confocal microscopy is currently the most promising noninvasive diagnostic tool for studying cutaneous structures between the stratum corneum and the superficial reticular dermis. This tool gives real-time images parallel to the skin surface; the microscopic resolution is similar to that of conventional histology. Numerous studies have identified the main confocal features of various inflammatory skin diseases and tumors, demonstrating the good correlation of these features with certain dermatoscopic patterns and histologic findings. Confocal patterns and diagnostic algorithms have been shown to have high sensitivity and specificity in melanoma and nonmelanoma skin cancer. Possible present and future applications of this noninvasive technology are wide ranging and reach beyond its use in noninvasive diagnosis. This tool can also be used, for example, to evaluate dynamic skin processes that occur after UV exposure or to assess tumor response to noninvasive treatments such as photodynamic therapy. We explain the characteristic confocal features found in the main nonmelanoma skin tumors and discuss possible applications for this novel diagnostic technique in routine dermatology practice

Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD.

The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non-alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed with high fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 human hepatocytes loaded with palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8 h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24 h) induced ER stress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD.

Non-linear recursive models for growth traits in the Pirenaica beef cattle breed.

One of the main goals of selection schemes in beef cattle populations is to increase carcass weight at slaughter. Live weights at different growth stages are frequently used as selection criteria under the hypothesis that they usually have a high and positive genetic correlation with weight at slaughter. However, the presence of compensatory growth may bias the prediction ability of early weights for selection purposes. Recursive models may represent an interesting alternative for understanding the genetic and phenotypic relationship between weight traits during growth. For the purposes of this study, the analysis was performed for three different set of data from the Pirenaica beef cattle breed: weight at 120 days (W120) and at 210 days (W210); W120 and carcass weight at slaughter at 365 days (CW365); W210 and CW365. The number of records for each analysis was 8592, 4648 and 3234, respectively. A pedigree composed of 56323 individuals was also included. The statistical model comprised sex, year-season of birth, herd and slaughterhouse, plus a non-linear recursive dependency between traits. The dependency was modeled as a polynomial up to the 4th degree and models were compared using a Logarithm of Conditional Predictive Ordinates. The results of model comparison suggest that the best models were the 3rd degree polynomial for W120-W210 and W120-CW365 and the 2nd degree polynomial for W210-CW365. The posterior mean estimates for heritabilities ranged between 0.29 and 0.44 and the posterior mean estimates of the genetic correlations were null or very low, indicating that the relationship between traits is fully captured by the recursive dependency. The results imply that the predictive ability of the performance of future growth is low if it is only based on records of early weights. The usefulness of slaughterhouse records in beef cattle breeding evaluation is confirmed.