Genomic Loci Influencing Cue-Reactivity in Heterogeneous Stock Rats.

Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues; both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1,645 genetically diverse heterogeneous stock (HS) rats. We tested HS rats in a Pavlovian conditioned approach task, in which we characterized the individual responses to food-associated stimuli ("cues"). Rats exhibited either cue-directed "sign-tracking" behavior or food-cup directed "goal-tracking" behavior. We then used the conditioned reinforcement procedure to determine whether rats would perform a novel operant response for unrewarded presentations of the cue. We found that these measures were moderately heritable (SNP heritability, h2 = .189-.215). GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits we examined. Interval sizes of these QTLs varied widely. 7 traits shared a QTL on chromosome 1 that contained a few genes (e.g. Tenm4, Mir708) that have been associated with substance use disorders and other mental health traits in humans. Other candidate genes (e.g. Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on other behavioral measures in HS rats and found that regions containing QTLs on chromosome 1 were also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive salience and provide further support for a relationship between attribution of incentive salience and drug abuse-related traits.

Adiponectin and resistin modulate the progression of Alzheimer´s disease in a metabolic syndrome model.

Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aß42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aß42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aß pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.

Electrophysiological assessment of peripheral and central autonomic disorders.

The autonomic nervous system (ANS) coordinates multiple reflex actions which are essential for life. The tests employed to evaluate the ANS provide valuable information of the functional state of these reflex arcs. The ideal test should be simple to perform, noninvasive, reproducible, sensitive, specific, safe, and appropriate for longitudinal studies. The availability of computer-based techniques has facilitated the electrophysiological assessment of ANS-mediated reflexes. The information provided by autonomic testing must be analyzed in combination with the clinical history and physical examination of the patient, allowing for a hypothesis that can be tested. Properly performed and interpreted, ANS testing can be used to confirm the presence of an ANS disturbance and the involved functional pathways, as well as the extent, intensity, and site of injury. This chapter describes the most important electrophysiological tests used to evaluate the ANS control of cardiovascular reflexes and sweat gland activity.

Spinal Cord Compression Due to Tophaceous Vertebral Gout: A Case Report.

Gout tophi are deposits of urate crystals in subcutaneous tissues and joints which commonly affect the small joints of the feet and hands, causing painful arthritis. The axial skeleton is considered to be seldom affected by gout arthritis. Here we describe the clinical, MRI, and pathologic findings of a 61-year-old male patient with a previous diagnosis of gout who presented with progressive paraparesis and radicular pain. MRI showed extradural masses compressing the spinal cord and roots at two spinal levels. Two surgical interventions were performed to remove these extradural masses, which were pathologically identified as gout tophi. Pain and paraparesis had clinical improvement after surgery. This report highlights that gout can be a cause of paraparesis.

[Leuko-glycemic index in patients with ST elevation myocardial infarction]. / Índice leucoglucémico en pacientes con infarto miocárdico con elevación del ST.

Background: The myocardial infarction-associated (MI) mortality is not only due cardiovascular complications, but intrahospital non-cardiovascular complications (IHnCVCs). The leuko-glycemic index (LGI) has been used as a prognostic marker for the development of cardiovascular complications in MI. We focused this study on identifying the cut-off point of LGI for the IHnCVCs development in patients with ST-segment elevation myocardial infarction (STEMI). Material and methods: In this single-center and crosssectional design, we included patients with STEMI. The biochemical analysis included glucose and leucocytes; with them we calculated the LGI. Receiver operating characteristic curve, univariate and bivariate analysis, and multivariate analysis for IHnCVCs development were performed. A p < 0.05 was considered statistically significant. Results: We included 1294 patients, 79.8% were men and 20.2% women. The main comorbidities were hypertension, diabetes mellitus and dyslipidemia. Six hundred forty-four (49.8%) patients presented IHNCVCs. The LGI > 1200 (AUC 0.817) predict the IHNCVCs development in STEMI patients. The variables that increased the IHNCVCs development were LGI > 1200, creatinine > 0.91 mg/dL, diabetes mellitus and age > 65 years. Hospital acquired pneumonia and cardiovascular complications increase the risk of death among STEMI patients. Conclusion: A LGI > 1200 increased, just over nine times, the risk of IHnCVC development in STEMI patients.

Introducción: la mortalidad asociada a infarto del miocardio (IM) no solo se debe a complicaciones cardiovasculares, sino tambien a complicaciones intrahospitalarias no cardiovasculares (CIHNC). El índice leuco-glucémico (ILG) se ha utilizado como un marcador pronóstico para el desarrollo de complicaciones cardiovasculares en el IM. Centramos este estudio en identificar el punto de corte de ILG para el desarrollo de CIHNC en pacientes con infarto de miocardio con elevación del segmento ST (IAMCEST). Material y métodos: en este diseño de un solo centro y transversal, incluimos pacientes con IAMCEST. El análisis bioquímico incluyó glucosa y leucocitos; se calculó ILG. Se realizaron análisis univariados y bivariados, curva ROC y análisis multivariado para el desarrollo de IAMCEST. Resultados: incluimos 1294 pacientes, 79.8% hombres y 20.2% mujeres. Las principales comorbilidades fueron: hipertensión arterial sistémica, diabetes mellitus y dislipidemia. Seiscientos cuarenta y cuatro pacientes (49.8%) presentaron CIHNC. El ILG > 1200 con área bajo la curva (AUC) 0.817 predice el desarrollo de CIHNC en pacientes con IAMCEST. Las variables que aumentaron el desarrollo de CIHNC fueron: ILG > 1200, creatinina > 0.91 mg/dL, diabetes mellitus y edad > 65 años. La neumonía intrahospitalaria y las complicaciones cardiovasculares aumentaron el riesgo de muerte entre los pacientes con IAMCEST. Conclusión: un LGI > 1200 aumentó más de nueve veces el riesgo de desarrollo de CIHNC en pacientes con IAMCEST.

Risk Factors and Outcomes for COVID-19 in Autoimmune Inflammatory Diseases during the SARS-CoV-2 Pandemic: A Comparative Study.

BACKGROUND: Patients with autoimmune disease (AID) and coronavirus disease 2019 (COVID-19) could have higher mortality due to the co-morbidity and the use of immunosuppressive therapy. OBJECTIVES: To analyze the risk factors and outcomes of patients with AID and COVID-19 versus a control group. METHODS: A prospective cohort study included patients with and without AID and COVID-19. Patients were paired by age and sex. Clinical, biochemical, immunological treatments, and outcomes (days of hospital stay, invasive mechanical ventilation [IMV], oxygen at discharge, and death) were collected. RESULTS: We included 226 COVID-19 patients: 113 with AID (51.15 ± 14.3 years) and 113 controls (53.45 ± 13.3 years). The most frequent AIDs were Rheumatoid arthritis (26.5%), systemic lupus erythematosus (21%), and systemic sclerosis (14%). AID patients had lower lactate dehydrogenas, C-reactive protein, fibrinogen, IMV (P = 0.027), and oxygen levels at discharge (P ≤ 0.0001) and lower death rates (P ≤ 0.0001). Oxygen saturation (SaO2) ≤ 88% at hospitalization provided risk for IMV (RR [relative risk] 3.83, 95% confidence interval [95%CI] 1.1-13.6, P = 0.038). Higher creatinine and LDH levels were associated with death in the AID group. SaO2 ≤ 88% and CO-RADS ≥ 4 were risk factors for in-hospital mortality (RR 4.90, 95%CI 1.8-13.0, P = 0.001 and RR 7.60, 95%CI 1.4-39.7, P = 0.016, respectively). Anticoagulant therapy was protective (RR 0.36, 95%CI 0.1-0.9, P = 0.041). CONCLUSIONS: Patients with AID had better outcomes with COVID-19 than controls. Anticoagulation was associated with a lower death in patients with AID.

Índice leucoglucémico en pacientes con infarto miocárdico con elevación del ST / Leuko-glycemic index in patients with ST elevation myocardial infarction

Introducción: la mortalidad asociada a infarto del miocardio (IM) no solo se debe a complicaciones cardiovasculares, sino también a complicaciones intrahospitalarias no cardiovasculares (CIHNC). El índice leuco-glucémico (ILG) se ha utilizado como un marcador pronóstico para el desarrollo de complicaciones cardiovasculares en el IM. Centramos este estudio en identificar el punto de corte de ILG para el desarrollo de CIHNC en pacientes con infarto de miocardio con elevación del segmento ST (IAMCEST). Material y métodos: en este diseño de un solo centro y transversal, incluimos pacientes con IAMCEST. El análisis bioquímico incluyó glucosa y leucocitos; se calculó ILG. Se realizaron análisis univariados y bivariados, curva ROC y análisis multivariado para el desarrollo de IAMCEST. Resultados: incluimos 1294 pacientes, 79.8% hombres y 20.2% mujeres. Las principales comorbilidades fueron: hipertensión arterial sistémica, diabetes mellitus y dislipidemia. Seiscientos cuarenta y cuatro pacientes (49.8%) presentaron CIHNC. El ILG > 1200 con área bajo la curva (AUC) 0.817 predice el desarrollo de CIHNC en pacientes con IAMCEST. Las variables que aumentaron el desarrollo de CIHNC fueron: ILG > 1200, creatinina > 0.91 mg/dL, diabetes mellitus y edad > 65 años. La neumonía intrahospitalaria y las complicaciones cardiovasculares aumentaron el riesgo de muerte entre los pacientes con IAMCEST. Conclusión: un LGI > 1200 aumentó más de nueve veces el riesgo de desarrollo de CIHNC en pacientes con IAMCEST.

Background: The myocardial infarction-associated (MI) mortality is not only due cardiovascular complications, but intrahospital non-cardiovascular complications (IHnCVCs). The leuko-glycemic index (LGI) has been used as a prognostic marker for the development of cardiovascular complications in MI. We focused this study on identifying the cut-off point of LGI for the IHnCVCs development in patients with ST-segment elevation myocardial infarction (STEMI).Material and methods: In this single-center and cross-sectional design, we included patients with STEMI. The biochemical analysis included glucose and leucocytes; with them we calculated the LGI. Receiver operating characteristic curve, univariate and bivariate analysis, and multivariate analysis for IHnCVCs development were performed. A p < 0.05 was considered statistically significant. Results: We included 1294 patients, 79.8% were men and 20.2% women. The main comorbidities were hypertension, diabetes mellitus and dyslipidemia. Six hundred forty-four (49.8%) patients presented IHNCVCs. The LGI > 1200 (AUC 0.817) predict the IHNCVCs development in STEMI patients. The variables that increased the IHNCVCs development were LGI > 1200, creatinine > 0.91 mg/dL, diabetes mellitus and age > 65 years. Hospital acquired pneumonia and cardiovascular complications increase the risk of death among STEMI patients. Conclusion: A LGI > 1200 increased, just over nine times, the risk of IHnCVC development in STEMI patients.

[Body composition and physical activity in resident physicians]. / Composición corporal y actividad física en médicos residentes.

BACKGROUND: Mexico is ranked second in obesity in adults worldwide and resident physicians are not exempt from this problem. Inadequate diet and physical inactivity are associated factors. Bioimpedance has greater precision than anthropometry. OBJECTIVE: To analyze the difference between degree of physical activity, caloric intake and body composition in Internal Medicine residents according to their degree of residence. MATERIAL AND METHODS: Cross-sectional study. Resident physicians of both sexes, from second, third and fourth degree of training were included; they were fasting. Vital signs were taken; a Rapid Assessment of Physical Activity (RAPA) questionnaire, anthropometry, a 24-hour reminder, and bioelectrical impedance analysis were administered. Descriptive statistics, Kruskal-Wallis and chi squared tests were used. RESULTS: 84 resident physicians were included, 48 were male. The median age was of 27 years (26-28). There was a prevalence of 46.4% of overweight and obesity, despite the hypocaloric diet in 89%. Bioelectrical impedance analysis showed that 72.6% of residents had elevated body fat, 71% sub-optimal degree of physical activity and 23.7% arterial hypertension. CONCLUSIONS: A high prevalence of overweight and obesity was found with differences in body composition and suboptimal level of physical activity. It is important to correct bad eating habits and improve physical activity to reduce risks in this population.

INTRODUCCIÓN: México es segundo lugar mundial en obesidad en adultos y los médicos residentes no están exentos de este problema. La dieta inadecuada y la inactividad física son factores asociados. La bioimpedancia tiene mayor precisión que la antropometría. OBJETIVO: analizar la diferencia entre grado de actividad física, ingesta calórica y composición corporal en residentes de Medicina Interna de acuerdo con su grado de residencia. MATERIAL Y MÉTODOS: estudio transversal. Se incluyeron médicos residentes de ambos sexos de segundo, tercero y cuarto grado, quienes participaron en ayuno. Se les tomaron signos vitales, se les otorgó el cuestionario Rapid Assesment of Physical Activity (RAPA), antropometría, recordatorio de 24 horas y medición de composición corporal por bioimpedancia. Se empleó estadística descriptiva, prueba de Kruskal-Wallis y chi cuadrada. RESULTADOS: se incluyeron 84 médicos residentes, 48 (57.14%) fueron del género masculino. La mediana de edad fue de 27 años (26-28). Se encontró una prevalencia de sobrepeso y obesidad de 46.4% a pesar de la dieta hipocalórica en el 89%. La medición por bioimpedancia indicó que 72.6% tuvo grasa corporal elevada, 71% grado de actividad física subóptimo y 23.7% hipertensión arterial. CONCLUSIONES: se encontró una alta prevalencia de sobrepeso y obesidad con diferencias en la composición corporal y el nivel subóptimo de actividad física. Es importante corregir los malos hábitos alimenticios y mejorar la actividad física para reducir riesgos en esta población.

Composición corporal y actividad física en médicos residentes / Body composition and physical activity in resident physicians

Introducción: México es segundo lugar mundial en obesidad en adultos y los médicos residentes no están exentos de este problema. La dieta inadecuada y la inactividad física son factores asociados. La bioimpedancia tiene mayor precisión que la antropometría. Objetivo: analizar la diferencia entre grado de actividad física, ingesta calórica y composición corporal en residentes de Medicina Interna de acuerdo con su grado de residencia. Material y métodos: estudio transversal. Se incluyeron médicos residentes de ambos sexos de segundo, tercero y cuarto grado, quienes participaron en ayuno. Se les tomaron signos vitales, se les otorgó el cuestionario Rapid Assesment of Physical Activity (RAPA), antropometría, recordatorio de 24 horas y medición de composición corporal por bioimpedancia. Se empleó estadística descriptiva, prueba de Kruskal-Wallis y chi cuadrada. Resultados: se incluyeron 84 médicos residentes, 48 (57.14%) fueron del género masculino. La mediana de edad fue de 27 años (26-28). Se encontró una prevalencia de sobrepeso y obesidad de 46.4% a pesar de la dieta hipocalórica en el 89%. La medición por bioimpedancia indicó que 72.6% tuvo grasa corporal elevada, 71% grado de actividad física subóptimo y 23.7% hipertensión arterial. Conclusiones: se encontró una alta prevalencia de sobrepeso y obesidad con diferencias en la composición corporal y el nivel subóptimo de actividad física. Es importante corregir los malos hábitos alimenticios y mejorar la actividad física para reducir riesgos en esta población.

Background: Mexico is ranked second in obesity in adults worldwide and resident physicians are not exempt from this problem. Inadequate diet and physical inactivity are associated factors. Bioimpedance has greater precision than anthropometry. Objective: To analyze the difference between degree of physical activity, caloric intake and body composition in Internal Medicine residents according to their degree of residence. Material and methods: Cross-sectional study. Resident physicians of both sexes, from second, third and fourth degree of training were included; they were fasting. Vital signs were taken; a Rapid Assessment of Physical Activity (RAPA) questionnaire, anthropometry, a 24-hour reminder, and bioelectrical impedance analysis were administered. Descriptive statistics, Kruskal-Wallis and chi squared tests were used. Results: 84 resident physicians were included, 48 were male. The median age was of 27 years (26-28). There was a prevalence of 46.4% of overweight and obesity, despite the hypocaloric diet in 89%. Bioelectrical impedance analysis showed that 72.6% of residents had elevated body fat, 71% sub-optimal degree of physical activity and 23.7% arterial hypertension. Conclusions: A high prevalence of overweight and obesity was found with differences in body composition and suboptimal level of physical activity. It is important to correct bad eating habits and improve physical activity to reduce risks in this population.

Genomic Approaches Reveal Pleiotropic Effects in Crossbred Beef Cattle.

Carcass and meat quality are two important attributes for the beef industry because they drive profitability and consumer demand. These traits are of even greater importance in crossbred cattle used in subtropical and tropical regions for their superior adaptability because they tend to underperform compared to their purebred counterparts. Many of these traits are challenging and expensive to measure and unavailable until late in life or after the animal is harvested, hence unrealistic to improve through traditional phenotypic selection, but perfect candidates for genomic selection. Before genomic selection can be implemented in crossbred populations, it is important to explore if pleiotropic effects exist between carcass and meat quality traits. Therefore, the objective of this study was to identify genomic regions with pleiotropic effects on carcass and meat quality traits in a multibreed Angus-Brahman population that included purebred and crossbred animals. Data included phenotypes for 10 carcass and meat quality traits from 2,384 steers, of which 1,038 were genotyped with the GGP Bovine F-250. Single-trait genome-wide association studies were first used to investigate the relevance of direct additive genetic effects on each carcass, sensory and visual meat quality traits. A second analysis for each trait included all other phenotypes as covariates to correct for direct causal effects from identified genomic regions with pure direct effects on the trait under analysis. Five genomic windows on chromosomes BTA5, BTA7, BTA18, and BTA29 explained more than 1% of additive genetic variance of two or more traits. Moreover, three suggestive pleiotropic regions were identified on BTA10 and BTA19. The 317 genes uncovered in pleiotropic regions included anchoring and cytoskeletal proteins, key players in cell growth, muscle development, lipid metabolism and fat deposition, and important factors in muscle proteolysis. A functional analysis of these genes revealed GO terms directly related to carcass quality, meat quality, and tenderness in beef cattle, including calcium-related processes, cell signaling, and modulation of cell-cell adhesion. These results contribute with novel information about the complex genetic architecture and pleiotropic effects of carcass and meat quality traits in crossbred beef cattle.

Andrographolide restores glucose uptake in rat hippocampal neurons.

Cerebral glucose hypometabolism is a common pathophysiological characteristic of many neurodegenerative diseases. This metabolic dysfunction includes alterations in glucose transport from the blood into the neurons by the facilitative glucose transporters (GLUTs). Several studies suggest that metabolic disturbances precede clinical symptoms and correlate with disease progression. Some groups have started to explore the use of therapeutic strategies that target decreased cerebral glucose metabolism to promote its availability. We selected Andrographolide (Andro), a natural product obtained from Andrographis paniculate that has both anti-hyperglycemic and anti-diabetic effects. Although it was shown to promote glucose uptake in vivo, the underlying mechanisms remain unclear. Here, we evaluated the acute effects of Andro on glucose transport and metabolism using primary rat hippocampal neuronal cultures. Our results showed that Andro enhances neuronal glucose uptake and stimulates glucose metabolism by inducing GLUT3 and 4 expression in neurons, as well as by promoting glycolysis. We also observed that Andro-mediated effects depend on the activity of AMP-activated protein kinase (AMPK), one of the central regulators of glucose metabolism. Our studies open the possibility to use Andro as a drug to restore glucose levels in neurodegenerative diseases.

Cardiovascular risk factors associated with coronary ectasia and acute myocardial infarction.

INTRODUCTION: Coronary ectasia has a low prevalence in the general population. Its risk factors may differ from those of coronary artery disease. OBJECTIVE: To identify the prevalence of coronary ectasia in patients with acute myocardial infarction (AMI) and cardiovascular risk factors (CVRFs). METHODS: Retrospective, cross-sectional study. Out of 3,254 cardiac catheterizations for AMI during one year, 2,975 had no coronary ectasia. We included 558 patients with coronary ectasia on coronary angiography and, as controls, subjects with similar characteristics except for coronary ectasia, and CVRFs were recorded. Descriptive statistics, bivariate and multivariate analysis were used; odds ratio (OR) was calculated. RESULTS: 279 patients with and without coronary ectasia were studied. The prevalence of coronary ectasia was 8.5 %. The platelet/lymphocyte ratio (PLR) was higher in patients with ectasia than in those without ectasia (p = 0.003). In the bivariate analysis, associated CVRFs were overweight, obesity and diabetes, and in the multivariate analysis, hypercholesterolemia (OR: 3.90; p = 0.0001) and exposure to herbicides (OR: 6.82; p = 0.020). CONCLUSIONS: A high prevalence of coronary ectasia was found, with the main risk factors being a history of herbicide use and hypercholesterolemia. PLR was found to be elevated in these patients. Early detection is important due to its association with acute coronary events.

INTRODUCCIÓN: La ectasia coronaria tiene baja prevalencia en población general, los factores de riesgo pueden diferir de la enfermedad arterial coronaria. OBJETIVO: Identificar la prevalencia de ectasia coronaria en pacientes con infarto agudo de miocardio (IAM) y factores de riesgo cardiovascular (FRCV). MÉTODOS: Estudio retrospectivo, transversal. De 3,254 cateterismos cardiacos por IAM durante un año, 2,975 no presentaron ectasia coronaria. Se incluyeron 558 pacientes clasificados como portadores de ectasia coronaria en coronariografía y controles aquellos con características similares exceptuando la ectasia coronaria y se registraron los FRCV. Empleamos estadística descriptiva, análisis bivariante, multivariante y calculamos el odds ratio (OR). RESULTADOS: Se estudiaron 279 pacientes con y sin ectasia coronaria. La prevalencia de ectasia coronaria fue del 8.5%. El índice plaqueta/linfocito (IPL) se encontró más elevado en pacientes con ectasia que en aquellos sin ectasia (p = 0.003). En el análisis bivariante los FRCV asociados fueron sobrepeso, obesidad y diabetes, y en el multivariante la hipercolesterolemia (OR: 3.90; p = 0.0001) y exposición a herbicidas (OR: 6.82; p = 0.020). CONCLUSIONES: Encontramos alta prevalencia de ectasia coronaria, los principales factores de riesgo fueron el antecedente de uso de herbicidas e hipercolesterolemia. Identificamos el IPL elevado en estos pacientes. Es importante la detección oportuna debido a su asociación con eventos coronarios agudos.

[Pulmonary alveolar proteinosis. Report of a case]. / Proteinosis alveolar pulmonar. Reporte de un caso.

BACKGROUND: The pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of lipoprotein material in the alveoli. It is classified as primary, secondary and congenital. The primary form, of autoimmune origin, is characterized by antibodies against granulocyte-macrophage colony stimulating factor (GM-CSF). The aim of this article is to present a case of PAP with adequate response to treatment with bronchoalveolar lavage (BAL) and GM-CSF. CLINICAL CASE: A 28-year-old female patient who started with mild to moderate effort dyspnea, distal cyanosis and lower respiratory tract infection. We found restrictive pattern respiratory function tests, chest X-ray with bilateral nodular reticulum pattern and high-resolution tomography with ground glass image and bronchiectasis, besides video bronchoscopy with inflammatory process. The open biopsy revealed data of alveolar proteinaceous material and mononuclear infiltrate. Treatment was given with BAL and GM-CSF which was suspended by dermal reaction. The patient had a satisfactory evolution and is currently asymptomatic. CONCLUSION: The present case had clinical, imaging and histological manifestations for the diagnosis of autoimmune PAP with a satisfactory response to treatment. Although PAP is a low prevalence entity, the diagnosis and therapeutic options must be taken into account, including BAL and GM-CSF, since this factor is required for surfactant factor homeostasis.

INTRODUCCIÓN: la proteinosis alveolar pulmonar (PAP) se caracteriza por la acumulación de material lipoproteináceo en los alveolos, y se clasifica en primaria, secundaria y congénita. La primaria, de origen autoinmune, se caracteriza por anticuerpos contra el factor estimulante de colonia de granulocitos y macrófagos (GM-CSF). El objetivo del presente trabajo es presentar un caso de PAP con buena respuesta al tratamiento con lavado broncoalveolar (LBA) y GM-CSF. CASO CLÍNICO: Caso clínico: distal e infección de vías respiratorias bajas. Se efectuaron pruebas de función respiratoria con patrón restrictivo, radiografía de tórax con patrón retículo nodular bilateral y tomografía de alta resolución con imagen de vidrio despulido y bronquiectasias, así como video broncoscopía con proceso inflamatorio. La biopsia a cielo abierto evidenció datos de material proteináceo alveolar e infiltrado mononuclear. Se dio tratamiento con LBA y GM-CSF, el cual fue suspendido por reacción dérmica. Tuvo evolución satisfactoria y actualmente se encuentra asintomática. CONCLUSIÓN: el presente caso tuvo manifestaciones clínicas, de imagen e histológicas para el diagnóstico de PAP autoinmune con respuesta satisfactoria. Para el tratamiento de la PAP, aunque es una entidad de baja prevalencia, se debe tener en cuenta el diagnóstico y las opciones terapéuticas, entre ellas, el LBA y el GM-CSF, puesto que este factor se requiere para la homeostasis del factor surfactante.

RNA-seq analysis identifies cytoskeletal structural genes and pathways for meat quality in beef.

RNA sequencing (RNA-seq) has allowed for transcriptional profiling of biological systems through the identification of differentially expressed (DE) genes and pathways. A total of 80 steers with extreme phenotypes were selected from the University of Florida multibreed Angus-Brahman herd. The average slaughter age was 12.91±8.69 months. Tenderness, juiciness and connective tissue assessed by sensory panel, along with marbling, Warner-Bratzler Shear Force (WBSF) and cooking loss, were measured in longissimus dorsi muscle. Total RNA was extracted from muscle and one RNA-seq library per sample was constructed, multiplexed, and sequenced based on protocols by Illumina HiSeq-3000 platform to generate 2×101 bp paired-end reads. The overall read mapping rate using the Btau_4.6.1 reference genome was 63%. A total of 8,799 genes were analyzed using two different methodologies, an expression association and a DE analysis. A gene and exon expression association analysis was carried out using a meat quality index on all 80 samples as a continuous response variable. The expression of 208 genes and 3,280 exons from 1,565 genes was associated with the meat quality index (p-value ≤ 0.05). A gene and isoform DE evaluation was performed analyzing two groups with extreme WBSF, tenderness and marbling. A total of 676 (adjusted p-value≤0.05), 70 (adjusted p-value≤0.1) and 198 (adjusted p-value≤0.1) genes were DE for WBSF, tenderness and marbling, respectively. A total of 106 isoforms from 98 genes for WBSF, 13 isoforms from 13 genes for tenderness and 43 isoforms from 42 genes for marbling (FDR≤0.1) were DE. Cytoskeletal and transmembrane anchoring genes and pathways were identified in the expression association, DE and the gene enrichment analyses; these proteins can have a direct effect on meat quality. Cytoskeletal proteins and transmembrane anchoring molecules can influence meat quality by allowing cytoskeletal interaction with myocyte and organelle membranes, contributing to cytoskeletal structure and architecture maintenance postmortem.

Whole Genome Sequence Data Provides Novel Insights Into the Genetic Architecture of Meat Quality Traits in Beef.

Tenderness is a major quality attribute for fresh beef steaks in the United States, and meat quality traits in general are suitable candidates for genomic research. The objectives of the present analysis were to (1) perform genome-wide association (GWA) analysis for marbling, Warner-Bratzler shear force (WBSF), tenderness, and connective tissue using whole-genome data in an Angus population, (2) identify enriched pathways in each GWA analysis; (3) construct a protein-protein interaction network using the associated genes and (4) perform a µ-calpain proteolysis assessment for associated structural proteins. An Angus-sired population of 2,285 individuals was assessed. Animals were transported to a commercial packing plant and harvested at an average age of 457 ± 46 days. After 48 h postmortem, marbling was recorded by graders' visual appraisal. Two 2.54-cm steaks were sampled from each muscle for recording of WBSF, and tenderness, and connective tissue by a sensory panel. The relevance of additive effects on marbling, WBSF, tenderness, and connective tissue was evaluated on a genome-wide scale using a two-step mixed model-based approach in single-trait analysis. A tissue-restricted gene enrichment was performed for each GWA where all polymorphisms with an association p-value lower than 1 × 10-3 were included. The genes identified as associated were included in a protein-protein interaction network and a candidate structural protein assessment of proteolysis analyses. A total of 1,867, 3,181, 3,926, and 3,678 polymorphisms were significantly associated with marbling, WBSF, tenderness, and connective tissue, respectively. The associate region on BTA29 (36,432,655-44,313,046 bp) harbors 13 highly significant markers for meat quality traits. Enrichment for the GO term GO:0005634 (Nucleus), which includes transcription factors, was evident. The final protein-protein network included 431 interations between 349 genes. The 42 most important genes based on significance that encode structural proteins were included in a proteolysis analysis, and 81% of these proteins were potential µ-Calpain substrates. Overall, this comprehensive study unraveled genetic variants, genes and mechanisms of action responsible for the variation in meat quality traits. Our findings can provide opportunities for improving meat quality in beef cattle via marker-assisted selection.

Acute Sensory and Autonomic Neuronopathy: A Devastating Disorder Affecting Sensory and Autonomic Ganglia.

Acute-onset and severe sensory and autonomic deficits with no motor dysfunction, typically preceded by a febrile illness, with poor recovery, and often fatal outcome are the hallmark features of acute sensory and autonomic neuronopathy (ASANN). Pathologically and electrophysiologically, ASANN is characterized by an extensive ganglionopathy affecting sensory and autonomic ganglia with preservation of motor neurons. Consequently, patients, usually children or young adult, develop acute-onset profound widespread loss of all sensory modalities resulting in automutilations, as well as autonomic failure causing neurogenic orthostatic hypotension, neurogenic underactive bladder, and gastroparesis and constipation. The diagnosis is clinical with support of nerve conduction studies and autonomic testing, as well as spinal cord magnetic resonance imaging showing characteristic posterior cord hyperintensities. Although the presumed etiology is immune-mediated, further studies are required to clarify the physiopathology of the disease. We here performed a systematic review of the epidemiology, pathophysiology, diagnosis, and management of ASANN, with three representative cases that recently presented at our clinic. All three patients had the typical clinical manifestations of ASANN but in different combinations, illustrating the variable phenotype of the disorder. Immunosuppression is seldom effective. Management options are limited to supportive and symptomatic care with the goal of minimizing complications and preventing death.

Identification of eQTLs and sQTLs associated with meat quality in beef.

BACKGROUND: Transcription has a substantial genetic control and genetic dissection of gene expression could help us understand the genetic architecture of complex phenotypes such as meat quality in cattle. The objectives of the present research were: 1) to perform eQTL and sQTL mapping analyses for meat quality traits in longissimus dorsi muscle; 2) to uncover genes whose expression is influenced by local or distant genetic variation; 3) to identify expression and splicing hot spots; and 4) to uncover genomic regions affecting the expression of multiple genes. RESULTS: Eighty steers were selected for phenotyping, genotyping and RNA-seq evaluation. A panel of traits related to meat quality was recorded in longissimus dorsi muscle. Information on 112,042 SNPs and expression data on 8588 autosomal genes and 87,770 exons from 8467 genes were included in an expression and splicing quantitative trait loci (QTL) mapping (eQTL and sQTL, respectively). A gene, exon and isoform differential expression analysis previously carried out in this population identified 1352 genes, referred to as DEG, as explaining part of the variability associated with meat quality traits. The eQTL and sQTL mapping was performed using a linear regression model in the R package Matrix eQTL. Genotype and year of birth were included as fixed effects, and population structure was accounted for by including as a covariate the first PC from a PCA analysis on genotypic data. The identified QTLs were classified as cis or trans using 1 Mb as the maximum distance between the associated SNP and the gene being analyzed. A total of 8377 eQTLs were identified, including 75.6% trans, 10.4% cis, 12.5% DEG trans and 1.5% DEG cis; while 11,929 sQTLs were uncovered: 66.1% trans, 16.9% DEG trans, 14% cis and 3% DEG cis. Twenty-seven expression master regulators and 13 splicing master regulators were identified and were classified as membrane-associated or cytoskeletal proteins, transcription factors or DNA methylases. These genes could control the expression of other genes through cell signaling or by a direct transcriptional activation/repression mechanism. CONCLUSION: In the present analysis, we show that eQTL and sQTL mapping makes possible positional identification of gene and isoform expression regulators.

Association study reveals Th17, Treg, and Th2 loci related to resistance to Haemonchus contortus in Florida Native sheep1.

The aim of this study was to identify for the first time single nucleotide polymorphisms (SNPs) associated with Haemonchus contortus resistance in Florida Native sheep, using a targeted sequencing approach. One hundred and fifty-three lambs were evaluated in this study. At the start of the trial, phenotypic records for fecal egg count (FEC), FAMACHA score, body condition score (BCS), and weight were recorded and deworming of sheep with levamisole (18 mg/kg of body weight) was performed. Ten days post-deworming (baseline) and 28 d post-baseline, a full hematogram of each sheep was obtained and FEC, FAMACHA score, BCS, and weight were assessed. Average daily gain was calculated at the end of the trial. Out of 153 animals, 100 sheep were selected for genotyping using a targeted sequencing approach. Targeted sequencing panel included 100 candidate genes for immune response against H. contortus. SNPs were discarded if call rate <95% and minor allele frequency ≤0.05. A mixed model was used to analyze the response variables and included the identity by state matrix to control for population structure. A contemporary group (age, group, and sex) was included as fixed effect. Bonferroni correction was used to control for multiple testing. Eighteen SNPs on chromosomes 1, 2, 3, 4, 6, 7, 11, 15, 18, 20, 24, and 26 were significant for different traits. Our results suggest that loci related to Th17, Treg, and Th2 responses play an important role in the expression of resistant phenotypes. Several genes including ITGA4, MUC15, TLR3, PCDH7, CFI, CXCL10, TNF, CCL26, STAT3, GPX2, IL2RB, and STAT6 were identified as potential markers for resistance to natural H. contortus exposure. This is the first study that evaluates potential genetic markers for H. contortus resistance in Florida Native sheep.

Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations.

OBJECTIVES: This study compares the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) within three clinic-based populations from Cuba, Uruguay and Ireland and determines the impact of known ALS-associated genetic variants on phenotypic manifestations within the Cuban population. METHODS: Demographic and clinical information was collected on 115 Cuban, 220 Uruguayan and 1038 Irish patients with ALS attending national specialist clinics through 1996-2017. All Cuban patients and 676 Irish patients underwent next-generation DNA sequencing and were screened for the pathogenic C9orf72 repeat expansion. RESULTS: The mean age of onset was younger in the Cuban (53.0 years, 95% CI 50.4 to 55.6) and Uruguayan (58.2 years, 95% CI 56.5 to 60.0) populations compared with the Irish population (61.6 years, 95% CI 60.9 to 62.4). No differences in survival between populations were observed. 1.7 % (95% CI 0.6 to 4.1) of Cubans with ALS carried the C9orf72 repeat expansion compared with 9.9% (95% CI 7.8 to 12.0) of Irish patients with ALS (p=0.004). Other known variants identified in the Cuban population included ANG (one patient), CHCHD10 (one patient) and DCTN1 (three patients). CONCLUSIONS AND RELEVANCE: This study is the first to describe the clinical characteristics of ALS in Cuban and Uruguayan populations and report differences between the Cuban and Irish genetic signature in terms of known ALS-associated genetic variants. These novel clinical and genetic data add to our understanding of ALS across different and understudied populations.

Genome wide association and gene enrichment analysis reveal membrane anchoring and structural proteins associated with meat quality in beef.

BACKGROUND: Meat quality related phenotypes are difficult and expensive to measure and predict but are ideal candidates for genomic selection if genetic markers that account for a worthwhile proportion of the phenotypic variation can be identified. The objectives of this study were: 1) to perform genome wide association analyses for Warner-Bratzler Shear Force (WBSF), marbling, cooking loss, tenderness, juiciness, connective tissue and flavor; 2) to determine enriched pathways present in each genome wide association analysis; and 3) to identify potential candidate genes with multiple quantitative trait loci (QTL) associated with meat quality. RESULTS: The WBSF, marbling and cooking loss traits were measured in longissimus dorsi muscle from 672 steers. Out of these, 495 animals were used to measure tenderness, juiciness, connective tissue and flavor by a sensory panel. All animals were genotyped for 221,077 markers and included in a genome wide association analysis. A total number of 68 genomic regions covering 52 genes were identified using the whole genome association approach; 48% of these genes encode transmembrane proteins or membrane associated molecules. Two enrichment analysis were performed: a tissue restricted gene enrichment applying a correlation analysis between raw associated single nucleotide polymorphisms (SNPs) by trait, and a functional classification analysis performed using the DAVID Bioinformatic Resources 6.8 server. The tissue restricted gene enrichment approach identified eleven pathways including "Endoplasmic reticulum membrane" that influenced multiple traits simultaneously. The DAVID functional classification analysis uncovered eleven clusters related to transmembrane or structural proteins. A gene network was constructed where the number of raw associated uncorrelated SNPs for each gene across all traits was used as a weight. A multiple SNP association analysis was performed for the top five most connected genes in the gene-trait network. The gene network identified the EVC2, ANXA10 and PKHD1 genes as potentially harboring multiple QTLs. Polymorphisms identified in structural proteins can modulate two different processes with direct effect on meat quality: in vivo myocyte cytoskeletal organization and postmortem proteolysis. CONCLUSION: The main result from the present analysis is the uncovering of several candidate genes associated with meat quality that have structural function in the skeletal muscle.