The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.

Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 

Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth.

BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats.

Compulsivity is considered a transdiagnostic dimension in obsessive-compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.

NMR-based Metabolomics and Fatty Acid Profiles to Unravel Biomarkers in Preclinical Animal Models of Compulsive Behavior.

Compulsivity is a key manifestation of inhibitory control deficit and a cardinal symptom of psychopathological conditions such as obsessive-compulsive and attention-deficit hyperactivity disorders, in which metabolic alterations have raised attention as putative biomarkers for early identification. The present study assessed the metabolic profile in a preclinical model of a compulsive phenotype of rats. We used the schedule-induced polydipsia (SIP) method to classify male Wistar rats into high drinkers (HDs) or low drinkers (LDs) according to their compulsive drinking rate developed by exposure to a fixed-time 60 s (FT-60) schedule of reinforcement with water available ad libitum during 20 sessions. Before and after SIP, blood samples were collected for subsequent serum analysis by nuclear magnetic resonance spectroscopy coupled to multivariate analysis. Although no differences existed in the pre-SIP set, the compulsive drinking behavior induced remarkable metabolic alterations: HD rats selected by SIP exhibited a hyperlipidemic, hypoglycemic, and hyperglutaminergic profile compared with their low-compulsive counterparts. Interestingly, these alterations were not attributable to the mere exposure to reward pellets because a control experiment did not show differences between HDs and LDs after 20 sessions of pellet consumption without intermittent reinforcement. Our results shed light toward the implication of dietary and metabolic factors underpinning the vulnerability to compulsive behaviors.

Socioemotional deficit and HPA axis time response in high compulsive rats selected by schedule-induced polydipsia.

Compulsivity is a failure to stop an ongoing behavior that has become inappropriate to the situation and is recognized as a transdiagnostic trait present in different neuropsychiatric disorders. The implication of motivation and emotion, as well as the stress response in compulsive population has not been fully understood. We assessed the motivation to reward and cues, the emotional response in different contexts and the hypothalamic-pituitary-adrenal (HPA) axis response in rats selected by a preclinical model of compulsive behavior. Firstly, high (HD) or low (LD) drinkers were selected according to their drinking behavior on schedule-induced polydipsia (SIP). Then, we assessed motivation by the propensity to attribute incentive salience to rewards on Pavlovian Conditioned Approach (PavCA) and motivation to gain reward on Progressive Ratio Schedule of Reinforcement (PRSR). Emotion was measured by Social Dominance on the Tube Test (SDTT) and emotional memory on Passive Avoidance (PA). Plasma corticosterone (CORT) levels in response to SIP were assessed. HD rats showed a socioemotional deficit by fewer victories on the SDTT, and an increased latency to enter the dark compartment on the PA. No differences were found between groups regarding to motivational assessment. Moreover, HD rats revealed a blunted time response in the increase of CORT levels at 45 min after SIP compared to LD rats. The findings show that the compulsive phenotype of HD rats exhibit less social dominance, more resistance to extinction and a differential CORT time response to SIP. These findings may contribute to highlight the relevance of assessing socioemotional behaviors and stress response for a better characterization of the vulnerability to compulsive spectrum disorders.

Multi-ancestry genome-wide association study of asthma exacerbations.

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Neuropsychiatric consequences of childhood group A streptococcal infection: A systematic review of preclinical models.

In recent years, clinical studies have shown strong epidemiological evidence of an increased risk of developing neuropsychiatric disorders after childhood exposure to streptococcal infection, including the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS). New preclinical studies on group A streptococcus (GAS) exposure investigate how to disentangle the influences of immune activation to induce long-term neurobehavioral effects associated with neuropsychiatric disorders such as obsessive-compulsive disorder, schizophrenia or autism. The present systematic review collects neurobehavioral evidence regarding the use of GAS exposure in animal models to study the vulnerability to different neuropsychiatric disorders, improving our understanding of its possible causes and consequences, and compares its contribution with other preclinical models of immune activation in a variety of paradigms. Specifically, we reviewed the effects of postnatal GAS exposure, in comparison with post- and prenatal exposure to Lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly I:C), on the long-term effects concerning psychomotor, cognition and socioemotional outcomes in rodents. GAS exposure in animal models has revealed different behavioral alterations such as reduced locomotion and motor coordination, a deficit in sensorimotor gating, learning, working memory, altered social behavior, and increased anxiety and stereotyped behavior. Most of the results found are in accordance with other immune activation models -LPS and Poly I:C-, with some discrepancies. The systematic review of the literature supports the preclinical model of GAS exposure as a valid model for studying the neurobehavioral consequences of streptococcal infections. Future studies on streptococcal infection could contribute increasing our knowledge on preventive actions or treatments for neuropsychiatric disorders.

Increased vulnerability to impulsive behavior after streptococcal antigen exposure and antibiotic treatment in rats.

RATIONALE: The inflammation induced by Group A Streptococcus (GAS) infection has been viewed as a vulnerability factor in mental disorders characterized by inhibitory control deficits, such as attention-deficit/hyperactivity disorder or obsessive-compulsive disorder. Antibiotic treatment reduces GAS symptoms; however, its effects on impulsivity have not been fully assessed. OBJECTIVES: We investigated whether GAS exposure during early adolescence might be a vulnerability factor for adult impulsivity, if antibiotic treatment acts as a protective factor, and whether these differences are accompanied by changes in the inflammatory cytokine frontostriatal regions. METHODS: Male Wistar rats were exposed to the GAS antigen or to vehicle plus adjuvants at postnatal day (PND) 35 (with two boosts), and they received either ampicillin (supplemented in the drinking water) or water alone from PND35 to PND70. Adult impulsivity was assessed using two different models, the 5-choice serial reaction time task (5-CSRT task) and the delay discounting task (DDT). The levels of interleukin-6 (IL-6) and IL-17 were measured in the prefrontal cortex (PFc), and the tumor necrosis factor α levels (TNFα) were measured in the PFc and nucleus accumbens (NAcc). RESULTS: GAS exposure and ampicillin treatment increased the waiting impulsivity by a higher number of premature responses when the animals were challenged by a long intertrial interval during the 5-CSRT task. The GAS exposure revealed higher impulsive choices at the highest delay (40 s) when tested by DDT, while coadministration with ampicillin prevented the impulsive choice. GAS exposure and ampicillin reduced the IL-6 and IL-17 levels in the PFc, and ampicillin treatment increased the TNFα levels in the NAcc. A regression analysis revealed a significant contribution of GAS exposure and TNFα levels to the observed effects. CONCLUSIONS: GAS exposure and ampicillin treatment induced an inhibitory control deficit in a different manner depending on the form of impulsivity measured here, with inflammatory long-term changes in the PFc and NAcc that might increase the vulnerability to impulsivity-related neuropsychiatric disorders.

Groupwise Non-Rigid Registration with Deep Learning: An Affordable Solution Applied to 2D Cardiac Cine MRI Reconstruction.

Groupwise image (GW) registration is customarily used for subsequent processing in medical imaging. However, it is computationally expensive due to repeated calculation of transformations and gradients. In this paper, we propose a deep learning (DL) architecture that achieves GW elastic registration of a 2D dynamic sequence on an affordable average GPU. Our solution, referred to as dGW, is a simplified version of the well-known U-net. In our GW solution, the image that the other images are registered to, referred to in the paper as template image, is iteratively obtained together with the registered images. Design and evaluation have been carried out using 2D cine cardiac MR slices from 2 databases respectively consisting of 89 and 41 subjects. The first database was used for training and validation with 66.6-33.3% split. The second one was used for validation (50%) and testing (50%). Additional network hyperparameters, which are-in essence-those that control the transformation smoothness degree, are obtained by means of a forward selection procedure. Our results show a 9-fold runtime reduction with respect to an optimization-based implementation; in addition, making use of the well-known structural similarity (SSIM) index we have obtained significative differences with dGW with respect to an alternative DL solution based on Voxelmorph.

Haplotype-Aware Detection of SERPINA1 Variants by Nanopore Sequencing.

α-1 Antitrypsin (AAT) is an acute-phase reactant with immunomodulatory properties that mainly inhibits neutrophil elastase. Low serum levels cause AAT deficiency (AATD), an underdiagnosed condition that predisposes to pulmonary and hepatic diseases. The SERPINA1 gene, which encodes AAT, contains >500 variants. PI∗Z and PI∗S alleles are the most diagnosed causes of AATD, but the role of the SERPINA1 haplotypes in AAT function remains unknown. SERPINA1 gene was PCR amplified from 94 patients with asthma, using primers with tails for indexing. Sequencing libraries were loaded into a MinION-Mk1C, and MinKNOW was used for basecalling and demultiplexing. Nanofilt and Minimap2 were used for filtering and mapping/alignment. Variant calling/phasing were performed with PEPPER-Margin-DeepVariant. SERPINA1 gene was 100% covered for all samples, with a minimum sequencing depth of 500×. A total of 75 single-nucleotide variants (SNVs) and 4 insertions/deletions were detected, with 45 and 2 of them highly polymorphic (minor allele frequency >0.1), respectively. Nine of the SNVs showed differences in allele frequencies when compared with the overall Spanish population. More than 90% of heterozygous SNVs were phased, yielding 91 and 58 different haplotypes for each SERPINA1 amplified region. Haplotype-based linkage disequilibrium analysis suggests that a recombination hotspot could generate variation in the SERPINA1 gene. The proposed workflow enables haplotype-aware genotyping of the SERPINA1 gene by nanopore sequencing, which will allow the development of novel AATD diagnostic strategies.

Differential Neurobiological Markers in Phenotype-stratified Rats Modeling High or Low Vulnerability to Compulsive Behavior: A Narrative Review.

Compulsivity is a key manifestation of inhibitory control deficit and a cardinal symptom in different neuropsychopathological disorders such as obsessive-compulsive disorder, schizophrenia, addiction, and attention-deficit hyperactivity disorder. Schedule-induced polydipsia (SIP), is an animal model to study compulsivity. In this procedure, rodents develop excessive and persistent drinking behavior under different food-reinforcement schedules, that are not related to homeostatic or regulatory requirements. However, there are important individual differences that support the role of high-drinker HD rats as a compulsive phenotype, characterized in different paradigms by inhibitory response deficit, cognitive inflexibility, and resistant to extinction behavior; with significant differences in response to pharmacological challenges, and relevant neurobiological alterations in comparison with the control group, the non-compulsive low drinker LD group on SIP. The purpose of this review is to collate and update the main findings on the neurobiological bases of compulsivity using the SIP model. Specifically, we reviewed preclinical studies on SIP, that have assessed the effects of serotonergic, dopaminergic, and glutamatergic drugs; leading to the description of the neurobiological markers, such as the key role of the serotonin 5-HT2A receptor and glutamatergic signaling in a phenotype vulnerable to compulsivity as high drinker HD rats selected by SIP. The review of the main findings of HD rats on SIP helps in the characterization of the preclinical compulsive phenotype, disentangles the underlying neurobiological, and points toward genetic hallmarks concerning the vulnerability to compulsivity.

Genomics of Treatable Traits in Asthma.

The astounding number of genetic variants revealed in the 15 years of genome-wide association studies of asthma has not kept pace with the goals of translational genomics. Moving asthma diagnosis from a nonspecific umbrella term to specific phenotypes/endotypes and related traits may provide insights into features that may be prevented or alleviated by therapeutical intervention. This review provides an overview of the different asthma endotypes and phenotypes and the genomic findings from asthma studies using patient stratification strategies and asthma-related traits. Asthma genomic research for treatable traits has uncovered novel and previously reported asthma loci, primarily through studies in Europeans. Novel genomic findings for asthma phenotypes and related traits may arise from multi-trait and specific phenotyping strategies in diverse populations.

Avoidance and inhibitory control are possible transdiagnostic traits? A systematic review in animal models.

In clinical research, aberrant avoidance behavior and inhibitory control deficit have a high comorbidity in different psychopathological disorders. Therefore, avoidance and impulsive and/or compulsive behaviors might be classified as transdiagnostic traits, where the assessment through animal models could address evidence of their contribution as neurobehavioral mechanisms in psychopathology. The objective of the present review has been to assess the avoidance trait and the implication of inhibitory control behaviors, through studies using passive and active avoidance tests in rodents, and a preclinical model using selective breeding of high- or low-avoidance Roman rats (RHA, RLA). A systematic search strategy was carried out in the PubMed and Web of Science databases, where a total of 40 studies were accepted in the qualitative synthesis. The results of the different studies reviewed pointed to a relation between a reduced avoidance profile in passive avoidance (PA) with impulsive decision making and novelty-seeking behaviors; an increased avoidance profile in PA with compulsive drinking; a high active avoidance profile, including RHA rats, with different types of impulsivity and novelty- seeking behaviors; and regarding compulsivity depending on its measure, a low active avoidance profile, including RLA rats, has been associated with increased anxiety in the EPM and increased grooming, while a high active avoidance profile, including RHA rats, has been associated with increased rearing, compulsive drinking including alcohol, and cognitive inflexibility. The results have been discussed in terms of environmental factors and the underlying mechanisms between these possible transdiagnostic traits in psychopathology.

Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats.

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC.

Behavioral domains in compulsive rats: implications for understanding compulsive spectrum disorders.

Introduction: Compulsive behavior has been proposed as a transdiagnostic trait observed in different neuropsychiatric disorders, such as obsessive-compulsive disorder, autism, and schizophrenia. Research Domain Criteria (RDoC) strategy could help to disentangle the neuropsychological basis of compulsivity for developing new therapeutic and preventive approaches. In preclinical research, the selection of high-drinker (HD) vs. low-drinker (LD) animals by schedule-induced polydipsia (SIP) is considered a putative model of compulsivity, which includes a well-differentiated behavioral pattern. Methods: The purpose of this research was to assess the cognitive control and the negative valence system domains in a phenotype of compulsive HD rats. After the selection of animals as HD or LD, we assessed behavioral inflexibility by probabilistic spatial reversal learning (PSRL), motor and cognitive impulsivity by variable delay-to-signal (VDS), and risky decision-making by rodent gambling task (rGT). Results: HD rats performed fewer reversals and showed less probability of pressing the same lever that was previously reinforced on PSRL, more premature responses after the exposure to longer delays on VDS, and more disadvantageous risky choices on rGT. Moreover, HD animals performed more perseverative responses under the punishment period on rGT. Discussion: These results highlight that HD compulsive phenotype exhibits behavioral inflexibility, insensitivity to positive feedback, waiting impulsivity, risky decision-making, and frustrative non-reward responsiveness. Moreover, these findings demonstrate the importance of mapping different behavioral domains to prevent, treat, and diagnose compulsive spectrum disorders correctly.

Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

INTRODUCTION AND OBJECTIVES: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. MATERIALS AND METHODS: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.

Negative valence system as a relevant domain in compulsivity: review in a preclinical model of compulsivity.

Compulsive behavior is observed in different neuropsychiatric disorders such as Obsessive-Compulsive Disorder (OCD), anxiety, phobia, schizophrenia and addiction. Compulsivity has been proposed as a transdiagnostic symptom, where the Research Domain Criteria (RDoC) strategy could help to understand its neuropsychological basis for a better understanding, and development of therapeutic and preventive strategies. However, research on compulsivity has been focused on the cognitive control domain, and the contribution of an altered negative valence system has been less considered. In this review, we collate the main findings in an animal model of compulsivity, the high drinker (HD) rats selected by Schedule-Induced Polydipsia (SIP) regarding these two research domains. This preclinical model of compulsivity has shown a phenotype characterized by a lack of behavioral inhibition, impulsive decision-making and cognitive inflexibility. Moreover, the results in compulsive HD rats, suggests that there is also a relevant alteration in the emotional dimension, linked to the negative valence system domain, as for example by: the increased perseverative responses in a withdrawal condition, associated with the behavioral construct of frustrative non-reward; and an inhibition or extinction deficit in memory retrieval associated with an alteration in the behavioral response to sustained threat. However, the precise nature of the link between these shared altered domains, cognitive control and negative valence system, remains unknown. These results point towards relevant behavioral aspects of the compulsive phenotype that should be taken into account when studying the vulnerability to compulsivity that could help in the development of a better transdiagnostic assessment, preventive and therapeutic strategies.

Increased Compulsivity in Adulthood after Early Adolescence Immune Activation: Preclinical Evidence.

Immune activation during early developmental stages has been proposed as a contributing factor in the pathogenesis of neuropsychiatric conditions such as obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and autism in both human and animal studies. However, its relationship with the vulnerability to inhibitory control deficit, which is a shared feature among those conditions, remains unclear. The present work studied whether postnatal immune activation during early adolescence, combined with exposure to early-life adverse events, could lead to adult vulnerability to impulsive and/or compulsive behaviors. Male Wistar rats were exposed to lipopolysaccharide (LPS) in early adolescence at postnatal day 26 (PND26). During peripuberal period, half of the animals were exposed to a mild stress protocol. In adulthood, behavioral assessment was performed with the aid of the sustained attentional 5-choice serial reaction time (5-CSRT) task, schedule-induced polydipsia (SIP), and open-field locomotor activity and novelty reactivity. Rats exposed to LPS showed more compulsive responses than their control counterparts on 5-CSRT task, although no differences were observed in SIP or locomotor responses. Our study contributes to the knowledge of the relationship between immune activation and inhibitory control deficit. Future studies should aim to disentangle how, and to what extent, immune activation impacts behavior, and to understand the role of early life mild stress.

The Role of Social Stress in the Development of Inhibitory Control Deficit: A Systematic Review in Preclinical Models.

Inhibitory control deficit and impulsivity and compulsivity behaviours are present in different psychopathological disorders such as addiction, obsessive-compulsive disorders and schizophrenia, among others. Social relationships in humans and animals are governed by social organization rules, which modulate inhibitory control and coping strategies against stress. Social stress is associated with compulsive alcohol and drug use, pointing towards a determining factor in an increased vulnerability to inhibitory control deficit. The goal of the present review is to assess the implication of social stress and dominance on the vulnerability to develop impulsive and/or compulsive spectrum disorders, with the aid of the information provided by animal models. A systematic search strategy was carried out on the PubMed and Web of Science databases, and the most relevant information was structured in the text and tables. A total of 34 studies were recruited in the qualitative synthesis. The results show the role of social stress and dominance in increased drug and alcohol use, aggressive and impulsive behaviour. Moreover, the revised studies support the role of Dopaminergic (DA) activity and the alterations in the dopaminergic D1/D2 receptors as key factors in the development of inhibitory control deficit by social stress.