RESUMEN

Generation of functionally mature organs requires exquisite control of transcriptional programs governing cell state transitions during development. Despite advances in understanding the behavior of adult intestinal stem cells and their progeny, the transcriptional regulators that control the emergence of the mature intestinal phenotype remain largely unknown. Using mouse fetal and adult small intestinal organoids, we uncover transcriptional differences between the fetal and adult state and identify rare adult-like cells present in fetal organoids. This suggests that fetal organoids have an inherent potential to mature, which is locked by a regulatory program. By implementing a CRISPR-Cas9 screen targeting transcriptional regulators expressed in fetal organoids, we establish Smarca4 and Smarcc1 as important factors safeguarding the immature progenitor state. Our approach demonstrates the utility of organoid models in the identification of factors regulating cell fate and state transitions during tissue maturation and reveals that SMARCA4 and SMARCC1 prevent precocious differentiation during intestinal development.

Asunto(s)

Células Madre Adultas , Sistemas CRISPR-Cas , Animales , Ratones , Diferenciación Celular/genética , Feto , Organoides

RESUMEN

Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells.

Asunto(s)

Neoplasias de la Mama , Lisosomas , Humanos , Femenino , Lisosomas/metabolismo , Homeostasis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Lípidos/farmacología , Ácido Ursólico

RESUMEN

Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case-control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.

Asunto(s)

Epigenómica , Genes Reguladores , Endofenotipos , Cognición , Epigénesis Genética

RESUMEN

BACKGROUND: Psychiatric disorders are highly polygenic and show patterns of partner resemblance. Partner resemblance has direct population-level genetic implications if it is caused by assortative mating, but not if it is caused by convergence or social homogamy. Using genetics may help distinguish these different mechanisms. Here, we investigated whether partner resemblance for schizophrenia and bipolar disorder is influenced by assortative mating using polygenic risk scores (PRSs). METHODS: PRSs from The Danish High-Risk and Resilience Study-VIA 7 were compared between parents in three subsamples: population-based control parent pairs (N=198), parent pairs where at least one parent had schizophrenia (N=193), and parent pairs where at least one parent had bipolar disorder (N=115). RESULTS: The PRS for schizophrenia was predictive of schizophrenia in the full sample and showed a significant correlation between parent pairs (r=0.121, p=0.0440), indicative of assortative mating. The PRS for bipolar disorder was also correlated between parent pairs (r=0.162, p=0.0067), but it was not predictive of bipolar disorder in the full sample, limiting the interpretation. CONCLUSIONS: Our study provides genetic evidence for assortative mating for schizophrenia, with important implications for our understanding of the genetics of schizophrenia.

Asunto(s)

Trastorno Bipolar , Esquizofrenia , Trastorno Bipolar/genética , Humanos , Padres , Esquizofrenia/genética

RESUMEN

BACKGROUND: The COVID-19 pandemic and lockdown evoked great worries among professionals in the field of domestic violence and abuse (DVA) as they expected a rise of the phenomenon. While many countries reported increased DVA, the Netherlands did not. To understand this discrepancy and the overall impact of the lockdown on DVA support services, we interviewed DVA professionals about their experiences with DVA during the rise of COVID-19, the impact of the lockdown on clients and working conditions, and views on eHealth and online tools. METHODS: Semi-structured interviews were conducted among 16 DVA professionals with various specializations. This data was analyzed using open thematic coding and content analysis. RESULTS: Most professionals did not see an increase in DVA reports but they did notice more severe violence. They experienced less opportunities to detect DVA and worried about their clients' wellbeing and the quality of (online) care. Furthermore, their working conditions rapidly changed, with working from home and online, and they expressed frustration, insecurity and loneliness. Professionals feel eHealth and online tools are not always suitable but they do see them as an opportunity to increase reach and maintain services when physical contact is not possible. CONCLUSION: This study suggests DVA was probably under-detected during the lockdown rather than not having increased. The Dutch system heavily relies on professionals to detect and report DVA, suggesting a need for critical evaluation of the accessibility of professional help. Professionals experienced significant challenges and should themselves be supported psychologically and in their changed work practices to maintain their ability to aid survivors.

Asunto(s)

COVID-19 , Violencia Doméstica , Control de Enfermedades Transmisibles , Humanos , Países Bajos , Pandemias , SARS-CoV-2

RESUMEN

Direct dynamics simulation of singly hydrated peroxide ion reacting with CH3Cl reveals a new product channel that forms CH3OH + Cl- + HOOH, besides the traditional channel that forms CH3OOH + Cl- + H2O. This finding shows that singly hydrated peroxide ion behaves as a dual nucleophile through proton transfer between HOO-(H2O) and HO-(HOOH). Trajectory analysis attributes the occurrence of the thermodynamically and kinetically unfavored HO--induced pathway to the entrance channel dynamics, where extensive proton transfer occurs within the deep well of the prereaction complex. This study represents the first example of a single solvent molecule altering the nucleophile in a gas-phase ion-molecule nucleophilic substitution reaction, in addition to reducing the reactivity and affecting the dynamics, signifying the importance of dynamical effects of solvent molecules.

RESUMEN

Introduction: Although attenuated psychotic symptoms often occur for the first time during adolescence, studies focusing on adolescents are scarce. Attenuated psychotic symptoms form the criteria to identify individuals at increased clinical risk of developing psychosis. The study of individuals with these symptoms has led to the release of the DSM-5 diagnosis of Attenuated Psychosis Syndrome (APS) as a condition for further research. We aimed to characterize and compare hospitalized adolescents with DSM-5-APS diagnosis vs. hospitalized adolescents without a DSM-5-APS diagnosis. Methods: Interviewing help-seeking, hospitalized adolescents (aged 12-18 years) and their caregivers independently with established research instruments, we (1) evaluated the presence of APS among non-psychotic adolescents, (2) characterized and compared APS and non-APS individuals regarding sociodemographic, illness and intervention characteristics, (3) correlated psychopathology with levels of functioning and severity of illness and (4) investigated the influence of individual clinical, functional and comorbidity variables on the likelihood of participants to be diagnosed with APS. Results: Among 248 consecutively recruited adolescents (age=15.4 ± 1.5 years, females = 69.6%) with non-psychotic psychiatric disorders, 65 (26.2%) fulfilled APS criteria and 183 (73.8%) did not fulfill them. Adolescents with APS had higher number of psychiatric disorders than non-APS adolescents (3.5 vs. 2.4, p < 0.001; Cohen's d = 0.77), particularly, disruptive behavior disorders (Cramer's V = 0.16), personality disorder traits (Cramer's V = 0.26), anxiety disorders (Cramer's V = 0.15), and eating disorders (Cramer's V = 0.16). Adolescents with APS scored higher on positive (Cohen's d = 1.5), negative (Cohen's d = 0.55), disorganized (Cohen's d = 0.51), and general symptoms (Cohen's d = 0.84), and were more severely ill (Cohen's d = 1.0) and functionally impaired (Cohen's d = 0.31). Negative symptoms were associated with lower functional levels (Pearson ρ = -0.17 to -0.20; p = 0.014 to 0.031). Global illness severity was associated with higher positive, negative, and general symptoms (Pearson ρ = 0.22 to 0.46; p = 0.04 to p < 0.001). APS status was independently associated with perceptual abnormalities (OR = 2.0; 95% CI = 1.6-2.5, p < 0.001), number of psychiatric diagnoses (OR = 1.5; 95% CI = 1.2-2.0, p = 0.002), and impaired stress tolerance (OR = 1.4; 95% CI = 1.1-1.7, p = 0.002) (r 2 = 0.315, p < 0.001). Conclusions: A considerable number of adolescents hospitalized with non-psychotic psychiatric disorders meet DSM-5-APS criteria. These help-seeking adolescents have more comorbid disorders and more severe symptoms, functional impairment, and severity of illness than non-APS adolescents. Thus, they warrant high intensity clinical care.

RESUMEN

BACKGROUND: Skill-mix imbalance is a global concern for primary healthcare in low-income countries. In Rwanda, primary healthcare facilities (health centres, HCs) are predominantly led by nurses. They have to diagnose a multitude of health complaints. Whether they feel capable of undertaking this responsibility has yet to be explored. AIM: This study explored how healthcare providers (HPs) at Rwandan HCs perceived their capability in the diagnostic practice. SETTING: Rural and urban HCs in Muhanga district, Rwanda. METHOD: Qualitative, semi-structured interviews with nurses and clinical officers, and observations of consultations were made. Findings were analysed thematically. RESULTS: Rwandan HPs were confident in their competences to perform diagnostic procedures although nurses felt that the responsibilities lay beyond their professional training. Clinical officers believed that their professional training prepared them to function competently and autonomously in the diagnostic practice, although all HPs experienced a high dependency on medical history taking, physical examination and laboratory tests for reaching a diagnosis. Resource constraints (time, rooms and laboratory tests) were seen as a barrier to perform diagnostic tasks optimally, and HPs experienced in-service training and supervision as insufficient. They increased their diagnostic competences through work experience, self-learning and supportive peer collaboration. CONCLUSION: Clinical officers perceived themselves as capable in the diagnostic practice. Nurses may compensate for insufficient school training through in-service learning opportunities and feel capable in the diagnostic practice. Formative mentorship schemes and tailored education may prove valuable, but further research on how to improve HPs' diagnostic capability in Rwanda's primary healthcare sector is needed.

Asunto(s)

Personal de Salud , Atención Primaria de Salud , Actitud del Personal de Salud , Humanos , Capacitación en Servicio , Percepción , Rwanda

RESUMEN

BACKGROUND: One of the most basic human traits is language. Linguistic ability, and disability, have been shown to have a strong genetic component in family and twin studies, but molecular genetic studies of language phenotypes are scarce, relative to studies of other cognitive traits and neurodevelopmental phenotypes. Moreover, most genetic studies examining such phenotypes do not incorporate parent-of-origin effects, which could account for some of the heritability of the investigated trait. We performed a genome-wide association study of receptive language, examining both child genetic effects and parent-of-origin effects. RESULTS: Using a family-based cohort with 400 children with receptive language scores, we found a genome-wide significant paternal parent-of-origin effect with a SNP, rs11787922, on chromosome 9q21.31, whereby the T allele reduced the mean receptive language score by ~ 23, constituting a reduction of more than 1.5 times the population SD (P = 1.04 × 10-8). We further confirmed that this association was not driven by broader neurodevelopmental diagnoses in the child or a family history of psychiatric diagnoses by incorporating covariates for the above and repeating the analysis. CONCLUSIONS: Our study reports a genome-wide significant association for receptive language skills; to our knowledge, this is the first documented genome-wide significant association for this phenotype. Furthermore, our study illustrates the importance of considering parent-of-origin effects in association studies, particularly in the case of cognitive or neurodevelopmental traits, in which parental genetic data are not always incorporated.

Asunto(s)

Predisposición Genética a la Enfermedad/genética , Genotipo , Lenguaje , Polimorfismo de Nucleótido Simple/genética , Alelos , Niño , Preescolar , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Fenotipo

RESUMEN

Objectives: Bipolar disorder (BD) is a debilitating illness that often starts at an early age. Prevention of first and subsequent mood episodes, which are usually preceded by a period characterized by subthreshold symptoms is important. We compared demographic and clinical characteristics including severity and duration of subsyndromal symptoms across adolescents with three different bipolar-spectrum disorders. Methods: Syndromal and subsyndromal psychopathology were assessed in adolescent inpatients (age = 12-18 years) with a clinical mood disorder diagnosis. Assessments included the validated Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P). We compared phenomenology across patients with a research consensus conference-confirmed DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnoses of BD-I, BD-not otherwise specified (NOS), or mood disorder (MD) NOS. Results: Seventy-six adolescents (age = 15.6 ± 1.4 years, females = 59.2%) were included (BD-I = 24; BD-NOS = 29; MD-NOS = 23) in this study. Median baseline global assessment of functioning scale score was 21 (interquartile range = 17-40; between-group p = 0.31). Comorbidity was frequent, and similar across groups, including disruptive behavior disorders (55.5%, p = 0.27), anxiety disorders (40.8%, p = 0.98), and personality disorder traits (25.0%, p = 0.21). Mania symptoms (most frequent: irritability = 93.4%, p = 0.82) and depressive symptoms (most frequent: depressed mood = 81.6%, p = 0.14) were common in all three BD-spectrum groups. Manic and depressive symptoms were more severe in both BD-I and BD-NOS versus MD-NOS (p < 0.0001). Median duration of subthreshold manic symptoms was shorter in MD-NOS versus BD-NOS (11.7 vs. 20.4 weeks, p = 0.002) and substantial in both groups. The most used psychotropics upon discharge were antipsychotics (65.8%; BD-I = 79.2%; BD-NOS = 62.1%; MD-NOS = 56.5%, p = 0.227), followed by mood stabilizers (43.4%; BD-I = 66.7%; BD-NOS = 31.0%; MD-NOS = 34.8%, p = 0.02) and antidepressants (19.7%; BD-I = 20.8%; BD-NOS = 10.3%; MD-NOS = 30.4%). Conclusions: Youth with BD-I, BD-NOS, and MD-NOS experience considerable symptomatology and are functionally impaired, with few differences observed in psychiatric comorbidity and clinical severity. Moreover, youth with BD-NOS and MD-NOS undergo a period with subthreshold manic symptoms, enabling identification and, possibly, preventive intervention of those at risk for developing BD or other affective episodes requiring hospitalization.

Asunto(s)

Trastorno Bipolar/fisiopatología , Trastornos del Humor/epidemiología , Psicotrópicos/administración & dosificación , Adolescente , Trastornos de Ansiedad/epidemiología , Déficit de la Atención y Trastornos de Conducta Disruptiva/epidemiología , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/tratamiento farmacológico , Niño , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , Trastornos del Humor/diagnóstico , Trastornos de la Personalidad/epidemiología , Psicotrópicos/farmacología , Índice de Severidad de la Enfermedad

RESUMEN

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome-wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome-wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age-matched controls and perform regression analyses across groups. The SLI-trained PRS significantly predicted risk in the SLI case-control group (adjusted R2 = 6.24%; P = 0.024) but not in the ASD or ADHD case-control groups (adjusted R2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common-variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369-381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome-wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno del Espectro Autista/complicaciones , Estudio de Asociación del Genoma Completo/métodos , Trastorno Específico del Lenguaje/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno del Espectro Autista/genética , Niño , Dinamarca , Femenino , Humanos , Masculino , Trastorno Específico del Lenguaje/genética

RESUMEN

Background: Skill-mix imbalance is a global concern for primary healthcare in low-income countries. In Rwanda, primary healthcare facilities (health centres, HCs) are predominantly led by nurses. They have to diagnose a multitude of health complaints. Whether they feel capable of undertaking this responsibility has yet to be explored. Aim: This study explored how healthcare providers (HPs) at Rwandan HCs perceived their capability in the diagnostic practice. Setting: Rural and urban HCs in Muhanga district, Rwanda. Method: Qualitative, semi-structured interviews with nurses and clinical officers, and observations of consultations were made. Findings were analysed thematically. Results: Rwandan HPs were confident in their competences to perform diagnostic procedures although nurses felt that the responsibilities lay beyond their professional training. Clinical officers believed that their professional training prepared them to function competently and autonomously in the diagnostic practice, although all HPs experienced a high dependency on medical history taking, physical examination and laboratory tests for reaching a diagnosis. Resource constraints (time, rooms and laboratory tests) were seen as a barrier to perform diagnostic tasks optimally, and HPs experienced in-service training and supervision as insufficient. They increased their diagnostic competences through work experience, self-learning and supportive peer collaboration. Conclusion: Clinical officers perceived themselves as capable in the diagnostic practice. Nurses may compensate for insufficient school training through in-service learning opportunities and feel capable in the diagnostic practice. Formative mentorship schemes and tailored education may prove valuable, but further research on how to improve HPs' diagnostic capability in Rwanda's primary healthcare sector is needed

Asunto(s)

Personal de Salud , Enfermeras y Enfermeros , Pobreza , Atención Primaria de Salud , Rwanda

RESUMEN

The sebaceous gland (SG) is an essential component of the skin, and SG dysfunction is debilitating1,2. Yet, the cellular bases for its origin, development and subsequent maintenance remain poorly understood. Here, we apply large-scale quantitative fate mapping to define the patterns of cell fate behaviour during SG development and maintenance. We show that the SG develops from a defined number of lineage-restricted progenitors that undergo a programme of independent and stochastic cell fate decisions. Following an expansion phase, equipotent progenitors transition into a phase of homeostatic turnover, which is correlated with changes in the mechanical properties of the stroma and spatial restrictions on gland size. Expression of the oncogene KrasG12D results in a release from these constraints and unbridled gland expansion. Quantitative clonal fate analysis reveals that, during this phase, the primary effect of the Kras oncogene is to drive a constant fate bias with little effect on cell division rates. These findings provide insight into the developmental programme of the SG, as well as the mechanisms that drive tumour progression and gland dysfunction.

Asunto(s)

Proliferación Celular/fisiología , Regulación del Desarrollo de la Expresión Génica/inmunología , Homeostasis/fisiología , Células Madre/citología , Animales , Progresión de la Enfermedad , Ratones Transgénicos

RESUMEN

OBJECTIVE: To characterize social cognition, language, and social behavior as potentially shared vulnerability markers in children at familial high-risk of schizophrenia (FHR-SZ) and bipolar disorder (FHR-BP). METHODS: The Danish High-Risk and Resilience Study VIA7 is a multisite population-based cohort of 522 7-year-old children extracted from the Danish registries. The population-based controls were matched to the FHR-SZ children on age, sex, and municipality. The FHR-BP group followed same inclusion criteria. Data were collected blinded to familial high-risk status. Outcomes were social cognition, language, and social behavior. RESULTS: The analysis included 202 FHR-SZ children (girls: 46%), 120 FHR-BP children (girls: 46.7%), and 200 controls (girls: 46.5%). FHR-SZ children displayed significant deficits in language (receptive: d = -0.27, P = .006; pragmatic: d = -0.51, P < .001), social responsiveness (d = -0.54, P < .001), and adaptive social functioning (d = -0.47, P < .001) compared to controls after Bonferroni correction. Compared to FHR-BP children, FHR-SZ children performed significantly poorer on adaptive social functioning (d = -0.29, P = .007) after Bonferroni correction. FHR-BP and FHR-SZ children showed no significant social cognitive impairments compared to controls after Bonferroni correction. CONCLUSION: Language, social responsiveness, and adaptive social functioning deficits seem associated with FHR-SZ but not FHR-BP in this developmental phase. The pattern of results suggests adaptive social functioning impairments may not be shared between FHR-BP and FHR-SZ in this developmental phase and thus not reflective of the shared risk factors for schizophrenia and bipolar disorder.

Asunto(s)

Trastorno Bipolar , Hijo de Padres Discapacitados , Lenguaje , Esquizofrenia , Conducta Social , Percepción Social , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Riesgo , Ajuste Social

RESUMEN

OBJECTIVE: There is no standard method for assessing symptoms of the prodrome to bipolar disorder (BD), which has limited progress toward early identification and intervention. We aimed to validate the Bipolar Prodrome Symptom Scale-Abbreviated Screen for Patients (BPSS-AS-P), a brief self-report derived from the validated, clinician-rated Bipolar Prodrome Symptom Interview and Scale-Full Prospective (BPSS-FP), as a means to screen and identify people for whom further evaluation is indicated. METHOD: Altogether, 134 participants (aged 12-18 years) were drawn from a study of the pre-syndromal stage of mood and psychotic disorders. All participants had chart diagnoses of a mood- or psychosis-spectrum disorder. Participants were interviewed with the BPSS-FP and completed measures of mania and non-mood psychopathology. Prior to being interviewed, patients completed the BPSS-AS-P. Scores on the BPSS-AS-P were determined by summing the severity and frequency ratings for each item. RESULTS: BPSS-AS-P scores were highly reliable (Cronbach's alpha = 0.94) and correlated with the interview-based BPSS-FP Mania Symptom Index (r = 0.55, p < .0001). BPSS-AS-P scores had good convergent validity, correlating with the General Behavior Inventory-10M (r = 0.65, p < .0001) and Young Mania Rating Scale; r = 0.48, p < .0001). The BPSS-AS-P had good discriminant validity, not being correlated with scales measuring positive and negative symptoms of psychotic disorders (p-values = 0.072-0.667). LIMITATIONS: Findings are limited by the cross-sectional nature of the study by the fact that the participants were all treatment-seeking. Future studies need to evaluate the predictive validity of the BPSS-AS-P for identifying those who develop BD in a community sample. CONCLUSION: BPSS-AS-P has promise as a screening tool for people at risk for BD. Adopting the BPSS-AS-P would support the goal of characterizing the prodrome systematically in order to facilitate research and clinical care.

Asunto(s)

Trastorno Bipolar/diagnóstico , Tamizaje Masivo/normas , Síntomas Prodrómicos , Evaluación de Síntomas/normas , Adolescente , Trastorno Bipolar/psicología , Estudios Transversales , Femenino , Humanos , Masculino , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Psicometría , Trastornos Psicóticos/diagnóstico , Autoinforme

RESUMEN

The electrocardiogram (ECG) reveals that heart chamber activation and repolarization are much faster in mammals and birds compared to ectothermic vertebrates of similar size. Temperature, however, affects electrophysiology of the heart and most data from ectotherms are determined at body temperatures lower than those of mammals and birds. The present manuscript is a review of the effects of temperature on intervals in the ECG of ectothermic and endothermic vertebrates rather than a hypothesis-testing original research article. However, the conclusions are supported by the inclusion of original data (Iguana iguana, N = 4; Python regius, N = 5; Alligator mississippiensis, N = 4). Most comparisons were of animals of approximately 1 kg. Compared to mammals and birds, the reptiles at 35-37 °C had 4 fold lower heart rates, 2 fold slower atrial and ventricular conduction (longer P- and QRS-wave durations), and 4 fold longer PR intervals (atrioventricular delay) and QT intervals (total ventricular repolarization). We conclude that the faster chamber activation in endotherms cannot be explained by temperature alone. Based on histology, we show that endotherms have a more compact myocardial architecture. In mammals, disorganization of the compact wall by fibrosis associates with conduction slowing and we suggest the compact tissue architecture allows for faster chamber activation. The short cardiac cycle that characterizes mammals and birds, however, is predominantly accommodated by shortening of the atrioventricular delay and the QT interval, which is so long in a 1 kg iguana that it compares to that of an elephant.

Asunto(s)

Evolución Biológica , Regulación de la Temperatura Corporal , Electrocardiografía , Vertebrados/fisiología , Animales , Corazón/fisiología , Humanos

RESUMEN

The processes involved in renewal of the epithelium that lines the mouse stomach remain unclear. Apart from the cells in the isthmus, several other populations located deeper in the gastric glands have been suggested to contribute to the maintenance of the gastric epithelium. Here, we reveal that Lrig1 is expressed in the basal layer of the forestomach and the lower part of glands in the corpus and pylorus. In the glandular epithelium of the stomach, Lrig1 marks a heterogeneous population comprising mainly non-proliferative cells. Yet, fate-mapping experiments using a knock-in mouse line expressing Cre specifically in Lrig1+ cells demonstrate that these cells are able to contribute to the long-term maintenance of the gastric epithelium. Moreover, when cultured in vitro, cells expressing high level of Lrig1 have much higher organoid forming potential than the corresponding cellular populations expressing lower levels of Lrig1. Taken together, these observations show that Lrig1 is expressed primarily by differentiated cells, but that these cells can be recruited to contribute to the maintenance of the gastric epithelium. This confirms previous observations that cells located in the lower segments of gastric glands can participate in tissue replenishment.

Asunto(s)

Biomarcadores , Proliferación Celular , Células Epiteliales/metabolismo , Mucosa Gástrica/metabolismo , Glicoproteínas de Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Animales , Biomarcadores/metabolismo , Desdiferenciación Celular/genética , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Células Epiteliales/citología , Células Epiteliales/fisiología , Mucosa Gástrica/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estómago/citología

RESUMEN

BACKGROUND & AIMS: The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution. METHODS: To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant. RESULTS: HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization. CONCLUSIONS: We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization. LAY SUMMARY: HCV is an RNA virus that exists as a quasispecies of closely related genomes that are under continuous selection by host innate and adaptive immune responses and antiviral drug therapy. The primary site of HCV replication is the liver and yet our understanding of the spatial distribution of viral variants within the liver is limited. High resolution sequencing of HCV and monitoring of innate immune responses at multiple sites across the liver identified a uniform pattern of diversity and argues against viral compartmentalization.

Asunto(s)

Enfermedad Hepática en Estado Terminal , Hepacivirus , Hepatitis C Crónica , Interferones/farmacología , Hígado , Replicación Viral/efectos de los fármacos , Adulto , Antivirales/farmacología , Compartimento Celular/efectos de los fármacos , Enfermedad Hepática en Estado Terminal/etiología , Enfermedad Hepática en Estado Terminal/metabolismo , Enfermedad Hepática en Estado Terminal/virología , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana Edad , ARN Viral/análisis , Análisis de Secuencia de ARN/métodos

RESUMEN

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV-infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX-treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype (GT) 1-infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1-infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies.

Asunto(s)

Antivirales/uso terapéutico , Enfermedad Hepática en Estado Terminal/cirugía , Hepatitis C Crónica/tratamiento farmacológico , Virus de Hepatitis/efectos de los fármacos , Trasplante de Hígado , Fenilendiaminas/uso terapéutico , Receptores Depuradores de Clase B/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Internalización del Virus/efectos de los fármacos , Antivirales/efectos adversos , Antivirales/farmacocinética , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/virología , Inglaterra , Femenino , Genotipo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Virus de Hepatitis/genética , Virus de Hepatitis/patogenicidad , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Fenilendiaminas/efectos adversos , Fenilendiaminas/farmacocinética , ARN Viral/sangre , ARN Viral/genética , Recurrencia , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Carga Viral

RESUMEN

OBJECTIVES: DSM-5 conceptualized attenuated psychosis syndrome (APS) as self-contained rather than as a risk syndrome, including it under "Conditions for Further Study," but also as a codable/billable condition in the main section. Since many major mental disorders emerge during adolescence, we assessed the frequency and characteristics of APS in adolescent psychiatric inpatients. METHODS: Consecutively recruited adolescents hospitalized for nonpsychotic disorders (September 2009-May 2013) were divided into APS youth versus non-APS youth, based on the Structured Interview of Prodromal Syndromes (SIPS) and according to DSM-5 criteria, and compared across multiple characteristics. RESULTS: Of 89 adolescents (mean ± SD age = 15.1 ± 1.6 years), 21 (23.6%) had APS. Compared to non-APS, APS was associated with more comorbid disorders (2.7 ± 1.0 vs 2.2 ± 1.3), major depressive disorder (61.9% vs 27.9%), oppositional defiant disorder/conduct disorder (52.4% vs 25.0%), and personality disorder traits (57.1% vs 7.4%, the only diagnostic category surviving Bonferroni correction). APS youth were more severely ill, having higher SIPS total positive, negative, and general symptoms; Brief Psychiatric Rating Scale total and positive scores; depression and global illness ratings; and lower Global Assessment of Functioning (GAF). Conversely, Young Mania Rating Scale scores, suicidal behavior, prescribed psychotropic medications, and mental disorder awareness were similar between APS and non-APS groups. In multivariable analysis, lowest GAF score in the past year (odds ratio [OR] = 51.15; 95% confidence interval [CI], 2.46-2,439.0) and social isolation (OR = 27.52; 95% CI, 3.36-313.87) were independently associated with APS (r(2) = 0.302, P < .0001). Although psychotic disorders were excluded, 65.2% (APS = 57.1%, non-APS = 67.7%, P = .38) received antipsychotics. CONCLUSION: One in 4 nonpsychotic adolescent inpatients met DSM-5 criteria for APS. APS youth were more impaired, showing a complex entanglement with a broad range of psychiatric symptoms and disorders, including depression, impulse-control, and, especially, emerging personality disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01383915.

Asunto(s)

Manual Diagnóstico y Estadístico de los Trastornos Mentales , Trastornos Mentales/epidemiología , Trastornos de la Personalidad/epidemiología , Trastornos Psicóticos/epidemiología , Adolescente , Comorbilidad , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Síndrome