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Puberty is a critical period of development marked by sexual, immune, and neural maturation. Exposure to stress during this period can lead to enduring changes in brain functioning and in behavior; however, the underlying mechanisms and the programming effects of stress during puberty remain unknown. Therefore, the objective of this study was to investigate the programming effects of pubertal immune challenge in response to a homotypic stressor later in life in CD-1 mice. Age and sex differences in the peripheral and central cytokine levels, along with sickness behavior and telemetry data, were analyzed following the secondary treatment. The results showed that pretreatment with LPS attenuated the immune response to a second homotypic challenge. Males pretreated with LPS during puberty and in early adulthood displayed an attenuated hypothermic response following the second LPS treatment compared with saline-pretreated controls, which is consistent with the attenuated peripheral IL-6 and IFN-γ concentrations. Females pretreated with LPS during puberty displayed lower IL-1ß, TNF-α, and IL-6 mRNA expression in the prefrontal cortex following the secondary immune challenge compared with saline controls. The results of this study show that exposure to LPS during puberty programs the peripheral and central immune responses, resulting in an attenuated immune response following a subsequent homotypic stressor. Thus, exposure to an immune challenge during puberty affects immune function later in life, which could permanently affect brain function and have implications on mental health.
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Fenómenos del Sistema Inmunológico/efectos de los fármacos , Lipopolisacáridos/toxicidad , Maduración Sexual/inmunología , Estrés Fisiológico/inmunología , Animales , Femenino , Masculino , RatonesRESUMEN
PURPOSE: Multimorbidity is increasing in younger adults but is understudied in this population. We used 22q11.2 deletion syndrome (22q11.2DS) as a genetic model to investigate multimorbidity in young to middle-aged adults. METHODS: Using the Anatomical Therapeutic Chemical (ATC) Classification System and setting five or more concurrent prescription medications as a proxy for multimorbidity, we compared data on 264 adults with 22q11.2DS (median age 27.8, range 17.3-68.3 years) with that for a community-based Canadian general population sample (n = 25,287). We used logistic regression to examine possible predictors of multimorbidity in 22q11.2DS. RESULTS: Multimorbidity in 22q11.2DS in the 25-44 year age group (34.7%) was significantly more prevalent than in the general population, both for the same age group (2.9%, prevalence ratio [PR] = 11.9, 95% CI 8.4-17.1) and compared with those aged 45-64 years (16.4%, PR = 2.1, 95% CI 1.6-2.7). Neuropsychiatric and endocrinological medication classes predominated. Within 22q11.2DS, older age and psychotic illness, but not sex, major congenital heart disease, or intellectual disability, were significant predictors of multimorbidity. CONCLUSION: The results indicate that adults with 22q11.2DS have a significant burden of illness with levels of multimorbidity comparable with those of the general population several decades older. In younger adults with multimorbidity, certain disease patterns may help identify genetic disorders in "big data."
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Síndrome de DiGeorge/genética , Modelos Genéticos , Multimorbilidad , Adolescente , Adulto , Anciano , Canadá/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polifarmacia , Prevalencia , Adulto JovenRESUMEN
PURPOSE: Given limited data available on long-term outcomes in 22q11.2 deletion syndrome (22q11.2DS), we investigated mortality risk in adults with this microdeletion syndrome. METHODS: We studied 309 well-characterized adults (age ≥17 years) with 22q11.2DS and their 1014 unaffected parents and siblings, using a prospective case-control design. We used Cox proportional hazards regression modeling and Kaplan-Meier curves to investigate effects of the 22q11.2 deletion and its associated features on all-cause mortality and survival. RESULTS: The 22q11.2 deletion (hazard ratio [HR] 8.86, 95% CI 2.87-27.37) and major congenital heart disease (CHD; HR 5.03, 95% CI 2.27-11.17), but not intellectual disability or psychotic illness, were significant independent predictors of mortality for adults with 22q11.2DS compared with their siblings. Amongst those with 22q11.2DS, there were 31 deaths that occurred at a median age of 46.4 (range 18.1-68.6) years; a substantial minority had outlived both parents. Probability of survival to age 45 years was approximately 72% for those with major CHD, and 95% for those with no major CHD (p < 0.0001). CONCLUSION: For adults with 22q11.2DS, the 22q11.2 deletion and more severe forms of CHD both contribute to a lower life expectancy than family-based expectations. The results have implications for genetic counseling and anticipatory care.
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Síndrome de DiGeorge/genética , Síndrome de DiGeorge/mortalidad , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Femenino , Asesoramiento Genético , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Puberty is an important developmental event that is marked by the reorganizing and remodeling of the brain. Exposure to stress during this critical period of development can have enduring effects on both reproductive and non-reproductive behaviors. The purpose of this study was to investigate age and sex differences in immune response by examining sickness behavior, body temperature changes, and serum cytokine levels following an immune challenge. The effects of circulating gonadal hormones on age and sex differences in immune response were also examined. Results showed that male mice display more sickness behavior and greater fluctuations in body temperature following LPS treatment than female mice. Moreover, adult male mice display more sickness behavior and a greater drop in body temperature following LPS treatment compared to pubertal male mice. Following gonadectomy, pubertal and adult males displayed steeper and prolonged drops in body temperature compared to sham-operated counterparts. Gonadectomy did not eliminate sex differences in LPS-induced body temperature changes, suggesting that additional factors contribute to the observed differences. LPS treatment increased cytokine levels in all mice. However, the increase in pro-inflammatory cytokines was higher in adult compared to pubertal mice, while the increase in anti-inflammatory cytokines was greater in pubertal than in adult mice. Our findings contribute to a better understanding of age and sex differences in acute immune response following LPS treatment and possible mechanisms involved in the enduring alterations in behavior and brain function following pubertal exposure to LPS.
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Envejecimiento/inmunología , Inmunidad , Caracteres Sexuales , Maduración Sexual/inmunología , Animales , Temperatura Corporal , Citocinas/sangre , Femenino , Conducta de Enfermedad , Inflamación/inmunología , Mediadores de Inflamación/inmunología , Lipopolisacáridos/administración & dosificación , Masculino , RatonesRESUMEN
Introduction: There is complexity to the success of faculty development (FD) programs at the departmental level, and many of the contributing factors can range from the individual to systems levels. The purpose of this study is to explore faculty perception of what FD encompasses, as well as their past/current experiences with FD, and perceptions regarding the importance, barriers, and facilitators to participating in FD. Methods: This is a single center, qualitative descriptive study guided through a social constructionist perspective. Faculty from a pediatrics department were asked to participate in 1-h focus groups of 4-5 faculty per group. All sessions were done virtually and audio-recorded for transcription. Inductive reflexive thematic analysis was performed on the transcribed data. Results: Overall, 5 major themes were identified: (1) purpose/meaning of FD for faculty, (2) perceptions of faculty regarding FD, (3) challenges that faculty encounter with FD, (4) designing and delivering FD to faculty, and (5) comparing FD and continuing professional development (CPD). Some of the main findings included (a) creating flexible and personalized FD curricula, (b) department focusing on bringing the faculty together as a community, and (c) department developing a broader definition of FD that could be used as a reference point in the whole department. Discussion: Our findings suggest that barriers and challenges for accessing and making the most of FD opportunities still persist. Going forward, departments interested in improving their FD initiatives should focus on individualized, flexible, and technology enhanced FD approaches that motivate participation.
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Reflective practice is important for learning, accurate self-assessment, and fostering a growth mindset as a resident physician. To help identify candidates with these traits, we designed a multiple mini interview (MMI) station to prompt applicants to demonstrate critical reflection of their performance on an unfamiliar task and provide a self-assessment. The results show us that this station had clear consequences in the eventual rank list of candidates suggesting that it might provide valuable insight for selection committees to identify applicants who lack skills in self-reflection.
La pratique réflexive est importante pour l'apprentissage, la précision de l'auto-évaluation et la promotion d'un état d'esprit de développement chez le médecin résident. Pour mieux cibler les candidats présentant ces caractéristiques, nous avons conçu une station de mini-entrevues multiples (MMI) pour inciter les candidats à auto-évaluer leur performance dans une tâche peu familière en faisant preuve de réflexion critique. D'après les résultats, cette station a eu des conséquences claires sur le classement final des candidats, ce qui suggère qu'elle serait utile aux comités de sélection pour repérer les candidats qui manquent de capacité d'autoréflexion.
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BACKGROUND: Because of the importance of identifying factors that affect late outcomes in the increasing population of those with tetralogy of Fallot (TOF), we aimed to determine the effect of a 22q11.2 microdeletion on adult mortality, while accounting for pulmonary atresia, known to be enriched in 22q11.2 deletion syndrome (22q11.2DS). METHODS: We studied 612 individuals with TOF recruited as adults at a single centre, 80 (13.1%) with molecularly confirmed 22q11.2 deletions and 532 without 22q11.2DS, followed for a total of 5961.3 person-years. Using a case-control design, Cox proportional hazard regression and Kaplan-Meier curves, we evaluated the effect of a 22q11.2 deletion on mortality and survival. RESULTS: All-cause mortality was 1.87% per person-year in the 22q11.2DS-TOF group and 0.80% in the other-TOF group. The presence of a 22q11.2 microdeletion was a significant predictor of adult mortality in TOF (hazard ratio, 5.00; P < 0.0001), after accounting for pulmonary atresia (hazard ratio, 2.71; P = 0.0106) and other factors. Overall, individuals with 22q11.2DS died on average 17.7 years earlier (P = 0.0055) than others with TOF, predominantly of cardiovascular causes, with proportionately more sudden cardiac deaths in those with 22q11.2DS-TOF (n = 5 [38.5%] vs n = 5 [11.9%], other-TOF; P = 0.0447). Kaplan-Meier curves showed reduced survival for those with 22q11.2DS (P < 0.0001); probability of survival to age 45 years, without pulmonary atresia, was 72% (22q11.2DS-TOF) and 98% (other-TOF). CONCLUSIONS: The results suggest that the 22q11.2 deletion significantly contributes to premature mortality in adults with TOF, mediated only in part by greater anatomic complexity. The interpretation of late outcome data in TOF will likely benefit from further genetic subtyping.
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Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Tetralogía de Fallot/genética , Adulto , Causas de Muerte/tendencias , Femenino , Humanos , Masculino , Ontario/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Tetralogía de Fallot/mortalidad , Adulto JovenRESUMEN
Naked mole-rats are highly social rodents that live in large groups and exhibit a strict reproductive and social hierarchy. Only a few animals in each colony breed; the remainder are non-reproductive and are socially subordinate to breeders. We have examined androgen receptor immunoreactive (AR+) cells in brain regions comprising the recently described social decision-making network in subordinate and breeder naked mole-rats of both sexes. We find that subordinates have a significantly higher percentage of AR+ cells in all brain regions expressing this protein. By contrast, there were no significant effects of sex and no sex-by-status interactions on the percentage of AR+ cells. Taken together with previous findings, the present data complete a systematic assessment of the distribution of AR protein in the social decision-making network of the eusocial mammalian brain and demonstrate a significant role for social status in the regulation of this protein throughout many nodes of this network.