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1.
Am J Hum Genet ; 111(2): 364-382, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38272033

RESUMO

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Cardiomiopatia Dilatada , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Animais , Humanos , Camundongos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Coração , Transtornos do Neurodesenvolvimento/genética
2.
Circulation ; 150(17): 1377-1390, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39355918

RESUMO

BACKGROUND: Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined. METHODS: Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome. RESULTS: Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P<0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P<0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P<0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction. CONCLUSIONS: Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.


Assuntos
Cardiomiopatia Hipertrófica , Sistema de Registros , Humanos , Cardiomiopatia Hipertrófica/terapia , Cardiomiopatia Hipertrófica/mortalidade , Cardiomiopatia Hipertrófica/cirurgia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Adulto , Septos Cardíacos/cirurgia , Seguimentos , Fatores de Tempo
3.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35046026

RESUMO

Adverse childhood experiences (ACEs) are extreme stressors that lead to negative psychosocial outcomes in adulthood. Nonhuman animals explore less after exposure to early stress. Therefore, in this preregistered study, we hypothesized that reduced exploration following ACEs would also be evident in human adults. Further, we predicted that adults with ACEs, in a foraging task, would adopt a decision-making policy that relies on the most-recent reward feedback, a rational strategy for unstable environments. We analyzed data from 145 adult participants, 47 with four or more ACEs and 98 with fewer than four ACEs. In the foraging task, participants evaluated the trade-off between exploiting a known patch with diminishing rewards and exploring a novel one with a fresh distribution of rewards. Using computational modeling, we quantified the degree to which participants' decisions weighted recent feedback. As predicted, participants with ACEs explored less. However, contrary to our hypothesis, they underweighted recent feedback. These unexpected findings indicate that early adversity may dampen reward sensitivity. Our results may help to identify cognitive mechanisms that link childhood trauma to the onset of psychopathology.


Assuntos
Experiências Adversas da Infância/psicologia , Comportamento Exploratório , Retroalimentação , Recompensa , Algoritmos , Análise de Variância , Humanos , Modelos Psicológicos
4.
Circulation ; 148(5): 394-404, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37226762

RESUMO

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS: Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]). CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.


Assuntos
Cardiomiopatia Hipertrófica , Disfunção Ventricular Esquerda , Adulto , Humanos , Masculino , Feminino , Criança , Função Ventricular Esquerda , Volume Sistólico , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/complicações , Prognóstico , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/epidemiologia , Sistema de Registros
5.
EMBO J ; 39(11): e102539, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32311122

RESUMO

Multiple mitochondrial quality control pathways exist to maintain the health of mitochondria and ensure cell homeostasis. Here, we investigate the role of the endosomal adaptor Tollip during the mitochondrial stress response and identify its interaction and colocalisation with the Parkinson's disease-associated E3 ubiquitin ligase Parkin. The interaction between Tollip and Parkin is dependent on the ubiquitin-binding CUE domain of Tollip, but independent of Tom1 and mitophagy. Interestingly, this interaction is independent of Parkin mitochondrial recruitment and ligase activity but requires an intact ubiquitin-like (UBL) domain. Importantly, Tollip regulates Parkin-dependent endosomal trafficking of a discrete subset of mitochondrial-derived vesicles (MDVs) to facilitate delivery to lysosomes. Retromer function and an interaction with Tom1 allow Tollip to facilitate late endosome/lysosome trafficking in response to mitochondrial stress. We find that upregulation of TOM20-positive MDVs upon mitochondrial stress requires Tollip interaction with ubiquitin, endosomal membranes and Tom1 to ensure their trafficking to the lysosomes. Thus, we conclude that Tollip, via an association with Parkin, is an essential coordinator to sort damaged mitochondrial-derived cargo to the lysosomes.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Endossomos/genética , Endossomos/metabolismo , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lisossomos/genética , Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Transporte Proteico , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Ubiquitina-Proteína Ligases/genética
6.
Horm Behav ; 160: 105500, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38316079

RESUMO

The immune system can be modulated when organisms are exposed to acute or chronic stressors. Glucocorticoids (GCs), the primary hormonal mediators of the physiological stress response, are suspected to play a crucial role in immune modulation. However, most evidence of stress-associated immunomodulation does not separate the effects of glucocorticoid-dependent pathways from those of glucocorticoid-independent mechanisms on immune function. In this study, we experimentally elevated circulating corticosterone, the main avian glucocorticoid, in free-living female tree swallows (Tachycineta bicolor) for one to two weeks to test its effects on immune modulation. Natural variation in bacteria killing ability (BKA), a measure of innate constitutive immunity, was predicted by the interaction between timing of breeding and corticosterone levels. However, experimental elevation of corticosterone had no effect on BKA. Therefore, even when BKA is correlated with natural variation in glucocorticoid levels, this relationship may not be causal. Experiments are necessary to uncover the causal mechanisms of immunomodulation and the consequences of acute and chronic stress on disease vulnerability. Findings in other species indicate that acute increases in GCs can suppress BKA; but our results support the hypothesis that this effect does not persist over longer timescales, during chronic elevations in GCs. Direct comparisons of the effects of acute vs. chronic elevation of GCs on BKA will be important for testing this hypothesis.


Assuntos
Corticosterona , Andorinhas , Animais , Corticosterona/farmacologia , Glucocorticoides/farmacologia , Andorinhas/fisiologia , Estresse Fisiológico , Imunidade Inata
7.
Muscle Nerve ; 69(5): 572-579, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38426616

RESUMO

INTRODUCTION/AIMS: Duchenne muscular dystrophy (DMD) is characterized by fibrofatty replacement of muscle. This has been documented in the ventricular myocardium of DMD patients, but there is limited description of atrial involvement. The purpose of this study is to examine the arrhythmia and ectopy burden in patients with DMD and non-DMD dilated cardiomyopathy (DCM) and to characterize the cardiac histopathologic changes in DMD patients across the disease spectrum. METHODS: This was a retrospective analysis of age-matched patients with DMD and non-DMD DCM who received a Holter monitor and cardiac imaging within 100 days of each other between 2010 and 2020. Twenty-four-hour Holter monitors were classified based on the most recent left ventricular ejection fraction at the time of monitoring. Cardiac histopathologic specimens from whole-heart examinations at the time of autopsy from three DMD patients and one DCM patient were reviewed. RESULTS: A total of 367 patients with 1299 Holter monitor recordings were included over the study period, with 94% representing DMD patients and 6% non-DMD DCM. Patients with DMD had more atrial ectopy across the cardiac function spectrum (p < 0.05). There was no difference in ventricular ectopy. Four DMD patients developed symptomatic atrial arrhythmias. Autopsy specimens from DMD patients demonstrated fibrofatty infiltration of both atrial and ventricular myocardium. DISCUSSION: The atrial myocardium in patients with DMD is unique. Autopsy specimens reveal fibofatty replacement of the atrial myocardium, which may be a nidus for both ectopy and arrhythmias in DMD patients.


Assuntos
Cardiomiopatia Dilatada , Distrofia Muscular de Duchenne , Complexos Ventriculares Prematuros , Humanos , Lactente , Distrofia Muscular de Duchenne/complicações , Volume Sistólico , Estudos Retrospectivos , Função Ventricular Esquerda
8.
Artigo em Inglês | MEDLINE | ID: mdl-36965830

RESUMO

Capricious environments often present wild animals with challenges that coincide or occur in sequence. Conceptual models of the stress response predict that one threat may prime or dampen the response to another. Although evidence has supported this for glucocorticoid responses, much less is known about the effects of previous challenges on energy mobilization. Food limitation may have a particularly important effect, by altering the ability to mobilize energy when faced with a subsequent challenge. We tested the prediction that challenging weather conditions, which reduce food availability, alter the energetic response to a subsequent acute challenge (capture and restraint). Using a three-year dataset from female tree swallows measured during three substages of breeding, we used a model comparison approach to test if weather (temperature, wind speed, and precipitation) over 3- or 72-hour timescales predicted baseline and post-restraint glucose levels, and if so which environmental factors were the strongest predictors. Contrary to our predictions, weather conditions did not affect baseline glucose; however, birds that had experienced lower temperatures over the preceding 72 h tended to have higher stress-induced glucose when faced with an acute stressor. We also saw some support for an effect of rainfall on stress-induced glucose: around the time that eggs hatched, birds that had experienced more rainfall over the preceding 72 h mounted lower responses. Overall, we find support in a wild animal for the idea that the glucose stress response may be primed by exposure to prior challenges.


Assuntos
Temperatura Baixa , Tempo (Meteorologia) , Animais , Temperatura , Animais Selvagens , Glucocorticoides , Aves
9.
Cardiol Young ; 33(4): 597-602, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35549789

RESUMO

Patients with Duchenne muscular dystrophy have multiple risk factors for lower extremity oedema. This study sought to define the frequency and predictors of oedema. Patients aged 15 years and older were screened by patient questionnaire, and the presence of oedema was confirmed by subsequent physical exam. Twenty-four of 52 patients (46%) had oedema, 12 of whom had swelling extending above the foot and two with sores/skin breakdown. There was no significant difference in age, frequency, or duration of glucocorticoid use, non-invasive respiratory support use, forced vital capacity, cardiac medication use, or ejection fraction between patients with and without oedema (all p > 0.2). Those with oedema had a greater time since the loss of ambulation (8.4 years versus 3.5 years; p = 0.004), higher body mass index (28.3 versus 24.8; p = 0.014), and lower frequency of deflazacort use (67% versus 89%; p = 0.008). Multivariate analysis revealed a longer duration of loss of ambulation (p = 0.02) and higher body mass index (p = 0.009) as predictors of oedema. Lower extremity oedema is common in Duchenne muscular dystrophy but independent of cardiac function. Interventions focused on minimising body mass index increases over time may be a therapeutic target.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/tratamento farmacológico , Caminhada , Edema/etiologia , Obesidade/complicações , Extremidade Inferior
10.
Perfusion ; : 2676591231220816, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38053305

RESUMO

INTRODUCTION: In children with myocarditis or dilated cardiomyopathy (DCM) on extracorporeal membrane oxygenation (ECMO) for cardiogenic shock, it is often necessary to decompress the left heart to minimize distension and promote myocardial recovery. We compare outcomes in those who underwent balloon atrial septostomy (BAS) versus direct left atrial (LA) drainage for left heart decompression in this population. METHODS: Retrospective study of the Extracorporeal Life Support Organization (ELSO) multicenter registry of patients ≤ 18 years with myocarditis or DCM on ECMO who underwent LA decompression. Descriptive and univariate statistics assessed association of patient factors with decompression type. Multivariable logistic regression sought independent associations with outcomes. RESULTS: 369 pediatric ECMO runs were identified. 52% myocarditis, 48% DCM, overall survival 74%. 65% underwent BAS and 35% LA drainage. Patient demographics including age, weight, gender, race/ethnicity, diagnosis, pre-ECMO pH, mean airway pressure, and arrest status were similar. 89% in the BAS group were peripherally cannulated onto ECMO, versus 3% in the LA drainage group (p < .001). On multivariable analysis, LA drainage (OR 3.96; 95% CI, 1.47-10.711; p = .007), renal complication (OR 2.37; 95% CI, 1.41-4.01; p = .001), cardiac complication (OR 3.14; 95% CI, 1.70-5.82; p < .001), and non-white race/ethnicity (OR 1.75; 95% CI, 1.04-2.94; p = .035) were associated with greater odds of mortality. There was a trend toward more episodes of pulmonary hemorrhage in BAS (n = 17) versus LA drainage group (n = 3), p = .08. Comparing only those with central cannulation, LA drainage group was more likely to be discontinued from ECMO due to recovery (72%) versus the BAS group (48%), p = .032. CONCLUSIONS: In children with myocarditis or DCM, there was a three times greater likelihood for mortality with LA drainage versus BAS for LA decompression. When adjusted for central cannulation groups only, there was better recovery in the LA drainage group and no difference in mortality. Further prospective evaluation is warranted.

11.
Ergonomics ; : 1-16, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37938127

RESUMO

Worker and work-related musculoskeletal symptoms are prevalent among surgeons operating on human patients. Despite incidence rates for accidents among veterinarians and their staff being 2.9 times higher than that of general practitioners of human medicine, little is known about musculoskeletal symptoms among veterinary surgeons. In this study, 212 board-certified members of the American College of Veterinary Surgeons responded to a survey regarding various work-related activities and their experience with musculoskeletal symptoms in 10 different body regions. Across all body regions, reported pain increased from before to after a typical day of surgery (p <.01). Gender, weight, age, and years performing surgery were worker factors that were related to pain (p <.05), while number of procedures, practice focus, and proportion of minimally invasive surgery were work factors related to pain (p <.05). Our findings suggest that musculoskeletal symptoms are prevalent among veterinary surgeons and may help provide evidence for guidelines for minimising musculoskeletal injuries in veterinary surgery.Practitioner summary: Little is known about the risk factors for musculoskeletal symptoms (MSS) among veterinary surgeons. This cross-sectional survey of veterinary surgeons investigates worker and work factors related to MSS. We show that MSS are prevalent and identify key factors providing evidence that MSS are a concern in veterinary surgery.

12.
Blood ; 135(13): 1049-1057, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31932840

RESUMO

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Adolescente , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Pré-Escolar , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Suscetibilidade a Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Masculino , Medição de Risco , Fatores de Risco , Sepse/epidemiologia , Sepse/etiologia , Microangiopatias Trombóticas/diagnóstico , Resultado do Tratamento
13.
J Exp Biol ; 225(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35072205

RESUMO

Animals respond to sudden challenges with a coordinated set of physiological and behavioral responses that enhance the ability to cope with stressors. While general characteristics of the vertebrate stress response are well described, it is not as clear how individual components covary between or within individuals. A rapid increase in glucocorticoids coordinates the stress response and one of the primary downstream results is an increase in glucose availability via reduced glucose utilization. Here, we asked whether between- and within-individual variation in corticosterone directly predict variation in glucose. We collected 2673 paired glucose and corticosterone measures from 776 tree swallows (Tachycineta bicolor) from four populations spanning the species range. In adults, glucose and corticosterone both increased during a standardized restraint protocol in all four populations. Moreover, in one population experimentally increasing a precursor that stimulates corticosterone release resulted in a further increase in both measures. In contrast, nestlings did not show a robust glucose response to handling or manipulation. Despite this group-level variation, there was very little evidence in any population that between-individual variation in corticosterone predicted between-individual variation in glucose regulation. Glucose was moderately repeatable within individuals, but within-individual variation in glucose and corticosterone were unrelated. Our results highlight the fact that a strong response in one aspect of the coordinated acute stress response (corticosterone) does not necessarily indicate that specific downstream components, such as glucose, will show similarly strong responses. These results have implications for understanding the evolution of integrated stress response systems.


Assuntos
Corticosterona , Andorinhas , Animais , Glucocorticoides , Glucose , Humanos , Estresse Fisiológico/fisiologia
14.
J Immunol ; 204(7): 1982-1987, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122998

RESUMO

GFP is frequently used as a marker for tracking donor cells adoptively transplanted into recipient animals. The human ubiquitin C promoter (UBC)-driven-GFP transgenic mouse is a commonly used source of donor cells for this purpose. This mouse was initially generated in the C57BL/6 inbred strain and has been backcrossed into the BALB/cBy strain for over 11 generations. Both the C57BL/6 inbred and BALB/cBy congenic UBC-GFP lines are commercially available and have been widely distributed. These UBC-GFP lines can be a convenient resource for tracking donor cells in both syngenic MHC-matched and in allogenic MHC-mismatched studies as C57BL/6 (H-2b) and BALB/cBy (H-2d) have disparate MHC haplotypes. In this report, we surprisingly discover that the UBC-GFP BALB/cBy congenic mice still retain the H-2b MHC haplotype of their original C57BL/6 founder, suggesting that the UBC-GFP transgene integration site is closely linked to the MHC locus on chromosome 17. Using linear amplification-mediated PCR, we successfully map the UBC-GFP transgene to the MHC locus. This study highlights the importance and urgency of mapping the transgene integration site of transgenic mouse strains used in biomedical research. Furthermore, this study raises the possibility of alternative interpretations of previous studies using congenic UBC-GFP mice and focuses attention on the necessity for rigor and reproducibility in scientific research.


Assuntos
Cromossomos/genética , Proteínas de Fluorescência Verde/genética , Complexo Principal de Histocompatibilidade/genética , Mutagênese Insercional/genética , Transgenes/genética , Ubiquitina C/genética , Animais , Haplótipos/genética , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Reprodutibilidade dos Testes
15.
Pediatr Crit Care Med ; 23(1): e20-e28, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560770

RESUMO

OBJECTIVES: Sepsis-associated myocardial dysfunction is common in pediatric septic shock and negatively impacts outcomes. Early estimation of sepsis-associated myocardial dysfunction risk has the potential to inform clinical care and improve clinical trial design. The Pediatric Sepsis Biomarker Risk Model II is validated as a biomarker-based enrichment algorithm to discriminate children with septic shock with high baseline mortality probability. The objectives were to determine if Pediatric Sepsis Biomarker Risk Model biomarkers are associated with risk for sepsis-associated myocardial dysfunction in pediatric septic shock and to develop a biomarker-based model to reliably estimate sepsis-associated myocardial dysfunction risk. DESIGN: Secondary analysis of prospective cohort study. SETTING: Single-center, quaternary-care PICU. PATIENTS: Children less than 18 years old admitted to the PICU from 2003 to 2018 who had Pediatric Sepsis Biomarker Risk Model biomarkers measured for determination of Pediatric Sepsis Biomarker Risk Model II mortality probability and an echocardiogram performed within 48 hours of septic shock identification. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pediatric Sepsis Biomarker Risk Model II mortality probability was calculated from serum biomarker concentrations and admission platelet count. Echocardiograms were reread by a single cardiologist blinded to Pediatric Sepsis Biomarker Risk Model II data, and sepsis-associated myocardial dysfunction was defined as left ventricular ejection fraction less than 45% for primary analyses. Multivariable logistic regression analyzed the association of Pediatric Sepsis Biomarker Risk Model II mortality probability with sepsis-associated myocardial dysfunction. Classification and regression tree methodology was employed to derive a Pediatric Sepsis Biomarker Risk Model biomarker-based model for sepsis-associated myocardial dysfunction. Thirty-two of 181 children with septic shock demonstrated sepsis-associated myocardial dysfunction. Pediatric Sepsis Biomarker Risk Model II mortality probability was independently associated with sepsis-associated myocardial dysfunction (odds ratio, 1.45; 95% CI, 1.17-1.81; p = 0.001). Modeling with Pediatric Sepsis Biomarker Risk Model biomarkers estimated sepsis-associated myocardial dysfunction risk with an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.85-0.95). Upon 10-fold cross-validation, the derived model had a summary area under the receiver operating characteristic curve of 0.74. Model characteristics were similar when sepsis-associated myocardial dysfunction was defined by both low left ventricular ejection fraction and abnormal global longitudinal strain. CONCLUSIONS: A newly derived Pediatric Sepsis Biomarker Risk Model biomarker-based model reliably estimates risk of sepsis-associated myocardial dysfunction in pediatric septic shock, but independent prospective validation is needed.


Assuntos
Sepse , Choque Séptico , Adolescente , Biomarcadores , Criança , Humanos , Estudos Prospectivos , Volume Sistólico , Função Ventricular Esquerda
16.
Fam Community Health ; 45(2): 103-107, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35125485

RESUMO

African American men are at a greater risk for contracting HIV infection, and geography may play an important role in the spread of the virus. This study aimed to quantitatively assess the readiness of rural African American men to participate in a barbershop-based HIV prevention program. A paper-and-pencil survey was administered to rural African American male barbershop attendees to assess their readiness for barbershop-based HIV prevention programs. The results suggested that participants were amenable to this form of programming in the barbershop setting. There was no significance detected by demographic variables in readiness for barbershop-based HIV prevention programs. The results of the study give health education specialists and other public health practitioners insight into ways to effectively research, communicate to, and develop culturally appropriate programming for this priority population in a setting in which they are more likely to frequent.


Assuntos
Barbearia , Infecções por HIV , Negro ou Afro-Americano , Infecções por HIV/prevenção & controle , Promoção da Saúde/métodos , Humanos , Masculino , População Rural
17.
J Thromb Thrombolysis ; 51(4): 854-869, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33230704

RESUMO

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for many malignancies, hemoglobinopathies, metabolic diseases, bone marrow failure syndromes, and primary immune deficiencies. Despite the significant improvement in survival afforded by HSCT, the therapy is associated with major short and long-term morbidity and mortality. Cardiovascular complications such as cardiomyopathy, arrhythmias, pulmonary hypertension, and pericardial effusions are increasingly recognized as potential outcomes following HSCT. The incidence of cardiac complications is related to various factors such as age, co-morbid medical conditions, whether patients received cardiotoxic chemotherapy prior to HSCT, the type of HSCT (autologous versus allogeneic), and the specific conditioning regimen. Thus, the cardiovascular evaluation has become a core component of the pre-transplant assessment, however, the practice differs from center to center as national guidelines and contemporary high-quality studies are lacking. We review the incidence of cardiotoxicity in pediatric and adult HSCT, potential mechanisms of injury, and effects on long-term outcomes. We also discuss the possible therapeutic approaches when disease arises, as well as the indications and need for surveillance before, during, and after transplantation.


Assuntos
Doenças Cardiovasculares , Transplante de Células-Tronco Hematopoéticas , Cardiotoxicidade , Doenças Cardiovasculares/etiologia , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Condicionamento Pré-Transplante , Transplante Homólogo
18.
Spinal Cord ; 59(2): 193-200, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32792655

RESUMO

STUDY DESIGN: Longitudinal study. OBJECTIVES: This study aimed to examine level and variations of life satisfaction (LS) across the seasons in persons with spinal cord injury (SCI). SETTING: Polish sample of persons with SCI. METHODS: The study included 56 persons with SCI, who repeatedly completed the Life Satisfaction Questionnaire (LiSaT-9), and a study-specific questionnaire across the four seasons in a calendar year. Mixed model analyses were performed to: (1) examine seasonal changes in LS; (2) explore the possible moderating factors on seasonal changes in LS. RESULTS: There were significant seasonal trends in overall and domain-specific LS scores; yet, these changes differed in terms of shape (i.e. linear vs. quadratic). In general, the highest LS scores occurred in spring across all domains, followed by a significant reduction in summer; yet, there were u-shape trends in LS domain scores for life as a whole, vocational, and financial situation and partner relations (P-for-quadratic trends ≤0.05). Five individual characteristics, i.e. place of living, education, gender, physical activity, and time since injury significantly moderated seasonal trends in LS scores (P's for interaction ≤ 0.05). CONCLUSION: Life satisfaction in persons with SCI differs significantly in relation to different seasons throughout a year. The season of the year should be considered in future studies on LS and included in evaluating and projecting healthcare interventions or programs for persons with SCI.


Assuntos
Satisfação Pessoal , Traumatismos da Medula Espinal , Humanos , Estudos Longitudinais , Qualidade de Vida , Estações do Ano , Traumatismos da Medula Espinal/epidemiologia , Inquéritos e Questionários
19.
Cardiol Young ; 31(6): 973-978, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33504397

RESUMO

BACKGROUND: Haematopoietic stem cell transplantation is an important and effective treatment strategy for many malignancies, marrow failure syndromes, and immunodeficiencies in children, adolescents, and young adults. Despite advances in supportive care, patients undergoing transplant are at increased risk to develop cardiovascular co-morbidities. METHODS: This study was performed as a feasibility study of a rapid cardiac MRI protocol to substitute for echocardiography in the assessment of left ventricular size and function, pericardial effusion, and right ventricular hypertension. RESULTS: A total of 13 patients were enrolled for the study (age 17.5 ± 7.7 years, 77% male, 77% white). Mean study time was 13.2 ± 5.6 minutes for MRI and 18.8 ± 5.7 minutes for echocardiogram (p = 0.064). Correlation between left ventricular ejection fraction by MRI and echocardiogram was good (ICC 0.76; 95% CI 0.47, 0.92). None of the patients had documented right ventricular hypertension. Patients were given a survey regarding their experiences, with the majority both perceiving that the echocardiogram took longer (7/13) and indicating they would prefer the MRI if given a choice (10/13). CONCLUSION: A rapid cardiac MRI protocol was shown feasible to substitute for echocardiogram in the assessment of key factors prior to or in follow-up after haematopoietic stem cell transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Função Ventricular Esquerda , Adolescente , Adulto , Criança , Estudos de Viabilidade , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imageamento por Ressonância Magnética , Masculino , Volume Sistólico , Adulto Jovem
20.
Prog Pediatr Cardiol ; 61: 101362, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36570378

RESUMO

Planning for the First International Pediatric Cardio-Oncology Meeting has been underway since early 2019, with the original date in October 2020 delayed due to the COVID-19 pandemic. But patients continue to need care, research carries on, and the ability to learn from our colleagues remains one of the most important tools in our collective ability to advance the field. Through collaboration with Heart University (www.heartuniversity.org), a free web-based global education resource and training tool with an emphasis on acquired and congenital heart disease, we are able to provide colleagues around the world with focused sessions similar to those that will be expanded at the in-person meeting. The first such two-hour webinar was presented live online on December 16, 2020, and moving forward similar webinars will be offered approximately every other month for the next year leading up to the in-person meeting in 2022, with all sessions available online afterward for on-demand viewing. Although we are excited to get together with our colleagues in person, why wait until then to share what we know? The future is now!

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