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Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.
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Proliferação de Células , Senescência Celular , Proteína 1 de Resposta de Crescimento Precoce , Miócitos Cardíacos , Regeneração , Animais , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Regeneração/fisiologia , Senescência Celular/fisiologia , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , Transdução de Sinais , Fibroblastos/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Cultivadas , Animais Recém-Nascidos , Modelos Animais de Doenças , Fenótipo Secretor Associado à Senescência , Proteômica , Análise de Célula Única , Masculino , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos Knockout , Quinase 1 de Adesão FocalRESUMO
Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here, we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction and a rat model of ischemic HF. We provide mechanistic evidence indicating that, in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis. Overall, these findings highlight the potential repurposing of GA as a future therapy for a myriad of heart diseases.
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Background: The aim of this study was to evaluate the natural history of patients after mitral valve intervention in the pediatric age. Methods: This is a retrospective study including all patients who underwent mitral valve surgery from 1998 to 2022. The patients' surgical reports, postoperative records, and ambulatory visits were reviewed. The endpoints of the study were survival and freedom from mitral valve reoperation. Results: Of the 70 patients included in the cohort, 61 patients (86.7%) had congenital mitral valve disease, of whom 46 patients (75.4%) had a predominantly mitral regurgitation lesion, and 15 patients (24.6%) had a predominantly mitral stenosis. In the mitral regurgitation group, all of the patients underwent valve repair with an operative mortality of one patient (2.1%), and with median follow-up of 4 years (range, 0.5-13 years), there was 4.3% mortality (n = 2) and 71.2% freedom from reoperation. In the mitral stenosis group, 11 patients underwent mitral valve repair, and 4 patients underwent valve replacement. There was an operative mortality of two patients (13.3%). With a 2-year median follow-up (range: 0.1-23 years), there were no additional mortality cases in the mitral stenosis group. All three patients who survived primary mitral valve replacement (100%) and four patients who survived a primary repair (40.0%) underwent reoperation. Conclusions: This study demonstrates encouraging outcomes for mitral valve repair. The mortality of patients with congenital mitral valve disease may also be related to a difficult postoperative course, rather than the MV lesion itself.
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BACKGROUND: Therapeutic dogma has been to treat acne scars no less than 6 months after isotretinoin (ITN) cessation. OBJECTIVE: To evaluate the safety and efficacy of fractional radiofrequency (FRF) in patients treated concurrently with ITN. METHODS: We conducted a prospective randomized control 3-arm comparative trial to evaluate the treatment of acne scars. Patients received one of three treatment options: (A) ITN and FRF concurrent treatment, (B) ITN monotherapy, and (C) FRF 6 months post-ITN treatment. Patients in the FRF cohorts received three monthly sessions. Patients were followed for adverse effects up to 6-9 months post-FRF treatment. Final cosmesis was scored by three independent dermatologists using two scales: the Echelle d'Evaluation Clinique des Cicatrices d'Acne (ECCA) and an internal 5-point investigator's scale, indicating the percentage of improvement. Subjective analyses by patients were also assessed. RESULTS: Objective and subjective analyses revealed improvement in the ITN-FRF cohort, which was superior to the delayed FRF cohort and the ITN monotherapy cohort. Specifically, the concurrently treated cohort (ITN-FRF) had a significant reduction in acne scar volume from baseline mean (151.1 ± 44.7 to 97.0 ± 31.2, p < 0.005), outperforming both the delayed FRF and monotherapy ITN treatment cohorts, respectively (155.4 ± 37.8 to 122.0 ± 46.2, 144.6 ± 82.8 to 132.4 ± 62.7). Additionally, the concurrently treated cohort demonstrated improved ECCA scores (36.8 ± 15.5), significantly better than the ITN monotherapy cohort (101.5 ± 20.1, p < 0.01). LIMITATIONS: Limited patient sample size: 38 patients completed the study; mostly Fitzpatrick Type II-III skin; photographic assessments utilized. CONCLUSION: Per our prospective trial, concurrent treatment of ITN-FRF is superior to delayed FRF treatment 6 months post-ITN cessation.
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Acne Vulgar , Cicatriz , Fármacos Dermatológicos , Isotretinoína , Humanos , Acne Vulgar/complicações , Cicatriz/etiologia , Cicatriz/terapia , Isotretinoína/uso terapêutico , Isotretinoína/administração & dosagem , Estudos Prospectivos , Feminino , Masculino , Adulto , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Resultado do Tratamento , Terapia Combinada , Adulto Jovem , Terapia por Radiofrequência/métodos , Administração OralRESUMO
BACKGROUND: Body composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity. METHODS: A retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, hospitalizations, time to treatment failure and overall survival. RESULTS: Sarcopenia was observed in half of the patients (n = 19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P = 0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P = 0.04) and hospitalizations (P = 0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity. CONCLUSION: Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to caution toxicity risk, allowing for personalized therapeutic observation and intervention.
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Composição Corporal , Neoplasias da Mama , Sarcopenia , Humanos , Feminino , Pessoa de Meia-Idade , Composição Corporal/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Idoso , Estudos Retrospectivos , Sarcopenia/induzido quimicamente , Sarcopenia/patologia , Adulto , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/diagnóstico por imagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Prognóstico , TiazóisRESUMO
Congenital heart defects (CHDs) are present at birth and require ongoing management of personal, family, and medical aspects of care, including communication between family and medical staff. Effective communication is considered one of the main objectives of patient-centered care. Communication in pediatric medicine is especially challenging because it includes children and their parent(s), and children's cognitive and communication skills are still developing. Based on the model of behavior in pediatric communication , this study focused on pediatric cardiologists' views of the roles of children, parents, and physicians in the triadic encounter and their experiences in communicating information on pediatric CHDs in medical encounters. Semi-structured interviews were conducted with 17 experienced pediatric cardiologists and cardiac surgeons (five women and 12 men) at three medical centers in Israel. The grounded theory approach was used to identify three main categories: (1) the positioning (centrality) of the child in the setting (ideal vs. actual situation), (2) addressing parents' emotional needs, and (3) the physician's role as mediator between parent(s) and child. In each category, three elements are discussed: The physician's agenda, obstacles and challenges, and the physician's practical methods. Physicians strongly support children's involvement in triadic encounters yet face challenges in effectively integrating them into the information exchange process during cardiology consultations. Struggling to balance the principles of patient- and family-centered care, and without clear guidelines, they rely on their personal beliefs and experiences to formulate communication strategies that address parents' and children's needs.
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PURPOSE: To date, there is no systematic method to quantify the medical burden of individuals with 22q11.2 deletion syndrome (22q11.2DS). This study aimed to design a Medical Burden Scale for 22q11.2DS to evaluate the effect of medical symptoms severity on quality of life (QoL) and functioning in individuals with this syndrome. METHODS: Individuals with 22q11.2DS (n = 76) were included in the study. A multidisciplinary group of physicians determined the severity of symptoms (on a scale of 0 to 4) of 8 major medical systems affected in 22q11.2DS, as well as the level of cognitive deficits and psychiatric morbidity. Regression models were used to evaluate the impact of medical, cognitive, and psychiatric symptoms' severity on global assessment of functioning (GAF) and QoL. RESULTS: The total Medical Burden Scale score was significantly associated with both QoL and GAF scores, beyond the effect of the psychiatric and cognitive deficits. We also found that QoL and GAF scores were associated with the severity scores of specific medical systems, particularly neurological symptoms, but also cardiovascular, ear-nose-throat, endocrinology, and orthopedics. CONCLUSION: Quantifying the medical burden of 22q11.2DS individuals is feasible and indicates the overall and specific contribution of medical symptoms to QoL and functioning of 22q11.2DS individuals.
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INTRODUCTION: Preeclampsia (PE) is a major pregnancy complication, posing considerable morbidity and mortality. The maternal serum angiogenic factors - PlGF and sFlt-1, and their ratio appear to be promising markers to predict PE. Aims: To assess whether the evaluation of PlGF and sFlt-1 adds to the clinical workup of women with suspected PE, and to estimate the cost/benefit. METHODS: We prospectively enrolled pregnant women with suspected PE who were admitted to the Maternal-Fetal Medicine Unit (MFM) at Shamir Medical Center. Pregnancy and delivery records were collected from their computerized electronic medical records. PlGF<150pg/ml and sFlt-1/PlGF>38 measured prospectively were used to predict PE. RESULTS: Of 105 women included, 28 were in the control group with unrelated complications and none developed PE. Among 66 women with suspected PE, 27(41%) developed the syndrome, with a positive predictive value (PPV) of 90.3% for PlGF<150 pg/ml and 88.9% for sFlt-1/PlGFabove 38. Out of 11 women with suspected intrauterine growth restriction (IUGR), six developed the syndrome, and among them, the negative predictive value (NPV) was ~ 90%. CONCLUSIONS: Angiogenic factors are reliable in predicting PE near delivery. Of 8355 annual deliveries, 584 were admitted for suspected PE. The annual test cost was NIS 66,576 (NIS 140 per single test). Cost-saving was NIS 2.18 million, the ratio of cost saved vs. test cost was 32.7. DISCUSSION: The angiogenic factors are efficient and cost-saving in PE prediction near delivery. A larger study is necessary to determine the inclusion of angiogenic factors in the workup for suspected PE.
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Pré-Eclâmpsia , Complicações na Gravidez , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Biomarcadores , Análise Custo-Benefício , Valor Preditivo dos TestesRESUMO
Introduction: Simpson's rule is generally used to estimate cardiac volumes. By contrast, modern methods such as Virtual Reality (VR) utilize mesh modeling to present the object's surface spatial structure, thus enabling intricate volumetric calculations. In this study, two types of semiautomated VR models for cardiac volumetric analysis were compared to the standard Philips dedicated cardiac imaging platform (PDP) which is based on Simpson's rule calculations. Methods: This retrospective report examined the cardiac computed tomography angiography (CCTA) of twenty patients with atrial fibrillation obtained prior to a left atrial appendage occlusion procedure. We employed two VR models to evaluate each CCTA and compared them to the PDP: a VR model with Philips-similar segmentations (VR-PS) that included the trabeculae and the papillary muscles within the luminal volume, and a VR model that only included the inner blood pool (VR-IBP). Results: Comparison of the VR-PS and the PDP left ventricle (LV) volumes demonstrated excellent correlation with a ρ c of 0.983 (95% CI 0.96, 0.99), and a small mean difference and range. The calculated volumes of the right ventricle (RV) had a somewhat lower correlation of 0.89 (95% CI 0.781, 0.95), a small mean difference, and a broader range. The VR-IBP chamber size estimations were significantly smaller than the estimates based on the PDP. Discussion: Simpson's rule and polygon summation algorithms produce similar results in normal morphological LVs. However, this correlation failed to emerge when applied to RVs and irregular chambers. Conclusions: The findings suggest that the polygon summation method is preferable for RV and irregular LV volume and function calculations.
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Background: The aim of this study was to evaluate left ventricular mechanical activation pattern by speckle tracking echocardiography (STE) as a predictor of response to cardiac resynchronization therapy (CRT) in patients with heart failure. Methods: Echocardiography was performed during no pacing, right ventricular pacing (RVP), biventricular pacing (BVP) and multipolar pacing (MPP) immediately after CRT implantation in 16 patients at a single centre. Seven patients were diagnosed as responders and 9 patients as non-responders after 6 months of standard CRT pacing. All had adequate short axis views, and 1 CRT responder and 2 CRT non-responders had limited longitudinal views. Results: Longitudinal and circumferential global strain (GS) and global strain rate (GSR) or their change analysis, did not yield any CRT response prediction. However, the longitudinal BVP/RVP GS ratio was significantly higher in the responder group (1.32 ± 0.2%, 2.0 ± 0.4% and 1.9 ± 0.4%), compared with the non-responder group (1.06 ± 0.2%, 1.1 ± 0.4% and 1.2 ± 0.4%) in the apical two-chamber, APLAX and four-chamber views, respectively. Similarly, the longitudinal BVP/RVP GSR at active systolic phase (GSRs) was significantly higher in the responder group (1.9 ± 0.9% and 1.7 ± 0.4%) compared with the non-responder group (1.0 ± 0.4% and 1.1 ± 0.2%) in the apical APLAX and four-chamber views, respectively. Measurements of the strain delay index showed predictive power regarding CRT response in non-paced patients. Conclusion: Post implantation, longitudinal BVP/RVP GS and GSRs ratios of 1.4% and above may be useful as a CRT response prediction tool. Furthermore, our findings support the usefulness of strain delay index prior to CRT implantation in non-paced patients.
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Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals. Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome. Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder. Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician's diagnostic toolbox and may aid in facilitating identification of affected individuals.
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Background: Noonan syndrome (NS) is a genetic syndrome, characterized by various dysmorphic features, cardiac anomalies, short stature, and developmental delay. NS is a leading cause of cardiovascular anomalies. The syndrome results from dysregulation in the RAS-MAPK pathway and is related to the RASopathy family syndromes. Pathogenic variants in more than 20 related genes have been identified in association with NS, and several genotype-phenotype correlations were suggested. The specific severity of the same cardiovascular anomalies has not been described as linked to a specific causative gene. Methods: For this retrospective, single-center study, data retrieved from medical charts of a multidisciplinary NS clinic included genetic diagnosis, cardiac malformations, the need for intervention, demographics, and prenatal diagnosis. We analyzed molecular genetics and the severity of cardiac malformations. Results: The cohort comprised 74 children with NS. Consistent with previous studies, pathogenic variants in PTPN11 were the most common (62%). Cardiovascular anomalies presented in 57%; pulmonary stenosis (PS) was the most common (about 79% of anomalies). In children with pathogenic variants in PTPN11, PS tended to be more severe and required intervention in 53%, compared to 25% of children with PS and a variant in other genes. Conclusion: This first Israeli cohort of NS showed similar rates of cardiac malformations and genetic breakdown as previously published. Variants in PTPN11 were prone to a higher risk for severe PS that requires intervention. This finding may assist in genetic counseling and cardiac treatment decisions, and stresses the importance of genetic in addition to clinical diagnosis of NS.
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OBJECTIVE: To study the applicability of transnasal echography for the internal carotid artery (ICA) imaging during endoscopic procedures, primarily nasopharyngectomy. STUDY DESIGN: Non-randomized controlled cohort. METHODS: The tip of a pediatric transducer for transesophageal echography was inserted into each nostril under endoscopic control and placed in the ipsilateral Rosenmuller's fossa. The ICA's internal diameter and distance between the nasopharyngeal wall and the artery's closest point were measured on each side. Two independent examiners measured the same parameters on the axial plane of the skull base computer tomography (CT). Agreement between CT and echography measurements was estimated by the Bland-Altman approach. RESULTS: Twenty-seven ICAs (sides) were available for the echography-CT agreement analysis. Inter method agreement for both parameters was similar to the inter examiner agreement for the CT measurements. CONCLUSIONS: Our first study on endoscopic echography demonstrated that this method is applicable, potentially allowing safer transnasal surgery in the ICA vicinity. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1184-1188, 2022.
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Artéria Carótida Interna , Base do Crânio , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Criança , Endoscopia/métodos , Humanos , Cavidade Nasal/diagnóstico por imagem , Cavidade Nasal/cirurgia , Base do Crânio/cirurgia , UltrassonografiaRESUMO
BACKGROUND: The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far. OBJECTIVE: We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques. METHODS: Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families. RESULTS: Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46. CONCLUSIONS: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.
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Cardiopatias Congênitas , Síndrome de Heterotaxia , Estudos de Coortes , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia/genética , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Mutação/genética , Sequenciamento do ExomaRESUMO
OBJECTIVES: To evaluate various clinical aspects, specifically regarding immune status, in a large cohort of patients with DiGeorge syndrome. STUDY DESIGN: Data were collected for 98 patients with DiGeorge syndrome treated at a tertiary medical center. This included general information, laboratory results, and clinical features. RESULTS: The median age at diagnosis was 2.0 years (range, 0.0-36.5 years). The most common symptoms that led to diagnosis were congenital heart defect, speech delay, palate anomalies, and developmental delay. Common clinical features included recurrent infections (76 patients), congenital heart diseases (61 patients), and otorhinolaryngology disorders (61 patients). Twenty patients had anemia; the incidence was relatively high among patients aged 6-59 months. Thrombocytopenia was present in 20 patients. Recurrent chest infections were significantly higher in patients with T cell and T cell subset deficiencies. Decreased T cell receptor excision circles were more common with increasing age (P < .001). Of the 27 patients hospitalized due to infection, pneumonia was a leading cause in 13. CONCLUSIONS: Awareness of DiGeorge syndrome's typical and uncommon characteristics is important to improve diagnosis, treatment, surveillance, and follow-up.
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Síndrome de DiGeorge/fisiopatologia , Anormalidades Múltiplas/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Patients with Down syndrome (DS) are at increased risk for infections and autoimmune disorders. Although several immunological abnormalities were previously found, differences in T cell receptor repertoire have never been shown. Thus we compared the T cell receptor gamma (TRG) repertoire in DS and non-syndromic pediatric patients by next-generation sequencing, in addition to other immunological markers. METHODS: Genomic DNA was extracted from thymuses of pediatric patients who underwent heart surgery, where six were with DS and six were non-syndromic patients. Peripheral blood counts, T cell subpopulations, thymus TCR excision circles (TRECs), spectratyping, and next-generation sequencing for TRG were analyzed. RESULTS: The mean age of the patients was 7 months and the mean lymphocyte count was slightly lower in patients with DS, whereas thymus TREC results were similar to non-syndromic patients (p = 0.197). The TRG repertoire analysis showed that patients with DS had a significantly larger number of unique TRG sequences, together with decreased clonal expansion. Lastly, the V and J gene usages in the thymus were similar in DS and non-syndromic patients. CONCLUSIONS: Patients with DS showed increased TRG repertoire diversity with decreased clonal expansion compared to non-syndromic patients. IMPACT: Alterations in T cell receptor gamma repertoire were found in patients with Down syndrome using next-generation sequencing (NGS) technique. Patients showed increased repertoire diversity and decreased clonal expansion compared to controls. These findings add to previous reports on abnormalities of other immune system components in patients with Down syndrome. NGS technique may point out differences not seen by previous methods. Repertoire abnormalities may contribute to those patients' predisposition to infections and autoimmune diseases.
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Síndrome de Down/genética , Síndrome de Down/imunologia , Genes Codificadores da Cadeia gama de Receptores de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Transcriptoma , Estudos de Casos e Controles , Síndrome de Down/diagnóstico , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Contagem de Linfócitos , MasculinoRESUMO
ABSTRACT: The use of automatic external defibrillators (AEDs) during pulseless resuscitations is considered safe and reliable, and was established as part of the guidelines in out-of-hospital events. Based on extensive studies, the use of the standard AED is now indicated in every age group with a preference of pediatric pad application for small children and babies. If unavailable, adult pads are recommended. We report a case of 2 inappropriate AED shocks that were delivered to a neonate during a pulseless resuscitation after application of adult pads. The 3.6-kg patient received 2 shocks, over 200 J each, for sinus bradycardia that was not detected by the device. Although treated inappropriately with high voltage, no cardiac or skin sequelae were detected, and the patient had normal cardiac and neurological development later on.
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Reanimação Cardiopulmonar , Cardioversão Elétrica , Adulto , Arritmias Cardíacas , Criança , Desfibriladores , Coração , Humanos , Recém-Nascido , RessuscitaçãoRESUMO
The genetic basis of congenital heart malformations associated with disruption of left-right (L-R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left-right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab-Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left-right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.
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Estudos de Associação Genética , Predisposição Genética para Doença , Fator 1 de Diferenciação de Crescimento/genética , Cardiopatias Congênitas/genética , Árabes/genética , Pré-Escolar , Consanguinidade , Feminino , Cardiopatias Congênitas/fisiopatologia , Homozigoto , Humanos , Lactente , Isomerismo , Masculino , Mutação/genética , Gravidez , Sequenciamento do ExomaRESUMO
INTRODUCTION: The Glenn procedure is generally performed as a second-stage palliative procedure toward the completion of Fontan circulation in patients with a functionally univentricular heart. Safe Fontan completion requires normal ventricular function, competent atrioventricular valves, normal pulmonary arteries anatomy, and low pulmonary vascular resistances (PVRs), which is merely an estimation that considers both lungs as a single unit. Clinical observations revealed that patients who previously underwent bilateral bidirectional cavopulmonary anastomosis (b-BCPA) had a stormier postoperative course in respect to other patients with previous unilateral BCPA (u-BCPA) postoperatively after Fontan completion. This retrospective study was designed to compare and analyze the outcomes of patients following Fontan completion with previous u-BCPA versus b-BCPA. PATIENTS AND METHODS: A total of 98 patients were divided into two groups based on the presence or absence of bilateral superior vena cava (SVC). Group 1 included 80 patients with unilateral SVC, and group 2 included 18 patients with bilateral SVC. Univariate and multivariate (SPSS) analyses were performed with regard to mortality and failure. P value of <.05 was considered as significant. RESULTS: Prior to the total cavopulmonary anastomosis operation, the G1 and G2 had similar demographic and physiological findings, ages and weights were 4.3 ± 1.72 years and 15.0 ± 3.71 kg in G1 and 4.8 ± 3.21 years and 17.5 ± 9.76 kg in G2. Mean end-diastolic ventricular pressures (in mm Hg) were 10.50 ± 2.86 in G1 and 10.28 ± 3.07 in G2 and the mean PVRs (in Woods units) were 1.66 ± 1.29 in G1 and 1.49 ± 0.82 in G2. The Stormy postoperative course, Fontan failure, and early mortality were all significantly higher in G2 in respect to G1 ( P value <.05). G1 mortality rate was 3.7%, 3 patients of 80, while in G2, the mortality rate was 22%, 4 patients of 18. Late Fontan failure rates were 6% for G1 patients where two patients developed pulmonary hypertension, two patients developed heart failure, and one patient had protein losing enteropathy (PLE), and 22% for the G2 patients of which two patients developed heart failure, one patient had PLE, and one patient had persistent low systemic venous saturation. CONCLUSIONS: Our results have demonstrated that patients after b-BCPA might have a tendency for worse outcomes upon Fontan completion. The b-BCPA is associated with pulmonary artery bifurcation stenosis and presents multiple sources of pulmonary blood flow where conventional PVR calculation might be imprecise and misleading since it considers the lungs as a single unit. Therefore, b-BCPA engenders correction of the conventional PVR calculation to consider each lung separately. Furthermore, the surgical approach for patients with persistent left SVC and univentricular heart should be modified.
Assuntos
Técnica de Fontan/métodos , Derivação Cardíaca Direita/métodos , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/anormalidades , Criança , Pré-Escolar , Feminino , Técnica de Fontan/efeitos adversos , Derivação Cardíaca Direita/efeitos adversos , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/cirurgia , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias , Artéria Pulmonar/cirurgia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Resistência Vascular , Veia Cava Superior/cirurgiaRESUMO
INTRODUCTION: The cardiopulmonary exercise test (CPET) permits the most accurate and reproducible quantification of cardiopulmonary fitness, a grading of the etiology and severity of cardiopulmonary impairments, and an objective assessment of the response to an intervention. Moreover, over the last three decades, a large volume of research has been directed toward the utility of CPET as a diagnostic and prognostic tool; these studies have established CPET as a scientifically sound and, therefore, clinically valuable method for accurately assessing exercise limitation and prognosis in various disease states. The CPET is relatively easy to perform, yet complex in the interpretation of the results. The current review presents the principles of the analytic process of the test results, in order to obtain possible diagnoses.