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Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.

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AIMS: The objective of this study was to identify the presence of human herpesvirus (HHV) in the plasma and saliva of hepatic-cirrhosis patients and correlate it with clinical data and laboratory tests. This is a pilot, observational, and cross-sectional study. METHODS AND RESULTS: Specimens of plasma and saliva from 72 cirrhotic individuals were analyzed by means of polymerase chain reaction. The patient population had a mean age of 54.84 years old (SD ± 10) and was 70% males (51/72). Approximately 47% (n = 34) of the patients had leukopenia and HHV was not identified in the plasma specimens. The main species of HHV identified in the saliva were HHV-7 (n = 42, 62%) and Epstein-Barr virus (EBV) (n = 30, 41%). Moreover, there was a significant decrease in the total number of leukocytes and lymphocytes in saliva containing EBV (P = .038 and P = .047, respectively). CONCLUSION: The results show that the presence of EBV in the saliva of cirrhotic patients was correlated with their circulating immune status. It may be possible that the immune dysfunction displayed by the cirrhotic patients plays a role in the shedding of EBV into saliva.

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UNASSIGNED: Background: Since to the prognosis of lung squamous cell carcinoma is generally poor, there is an urgent need to innovate new prognostic biomarkers and therapeutic targets to improve patient outcomes. Objectives: Our goal was to develop a novel multi-gene prognostic model linked to neutrophils for predicting lung squamous cell carcinoma prognosis. Methods: We utilized messenger RNA expression profiles and relevant clinical data of lung squamous cell carcinoma patients from the Cancer Genome Atlas database. Through K-means clustering, least absolute shrinkage and selection operator regression, and univariate/multivariate Cox regression analyses, we identified 12 neutrophil-related genes strongly related to patient survival and constructed a prognostic model. We verified the stability of the model in the Cancer Genome Atlas database and gene expression omnibus validation set, demonstrating the robust predictive performance of the model. Results: Immunoinfiltration analysis revealed remarkably elevated levels of infiltration for natural killer cells resting and monocytes in the high-risk group compared to the low-risk group, while macrophages had considerably lower infiltration in the high risk group. Most immune checkpoint genes, including programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4, exhibited high expression levels in the high risk group. Tumor immune dysfunction and exclusion scores and immunophenoscore results suggested a potential inclination toward immunotherapy in the "RIC" version V2 revised high risk group. Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. Conclusion: Overall, our study established a reliable prognostic risk model that possessed significant value in predicting the overall survival of lung squamous cell carcinoma patients and may guide personalized treatment strategies. (Rev Invest Clin. 2024;76(2):116-31).

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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Neutrófilos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Pronóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/tratamiento farmacológico , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética

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ABSTRACT Background: Since to the prognosis of lung squamous cell carcinoma is generally poor, there is an urgent need to innovate new prognostic biomarkers and therapeutic targets to improve patient outcomes. Objectives: Our goal was to develop a novel multi-gene prognostic model linked to neutrophils for predicting lung squamous cell carcinoma prognosis. Methods: We utilized messenger RNA expression profiles and relevant clinical data of lung squamous cell carcinoma patients from the Cancer Genome Atlas database. Through K-means clustering, least absolute shrinkage and selection operator regression, and univariate/multivariate Cox regression analyses, we identified 12 neutrophil-related genes strongly related to patient survival and constructed a prognostic model. We verified the stability of the model in the Cancer Genome Atlas database and gene expression omnibus validation set, demonstrating the robust predictive performance of the model. Results: Immunoinfiltration analysis revealed remarkably elevated levels of infiltration for natural killer cells resting and monocytes in the high-risk group compared to the low-risk group, while macrophages had considerably lower infiltration in the high risk group. Most immune checkpoint genes, including programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4, exhibited high expression levels in the high risk group. Tumor immune dysfunction and exclusion scores and immunophenoscore results suggested a potential inclination toward immunotherapy in the "RIC" version V2 revised high risk group. Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. Conclusion: Overall, our study established a reliable prognostic risk model that possessed significant value in predicting the overall survival of lung squamous cell carcinoma patients and may guide personalized treatment strategies. (Rev Invest Clin. 2024;76(2):116-31)

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Resumen Introducción: La disfunción inmunológica en el paciente críticamente enfermo es un compromiso de un sistema muy poco estudiado; adicionalmente, en la población infantil aún faltan guías que orienten la evaluación del sistema inmunológico. Objetivo: Determinar la asociación de disfunción inmunológica y los desenlaces en los pacientes que ingresan a la unidad de cuidado intensivo pediátrico. Materiales y método: Estudio observacional, con componente analítico, llevado a cabo durante cuatro años, en el que se revisaron los expedientes de todos los pacientes pediátricos consecutivos con estancia en la unidad de cuidados intensivos a quienes, por criterios médicos, se les realizó perfil inmunológico. Resultados: Durante el período de estudio se reportaron 188 pacientes quienes cumplieron con los criterios de inclusión. Se presentó disfunción inmunológica en el 83% de los casos y enfermedad cardiaca en el 65%. La disfunción inmunológica se asoció con peores desenlaces medidos en mortalidad (37 vs. 9%; p = 0.0021), tiempo de estancia mayor a 14 días (46 vs. 14%; p < 0.0001) y disfunción multiorgánica (72 vs. 25%; p < 0.0001). Conclusión: La disfunción inmunológica es frecuente en los pacientes que ingresan a la unidad de cuidado intensivo pediátrico y se asocia con un aumento de la mortalidad, la duración de la ventilación mecánica invasiva y la duración de la estancia en la unidad de cuidado intensivo pediátrico. Muchos factores se asociaron con el desarrollo de disfunción inmunológica en esta población. Se necesitan estudios prospectivos para dilucidar el manejo óptimo de la disfunción inmunológica en el paciente crítico.

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Abstract Introduction: Immune dysfunction in critical patients has not been clearly defined and has been insufficiently researched, particularly in pediatrics. Guidelines to standardize the immune system assessment and for routine use in clinical practice are lacking. Objective: To determine the association between immune dysfunction (here understood as the reduction of immunoglobulins and/or of the absolute count or populations of lymphocytes) and the outcome of patients admitted to the pediatric intensive care unit. Materials and method: This was an observational, analytical, descriptive, retrospective study, conducted over four years. The records of all patients who were admitted to the pediatric intensive care unit and had an immunity profile done were included in the database. Demographic and clinical variables were compared between patients with and without immune dysfunction. Results: A total of 188 patients with an immune profile were identified; 83% of patients had immune dysfunction and 65% had heart disease. The presence of immune dysfunction was associated with worse outcomes measured in mortality (37 vs. 9% p = 0.0021), length of stay greater than 14 days (46 vs. 14%; p < 0.0001) and multiple organ dysfunction syndrome (72 vs. 25%; p < 0.0001). Conclusion: Immune dysfunction is frequent in patients with a difficult disease course and in our study sample. It was found to be associated with increased mortality, duration of invasive mechanical ventilation and length of stay in the pediatric intensive care unit. Further prospective studies with other biomarkers are needed to determine the immune compromise and its impact on outcomes in the critically ill children.

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Introduction: Torque teno virus (TTV) has been pointed as an endogenous marker of immune function, the objective of this study was to investigate the TTV viral load in plasma and saliva of cirrhotic individuals and correlate it with clinical characteristics. Methods: Blood, saliva, clinical data from records and laboratory tests were collected from 72 cirrhotic patients. Plasma and saliva were submitted to real-time polymerase chain reaction for quantification of TTV viral load. Results: The majority of the patients presented decompensated cirrhosis (59.7%) and 47.2% had alterations in the white blood series. TTV was identified in 28 specimens of plasma (38.8%) and in 67 specimens of saliva (93.0%), with median values of TTV copies/mL of 90.6 in plasma and 245.14 in saliva. All the patients who were positive for TTV in plasma were also positive in saliva, with both fluids having a moderately positive correlation for the presence of TTV. There was no correlation between TTV viral load, either in plasma or in saliva, and any of the variables studied. Conclusion: TTV is more frequently found and in greater amount in the saliva than in the plasma of cirrhotic patients. There was no correlation between TTV viral load and clinical parameters.

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Endometriosis is a chronic inflammatory condition affecting up to 10% of women of reproductive age and this, depending on its severity, very often leads to infertility. New research has shed light on the role of underlying endometritis due to the presence of inflammatory, non-oestrogen metabolising microbiome at the mucosal interface and this in turn leads to the activation of aggressive, non-tolerant immune cells in the endometrium. These immune cells require the presence of tolerance-inducing commensals such as Lactobacilli so as to allow the implantation of the fertilised egg. New therapies should be holistic and address both the dysbiosis as well as immune abnormalities. Routine immune monitoring of the immune cells derived from the endometrium and/or microbial profiling should recommended to better predict assisted reproduction outcomes in these couples.

Asunto(s)

Endometriosis , Endometritis , Infertilidad Femenina , Infertilidad , Femenino , Humanos , Endometriosis/complicaciones , Endometritis/complicaciones , Infertilidad/etiología , Implantación del Embrión/fisiología , Endometrio , Infertilidad Femenina/etiología

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INTRODUCTION: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this study was to analyse the effect of combined chemotherapy on the immune function as determined by the neutrophil-lymphocyte ratio (NLR) and if it was associated with changes in the subtype of minimal residual disease and outcome in stage III colon cancer. METHODS AND PATIENTS: A prospective, single centre observational study; the NLR was determined immediately prior to and one, two and three months after completing chemotherapy. Circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) using immunocytochemistry with anti-CEA were determined prior to and one month after chemotherapy. The association of changes in the NLR with MRD subtypes classified as Group I (negative for CTCs and mM), Group II (positive for mM) and Group III (positive for CTCs) as a result of chemotherapy and five-year disease free progression (DFS) analysed. RESULTS: One hundred and eighty eight patients participated of whom 83 (44.9%) relapsed. In non-relapsing patients the NLR significantly increased and was higher after chemotherapy compared with relapsing patients. Significant increases in the NLR were associated with changes to a better MRD prognostic subtype and decreases with a worse MRD subtype. Neither baseline NLR nor MRD subtype predicted response to chemotherapy. DFS for MRD subgroups were 88%, 56% and 6% for Groups I to III respectively. CONCLUSIONS: Immune function as measured by the NLR is associated with MRD prognostic subtypes, improvements in the NLR are associated with improvements in MRD post chemotherapy but neither baseline NLR or MRD predicted outcome.

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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/sangre , Neoplasias del Colon/tratamiento farmacológico , Recuento de Leucocitos , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasia Residual , Células Neoplásicas Circulantes , Neutrófilos/efectos de los fármacos , Compuestos Organoplatinos/uso terapéutico , Pronóstico , Estudios Prospectivos , Resultado del Tratamiento

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AIM: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this work is to report the changes in MRD status and immune function (lymphocyte count) after FOLFOX chemotherapy, and the outcome in Stage III colon cancer patients. METHOD: This study is a prospective, single-centre observational study. Lymphocyte counts were determined prior to and 1, 2 and 3 months after the completion of chemotherapy. Circulating tumour cells (CTCs) and bone marrow micrometastases were determined using immunocytochemistry with anticarcinoembryonic antigen prior to and 1 month after chemotherapy. MRD was classified as negative (Group I), micrometastasis positive only (Group II) and CTC positive (Group III). Changes in lymphocyte counts and MRD subtype following chemotherapy and relapse-free progression were analysed. RESULTS: Of the total of 185 patients, 83 (44.9%) relapsed. The risk of relapse significantly increased from Groups I to III (p < 0.001) and with decreasing lymphocyte count (p < 0.01). The lymphocyte count significantly decreased from Groups I to III (p < 0.001). Multivariance Cox regression analysis showed hazard ratios of 3.58 (Group II), 17.43 (Group III) and 0.39 (lymphocyte count) in predicting relapse. Following chemotherapy, improved lymphocyte count was associated with improved MRD subtype (p < 0.0001). Neither baseline lymphocyte count nor MRD subtype predicted response to chemotherapy. Five-year relapse-free survival for combined lymphocyte-MRD subtypes was 95%, 57% and 5% for Groups I to III, respectively (p < 0.001). CONCLUSION: Following chemotherapy, improvements in immune function were associated with improved MRD subtype and a better relapse-free survival.

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Neoplasias del Colon , Recurrencia Local de Neoplasia , Neoplasias del Colon/tratamiento farmacológico , Supervivencia sin Enfermedad , Humanos , Neoplasia Residual , Pronóstico , Estudios Prospectivos , Resultado del Tratamiento

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OBJECTIVE: Within 5 years after curative surgery for stage II colon cancer 25% of patients will relapse due to minimal residual disease (MRD). MRD is the net result of the biological properties of subpopulations of primary tumour cells which enable them to disseminate, implant in distant tissues and survive and the immune system's ability to eliminate them. We hypothesize that markers of immune dysfunction such as the systemic inflammation index (SII) are associated with the sub-type of MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). A higher immune dysfunction being associated with a more aggressive MRD and worse prognosis. METHODS AND PATIENTS: Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-CEA one month after surgery. The SII, absolute neutrophil, platelet and lymphocyte counts (ANC, APC, ALC) were determined immediately pre-surgery and one month post-surgery. These were compared with the sub-types of MRD; Group I MRD (-); Group II mM positive and Group III CTC positive; cut-off values of SII of >700 and >900 were used. Follow-up was for up to 5 years or relapse and survival curves using Kaplan-Meier (KM) were calculated. RESULTS: One hundred and eighty one patients (99 women) participated, mean age 68 years, median follow up 4.04 years; I: = 105 patients, II: N= 36 patients, III: N=40 patients. The SII significantly decreased post-surgery only in Group I patients. The frequency of SII >700 and >900 was significantly higher in Group III, between Groups I and II there was no significant difference.  The SII was significantly associated with the number of CTCs detected. The 5-year KM was 98% Group I, 68% Group II and 7% Group III. CONCLUSIONS: The results of the study suggest that the severity of immune dysfunction as determined by the SII is associated with differing sub-types of MRD and a worse prognosis; increasing immune dysfunction is associated with a more aggressive CTC positive MRD sub-type; a more severe immune dysfunction is associated with a higher number of CTCs detected.
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Asunto(s)

Plaquetas/patología , Colectomía/mortalidad , Neoplasias del Colon/mortalidad , Inflamación/mortalidad , Linfocitos/patología , Neoplasia Residual/mortalidad , Neutrófilos/patología , Anciano , Biomarcadores de Tumor/análisis , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Femenino , Estudios de Seguimiento , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/cirugía , Masculino , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Neoplasia Residual/inmunología , Neoplasia Residual/patología , Neoplasia Residual/cirugía , Células Neoplásicas Circulantes/patología , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia

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Recurrencia Local de Neoplasia/epidemiología , Neoplasia Residual/inmunología , Células Neoplásicas Circulantes/patología , Escape del Tumor , Inmunidad Adaptativa , Antineoplásicos , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Humanos , Inmunidad Innata , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/mortalidad , Neoplasia Residual/patología , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/inmunología , Pronóstico

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The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5×10-4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10-3 to 3.77×10-8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent.

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Lead intoxication can generate pro-inflammatory conditions that have been proposed to be associated with cell injuries and oxidative stress. The pro-inflammatory state can participate in the pathophysiology of this toxicity to generate immune response dysfunctions, which could condition the presence of clinical manifestations and susceptibility to infections already described in lead-exposed patients. In the present work, we study workers of a battery recycler factory (n = 24) who are chronically exposed to lead and compared them with non-lead exposed workers (n = 17). Lead-exposed workers had high lead concentrations in blood (med 69.8 vs. 1.7 µg/dL), low δ-ALAD activity (med 149 vs. 1100 nmol PBG/h/mL), high lipid peroxidation (med 0.86 vs. 0.69 nmol/mL) and high erythrocytes apoptosis (med 0.81 vs. 0.50% PS externalization) in relation to non-lead exposed workers. Also, lead-exposed workers had a high incidence of signs and symptoms related to lead intoxication and a higher frequency of infections. The higher leukocyte apoptosis (med 18.3 vs. 8.2% PS externalization) and lower basal TNF-α concentration (med 0.38 vs. 0.94 pg/mL) in lead-exposed workers imply an immune response dysfunction; however, there was no difference in the TNF-α concentration when leukocytes were stimulated with lipopolysaccharide in whole blood (med 44 vs. 70 pg/mL), suggesting that lead-exposed workers might develop adaptation mechanisms to reduce basal TNF-α release through downregulation processes proposed for this cytokine.

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Apoptosis/efectos de los fármacos , Intoxicación por Plomo/patología , Leucocitos/patología , Exposición Profesional , Factor de Necrosis Tumoral alfa/sangre , Adulto , Estudios de Casos y Controles , Eritrocitos/patología , Femenino , Humanos , Inmunidad/efectos de los fármacos , Plomo/sangre , Peroxidación de Lípido , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Porfobilinógeno Sintasa/sangre

RESUMEN

OBJECTIVES: In cirrhotic children, infection events and sepsis are more frequent and more severe due to immune dysfunction. The objectives of the current study were therefore to develop an experimental model of infection and sepsis in cirrhotic weaning growing rats, by the use of bile duct ligation (BDL) and cecal ligation and puncture (CLP). Additionally, the correlation of the clinico-histopathological data and serial cytokine levels in septic cirrhotic and non-cirrhotic animals was studied. METHODS: Young Wistar rats of age 21 days and of weight between 70-90 g were divided into 12 groups according to the surgical procedure performed: sham (sacrificed after 2 or 4 weeks), BDL (sacrificed after 2 or 4 weeks), CLP (2- or 4-week old animals sacrificed after 12 or 24 hours), BDL+CLP (2- or 4-week old animals sacrificed after 12 hours). Histopathological studies and determination of serum levels of cytokines IL-1 beta, IL-10, and TNF-alpha, for studies of systemic infection, were performed. Murine sepsis scores (MSS) based on the clinical aspects just before euthanasia were also included. RESULTS: A transitory increase in IL-1, IL-10, and TNF-alpha levels was observed, with different patterns according to the groups. Two-hit groups tended to present with higher values of serum cytokines and histopathological scores than their septic non-cirrhotic counterparts. There was a correlation between mortality rate and MSS (p<0.0001). CONCLUSION: The model is feasible and may be utilized in studies on liver cirrhosis and infection in growing animals.

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Animales , Ratones , Ratas , Sepsis , Cirrosis Hepática , Reproducibilidad de los Resultados , Ratas Wistar , Modelos Teóricos

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OBJECTIVES: To determine if children with congenital heart disease (CHD) have lower newborn T-cell receptor excision circles (TREC) levels than the general population and to evaluate if low TREC levels in newborns with CHD are associated with clinical complications such as hospitalization for infection. STUDY DESIGN: The Connecticut Newborn Screening Program reported TREC levels for newborns with CHD delivered between October 2011 and September 2016 at 2 major Connecticut children's hospitals. TREC levels for children with CHD were compared with the general population. TREC levels and outcome measures, including hospitalization for infection, were compared. RESULTS: We enrolled 575 participants with CHD in the study. The median TREC level for newborns with CHD was lower than the general population (180.1 copies/µL vs 312.5 copies/µL; P < .01). patients with CHD requiring hospitalization for infection had lower median TREC levels than their counterparts (143.0 copies/µL vs 186.7 copies/µL; P < .01). The combination of prematurity and low TREC level had a strong relationship to hospitalization for infection (area under the receiver operative characteristic curve of 0.89). There was no association between TREC level and CHD severity. CONCLUSIONS: Newborns with CHD demonstrated lower TREC levels than the general population. Low TREC levels were associated with hospitalization for infection in preterm children with CHD. Study limitations include that this was a retrospective chart review. These findings may help to identify newborns with CHD at highest risk for infection, allowing for potential opportunities for intervention.

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Cardiopatías Congénitas/sangre , Receptores de Antígenos de Linfocitos T/sangre , Estudios de Casos y Controles , Connecticut , Femenino , Hospitalización , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Sensibilidad y Especificidad

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ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

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OBJECTIVE: To characterize antinuclear antibody (ANA) prevalence according to distinct assay methodologies in a pediatric cohort from Mexico City, and to further examine associations with age and sex. METHODS: Serum ANA were measured by indirect immunofluorescence assay (IFA) and multiplex immunoassay in 114 children aged 9-17 years. IFA was considered positive at a cutoff titer of ≥1:80. Agreement between assay methods was assessed by kappa statistic. Sensitivity, specificity, and 95% confidence intervals (CIs) of the multiplex were computed with IFA as the reference standard. RESULTS: Of the 114 children (mean age 14.7 [standard deviation 2.1] years; 54 [47%] female), 18 of 114 (15.8%) were ANA positive by IFA, and 11 of 114 (9.6%) by 11-antigen multiplex assay. ANA prevalence was higher in females compared with males by both of the methods (ratios 1.6-1.9 to 1). Agreement between tests was classified as slight by kappa (κ=0.177 [95% CI -0.051, 0.406]). The multiplex immunoassay had sensitivity of 22.2% (95% CI 6.4, 47.6) and specificity of 92.7% (95% CI 85.6, 97.0), and failed to capture 3 of 4 (75%) of the high-titer (≥1:1280) IFA-positives. CONCLUSION: Up to 15% of children in this general population cohort were ANA positive, with a higher rate of positivity among females according to both assay methods. Substantial discordance in ANA results was found between IFA and multiplex methods, even for high-titer IFA positives. These findings underscore the need to sufficiently account for assay characteristics when interpreting ANA test results, and support IFA as the more appropriate assay for studies of subclinical autoimmunity.

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The natural history of cirrhosis can be divided into an initial stage, known as compensated cirrhosis, and an advanced stage which encompasses both decompensated cirrhosis and acute-on-chronic liver failure (ACLF). The latter syndrome has been recently described as an acute deterioration of liver function in patients with cirrhosis, which is usually triggered by a precipitating event and results in the failure of one or more organs and high short-term mortality rates. Each stage is characterized by distinctive clinical manifestations and prognoses. One of the key elements involved in cirrhosis physiopathology is systemic inflammation, recently described as one of the components in the cirrhosis-associated immune dysfunction syndrome. This syndrome refers to the combination of immune deficiency and exacerbated inflammation that coexist during the course of cirrhosis and relates to the appearance of clinical complications. Since systemic inflammation is often difficult to assess in cirrhosis patients, new objective, reproducible and readily-available markers are needed in order to optimize prognosis and lengthen survival. Thus, surrogate serum markers and clinical parameters of systemic inflammation have been sought to improve disease follow-up and management, especially in decompensated cirrhosis and ACLF. Leukocyte counts (evaluated as total leukocytes, total eosinophils or neutrophil:lymphocyte ratio) and plasma levels of procalcitonin or C-reactive protein have been proposed as prognostic markers, each with advantages and shortcomings. Research and prospective randomized studies that validate these and other markers are clearly warranted.

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Uma nova apresentação da insensibilidade ao hormônio de crescimento (IGH), causada por mutações em homozigose no gene STAT5B (transdutor de sinal e ativador de transcrição tipo 5B), foi caracterizada nos últimos anos. Sua particularidade é a associação com quadros de disfunção imunológica grave, sendo o mais característico a pneumonite intersticial linfocítica. A presença concomitante de doenças crônicas imunológicas pode fazer com que a baixa estatura seja erroneamente considerada uma consequência do quadro clínico, levando ao subdiagnóstico dessa forma de IGH. O objetivo desta revisão é divulgar o conhecimento atual sobre essa rara patologia, facilitando o reconhecimento de pacientes com IGH secundária a mutações no gene STAT5B em ambulatórios de endocrinologia e de outras especialidades.

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A new presentation of growth hormone insensitivity (GHI) caused by homozygous mutations in STAT5B (signal transducer and activator of transcription 5B) gene has been characterized in the last years. Its particularity is the association with severe immune dysfunction, especially with lymphocytic interstitial pneumonitis. This may mislead physicians into considering short stature as secondary to chronic immunological disease and consequently into underdiagnosing this form of GHI. The objective of this review is to propagate current knowledge about this rare pathology, facilitating the diagnosis of patients with GHI due to STAT5B mutations in endocrinology and other specialties clinics.

Asunto(s)

Humanos , Hormona de Crecimiento Humana/genética , Enfermedades del Sistema Inmune/genética , Síndrome de Laron/genética , Mutación , Enfermedades Raras/genética , /deficiencia , Enfermedades del Sistema Inmune/inmunología , Interleucinas/metabolismo , Síndrome de Laron/terapia , Enfermedades Raras/inmunología , Transducción de Señal , /genética , /inmunología