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BACKGROUND: Nowadays one of the most critical aspects of innovative cell-based therapies is the unregulated industry, as it is becoming a competitor of the regulated system. Many private clinics, worldwide, advertise and offer cell-based interventions treatments directly to the consumer and this poses a risk to both vulnerable patients and health systems. Several countries have implemented Compassionate Use Programmes (CUP) that provide patients with medicines that have not yet completed the approval pathway, in the event that no reasonable alternative exists. Recently, in the public discourse, compassionate use has been increasingly associated with a patient's right to try. Thus, the aim of this study was to assess public knowledge of the clinical trials process with specific reference to innovative stem cell treatments, and trust in the institutions responsible for regulatory activities. We also asked people about their "right" to use unregulated therapies. METHODS: We developed an ad hoc questionnaire on three main areas of concern and administered it to 300 people in the patient waiting room at an Italian university hospital. RESULTS: Our findings suggest that people have a good knowledge of the clinical trials process and trust in healthcare institutions. Nonetheless, one person in two believes it is a right to use unregulated therapies. CONCLUSIONS: We stress the need, in the age of cellular therapies, for a commitment to support vulnerable patients and to strengthen awareness among the public about the substantial boundary that differentiates experimental therapies from unproven therapies. There should not be a "right to try" something that is unsafe but rather approved treatments and in line with good clinical practice. The trend, which emerged on this issue from our study, is quite different, confirming the urgent need to improve health information so that it is as complete as possible.
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Ensayos de Uso Compasivo , Derechos del Paciente , Derecho a la Salud , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Ensayos de Uso Compasivo/ética , Ensayos de Uso Compasivo/legislación & jurisprudencia , Cultura , Unión Europea , Femenino , Humanos , Italia , Masculino , Turismo Médico , Persona de Mediana Edad , Derechos del Paciente/ética , Derechos del Paciente/legislación & jurisprudencia , Seguridad del Paciente , Derecho a la Salud/ética , Derecho a la Salud/legislación & jurisprudencia , Riesgo , Trasplante de Células Madre/ética , Trasplante de Células Madre/legislación & jurisprudencia , Terapias en Investigación/ética , Confianza , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVE: The study proposes a possible roadmap for the ethical assessment of sham surgery clinical trials (CTs), focusing on methodological aspects, as a result of the lack of this type of practical tool in the literature/practice. BACKGROUND: Surgical procedures are frequently conducted without closely controlled studies. For this reason, these procedures are less rigorous than those for drug/device clinical trials. The aim of a sham (placebo) surgery CT is to carry out a surgical CT with a legitimate control group. The use of sham surgery is controversial from an ethical point of view. METHODS: This evaluation system is set up according to ICH/GCP, World Medical Association Declaration of Helsinki, CONSORT 2010 standards. The proposed roadmap is based on the following 4 steps/levels: safety/clinical indications; adequacy of trial methodology/design adopted for a sham surgery CT; specific informed consent, and economic issues. RESULTS: A flowchart is proposed which can be used at two levels: as a basic guideline for the design of a surgical protocol representing a benchmark level of care; and a multiaxial assessment considering the first two sources of morality of human acts according to Aristotelian ethics: the object of the act (step 1) and some of its circumstances (steps 2-4). CONCLUSIONS: The use of a placebo and of double-blind control groups in surgery CTs would improves the quality of results, providing that an accurate ethical assessment procedure is in place, firstly to ensure patient safety and secondly to prevent abuses/procedural biases. Future testing of the proposed flowchart is outlined.
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Ética en Investigación , Evaluación de Resultado en la Atención de Salud , Seguridad del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/economía , Procedimientos Quirúrgicos Operativos/ética , Método Doble Ciego , Femenino , Humanos , Consentimiento Informado/ética , Masculino , Placebos , Guías de Práctica Clínica como Asunto/normas , Calidad de la Atención de Salud , Medición de Riesgo , Procedimientos Quirúrgicos Operativos/métodosRESUMEN
OBJECTIVE: Sham surgery (placebo surgery) is an intervention that omits the step thought to be therapeutically necessary. In surgical clinical trials, sham surgery serves an analogous purpose to placebo drugs, neutralizing biases such as the placebo effect. A critical review was performed to study the statistical relevance of the clinical trials about sham surgery in the light of potential confounding factors. MATERIALS AND METHODS: For the critical review 52 articles were included. The possible confounding factors have been studied using a structured interpretative research form designed by the authors. This form includes the following ten confounding factors: I), lack of homogeneity among inclusion/exclusion criteria. II), false double blind. III), lack of post-surgery double blind. IV), power of the study. V), sample characteristics. VI), lost patients to Follow-up. VII), gender distribution. VIII), age equilibrium. IX), lack of psychological patient evaluation. X), lack of psychiatric patient evaluation. In most of the studies, at least one confounding factor was present. RESULTS: The analysis of the confounding factors showed that they could influence the reliability of the surgical placebo effects. CONCLUSIONS: The validity of sham surgery should be reconsidered.
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OBJECTIVES: Impairment in early B-cell development can cause a predominantly antibody deficiency with severe depletion of peripheral B-cells. Mutations in the gene encoding for Bruton's-tyrosine-kinase (BTK) and the components of the pre-B-cell receptor complex or downstream signaling molecules have been related to this defect in patients with agammaglobulinemia. METHODS: Iranian patients with congenital agammaglobulinemia were included and the correlation between disease-causing mutations and parameters such as clinical and immunologic phenotypes were evaluated in available patients. RESULTS: Out of 87 patients, a molecular investigation was performed on 51 patients leading to identification of 39 cases with BTK (1 novel mutation), 5 cases of µ-heavy chain (3 novel mutations) and 1 case of Igα-deficiencies. CONCLUSION: Although there is no comprehensive correlation between type of responsible BTK mutation and severity of clinical phenotype, our data suggest that BTK-deficient and autosomal recessive agammaglobulinemia patients differ significantly regarding clinical/immunologic characteristics.
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Agammaglobulinemia/genética , Linfocitos B/fisiología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Inmunoglobulina A/genética , Cadenas mu de Inmunoglobulina/genética , Proteínas Tirosina Quinasas/genética , Agammaglobulinemia Tirosina Quinasa , Trastornos de los Cromosomas , Estudios de Cohortes , Análisis Mutacional de ADN , Estudios de Asociación Genética , Genotipo , Irán , Mutación/genética , Fenotipo , Factores de TiempoRESUMEN
Senescent fibroblasts, which are present in chronic ulcers, are the reason for the wound becoming chronic. In this study, we introduce full-thickness micro skin grafts in the ulcer, a surgical technique known as a 'nested graft', which gave encouraging results leading to complete wound healing in all patients. The assessment of fibroblast cultures taken from the wound before and after treatment and comparison with fibroblasts from healthy skin showed that the fibroblasts taken from the ulcer after the nested graft treatment acquire morpho-functional characteristics overlapping those of fibroblasts from healthy skin. This surgical approach is, therefore, able to lead to the healing of chronic ulcers through the de-senescence of the fibroblasts.
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Úlcera Varicosa , Células Cultivadas , Enfermedad Crónica , Fibroblastos , Humanos , Cicatrización de HeridasRESUMEN
Carbapenem-resistant Klebsiella pneumoniae isolates are an important cause of nosocomial infections. This study evaluated a rapid cost-saving method based on MALDI-TOF technology, was and compared it with phenotypic, genotypic and epidemiological data for characterization of KPC-Kp strains consecutively isolated during a supposed outbreak. Twenty-five consecutive KPC Klebsiella pneumoniae isolates were identified and clustered by the MALDI Biotyper (Bruker, Daltonics). To display and rank the variance within a data set, principal component analysis (PCA) was performed. ClinProTools models were generated to investigate the highest sum of recognition capability and cross-validation. A Class dendrogram of isolates was constructed using ClinproTool. MLST was performed sequencing gapA, infB, mdh, pgi, rpoB, phoE and tonB genes. blakpc and cps genes were typed. Phylogenetic analysis and genetic distance of the KPC gene were performed using the MEGA6 software. PCA analysis defined two clusters, I and II, which were identified in a dendrogram by both temporal split and different antimicrobial susceptibility profiles. These clusters were composed mostly of strains of the same sequence type (ST512), the most prevalent ST in Italy, and the same cps (type 2). In cluster II, blakpc genotype resulted more variable than in cluster I. Phylogenetic analysis confirmed the genetic diversity in both clusters supported by the epidemiological data. Our study confirms that MALDI-TOF can be a rapid and cost-saving method for epidemiological clustering of KPC K. pneumoniae isolates and its association with blakpc genotyping represents a reliable method to recognize possible clonal strains in nosocomial settings.
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Carbapenémicos/farmacología , Infección Hospitalaria/microbiología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/química , Klebsiella pneumoniae/genética , Filogenia , Espectrometría de Masas en Tándem/métodos , beta-Lactamasas/genética , Proteínas Bacterianas/genética , Infección Hospitalaria/epidemiología , Brotes de Enfermedades , Farmacorresistencia Bacteriana , Genotipo , Humanos , Italia/epidemiología , Infecciones por Klebsiella/epidemiología , Klebsiella pneumoniae/clasificación , Klebsiella pneumoniae/efectos de los fármacos , Tipificación de Secuencias Multilocus , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosRESUMEN
BACKGROUND: To date, topical therapies guarantee a better delivery of high concentrations of pharmacologic agents to the mucosa of the upper aerodigestive tract (UADT). The use of topical drugs, which are able to reduce mucosal inflammation and to improve healing tissues, can represent a relevant therapeutic advance. Topical sodium hyaluronate (SH) has recently been recognized as adjuvant treatment in the chronic inflammatory disease of the UADT. AIMS: The aim of our work was to review the published literature regarding all the potential therapeutic effects of SH in the chronic inflammatory disease of UADT. METHODS: Relevant published studies were searched in Pubmed, Google Scholar, Ovid using keywords ("sodium hyaluronate" and "upper airways") or Medical Subject Headings. RESULTS: At the end of our selection process, sixteen publications have been included. Six of them in the post-operative period of nasal-sinus surgery, 2 of them in pediatric patients affected by recurrent upper respiratory tract infections, 4 of them in reducing symptoms and preventing exacerbations of chronic upper airways in adult population, 4 of them in patients with chronic inflammatory disease of UADT, including gastro-esophageal reflux disease (GERD). CONCLUSIONS: Topical administration of SH plays a pivotkey role in the postoperative phase of patients undergoing FESS and nasal surgery, and positive results are generally observed in all the patients suffering from UADT chronic inflammatory disease.
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Tracto Gastrointestinal/patología , Ácido Hialurónico/farmacología , Sistema Respiratorio/patología , Adulto , Niño , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Ácido Hialurónico/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/patología , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/patología , Nariz/cirugía , Senos Paranasales/efectos de los fármacos , Senos Paranasales/cirugía , Sistema Respiratorio/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Intra-laboratory turnaround time (TAT) is a key indicator of laboratory performance. Improving TAT is a complex task requiring staff education, equipment acquisition, and adequate TAT monitoring. The aim of the present study was to evaluate the intra-laboratory TAT after laboratory automation implementation (June 2013-June 2014) and to compare it to that in the preautomation period (July 2012-May 2013). Intra-laboratory TAT was evaluated both as the mean TAT registered and the percentage of outlier (OP) exams. The mean TAT was 36, 38, and 34 min during the study periods, respectively. These values respected the goal TAT established at 45 min. The OP, calculated at 45 min as well as at 60 min, decreased from 26 to 21 and from 11 to 5, respectively. From a focused analysis on blood count cell, troponin I, and prothrombin (PT) test, TAT improvement was more evident for tests requiring longer preanalytical process. The follow-up of TAT from June 2013 to June 2014 revealed the reduction of the mean TAT as well as of the OP exams after automation implementation and that automation more strongly affects the test in the preanalytical phase including centrifugation of the sample, such as troponin I and PT.
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Automatización de Laboratorios/métodos , Pruebas Diagnósticas de Rutina/métodos , Hospitales Universitarios , Humanos , Ciudad de Roma , Factores de TiempoAsunto(s)
Hormona Adrenocorticotrópica/deficiencia , Alopecia/inmunología , Inmunodeficiencia Variable Común/inmunología , Enfermedades del Sistema Endocrino/inmunología , Enfermedades Genéticas Congénitas/inmunología , Hipoglucemia/inmunología , Células Asesinas Naturales/inmunología , Mutación , Subunidad p52 de NF-kappa B/inmunología , Infecciones del Sistema Respiratorio/inmunología , Hormona Adrenocorticotrópica/genética , Hormona Adrenocorticotrópica/inmunología , Adulto , Alopecia/complicaciones , Alopecia/genética , Alopecia/patología , Linfocitos B/inmunología , Linfocitos B/patología , Secuencia de Bases , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/patología , Citotoxicidad Inmunológica , Enfermedades del Sistema Endocrino/complicaciones , Enfermedades del Sistema Endocrino/genética , Enfermedades del Sistema Endocrino/patología , Expresión Génica , Enfermedades Genéticas Congénitas/complicaciones , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Heterocigoto , Humanos , Hipoglucemia/complicaciones , Hipoglucemia/genética , Hipoglucemia/patología , Células Asesinas Naturales/patología , Masculino , Datos de Secuencia Molecular , Subunidad p52 de NF-kappa B/genética , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/patología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
OBJECTIVE: Monocyte inflammatory processes are fundamental events in AIDS pathogenesis. HIV-1 matrix protein p17, released from infected cells, was found to exert an interleukin (IL)-8 chemokine-like activity on human monocytes, promoting their trafficking and sustaining inflammatory processes, after binding to CXCR1. A haplotype of the CXCR1 gene (CXCR1_300_142) has been associated with slow HIV disease progression. Here, we determine how CXCR1 genetic variations impact on p17 biological activity. DESIGN/METHODS/RESULTS: Our results show that Jurkat cells overexpressing CXCR1 or the receptor carrying single polymorphism CXCR1_300 or CXCR1_142 are able to adhere and migrate in response to both IL-8 and p17. On the contrary, Jurkat cells overexpressing CXCR1_300_142 and monocytes of individuals with such CXCR1 polymorphisms lose the capacity to adhere and migrate in response to p17, but not to their physiological ligand IL-8. Surface plasmon resonance (SPR) and multispectral imaging flow cytometry showed that p17 bound with similar affinity to CXCR1 and CXCR1_300_142. Moreover, whereas p17 was able to activate CXCR1, it was incapable of functionally interacting with CXCR1_300_142 by phosphorylating extracellular signal-regulated kinase 1/2, which regulates chemokine-induced cellular responses. Finally, mutagenesis studies showed that, unlike IL-8, p17 does not use Glu-Leu-Arg-like motifs to activate CXCR1. CONCLUSIONS: Our results, showing the inability of p17 to activate CXCR1_300_142, a receptor found to be expressed on immune cells of patients with a low progression of HIV disease, point to a crucial role of p17 in AIDS pathogenesis. Our findings herein call for an exploration of the therapeutic potential of blocking the p17/CXCR1 axis in HIV infection.
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Antígenos VIH/metabolismo , Antígenos VIH/fisiología , Haplotipos , Interacciones Huésped-Patógeno , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/metabolismo , Linfocitos T/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/fisiología , Movimiento Celular , Citometría de Flujo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Interleucina-8/metabolismo , Células Jurkat , Unión Proteica , Resonancia por Plasmón de Superficie , Linfocitos T/virologíaRESUMEN
Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive disorder, caused by the absence or reduced expression of the beta-2 integrins on granulocytes, and characterized by the inability of these cells to emigrate from the bloodstream towards the sites of tissue inflammation. A twelve-year-old girl with a diagnosis of LAD-1 syndrome and recurrent skin and mucosal infections since birth, presented with a two week history of fever, abdominal pain, vomiting, weight loss and polyarthralgia. She underwent an exploratory laparotomy with the finding of inflamed terminal ileum and colon and a normal appendix. Colonoscopy and videocapsule endoscopy showed multiple ileal and colonic mucosal ulcerations, which were compatible with inflammatory bowel disease, confirmed on histological examination. Given the lack of response to conventional therapy (prednisone and mesalamine), a monoclonal anti-TNF-α antibody was started at a dosage of 5 mg/kg at weeks 0,2,4,6 and then every 8 weeks. We observed a significant improvement of all clinical and laboratory parameters after the first weeks of therapy. Five months later, we anticipated the drug's administration every 5 weeks because of a precocious recurrence of symptoms. After 30 months of treatment no relapse nor any relevant side effects have been observed, and corticosteroids were withdrawn. Interestingly, our patient presented a small subset of CD18+ T cells, similarly to previously reported LAD-1 patients with mild phenotype, inflammatory bowel disease and CD18+ somatic revertant T cells. To the best of our knowledge, this is the first LAD-1 pediatric patient with inflammatory autoimmune complications who experienced a positive response to anti-TNF-α treatment.
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Granulocitos/fisiología , Inmunoterapia/métodos , Enfermedades Inflamatorias del Intestino/terapia , Cadenas beta de Integrinas/metabolismo , Síndrome de Deficiencia de Adhesión del Leucocito/terapia , Anticuerpos Monoclonales/administración & dosificación , Movimiento Celular/genética , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Cadenas beta de Integrinas/genética , Síndrome de Deficiencia de Adhesión del Leucocito/genética , Síndrome de Deficiencia de Adhesión del Leucocito/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
This study describes the third case worldwide of autosomal recessive agammaglobulinemia due to a novel non-sense mutation in Igß presenting with neutropenia, ecthyma and mild respiratory infections.
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Agammaglobulinemia/genética , Codón sin Sentido , Inmunoglobulinas/genética , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/inmunología , Agammaglobulinemia/patología , Secuencia de Bases , Consanguinidad , Ectima/inmunología , Ectima/patología , Femenino , Homocigoto , Humanos , Inmunoglobulinas/deficiencia , Inmunoglobulinas/inmunología , Lactante , Datos de Secuencia Molecular , Neutropenia/inmunología , Neutropenia/patología , Linaje , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/patologíaRESUMEN
BACKGROUND: Bruton tyrosine kinase (BTK) plays an essential role in various biologic functions of different cell types. Mutations in BTK lead to X-linked agammaglobulinemia (XLA) in humans. BTK was recently linked to the innate immune system, in particular, the Toll-like receptor (TLR) pathway; however, the TLR9 pathway has never been studied in dendritic cells (DCs) of patients with XLA. OBJECTIVE: The aim of this study was to investigate the role of BTK in human DC activation upon TLR9 stimulation. METHODS: DCs of patients with XLA and healthy donors were stimulated via TLR4/9 and evaluated for cell activation and cytokine production. RESULTS: We showed that BTK plays an essential role in DC responses to unmethylated CpG oligodeoxynucleotide: although responses to lipopolysaccaride/TLR4 induce normal DC activation in terms of upregulation of specific markers (CD86, CD83, CD80, HLA-DR), the CpG/TLR9 pathway is completely impaired in patients with XLA. Furthermore, cytokine production upon TLR9 activation in patients with XLA is radically impaired in terms of IL-6, IL-12, TNF-α, and IL-10 production. Interestingly, BTK mediated STAT1/3 upregulation in a TLR9-dependent manner. The important role of BTK in human DC activation was confirmed after incubation of healthy DCs with ibrutinib, the specific BTK inhibitor, which resulted in impairment of TLR9 responses as seen in patients with XLA. CONCLUSION: Analysis of these data suggests that BTK regulates human DC responses upon TLR9 engagement in terms of activation, cytokine production, and STAT1/3 upregulation. These findings may be of important significance for better understanding and managing different clinical conditions, such as agammaglobulinemia and lymphoid malignancies.
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Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Receptor Toll-Like 9/metabolismo , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Agammaglobulinemia/metabolismo , Citocinas/biosíntesis , Células Dendríticas/efectos de los fármacos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Humanos , Inmunofenotipificación , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Oligodesoxirribonucleótidos/farmacología , Fenotipo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
This study describes the fifth case worldwide of autosomal recessive agammaglobulinemia due to a novel non-sense mutation in CD79a gene with a severe unusual onset due to an invasive central nervous system infection.
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Agammaglobulinemia/genética , Antígenos CD79/genética , Mutación , Agammaglobulinemia/diagnóstico , Análisis Mutacional de ADN , Femenino , Humanos , Isotipos de Inmunoglobulinas/sangre , Lactante , Masculino , LinajeRESUMEN
A Real-time polymerase chain reaction (PCR) with melting analysis was devised to target bacterial and fungal genes together with the most prevalent antimicrobial resistance genes in 250 positive blood culture broths. This method allowed the blood culture cultivated pathogens to be classified into clinically relevant groups such as Enterobacteriaceae, oxidase-positive bacilli, oxidase-positive coccobacilli, S. aureus and yeast. Enterococci and streptococci could be distinguished from CoNS only by the Gram stain. Gram-positive bacilli were discriminated from Gram-positive cocci by Gram stain. Furthermore, the most important antimicrobial resistant genes such as mecA, vanA, bla TEM , bla SHV and bla CTX-M could be identified. All results were obtained with a turnaround time of three hours from the moment of blood culture positivity compared to 24-72 hours for phenotypic methods. In conclusion, the proposed approach can allow the clinician to implement proper early management of sepsis patients.
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Farmacorresistencia Bacteriana Múltiple/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Sepsis/microbiología , Humanos , Italia , Pruebas de Sensibilidad Microbiana , Sepsis/diagnóstico , Factores de TiempoRESUMEN
Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
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Proteínas Adaptadoras Transductoras de Señales/genética , Autoinmunidad/genética , Síndromes de Inmunodeficiencia/genética , Agammaglobulinemia/genética , Apoptosis , Autofagia , Linfocitos B/citología , Proliferación Celular , Niño , Preescolar , Mapeo Cromosómico , Femenino , Ligamiento Genético , Genotipo , Homocigoto , Humanos , Inmunofenotipificación , Masculino , Microscopía Electrónica de Transmisión/métodos , Modelos Genéticos , Mutación , Linaje , FenotipoRESUMEN
Broad Toll-like receptor 9 (TLR9) signalling defects after CpG in vitro stimulation have been described in common variable immunodeficiency (CVID). CXCL16, a surface receptor, was recently shown to influence cell responses to CpG. We evaluated the expression and function of CXCL16 on B cells from healthy controls and CVID patients. We report that CXCL16 is normally expressed on B cells throughout peripheral maturation. Decreased B cell expression of CXCL16 was observed in a subgroup of CVID patients that correlated with defective in vitro responses to CpG (such as upregulation of CD69, CD86, AICDA, IL-6, and TLR9). Our data suggest that expression levels of a surface receptor, namely, CXCL16, correlate with B cell responses mediated by TLR9 in common variable immunodeficiency.
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Linfocitos B/inmunología , Quimiocinas CXC/genética , Inmunodeficiencia Variable Común/inmunología , Islas de CpG/inmunología , Receptores Depuradores/genética , Adolescente , Adulto , Estudios de Casos y Controles , Quimiocina CXCL16 , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Nasal obstruction is one of the most frequent symptoms in the ear, nose, and throat (ENT) setting. It can be evaluated either subjectively or objectively. In a subjective way, a visual analog scale (VAS) and the Sino-Nasal Outcome Test 20 (SNOT 20) can rapidly quantify the degree of obstruction, whereas the most commonly used objective methods are nasal endoscopy and active anterior rhinomanometry (AAR). It is still a matter of controversy to what extent the sense of nasal obstruction is associated with objective measures for nasal space and airflow. The aim of the study was to evaluate nasal breathing before and after functional nasal surgery by video-rhino-hygrometer (VRH) comparing the results with widely accepted methods. METHODS: Twenty patient candidates for septoplasty and inferior turbinate reduction were included in the study. SNOT-20, VAS, nasal endoscopy, and AAR were analyzed and compared with VRH values. RESULTS: Before surgery VRH showed variability of nasal respiratory flow between individuals and between nostrils. After surgery we had an increase (p < 0.05) of airflow in both nostrils. VRH data were found to be correlated with VAS and SNOT-20 values (p < 0.05) both pre- and postoperatively. Despite the statistically significant correlation of AAR with SNOT-20 and VAS, no statistically significant correlation between AAR and VRH was found. CONCLUSION: VRH provides an immediate, easy, and noninvasive assessment of nasal respiration. For these reasons it can be used, in association with rhinoscopic data and other instrumental tests, to evaluate nasal breathing in daily ENT practice.