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A prolonged preoperatory aPTT in children is often the cause of a delay of scheduled surgeries and the repetition of multiple blood tests, with the consequent wasting of resources and significant discomfort for children and parents. The aim of this review is to analyze the situations in which an isolated prolongation of aPTT is found during preoperative evaluation in children, especially when it is due to the presence of antiphospholipid antibodies, providing the readers with the keys to interpret this situation and the possibility to correctly evaluate the hemorrhagic risk of a patient.
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Successful management of surgery in severe coagulation disorders depends on adequate replacement of the deficient factors from intervention until wound healing. Extended half-life (EHL) recombinant factor IX (rFIX) has been increasingly used in hemophilia B (HB) patients. Monitoring of blood levels of EHL rFIX allows to obtain pharmacokinetic (PK) parameters in order to optimize and personalize therapeutic scheme. We describe a case of a young male with severe HB who successfully underwent aortic valve repair. This is the first reported open-heart surgery in a patient with severe HB using EHL rFIX. The success was based on accurate PK evaluation and on meticulous preoperative planning and close cooperation among surgeons, hemophilia specialists, and laboratory team despite the long distance between hemophilia center and surgical clinic.
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Procedimientos Quirúrgicos Cardíacos , Hemofilia A , Hemofilia B , Humanos , Masculino , Factor IX/uso terapéutico , Hemofilia B/tratamiento farmacológico , Hemofilia A/tratamiento farmacológico , Semivida , Válvula AórticaRESUMEN
: Anticoagulation in a neonate is a challenge and the availability of anticoagulant options is extremely limited. Here we describe the use of a direct thrombin inhibitor, bivalirudin, in a full-term neonate with symptomatic cerebral sinovenous thrombosis complicated by bilateral thalamic hemorrhagic stroke and intraventricular hemorrhage, who could not be effectively treated with sodium heparin due to heparin resistance (HR) and showed thrombosis regression after start of bivalirudin treatment, without worsening of the hemorrhage. While the use of bivalirudin in neonates has been previously described, the indication of cerebral sinovenous thrombosis and the setting of HR are unique.
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Antitrombinas/uso terapéutico , Trombosis Intracraneal/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Antitrombinas/farmacología , Hirudinas/farmacología , Humanos , Recién Nacido , Masculino , Fragmentos de Péptidos/farmacología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures-for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care.
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OBJECTIVE: Concerns over adverse effects of mercury released from dental amalgam sometimes lead patients to request removal of their amalgam restorations. Several studies report improvement of subjective health after removal of amalgam restorations, but the mechanisms are unclear. The aim of this paper is to present data on long term changes in intensity of health complaints after amalgam removal in a group of patients with health complaints self-attributed to dental amalgam. Data from the five years follow-up in a clinical trial are presented and related to potential determinants of change. MATERIALS AND METHODS: Patients previously referred to a specialty unit for health complaints attributed to amalgam restorations were included in the study. The 20 participants who were allocated to the treatment group had all amalgam restorations removed and replaced with other dental restorative materials. Intensity of health complaints was calculated from questionnaire data and personality variables were measured by MMPI-2. RESULTS: At the follow-up five years after the amalgam removal was completed, intensity of general health complaints was significantly reduced (p=.001), but the symptom load was still high. The reduction was significantly correlated with concentration of mercury in urine at pre-treatment. There were no significant correlations with personality variables. CONCLUSIONS: Removal of amalgam restorations was followed by a long term reduction of general health complaints, which was associated with mercury concentration in urine before amalgam removal. Additional studies are needed to confirm the potential mechanisms for the observed reduction.
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Amalgama Dental/efectos adversos , Desconsolidación Dental , Restauración Dental Permanente/efectos adversos , Estado de Salud , Intoxicación por Mercurio/prevención & control , Adulto , Femenino , Humanos , Masculino , Mercurio/sangre , Persona de Mediana EdadRESUMEN
We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.
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Anemia de Fanconi/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Adulto , Niño , Preescolar , Toma de Decisiones , Anemia de Fanconi/mortalidad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Prueba de Histocompatibilidad , Humanos , Lactante , Recién Nacido , Italia , Masculino , Pancitopenia/inducido químicamente , Fenotipo , Hermanos , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
The management of refractory autoimmune cytopenias in childhood is challenging due to the lack of established evidence on escalating treatments. The long-term efficacy of immunosuppressive drugs was evaluated in children with refractory autoimmune cytopenias referred to the Haematology Unit of the Gaslini Children's Hospital between 2001 and 2014. Patients were grouped into three categories: autoimmune lymphoproliferative syndrome (ALPS), ALPS-related syndrome (at least one absolute/primary additional criterion for ALPS) and primary autoimmune cytopenia (PAC, cytopenia with no other immunological symptoms/signs). Fifty-eight children (aged 1-16 years) entered the study: 12 were categorized with ALPS, 24 were ALPS-related and 22 had PAC. Five didn't receive treatment. Fifty-three were initially treated with steroids/intravenous immunoglobulin. Fourteen responded, whereas 39 did not. Of these 39 patients, 34 (87%) received mycophenolate mofetil (MMF) as second/further-line treatment and 22 (65%) responded. Within these 34 subjects, ALPS patients responded better (11/11, 100%) than the two other groups pooled together (11/23, 48%; P = 0·002). Sirolimus was given as second/further-line treatment to 16 children, and 12 (75%) responded, including 8 who previously failed MMF therapy. Median follow-up was 3·46 years. MMF and Sirolimus were well-tolerated and enabled partial/complete and sustained remission in most children. These drugs may be successfully and safely used in children with refractory autoimmune cytopenias with or without ALPS/ALPS-related disorders and may represent a valid second/further line option.
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BACKGROUND: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations, aplastic anemia and increased risk of developing malignancies. FA is genetically heterogeneous as it is caused by at least 17 different genes. Among these, FANCA, FANCC, and FANCG account for approximately 85% of the patients whereas the remaining genes are mutated in only a small percentage of cases. For this reason, the molecular diagnostic process is complex and not always extended to all the FA genes, preventing the characterization of individuals belonging to rare groups. METHODS: The FA genes were analyzed using a next generation sequencing approach in two unrelated families. RESULTS: The analysis identified the same, c.484_485del, homozygous mutation of FANCF in both families. A careful examination of three electively aborted fetuses in one family and one affected girl in the other indicated an association of the FANCF loss-of-function mutation with a severe phenotype characterized by multiple malformations. CONCLUSION: The systematic use of next generation sequencing will allow the recognition of individuals from rare complementation groups, a better definition of their clinical phenotypes, and consequently, an appropriate genetic counseling.
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Anemia de Fanconi/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Preescolar , Femenino , Humanos , Masculino , LinajeRESUMEN
Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3/million inhabitants/year, in Europe, but higher in East Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of "Consensus Conferences" according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA.
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Anemia Aplásica/diagnóstico , Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/uso terapéutico , Pancitopenia/diagnóstico , Pancitopenia/terapia , Anemia Aplásica/inducido químicamente , Anemia Aplásica/inmunología , Antibacterianos/efectos adversos , Antiinflamatorios/efectos adversos , Suero Antilinfocítico/uso terapéutico , Antirreumáticos/efectos adversos , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/patología , Niño , Ciclosporina/uso terapéutico , Manejo de la Enfermedad , Prueba de Histocompatibilidad , Humanos , Organofosfatos/toxicidad , Pancitopenia/inducido químicamente , Pancitopenia/inmunología , Hermanos , Donante no EmparentadoRESUMEN
Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. Several studies show alterations of the immunological status of FA patients including defects in peripheral blood lymphocyte subsets, serum immunoglobulin levels, and inflammatory cytokines. However scanty information is available on the response of FA cells to specific infectious antigens. In this work we examined the response of FA cells to different immunological stimuli and found a defective response of IL-1ß, TNF-α and IL-17 to Candida albicans stimulation thus pointing to a potentially impaired response to fungal infections of FA patients.
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Candida albicans/inmunología , Anemia de Fanconi/inmunología , Anemia de Fanconi/microbiología , Inmunidad , Adolescente , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Células Cultivadas , Niño , Preescolar , Citocinas/biosíntesis , Anemia de Fanconi/patología , Humanos , Lactante , Adulto JovenRESUMEN
Bone marrow failure in Fanconi anemia (FA) has been linked in part to overproduction of inflammatory cytokines, to which FA stem and progenitor cells are hypersensitive. In cell lines and murine models p38 mitogen-activated protein kinase (MAPK)-dependent tumor necrosis factor α (TNF-α) overexpression can be induced by the Toll-like receptors (TLRs) 4 and 7/8 ligands Lipopolysaccharide (LPS) and R848. Ex vivo exposure of FA stem cells to TNF-α suppresses their replication and selects preleukemic clones. Here we show that inhibition of p38 MAPK also reduces TLR4 and 7/8-mediated TNF-α production in primary human FA complementation group A (FANCA)-deficient monocytes from nine patients and demonstrate that, while p38 MAPK inhibition also enhances clonal growth of FANCA-deficient erythroid progenitors, the effect was mediated indirectly by the influence of the inhibitor on auxiliary cells, not erythroid colony-forming units themselves. Taken together, these results support the view that inhibition of the p38 MAPK pathway in monocytes may improve hematopoiesis in FANCA patients.
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Células de la Médula Ósea/metabolismo , Eritropoyesis , Anemia de Fanconi/fisiopatología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Adolescente , Western Blotting , Células de la Médula Ósea/patología , Niño , Anemia de Fanconi/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas In Vitro , MasculinoAsunto(s)
Anemia Hemolítica Autoinmune/tratamiento farmacológico , Resistencia a Medicamentos/efectos de los fármacos , Inmunosupresores/administración & dosificación , Sirolimus/administración & dosificación , Anemia Hemolítica Autoinmune/diagnóstico , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
A multicentre study evaluating the presence of glycosil phosphatidyl-inositol (GPI)-negative populations was performed in 85 children with acquired aplastic anemia (AA). A GPI-negative population was observed in 41% of patients at diagnosis, 48% during immune-suppressive therapy (IST), and 45% in patients off-therapy. No association was found between the presence of a GPI-negative population at diagnosis and the response to IST. In addition, the response rate to IST did not differ between the patients who were GPI-positive at diagnosis and later developed GPI-negative populations and the 11 patients who remained GPI-positive. Two patients with a GPI-negative population >10%, and laboratory signs of hemolysis without hemoglobinuria were considered affected by paroxysmal nocturnal hemoglobinuria (PNH) secondary to AA; no thrombotic event was reported. Excluding the 2 patients with a GPI-negative population greater than 10%, we did not observe a significant correlation between LDH levels and GPI-negative population size. In this study monitoring for laboratory signs of hemolysis was sufficient to diagnose PNH in AA patients. The presence of minor GPI-negative populations at diagnosis in our series did not influence the therapeutic response. As occasionally the appearance of a GPI-negative population was observed at cyclosporine (CSA) tapering or AA relapse, a possible role of GPI-negative population monitoring during IST modulation may need further investigation.
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Anemia Aplásica/tratamiento farmacológico , Ciclosporina/uso terapéutico , Glicosilfosfatidilinositoles/metabolismo , Hemoglobinuria Paroxística/diagnóstico , Inmunosupresores/uso terapéutico , Adolescente , Anemia Aplásica/complicaciones , Anemia Aplásica/metabolismo , Niño , Preescolar , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemoglobinuria Paroxística/metabolismo , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Resultado del TratamientoRESUMEN
Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.
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Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutación , Sustitución de Aminoácidos , Línea Celular , Estudios de Cohortes , Biología Computacional , Bases de Datos de Ácidos Nucleicos , Efecto Fundador , Genotipo , Humanos , Italia , Mosaicismo , Polimorfismo de Nucleótido SimpleRESUMEN
A 9-month-old boy with life-threatening multiresistant pure red cell anemia/autoimmune hemolytic anemia within the frame of a possible, undiagnosed immune-mediated disease was initially treated with prednisone. Further-line therapies of the following 7 relapses included immunoglobulins, rituximab, cyclophosphamide, and alentuzumab followed by other maintenance treatments as cyclosporine, methotrexate, and mycophenolate. After all the administered therapies failed, the patient was successfully treated by splenectomy followed by fludarabine and then sirolimus as maintenance treatment. Relapses might have been caused by the lack of a complete debulking of triggering cells and/or ineffective maintenance therapy. Splenectomy and sirolimus may have played a complementary role in the management of both situations.
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Anemia Hemolítica Autoinmune/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Medicamentos , Aplasia Pura de Células Rojas/terapia , Esplenectomía , Anemia Hemolítica Autoinmune/diagnóstico , Terapia Combinada , Humanos , Lactante , Masculino , Aplasia Pura de Células Rojas/diagnóstico , Sirolimus/administración & dosificación , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Fanconi anemia (FA) is a recessive DNA repair disease characterized by a high predisposition to developing neoplasms. DNA tumor polyomavirus simian virus 40 (SV40) transforms FA fibroblasts at high efficiency suggesting that FA patients could be highly susceptible to SV40 infection. To test this hypothesis, the large tumor (LT) antigen of SV40, BKV, JCV and Merkel Cell (MC) polyomaviruses were tested in blood samples from 89 FA patients and from 82 of their parents. Two control groups consisting of 47 no-FA patients affected by other genetic bone marrow failure diseases and 91 healthy subjects were also evaluated. Although JCV, BKV and MC were not found in any of the FA samples, the prevalence and viral load of SV40 were higher in FA patients (25%; mean viral load: 1.1×10(2) copies/10(5)cells) as compared with healthy individuals (4.3%; mean viral load: 0.8×10(1) copies/10(5)cells) and genetic controls (0%) (p<0.005). A marked age-dependent frequency of SV40 was found in FA with respect to healthy subjects suggesting that, although acquired early in life, the virus can widespread more easily in specific groups of population. From the analysis of family pedigrees, 60% of the parents of SV40-positive probands were positive for the virus compared to 2% of the parents of the SV40-negative probands (p<0.005). It is worthy of note that the relative frequency of SV40-positive relatives detected in this study was the highest ever reported, showing that asymptomatic FA carriers are also more susceptible to SV40. In conclusion, we favor the hypothesis that SV40 spread could be facilitated by individuals who are genetically more susceptible to infection, such as FA patients. The increased susceptibility to SV40 infection seems to be associated with a specific defect of the immune system which supports a potential interplay of SV40 with an underlying genetic alteration that increases the risk of malignancies.
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Anemia de Fanconi/virología , Infecciones por Polyomavirus/epidemiología , Virus 40 de los Simios/patogenicidad , Niño , Preescolar , Humanos , Factores de RiesgoRESUMEN
Although allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for patients with Fanconi anemia (FA), published series mostly refer to single-center experience with limited numbers of patients. We analyzed results in 795 patients with FA who underwent first HSCT between May 1972 and January 2010. With a 6-year median follow-up, overall survival was 49% at 20 years (95% confidence interval, 38-65 years). Better outcome was observed for patients transplanted before the age of 10 years, before clonal evolution (ie, myelodysplastic syndrome or acute myeloid leukemia), from a matched family donor, after a conditioning regimen without irradiation, the latter including fludarabine. Chronic graft-versus-host disease and secondary malignancy were deleterious when considered as time-dependent covariates. Age more than 10 years at time of HSCT, clonal evolution as an indication for transplantation, peripheral blood as source of stem cells, and chronic graft-versus-host disease were found to be independently associated with the risk for secondary malignancy. Changes in transplant protocols have significantly improved the outcome of patients with FA, who should be transplanted at a young age, with bone marrow as the source of stem cells.
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Anemia de Fanconi/mortalidad , Anemia de Fanconi/terapia , Trasplante de Células Madre Hematopoyéticas/mortalidad , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
In this study, the immunological status of 61 patients with Fanconi anemia (FA) with advanced marrow failure before hematopoietic stem cell transplantation was analyzed by assessing the phenotype of peripheral blood lymphocytes, serum immunoglobulin (Ig) levels, and inflammatory cytokines. In patients with FA, total absolute lymphocytes (P < 0.0001), B cells (P < 0.0001), and NK cells (P = 0.003) were reduced when compared with normal controls. T cells (CD3), that is, cytotoxic T cells, naïve T cells, and regulatory T cells, showed a relative increase when compared with controls. Serum levels of IgG (P < 0.0001) and IgM (P = 0.004) were significantly lower, whereas IgA level was higher (P < 0.0001) than in normal controls. TGF-ß (P = 0.007) and interleukin (IL)-6 (P = 0.0007) levels were increased in the serum of patients when compared with controls, whereas sCD40L level decreases (P < 0.0001). No differences were noted in the serum levels of IL-1ß, IL-2, IL-4, IL-10, IL-13, IL-17, and IL-23 between FA subjects and controls. This comprehensive immunological study shows that patients with FA with advanced marrow failure have an altered immune status. This is in accordance with some characteristics of FA such as the proinflammatory and proapoptotic status. In addition, B lymphocyte failure may make tight and early immunological monitoring advisable.
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Anemia de Fanconi/inmunología , Adolescente , Adulto , Niño , Preescolar , Citocinas/sangre , Citocinas/inmunología , Anemia de Fanconi/sangre , Femenino , Humanos , Inmunoglobulinas/sangre , Inmunoglobulinas/inmunología , Inmunofenotipificación , Subgrupos Linfocitarios/inmunología , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: Some patients attribute health complaints to amalgam fillings and report improvement of health after replacement of amalgam fillings. The aim of the present study was to characterize the changes of different health complaints after replacement of amalgam fillings and compare with an external reference group from the general population. MATERIALS AND METHODS: The study group included 20 patients with health complaints attributed to amalgam fillings who were participants in the treatment group of a clinical trial at the Norwegian Dental Biomaterials Adverse Reaction Unit. The patients were asked to indicate the intensity of local and general health complaints on numeric rating scales (0-10) before removal of amalgam fillings and at follow-up 3 years after removal. Data from the patient group were compared with data from an external reference group (n = 441). RESULTS: Before treatment the mean intensity of complaints were on a higher level in the treatment group compared to the reference group. The most frequently reported complaints in the treatment group were gastrointestinal symptoms, fatigue, pain from muscles and joints, symptoms from ear/nose/throat and difficulty concentrating. From pre-treatment examination to the 3-year follow-up 20 of 23 health complaints decreased, being statistically significant for taste disturbances, pain from muscles and joints, gastrointestinal complaints, complaints from ear/nose/throat and fatigue. CONCLUSIONS: The inter-individual variation of intensities of health complaints was considerable and the reduction of health complaints varied for the different complaints. Several factors may be of importance for the observed reduction of complaint intensity.