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Background With improvements in survival rates, health-related quality of life is an important outcome parameter to evaluate the effectiveness of transplantation. We aimed to identify potential immunologic abnormalities as factors associated with poorer health-related quality of life at distinct scales of the 36-Item Short Form Health Survey in heart transplant recipients long term after transplantation. Methods One hundred heart transplant recipients were evaluated in a single center. Short-form 36 questionnaires were sent by mail to participants. All patients were clinically and immunologically evaluated after the first year of heart transplantation. Results A high prevalence of several immunologic abnormalities persisted even after the first year of transplantation, including IgG hypogammaglobulinemia, low IgG-specific antipneumococcal antibodies, C4 hypocomplementemia, CD8 T-cell lymphocytopenia, and CD19 B-cell lymphocytopenia. Older recipients (>55 years), posttransplant diabetes, digestive complications, and posttransplant infections were associated with lower physical functioning scores (scale 55 years), pretransplant diabetes, pretransplant arterial hypertension, posttransplant digestive complications, and lower CD8 counts were associated with lower physical role scores (scale Conclusion In a single center study, lower CD8 cell counts were found to be associated with poorer health status in heart recipients after the first year of transplantation.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

[EN] Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available., [ES] Las inmunodeficiencias primarias (IDP) son unas enfermedades raras, frecuentemente infradiagnosticadas y potencialmente fatales. Las manifestaciones clínicas de las IDP pueden ser muy graves y ocasionar secuelas que empeoran la calidad de vida de los pacientes. Tradicionalmente, el tratamiento de las IDP ha sido fundamentalmente de soporte, con excepción del trasplante de progenitores hematopoyéticos y, más recientemente, la terapia génica. El descubrimiento de nuevos mecanismos patogénicos, el desarrollo de nuevas moléculas y fármacos biológicos y los avances en el conocimiento de las bases moleculares de estas enfermedades han abierto oportunidades para el tratamiento de esta afección. El objetivo de este documento es revisar el conocimiento actual y aportar recomendaciones para el diagnóstico y el tratamiento clínico de los pacientes adultos y pediátricos con IDP basado en la evidencia científica disponible y teniendo en cuenta la actual práctica y los retos futuros. Se realizó una revisión sistemática, que justifica los niveles de evidencia para cada recomendación.

Background One hundred fifty million contagions, more than 3 million deaths and little more than 1 year of COVID-19 have changed our lives and our health management systems forever. Ageing is known to be one of the significant determinants for COVID-19 severity. Two main reasons underlie this: immunosenescence and age correlation with main COVID-19 comorbidities such as hypertension or dyslipidaemia. This study has two aims. The first is to obtain cut-off points for laboratory parameters that can help us in clinical decision-making. The second one is to analyse the effect of pandemic lockdown on epidemiological, clinical, and laboratory parameters concerning the severity of the COVID-19. For these purposes, 257 of SARSCoV2 inpatients during pandemic confinement were included in this study. Moreover, 584 case records from a previously analysed series, were compared with the present study data. Results Concerning the characteristics of lockdown series, mild cases accounted for 14.4, 54.1% were moderate and 31.5%, severe. There were 32.5% of home contagions, 26.3% community transmissions, 22.5% nursing home contagions, and 8.8% corresponding to frontline worker contagions regarding epidemiological features. Age > 60 and male sex are hereby confirmed as severity determinants. Equally, higher severity was significantly associated with higher IL6, CRP, ferritin, LDH, and leukocyte counts, and a lower percentage of lymphocyte, CD4 and CD8 count. Comparing this cohort with a previous 584-cases series, mild cases were less than those analysed in the first moment of the pandemic and dyslipidaemia became more frequent than before. IL-6, CRP and LDH values above 69 pg/mL, 97 mg/L and 328 U/L respectively, as well as a CD4 T-cell count below 535 cells/μL, were the best cut-offs predicting severity since these parameters offered reliable areas under the curve. Conclusion Age and sex together with selected laboratory parameters on admission can help us predict COVID-19 severity and, therefore, make clinical and resource management decisions. Demographic features associated with lockdown might affect the homogeneity of the data and the robustness of the results.

We present the case of a male patient with severe SARS-CoV-2 pneumonia, with simultaneous onset of p-ANCA positive rapidly progressive glomerulonephritis. We discuss the different therapeutic possibilities, emphasising the appropriateness of their administration according to the time in the course of the infection.

Background The SARS-CoV-2 infection has widely spread to become the greatest public health challenge to date, the COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. The Spanish case-fatality rate is 11.22%, far higher than those reported in Asia or by other European countries. A multicentre retrospective study of demographic, clinical, laboratory and immunological features of 584 Spanish COVID-19 hospitalized patients and their outcomes was performed. The use of renin-angiotensin system blockers was also analysed as a risk factor. Results In this study, 27.4% of cases presented a mild course, 42.1% a moderate one and for 30.5% of cases, the course was severe. Ages ranged from 18 to 98 (average 63). Almost 60 % (59.8%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19, and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of angiotensin-converting enzyme inhibitors was associated with a better prognosis. The angiotensin II receptor blocker use was associated with a more severe course. Conclusions Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and the clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for the hampering of immune system effectors. The adaptive immunity would become exhausted and a strong but ineffective and almost deleterious innate response would account for COVID-19 severity. Angiotensin-converting enzyme inhibitors used by hypertensive patients have a protective effect in regards to COVID-19 severity in our series. Conversely, patients on angiotensin II receptor blockers showed a severer disease., The authors thank all caregivers who indirectly contributed to this multicentre study. They also thank Sharleen Opia for her review of the English translation. They also thank the Spanish Society for Immunology (Sociedad Espanola de Inmunologia, SEI) for its support and endorsement.

BackgroundSARS-CoV-2 infection has widely spread to the hugest public health challenge to date, COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. Spanish case-fatality rate is 11.94%, far higher to those reported in Asia or by other European countries. A multicenter retrospective study was performed of demographic, clinical, laboratory and immunological features of 574 Spanish COVID-19 hospitalized patients and their outcomes. The use of use of renin-angiotensin system blockers was also analyzed as a risk factor.ResultsIn this study, 27.7% of cases presented a mild curse, 42% a moderate one and for 30.3% of cases, the course was severe. Ages ranged from 18 to 98 (average 63.2). Fifty eight percent (58.9%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19 and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of renin-angiotensin system blockers was associated with moderate or mild disease courses.ConclusionsAge and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for immune system effectors severity-related hampering. Adaptive immunity would go exhausted and a huge ineffective and almost deleterious innate response would account for COVID-19 severity. Renin-angiotensin system blockers treatment in hypertensive patients has a protective effect as regarding COVID-19 severity.

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

En un muy citado artículo sobre percepción del habla, Noël Nguyen 2005 hace una afirmación que resume de modo extraordinariamente sucinto un hecho incuestionable sobre el que se han escrito infinidad de tratados: «la forme sonore du langage est d’abord appréhendée à travers l’oreille» (p. 425). Es decir, no puede entenderse el estudio de las propiedades fonéticas y de los sistemas fonológicos de las lenguas, ni su relación con los procesos cognitivos implicados en el fenómeno del habla, sin tener en cuenta ineludiblemente el papel del oyente y el propio mecanismo de la percepción. Esta realidad, ya por sí sola, justifica toda la atención que pueda brindarse al fenómeno perceptivo; pero sucede, además, que en los últimos años se han realizado importantes avances en este terreno y se han abierto nuevas perspectivas de análisis –algunas de ellas representadas en este volumen, como se verá– que hacen aún más recomendable, si cabe, tomarlo en consideración.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

Background and objectives: Percentages of blood CD19 + CD5 + B cells and CD8 + perforin + T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice. Methods: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values. Results: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19 + CD5 + B cell and 0.89 (CI: 0.85-0.93) for CD8 + perforin + T cell quantification; Spearman r was 0.92 (0.89-0.95; p < 0.0001) and 0.92 (0.88-0.95; p < 0.0001) respectively. All centres obtained z-scores 5 0.5 for both biomarkers. Conclusion: Homogenous percentages of CD19 + CD5 + B cells and CD8 perforin + T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.

Background: Three substitutions at either Gly305 or Gly306 within the membrane attack/complex perforin domain (MACPF) of perforin have been previously identified in a number of patients with hemophagocytic lymphohistiocytosis (HLH). However, their pathogenic impact remains unclear since all the cases reported so far carried heterozygous genotypes and showed very heterogeneous clinical presentations. Here, we report a new substitution (p.Gly306Asp) and use in silico tools to elucidate the pathogenic mechanisms and severity associated with human Gly306 and Gly305 mutations.Methods: The immunological workup included perforin expression and perforin gene (PRF1) mutation analysis. Computer algorithms based on conservation, secondary, and tertiary protein structure analyses were applied to assess the role of the mutations in disease pathogenesis.Results: In our patient, we found a previously undescribed homozygous c. 917G>A (p.Gly306Asp) mutation in the PRF1 gene that was associated with null perforin expressio...

Problem Recurrent reproductive failure (RRF) has been associated with expansion of circulating NK cells, key cells for maternal tolerance, decidual vasculogenesis and embryo growth. This study reports our experience in intravenous immunoglobulin (IVIg) therapy of a large cohort of women with RRF with expanded circulating NK and/or NKT-like cells (blood NKT cells are a heterogeneous subset of T cells that share properties of both T cells and NK cells). Method of study Observational study of RRF women with NK or NKT-like expansion (>12% or 10% cutoff levels of total lymphocytes, respectively), treated with IVIg for the next gestation. Results By multivariant logistic regression analysis after adjusting for age, NK cells subsets and other therapies, IVIg significantly improved the live birth rate to 96.3% in women with recurrent miscarriage (RM) compared with 30.6% in case not receiving IVIg (P

Problem Natural killer (NK) cells play a key role in embryo implantation and pregnancy success, whereas blood and uterine NK expansions have been involved in the pathophysiology of reproductive failure (RF). Our main goal was to design in a large observational study a tree-model decision for interpretation of risk factors for RF. Methods of study A hierarchical multivariate decision model based on a classification and regression tree was developed. NK and NKT-like cell subsets were analyzed by flow cytometry. Results By multivariate analysis, blood NK cells expansion was an independent risk factor for RF (both recurrent miscarriages and implantation failures). We propose a new decision-tree model for the risk interpretation of women with RF based on a combination of main risk factors. Conclusions Women with age above 35 years and >13% CD56+CD16+ NK cells showed the highest risk of further pregnancy loss (100%).

espanolEn el presente articulo, se revisan el concepto y las funciones de la vocal de relleno y se alude a los estudios que han abordado su estructura acustica en distintas lenguas, particularmente en espanol y en ruso, trabajos cuyos resultados permiten avanzar algunas hipotesis sobre la autentica naturaleza de esta vocal. Para tratar de confirmar o falsar dichas hipotesis se ha analizado acusticamente una amplia muestra de vocales de las dos lenguas mencionadas. La discusion de los resultados de este analisis interlinguistico permite extraer algunas conclusiones potencialmente interesantes para la teoria fonetico-fonologica. En concreto, se argumenta que la vocal de relleno puede constituir una unidad acustico-articulatoria claramente diferenciada de las vocales que integran los respectivos sistemas fonologicos y estrechamente relacionada con los ajustes articulatorios propios de cada lengua, esto es, con su base de articulacion. EnglishThis paper addresses the concept and function of vocalic fillers, reviews other studies that have described their acoustic structure in different languages, especially focusing on those about Spanish and Russian, and outlines some hypotheses about the real nature of these vowels. Next, in order to check those hypotheses, an acoustic analysis is presented, based on large samples of fillers produced by speakers of the two aforementioned languages. The results of this crosslinguistic analysis are then discussed and conclusions are drawn which are potentially interesting for phonetic and phonological theory. Specifically, it is argued that vocalic fillers may constitute an acoustic and articulatory unit clearly differentiated from the vowels that form part of the respective phonological systems, and that their precise characteristics may be highly dependent on language-specific overall articulatory settings (namely, on the base of articulation).

International audience; Reported synonymous substitutions are generally non-pathogenic, and rare pathogenic synonymous variants may be disregarded unless there is a high index of suspicion. In a case of IL7 receptor deficiency severe combined immunodeficiency (SCID), the relevance of a non-reported synonymous variant was only suspected through the use of additional in silico computational tools, which focused on the impact of mutations on gene splicing. The pathogenic nature of the variant was confirmed using experimental validation of the effect on mRNA splicing and IL7 pathway function. This case reinforces the need to use additional experimental methods to establish the functional impact of specific mutations, in particular for cases such as SCID where prompt diagnosis can greatly impact on diagnosis, treatment, and survival.

Aim of the study B-cell chronic lymphocytic leukemia (B-CLL) is a neoplasia of the immune system due to an accumulation of clonal B lymphocytes resistant to apoptosis. B-cell abnormal infiltration impairs normal architecture of lymph nodes and other organs of the immune system and therefore the defense against infectious diseases. Single new therapeutic strategies are currently under investigation for triggering specific death of malignant B-CLL cells. Moreover, therapies including combination of several new antitumor agents more effective against tumor processes are being developed. Methods We used an active fraction obtained from Ganoderma lucidum fruiting bodies. This fraction was isolated by methanol extraction and column chromatography on silica gel using butanol:acetic acid:water for elution. This fraction was collected at an Rf of 0.74. Results In this study, we show induction of cytotoxicity, DNA fragmentation and apoptosis on fresh human B-CLL cells by this active fraction from G. lucidum. Different dose-dependent cytotoxic effects were observed depending on the individual immunophenotypes. Even at low concentration, this fraction induced cell death with DNA fragmentation and changes in phosphatidylserine localization in cell membrane on B-cells from CLL patients. It is at low concentration where this active fraction shows a balance between the apoptotic effect and cell viability. Conclusion The high cytotoxic effect observed in peripheral blood mononuclear cells from B-CLL patients as compared with the effect on healthy donors’ cells support its potential antileukemia role in combined therapeutic strategies.

Resume Ces dernieres annees, dans le domaine de la formation des professeurs de L2 et, plus particulierement, des professeurs de prononciation, la fracture s’est encore creusee entre la recherche fondamentale et l’application de ses decouvertes dans les salles de classe. Cela est du, en partie, au fait que l’on a insiste sur les aspects methodologiques au detriment de la connaissance meme de la matiere. Dans cet article, nous defendons, a partir de deux exemples concrets, le besoin de tenir en permanence les professeurs de prononciation au courant des decouvertes faites par la recherche en phonetique / phonologie, creant ainsi un dialogue profitable aux deux facettes de la discipline.

Aim Haemophagocytic lymphohistiocytosis (HLH) is characterised by T cell and macrophage activation and excessive production of inflammatory cytokines. Genetic diagnosis is required to discriminate between primary forms (familial HLH, FHL), due to mutations in genes involved in cytolysis, and secondary forms. We aimed to analyse the genes coding for Munc13-4 (UNC13D) and syntaxin-11 (STX11) proteins in search of mutations that might explain HLH in 5 patients without perforin defects. Materials and methods Perforin expression was evaluated by flow cytometry, sCD25 was measured by ELISA and NK activity was investigated by the conventional functional assay. Coding regions and exons surroundings were sequenced for PRF1, UNC13D and STX11 genes. Results P1 and P2 developed severe early-onset HLH, P1 died at 6 months. P3, with a sister who died after HLH, responded well to treatment (HLH-2004), and had a second HLH episode two years later. P2 developed HLH at year 7 while in complete remission after lymphoblastic leukaemia. P4 and P5 were brothers who died at 5 and 6 years old due to an HLH and EBV mononucleosis infection. XLP was discarded because P4 was a girl. P1 and P3 showed mutations in UNC13D previously described as pathogenic. There were no changes in STX11. Conclusions UNC13D mutations were found in 50% of the HLH families without perforin defects and STX11 defects were not detected. These results agree with published series in which mutations in UNC13D explain up to 50% of FHL without PRF1 mutations, supporting a heterogeneous genetic background for this disease.

Background CD3δ deficiency is a fatal form of severe combined immunodeficiency that can be cured by hematopoietic stem cell transplantation (HSCT). The presence of a thymus loaded with T-cell progenitors in patients with CD3δ deficiency may require special considerations in choosing the regimen of conditioning and the type of HSCT. Objectives To study the outcome of CD3δ deficiency by using various modalities of stem cell transplantation. Methods We analyzed data on 13 patients with CD3δ deficiency who underwent HSCT in 7 centers. HSCT was performed by using different sources of donor stem cells as well as various conditioning regimens. Results One patient received stem cells from a matched related donor and survived after a second transplant, needing substantial conditioning in order to engraft. Only 2 of 7 other patients who received a mismatched related donor transplant survived; 2 of them had no conditioning, whereas the others received various combinations of conditioning regimens. Engraftment of T cells in the survivors appears incomplete. Three other patients who received stem cells from a matched unrelated donor survived and enjoyed full immune reconstitution. Two patients received unrelated cord blood without conditioning. One of them has had a partial but stable engraftment, whereas the other engrafted well but is only 12 months after HSCT. We also report here for the first time that patients with CD3δ deficiency can present with typical features of Omenn syndrome. Conclusions HSCT is a successful treatment for patients with CD3δ deficiency. The small number of patients in this report prevents definitive statements on the importance of survival factors, but several are suggested: (1) HLA-matched donor transplants are associated with superior reconstitution and survival than are mismatched donor transplants; (2) substantial conditioning appears necessary; and (3) early diagnosis and absence of opportunistic infections may affect outcome.

T cells recognize antigens via their cell surface TCR and are classified as either αβ or γδ depending on the variable chains in their TCR, α and β or γ and δ, respectively. Both αβ and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. However, CD3δ-KO mice have an αβ T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αβ but not in γδ T cell development, associated with a new splicing mutation in the CD3D gene. The patients' T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant αβ T cells were oligoclonal. T cell-dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αβ versus γδ T cell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected.

Clonal natural killer (NK) and T cell expansions induced by Epstein- Barr virus (EBV) and genetic alterations compromising NK cell killing are the most common causes of hemophagocytic lymphohistocytosis (HLH). Generally, HLH is induced by an immune dysfunction where hypercytokinemia develops into reactive hemophagocytosis. In this work we review the causes of HLH and describe a case of a monoclonal expansion of EBV-negative NK cells associated to HLH in a seventeen-month-old girl suffering of Griscelli syndrome type-2 with novel RAB27A mutation and showing partial albinism, persistent fever, hepatosplenomegaly, adenopaties and cytopenias. At diagnosis, no evidence of active viral infections, including EBV, was found. Expansion of NK cells (5300/μl in peripheral blood) CD2+CD7+CD8+CD16+CD56+CD94+CD158a/h+CD158b/j–Perforin+ Granzyme B+ was found. After treatment (HLH-2004 protocol: Cyclosporin, Etoposide and Dexamethasone), NK cell count fell to 850/μl and progressively increased to pre-therapy levels by week 28. X-chromosome inactivation assay demonstrated NK cell monoclonality. NK cells sustained a strong killing and secreted high amounts of IFN-γ. At diagnosis, serum levels of sIL-2R (36,8 ng/ml) and IFN-γ (400 pg/ml) were elevated. In conclusion, we describe a monoclonal expansion of EBV-negative NK cells highly secretory of IFN-γ as the most probable cause of HLH episode in a patient with Griscelli syndrome type-2. NK cell count recovered normal levels and phenotype after bone marrow transplantation from her HLA identical sister.

Resumen Introduccion Muchos pacientes presbiacusicos presentan dificultad para entender ciertas palabras, hecho que podria estar justificado porque determinados sonidos en espanol presentan una dificultad mayor de perceptibilidad, en concreto los de energia en altas frecuencias. Se propone utilizar una oracion como herramienta para comprobar la hipotesis de partida. Material y metodo Se analizaron todos los sonidos del espanol, midiendo el grado de energia acustica que presenta cada una de las frecuencias. Las conclusiones extraidas de la comparacion de sus resultados permitieron el diseno de la herramienta que aqui se propone. Resultados Se establece una gradacion de dificultad perceptiva, por lo que se puede decir que las oclusivas aparecen como los sonidos menos perceptibles, seguido de las fricativas y, finalmente, todos los segmentos que presentan armonicidad y una estructura formantica definida. Como herramienta para la practica clinica, se propone la frase espanola “Ana vio ese coche rojizo fino”, frase que cumple una serie de particularidades que la hacen especialmente util para tal fin. Esta oracion permitira comprobar si la comprension se va deteriorando a medida que se avanza desde la primera a la ultima de sus secciones, y asi poder suponer que la capacidad para detectar auditivamente la presencia de energia reforzada en las altas frecuencias es indispensable para la inteligibilidad. Conclusiones Un resultado positivo podria tener como consecuencia el diseno de sistemas de amplificacion que mejoren la inteligibilidad de la palabra. Ademas, el hecho de tener una herramienta exploratoria podria permitir la exploracion neuroacustica, de utilidad en el estudio de la enfermedad auditiva.

We report the first case of hemophagocytic lymphohistiocytosis (HLH) induced by the monoclonal expansion of Epstein-Barr virus (EBV)-negative NK cells. Consanguinity of the patient's parents made it necessary to discard familial HLH in the patient and her sister with identical HLA markers and demonstrate that no cause other than the expansion of NK cells, which secrete high levels of gamma interferon, was inducing HLH in this patient.

Follicular lymphomas (FLs) usually carry BCL2 translocations although BCL6 translocations are also present. We explored relationships between translocations status and clinical or histological parameters at diagnosis in 182 patients stratified in four groups: BCL2-/BCL6-, BCL2+/BCL6-, BCL2-/BCL6+ and BCL2+/BCL6+. BCL2-/BCL6- and BCL2+/BCL6-. Double negative cases were ascribed to lower histological grades. In contrast, BCL2-/BCL6+ cases corresponded to higher grades. However, a majority of BCL2+/BCL6+ tumours were classified as lower grades. These results were reinforced by the finding that double positive patients had lower LDH levels and PS than those with solitary BCL6 rearrangements. Bone marrow involvement was more frequent in BCL2+/BCL6+ compared with BCL2-/BCL6+ tumours. Our data confirm the presence of a relationship between histological grade and translocation status, suggesting that FLs carrying BCL6 translocations probably constitute a special biological subtype. Clinical and histological differences between BCL2-/BCL6+ and BCL2+/BCL6+ tumours could reflect an interplay between both translocations.

Introduccion Uno de los elementos que mayor peso tiene en la decision del momento de inicio de terapia antirretroviral es el riesgo de progresion a sida. El objetivo del presente trabajo fue caracterizar el perfil inmunofenotipico basal de pacientes que progresan a sida. Material y metodos Estudio transversal de la distribucion de subpoblaciones funcionales de linfocitos T CD4+ y CD8+ en 85 pacientes adictos a drogas por via parenteral (ADVP) con infeccion por el virus de la inmunodeficiencia humana (VIH). Se analizaron los valores observados a la entrada de los pacientes en un estudio prospectivo. Los valores de los pacientes progresores y no progresores se compararon con grupos control sin infeccion VIH. Las subpoblaciones linfocitarias se estudiaron mediante citometria de flujo incluyendo los marcadores CD3, CD4, CD7, CD8, CD45RO, CD38, HLA-DR y CD25. Resultados El perfil inmunofenotipico que precede a la progresion a sida se caracteriza principalmente por un aumento de celulas e memoria (CD45RO+) CD4+ y CD8+ activadas, aumento de celulas CD4+ y CD8+ totales activadas y por un incremento de celulas T CD4+ que han perdido la expresion de marcadores como el receptor de la IL-2 (CD25–) o del marcador de diferenciacion CD7 (CD7–). Los pacientes que no reunian en el estudio basal criterios de laboratorio para iniciar tratamiento antirretroviral (> 350 celulas CD4+ y Discusion El que la activacion inmunologica pueda contribuir al deterioro clinico e inmunologico de los pacientes es un elemento adicional que podria tenerse en cuenta a la hora de decidir cuando iniciar terapia antiretroviral

Supported by grants from MINECO (SAF 2011-24235, BES-2012-055054, SAF2014- 54708-R, and SAF2014-53563-REDT) CAM (S2010/BMD-2316) ISCIII (RD08- 0075-0002 and PI12/02761)

[EN] In the context of Judiciary or Forensic Linguistics, this paper shows the results of a study on rhotic consonants in prepausal position (in the spontaneous speech of central peninsular Spanish) in order to assess their forensic value for identifying speakers. The variables that have been ana lysed are the number of components and the acoustic features of the first and second components of the consonant, which correspond to the closure and opening phases, respectively. The results have shown some significant differences amongst speakers, which is why the rhotics are consi dered a useful segmental element in comparing speech samples on judiciary purposes., [ES] En el marco de la Lingüística Forense o Judicial, este artículo presenta los resultados de un estu dio sobre las consonantes róticas en posición prepausal (en habla espontánea del español centro peninsular) con el fin de evaluar su valor forense en la identificación de hablantes. Las variables que se han analizado son el número de componentes y las características acústicas del primer y segundo componentes de la consonante, que corresponden a la fase de cierre y de abertura, res pectivamente. Los resultados han puesto de manifiesto algunas diferencias significativas entre hablantes, por lo que se concluye que las róticas pueden ser un elemento segmental útil en la comparación de muestras de habla con fines judiciales.

Background: Rapid screening for the detection of HLA-B*57:01 in the prevention of abacavir hypersensitivity in HIV-1-infected patients is a hallmark for clinical services. Objective: The aim of this work was to analyze the utility of flow cytometry with a new FITC-conjugated B-17 monoclonal antibody (mAb3E12) for HLA-B*57:01 screening in a Spanish cohort of 577 HIV-1+ individuals. Methods: Cryopreserved peripheral blood mononuclear cell samples from HIV-1+ individuals were analyzed by flow cytometry with the mAb 3E12 that recognizes both HLA-B*57 and HLA-B*58 alleles (members of the group specificity, HLA-B17). Patients' DNA samples had been previously typed for HLA-B*57:01 with PCR-SSO or PCR-SSP and additional DNA sequencing (EPI Study). The results obtained by flow cytometry were compared with the results obtained by the DNA-PCR techniques. Results: By flow cytometry, 46 samples (7.97%) were positive for HLA-B17, 530 (91.86%) were negative, and 1 (0.17%) was undetermined. All samples found negative by flow cytometry were negative for HLA-B*57:01 by DNA-PCR. Of the HLA-B17 positive samples, 31 (67.4%) were positive for HLA-B*57:01, 2 (3.25%) were positive for HLA-B*57:03, 11 (26.1%) were positive for HLA-B*58, and 2 (3.25%) were negative for both HLA-B*57 and HLA-B*58 antigens. The undetermined sample was negative for HLA-B*57 and HLA-B*58 alleles by DNA-PCR. Conclusions: This study shows that flow cytometry with mAb3E12 is a highly sensitive method (no false negatives) to implement prior to DNA-PCR analysis for rapid screening of HLA-B*57:01. Additional confirmation by molecular HLA typing method would be required in less than 10% of the cohort of HIV-1-infected individuals.

Natural suppressor (NS) activity is mediated by cells (NS cells) of bone marrow origin with ability to suppress nonspecifically proliferative responses of lymphocytes. Here we show that pharmacologic concentrations (10(-6)-10(-8) M) of glucocorticoids (GC) greatly inhibit NS activity, as detected by coculturing bone marrow and spleen cells stimulated with B cell (LPS) or T cell (concanavalin A) mitogens. Progesterone antagonizes GC-mediated inhibition of NS activity, suggesting that GC were acting through a receptor-dependent mechanism. A prior treatment of NS cells with GC (10(-5) M) has no effect on the NS activity mediated by these cells. GC are required in culture during the first 24 hr of the suppressor assay. Addition of low amounts of IFN-gamma to GC-treated cultures fully reverses NS cell-mediated suppression. IL-2 produces a reversion as well, while addition of IL-3 or IL-4 does not prevent the GC effect. Neutralizing anti-IFN-gamma antibodies, but not anti-IL-2 or anti-TGF-beta, greatly inhibit NS activity in absence of GC. Taken together, these results indicate that GC inhibit NS activity by impairing endogenous cytokine production required to obtain successful NS cell activation, and not by acting directly on NS cells (i.e., inhibiting the secretion of putative NS factors). Among the cytokines involved in NS cell activation, IFN-gamma appears to be critical, since its addition readily overrides the GC effect and its neutralization results in strong inhibition of NS activity.