Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management.

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management.

Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management

La inmunodeficiencia variable común (CVID) es un trastorno heterogéneo caracterizado por una hipogammaglobulinemia y por una mayor susceptibilidad a infecciones bacterianas recurrentes. Se trata de la inmunodeficiencia humoral sintomática más frecuente y cursa con una extensa variedad de complicaciones infecciosas y no infecciosas. En la patogenia de la CVID están involucrados diferentes defectos inmunológicos y genéticos. Sin embargo, en la mayoría de los casos, el fondo genético de la enfermedad permanece sin identificar. Esta revisión tiene como objetivo discutir diferentes aspectos de la CVID, incluyendo epidemiología, patogenia, síntomas, diagnóstico, clasificaciones y tratamiento de la enfermedad

Recurrent infective endocarditis due to Aggregatibacter aphrophilus and Staphylococcus lugdunensis.

Uncommon microorganisms are increasingly being recognized as causative agents of paediatric infectious endocarditis (IE). We report a 4-year old girl with congenital heart disease, who suffered from 2 IE episodes secondary to Aggregatibacter aphrophilus (formerly Haemophilus aphrophilus) and Staphylococcus lugdunensis, both rarely reported pathogens in this age group. The patient was initially successfully treated with prolonged intravenous antibiotic courses, however removal of the Contegra valved conduit during the second episode was required due to recurrence of fever and development of pulmonary embolism despite completion of antibiotic therapy. A. aphrohilus is a member of the fastidious gram negative microorganisms of the HACEK group (Haemophilus spp., Aggregatibacter spp, Cardiobaterium hominis, Eikenella corrodens and Kingella kingae), that colonize the oropharynx and are a recognised cause of IE. Prognosis of children with IE due to HACEK group members varies, half of them suffering from complications and mortality rates of 10-12.5%. Although S. lugdunensis belongs to coagulase negative staphylococci (CONS), it behaves more like S. aureus species rather than CONS. This microorganism is a well-described cause of endocarditis in adult patients, associated with high requirements of surgical procedures and mortality (42-78%). In conclusion, paediatric IE can be caused by uncommon microorganisms associated with severe complications and potential fatality. The isolation of S. lugdunensis or A. aphrophilus in febrile patients should be considered clinically relevant and cardiac involvement must be ruled out. Those patients with proved IE will require prolonged intravenous antibiotic courses and in complicated cases surgical intervention.

Primer estudio piloto en España sobre el cribado neonatal de las inmunodeficiencias primarias: TRECS y KRECS identifican linfopenias T y B graves / A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopenia

INTRODUCCIÓN: El diagnóstico precoz de inmunodeficiencias primarias, como la inmunodeficiencia combinada grave (IDCG) y la agammaglobulinemia ligada al cromosoma X (ALX), mejora el pronóstico de los ni˜nos afectados. La medida de los T-cell receptor excision circles (TRECS) y kappa-deleting recombination excision circles (KRECS) puede identificar neonatos con linfopenias T y/o B graves. OBJETIVO: Cuantificar los niveles de TRECS y de KRECS de manera prospectiva a partir de muestras de sangre seca de talón para identificar de manera correcta linfopenias T y/o B. MATERIALES Y MÉTODOS: Determinación de TRECS y de KRECS mediante reacción en cadena de polimerasa multiplex en neonatos nacidos entre febrero y mayo del 2014. Los puntos de corte empleados fueron: TRECS < 15 copias/_l, KRECS < 10 copias/_l, ACTB (_-actina) > 1.000 copias/_l. Se incluyeron controles internos (ALX, ataxia) y externos (IDCG). RESULTADOS: Fueron analizadas 1.068 muestras de las 1.088 recogidas (edad gestacional media: 39 semanas [38-40]; peso al nacer medio 3.238 g [2.930-3.520]). La media (mediana, min/máx) copias/_l obtenidas fueron las siguientes; TRECS 145 (132, 8/503), KRECS 82 (71, 7/381) y ACTB 2838 (2763, 284/7710). Veinte muestras (1,87%) fueron insuficientes para el análisis. El retest fue necesario en un neonato (0,09%), confirmándose resultados normales posteriormente. Empleando puntos de corte inferiores (TREC < 8 y KREC < 4 copias/_l), todas las muestras resultaron normales y se identificaron los controles internos y externos correctamente. CONCLUSIÓN: Es el primer estudio prospectivo realizado en Espa˜na usando el ensayo TREC/KREC/ACTB para identificar linfopenias graves. Es necesario establecer puntos de corte adecuados para nuestra población, mejorar la toma de muestras, su almacenamiento y la preparación de las mismas

INTRODUCTION: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappadeleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopenia. OBJECTIVES: To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopenia. MATERIAL AND METHODS: Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<15 copies/_l, KRECS<10copies/_l, ACTB (_-actin)>1000 copies/_l. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included. RESULTS: A total of 1068 out of 1088 neonates (mean GA 39 weeks (38-40) and BW 3238 g (2930-3520) were enrolled in the study. Mean (median, min/max) copies/_l, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<8 and KRECS<4 copies/_l), all the samples tested were normal and the internal and external controls were correctly identified. CONCLUSION: This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved

[A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopenia]. / Primer estudio piloto en España sobre el cribado neonatal de las inmunodeficiencias primarias: TRECS y KRECS identifican linfopenias T y B graves.

INTRODUCTION: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappa-deleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopenia. OBJECTIVES: To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopenia. MATERIAL AND METHODS: Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<15 copies/µl, KRECS<10 copies/µl, ACTB (ß-actin)>1000 copies/µl. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included. RESULTS: A total of 1068 out of 1088 neonates (mean GA 39 weeks (38-40) and BW 3238g (2930-3520) were enrolled in the study. Mean (median, min/max) copies/µl, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<8 and KRECS<4 copies/µl), all the samples tested were normal and the internal and external controls were correctly identified. CONCLUSION: This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved.

Room-temperature high-frequency transport of dirac fermions in epitaxially grown Sb2Te3- and Bi2Te3-based topological insulators.

We report on the observation of photogalvanic effects in epitaxially grown Sb2Te3 and Bi2Te3 three-dimensional (3D) topological insulators (TI). We show that asymmetric scattering of Dirac fermions driven back and forth by the terahertz electric field results in a dc electric current. Because of the "symmetry filtration" the dc current is generated by the surface electrons only and provides an optoelectronic access to probe the electron transport in TI, surface domains orientation, and details of electron scattering in 3D TI even at room temperature.

Catheter-related Mycobacterium fortuitum bloodstream infection: rapid identification using MALDI-TOF mass spectrometry.

We present the case of a 6-year-old boy diagnosed with stage III mediastinal Non Hodgkin Lymphoblastic T cell Lymphoma who suffered from catheter-related bloodstream infection (CRBI) due to Mycobacterium fortuitum whilst receiving chemotherapy. Isolation of this rare pathogen was done directly from blood culture and identification was made rapidly within 48 h using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectro-metry as well as specific polymerase chain reaction (PCR)-reverse hybridization method. This allowed prompt directed antibiotic therapy apart from central venous catheter removal and resulted in an excellent clinical response. This case highlights the potential benefit of using MALDI-TOF mass spectrometry, a fast, cost-effective and precise methodology, in the diagnosis and subsequent management of invasive bacterial infection.

Chryseobacterium indologenes central nervous system infection in infancy: an emergent pathogen?

The isolation of Chryseobacterium indologenes as a causative micro-organism in human diseases is rare. Risk factors for infections caused by this pathogen include very young and very old age, indwelling devices, immune suppression and recent use of broad-spectrum antibiotics. Most cases suffer from bacteraemia or nosocomial pneumonia, whilst infection of the central nervous system (CNS) is extremely rare. We present a term-born infant diagnosed prenatally with holoprosencephaly and obstructive hydrocephalus, requiring post-natal ventriculoperitoneal shunt insertion. At 6 weeks of age, he suffered from Escherichia coli meningitis, showing satisfactory clinical response with antimicrobial therapy. Aged 11 months, he suffered from hyper-drainage syndrome, resulting in the removal of the shunt system. He represented 11 days post-operatively, with low-grade fever, irritability and cerebrospinal fluid (CSF) leakage. C. indologenes from CSF was isolated and antimicrobial therapy with ceftazidime and trimethoprim-sulfamethoxazole for 3 weeks resulted in good clinical response. This is the first documented community-acquired CNS infection due to C. indologenes in an infant without concomitant indwelling device or previous antibiotic pressure.

Variante otogénica del síndrome de Lemierre / Otogenic variant of Lemierre syndrome

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Magnetic quantum ratchet effect in graphene.

A periodically driven system with spatial asymmetry can exhibit a directed motion facilitated by thermal or quantum fluctuations. This so-called ratchet effect has fascinating ramifications in engineering and natural sciences. Graphene is nominally a symmetric system. Driven by a periodic electric field, no directed electric current should flow. However, if the graphene has lost its spatial symmetry due to its substrate or adatoms, an electronic ratchet motion can arise. We report an experimental demonstration of such an electronic ratchet in graphene layers, proving the underlying spatial asymmetry. The orbital asymmetry of the Dirac fermions is induced by an in-plane magnetic field, whereas the periodic driving comes from terahertz radiation. The resulting magnetic quantum ratchet transforms the a.c. power into a d.c. current, extracting work from the out-of-equilibrium electrons driven by undirected periodic forces. The observation of ratchet transport in this purest possible two-dimensional system indicates that the orbital effects may appear and be substantial in other two-dimensional crystals such as boron nitride, molybdenum dichalcogenides and related heterostructures. The measurable orbital effects in the presence of an in-plane magnetic field provide strong evidence for the existence of structure inversion asymmetry in graphene.

Terahertz radiation driven chiral edge currents in graphene.

We observe photocurrents induced in single-layer graphene samples by illumination of the graphene edges with circularly polarized terahertz radiation at normal incidence. The photocurrent flows along the sample edges and forms a vortex. Its winding direction reverses by switching the light helicity from left to right handed. We demonstrate that the photocurrent stems from the sample edges, which reduce the spatial symmetry and result in an asymmetric scattering of carriers driven by the radiation electric field. The developed theory based on Boltzmann's kinetic equation is in a good agreement with the experiment. We show that the edge photocurrents can be applied for determination of the conductivity type and the momentum scattering time of the charge carriers in the graphene edge vicinity.

Dynamic Hall effect driven by circularly polarized light in a graphene layer.

We report the observation of the circular ac Hall effect where the current is solely driven by the crossed ac electric and magnetic fields of circularly polarized radiation. Illuminating an unbiased monolayer sheet of graphene with circularly polarized terahertz radiation at room temperature generates--under oblique incidence--an electric current perpendicular to the plane of incidence, whose sign is reversed by switching the radiation helicity. Alike the classical dc Hall effect, the voltage is caused by crossed E and B fields which are, however rotating with the light's frequency.

Orbital photogalvanic effects in quantum-confined structures.

We report on the circular and linear photogalvanic effects caused by free-carrier absorption of terahertz radiation in electron channels on (001)-oriented and miscut silicon surfaces. The photocurrent behaviour upon variation of the radiation polarization state, wavelength, gate voltage, and temperature is studied. We present the microscopic and phenomenological theory of the photogalvanic effects, which describes well the experimental results. In particular, it is demonstrated that the circular (photon-helicity sensitive) photocurrent in silicon-based structures is of pure orbital nature originating from the quantum interference of different pathways contributing to the absorption of monochromatic radiation.

Ratchet effects induced by terahertz radiation in heterostructures with a lateral periodic potential.

We report on the observation of the Seebeck ratchet effect. The effect is measured in semiconductor heterostructures with a one-dimensional lateral potential excited by terahertz radiation. The photocurrent generation is based on the combined action of a spatially periodic in-plane potential and a spatially modulated light, which gives rise to a modulation of the local temperature. In addition to the polarization-independent current due to the Seebeck ratchet effect, we observe a photon helicity dependent response and propose a microscopic mechanism to interpret the experimental findings.

Spin currents in diluted magnetic semiconductors.

We study zero-bias spin separation in (Cd,Mn)Te/(Cd,Mg)Te diluted magnetic semiconductor structures. The spin current generated by electron gas heating under terahertz radiation is converted into a net electric current by applying an external magnetic field. The experiments show that the spin polarization of the magnetic ion system enhances drastically the conversion process due to giant Zeeman splitting of the conduction band and spin-dependent electron scattering on localized Mn(2+) ions.

Symmetry and spin dephasing in (110)-grown quantum wells.

Symmetry and spin dephasing in (110)-grown GaAs quantum wells (QWs) are investigated applying magnetic field induced photogalvanic effect and time-resolved Kerr rotation. We show that magnetic field induced photogalvanic effect provides a tool to probe the symmetry of (110)-grown quantum wells. The photocurrent is only observed for asymmetric structures but vanishes for symmetric QWs. Applying Kerr rotation we prove that in the latter case the spin relaxation time is maximal; therefore, these structures set the upper limit of spin dephasing in GaAs QWs. We also demonstrate that structure inversion asymmetry can be controllably tuned to zero by variation of delta-doping layer positions.