Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Identification and characterization of human pulmonary dendritic cells

Dendritic cells (DC) are specialized antigen-presenting cells, linking innate and adaptive immune responses, and thus play an important role in immunologically mediated diseases, including pulmonary diseases such as asthma and respiratory viral infections. Although much is known about the characteristics of lung DC in animal models, very few data concerning human lung DC are available. The goal of our study was to identify and characterize dendritic cells in human lung by preparing single-cell suspensions from surgical resection specimens and subsequent labeling with the recently developed blood dendritic cell antigen (BDCA) markers. A straightforward isolation procedure was developed to avoid phenotypical and functional changes induced by extensive purification methods. In this way, human lung DC were directly identified without the need for an additional adherence step for further purification. For the first time, we demonstrate the presence of three previously unidentified DC subsets in human lung digests: myeloid DC type 1 (BDCA1+/HLA-DR+), myeloid DC type 2 (BDCA3+/HLA-DR+), and plasmacytoid DC (BDCA2+/CD123+). The presence of CD1a+ DC in the human lung was confirmed. The identification and characterization of different human pulmonary DC subtypes is of great importance for the future development of DC-based immunotherapies.     

Thoracic aortic dissection in a patient with autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease is one of the most common hereditary diseases, and frequently has well defined extrarenal manifestations. Very few cases of aortic aneurysms associated with this disorder are described in literature. We report a 42-year-old male with autosomal dominant polycystic kidney disease presenting with dissecting aneurysm of the thoracic aorta.     

A European multicenter study of immunoblotting in serodiagnosis of lyme borreliosis

A European multicenter study of immunoblotting for the serodiagnosis of Lyme borreliosis showed considerable variation in results obtained from tests with a panel of 227 serum samples. Six laboratories used different immunoblot methods, and a wide range of bands was detected in all the assays. Multivariable logistic regression analysis of data from individual laboratories was used to determine the most discriminatory bands for reliable detection of antibodies to Borrelia burgdorferi sensu lato. These bands were used to construct individual interpretation rules for the immunoblots used in the six laboratories. Further analysis identified a subset of eight bands, which were important in all the laboratories, although with variations in significance. Possible European rules, all closely related, were formulated from these bands, although there was no single rule that gave high levels of sensitivity and specificity for all the laboratories. This is a reflection of the wide range of methodologies used, especially the use of different species and strains of B. burgdorferi sensu lato. The panel of European rules provides a framework for immunoblot interpretation which may be adapted in relation to the characteristics of Lyme borreliosis in local areas.     

Differential expression and serologically distinct subpopulations of human Ia antigens detected with monoclonal antibodies to Ia alpha and beta chains

Studies with two monoclonal antibodies (DA6.147 and DA6.231) which react, respectively, with isolated human Ia alpha and beta chains are reported. Both antibodies detect epitopes expressed on all DR-heterozygous and DR-homozygous cell lines tested (n = 17) and bind to the Epstein-Barr virus-negative cell line Ramos. Ia subunit specificity of the antibodies was determined by an adaptation of an electroblot technique which transfers separated Ia chains from polyacrylamide gels to nitrocellulose paper. In radioimmunobinding assays, peripheral blood B cell-enriched fractions, phytohemagglutinin-activated T cells and pokeweed mitogen-activated cells gave strong reactions with DA6.231 (anti-Ia beta). In contrast, DA6.147 (anti-Ia alpha) reacted only weakly, if at all, with peripheral B cells, pokeweed mitogen blasts and activated T cells. However, both antibodies bound to isolated Ia from activated T cells and peripheral B cells after Nonidet-P40 solubilization of the cells and DA6.147+ antigens could be found in the cytoplasm of activated T cells by indirect immunofluorescence techniques. Results of serological inhibition procedures following fractionation of lymphoblastoid cell lysates on monoclonal antibody affinity columns showed that the DA6.147 alpha chain epitope is carried on only a minor subpopulation of human Ia.     

Semi-automated method for the determination of free fatty acids in plasma

A semi-automated method for the determination of free fatty acids in plasma based on Mosinger's manual method (Mosinger, 1965) is described and the results of a comparison with Dole's titrimetric method (Dole, 1956) are presented. There is almost perfect correlation between the two methods, and the automated technique is simple, reliable, and significantly more accurate and precise than the titrimetric method.     

Location and morphology of chloride cells during the post-embryonic development of the european sea bass,Dicentrarchus labrax

Location and morphology of chloride cells were studied in the sea bass ( Dicentrarchus labrax) from hatching to the juvenile stage to determine the development of the adult osmoregulatory function as seen in adult fish. During the studied developmental sequence changes were observed in the location, number, size and structure of these cells, that were studied by microscopy (light, scanning electron, transmission electron and confocal) and immunocytochemistry. Chloride cells were found on the tegument and on the gills. They were present on the tegument already at hatching, before the development of the gills. Their density as well as their association in multicellular complexes decreased during the postembryonic development. In old larvae and in juveniles, cutaneous chloride cells were associated with the fins, the developing scales and the lateral line. Gills developed gradually during the prelarval stage and the gill arches were present at mouth opening. At that time chloride cells were already numerous on the gill arches. In older larvae, during the progressive development of the gill filaments, chloride cells were numerous on these structures and formed multicellular complexes. Several stages in the differentiation of these cells were studied, including the development of the tubulovesicular system at the end of the prelarval stage, as well as the stratification appearance of the cytoplasm that was concomitant with the considerable development of the tubular system and its association with the endoplasmic reticulum during the larval period. The involvement of different epithelia in the osmoregulatory process during the postembryonic development of this species, as well as the role of chloride cells during successive developmental stages, is discussed.     

Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

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