Clinical outcome of transfusions with extended red blood cell matching in β-thalassemia patients: A single-center experience

Background

The development of alloantibodies may complicate the management of patients with β-thalassemia. An extended antigenic matching may reduce the risk of alloimmunization. Our previous study showed that the introduction of molecular red blood cell (RBC) typing allows finding suitable blood units for multi-transfused patients. The aim of this study was to evaluate the benefit of RBC transfusion with extended antigenic match.

Circadian rhythm of human lymphocyte subpopulations

Circadian rhythm of lymphocyte subsets was investigated in four healthy subjects, males, aged 35-58 years old. After a period of ambiental synchronization, venous blood samples were taken during a span of a day at 0.00 a.m., 4.00 a.m., 8.00 a.m., noon, 4.00 p.m. and 8.00 p.m. Lymphocyte subsets (OKT3, OKT4, OKT8, OKB7, OKJa1) were determined by monoclonal antibodies method, and serum level of cortisol by radioimmunoassay method. The OKT4/OKT8 ratio was also calculated. Data were analyzed by chronograms (mean +/- 1SD) and by cosinor method. Results show a significant circadian rhythm for each lymphocyte subset and for serum cortisol levels. The lowest levels of all circulating subsets were seen between noon and 4.00 p.m. and the highest levels around midnight, inversely related with the circadian rhythm of serum cortisol. The OKT4/OKT8 ratio, on the contrary, was relatively constant during the day, without a significant circadian rhythm. These observations have laboratoristic, clinical, and therapeutic implications and should be considered in the course of immunological studies.     

The Wnt Pathway in Mood Disorders

Objectives:

To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders.

Methods:

We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion.

Results:

Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders.

Conclusions:

Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.     

Allergic rhinitis and asthma: celebrating 100 years of immunotherapy

Since Noon first described allergen immunotherapy a century ago the basic premise of subcutaneous injections (SCIT) of relevant aeroallergens to induce clinical tolerance has remained true [1]. Indeed, allergen immunotherapy did not change dramatically over the first 75 years, but over the past 25 years there have been a number of important advancements leading to newer approaches and novel formulations. Here we review the top 50 articles published in the past 2 years on allergens, environmental control, and immunotherapy for asthma and allergic rhinitis and the use of immunomodulators in allergic disease.     

The Effects of Binding Ligand Variation on the Nickel Catalyzed Externally Initiated Polymerization of 2‐Bromo‐3‐hexyl‐5‐iodothiophene

The effects of binding ligand variation on the externally initiated Ni catalyzed polymerization of P3HT were investigated using a novel methodology allowing facile screening of ligands. P3HT was synthesized with >80% initiator incorporation for both mono‐ and bidentate phosphine ligands. Variation of the initiating aryl group demonstrated vastly superior results for o‐tolyl over p‐tolyl substituents.

     

Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease

Huntington's Disease (HD) is characterized primarily by neuropathological changes in the striatum, including loss of medium-spiny neurons, nuclear inclusions of the huntingtin protein, gliosis, and abnormally high iron levels. Information about how these conditions interact, or about the temporal order in which they appear, is lacking. This study investigated if, and when, iron-related changes occur in the R6/2 transgenic mouse model of HD and compared the results with those from HD patients. Relative to wild-type mice, R6/2 mice had increased immunostaining for ferritin, an iron storage protein, in the striatum beginning at 2-4 weeks postnatal and in cortex and hippocampus starting at 5-7 weeks. The ferritin staining was found primarily in microglia, and became more pronounced as the mice matured. Ferritin-labeled microglia in R6/2 mice appeared dystrophic in that they had thick, twisted processes with cytoplasmic breaks; some of these cells also contained the mutant huntingtin protein. Brains from HD patients (Vonsattel grades 0-4) also had increased numbers of ferritin-containing microglia, some of which were dystrophic. The cells were positive for Perl's stain, indicating that they contained abnormally high levels of iron. These results provide the first evidence that perturbations to iron metabolism in HD are predominately associated with microglia and occur early enough to be important contributors to HD progression.     

A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes

Several therapeutic self-proteins elicit immune responses when administered to patients. Such adverse immune responses reduce drug efficacy. To induce an immune response, a protein must interact with different immune cells, including antigen-presenting cells, T cells, and B cells. Each cell type recognizes distinct immunogenic patterns on antigens. Mannose-terminating glycans have been identified as pathogen-associated molecular patterns that are essential for internalization of microbes by antigen-presenting cells, leading to presentation. Here, we have investigated the importance of exposed mannosylation on an immunogenic therapeutic self-protein, procoagulant human factor VIII (FVIII). Administration of therapeutic FVIII to hemophilia A patients induces inhibitory anti-FVIII antibodies in up to 30% of the cases. We demonstrate that entry of FVIII into human dendritic cells (DC) leading to T cell activation, is mediated by mannose-terminating glycans on FVIII. Further, we identified macrophage mannose receptor (CD206) as a candidate endocytic receptor for FVIII on DC. Saturation of mannose receptors on DC with mannan, and enzymatic removal of mannosylated glycans from FVIII lead to reduced T cell activation. The interaction between FVIII and CD206 was blocked by VWF, suggesting that, under physiological conditions, the intrinsic mannose-dependent immunogenicity of FVIII is quenched by endogenous immunochaperones. These data provide a link between the mannosylation of therapeutic self-proteins and their iatrogenic immunogenicity. Such a link would be of special relevance in the context of replacement therapy where mechanisms of central and peripheral tolerance have not been established during ontogeny because of the absence of the antigen.     

A conserved role for Hox paralog group 4 in regulation of hematopoietic progenitors

Regulatory circuits that control stem cell fate decisions can be identified and understood by manipulating individual regulatory elements genetically. While impractical in the rare somatic stem cells of primary tissue, this approach is feasible in embryonic stem cells differentiated in vitro into the somatic stem cell type of interest. We present an improved highly efficient targeting system allowing genes to be integrated into a predetermined, doxycycline-inducible locus, and corresponding inducible embryonic stem cell lines to be generated rapidly. We apply this system to evaluate a key hematopoietic progenitor cell regulatory element, HoxB4, and its mammalian paralogs, whose effects have not yet been tested in this context. We show that all Hox paralog group 4 members, A4, B4, C4, and D4, have similar effects on hematopoietic stem and progenitor self-renewal in vitro, and thus classify Hox paralog group 4 as promoting self-renewal. Each paralog group 4 member both promotes proliferation and inhibits differentiation, enabling the exponential expansion of hematopoietic progenitors from the c-kit(+)/CD41(+) cell fraction of day 6 murine embryoid bodies. By evaluating a set of deletion mutants we show that sequences in addition to the homeodomain and hexapeptide motif are required for this activity. These results highlight the utility of this expression system to perform functional and structural analyses of genetic regulators of cell fate decisions.