Expansion of immature, nucleated red blood cells by transient low-dose methotrexate immune tolerance induction in mice.

Biological treatments such as enzyme-replacement therapies (ERT) can generate anti-drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low-dose methotrexate (TLD-MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long-lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD-MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high-risk, cross-reactive immunological material (CRIM)-negative infantile-onset Pompe disease (IOPD) patients. More recently, evaluation of TLD-MTX demonstrated benefit in CRIM-positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD-MTX, non-targeted transcriptional and proteomic screens were conducted and revealed up-regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter-119+ CD71+ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD-MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.

Modeling the time-dependent water wave stability of human hair.

The viscoelastic bending recovery of human hair is described by a hydro-rheologically complex, two-phase model, where the humidity dependence of the pertinent parameters as well as the effects of physical aging are known. Model calculations are conducted to assess the consequences of the time- and humidity-dependent bending recovery of human hair for the formation and the stability of the water wave. It is shown that a hair fiber that has been set in bending will achieve at 65% RH a recovery of about 50% after about ten times its storage time prior to release, if it is a non-aging material. However, aging drastically slows the recovery process so that it approaches an apparent "equilibrium," final recovery value of about 60%. The values of final recovery decrease linearly with water content, vanishing as expected at maximum water content, where the hair fiber is above its glass transition. The calculations further show that damage to the elastic modulus, attributed to the intermediate filaments, is expected to reduce recovery and thus enhance fiber set. The calculations demonstrate that it is in fact the phenomenon of physical aging that makes water waving a feasible and practically successful process for hair styling.

The effect of water on the glass transition of human hair.

The glass transition of human hair and its dependence on water content were determined by means of differential scanning calorimetry (DSC). The relationship between the data is suitably described by the Fox equation, yielding for human hair a glass transition temperature of T(g) = 144 degrees C, which is substantially lower than that for wool (174 degrees C). This effect is attributed to a higher fraction of hydrophobic proteins in the matrix of human hair, which acts as an internal plasticizer. The applicability of the Fox equation for hair as well as for wool implies that water is homogeneously distributed in alpha-keratins, despite their complex morphological, semicrystalline structure. To investigate this aspect, hair was rendered amorphous by thermal denaturation. For the amorphous hair neither the water content nor T(g) were changed compared to the native state. These results provide strong support for the theory of a quasi-homogeneous distribution of water within alpha-keratins.