Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death

Depletion of T lymphocytes from allogeneic bone marrow transplants successfully prevents the development of graft-versus-host disease (GvHD) but is associated with impaired engraftment, immunosuppression, and abrogation of the graft-versus-leukemia effect. We therefore explored the possibility of selectively eliminating alloreactive T cells by CD95/CD95L-mediated activation-induced cell death (AICD) in a major histocompatibility complex allogeneic murine model system. Activation of resting or preactivated T lymphocytes from C3H/HeJ (H-2(k)) mice was induced with irradiated BALB/cJ (H-2(d)) mouse-derived stimulators. Substantial decrease (> or = 80%) of proliferative and lytic responses by activated alloreactive T cells was subsequently achieved by incubating the mixed lymphocyte culture with an agonistic monoclonal antibody to CD95, and residual T cells recovered did not elicit alloreactivity upon challenge to H-2(d). Depletion of alloreactive T lymphocytes by AICD was specific because reactivity to an I-A(d)-restricted ovalbumin (OVA) peptide by OVA-specific CD4(+) T cells mixed into the allogeneic T-cell pool and subjected to induction of AICD in the absence of OVA peptide could be preserved. Adoptive transfer of donor-derived allogeneic T lymphocytes, depleted from alloreactive T cells by AICD in vitro, in the parent (C3H/He) to F(1) (C3H/He x BALB/c) GvHD model prevented lethal GvHD. The results presented suggest that alloreactive T cells can effectively be depleted from allogeneic T cells by induction of AICD to prevent GvHD and might introduce a new strategy for the separation of GvH-reactive T cells and T cells mediating antiviral and possibly graft-versus-leukemia effects.     

Years of good life is a well-being indicator designed to serve research on sustainability

Sustainable development (SD) as popularized by the Brundtland Commission and politically enshrined in the Sustainable Development Goals has been the explicit focus of sustainability science. While there is broad agreement that the trend of human well-being (W) over time should serve as a sustainability criterion, the literature so far has mostly addressed this in terms of its determinants rather than focusing on W itself. There is broad agreement that an indicator for W should have multiple constituents, clearly going beyond gross domestic product. Here, we propose a tailor-made indicator to serve precisely this purpose following a set of specified desiderata, including its applicability to flexibly defined subnational populations by gender, place of residence, ethnicity, and other relevant characteristics. The indicator, years of good life (YoGL), reflects the evident fact that in order to be able to enjoy any quality of life, one has to be alive and thus is primarily based on life expectancy. However, since mere survival is not considered good enough, life years are counted conditional on meeting minimum standards in two dimensions: the objective dimension of capable longevity (consisting of being out of absolute poverty and enjoying minimal levels of physical and cognitive health) and the subjective dimension of overall life satisfaction. We illustrate the calculation of this indicator for countries and subpopulations at different stages of development and with different degrees of data availability.

Sustainability science refers to the most comprehensive scholarly effort to understand the interactions between natural and social systems in order to assess whether certain developmental pathways can be considered sustainable. This should also include the possible negative effects of environmental changes, such as climate change and biodiversity loss, on future human well-being. In this paper, we propose a tailor-made indicator to assess long-term human well-being as the ultimate end of sustainable development. This indicator, called “years of good life” (YoGL), is designed in such a way that it can be both empirically measured—which is the focus of this paper—and modeled in its long-term future trends—which will be the focus of future work.When assessing changes over time in the well-being of certain human populations (or subpopulations, as defined, e.g., by gender, ethnicity, urban/rural place of residence, or other social groupings), one can focus on the determinants or the constituents of well-being. In sustainability science, thus far, empirical and theoretical research has placed more emphasis on studying the determinants, including environmental services (1), whereas specifying its constituents has received less systematic attention, often leaving us with nothing but the unspecific notion of “utility.” The focus on determinants has led to the concept of “inclusive wealth” (IW) which can be used to assess whether a society is on a sustainable development trajectory in terms of the productive base necessary to maintain a high standard of living in the future (2). However, empirically measuring the values and relative effects of the different capitals determining human well-being remains extremely challenging and “no current attempt to date can be said to be fully inclusive” (3).The idea behind YoGL, on the other hand, is to study sustainability by focusing explicitly on the constituents of well-being and its change over time. In doing so, YoGL avoids several of the pitfalls by which the IW approach is plagued (3, 4). For example, rather than making contestable quantitative assessments of the relative contributions of the different determinants of well-being, the demographic approach underlying YoGL provides numerical values of human well-being directly, expressed as the average number of years of good life a person can expect to live as part of a given subpopulation under the conditions of a specified point in time. Based on the assumed universal nature of its unit of measurement—YoGL lived today in one specific population has the same meaning as YoGL lived in the future or in another population—the indicator has a time-independent meaning. This also avoids the pitfalls of specifying a rate at which to discount future well-being, which have become apparent at least since the debates around the Stern report (5). YoGL allows us to directly compare human well-being across different subpopulations and generations. Moreover, while all estimates of the different determinants of future human well-being are highly sensitive to population growth, as a measure referring to per-person well-being the derivation of YoGL is not directly affected by assumptions about the future trajectory of population size. Finally, as stressed by Dasgupta (6), the nature of determinants can change over time and across places depending on different commodities and technological regimes, whereas the constituents of well-being—as used in YoGL—are arguably shared across space and time.In the following, we will first present the proposed design of the indicator. We will then provide a step-by-step user’s guide for empirically deriving YoGL based on the most appropriate available data source, before offering examples of how it can be calculated based on auxiliary information on populations for which the necessary data are not yet fully available. We will close with a discussion and brief outlook as to what is still needed to use this indicator for the assessment of sustainability.     

In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia

Gene therapy for β-thalassemia requires stable transfer of a β-globin gene into hematopoietic stem cells (HSCs) and high and regulated hemoglobin expression in the erythroblastic progeny. We developed an erythroid-specific lentiviral vector driving the expression of the human β-globin gene from a minimal promoter/enhancer element containing two hypersensitive sites from the β-globin locus control region. Transplantation of transduced HSCs into thalassemic mice leads to stable and long-term correction of anemia with all red blood cells expressing the transgene. A frequency of 30–50% of transduced HSCs, harboring an average vector copy number per cell of 1, was sufficient to fully correct the thalassemic phenotype. In the mouse model of Cooley's anemia transplantation of transduced cells rescues lethality, leading to either a normal or a thalassemia intermedia phenotype. We show that genetically corrected erythroblasts undergo in vivo selection with preferential survival of progenitors harboring proviral integrations in genome sites more favorable to high levels of vector-derived expression. These data provide a rationale for a gene therapy approach to β-thalassemia based on partially myeloablative transplantation protocols.     

Desferioxamine increases iron depletion and apoptosis induced by ara-C of human myeloid leukaemic cells

We investigated whether changes in iron metabolism and the transferrin receptor (TRF-R) expression were involved in the antileukaemic effects of arabinoside cytosine (ara-C). Treatment with 100 n M ara-C for 48 h reduced thymidine uptake and increased the surface expression of the TRF-R on leukaemic blasts derived from 13/16 (81%) patients and on the HL-60 and U-937 cell lines. Whereas intracellular non-haem iron was strongly depleted 24 h after ara-C addition, TRF-R up-regulation and recovery of intracellular non-haem iron concentration occurred together after a longer exposure of the cultured cells to the drug. Since iron is an essential regulator of cell proliferation we have evaluated the effects of the combination between ara-C and the iron chelator desferioxamine (DSF) on the growth of HL-60 and U-937 cells. We found that desferioxamine strongly potentiated the effects of ara-C on leukaemic cell growth inhibition and apoptosis. This is the first report of a positive interaction between ara-C and an iron chelator in terms of antileukaemic effects.     

The integrated care of asthma in Switzerland (INCAS)–study: Patients' perspective of received asthma care and their interest in asthma education

Objective: For successful long-term asthma care, self-management education is a cornerstone. Little is known about associations between patients' interest in education, asthma control and care delivery. We compared patients' characteristics, asthma control and patients' perspective about asthma care in subjects with and without interest in asthma education. Moreover, we assessed reasons, why patients denied participating in asthma education. Methods: Baseline data of 223 patients with asthma (age 43 ± 12 years, 38% male, 58% non-smokers, 13% current smokers), who participated in a multicentre longitudinal controlled study, are reported. At baseline, patients completed the Asthma Control Test (ACT), the Patient Assessment Chronic Illness Care questionnaire (PACIC 5A) and stated their interest in an asthma education programme. Results: Overall, 34% of all participants showed uncontrolled asthma. One hundred and twenty-five (56%) patients were interested in education. Compared to patients without interest, they were characterised by male gender (p = 0.013), worse asthma control (p < 0.001), and perception of lower quality of chronic asthma care delivery, in particular lower self-management support (p < 0.001). Main reasons for rejecting asthma education were having sufficient asthma knowledge, having only mild asthma, receiving adequate medical support and lack of time. Conclusions: More than half of the patients were interested in asthma education. Interest was associated with worse asthma control and lower receipt of care according to the Chronic Care Model. Considering these aspects, this approach may help to improve care quality and allow targeting interventions to those patients who are interested in becoming active participants in their care and who might benefit most.     

Additive effect of erythropoietin and heme on murine hematopoietic recovery after azidothymidine treatment [see comments]

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT- treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.     

Collaborative signaling by mixed chemoreceptor teams in Escherichia coli

Chemoreceptors of the methyl-accepting chemotaxis protein family form clusters, typically at the cell pole(s), in both Bacteria and Archaea. To elucidate the architecture and signaling role of receptor clusters, we investigated interactions between the serine (Tsr) and aspartate (Tar) chemoreceptors in Escherichia coli by constructing Tsr mutations at the six hydrophobic and five polar residues implicated in "trimer of dimers" formation. Tsr mutants with proline replacements could not mediate serine chemotaxis, receptor clustering, or clockwise flagellar rotation. Alanine and tryptophan mutants, although also nonchemotactic, formed receptor clusters, and some produced clockwise flagellar rotation, indicating receptor-coupled activation of the signaling CheA kinase. The alanine and tryptophan mutants evidently assemble defective receptor complexes that cannot modulate CheA activity in response to serine stimuli. In cells containing wild-type Tar receptors, tryptophan replacements in Tsr interfered with Tar function, whereas four Tsr mutants with alanine replacements regained Tsr function. These epistatic and rescuable phenotypes imply interactions between Tsr and Tar dimers in higher-order signaling teams. The bulky side chain in tryptophan mutants may prevent stimulus-induced conformational changes in the team, whereas the small side chain in alanine mutants may permit signaling control when teamed with functional receptor molecules. Direct physical interactions between Tsr and Tar molecules were observed by in vivo chemical crosslinking. Wild-type Tsr crosslinked to Tar, whereas a clustering-defective proline replacement mutant did not. These findings indicate that bacterial chemoreceptor clusters are comprised of signaling teams, seemingly based on trimers of dimers, that can contain different receptor types acting collaboratively.     

Usefulness of the vibration perception thresholds measurement as a diagnostic method for diabetic peripheral neuropathy: Results from the Rio de Janeiro type 2 diabetes cohort study

Aims

To investigate the associated factors with the vibration threshold perception (VPT) in patients with type 2 diabetes and to assess whether it is useful for detection of diabetic peripheral neuropathy (DPN).

De novo T-cell generation in patients at different ages and stages of HIV-1 disease

We assessed de novo T-cell generation by determining T-cell receptor-rearrangement excision circles (TRECs) based on patient age and on stage of HIV-1 infection. TRECs were measured in purified CD4 and CD8 T cells of a large cohort of HIV-1-infected subjects (n = 297) with chronic infection but no previous antiretroviral treatment and of a control group of HIV-negative subjects (n = 120). HIV-1-infected subjects were stratified on the basis of CD4 T-cell counts in 3 groups, early-stage disease (more than 500 CD4 T cells), intermediate-stage disease (200-500 CD4 T cells), and late-stage disease (fewer than 200 CD4 T cells). Compared with the control group, CD8 TREC contents were severely reduced (P <.001) in HIV-1-infected subjects regardless of the stage of HIV disease. In contrast, CD4 TREC contents were significantly increased (P =.003) in HIV-1-infected subjects during early-stage disease, similar at intermediate-stage disease, and severely reduced only at late-stage disease. We show that the increase in CD4 TRECs was mostly limited to younger (younger than 45 years) patients at early-stage disease. Our results demonstrate a dichotomy between TREC contents in CD4 and CD8 T-cell populations in HIV-1 infection and indicate that thymus function in younger subjects is preserved at early and intermediate stages of HIV infection.