Patterns of CD16 and CD56 expression in persistent expansions of CD3+NKa+ lymphocytes are predictive for clonal T-cell receptor gene rearrangements

Phenotypic characteristics, and correlations between the expression of membrane NK-associated (NKa) determinants (CD11b, CD16, CD56 and CD57) and T cell receptor (TCR) genotypic patterns, were examined in 25 patients with persistent (greater than 6 months) expansions of CD3+WT31+NKa+ (CD8+ and CD8dim+) lymphocytes. These studies showed that distinct NKa phenotypic profiles were restricted to cases with rearranged TCR configurations and that clonal CD3+NKa+ components could be predicted in most cases by assessing relationships between membrane CD16 and CD56 expression. For all normal NKa subpopulations, there was a high correlation (P less than 0.0001; n = 31) between the expression of these two membrane determinants. Markedly increased CD16 expression by CD3+NKa+ cells, in relation to CD56 (i.e. a high CD16:CD56 ratio), was found exclusively in cases with rearranged TCR (13/16 cases); 2/3 of the remaining cases showing significantly reduced CD16:CD56 ratios and high (greater than 2.0) CD3+CD56+ absolute numbers. In contrast, 7/9 of the germline TCR cases had a normal CD16:CD56 ratio and 2/9 a decreased ratio with low (less than 1.0) CD3+CD56+ absolute numbers. A high ratio of CD16:CD56 expression by CD3+NKa+ lymphocytes was therefore informative for 82% of TCR rearrangements in this series; and analysis of CD16 and CD56 expression was predictive for germline and rearranged TCR configurations in 24/25 persistent CD3+NKa+ expansions.     

Correlates of well-being in mothers of children and adolescents with cystic fibrosis

Fifty mothers and 44 well siblings of children and adolescents with cystic fibrosis (CF) participated in this study to identify correlates of maternal well-being. Participants completed postal questionnaires which assessed maternal well-being, problems experienced surrounding the illness and treatment and the nature of the sibling relationship. Due to the demanding nature of treatment and the fact that CF is both genetic and incurable at present we anticipate mothers of these children will experience higher levels of stress and consequently poorer well-being than the normal population. In addition, illness severity, problems with adherence to treatment, child communication, maternal support and the sibling relationship are expected to relate to maternal well-being. Mothers in this sample did not rate their well-being as any different to the normal population. Results suggest that mothers are likely to rate their own well-being as poor when they report more frequent problems surrounding the illness and treatment and well children rate their sibling relationship as having frequent disagreements and aggression. This study highlights factors that are related to maternal well-being in families where one child has CF. These mothers as a group do not appear to be experiencing more stress in their daily lives than the normal population but certain illness and family variables are related to their well-being when examining the mothers on certain dimensions.     

Graft-versus-leukemia and graft-versus-host reactions after donor lymphocyte infusion are initiated by host-type antigen-presenting cells and regulated by regulatory T cells in early and long-term chimeras.

Regulatory T (T(reg)) cells and host antigen-presenting cells (APCs) have been implicated in graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect after donor lymphocyte infusion (DLI), but their relative contributions remain unclear in early versus long-term complete donor or mixed murine allogeneic hematopoietic stem cell (HSC) chimeras. We have previously demonstrated that donor HSC-derived Thy1(+) T(reg) cells, consisting primarily of CD4(+)CD25(+) cells, play an important role in the suppression of graft-versus-host (GVH) reactivity when DLI is given to complete donor chimeras 28 days after HSC transplantation. Data presented here demonstrate that protection against GVHD exerted by Thy1(+) T(reg) cells is less evident with time and eventually is not required in long-term complete donor chimeras because of an absence of host-type APCs to activate alloreactive T cells. Lethal GVHD was observed when Thy1(+) T(reg) cells were depleted from complete donor chimeras given by DLI at day 28, 35, or 42; however, T(reg) cell depletion and DLI at day 70 no longer induced GVHD-associated mortality. Moreover, the failure of DLI to induce GVHD with T(reg) depletion correlated with a loss of the DLI-induced GVL effect in long-term (day 100) complete donor chimeras. In contrast to the results from complete donor chimeras, GVL reactivity in day 100 mixed chimeras was robust after DLI. Loss of a DLI-induced GVL effect in long-term complete donor chimeras was attributed to the absence of host APCs because the infusion of exogenous host-type dendritic cells partially restored both DLI-induced GVL and GVH reactions in day 100 complete donor chimeras. The GVL and GVH reactions restored by infusion of host dendritic cells in day 100 complete donor chimeras were at least partially regulated by T(reg) cells because transient depletion of CD25(+) cells increased both the GVL effect and the severity of GVHD after DLI. Taken together, these data suggest that T(reg) cells can regulate DLI-induced GVL and GVH reactions in both early and long-term complete donor chimeras, and a state of mixed chimerism is superior to complete donor chimerism because host-type APCs facilitate a DLI-induced GVL effect without severe GVHD.     

Nonlinear functional network connectivity in resting functional magnetic resonance imaging data

In this work, we focus on explicitly nonlinear relationships in functional networks. We introduce a technique using normalized mutual information (NMI) that calculates the nonlinear relationship between different brain regions. We demonstrate our proposed approach using simulated data and then apply it to a dataset previously studied by Damaraju et al. This resting‐state fMRI data included 151 schizophrenia patients and 163 age‐ and gender‐matched healthy controls. We first decomposed these data using group independent component analysis (ICA) and yielded 47 functionally relevant intrinsic connectivity networks. Our analysis showed a modularized nonlinear relationship among brain functional networks that was particularly noticeable in the sensory and visual cortex. Interestingly, the modularity appears both meaningful and distinct from that revealed by the linear approach. Group analysis identified significant differences in explicitly nonlinear functional network connectivity (FNC) between schizophrenia patients and healthy controls, particularly in the visual cortex, with controls showing more nonlinearity (i.e., higher normalized mutual information between time courses with linear relationships removed) in most cases. Certain domains, including subcortical and auditory, showed relatively less nonlinear FNC (i.e., lower normalized mutual information), whereas links between the visual and other domains showed evidence of substantial nonlinear and modular properties. Overall, these results suggest that quantifying nonlinear dependencies of functional connectivity may provide a complementary and potentially important tool for studying brain function by exposing relevant variation that is typically ignored. Beyond this, we propose a method that captures both linear and nonlinear effects in a “boosted” approach. This method increases the sensitivity to group differences compared to the standard linear approach, at the cost of being unable to separate linear and nonlinear effects.     

B-cell acute lymphoblastic leukaemia: clinical and biological aspects

Acute lymphoblastic leukaemia of B-cell phenotype (B-ALL) is uncommon. We studied eight cases of B-ALL, investigating the clinical characteristics as well as the biological features. Cytology revealed a typical L3 profile in most cases, but in one case the morphological diagnosis was L2 and morphometric analysis indicated that the blasts in B-ALL were larger than in other ALLs. Cytogenetic study detected the typical translocations (8; 14) and (8; 22) in most of the cases. Abnormalities of the long arm of the chromosome 1 were found in four cases and a major aneuploidy was observed in one case. Cell-cycle analysis showed a high degree of proliferation with, in all cases, a small fraction of cells in G1 with low protein content (corresponding to early G1). All these biological characteristics must be related to the poor prognosis of this disease.