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.     

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.     

Diagnostic and prognostic factors in acute monocytic leukaemia: an analysis of 51 cases

Diagnostic features (cytochemistry, immunophenotyping and serum biochemistry) were examined in 51 cases of acute monocytic leukaemia (AMoL). Peroxidase, Sudan black B and alpha naphthyl acetate esterase (ANAE) cytochemical reactions were unrelated to morphological (FAB groups M5a and M5b) or immunological subtype. ANAE cytochemistry, however, indicated that AMoL cases could be subdivided into those with typical (M-type) reactions and those with insignificant staining or monocytic ANAE isoenzymes (defined by IEF). All cases were phenotypically CD13/CD33 positive and, with one exception, had greater than 30% HLA-DR positive cells. Membrane CD14 expression was insignificant or variable in 33% of M5a cases in contrast to 23/24 M5b cases which showed high proportions of CD14-staining cells with at least two monoclonal antibodies. Serum lysozyme, LDH and beta-2 microglobulin (beta 2m) were increased in 88%, 68% and 81% of cases respectively but, with the exception of statistically higher lysozyme levels in CD14+ cases, were unrelated to the morphological, cytochemical or immunological diagnostic subgroups. Clinical and diagnostic features were also examined as possible prognostic indicators. The morphological, cytochemical and immunological subgroups of AMoL were not found to be of prognostic relevance but age (P = 0.004), renal failure (P = 0.005) and serum beta 2m levels (P = 0.002) were related to patient survival. Moreover, renal failure and serum beta 2m remained significant (P = 0.012 respectively) when age was taken into account and were shown to be independent prognostic variables.     

Reproducibility of a ramping protocol to measure cerebral vascular reactivity using functional magnetic resonance imaging

Though individual differences in arterial carbon dioxide and oxygen levels inherently exist, the degree of their influence on cerebral vascular reactivity (CVR) is less clear. We examined the reproducibility of BOLD signal changes to an iso‐oxic ramping P_etCO₂ protocol. CVR changes were induced by altering P_etCO₂ while holding P_etO₂ constant using a computer‐controlled sequential gas delivery (SGD) device. Two MRI scans, each including a linear change in P_etCO₂, were performed using a 3‐Tesla (3T) scanner. This ramp sequence consisted of 1 min at 30 mmHg followed by 4 min period during where P_etCO₂ was linearly increased from 30 to 50 mmHg, 1 min at 51 mmHg, and concluded with 4 min at baseline. The protocol was repeated at a separate visit with 3 days between visits (minimum). Intraclass correlation coefficients (ICC) and coefficients of variation (CV) were used to verify reproducibility. Eleven subjects (6 females; mean age 26.5 ± 5.7 years) completed the full testing protocol. Good reproducibility was observed for the within‐visit ramp sequence (Visit 1: ICC = 0.82, CV = 6.5%; Visit 2: ICC = 0.74, CV = 6.4%). Similarly, ramp sequence were reproducible between visits (Scan 1: ICC = 0.74, CV = 6.5%; Scan 2: ICC = 0.66, CV = 6.1%). Establishing reproducible methodologies for measuring BOLD signal changes in response to P_etCO₂ alterations using a ramp protocol will allow researchers to study CVR functionality. Finally, adding a ramping protocol to CVR studies could provide information about changes in CVR over a broad range of P_etCO₂.     

Parallel group ICA+ICA: Joint estimation of linked functional network variability and structural covariation with application to schizophrenia

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second‐level 3D features, rather than the original 4D fMRI data. This trade‐off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called “parallel group ICA+ICA” that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first‐level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI‐sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.     

The spatial chronnectome reveals a dynamic interplay between functional segregation and integration

The brain is highly dynamic, reorganizing its activity at different interacting spatial and temporal scales, including variation within and between brain networks. The chronnectome is a model of the brain in which nodal activity and connectivity patterns change in fundamental and recurring ways over time. Most literature assumes fixed spatial nodes/networks, ignoring the possibility that spatial nodes/networks may vary in time. Here, we introduce an approach to calculate a spatially fluid chronnectome (called the spatial chronnectome for clarity), which focuses on the variations of networks coupling at the voxel level, and identify a novel set of spatially dynamic features. Results reveal transient spatially fluid interactions between intra‐ and internetwork relationships in which brain networks transiently merge and separate, emphasizing dynamic segregation and integration. Brain networks also exhibit distinct spatial patterns with unique temporal characteristics, potentially explaining a broad spectrum of inconsistencies in previous studies that assumed static networks. Moreover, we show anticorrelative connections to brain networks are transient as opposed to constant across the entire scan. Preliminary assessments using a multi‐site dataset reveal the ability of the approach to obtain new information and nuanced alterations that remain undetected during static analysis. Patients with schizophrenia (SZ) display transient decreases in voxel‐wise network coupling within visual and auditory networks, and higher intradomain coupling variability. In summary, the spatial chronnectome represents a new direction of research enabling the study of functional networks which are transient at the voxel level, and the identification of mechanisms for within‐ and between‐subject spatial variability.     

Function biomedical informatics research network recommendations for prospective multicenter functional MRI studies

This report provides practical recommendations for the design and execution of multicenter functional MRI (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The study was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multisite aspects include: (i) establishing and verifying scan parameters including scanner types and magnetic fields, (ii) establishing and monitoring of a scanner quality program, (iii) developing task paradigms and scan session documentation, (iv) establishing clinical and scanner training to ensure consistency over time, (v) developing means for uploading, storing, and monitoring of imaging and other data, (vi) the use of a traveling fMRI expert, and (vii) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.