Early T precursor acute lymphoblastic leukaemia/lymphoma shows differential immunophenotypic characteristics including frequent CD33 expression and in vitro response to targeted CD33 therapy

The differential immunophenotypic characteristics of early T precursor (ETP) acute lymphoblastic leukaemia/lymphoma (ALL) remain incompletely characterized. The study group (n = 142) included 106 (74·7%) men and 36 (25·3%) women with a median age of 34·9 years (range, 2–79) at diagnosis. Patients were subtyped by flow cytometry immunophenotyping as follows: 33 (23·2%) ETP; 32 (22·5%) early non-ETP; 60 (42·2%) thymic; and 17 (12·1%) mature. Excepting definitional markers, there was a significant differential expression of the markers CD2, CD10, CD33 and TdT between ETP-ALL and non-ETP-ALL. Positive CD33 expression (≥20% of leukaemic blasts) was detected in 21/33 (63%) ETP-ALL compared with 17/95 (17·9%) non-ETP-ALL (P < 0·001). Notably, targeted anti-CD33 therapy with IMGN779 resulted in significant growth inhibition and increased apoptosis in ETP-ALL cells in vitro. An 11-marker T-ALL immunophenotype score discriminated reliably between ETP and non-ETP ALL. Longitudinal analysis of ETP-ALL cases in this study demonstrated that the immunophenotype may be occasionally dynamic but is largely stable over the disease course. In summary, identification of ETP-ALL might be enhanced by using an 11-marker T-ALL immunophenotype score. CD33 expression is frequent in ETP-ALL, and in vitro data suggest that exploring anti-CD33 therapy in ETP-ALL is warranted.     

Modelling of increased homocysteine in ischaemic stroke: post-hoc cross-sectional matched case-control analysis in young patients

BACKGROUND & PURPOSE: Hyperhomocysteinaemia has been postulated to participate in pathogenesis of ischaemic stroke (IS). However, especially in young adults, there is possibility of significantly increased IS risk due to increased normal homocysteinaemia, i.e., hidden (pathologically dormant) prevalence within a healthy, normally-defined range. We performed a post-hoc modelling investigation on plasma total homocysteinaemia (THCY) in gender- and age-matched young patients in the acute IS phase. We evaluated relationships between THCY and prevalence of other potential risk factors in 41 patients vs. 41 healthy controls. METHOD: We used clinical methods, instrumental and neuroimmaging procedures, risk factors examination, total plasma homocysteine measurements and other laboratory and statistical modelling techniques. RESULTS: IS patients and healthy controls were similar not only for matching variables, but also for smoking, main vitamin status, serum creatinine and lipid profile. Patients with IS, however, had lower vitamin B6 levels and higher THCY, fibrinogen and triglycerides (TGL). At multivariate stepwise logistic regression only increased THCY and TGL were significantly and independently associated with the risk for stroke (72% model accuracy, p model=0.001). An increase of THCY with 1.0 micromol/L was associated with 22% higher risk of ischaemic stroke [adjusted OR=1.22 (95%CI 1.03?1.44)]. In this way, novel lower cut-off value for HCY of 11.58 micromol/L in younger patients has been revealed (ROC AUC= 0.67, 95CI% 0.55-0.78, p=0.009). CONCLUSION: The new THCY cut-off clearly discriminated between absence and presence of IS (sensitivity>63%, specificity>68%) irrespectively of age and gender and may be applied to better evaluate and more precisely define, as earlier as possible, the young patients at increased IS risk.     

Scope and severity index: a metric for quantifying nursing home survey deficiency number, scope, and severity adjusted for the state-related measurement bias

ObjectivesTo develop a metric (scope and severity index [SSI]) to measure nursing home deficiency number, scope, and severity adjusted for the state-related bias and to test its convergent and predictive validity.DesignWe assigned scope and severity weights to each level of scope and severity (A-L). SSI was calculated as a sum of all weights per survey which was further corrected for the state-level bias by dividing by the state average number of health deficiencies and multiplying by the national average number of health deficiencies. Data source - National Online Survey, Certification, and Reporting system.SettingAll Medicare/Medicaid-certified skilled nursing facilities.MeasurementsWe correlated SSI with nursing home staffing levels (convergent validity) and denial of payment for new admissions (predictive validity).ResultsThe expert panel reached agreement on the scope and severity weights: Level A = 5, B = 10, C = 15, D = 20, E = 30, F = 40, G = 35, H = 50, I = 65, J = 55, K = 75, and L = 100 points. Scope and severity per deficiency was positively correlated with the number of deficiencies in that survey. SSI contained almost no state-related bias, but yet related state-level variability. It demonstrated strong face, convergent, and predictive validity.ConclusionsSSI rendered a valuable metric to conduct quantitative analyses of nursing home deficiency number, scope, and severity across states. Future research should investigate the positive relationship between scope and severity of deficiencies and their number. Better understanding and correction of other factors introducing systematic bias to the survey results (e.g. regional impact) can further improve the accuracy of survey result evaluation.     

Changing the pathogenetic roadmap of liver fibrosis? Where did it start; where will it go?

The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes – formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) – the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrix–producing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts. Currently, the generation of matrix-synthesizing fibroblasts by epithelial–mesenchymal transition, by influx of bone marrow–derived fibrocytes into damaged liver tissue, and by differentiation of circulating monocytes to fibroblasts after homing in the injured liver are discussed as important complementary mechanisms to enlarge the pool of (myo-)fibroblasts in the fibrosing liver. Among the molecular mediators, transforming growth factor-beta (TGF-β) plays a central role, which is controlled by the bone-morphogenetic protein (BMP)-7, an important antagonist of TGF-β action. The newly discovered pathways supplement the linear concept of HSC activation to myofibroblasts, point to fibrosis as a systemic response involving extrahepatic organs and reactions, add further evidence to a more or less uniform concept of organ fibrosis in general (e.g. liver, lung, kidney), and offer innovative approaches for the development of non-invasive biomarkers and antifibrotic trials.     

Lineage II of Southeast Asian/American DENV-2 Is Associated with a Severe Dengue Outbreak in the Peruvian Amazon

During 2010 and 2011, the Loreto region of Peru experienced a dengue outbreak of unprecedented magnitude and severity for the region. This outbreak coincided with the reappearance of dengue virus-2 (DENV-2) in Loreto after almost 8 years. Whole-genome sequence indicated that DENV-2 from the outbreak belonged to lineage II of the southeast Asian/American genotype and was most closely related to viruses circulating in Brazil during 2007 and 2008, whereas DENV-2 previously circulating in Loreto grouped with lineage I (DENV-2 strains circulating in South America since 1990). One amino acid substitution (NS5 A811V) in the 2010 and 2011 isolates resulted from positive selection. However, the 2010 and 2011 DENV-2 did not replicate to higher titers in monocyte-derived dendritic cells and did not infect or disseminate in a higher proportion of Aedes aegypti than DENV-2 isolates previously circulating in Loreto. These results suggest that factors other than enhanced viral replication played a role in the severity of this outbreak.     

T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients

BACKGROUND. Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury.METHODS. Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI.RESULTS. In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8⁺ T cells decreased more than CD4⁺ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r² = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir.CONCLUSIONS. Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells.TRIAL REGISTRATION. Not applicable.FUNDING. British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.