GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

International audienceBACKGROUND:In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease.METHODS:We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively.RESULTS:Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples.CONCLUSIONS:These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study

Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR?

The increase in numbers of adults with cystic fibrosis (CF) has allowed us to identify previously unrecognized chronic complications of CF, as well as appreciate unique presentations of cystic fibrosis-related diseases. Do these chronic complications and unique presentations provide us with new insight into cystic fibrosis transmembrane conductance regulator (CFTR) function? Current data suggest that the 'chronic complications' reveal mainly the effect of a long-term absence of previously recognized CFTR functions. In contrast, the 'unique presentations' provide new insight into the role of CFTR in different tissues

Reliability of the tuck jump injury risk screening assessment in elite male youth soccer players

Altered neuromuscular control has been suggested as a mechanism for injury in soccer players. Ligamentous injuries most often occur during dynamic movements, such as decelerations from jump-landing maneuvers where high risk movement patterns are present. The assessment of kinematic variables during jump-landing tasks as part of a pre-participation screen is useful in the identification of injury risk. An example of a field-based screening tool is the repeated tuck jump assessment. The purpose of this study was to analyze the within-subject variation of the tuck jump screening assessment in elite male youth soccer players. 25 pre and 25 post-peak height velocity (PHV) elite male youth soccer players from the academy of a professional English soccer club completed the assessment. A test, re-test design was used to explore the within-subject inter-session reliability. Technique was graded retrospectively against the 10-point criteria set out in the screening protocol using two-dimensional video cameras. The typical error range reported for tuck jump total score (0.90 – 1.01 in pre and post-PHV players respectively) was considered acceptable. When each criteria was analyzed individually, Kappa coefficient determined that knee valgus was the only criterion to reach substantial agreement across the two test sessions for both groups. The results of this study suggest that although tuck jump total score may be reliably assessed in elite male youth soccer players, caution should be applied in solely interpreting the composite score due to the high within-subject variation in a number of the individual criteria. Knee valgus may be reliably used to screen elite youth male soccer players for this plyometric technique error and for test, re-test comparison

Consistency of Field-Based Measures of Neuromuscular Control Using Force Plate Diagnostics in Elite Male Youth Soccer Players

Consistency of field-based measures of neuromuscular control using force-plate diagnostics in elite male youth soccer players. J Strength Cond Res 30(12): 3304–3311, 2016—Deficits in neuromuscular control during movement patterns such as landing are suggested pathomechanics that underlie sport-related injury. A common mode of assessment is measurement of landing forces during jumping tasks; however, these measures have been used less frequently in male youth soccer players, and reliability data are sparse. The aim of this study was to examine the reliability of a field-based neuromuscular control screening battery using force-plate diagnostics in this cohort. Twenty-six pre–peak height velocity (PHV) and 25 post-PHV elite male youth soccer players completed a drop vertical jump (DVJ), single-leg 75% horizontal hop and stick (75%HOP), and single-leg countermovement jump (SLCMJ). Measures of peak landing vertical ground reaction force (pVGRF), time to stabilization, time to pVGRF, and pVGRF asymmetry were recorded. A test-retest design was used, and reliability statistics included change in mean, intraclass correlation coefficient, and coefficient of variation (CV). No significant differences in mean score were reported for any of the assessed variables between test sessions. In both groups, pVGRF and asymmetry during the 75%HOP and SLCMJ demonstrated largely acceptable reliability (CV ≤ 10%). Greater variability was evident in DVJ pVGRF and all other assessed variables, across the 3 protocols (CV range = 13.8–49.7%). Intraclass correlation coefficient values ranged from small to large and were generally higher in the post-PHV players. The results of this study suggest that pVGRF and asymmetry can be reliably assessed using a 75%HOP and SLCMJ in this cohort. These measures could be used to support a screening battery for elite male youth soccer players and for test-retest comparison

Deliberate termination of life of newborns with spina bifida, a critical reappraisal

Objects: Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. 'Unbearable and hopeless suffering' is the single most cited criterion for this termination, together with the notion that 'there are no other proper medical means to alleviate this suffering'. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective. Methods: First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a 'reference case'. Conclusion: 'Unbearable and hopeless suffering' cannot be applied to newborns with MMC. They are not 'terminally ill' and do have 'prospects of a future'. In these end-of-life decisions, 'quality of life judgments' should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns