FLT3 mutations in Early T-Cell Precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup

Assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: Systematic review and meta-regression

Objective: To assess the impact of inadequate water and sanitation on diarrhoeal disease in low- and middle-income settings. Methods: The search strategy used Cochrane Library, MEDLINE & PubMed, Global Health, Embase and BIOSIS supplemented by screening of reference lists from previously published systematic reviews, to identify studies reporting on interventions examining the effect of drinking water and sanitation improvements in low- and middle-income settings published between 1970 and May 2013. Studies including randomised controlled trials, quasi-randomised trials with control group, observational studies using matching techniques and observational studies with a control group where the intervention was well defined were eligible. Risk of bias was assessed using a modified Ottawa-Newcastle scale. Study results were combined using meta-analysis and meta-regression to derive overall and intervention-specific risk estimates. Results: Of 6819 records identified for drinking water, 61 studies met the inclusion criteria, and of 12 515 records identified for sanitation, 11 studies were included. Overall, improvements in drinking water and sanitation were associated with decreased risks of diarrhoea. Specific improvements, such as the use of water filters, provision of high-quality piped water and sewer connections, were associated with greater reductions in diarrhoea compared with other interventions. Conclusions: The results show that inadequate water and sanitation are associated with considerable risks of diarrhoeal disease and that there are notable differences in illness reduction according to the type of improved water and sanitation implemented

The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth

Cilia are specialized organelles that play an important role in several biological processes, including mechanosensation, photoperception, and osmosignaling. Mutations in proteins localized to cilia have been implicated in a growing number of human diseases. In this study, we demonstrate that the von Hippel-Lindau (VHL) protein (pVHL) is a ciliary protein that controls ciliogenesis in kidney cells. Knockdown of pVHL impeded the formation of cilia in mouse inner medullary collecting duct 3 kidney cells, whereas the expression of pVHL in VHL-negative renal cancer cells rescued the ciliogenesis defect. Using green fluorescent protein–tagged end-binding protein 1 to label microtubule plus ends, we found that pVHL does not affect the microtubule growth rate but is needed to orient the growth of microtubules toward the cell periphery, a prerequisite for the formation of cilia. Furthermore, pVHL interacts with the Par3–Par6–atypical PKC complex, suggesting a mechanism for linking polarity pathways to microtubule capture and ciliogenesis

The multi-modality cardiac imaging approach to the Athlete's heart: an expert consensus of the European Association of Cardiovascular Imaging

The term 'athlete's heart' refers to a clinical picture characterized by a slow heart rate and enlargement of the heart. A multi-modality imaging approach to the athlete's heart aims to differentiate physiological changes due to intensive training in the athlete's heart from serious cardiac diseases with similar morphological features. Imaging assessment of the athlete's heart should begin with a thorough echocardiographic examination. Left ventricular (LV) wall thickness by echocardiography can contribute to the distinction between athlete's LV hypertrophy and hypertrophic cardiomyopathy (HCM). LV end-diastolic diameter becomes larger (>55 mm) than the normal limits only in end-stage HCM patients when the LV ejection fraction is <50%. Patients with HCM also show early impairment of LV diastolic function, whereas athletes have normal diastolic function. When echocardiography cannot provide a clear differential diagnosis, cardiac magnetic resonance (CMR) imaging should be performed. With CMR, accurate morphological and functional assessment can be made. Tissue characterization by late gadolinium enhancement may show a distinctive, non-ischaemic pattern in HCM and a variety of other myocardial conditions such as idiopathic dilated cardiomyopathy or myocarditis. The work-up of athletes with suspected coronary artery disease should start with an exercise ECG. In athletes with inconclusive exercise ECG results, exercise stress echocardiography should be considered. Nuclear cardiology techniques, coronary cardiac tomography (CCT) and/or CMR may be performed in selected cases. Owing to radiation exposure and the young age of most athletes, the use of CCT and nuclear cardiology techniques should be restricted to athletes with unclear stress echocardiography or CMR

Development and Validation of the Behavioral Tendencies Questionnaire

At a fundamental level, taxonomy of behavior and behavioral tendencies can be described in terms of approach, avoid, or equivocate (i.e., neither approach nor avoid). While there are numerous theories of personality, temperament, and character, few seem to take advantage of parsimonious taxonomy. The present study sought to implement this taxonomy by creating a questionnaire based on a categorization of behavioral temperaments/tendencies first identified in Buddhist accounts over fifteen hundred years ago. Items were developed using historical and contemporary texts of the behavioral temperaments, described as “Greedy/Faithful”, “Aversive/Discerning”, and “Deluded/Speculative”. To both maintain this categorical typology and benefit from the advantageous properties of forced-choice response format (e.g., reduction of response biases), binary pairwise preferences for items were modeled using Latent Class Analysis (LCA). One sample (n1 = 394) was used to estimate the item parameters, and the second sample (n2 = 504) was used to classify the participants using the established parameters and cross-validate the classification against multiple other measures. The cross-validated measure exhibited good nomothetic span (construct-consistent relationships with related measures) that seemed to corroborate the ideas present in the original Buddhist source documents. The final 13-block questionnaire created from the best performing items (the Behavioral Tendencies Questionnaire or BTQ) is a psychometrically valid questionnaire that is historically consistent, based in behavioral tendencies, and promises practical and clinical utility particularly in settings that teach and study meditation practices such as Mindfulness Based Stress Reduction (MBSR)

Hybrid Wing Body Aircraft Acoustic Test Preparations and Facility Upgrades

NASA is investigating the potential of acoustic shielding as a means to reduce the noise footprint at airport communities. A subsonic transport aircraft and Langley's 14- by 22-foot Subsonic Wind Tunnel were chosen to test the proposed "low noise" technology. The present experiment studies the basic components of propulsion-airframe shielding in a representative flow regime. To this end, a 5.8-percent scale hybrid wing body model was built with dual state-of-the-art engine noise simulators. The results will provide benchmark shielding data and key hybrid wing body aircraft noise data. The test matrix for the experiment contains both aerodynamic and acoustic test configurations, broadband turbomachinery and hot jet engine noise simulators, and various airframe configurations which include landing gear, cruise and drooped wing leading edges, trailing edge elevons and vertical tail options. To aid in this study, two major facility upgrades have occurred. First, a propane delivery system has been installed to provide the acoustic characteristics with realistic temperature conditions for a hot gas engine; and second, a traversing microphone array and side towers have been added to gain full spectral and directivity noise characteristics

Development of a Microphone Phased Array Capability for the Langley 14- by 22-Foot Subsonic Tunnel

A new aeroacoustic measurement capability has been developed for use in open-jet testing in the NASA Langley 14- by 22-Foot Subsonic Tunnel (14x22 tunnel). A suite of instruments has been developed to characterize noise source strengths, locations, and directivity for both semi-span and full-span test articles in the facility. The primary instrument of the suite is a fully traversable microphone phased array for identification of noise source locations and strengths on models. The array can be mounted in the ceiling or on either side of the facility test section to accommodate various test article configurations. Complementing the phased array is an ensemble of streamwise traversing microphones that can be placed around the test section at defined locations to conduct noise source directivity studies along both flyover and sideline axes. A customized data acquisition system has been developed for the instrumentation suite that allows for command and control of all aspects of the array and microphone hardware, and is coupled with a comprehensive data reduction system to generate information in near real time. This information includes such items as time histories and spectral data for individual microphones and groups of microphones, contour presentations of noise source locations and strengths, and hemispherical directivity data. The data acquisition system integrates with the 14x22 tunnel data system to allow real time capture of facility parameters during acquisition of microphone data. The design of the phased array system has been vetted via a theoretical performance analysis based on conventional monopole beamforming and DAMAS deconvolution. The performance analysis provides the ability to compute figures of merit for the array as well as characterize factors such as beamwidths, sidelobe levels, and source discrimination for the types of noise sources anticipated in the 14x22 tunnel. The full paper will summarize in detail the design of the instrumentation suite, the construction of the hardware system, and the results of the performance analysis. Although the instrumentation suite is designed to characterize noise for a variety of test articles in the 14x22 tunnel, this paper will concentrate on description of the instruments for two specific test campaigns in the facility, namely a full-span NASA Hybrid Wing Body (HWB) model entry and a semi-span Gulfstream aircraft model entry, tested in the facility in the winter of 2012 and spring of 2013, respectively

Impact of drinking water, sanitation and handwashing with soap on childhood diarrhoeal disease: updated meta‐analysis and meta‐regression

Objectives: Safe drinking water, sanitation and hygiene are protective against diarrhoeal disease; a leading cause of child mortality. The main objective was an updated assessment of the impact of unsafe water, sanitation and hygiene (WaSH) on childhood diarrhoeal disease.  Methods: We undertook a systematic review of articles published between 1970 and February 2016. Study results were combined and analysed using meta‐analysis and meta‐regression.  Results: A total of 135 studies met the inclusion criteria. Several water, sanitation and hygiene interventions were associated with lower risk of diarrhoeal morbidity. Point‐of‐use filter interventions with safe storage reduced diarrhoea risk by 61% (RR = 0.39; 95% CI: 0.32, 0.48); piped water to premises of higher quality and continuous availability by 75% and 36% (RR = 0.25 (0.09, 0.67) and 0.64 (0.42, 0.98)), respectively compared to a baseline of unimproved drinking water; sanitation interventions by 25% (RR = 0.75 (0.63, 0.88)) with evidence for greater reductions when high sanitation coverage is reached; and interventions promoting handwashing with soap by 30% (RR = 0.70 (0.64, 0.77)) vs. no intervention. Results of the analysis of sanitation and hygiene interventions are sensitive to certain differences in study methods and conditions. Correcting for non‐blinding would reduce the associations with diarrhoea to some extent.  Conclusions: Although evidence is limited, results suggest that household connections of water supply and higher levels of community coverage for sanitation appear particularly impactful which is in line with targets of the Sustainable Development Goals

On-plot drinking water supplies and health: a systematic review

Many studies have found that household access to water supplies near to or on the household plot can reduce the probability of diarrhea, trachoma, and other water-related diseases, and it is generally accepted that on-plot water supplies produce health benefits for households. However, the collective body of research literature has not been analyzed to weigh the evidence supporting this. A systematic literature review was conducted to investigate the impacts of on-plot water supplies on diarrhea, trachoma, child growth, and water-related diseases, to further examine the relationship between household health and distance to water source and to assess whether on-plot water supplies generate health gains for households. Studies provide evidence that households with on-plot water supplies experience fewer diarrheal and helminth infections and greater child height. Findings suggest that water-washed diseases are more strongly impacted by on-plot water access than waterborne diseases. Few studies analyzed the effects of on-plot water access on quantity of domestic water used, hygiene behavior, and use of multiple water sources, and the lack of evidence for these relationships reveals an important gap in current literature. The review findings indicate that on-plot water access is a useful health indicator and benchmark for the progressive realization of the Sustainable Development Goal target of universal safe water access as well as the human right to safe water

NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

The cilia-associated protein NPHP4 is a negative regulator of Hippo signaling that modulates cell proliferation in mammals