K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors

To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-Ras(G12D) murine knockin model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double-negative 1 stage. With progression of disease, approximately 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to gamma-secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by down-regulation of Notch1 target genes and intracellular cleaved Notch. We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways.     

Effects of manipulating sedentary behavior on physical activity and food intake

OBJECTIVES: Sedentary behaviors have been correlated with obesity. We investigated whether changes in sedentary behaviors relate to changes in energy intake and/or physical activity. STUDY DESIGN: Experimental within-subject crossover design in which children participated in three 3-week phases: baseline and increased and decreased targeted sedentary behaviors. PARTICIPANTS: Thirteen 8- to 12-year-old, nonobese children. MEASUREMENTS: Sedentary behaviors were measured through the use of daily activity logs, physical activity measured with accelerometers, and energy intake measured by means of repeated 24-hour recalls collected during each phase. Energy intake, energy expenditure, and energy balance per day were calculated. RESULTS: Children showed significant (P <.001) increases of 50% and decreases of 53% in targeted sedentary behaviors from baseline during the increase and decrease phases, respectively. There was a significant (P =.05) increase in energy balance per day (+350.7 kcal) when sedentary behaviors were increased, as the result of an increase in energy intake per day (+250.9 kcal) and a decrease in energy expenditure (-99.8 kcal). No significant changes in energy balance were observed when sedentary behaviors were decreased. CONCLUSIONS: Increasing sedentary behaviors had a greater influence on physical activity and energy intake than reducing sedentary behavior in nonobese youth. In some children, changes in sedentary behaviors may be important to modify energy balance and prevent obesity.     

Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA‐rich mucus plugs are characteristic features of severe RSV–LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first‐line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti‐viral effect in vitro. Second, we studied NET formation in vivo during severe RSV–LRTD in infants and bovine RSV–LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV–LRTD. Detailed histopathological examination of calves with RSV–LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV–LRTD contributes to airway obstruction. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Information and Communication Technology to Support Self-Management of Patients with Mild Acquired Cognitive Impairments: Systematic Review

Background

Mild acquired cognitive impairment (MACI) is a new term used to describe a subgroup of patients with mild cognitive impairment (MCI) who are expected to reach a stable cognitive level over time. This patient group is generally young and have acquired MCI from a head injury or mild stroke. Although the past decade has seen a large amount of research on how to use information and communication technology (ICT) to support self-management of patients with chronic diseases, MACI has not received much attention. Therefore, there is a lack of information about what tools have been created and evaluated that are suitable for self-management of MACI patients, and a lack of clear direction on how best to proceed with ICT tools to support self-management of MACI patients.

Objective

This paper aims to provide direction for further research and development of tools that can support health care professionals in assisting MACI patients with self-management. An overview of studies reporting on the design and/or evaluation of ICT tools for assisting MACI patients in self-management is presented. We also analyze the evidence of benefit provided by these tools, and how their functionality matches MACI patients’ needs to determine areas of interest for further research and development.

Methods

A review of the existing literature about available assistive ICT tools for MACI patients was conducted using 8 different medical, scientific, engineering, and physiotherapy library databases. The functionality of tools was analyzed using an analytical framework based on the International Classification of Functioning, Disability and Health (ICF) and a subset of common and important problems for patients with MACI created by MACI experts in Sweden.

Results

A total of 55 search phrases applied in the 8 databases returned 5969 articles. After review, 7 articles met the inclusion criteria. Most articles reported case reports and exploratory research. Out of the 7 articles, 4 (57%) studies had less than 10 participants, 5 (71%) technologies were memory aids, and 6 studies were mobile technologies. All 7 studies fit the profile for patients with MACI as described by our analytical framework. However, several areas in the framework important for meeting patient needs were not covered by the functionality in any of the ICT tools.

Conclusions

This study shows a lack of ICT tools developed and evaluated for supporting self-management of MACI patients. Our analytical framework was a valuable tool for providing an overview of how the functionality of these tools matched patient needs. There are a number of important areas for MACI patients that are not covered by the functionality of existing tools, such as support for interpersonal interactions and relationships. Further research on ICT tools to support self-management for patients with MACI is needed.     

“Many miles to go …”: a systematic review of the implementation of patient decision support interventions into routine clinical practice

Background

Two decades of research has established the positive effect of using patient-targeted decision support interventions: patients gain knowledge, greater understanding of probabilities and increased confidence in decisions. Yet, despite their efficacy, the effectiveness of these decision support interventions in routine practice has yet to be established; widespread adoption has not occurred. The aim of this review was to search for and analyze the findings of published peer-reviewed studies that investigated the success levels of strategies or methods where attempts were made to implement patient-targeted decision support interventions into routine clinical settings.

Methods

An electronic search strategy was devised and adapted for the following databases: ASSIA, CINAHL, Embase, HMIC, Medline, Medline-in-process, OpenSIGLE, PsycINFO, Scopus, Social Services Abstracts, and the Web of Science. In addition, we used snowballing techniques. Studies were included after dual independent assessment.

Results

After assessment, 5322 abstracts yielded 51 articles for consideration. After examining full-texts, 17 studies were included and subjected to data extraction. The approach used in all studies was one where clinicians and their staff used a referral model, asking eligible patients to use decision support. The results point to significant challenges to the implementation of patient decision support using this model, including indifference on the part of health care professionals. This indifference stemmed from a reported lack of confidence in the content of decision support interventions and concern about disruption to established workflows, ultimately contributing to organizational inertia regarding their adoption.

Conclusions

It seems too early to make firm recommendations about how best to implement patient decision support into routine practice because approaches that use a ‘referral model’ consistently report difficulties. We sense that the underlying issues that militate against the use of patient decision support and, more generally, limit the adoption of shared decision making, are under-investigated and under-specified. Future reports from implementation studies could be improved by following guidelines, for example the SQUIRE proposals, and by adopting methods that would be able to go beyond the ‘barriers’ and ‘facilitators’ approach to understand more about the nature of professional and organizational resistance to these tools. The lack of incentives that reward the use of these interventions needs to be considered as a significant impediment.

     

Patellofemoral joint: kinematic MR imaging to assess tracking abnormalities

The patellofemoral joint was imaged with magnetic resonance (MR) in the axial plane while the knee was positioned from 0 degrees to 32 degrees of flexion (nine positions). These multiple sequential images obtained within the early phases of flexion of the knee were viewed in a "cine-loop" format, producing a kinematic study that clearly demonstrated the relationship of the patella to the trochlear groove. Four healthy subjects and one patient with known bilateral subluxing patellae were studied. The preliminary results suggest that kinematic MR imaging of the patellofemoral joint is potentially useful for the evaluation of patellar tracking abnormalities.     

Quantifying the blood oxygenation level dependent effect in cerebral blood volume-weighted functional MRI at 9.4T.

In cerebral blood volume (CBV)-weighted functional MRI (fMRI) employing superparamagnetic contrast agent, iron dose and blood oxygenation level dependent (BOLD) contamination are two important issues for experimental design and CBV quantification. Both BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo sequences have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin-echo and gradient-echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extravascular (EV) BOLD effect. With a TE of 35 ms, the EV BOLD effect was estimated to account for 76+/-12% of the observed spin-echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field.