Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM), a multisystem disease occurring primarily in women, is characterized by cystic lung destruction, and kidney and lymphatic tumors, caused by the proliferation of abnormal-appearing cells (ie, LAM cells) with a smooth muscle cell phenotype that express melanoma antigens and are capable of metastasizing. Estrogen receptors are present in LAM cells, and this finding, along with reports of disease progression during pregnancy or following exogenous estrogen administration, suggest the involvement of estrogens in the pathogenesis of LAM. Consequentiy, antiestrogen therapies have been employed in treatment. The goal of this prospective study was to evaluate the efficacy of triptorelin, a gonadotrophin-releasing hormone analogue, in 11 premenopausal women with LAM. Methods: Patients were evaluated at baseline and every 3 to 6 months thereafter, for a total of 36 months. Hormonal assays, pulmonary function tests, 6-min walk tests, high-resolution CT scans of the chest, and bone mineral density studies were performed. Results: Gonadal suppression was achieved in all patients. Overall, a significant decline in lung function was observed; two patients underwent lung transplantation 1 year after study enrollment, and another patient was lost to follow-up. Treatment with triptorelin was associated with a decline in bone mineral density. Conclusions: Triptorelin appears not to prevent a decline in lung function in patients with LAM. Its use, however, may be associated with the loss of bone mineral density

T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice.

Chronic lymphocytic leukaemia (CLL) cells require microenvironmental support for their proliferation. This can be recapitulated in highly immunocompromised hosts in the presence of T cells and other supporting cells. Current primary CLL xenograft models suffer from limited duration of tumour cell engraftment coupled with gradual T-cell outgrowth. Thus, a greater understanding of the interaction between CLL and T cells could improve their utility. In this study, using two distinct mouse xenograft models, we investigated whether xenografts recapitulate CLL biology, including natural environmental interactions with B-cell receptors and T cells, and whether manipulation of autologous T cells can expand the duration of CLL engraftment. We observed that primary CLL xenografts recapitulated both the tumour phenotype and T-cell repertoire observed in patients and that engraftment was significantly shorter for progressive tumours. A reduction in the number of patient T cells that were injected into the mice to 2-5% of the initial number or specific depletion of CD8+ cells extended the limited xenograft duration of progressive cases to that characteristic of indolent disease. We conclude that manipulation of T cells can enhance current CLL xenograft models and thus expand their utility for investigation of tumour biology and pre-clinical drug assessment

Which behavioural and exercise interventions targeting fatigue show the most promise in multiple sclerosis? A systematic review with narrative synthesis and meta-analysis

Fatigue is a common and highly debilitating symptom of multiple sclerosis (MS). This meta-analytic systematic review with detailed narrative synthesis examined randomised-controlled (RCTs) and controlled trials of behavioural and exercise interventions targeting fatigue in adults with MS to assess which treatments offer the most promise in reducing fatigue severity/impact. Medline, EMBASE and PsycInfo electronic databases, amongst others, were searched through to August 2018. Thirty-four trials (12 exercise, 16 behavioural and 6 combined; n = 2,434 participants) met inclusion criteria. Data from 31 studies (n = 1,991 participants) contributed to the meta-analysis. Risk of bias (using the Cochrane tool) and study quality (GRADE) were assessed. The pooled (SMD) end-of-treatment effects on self-reported fatigue were: exercise interventions (n = 13) -.84 (95% CI -1.20 to -.47); behavioural interventions (n = 16) -.37 (95% CI -.53 to -.22); combined interventions (n = 5) -.16 (95% CI: -.36 to .04). Heterogeneity was high overall. Study quality was very low for exercise interventions and moderate for behavioural and combined interventions. Considering health care professional time, subgroup results suggest web-based cognitive behavioural therapy for fatigue, balance and/or multicomponent exercise interventions may be the cost-efficient therapies. These need testing in large RCTs with long-term follow-up to help define an implementable fatigue management pathway in MS.MS Society, U

Inhibition of somatosensory mechanotransduction by annexin A6

Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron-derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6-deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cation channel Piezo2, which mediates a rapidly adapting mechano-gated current linked to proprioception and touch, and a decrease in mechanically activated, slowly adapting currents. Conversely, overexpression of annexin A6 in sensory neurons inhibited rapidly adapting currents that were partially mediated by Piezo2. Furthermore, overexpression of annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis, a disease in which mechanically evoked pain is particularly problematic. These data suggest that annexin A6 can be exploited to inhibit chronic mechanical pain

The role of stationary intraoral tomosynthesis in reducing proximal overlap in bitewing radiography

objectives: This study examined the utility of stationary intraoral tomosynthesis (s-IOT) in opening proximal contacts in bitewing radiography. Methods: 11 DENTSPLY Rinn Dental X-ray Teaching and Training Replica mannequins (Model #546002, Elgin, Ill) were imaged with a prototype s-IOT device (Surround Medical Systems, Morrisville, NC) and standard bitewing (SBW) technique. Premolar and molar bite-wings were acquired with each system. Image receptor holders were used to position receptors and aid in the alignment of the position indicating devices. An expert operator (having more than 5 years of experience in intraoral radiography) acquired the images with the s-IOT prototype and standard intraoral X-ray devices. Images were assessed to analyze percentage overlap of the proximal surfaces using the tools available in ImageJ (NIH, Bethesda Maryland). Results: 253-paired surfaces were included in the analysis. The difference in overlap was statistically significant with standard bitewing (SBW) images resulting in a median overlap of 13%, a minimum of 0%, a maximum of 100% and an interquartile range of 40%. s-IOT resulted in a median overlap of 1%, a minimum of 0%, a maximum of 37% and an interquartile range of 0%. The s-IOT prototype substantially reduced proximal surface overlap compared to conventional bitewing radiography. conclusions: The use of s-IOT reduced proximal contact overlap compared to standard bitewing radiography for an experienced radiographer. Stationary intraoral tomosynthesis may be a potential alternative to SBW radiography, reducing the number of retakes due to closed contacts

Centrality Dependence of the High p_T Charged Hadron Suppression in Au+Au collisions at sqrt(s_NN) = 130 GeV

PHENIX has measured the centrality dependence of charged hadron p_T spectra from central Au+Au collisions at sqrt(s_NN)=130 GeV. The truncated mean p_T decreases with centrality for p_T > 2 GeV/c, indicating an apparent reduction of the contribution from hard scattering to high p_T hadron production. For central collisions the yield at high p_T is shown to be suppressed compared to binary nucleon-nucleon collision scaling of p+p data. This suppression is monotonically increasing with centrality, but most of the change occurs below 30% centrality, i.e. for collisions with less than about 140 participating nucleons. The observed p_T and centrality dependence is consistent with the particle production predicted by models including hard scattering and subsequent energy loss of the scattered partons in the dense matter created in the collisions.Comment: 7 pages text, LaTeX, 6 figures, 2 tables, 307 authors, resubmitted to Phys. Lett. B. Revised to address referee concerns. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm

“Re-Culturing” Teacher Education: Inquiry, Evidence, and Action

Currently the press to make policy and practice decisions on the basis of evidence is being coupled with recognition that real change requires shifts in organizational culture. Consequently, there are now many efforts to “re-culture” organizations by making evidence central to decision making. In this article, the authors problematize the notion of a “culture of evidence” in teacher education. Then the article identifies four key aspects involved in efforts to create a culture of evidence at one institution over a five-year period: (1) development of a portfolio of studies about processes and outcomes; (2) recognition that teacher education always poses values questions as well as empirical questions; (3) an exploratory, open-ended approach to evidence construction; and, (4) multiple structures that institutionalize evidence collection and use locally and beyond. The authors suggests that building cultures of evidence has the potential to be transformative in teacher education, but only if challenges related to sustainability, complexity, and balance are addressed

Experimental and Theoretical Challenges in the Search for the Quark Gluon Plasma: The STAR Collaboration's Critical Assessment of the Evidence from RHIC Collisions

We review the most important experimental results from the first three years of nucleus-nucleus collision studies at RHIC, with emphasis on results from the STAR experiment, and we assess their interpretation and comparison to theory. The theory-experiment comparison suggests that central Au+Au collisions at RHIC produce dense, rapidly thermalizing matter characterized by: (1) initial energy densities above the critical values predicted by lattice QCD for establishment of a Quark-Gluon Plasma (QGP); (2) nearly ideal fluid flow, marked by constituent interactions of very short mean free path, established most probably at a stage preceding hadron formation; and (3) opacity to jets. Many of the observations are consistent with models incorporating QGP formation in the early collision stages, and have not found ready explanation in a hadronic framework. However, the measurements themselves do not yet establish unequivocal evidence for a transition to this new form of matter. The theoretical treatment of the collision evolution, despite impressive successes, invokes a suite of distinct models, degrees of freedom and assumptions of as yet unknown quantitative consequence. We pose a set of important open questions, and suggest additional measurements, at least some of which should be addressed in order to establish a compelling basis to conclude definitively that thermalized, deconfined quark-gluon matter has been produced at RHIC.Comment: 101 pages, 37 figures; revised version to Nucl. Phys.