Rationale for the evaluation of nintedanib as a treatment for systemic sclerosis–associated interstitial lung disease

Interstitial lung disease is a common manifestation of systemic sclerosis. Systemic sclerosis–associated interstitial lung disease is characterized by progressive pulmonary fibrosis and a reduction in pulmonary function. Effective treatments for systemic sclerosis–associated interstitial lung disease are lacking. In addition to clinical similarities, systemic sclerosis–associated interstitial lung disease shows similarities to idiopathic pulmonary fibrosis in the pathophysiology of the underlying fibrotic processes. Idiopathic pulmonary fibrosis and systemic sclerosis–associated interstitial lung disease culminate in a self-sustaining pathway of pulmonary fibrosis in which fibroblasts are activated, myofibroblasts accumulate, and the excessive extracellular matrix is deposited. Nintedanib is a tyrosine kinase inhibitor that has been approved for the treatment of idiopathic pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, nintedanib slows disease progression by decreasing the rate of lung function decline. In this review, we summarize the antifibrotic, anti-inflammatory, and attenuated vascular remodeling effects of nintedanib demonstrated in in vitro studies and in animal models of aspects of systemic sclerosis. Nintedanib interferes at multiple critical steps in the pathobiology of systemic sclerosis–associated interstitial lung disease, providing a convincing rationale for its investigation as a potential therapy. Finally, we summarize the design of the randomized placebo-controlled SENSCIS ® trial that is evaluating the efficacy and safety of nintedanib in patients with systemic sclerosis–associated interstitial lung disease

Egg-Phosphatidylcholine Attenuates T-Cell Dysfunction in High-Fat Diet Fed Male Wistar Rats

Obesity is associated with immune dysfunction including an impaired T-cell function characterized by a lower IL-2 (proliferation marker) production after stimulation. Phosphatidylcholine (PC), a form of choline mostly found in eggs, has been shown to beneficially modulate T-cell responses during the lactation period by increasing the production of IL-2. To determine the impact of egg-PC as part of a high-fat diet on immune function we randomly fed male Wistar rats one of three diets containing the same amount of total choline but differing in the form of choline: 1—Control low fat [CLF, 10% wt/wt fat, 100% free choline (FC)]; 2— Control high-fat (CHF, 25% wt/wt fat, 100% FC); 3— PC high-fat (PCHF, 25% wt/wt, 100% PC). After 9 weeks of feeding, rats were euthanized. Cell phenotypes and ex vivo cytokine production by splenocytes stimulated with phorbol 12-myristate 13-acetate plus ionomycin (PMA+I), lipopolysaccharide (LPS) and pokeweed (PWM) were measured by flow cytometry and ELISA, respectively. Rats fed the PCHF diet had a lower proportion of CD3+ cells when compared to both the CLF and the CHF. Following PMA+I stimulation, splenocytes from the CHF group produced less IL-2 and TNF-α compared to CLF and PCHF groups. No significant differences in cytokine production were found among groups after LPS and PWM stimulation. Our results show that feeding a high-fat diet impairs T-cell responses, as measured by ex vivo cytokine production, which can be attenuated by providing egg-PC

Mechanistic insight into the sensing of nitroaromatic compounds by metal-organic frameworks

There has been extensive research on the sensing of explosive nitroaromatic compounds (NACs) using fluorescent metal-organic frameworks (MOFs). However, ambiguity in the sensing mechanism has hampered the development of efficient explosive sensors. Here we report the synthesis of a hydroxyl-functionalized MOF for rapid and efficient sensing of NACs and examine in detail its fluorescence quenching mechanisms. In chloroform, quenching takes place primarily by exciton migration to the ground-state complex formed between the MOF and the analytes. A combination of hydrogen-bonding interactions and ??????? stacking interactions are responsible for fluorescence quenching, and this observation is supported by single-crystal structures. In water, the quenching mechanism shifts toward resonance energy transfer and photo-induced electron transfer, after exciton migration as in chloroform. This study provides insight into florescence-quenching mechanisms for the selective sensing of NACs and reduces the ambiguity regarding the nature of interactions between the MOF and NACs

A systematic review of the literature on the effectiveness of exercise therapy for groin pain in athletes

<p>Abstract</p> <p>Background</p> <p>Athletes competing in sports that require running, changes in direction, repetitive kicking and physical contact are at a relatively higher risk of experiencing episodes of athletic groin pain. To date, there has been no systematic review that aims to inform clinicians about the best available evidence on features of exercise interventions for groin pain in athletes. The primary aim of this systematic review was to evaluate the available evidence on the effectiveness of exercise therapy for groin pain in athletes. The secondary aim of this review was to identify the key features of exercise interventions used in the management of groin pain in an athletic population.</p> <p>Methods</p> <p>MEDLINE, CINAHL, PubMed, SPORTSDiscus, Embase, AMED, Ovid, PEDro, Cochrane Controlled Trials Register and Google Scholar databases were electronically searched. Data relating to research design, sample population, type of sport and exercise intervention was extracted. The methodological evaluation of included studies was conducted by using a modified quantitative critical appraisal tool.</p> <p>Results</p> <p>The search strategy identified 468 studies, 12 of which were potentially relevant. Ultimately five studies were included in this review. Overall the quality of primary research literature was moderate, with only one randomised controlled trial identified. All included studies provided evidence that an exercise intervention may lead to favourable outcomes in terms of return to sport. Four of the five studies reviewed included a strengthening component and most utilised functional, standing positions similar to those required by their sport. No study appropriately reported the intensity of their exercise interventions. Duration of intervention ranged from 3.8 weeks to 16 weeks. All five studies reported the use of one or more co-intervention.</p> <p>Conclusion</p> <p>Best available evidence to date, with its limitations, continues to support common clinical practice of exercise therapy as a key component of rehabilitation for groin pain in athletes. Overall, the available evidence suggests that exercise, particularly strengthening exercise of the hip and abdominal musculature could be an effective intervention for athletes with groin pain. Literature provides foundational evidence that this may need to be in the form of progressive exercises (static to functional) and performed through range. There is currently no clear evidence regarding the most effective intensity and frequency of exercise, because of a lack of reporting in the primary literature.</p

Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by lipoic acid: role in cancer prevention and therapy

<p>Abstract</p> <p>Background</p> <p>Lipoic acid (LA), a potent antioxidant, has been used as a dietary supplement to prevent and treat many diseases, including stroke, diabetes, neurodegenerative and hepatic disorders. Recently, potent anti-tumorigenic effects induced by LA were also reported and evident as assayed by suppression of cell proliferation and induction of apoptosis in malignant cells. However, the mechanism by which LA elicits its chemopreventive effects remains unclear.</p> <p>Methods and Results</p> <p>Herein, we investigated whether LA elicits its anti-tumor effects by inducing cell cycle arrest and cell death in human promyelocytic HL-60 cells. The results showed that LA inhibits both cell growth and viability in a time- and dose-dependent manner. Disruption of the G₁/S and G₂/M phases of cell cycle progression accompanied by the induction of apoptosis was also observed following LA treatment. Cell cycle arrest by LA was correlated with dose-dependent down regulation of Rb phosphorylation, likely via suppression of E2F-dependent cell cycle progression with an accompanying inhibition of cyclin E/cdk2 and cyclin B1/cdk1 levels. Evidence supporting the induction of apoptosis by LA was based on the appearance of sub-G₁peak in flow cytometry analysis and the cleavage of poly(ADP-ribose) polymerase (PARP) from its native 112-kDa form to the 89-kDa truncated product in immunoblot assays. Apoptosis elicited by LA was preceded by diminution in the expression of anti-apoptotic protein bcl-2 and increased expression of apoptogenic protein bax, and also the release and translocation of apoptosis inducing factor AIF and cytochrome c from the mitochondria to the nucleus, without altering the subcellular distribution of the caspases.</p> <p>Conclusion</p> <p>This study provides evidence that LA induces multiple cell cycle checkpoint arrest and caspase-independent cell death in HL-60 cells, in support of its efficacious potential as a chemopreventive agent.</p

Promoting the use of the PI-QUAL score for prostate MRI quality: results from the ESOR Nicholas Gourtsoyiannis teaching fellowship

OBJECTIVES: The Prostate Imaging Quality (PI-QUAL) score is a new metric to evaluate the diagnostic quality of multiparametric magnetic resonance imaging (MRI) of the prostate. This study assesses the impact of an intervention, namely a prostate MRI quality training lecture, on the participant's ability to apply PI-QUAL. METHODS: Sixteen participants (radiologists, urologists, physicists, and computer scientists) of varying experience in reviewing diagnostic prostate MRI all assessed the image quality of ten examinations from different vendors and machines. Then, they attended a dedicated lecture followed by a hands-on workshop on MRI quality assessment using the PI-QUAL score. Five scans assessed by the participants were evaluated in the workshop using the PI-QUAL score for teaching purposes. After the course, the same participants evaluated the image quality of a new set of ten scans applying the PI-QUAL score. Results were assessed using receiver operating characteristic analysis. The reference standard was the PI-QUAL score assessed by one of the developers of PI-QUAL. RESULTS: There was a significant improvement in average area under the curve for the evaluation of image quality from baseline (0.59 [95 % confidence intervals: 0.50-0.66]) to post-teaching (0.96 [0.92-0.98]), an improvement of 0.37 [0.21-0.41] (p < 0.001). CONCLUSIONS: A teaching course (dedicated lecture + hands-on workshop) on PI-QUAL significantly improved the application of this scoring system to assess the quality of prostate MRI examinations. KEY POINTS: • A significant improvement in the application of PI-QUAL for the assessment of prostate MR image quality was observed after an educational intervention. • Appropriate training on image quality can be delivered to those involved in the acquisition and interpretation of prostate MRI. • Further investigation will be needed to understand the impact on improving the acquisition of high-quality diagnostic prostate MR examinations

Health Locus of Control and Assimilation of Cervical Cancer Information in Deaf Women

This study assessed the relationship between Deaf women's internal health locus of control (IHLC) and their cervical cancer knowledge acquisition and retention. A blind, randomized trial evaluated Deaf women's (N = 130) baseline cancer knowledge and knowledge gained and retained from an educational intervention, in relation to their IHLC. The Multidimensional Health Locus of Control scales measured baseline IHLC, and a cervical cancer knowledge survey evaluated baseline to post-intervention knowledge change. Women's IHLC did not significantly predict greater cervical cancer knowledge at baseline or over time. IHLC does not appear to be a characteristic that must be considered when creating Deaf women's cancer education programs