Management of Lateral Epicondylitis Using Transdermal Nitroglycerin: A Systematic Review.

Lateral epicondylitis (LE), also known as tennis elbow, is an overuse tendinopathy originating from the forearm extensor tendons of the elbow. An emerging therapy for the treatment of LE is the use of transdermal nitroglycerin (NTG) patches for pain relief and improved function. The aim of this systematic review was to assess the current literature on the effect of a transdermal NTG patch for the treatment of LE. A literature search using MEDLINE, EMBASE, SportDiscus, and the Cochrane Database of Systematic Reviews was conducted. Studies selected for inclusion were those in which patients were clinically diagnosed with LE, RCTs, observational studies, and only articles published in English. Studies were excluded if they involved patients <18 years of age or involved patients with a potential alternative source of elbow pain such as previous surgery to the elbow, a previous history of dislocation, fracture of the elbow or tendon rupture, or a referred pain source such as cervical radiculopathy or peripheral nerve involvement. Studies were also excluded if they involved patients who were already prescribed topical NTG for any other indication (i.e., angina), and if the studies had no measurement of symptom relief or measurement or functional scoring. The initial search strategy yielded 69 articles, out of which four met the eligibility criteria and were included in this systematic review. The studies showed improvement in elbow pain in the short-term and mid-term (up to six months), while one study that followed participants for a five-year duration post-treatment, showed no benefit. Three studies used an effective NTG dose of 1.25mg/24h and one study used an effective dose of 1.44mg/24h. Topical NTG was more effective when combined with a tendon rehabilitation program. The most commonly reported side effects of topical NTG were headaches and dermatitis. Overall, the current literature demonstrates that the use of NTG patches for LE improves short- and mid-term pain as well as elbow function. However, more studies are required to fully understand the effect of topical NTG on LE, particularly the effective dose range and the long-term benefits.

mRNA levels are buffered upon knockdown of RNA decay and translation factors via adjustment of transcription rates in human HepG2 cells.

Evidence from yeast and mammals argues the existence of cross-talk between transcription and mRNA decay. Stabilization of transcripts upon depletion of mRNA decay factors generally leads to no changes in mRNA abundance, attributing this to decreased transcription rates. We show that knockdown of human XRN1, CNOT6 and ETF1 genes in HepG2 cells led to significant alteration in stability of specific mRNAs, alterations in half-life were inversely associated with transcription rates, mostly not resulting in changes in abundance. We demonstrate the existence of the gene expression buffering mechanism in human cells that responds to both transcript stabilization and destabilization to maintain mRNA abundance via altered transcription rates and may involve translation. We propose that this buffering may hold novel cancer therapeutic targets.

Assessing the credibility and transferability of the patient compassion model in non-cancer palliative populations.

BACKGROUND: A lack of evidence and psychometrically sound measures of compassion necessitated the development of the first known, empirically derived, theoretical Patient Compassion Model (PCM) generated from qualitative interviews with advanced cancer inpatients. We aimed to assess the credibility and transferability of the PCM across diverse palliative populations and settings. METHODS: Semi-structured, audio-recorded qualitative interviews were conducted with 20 patients with life-limiting diagnoses, recruited from 4 settings (acute care, homecare, residential care, and hospice). Participants were first asked to share their understandings and experiences of compassion. They were then presented with an overview of the PCM and asked to determine whether: 1) the model resonated with their understanding and experiences of compassion; 2) the model required any modification(s); 3) they had further insights on the model's domains and/or themes. Members of the research team analyzed the qualitative data using constant comparative analysis. RESULTS: Both patients' personal perspectives of compassion prior to viewing the model and their specific feedback after being provided an overview of the model confirmed the credibility and transferability of the PCM. While new codes were incorporated into the original coding schema, no new domains or themes emerged from this study sample. These additional codes provided a more comprehensive understanding of the nuances within the domains and themes of the PCM that will aid in the generation of items for an ongoing study to develop a patient reported measure of compassion. CONCLUSIONS: A diverse palliative patient population confirmed the credibility and transferability of the PCM within palliative care, extending the rigour and applicability of the PCM that was originally developed within an advanced cancer population. The views of a diverse palliative patient population on compassion helped to validate previous codes and supplement the existing coding schema, informing the development of a guiding framework for the generation of a patient-reported measure of compassion.

Healthcare providers' perspectives on perceived barriers and facilitators of compassion: Results from a grounded theory study.

AIMS AND OBJECTIVES: To explore healthcare provider perspectives and experiences of perceived barriers and facilitators of compassion. BACKGROUND: Compassion is considered a component of quality health care that healthcare providers are increasingly expected to provide. While there have been some studies exploring facets of healthcare providers' perspectives on the barriers and facilitators to providing compassion, a comprehensive understanding based on direct reports from healthcare providers is lacking. DESIGN: Data were collected via focus groups and semi-structured interviews. Data was analyzed in accordance with Straussian grounded theory. METHODS: Semistructured focus groups with frontline healthcare providers and individual interviews with peer-nominated exemplary compassionate care providers were audio-recorded, professionally transcribed and analysed. Fifty-seven participants were recruited from three healthcare settings within both rural and urban settings in Alberta, Canada, using convenience, snowball and theoretical sampling. RESULTS: Qualitative analysis of the data generated two categories and associated themes and subthemes delineating perceived barriers and facilitators to compassion. The first category, challenges to compassion, reflects participants' discomfort associating the notion of barriers to compassion and contained several themes participants conceptualised as challenges: personal challenges, relational challenges, systemic challenges and maladaptive responses. The second category, facilitators of compassion, included the themes of personal facilitators, relational facilitators, systemic facilitators and adaptive responses of intentional action. CONCLUSION: Although participants described certain factors such as system and time constraints along with interaction styles of patients and families that can challenge healthcare provider compassion, these challenges were not considered insurmountable. While acknowledging these as challenges, participants identified healthcare providers themselves, including their responses towards the identified challenges of compassion, as significant factors in this process-a novel finding from this study. This study provides insight into healthcare providers' perspectives on the notion of barriers and facilitators in the provision of compassion. RELEVANCE TO CLINICAL PRACTICE: This study provides a blueprint for optimising compassion on a personal, relational and system level.

Dual regulation of myocardin expression by tumor necrosis factor-α in vascular smooth muscle cells.

De-differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis, a chronic inflammatory disease involving various cytokines such as tumor necrosis factor-α (TNFα). Myocardin is a co-factor of serum response factor (SRF) and is considered to be the master regulator of VSMC differentiation. It binds to SRF and regulates the expression of contractile proteins in VSMCs. Myocardin is also known to inhibit VSMC proliferation by inhibiting the NF-κB pathway, whereas TNFα is known to activate the NF-κB pathway in VSMCs. NF-κB activation has also been shown to inhibit myocardin expression and smooth muscle contractile marker genes. However, it is not definitively known whether TNFα regulates the expression and activity of myocardin in VSMCs. The current study aimed to investigate the role of TNFα in regulating myocardin and VSMC function. Our studies showed that TNFα down-regulated myocardin expression and activity in cultured VSMCs by activating the NF-κB pathway, resulting in decreased VSMC contractility and increased VSMC proliferation. Surprisingly, we also found that TNFα prevented myocardin mRNA degradation, and resulted in a further significant increase in myocardin expression and activity in differentiated VSMCs. Both the NF-κB and p44/42 MAPK pathways were involved in TNFα regulation of myocardin, which further increased the contractility of VSMCs. These differential effects of TNFα on myocardin seemingly depended on whether VSMCs were in a differentiated or de-differentiated state. Taken together, our results demonstrate that TNFα differentially regulates myocardin expression and activity, which may play a key role in regulating VSMC functions.

Estrogen metabolite 2-methoxyestradiol prevents hypertension in deoxycorticosterone acetate-salt rats.

PURPOSE: Our early work showed that the estrogen metabolite 2-methoxyestradiol (2ME) inhibits proliferation of vascular smooth muscle cells (SMCs) and vascular contractility through an endothelium-dependent mechanism. The aim of this study was to examine whether 2ME prevents the development of hypertension in rats. METHODS: A hypertensive model was established in uninephrectomized rats using deoxycorticosterone acetate (DOCA)-salt. Blood pressure in response to 2ME (treatment up to 10 weeks or single bolus) was monitored. RESULTS: Our results showed that systolic blood pressure, as measured by tail-cuff plethysmography, was significantly increased in conscious rats treated with DOCA-salt for 3-10 weeks. Co-treatment with 2ME (100-300 µg/kg), but not dimethyl sulfoxide (DMSO), completely prevented the increase in blood pressure of DOCA-salt rats. After 10-week treatment, the mean arterial blood pressure (MABP) of anesthetized rats measured using PowerLab Data Acquisition System was: 84 ± 16 mmHg in normotensive control rats and 150 ± 9 mmHg in DOCA-salt rats, which was similar to that of DMSO-treated rats. Treatment with 2ME at low or high doses reduced MABP of DOCA-salt rats close to that of control normotensive rats. In addition, MABP of hypertensive DOCA-salt rats was significantly reduced in response to a single injection of 2ME. Delayed administration of 2ME reduced the further increase of blood pressure in DOCA-salt rats. However, inhibition of 2ME production by entacapone did not significantly affect blood pressure in either control or DOCA-salt rats. CONCLUSIONS: 2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of 2ME in hypertension treatment.

Sonic hedgehog promotes autophagy of vascular smooth muscle cells.

Sonic hedgehog (Shh) is a morphogen critically involved in development that is reexpressed in atherosclerotic lesions. It also stimulates proliferation of vascular smooth muscle cells (SMCs). Autophagy in vascular SMCs is known to promote SMC survival and increase plaque stability. The aim of this study was to investigate whether Shh induces autophagy of vascular SMCs. Our study showed that both Shh protein and microtubule-associated protein 1 light chain 3 (LC3)-II were increased in SMCs within neointimal lesions of mouse common carotid arteries. In cultured mouse aortic SMCs, recombinant mouse Shh stimulated LC3-II levels. Overexpression of wild-type mouse Shh through the tetracycline-regulated expression-inducible system in human aortic SMCs time-dependently increased the levels of LC3-II and also stimulated protein kinase B (AKT) phosphorylation. Pretreatment with AKT inhibitor IV (AKTI IV) inhibited AKT phosphorylation and the increase in LC3-II. Shh-induced autophagy was further confirmed by the formation of autophagosomes as detected by immunostaining and transmission electron microscopy, which was inhibited by AKTI IV. Shh further increased SMC LC3-II in the presence of bafilomycin A1, (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester, and pepstatin A or siRNA for the autophagy-related gene 7 (ATG7). In addition, Shh induced SMC proliferation, which was inhibited not only by AKTI IV but also by cyclopamine, an inhibitor of Shh receptor. Inhibition of autophagy with 3-methyladenine (3-MA), bafilomycin A1, or ATG7 siRNA resulted in inhibition of cell proliferation. Treatment with 3-MA, AKTI IV, or cyclopamine inhibited neointima formation in mouse common carotid arteries. Taken together, our results have shown that Shh induces autophagy of vascular SMCs involving AKT activation, suggesting a role of autophagy in Shh-induced cellular responses.