Phenotypic Switching of Nonpeptidergic Cutaneous Sensory Neurons following Peripheral Nerve Injury

In adult mammals, the phenotype of half of all pain-sensing (nociceptive) sensory neurons is tonically modulated by growth factors in the glial cell line-derived neurotrophic factor (GDNF) family that includes GDNF, artemin (ARTN) and neurturin (NRTN). Each family member binds a distinct GFRα family co-receptor, such that GDNF, NRTN and ARTN bind GFRα1, -α2, and -α3, respectively. Previous studies revealed transcriptional regulation of all three receptors in following axotomy, possibly in response to changes in growth factor availability. Here, we examined changes in the expression of GFRα1-3 in response to injury in vivo and in vitro. We found that after dissociation of adult sensory ganglia, up to 27% of neurons die within 4 days (d) in culture and this can be prevented by nerve growth factor (NGF), GDNF and ARTN, but not NRTN. Moreover, up-regulation of ATF3 (a marker of neuronal injury) in vitro could be prevented by NGF and ARTN, but not by GDNF or NRTN. The lack of NRTN efficacy was correlated with rapid and near-complete loss of GFRα2 immunoreactivity. By retrogradely-labeling cutaneous afferents in vivo prior to nerve cut, we demonstrated that GFRα2-positive neurons switch phenotype following injury and begin to express GFRα3 as well as the capsaicin receptor, transient receptor potential vanilloid 1(TRPV1), an important transducer of noxious stimuli. This switch was correlated with down-regulation of Runt-related transcription factor 1 (Runx1), a transcription factor that controls expression of GFRα2 and TRPV1 during development. These studies show that NRTN-responsive neurons are unique with respect to their plasticity and response to injury, and suggest that Runx1 plays an ongoing modulatory role in the adult

A study to explore specific stressors and coping strategies in primary dental care practice

Background and Aims: It is widely acknowledged that dentists experience occupational stress. This qualitative study aimed to explore previously identified specific stressors in more detail in order to inform the development of a future stress management programme. Method: Two focus groups of dentists (N: 7 & 6) were conducted to explore, in more detail, nine specific stressors and concepts; being out of one’s comfort zone, zoning out from the patient, celebrating the positive aspects of work, thinking aloud, the effect of hurting patients, the impact of perfectionism, responsibility for patient’s self-care, the emotional impact of difficult situations as a foundation dentist. Participants were also asked for their views on the structure and contents of the proposed stress management package. Verbatim transcripts were subjected to thematic analysis. Results and Discussion: Dentists described the impact of these stressors and their current coping methods; thematic analysis revealed 9 themes which covered the above concepts and a further overall theme of need for control. The findings are elaborated in connection to their relevant stress, coping and emotion psychological theory. Their implications for personal well-being and clinical outcomes are discussed. Conclusion: Dentists’ stressful and coping experiences are complex and it is essential that any stress management programme reflects this and that the skills are easily accessible and sustainable within the context of a busy dental practice

Enhancing Mental and Physical Health of Women through Engagement and Retention (EMPOWER): a protocol for a program of research

Abstract Background The Enhancing Mental and Physical health of Women through Engagement and Retention or EMPOWER program represents a partnership with the US Department of Veterans Health Administration (VA) Health Service Research and Development investigators and the VA Office of Women’s Health, National Center for Disease Prevention and Health Promotion, Primary Care-Mental Health Integration Program Office, Women’s Mental Health Services, and the Office of Patient Centered Care and Cultural Transformation. EMPOWER includes three projects designed to improve women Veterans’ engagement and retention in evidence-based care for high-priority health conditions, i.e., prediabetes, cardiovascular, and mental health. Methods/Design The three proposed projects will be conducted in VA primary care clinics that serve women Veterans including general primary care and women’s health clinics. The first project is a 1-year quality improvement project targeting diabetes prevention. Two multi-site research implementation studies will focus on cardiovascular risk prevention and collaborative care to address women Veterans’ mental health treatment needs respectively. All projects will use the evidence-based Replicating Effective Programs (REP) implementation strategy, enhanced with multi-stakeholder engagement and complexity theory. Mixed methods implementation evaluations will focus on investigating primary implementation outcomes of adoption, acceptability, feasibility, and reach. Program-wide organizational-, provider-, and patient-level measures and tools will be utilized to enhance synergy, productivity, and impact. Both implementation research studies will use a non-randomized stepped wedge design. Discussion EMPOWER represents a coherent program of women’s health implementation research and quality improvement that utilizes cross-project implementation strategies and evaluation methodology. The EMPOWER Quality Enhancement Research Initiative (QUERI) will constitute a major milestone for realizing women Veterans’ engagement and empowerment in the VA system. EMPOWER QUERI will be conducted in close partnership with key VA operations partners, such as the VA Office of Women’s Health, to disseminate and spread the programs nationally. Trial registration The two implementation research studies described in this protocol have been registered as required: Facilitating Cardiovascular Risk Screening and Risk Reduction in Women Veterans: Trial registration NCT02991534 , registered 9 December 2016. Implementation of Tailored Collaborative Care for Women Veterans: Trial registration NCT02950961 , registered 21 October 2016

Brain-Derived Neurotrophic Factor Ameliorates Brain Stem Cardiovascular Dysregulation during Experimental Temporal Lobe Status Epilepticus

Background: Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20–30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action. Methodology/Principal Findings: In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47 phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47 phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdn

Design of price incentives for adjunct policy goals in formula funding for hospitals and health services

Background. Hospital policy involves multiple objectives: efficiency of service delivery, pursuit of high quality care, promoting access. Funding policy based on hospital casemix has traditionally been considered to be only about promoting efficiency. Discussion. Formula-based funding policy can be (and has been) used to pursue a range of policy objectives, not only efficiency. These are termed 'adjunct' goals. Strategies to incorporate adjunct goals into funding design must, implicitly or explicitly, address key decision choices outlined in this paper. Summary. Policy must be clear and explicit about the behaviour to be rewarded; incentives must be designed so that all facilities with an opportunity to improve have an opportunity to benefit; the reward structure is stable and meaningful; and the funder monitors performance and gaming

Th1 Disabled Function in Response to TLR4 Stimulation of Monocyte-Derived DC from Patients Chronically-Infected by Hepatitis C Virus

Background: Lack of protective antibodies and inefficient cytotoxic responses are characteristics of chronic hepatitis C infection. A defect in dendritic cell (DC) function has thus been suspected, but this remains a controversial issue. Methods and Findings: Here we show that monocyte-derived DC (MoDC) from chronically-infected patients can mature in response to TLR1/2, TLR2/6 or TLR3 ligands. In contrast, when stimulated with the TLR4 ligand LPS, MoDC from patients show a profound defect in inducing IFNc secretion by allogeneic T cells. This defect is not due to defective phenotypic maturation or to the presence of HCV-RNA in DC or monocytes but is correlated to reduced IL-12 secretion by DC. Restoration of DC ability to stimulate IFNc secretion can be obtained by blocking MEK activation in DC, indicating that MEK/ ERK pathway is involved in the Th1 defect of MoDC. Monocytes from HCV patients present increased spontaneous secretion of cytokines and chemokines, especially MIP-1b. Addition of MIP-1b on healthy monocytes during differentiation results in DC that have Th1 defect characteristic of MoDC from HCV patients, suggesting that MIP-1b secretion by HCV monocytes participates in the Th1 defect of DC. Conclusions: Our data indicate that monocytes from HCV patients are activated in vivo. This interferes with their differentiation into DC, leading to deficient TLR4 signaling in these cells that are enable to induce a Th1 response. Thi

A road map for designing and implementing a biological monitoring program

Designing and implementing natural resource monitoring is a challenging endeavor undertaken by many agencies, NGOs, and citizen groups worldwide. Yet many monitoring programs fail to deliver useful information for a variety of administrative (staffing, documentation, and funding) or technical (sampling design and data analysis) reasons. Programs risk failure if they lack a clear motivating problem or question, explicit objectives linked to this problem or question, and a comprehensive conceptual model of the system under study. Designers must consider what “success” looks like from a resource management perspective, how desired outcomes translate to appropriate attributes to monitor, and how they will be measured. All such efforts should be filtered through the question “Why is this important?” Failing to address these considerations will produce a program that fails to deliver the desired information. We addressed these issues through creation of a “road map” for designing and implementing a monitoring program, synthesizing multiple aspects of a monitoring program into a single, overarching framework. The road map emphasizes linkages among core decisions to ensure alignment of all components, from problem framing through technical details of data collection and analysis, to program administration. Following this framework will help avoid common pitfalls, keep projects on track and budgets realistic, and aid in program evaluations. The road map has proved useful for monitoring by individuals and teams, those planning new monitoring, and those reviewing existing monitoring and for staff with a wide range of technical and scientific skills

An Extended Model of Moral Outrage at Corporate Social Irresponsibility

The final publication is available at Springer via http://dx.doi.org/ 10.1007/s10551-014-2487-