MicroRNA-132/212 family enhances arteriogenesis after hindlimb ischaemia through modulation of the Ras-MAPK pathway

Arteriogenesis is a complicated process induced by increased local shear-and radial wall-stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR-132/212 expression was significantly upregulated after occlusion of the femoral artery. miR-132/212 knockout (KO) mice display a slower perfusion recovery after hind-limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR-132/212 KO mice compared to WT, it can be stimulated with exogenous miR-132, a dominant member of the miR-132/212 family. Moreover, in in vitro pericyte-endothelial co-culture cell assays, overexpression of miR-132 and mir-212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR-132/212 may exert their effects by enhancing the Ras-Mitogen-activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR-132/212 cluster promotes arteriogenesis by modulating Ras-MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Undergraduate medical students need more training in craniomaxillofacial surgery: a comparative study between medical and dental students

To compare the performance in oral, craniomaxillofacial, and facial plastic surgery (CMF)-specific surgical skills between medical students (MS) and dental students (DS) and hence adjust the current CMF training to student-specific needs. The investigators hypothesized that there would be no performance differences between MS and DS

A nationwide survey of undergraduate training in oral and maxillofacial surgery

To investigate the current status of undergraduate training in oral and maxillofacial (OMF) surgery in Germany using a nationwide survey and hence contribute to an educational improvement in the field.; A 39-item questionnaire was sent to all university clinics with an OMF surgery chair in Germany (n = 34).; Ninety-two percent of OMF clinics are involved in the curricular training in medicine and 100% in dentistry. Eighty-one percent of OMF clinics perform curricular examinations and, respectively, 86% in dentistry. Examinations are mainly performed written with multiple-choice tests (62% medicine, 76% dentistry) and using non-structured oral examinations (57% medicine, 86% dentistry). Objective structured clinical examinations (OSCEs) are only used in 19% of all faculties.; OMF surgery with its involvement both in medical and dental education has a special position as a surgical discipline. Our results show that OMF as a specialty is underrepresented in dental and especially in medical education considering the numerical and health economic importance of OMF consultations. Enhancing curricular integration and developing more structured examination forms is necessary to guarantee a high quality of OMF education

Conveying practical clinical skills with the help of teaching associates—a randomised trial with focus on the long term learning retention

Abstract Background Ensuring that all medical students achieve adequate clinical skills remains a challenge, yet the correct performance of clinical skills is critical for all fields of medicine. This study analyzes the influence of receiving feedback by teaching associates in the context of achieving and maintaining a level of expertise in complex head and skull examination. Methods All third year students at a German university who completed the obligatory surgical skills lab training and surgical clerkship participated in this study. The students were randomized into two groups. Control group: lessons by an instructor and peer-based practical skills training. Intervention group: training by teaching associates who are examined as simulation patients and provided direct feedback on student performance. Their competency in short- and long-term competence (directly after intervention and at 4 months after the training) of head and skull examination was measured. Statistical analyses were performed using SPSS Statistics version 19 (IBM, Armonk, USA). Parametric and non-parametric test methods were applied. As a measurement of correlation, Pearson correlations and correlations via Kendall’s-Tau-b were calculated and Cohen’s d effect size was calculated. Results A total of 181 students were included (90 intervention, 91 control). Out of those 181 students 81 agreed to be videotaped (32 in the control group and 49 in the TA group) and examined at time point 1. At both time points, the intervention group performed the examination significantly better (time point 1, p = <.001; time point 2 (rater 1 p = .009, rater 2 p = .015), than the control group. The effect size (Cohens d) was up to 1.422. Conclusions The use of teaching associates for teaching complex practical skills is effective for short- and long-term retention. We anticipate the method could be easily translated to nearly every patient-based clinical skill, particularly with regards to a competence-based education of future doctors

Anti-tumor necrosis factor-alpha therapies attenuate adaptive arteriogenesis in the rabbit

The specific antagonists of tumor necrosis factor-alpha (TNF-alpha), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although the importance of TNF-alpha in chronic inflammatory diseases is well established, little is known about its implications in the cardiovascular system. Because proliferation of arteriolar connections toward functional collateral arteries (arteriogenesis) is an inflammatory-like process, we tested in vivo the hypothesis that infliximab and etanercept have antiarteriogenic actions. Sixty-three New Zealand White rabbits underwent femoral artery occlusion and received infliximab, etanercept, or vehicle according to clinical dosage regimes. After 1 wk, collateral conductance, assessed with fluorescent microspheres, revealed significant inhibition of arteriogenesis (collateral conductance): 52.4 (SD 8.1), 35.2 (SD 7.7), and 33.3 (SD 10.1) ml.min(-1).100 mmHg(-1) with PBS, infliximab, and etanercept, respectively (P <0.001). High-resolution angiography showed no significant differences in number of collateral arteries, but immunohistochemical analysis demonstrated a decrease in mean collateral diameter, proliferation of vascular smooth muscle cells, and reduction of leukocyte accumulation around collateral arteries in treated groups. Infliximab and etanercept bound to infiltrating leukocytes, which are important mediators of arteriogenesis. Infliximab induced monocyte apoptosis, and neither substance affected monocyte expression of the adhesion molecule Mac-1. We demonstrated that TNF-alpha serves as a pivotal modulator of arteriogenesis, which is attenuated by treatment with TNF-alpha inhibitors. Reduction of collateral conductance is most likely due to inhibition of perivascular leukocyte infiltration and subsequent lower vascular smooth muscle cell proliferation. This is the first report showing a negative influence of TNF-alpha inhibitors on collateral artery growt

Leukocyte subpopulations and arteriogenesis: Specific role of monocytes, lymphocytes and granulocytes

Objective: Circulating leukocytes play a crucial role during arteriogenesis. However, known pro-arteriogenic compounds (MCP-1, GM-CSF) acting via monocytic pathways also exert positive effects on granulocytes and lymphocytes. The role of these two cell types in arteriogenesis remains yet to be clarified, which was the aim of the current study. Methods: Ninety New Zealand White Rabbits received either phosphate buffered saline (PBS), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8). neutrophil activating protein-2 (NAP-2) or lymphotactin (Ltn) via osmotic minipumps after unilateral femoral artery ligation. In vitro stimulation and in vivo assessment of chemoattraction confirmed cell-specific action of the compounds in rabbits. Arteriogenesis was evaluated by angiography and collateral conductance measurements using fluorescent microspheres. Quantitative immunohistology was used to quantify transmigrated leukocyte subtypes after infusion of the factors. Results: MCP-1 infusion attracts monocytes and granulocytes, whereas IL-8 attracts all three cell types albeit monocytes to a significantly lower degree than MCP-1. NAP-2 and lymphotactin selectively attract granulocytes, respectively, lymphocytes. Of the tested cytokines, only MCP-1 stimulates arteriogenesis, as assessed by collateral conductance measurements ((ml/(min 100 mm/Hg)): PBS, 50.70 +/- 5.15; MCP-1, 216.30 +/- 12.30: IL-8. 58.91 +/- 5.56; NAP-2, 66.83 +/- 8.72; Ltn, 52.80 +/- 5.37) and angiographic findings. Conclusion: This study for the first time provides evidence that not granulocytes or T-lymphocytes but monocytes are the key mediators of arteriogenesis. (c) 2005 Elsevier Ireland Ltd. All rights reserve