Sequential Sectioning of the Ulnar Collateral Ligament of the Elbow in Cadaveric Arms with Ulnohumeral Laxity Assessed by Dynamic Ultrasonography

Objectives: Injury of the ulnar collateral ligament (UCL), whether acute or chronic, is potentially career-threatening for elite overhead throwing athletes. Dynamic ultrasound (DUS) allows for rapid, cost-effective, non-invasive, and non-radiating evaluation of the UCL and elbow joint both at rest and with applied stress. The purpose of this study was to determine the amount of cadaveric elbow valgus laxity with sequential UCL sectioning using DUS. Our objective was to quantify which portions of the UCL must be injured to cause the varying levels of laxity seen clinically on DUS testing. No prior study has used DUS to quantify valgus joint laxity with sequential cadaveric UCL sectioning. It was hypothesized that the change in laxity due to release of the anterior band of the UCL would be greater than that seen when the posterior and transverse bands were cut. Methods: Twelve cadaveric elbows were dissected free of skin and subcutaneous tissue by an experienced orthopaedic surgeon. Baseline DUS at rest and with applied valgus stress was then performed by an experienced ultrasonographer. Sequential sectioning of the medial elbow soft-tissue stabilizing structures was then carried out with valgus stress applied to the joint at each sectioning interval utilizing a standardized device (Telos, Marburg, Germany). First the transverse band of the UCL was released, followed by the posterior band, then the anterior bundle of the anterior band, the remaining posterior bundle of the anterior band, and finally the complete flexor pronator mass. Results: Mean ulnohumeral laxity in millimeters with 95% CIs was calculated for each step of the sequence. The deltas between each step of the dissection were also calculated with means and 95% CIs. Mean baseline laxity of the unstressed ulnohumeral joint at rest was 3.2 mm (CI, 2.2-4.2); with the addition of valgus stress, mean laxity was 4.7 mm (CI, 3.5-6.0). When the transverse band was cut, ulnohumeral laxity increased to a mean of 5.5 mm (CI, 4.0-7.0). With release of the posterior band, mean laxity was 6.4 mm (CI, 4.3-8.5). When the anterior bundle of the anterior band of the UCL was cut, mean ulnohumeral laxity was 8.4 mm (CI, 5.7-11.0) and when the entire anterior band was released, mean laxity was 10.9 mm (CI, 7.8-14.0). Complete release of the flexor pronator muscle mass resulted in mean ulnohumeral laxity of 15.5 mm (CI, 12.9-18.1). The largest deltas were observed with release of the anterior bundle of the anterior band (2.0 mm; CI, 1.0-3.0), the entire anterior band (2.6 mm; CI, 1.3-3.8), and flexor pronator mass (4.6 mm; CI, 1.3-3.8). Release of the transverse and posterior bands of the UCL resulted in deltas of 0.74 mm (CI, 0.1-1.3) and 0.9 mm (CI, 0.3-1.5) respectively. Conclusion: DUS allows for rapid, cost-effective, non-invasive, non-radiating evaluation of the elbow joint and UCL both at rest and with applied valgus stress. Previous studies have indicated that DUS can identify abnormalities of the UCL associated with chronic degeneration and ligamentous injury including thickening of the anterior band of the UCL as well as hypoechoic foci/calcifications. The results of the current cadaveric study suggest that different changes in clinical laxity are seen on DUS with injury of particular bands of the UCL. Early identification and localization of injury to a particular band of the UCL may allow more appropriate selection of patients who will benefit from operative treatment. © The Author(s) 2013

Design and manufacture of a novel system to simulate the biomechanics of basic and pitching shoulder motion

Objectives: Cadaveric models of the shoulder evaluate discrete motion segments using the glenohumeral joint in isolation over a defined trajectory. The aim of this study was to design, manufacture and validate a robotic system to accurately create three-dimensional movement of the upper body and capture it using high-speed motion cameras. Methods: In particular, we intended to use the robotic system to simulate the normal throwing motion in an intact cadaver. The robotic system consists of a lower frame (to move the torso) and an upper frame (to move an arm) using seven actuators. The actuators accurately reproduced planned trajectories. The marker setup used for motion capture was able to determine the six degrees of freedom of all involved joints during the planned motion of the end effector. Results: The testing system demonstrated high precision and accuracy based on the expected versus observed displacements of individual axes. The maximum coefficient of variation for displacement of unloaded axes was less than 0.5% for all axes. The expected and observed actual displacements had a high level of correlation with coefficients of determination of 1.0 for all axes. Conclusions: Given that this system can accurately simulate and track simple and complex motion, there is a new opportunity to study kinematics of the shoulder under normal and pathological conditions in a cadaveric shoulder model

Social perception drives eye-movement related brain activity: evidence from pro- and anti-saccades to faces

Social stimuli such as faces attract and retain attention to a greater extent than other objects. Using fMRI, we investigated how the activity of oculomotor and visual brain regions is modulated when participants look towards or away from visual stimuli belonging to different categories (faces and cars). We identified a region within the superior frontal sulcus showing greater difference between anti- and pro-saccades to faces than to cars, and thereby supporting inhibitory control in a social context. In contrast, ventral occipito-temporal regions and the amygdala, which are associated with face perception, showed higher activity for pro-saccades than anti-saccades for faces, but the reverse for cars, suggesting that contextual, top-down mechanisms modulate the functional specialisation of areas involved in perception. In addition, during saccades in the presence of faces, we found increased functional connectivity between the frontal eye-fields and other cortical and subcortical oculomotor structures, namely the inferior frontal eye field, the posterior parietal cortex and the basal ganglia, possibly reflecting the higher demand put on the oculomotor system to inhibit responses to socially salient stimuli. For the first time, these data highlight neural bases for the different orienting responses towards or away from faces as compared to other objects

Excess of health care use in general practice and of comorbid chronic conditions in cancer patients compared to controls

<p>Abstract</p> <p>Background</p> <p>The number of cancer patients and the number of patients surviving initial treatments is expected to rise. Traditionally, follow-up monitoring takes place in secondary care. The contribution of general practice is less visible and not clearly defined.</p> <p>This study aimed to compare healthcare use in general practice of patients with cancer during the follow-up phase compared with patients without cancer. We also examined the influence of comorbid conditions on healthcare utilisation by these patients in general practice.</p> <p>Methods</p> <p>We compared health care use of N=8,703 cancer patients with an age and gender-matched control group of patients without cancer from the same practice. Data originate from the Netherlands Information Network of General Practice (LINH), a representative network consisting of 92 general practices with 350,000 enlisted patients. Health care utilisation was assessed using data on contacts with general practice, prescription and referral rates recorded between 1/1/2001 and 31/12/2007. The existence of additional comorbid chronic conditions (ICPC coded) was taken into account.</p> <p>Results</p> <p>Compared to matched controls, cancer patients had more contacts with their GP-practice (19.5 vs. 11.9, p<.01), more consultations with the GP (3.5 vs. 2.7, p<.01), more home visits (1.6 vs. 0.4, p<.01) and they got more medicines prescribed (18.7 vs. 11.6, p<.01) during the follow-up phase. Cancer patients more often had a chronic condition than their matched controls (52% vs. 44%, p<.01). Having a chronic condition increased health care use for both patients with and without cancer. Cancer patients with a comorbid condition had the highest health care use.</p> <p>Conclusion</p> <p>We found that cancer patients in the follow-up phase consulted general practice more often and suffered more often from comorbid chronic conditions, compared to patients without cancer. It is expected that the number of cancer patients will rise in the years to come and that primary health care professionals will be more involved in follow-up care. Care for comorbid chronic conditions, communication between specialists and GPs, and coordination of tasks then need special attention.</p

Risk Factors for Nonplatelet Thromboxane Generation After Coronary Artery Bypass Graft Surgery

BACKGROUND: Persistent thromboxane (TX) generation while receiving aspirin therapy is associated with an increased risk of cardiovascular events. The Reduction in Graft Occlusion Rates (RIGOR) study found that aspirin-insensitive TXA2 generation, indicated by elevated urine 11-dehydro-TXB2 (UTXB2) 6 months after coronary artery bypass graft surgery, was a potent risk factor for vein graft thrombosis and originated predominantly from nonplatelet sources. Our goal was to identify risks factors for nonplatelet TXA2 generation. METHODS AND RESULTS: Multivariable modeling was performed by using clinical and laboratory variables obtained from 260 RIGOR subjects with verified aspirin-mediated inhibition of platelet TXA2 generation. The strongest variable associated with UTXB2 6 months after surgery, accounting for 47.2% of the modeled effect, was urine 8-iso-prostaglandin (PG)F2alpha, an arachidonic acid metabolite generated nonenzymatically by oxidative stress (standardized coefficient 0.442, P \u3c 0.001). Age, sex, race, lipid therapy, creatinine, left ventricular ejection fraction, and aspirin dose were also significantly associated with UTXB2 (P \u3c 0.03), although they accounted for only 4.8% to 10.2% of the modeled effect. Urine 8-iso-PGF2alpha correlated with risk of vein graft occlusion (odds ratio 1.67, P=0.001) but was not independent of UTXB2. In vitro studies revealed that endothelial cells generate TXA2 in response to oxidative stress and direct exposure to 8-iso-PGF2alpha. CONCLUSIONS: Oxidative stress-induced formation of 8-iso-PGF2alpha is strongly associated with nonplatelet thromboxane formation and early vein graft thrombosis after coronary artery bypass graft surgery. The endothelium is potentially an important source of oxidative stress-induced thromboxane generation. These findings suggest therapies that reduce oxidative stress could be useful in reducing cardiovascular risks associated with aspirin-insensitive thromboxane generation

The effects of grape seed extract on glycemic control, serum lipoproteins, inflammation, and body weight: A systematic review and meta-analysis of randomized controlled trials

The aim of this systematic review and meta-analysis was to analyze the effects of grape seed extract (GSE) on glycemic control and serum lipoproteins, inflammation and body weight. Two independent authors systematically searched online databases including EMBASE, Scopus, PubMed, Cochrane Library, and Web of Science from inception until May 30, 2019. Cochrane Collaboration risk of bias tool was applied to assess the methodological quality of included trials. The heterogeneity among the included studies was assessed using Cochrane's Q test and I-square (I2) statistic. Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size. Fifty trials were included in this meta-analysis. Pooling effect sizes from studies demonstrated a significant decrease in fasting plasma glucose (FPG) (WMD): �2.01; 95 confidence interval (CI): �3.14, �0.86), total cholesterol (TC; WMD: �6.03; 95 CI: �9.71, �2.35), low-density lipoprotein (LDL) cholesterol (WMD: �4.97; 95 CI: �8.37, �1.57), triglycerides (WMD: �6.55; 95 CI: �9.28, �3.83), and C-reactive protein (CRP) concentrations (WMD: �0.81; 95 CI: �1.25, �0.38) following GSE therapy. Grape seed did not influence HbA1c, HDL cholesterol levels, and anthropometric measurements. This meta-analysis demonstrated that GSE intake significantly reduced FPG, TC, LDL cholesterol, triglycerides, and CRP levels. © 2019 John Wiley & Sons, Ltd

Tumour Cell Heterogeneity.

The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment

Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells

BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naive cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGF beta/SMAD (transforming growth factor-beta/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naive cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.Fapesp-grant number 2012/04194-1, 2013/05172-4, 2014/24400-0 and 2015/10821-7, CNPq-grant number 150447/2013-2 and 471512/2013-3 and PRODOC-grant no 3193-32/2010. Work in the lab of KS Smalley was supported by the National Institutes of Health grants R01 CA161107, R21 CA198550, and Skin SPORE grant P50 CA168536info:eu-repo/semantics/publishedVersio

Bilateral alternating auditory stimulations facilitate fear extinction and retrieval

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.info:eu-repo/semantics/publishedVersio

Consensus-based care recommendations for adults with myotonic dystrophy type 1

Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. Summary The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments. Described as “one of the more variable diseases found in medicine,” myotonic dystrophy type 1 (DM1) is an autosomal dominant, triplet-repeat expansion disorder that affects somewhere between 1:3,000 and 1:8,000 individuals worldwide.1 There is a modest association between increased repeat expansion and disease severity, as evidenced by the average age of onset and overall morbidity of the condition. An expansion of over 35 repeats typically indicates an unstable and expanding mutation. An expansion of 50 repeats or higher is consistent with a diagnosis of DM1. DM1 is a multisystem and heterogeneous disease characterized by distal weakness, atrophy, and myotonia, as well as symptoms in the heart, brain, gastrointestinal tract, endocrine, and respiratory systems. Symptoms may occur at any age. The severity of the condition varies widely among affected individuals, even among members of the same family. Comprehensive evidence-based guidelines do not currently exist to guide the treatment of DM1 patients. As a result, the international patient community reports varied levels of care and care quality, and difficulty accessing care adequate to manage their symptoms, unless they have access to multidisciplinary neuromuscular clinics. Consensus-based care recommendations can help standardize and improve the quality of care received by DM1 patients and assist clinicians who may not be familiar with the significant variability, range of symptoms, and severity of the disease. Care recommendations can also improve the landscape for clinical trial success by eliminating some of the inconsistencies in patient care to allow more accurate understanding of the benefit of potential therapies