Is tapentadol different from classical opioids?: a review of the evidence

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids

Hip morphology in elite golfers : asymmetry between lead and trail hips

Aim: During a golf swing, the lead hip (left hip in a right-handed player) rotates rapidly from external to internal rotation, while the opposite occurs in the trail hip. This study assessed the morphology and pathology of golfers’ hips comparing lead and trail hips. Methods: A cohort of elite golfers were invited to undergo MRI of their hips. Hip morphology was evaluated by measuring acetabular depth (pincer shape=negative measure), femoral neck antetorsion (retrotorsion=negative measure) and α angles (cam morphology defined as α angle >55° anteriorly) around the axis of the femoral neck. Consultant musculoskeletal radiologists determined the presence of intra-articular pathology. Results: 55 players (mean age 28 years, 52 left hip lead) underwent MRI. No player had pincer morphology, 2 (3.6%) had femoral retrotorsion and 9 (16%) had cam morphology. 7 trail hips and 2 lead hips had cam morphology (p=0.026). Lead hip femoral neck antetorsion was 16.7° compared with 13.0° in the trail hip (p<0.001). The α angles around the femoral neck were significantly lower in the lead compared with trail hips (p<0.001), with the greatest difference noted in the anterosuperior portion of the head neck junction; 53° vs 58° (p<0.001) and 43° vs 47° (p<0.001). 37% of trail and 16% of lead hips (p=0.038) had labral tears. Conclusions: Golfers’ lead and trail hips have different morphology. This is the first time side-to-side asymmetry of cam prevalence has been reported. The trail hip exhibited a higher prevalence of labral tears

The Hydrogen Epoch of Reionization Array Dish II: Characterization of Spectral Structure with Electromagnetic Simulations and its science Implications

We use time-domain electromagnetic simulations to determine the spectral characteristics of the Hydrogen Epoch of Reionization Arrays (HERA) antenna. These simulations are part of a multi-faceted campaign to determine the effectiveness of the dish's design for obtaining a detection of redshifted 21 cm emission from the epoch of reionization. Our simulations show the existence of reflections between HERA's suspended feed and its parabolic dish reflector that fall below -40 dB at 150 ns and, for reasonable impedance matches, have a negligible impact on HERA's ability to constrain EoR parameters. It follows that despite the reflections they introduce, dishes are effective for increasing the sensitivity of EoR experiments at relatively low cost. We find that electromagnetic resonances in the HERA feed's cylindrical skirt, which is intended to reduce cross coupling and beam ellipticity, introduces significant power at large delays ($-40$ dB at 200 ns) which can lead to some loss of measurable Fourier modes and a modest reduction in sensitivity. Even in the presence of this structure, we find that the spectral response of the antenna is sufficiently smooth for delay filtering to contain foreground emission at line-of-sight wave numbers below $k_\parallel \lesssim 0.2$ $h$Mpc$^{-1}$, in the region where the current PAPER experiment operates. Incorporating these results into a Fisher Matrix analysis, we find that the spectral structure observed in our simulations has only a small effect on the tight constraints HERA can achieve on parameters associated with the astrophysics of reionization.Comment: Accepted to ApJ, 18 pages, 17 Figures. Replacement matches accepted manuscrip

The Hydrogen Epoch of Reionization Array Dish I: Beam Pattern Measurements and Science Implications

The Hydrogen Epoch of Reionization Array (HERA) is a radio interferometer aiming to detect the power spectrum of 21 cm fluctuations from neutral hydrogen from the Epoch of Reionization (EOR). Drawing on lessons from the Murchison Widefield Array (MWA) and the Precision Array for Probing the Epoch of Reionization (PAPER), HERA is a hexagonal array of large (14 m diameter) dishes with suspended dipole feeds. Not only does the dish determine overall sensitivity, it affects the observed frequency structure of foregrounds in the interferometer. This is the first of a series of four papers characterizing the frequency and angular response of the dish with simulations and measurements. We focus in this paper on the angular response (i.e., power pattern), which sets the relative weighting between sky regions of high and low delay, and thus, apparent source frequency structure. We measure the angular response at 137 MHz using the ORBCOMM beam mapping system of Neben et al. We measure a collecting area of 93 m^2 in the optimal dish/feed configuration, implying HERA-320 should detect the EOR power spectrum at z~9 with a signal-to-noise ratio of 12.7 using a foreground avoidance approach with a single season of observations, and 74.3 using a foreground subtraction approach. Lastly we study the impact of these beam measurements on the distribution of foregrounds in Fourier space.Comment: 13 pages, 9 figures. Replaced to match accepted ApJ versio

Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma

Cancer-induced bone pain (CIBP) is common in patients with bone metastases (BM), significantly impairing quality of life. The current treatments for CIBP are limited since they are often ineffective. Local acidosis derived from glycolytic carcinoma and tumor-induced osteolysis is only barely explored cause of pain. We found that breast carcinoma cells that prefer bone as a metastatic site have very high extracellular proton efflux and expression of pumps/ion transporters associated with acid-base balance (MCT4, CA9, and V-ATPase). Further, the impairment of intratumoral acidification via V-ATPase targeting in xenografts with BM significantly reduced CIBP, as measured by incapacitance test. We hypothesize that in addition to the direct acid-induced stimulation of nociceptors in the bone, a novel mechanism mediated by the acid-induced and tumor-associated mesenchymal stroma might ultimately lead to nociceptor sensitization and hyperalgesia. Consistent with this, short-term exposure of cancer-associated fibroblasts, mesenchymal stem cells, and osteoblasts to pH 6.8 promotes the expression of inflammatory and nociceptive mediators (NGF, BDNF, IL6, IL8, IL1b and CCL5). This is also consistent with a significant correlation between breakthrough pain, measured by pain questionnaire, and combined high serum levels of BDNF and IL6 in patients with BM, and also by immunofluorescence staining showing IL8 expression that was more in mesenchymal stromal cells rather than in tumors cells, and close to LAMP-2 positive acidifying carcinoma cells in BM tissue sections.In summary, intratumoral acidification in BM might promote CIBP also by activating the tumor-associated stroma, offering a new target for palliative treatments in advanced cancer

Professional golfers’ hips : prevalence and predictors of hip pain with clinical and MR examinations

Abstract Aims This study aimed to determine the prevalence of hip pain in professional golfers, comparing the lead (left hip in right-handed golfer) and trail hips, and to establish what player characteristics predicted hip symptoms. Methods Male elite professional golf players were invited to complete questionnaires and undergo clinical and MR examinations while attending the Scottish Hydro Challenge 2015. Questionnaires determined player demographics, self-reported hip pain and an International Hip Outcome Tool 12 (iHOT12) score (hip-related quality of life). Clinical examinations determined hip range of motion and the presence of a positive impingement test. MR scans determined the presence of labral pathology and player hip morphology with measures of α angle (cam), acetabular depth (pincer) and femoral neck antetorsion. Results A total of 109 (70% of tournament field) of players completed questionnaires, 73 (47%) underwent clinical examination and 55 (35%) underwent MR examination. 19.3% of players reported of hip pain. 11.9% of lead and 9.1% of trail hips were painful (p=0.378), iHOT12 scores were lower in the lead (94.1) compared to the trail hip (95.3) (p=0.007). Stepwise multiple linear regression modelling was able to predict 20.7% of the variance in iHOT12 scores with mean α angles between 12 and 3 o'clock, and increasing age-significant variables (R2=0.207, p<0.001; β=−0.502, p<0.001 and β=−0.399, p=0.031, respectively). Conclusions 19.3% of male professional golfers reported hip pain. The presence of an increasing α angle and increasing age were significant predictors of reduced hip-related quality of life

Professional golfers’ hips: prevalence and predictors of hip pain with clinical and MR examinations

Aims This study aimed to determine the prevalence of hip pain in professional golfers, comparing the lead (left hip in right-handed golfer) and trail hips, and to establish what player characteristics predicted hip symptoms.Methods Male elite professional golf players were invited to complete questionnaires and undergo clinical and MR examinations while attending the Scottish Hydro Challenge 2015. Questionnaires determined player demographics, self-reported hip pain and an International Hip Outcome Tool 12 (iHOT12) score (hip-related quality of life). Clinical examinations determined hip range of motion and the presence of a positive impingement test. MR scans determined the presence of labral pathology and player hip morphology with measures of ? angle (cam), acetabular depth (pincer) and femoral neck antetorsion.Results A total of 109 (70% of tournament field) of players completed questionnaires, 73 (47%) underwent clinical examination and 55 (35%) underwent MR examination. 19.3% of players reported of hip pain. 11.9% of lead and 9.1% of trail hips were painful (p=0.378), iHOT12 scores were lower in the lead (94.1) compared to the trail hip (95.3) (p=0.007). Stepwise multiple linear regression modelling was able to predict 20.7% of the variance in iHOT12 scores with mean ? angles between 12 and 3 o'clock, and increasing age-significant variables (R2=0.207, p&lt;0.001; ?=?0.502, p&lt;0.001 and ?=?0.399, p=0.031, respectively).Conclusions 19.3% of male professional golfers reported hip pain. The presence of an increasing ? angle and increasing age were significant predictors of reduced hip-related quality of life

Influence of behavioral traits in the inter-individual variability of nociceptive, emotional and cognitive manifestations of neuropathic pain

Neuropathic pain is a complex disorder associated with emotional and cognitive deficits that may impair nociceptive manifestations. There is high inter-individual variability in the manifestations of human neuropathic pain, which largely depends on personality traits. We aim to identify the influence of different behavioral traits in the interindividual vulnerability to neuropathic pain manifestations using behavioral, electrophysiological and genetic approaches. We first selected mice with extreme social and emotional traits and look for correlation with the spontaneous neuronal activity in the central amygdala. Neuropathic pain was induced to these mice to evaluate the influence of behavioral traits on nociceptive manifestations and gene expression profiles in the amygdala. Our results show an association of the spontaneous central amygdala neuronal activity with the sociability behavior. We demonstrate that low sociable, high anxious and low depressive phenotypes develop enhanced nociceptive hypersensitivity after nerve injury. However, greater emotional alterations and cognitive impairment are observed in high sociable, anxious-like and depressive-like mice, indicating that nociceptive, emotional and cognitive manifestations of neuropathic pain do not correlate with each other. Gene analyses identify high Pdyn and Il6 levels in the amygdala as indicative of enhanced nociceptive hypersensitivity and reveal an association between high Gadd45 expression and attenuated emotional and cognitive manifestations of neuropathic pain.This work was supported by the European Commission, FP7 (#HEALTH-F2-2013- 602891), the Spanish Ministerio de Economía y Competitividad MINECO (#SAF2014-59648-P and #SAF2017-84060-R), the Spanish Instituto de Salud Carlos III, RETICS-RTA (#RD12/0028/0023) and the Generalitat de Catalunya, AGAUR (#2014-SGR-1547) and Polish Ministry of Science and Education (#3070/7.PR/2014/2). M.M.N. and R.N. are recipients of a predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (MECD). I.M.L.M. is recipient of a predoctoral fellowship from the Mexican Consejo Nacional de Ciencia y Tecnología (CONACyT). FEDER partial funding is also acknowledged. W.B. and A.B. are recipients of Polish Ministry of Science and Education and European Commission grant