Morphine and Clonidine Synergize to Ameliorate Low Back Pain in Mice

Chronic low back pain (LBP) is a debilitating condition associated with signs of axial and radiating pain. In humans with chronic LBP, opioids are often prescribed with varying outcomes and a multitude of side effects. Combination therapies, in which multiple pharmacological agents synergize to ameliorate pain without similar potentiation of adverse reactions, may be useful in improving therapeutic outcome in these patients. The SPARC-null mouse model of low back pain due to disc degeneration was used to assess the effects of opioid (morphine) and α2-adrenergic agonist (clonidine) coadministration on measures of axial and radiating pain. The results indicate that systemic morphine and clonidine, coadministered at a fixed dose of 100 : 1 (morphine : clonidine), show a synergistic interaction in reversing signs of axial LBP, in addition to improving the therapeutic window for radiating LBP. Furthermore, these improvements were observed in the absence of synergy in assays of motor function which are indicative of side effects such as sedation and motor incoordination. These data show that the addition of low-dose systemic clonidine improves therapeutic outcome in measures of both axial and radiating pain. Combination therapy could be of enormous benefit to patients suffering from chronic LBP

Analysis of the Effects of Pre-processing and Dual-Tasking on Gait Accelerometry Signals

One-third of older adults over 65 years of age fall each year. Falls are the main cause of injury and death among this population. Understanding the causes of falling is therefore a necessity for gerontologists. Gait accelerometry is an important approach for the quantitative assessment of human walking. It is an inexpensive, portable and reliable method to measure trunk accelerations. The latter may give indications on balance control even though there is no agreed measure of it. Accelerometry requires the measured accelerations to be preprocessed, but previous studies have not studied thoroughly its effects on signal features. We therefore constituted a set of features in the time, frequency and time-frequency domains and we evaluated the impact of tilt correction and wavelet denoising - two pre-processing operations - on these features. Signals used in this thesis were collected on 35 participants aged 65-year-old and over: 14 were healthy controls (HC), 10 had Parkinson's disease (PD) and 11 had peripheral neuropathy (PN). They walked on a treadmill at preferred speed. We first applied tilt correction and wavelet denoising separately, then we applied operations one after another. Denoising had nearly no effect on features compared to the raw accelerations. Tilt correction led to better discrimination between groups. Joint pre-processing operations showed trends that were similar to the tilt correction alone. Older adults also face increasing difficulties to perform an activity during walking and this threatens their stability. Thus, during another trial, the same groups of subjects were asked to press a button at hearing a tone. We observed the impact of dual-tasking on the features. Several features such as Lempel-Ziv complexity, bandwidth of accelerations and harmonic ratios remained unaffected by dual-task walking while the remaining features were affected. We also examined the impact of dual-tasking on each group. Task differences were almost the same for every group and revealed lower harmonic ratios during dual-task walking

Morphine and Clonidine Synergize to Ameliorate Low Back Pain in Mice

Chronic low back pain (LBP) is a debilitating condition associated with signs of axial and radiating pain. In humans with chronic LBP, opioids are often prescribed with varying outcomes and a multitude of side effects. Combination therapies, in which multiple pharmacological agents synergize to ameliorate pain without similar potentiation of adverse reactions, may be useful in improving therapeutic outcome in these patients. The SPARC-null mouse model of low back pain due to disc degeneration was used to assess the effects of opioid (morphine) andα2-adrenergic agonist (clonidine) coadministration on measures of axial and radiating pain. The results indicate that systemic morphine and clonidine, coadministered at a fixed dose of 100 : 1 (morphine : clonidine),show a synergistic interaction in reversing signs of axial LBP, in addition to improving the therapeutic window for radiating LBP.Furthermore, these improvements were observed in the absence of synergy in assays of motor function which are indicative of side effects such as sedation and motor incoordination. These data show that the addition of low-dose systemic clonidine improves therapeutic outcome in measures of both axial and radiating pain. Combination therapy could be of enormous benefit to patients suffering from chronic LBP

Analysis of the DNA adducts of phenyl glycidyl ether in a calf thymus DNA hydrolysate by capillary zone electrophoresis-electrospray mass spectrometry: evidence for phosphate alkylation

Calf thymus DNA was reacted irt vitro with phenyl glycidyl ether (PGE) and was hydrolysed enzymatically, to the 5'-monophosphate nucleotides using deoxyribonuclease I (DNA-ase I) and nuclease P1, The adducts were concentrated using solid phase extraction (SPE), on a polystyrene divinylbenzene copolymer in order to remove the unmodified nucleotides. The adducts could be identified using capillary zone electrophoresis-electrospray tandem mass spectrometry (CZE ES-MS/MS), using sample stacking. In addition to the base alkylated 2'-deoxynucleotides present in the DNA-hydrolysate, also phosphate alkylated 2'-deoxynucleotide adducts were identified for TMP and dAMP, An additional adduct, dUMP alkylated on the uridine moiety was found originating from the hydrolytic deamination of dCMP alkylated on N-3 Of the cytosine moiety, Enzymatic hydrolysis using nuclease P1 was incomplete as shown by the presence of dinucleotides alkylated on the base moiety, They were successfully hydrolysed to the corresponding 2'-deoxynucleotides by snake venom phosphodiesterase (SVP), Data are shown indicating that alkylations on the pyrimidine bases were more resistant to enzymatic hydrolysis with nuclease P1 than the purine alkylated products

Diet-induced obesity leads to behavioral indicators of pain preceding structural joint damage in wild-type mice

Introduction: Obesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain. Despite the clinical association, no studies have directly assessed whether diet-induced obesity accelerates IVD degeneration, back pain, or investigated the biological mediators underlying this association. In this study, we examine the effects of chronic consumption of a high-fat or high-fat/high-sugar (western) diet on the IVD, knee joint, and pain-associated outcomes. Methods: Male C57BL/6N mice were randomized into one of three diet groups (chow control; high-fat; high-fat, high-sugar western diet) at 10 weeks of age and remained on the diet for 12, 24, or 40 weeks. At endpoint, animals were assessed for behavioral indicators of pain, joint tissues were collected for histological and molecular analysis, serum was collected to assess for markers of systemic inflammation, and IBA-1, GFAP, and CGRP were measured in spinal cords by immunohistochemistry. Results: Animals fed obesogenic (high-fat or western) diets showed behavioral indicators of pain beginning at 12 weeks and persisting up to 40 weeks of diet consumption. Histological indicators of moderate joint degeneration were detected in the IVD and knee following 40 weeks on the experimental diets. Mice fed the obesogenic diets showed synovitis, increased intradiscal expression of inflammatory cytokines and circulating levels of MCP-1 compared to control. Linear regression modeling demonstrated that age and diet were both significant predictors of most pain-related behavioral outcomes, but not histopathological joint degeneration. Synovitis was associated with alterations in spontaneous activity. Conclusion: Diet-induced obesity accelerates IVD degeneration and knee OA in mice; however, pain-related behaviors precede and are independent of histopathological structural damage. These findings contribute to understanding the source of obesity-related back pain and the contribution of structural IVD degeneration

Modélisation thermomécanique du contact aube-abradable dans les turboréacteurs.

Pour répondre aux challenges des motoristes aéronautiques concernant l'optimisation des performances des turboréacteurs, il est nécessaire de s'intéresser à la maîtrise des jeux entre rotor et stator. Une solution technologique couramment employée consiste à déposer un revêtement, dit abradable, par projection thermique sur les parois internes du carter. L'objectif est de réduire le jeu à l'extrémité des aubes tournantes tout en garantissant la fiabilité de la turbomachine en cas de contact. Le matériau utilisé offre des propriétés d'abradabilité, jouant le rôle de fusible afin de préserver les étages mobiles du moteur lors d'éventuelles interactions. Cependant, certaines conditions de fonctionnement défavorables peuvent conduire à l'endommagement des structures suite à des phénomènes vibratoires divergents résultants des interactions, des échauffements sévères localisés et une usure du revêtement. L'approche dynamique est insuffisance pour expliquer ces phénomènes et nécessite d'être complétée avec l'introduction des aspects thermomécaniques dans l'étude des conditions de contact aube-abradable. En effet, les phénomènes dynamiques sont couplés aux phénomènes thermomécaniques [1], les dilatations thermiques résultent directement des échauffements et peuvent modifier les mécanismes physiques au contact. L'objectif est de proposer des outils de modélisations numériques pour représenter les physiques thermiques et mécaniques mises en jeu. La compréhension des phénomènes thermomécaniques suggère une approche énergétique locale de l'interaction [2,3] pour quantifier notamment la part d'énergie générée qui est convertie en chaleur. Les premiers éléments de réponse ont été apportés avec la réalisation d'essais expérimentaux pour reproduire une configuration simplifiée d'interaction entre une aube en titane et un tambour rotatif recouvert d'abradable selon le dispositif développé dans [4]. Des méthodes directes de recalage en flux permettent de remonter aux quantités de chaleur et de suivre l'évolution de la partition du flux entre les deux corps en interaction. Différentes configurations d'interaction ont été étudiées pour prédire l'influence des paramètres procédés et matériaux qui pilotent la distribution de flux de chaleur et qui sont à considérer dans le cadre de simulations thermomécaniques. Le partage de flux est introduit dans une approche numérique thermomécanique en éléments finis découplée afin d'étudier l'influence des dilatations thermiques sur la dynamique du contact rotor-stator. La participation des phénomènes thermomécaniques est mise en évidence avec la simulation d'essais d'interaction types. Les échauffements localisés en surface d'abradable conduisent à postériori à des déformations d'ensemble résultant de la diffusion du gradient thermique dans le reste du carter. Les dilatations thermiques sont prises en compte pour mettre à jour la géométrie déformée du carter dans la résolution du problème dynamique de contact. Les effets sur la dynamique ne sont pas instantanés car les dilatations thermiques ne sont pas maximales sous le contact, et peuvent s'amplifier dans le temps avec le cumul d'énergie. L'ouverture ou la fermeture du jeu sont conditionnées par le temps de diffusion, la forme du chargement thermique à l'interface, la géométrie du carter et les conditions aux limites considérées. Les échelles spatiales et temporelles des dilatations thermiques sont étudiées sur des dynamiques plus complexes mettant en jeux des essais d'interaction échelle 1 entre un disque complet aubagé et son carter. L'objectif à terme est d'essayer d'expliquer les conditions qui différencient les cas d'interaction divergents et non-divergents sur la divergence vibratoire.  Références [1] A. Millecamps et al. (2009) « Influence of thermal effects during blade-casing contact experiments. », In ASME 2009 , 855?862. American Society of Mechanical Engineers [2] W.F Laverty. (1982) « Rub energetics of compressor blade tip seals. », Wear, 75 :1?20 [3] M. Banjac, A. Vencl, S. Otovi?. (2014) « Friction and Wear Processes ? Thermodynamic Approach. », Tribology in Industry, Vol. 36, No. 4 (2014) 341?347 [4] R. Mandard and al. (2015) « Identification expérimentale des mécanismes d'accommodation de l'incursion aube-abradable », JIFT 201

An energy balance of blade-casing interaction

International audienc

Cutaneous tactile allodynia associated with microvascular dysfunction in muscle

<p>Abstract</p> <p>Background</p> <p>Cutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia.</p> <p>Results</p> <p>Persistent cutaneous allodynia is produced in rats following a hind paw ischemia-reperfusion injury that induces microvascular dysfunction, including arterial vasospasms and capillary slow flow/no-reflow, in muscle. Microvascular dysfunction leads to persistent muscle ischemia, a reduction of intraepidermal nerve fibers, and allodynia correlated with muscle ischemia, but not with skin nerve loss. The affected hind paw muscle shows lipid peroxidation, an upregulation of nuclear factor kappa B, and enhanced pro-inflammatory cytokines, while allodynia is relieved by agents that inhibit these alterations. Allodynia is increased, along with hind paw muscle lactate, when these rats exercise, and is reduced by an acid sensing ion channel antagonist.</p> <p>Conclusion</p> <p>Our results demonstrate how microvascular dysfunction and ischemia in muscle can play a critical role in the development of cutaneous allodynia, and encourage the study of how these mechanisms contribute to chronic pain. We anticipate that focus on the pain mechanisms associated with microvascular dysfunction in muscle will provide new effective treatments for chronic pain patients with cutaneous tactile allodynia.</p

Quantification of upper body movements during gait in older adults and in those with Parkinson's disease: impact of acceleration realignment methodologies.

The upper body accelerations of people with Parkinson’s disease (PD) measured by inertial measurement units (IMUs) may contribute towards diagnostic algorithms and help track disease progression. Before extracting variables related to upper body motion, acceleration signals require realignment to a global reference; however, the impact of these techniques on the resulting upper body variables is unclear. Therefore, the aim of this investigation was to examine the impact of four different realignment methods designed to correct acceleration signals on a range of upper body variables in older adults and in patients with PD. Two minutes of continuous gait were measured in 54 community-dwelling older adults (71.1 �6.7 years) and 60 people with PD (age: 68.5 � 9.1 years). Three IMUs placed on the 5th lumbar vertebra, 7th cervical vertebra and the back of the head recorded the acceleration of the upper body. A selection of upper body variables sensitive to impaired upper body control in PD and four acceleration realignment methods were compared. A mixed-model ANOVA showed that the choice of realignment method significantly affected the values of upper body variables as well as their ability to discriminate between the PD and control group. Our findings indicate researchers and clinicians should be cautious when comparing upper body variables extracted from IMUs using different realignment methods, and consideration of realignmenttechnique will be important when identifying the most sensitive markers of disease presence and progression. Therefore, it’s strongly recommend that researchers consider and report their realignment methods when assessing upper body variables during gai