Manual therapy followed by specific active exercises versus a placebo followed by specific active exercises on the improvement of functional disability in patients with chronic non specific low back pain: a randomized controlled trial.

BACKGROUND: Recent clinical recommendations still propose active exercises (AE) for CNSLBP. However, acceptance of exercises by patients may be limited by pain-related manifestations. Current evidences suggest that manual therapy (MT) induces an immediate analgesic effect through neurophysiologic mechanisms at peripheral, spinal and cortical levels. The aim of this pilot study was first, to assess whether MT has an immediate analgesic effect, and second, to compare the lasting effect on functional disability of MT plus AE to sham therapy (ST) plus AE. METHODS: Forty-two CNSLBP patients without co-morbidities, randomly distributed into 2 treatment groups, received either spinal manipulation/mobilization (first intervention) plus AE (MT group; n = 22), or detuned ultrasound (first intervention) plus AE (ST group; n = 20). Eight therapeutic sessions were delivered over 4 to 8 weeks. Immediate analgesic effect was obtained by measuring pain intensity (Visual Analogue Scale) before and immediately after the first intervention of each therapeutic session. Pain intensity, disability (Oswestry Disability Index), fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), erector spinae and abdominal muscles endurance (Sorensen and Shirado tests) were assessed before treatment, after the 8th therapeutic session, and at 3- and 6-month follow-ups. RESULTS: Thirty-seven subjects completed the study. MT intervention induced a better immediate analgesic effect that was independent from the therapeutic session (VAS mean difference between interventions: -0.8; 95% CI: -1.2 to -0.3). Independently from time after treatment, MT + AE induced lower disability (ODI mean group difference: -7.1; 95% CI: -12.8 to -1.5) and a trend to lower pain (VAS mean group difference: -1.2; 95% CI: -2.4 to -0.30). Six months after treatment, Shirado test was better for the ST group (Shirado mean group difference: -61.6; 95% CI: -117.5 to -5.7). Insufficient evidence for group differences was found in remaining outcomes. CONCLUSIONS: This study confirmed the immediate analgesic effect of MT over ST. Followed by specific active exercises, it reduces significantly functional disability and tends to induce a larger decrease in pain intensity, compared to a control group. These results confirm the clinical relevance of MT as an appropriate treatment for CNSLBP. Its neurophysiologic mechanisms at cortical level should be investigated more thoroughly. TRIAL REGISTRATION: Trial registration number: NCT01496144.

Impact of a pain protocol including hypnosis in major burns.

BACKGROUND: Pain is a major issue after burns even when large doses of opioids are prescribed. The study focused on the impact of a pain protocol using hypnosis on pain intensity, anxiety, clinical course, and costs. METHODS: All patients admitted to the ICU, aged >18 years, with an ICU stay >24h, accepting to try hypnosis, and treated according to standardized pain protocol were included. Pain was scaled on the Visual Analog Scale (VAS) (mean of daily multiple recordings), and basal and procedural opioid doses were recorded. Clinical outcome and economical data were retrieved from hospital charts and information system, respectively. Treated patients were matched with controls for sex, age, and the burned surface area. FINDINGS: Forty patients were admitted from 2006 to 2007: 17 met exclusion criteria, leaving 23 patients, who were matched with 23 historical controls. Altogether patients were 36+/-14 years old and burned 27+/-15%BSA. The first hypnosis session was performed after a median of 9 days. The protocol resulted in the early delivery of higher opioid doses/24h (p<0.0001) followed by a later reduction with lower pain scores (p<0.0001), less procedural related anxiety, less procedures under anaesthesia, reduced total grafting requirements (p=0.014), and lower hospital costs per patient. CONCLUSION: A pain protocol including hypnosis reduced pain intensity, improved opioid efficiency, reduced anxiety, improved wound outcome while reducing costs. The protocol guided use of opioids improved patient care without side effects, while hypnosis had significant psychological benefits.

Cardiac Lineage Protein-1 (CLP-1) Regulates Cardiac Remodeling via Transcriptional Modulation of Diverse Hypertrophic and Fibrotic Responses and Angiotensin II-transforming Growth Factor β (TGF-β1) Signaling Axis.

It is well known that the renin-angiotensin system contributes to left ventricular hypertrophy and fibrosis, a major determinant of myocardial stiffness. TGF-β1 and renin-angiotensin system signaling alters the fibroblast phenotype by promoting its differentiation into morphologically distinct pathological myofibroblasts, which potentiates collagen synthesis and fibrosis and causes enhanced extracellular matrix deposition. However, the atrial natriuretic peptide, which is induced during left ventricular hypertrophy, plays an anti-fibrogenic and anti-hypertrophic role by blocking, among others, the TGF-β-induced nuclear localization of Smads. It is not clear how the hypertrophic and fibrotic responses are transcriptionally regulated. CLP-1, the mouse homolog of human hexamethylene bis-acetamide inducible-1 (HEXIM-1), regulates the pTEFb activity via direct association with pTEFb causing inhibition of the Cdk9-mediated serine 2 phosphorylation in the carboxyl-terminal domain of RNA polymerase II. It was recently reported that the serine kinase activity of Cdk9 not only targets RNA polymerase II but also the conserved serine residues of the polylinker region in Smad3, suggesting that CLP-1-mediated changes in pTEFb activity may trigger Cdk9-dependent Smad3 signaling that can modulate collagen expression and fibrosis. In this study, we evaluated the role of CLP-1 in vivo in induction of left ventricular hypertrophy in angiotensinogen-overexpressing transgenic mice harboring CLP-1 heterozygosity. We observed that introduction of CLP-1 haplodeficiency in the transgenic α-myosin heavy chain-angiotensinogen mice causes prominent changes in hypertrophic and fibrotic responses accompanied by augmentation of Smad3/Stat3 signaling. Together, our findings underscore the critical role of CLP-1 in remodeling of the genetic response during hypertrophy and fibrosis.

Down-modulation of lymphoproliferation and interferon-gamma production by beta-glucan derived from Saccharomyces cerevisiae

beta-glucan, one of the major cell wall components of Saccharomyces cerevisiae, has been found to enhance immune functions. This study investigated in vivo and in vitro effects of beta-glucan on lymphoproliferation and interferon-gamma (IFN-gamma) production by splenic cells from C57BL/6 female mice. All experiments were performed with particulate beta-glucan derived from S. cerevisiae. Data demonstrated that both, i.p administration of particulate beta-glucan (20 or 100 µg/animal) and in vitro stimulation of splenic cells (20 or 100 µg/ml of culture) decreased lymphoproliferation and IFN-gamma production induced by concanavalin A. These results suggest that beta-glucan can trigger a down-modulatory effect regulating a deleterious immune system hyperactivity in the presence of a strong stimulus.

Premature epiphyseal closure in an adolescent treated by retinoids for acne: an unusual cause of anterior knee pain.

Retinoids are effective and widely prescribed in the treatment of severe acne. However their use can be associated with numerous side effects. Some rare cases of premature epiphyseal closure were reported. We present the case of a sixteen-year-old soccer player referred for progressive anterior pain in both knees, evoking a patellar problem. Careful pharmacological questioning revealed use of isotretinoin for several months. MRI findings showed an irregularity of the growth plate and an important metaphyso-epiphyseal oedema, more noticeable in the left knee. Retinoid-induced premature epiphyseal closure was diagnosed. The treatment was stopped, with a resolution of pain within two months. After recovery a persisting small sequelar thumbprint-like growth plate lesion was observed on the control MRI. Retinoids induce an invasion of the growth plate by osteoclasts and a decrease in proteoglycans synthesis. It seems that the knee is the most affected joint. This complication being rare, a radiological follow-up of the young patients treated by retinoids is not proposed.

Douleurs chroniques chez les personnes âgées: dimensions psychologiques [Chronic pain in elderly people: psychosocial dimension].

Chronic pain in elderly people requires to take into account somatic co-morbidities as well as its psychosocial dimensions. Chronic pain often represents a distress signal addressed to the environment and the care providers. Psychological suffering or mood disorders can be presented in the form of somatic complaints often associated with functional impairments, sometimes severe. Therapeutic care has to address functionality through an image-enhancing approach aiming to summon the patients' resources. The treatment of a concomitant depressive state necessitates a true commitment from the therapist. Its benefits are documented in elderly patients. Analgesic treatment as a whole will seek in particular to restore feelings of self-esteem and help the patient recover a good quality of life.

Reverse transcription quantitative real-time polymerase chain reaction reference genes in the spared nerve injury model of neuropathic pain : validation and literature search

La douleur neuropathique est définie comme une douleur causée par une lésion du système nerveux somato-sensoriel. Elle se caractérise par des douleurs exagérées, spontanées, ou déclenchées par des stimuli normalement non douloureux (allodynie) ou douloureux (hyperalgésie). Bien qu'elle concerne 7% de la population, ses mécanismes biologiques ne sont pas encore élucidés. L'étude des variations d'expressions géniques dans les tissus-clés des voies sensorielles (notamment le ganglion spinal et la corne dorsale de la moelle épinière) à différents moments après une lésion nerveuse périphérique permettrait de mettre en évidence de nouvelles cibles thérapeutiques. Elles se détectent de manière sensible par reverse transcription quantitative real-time polymerase chain reaction (RT- qPCR). Pour garantir des résultats fiables, des guidelines ont récemment recommandé la validation des gènes de référence utilisés pour la normalisation des données ("Minimum information for publication of quantitative real-time PCR experiments", Bustin et al 2009). Après recherche dans la littérature des gènes de référence fréquemment utilisés dans notre modèle de douleur neuropathique périphérique SNI (spared nerve injury) et dans le tissu nerveux en général, nous avons établi une liste de potentiels bons candidats: Actin beta (Actb), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ribosomal proteins 18S (18S), L13a (RPL13a) et L29 (RPL29), hypoxanthine phosphoribosyltransferase 1 (HPRT1) et hydroxymethyl-bilane synthase (HMBS). Nous avons évalué la stabilité d'expression de ces gènes dans le ganglion spinal et dans la corne dorsale à différents moments après la lésion nerveuse (SNI) en calculant des coefficients de variation et utilisant l'algorithme geNorm qui compare les niveaux d'expression entre les différents candidats et détermine la paire de gènes restante la plus stable. Il a aussi été possible de classer les gènes selon leur stabilité et d'identifier le nombre de gènes nécessaires pour une normalisation la plus précise. Les gènes les plus cités comme référence dans le modèle SNI ont été GAPDH, HMBS, Actb, HPRT1 et 18S. Seuls HPRT1 and 18S ont été précédemment validés dans des arrays de RT-qPCR. Dans notre étude, tous les gènes testés dans le ganglion spinal et dans la corne dorsale satisfont au critère de stabilité exprimé par une M-value inférieure à 1. Par contre avec un coefficient de variation (CV) supérieur à 50% dans le ganglion spinal, 18S ne peut être retenu. La paire de gènes la plus stable dans le ganglion spinal est HPRT1 et Actb et dans la corne dorsale il s'agit de RPL29 et RPL13a. L'utilisation de 2 gènes de référence stables suffit pour une normalisation fiable. Nous avons donc classé et validé Actb, RPL29, RPL13a, HMBS, GAPDH, HPRT1 et 18S comme gènes de référence utilisables dans la corne dorsale pour le modèle SNI chez le rat. Dans le ganglion spinal 18S n'a pas rempli nos critères. Nous avons aussi déterminé que la combinaison de deux gènes de référence stables suffit pour une normalisation précise. Les variations d'expression génique de potentiels gènes d'intérêts dans des conditions expérimentales identiques (SNI, tissu et timepoints post SNI) vont pouvoir se mesurer sur la base d'une normalisation fiable. Non seulement il sera possible d'identifier des régulations potentiellement importantes dans la genèse de la douleur neuropathique mais aussi d'observer les différents phénotypes évoluant au cours du temps après lésion nerveuse.

Modulation of fructose metabolism by dietary factors

High fructose consumption is associated with obesity and characteristics of metabolic syndrome. This includes insulin resistance, dyslipidemia, type II diabetes and hepatic steatosis, the hepatic component of metabolic syndrome. Short term high fructose consumption in healthy humans is considered as a study model to increase intrahepatocellular lipids (IHCL). Protein supplementation added to a short term high fructose diet exerts a protective role on hepatic fat accumulation. Fructose disposal after an acute fructose load is well established. However, fructose disposal is usually studied when a high intake of fructose is ingested. Interaction of fructose with other macronutrients on fructose disposal is not clearly established. We wanted to assess how fructose disposal is modulated with nutritional factors. For the first study, we addressed the question of how would essential amino acid (EAA) supplemented to a high fructose diet have an impact on hepatic fat accumulation? We tried to distinguish which metabolic pathways were responsible for the increase in IHCL induced by high fructose intake and how those pathways would be modulated by EAA. After 6 days of hypercaloric high fructose diet, we observed, as expected an increase in IHCL modulated by an increase in VLDL-triglycerides and an increase in VLDL-13C-palmitate production. When adding a supplementation in EAA, we observed a decrease in IHCL but we could not define which mechanism was responsible for this process. With the second study, we were interested to observe fructose disposal after a test meal that contained lipid, protein and a physiologic dose of fructose co-ingested or not with glucose. When ingested with other macronutrients, hepatic fructose disposal is similar as when ingested as pure fructose. It induced oxidation, gluconeogenesis followed by glycogen synthesis, conversion into lactate and to a minor extent by de novo lipogenesis. When co- ingested with glucose decreased fructose oxidation as well as gluconeogenesis and an increased glycogen synthesis without affecting de novo lipogenesis or lactate. We were also able to observe induction of intestinal de novo lipogenesis with both fructose and fructose co- ingested with glucose. In summary, essential amino acids supplementation blunted increase in hepatic fat content induced by a short term chronic fructose overfeeding. However, EAA failed to improve other cardiovascular risk factors. Under isocaloric condition and in the frame of an acute test meal, physiologic dose of fructose associated with other macronutrients led to the same fructose disposal as when fructose is ingested alone. When co-ingested with glucose, we observed a decrease in fructose oxidation and gluconeogenesis as well as an increased in glycogen storage without affecting other metabolic pathways. - Une consommation élevée en fructose est associée à l'obésité et aux caractéristiques du syndrome métabolique. Ces dernières incluent une résistance à l'insuline, une dyslipidémie, un diabète de type II et la stéatose hépatique, composant hépatique du syndrome métabolique. À court terme une forte consommation en fructose chez l'homme sain est considérée comme un modèle d'étude pour augmenter la teneur en graisse hépatique. Une supplémentation en protéines ajoutée à une alimentation riche en fructose de courte durée a un effet protecteur sur l'accumulation des graisses au niveau du foie. Le métabolisme du fructose après une charge de fructose aiguë est bien établi. Toutefois, ce dernier est généralement étudié quand une consommation élevée de fructose est donnée. L'interaction du fructose avec d'autres macronutriments sur le métabolisme du fructose n'est pas connue. Nous voulions évaluer la modulation du métabolisme du fructose par des facteurs nutritionnels. Pour la première étude, nous avons abordé la question de savoir quel impact aurait une supplémentation en acides aminés essentiels (AEE) associé à une alimentation riche en fructose sur l'accumulation des graisses hépatiques. Nous avons essayé de distinguer les voies métaboliques responsables de l'augmentation des graisses hépatiques induite par l'alimentation riche en fructose et comment ces voies étaient modulées par les AEE. Après 6 jours d'une alimentation hypercalorique riche en fructose, nous avons observé, comme attendu, une augmentation des graisses hépatiques modulée par une augmentation des triglycérides-VLDL et une augmentation de la production de VLDL-13C-palmitate. Lors de la supplémentation en AEE, nous avons observé une diminution des graisses hépatiques mais les mécanismes responsables de ce processus n'ont pas pu être mis en évidence. Avec la seconde étude, nous nous sommes intéressés à observer le métabolisme du fructose après un repas test contenant des lipides, des protéines et une dose physiologique de fructose co-ingéré ou non avec du glucose. Lorsque le fructose était ingéré avec les autres macronutriments, le devenir hépatique du fructose était similaire à celui induit par du fructose pur. Il a induit une oxydation, suivie d'une néoglucogenèses, une synthèse de glycogène, une conversion en lactate et dans une moindre mesure une lipogenèse de novo. Lors de la co-ngestion avec du glucose, nous avons observé une diminution de l'oxydation du fructose et de la néoglucogenèse et une augmentation de la synthèse du glycogène, sans effet sur la lipogenèse de novo ni sur le lactate. Nous avons également pu mettre en évidence que le fructose et le fructose ingéré de façon conjointe avec du glucose ont induit une lipogenèse de novo au niveau de l'intestin. En résumé, la supplémentation en acides aminés essentiels a contrecarré l'augmentation de la teneur en graisse hépatique induite par une suralimentation en fructose sur le court terme. Cependant, la supplémentation en AEE a échoué à améliorer d'autres facteurs de risque cardiovasculaires. Dans la condition isocalorique et dans le cadre d'un repas test aiguë, la dose physiologique de fructose associée à d'autres macronutriments a conduit aux mêmes aboutissants du métabolisme du fructose que lorsque le fructose est ingéré seul. Lors de la co-ngestion avec le glucose, une diminution de l'oxydation du fructose est de la néoglucogenèse est observée en parallèle à une augmentation de la synthèse de glycogène sans affecter les autres voies métaboliques.

Family doctors' consultations with people suffering from chronic pain without objective findings: Which protective practices might they develop in these challenging medical encounters?

Introduction: Consultations with patients suffering from chronic pain without objective findings represent a challenge fo r family doctors (FDs). A mutual lack of understanding may arise, which threatens the doctor-patient relationship and may lead to dissatisfaction of both patient and doctor and to a breakdown of the therapeutic alliance. Objectives: This study aims to investigate FDs' potential protective practices to preserve the doctor-patient relationship during this type of consultation. Method: In the first step of this qualitative research, I carried out a range of 10 se- mi-structured interviews with FDs to explore their reported practices and repre- sentations during consultations with people suffering from chronic pain without objective findings. The interviews' transcripts were integrally analysed with computer-assisted thematic content analysis (QSR NVivo ® ) to highlight the main themes related to the topic in the participants' talk. Results: At this point of the research, two types of FDs' protective practices can be identified: first the use of complementary sources of knowledge in addition to the medical model to provide explanations to patients, second the collaboration with multidisciplinary teams or support gr oups that allow them to share profes- sional expertise and emotional experiences. Conclusion: The findings could be useful to develop ways to improve the follow- up of patients suffering from chronic pain without objective findings and conse- quently the FDs' work satisfaction.

p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder.

BACKGROUND: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.