D-JNKi, a peptide inhibitor of c-Jun N-terminal kinase, promotes functional recovery after transient focal cerebral ischemia in rats

The c-Jun-N-terminal kinase (JNK) pathway has been shown to play an important role in excitotoxic neuronal death and several studies have demonstrated a neuroprotective effect of D-JNKi, a peptide inhibitor of JNK, in various models of cerebral ischemia. We have now investigated the effect of D-JNKi in a model of transient focal cerebral ischemia (90 min) induced by middle cerebral artery occlusion (MCAo) in adult male rats. D-JNKi (0.1 mg/kg), significantly decreased the volume of infarct, 3 days after cerebral ischemia. Sensorimotor and cognitive deficits were then evaluated over a period of 6 or 10 days after ischemia and infarct volumes were measured after behavioral testing. In behavioral studies, D-JNKi improved the general state of the animals as demonstrated by the attenuation of body weight loss and improvement in neurological score, as compared with animals receiving the vehicle. Moreover, D-JNKi decreased sensorimotor deficits in the adhesive removal test and improved cognitive function in the object recognition test. In contrast, D-JNKi did not significantly affect the infarct volume at day 6 and at day 10. This study shows that D-JNKi can improve functional recovery after transient focal cerebral ischemia in the rat and therefore supports the use of this molecule as a potential therapy for stroke.

Comparison of a multiplexed bead-based assay with an immunofluorescence and an enzyme-immuno assay for the assessment of Epstein-Barr virus serologic status

Dans cette étude, nous avons testé la performance diagnostique d'une nouvelle technique d'analyse multiplexée qui permet la détection d'anticorps de différentes spécificités dans la même réaction. En l'absence de gold standard, nous avons choisi de comparer la performance diagnostique de l'analyse avec deux méthodes de référance que sont l'IF et EIA, et avec un consensus déterminé selon une règle de majorité entre les trois méthodes.¦393 sérums analysés par IF, conservés par congélation, ont été décongelés pour être analysés par EIA et BBA. Pour chaque sérum, les anticorps recherchés ont été les anti-VCA (Viral Capsid Antigen) IgM, anti-VCA IgG et anti-EBNA (Epstein-Barr Nuclear Associated) IgG. Les échantillons ont été classés en cinq groupes selon les résultats de l'IF : séronégatifs, infections aiguës, infections anciennes et deux types d'indéterminés.¦Pour chaque méthode, le résultat numérique (index ou titre) des analyses est converti en termes de positif, négatif ou douteux. Pour le résultat de chaque type d'anticorps, un consensus est établi selon une règle de majorité entre les trois méthodes, permettant une interprétation du stade de l'infection. Puis l'interprétation de chacune des méthodes a été comparée au consensus. Nous avons également comparé les trois méthodes les unes aux autres concernant la détection des anticorps.¦Globalement, nous observons une bonne corrélation qualitative entre les trois approches pour détecter les anti-VCA IgG et IgM. Pour pour les anti-EBNA IgG, il y a une divergence notable entre l'IF et les deux autres méthodes, l'IF apparaissant moins sensible que les autres méthodes, résultant en un nombre accru d'interprétations indéterminées du stade de l'infection.¦L'origine de cette divergence ne peut être due à une perte d'anticorps liée au stockage de longue durée des échantillons. En effet, EIA et BBA restent plus sensibles que IF, dont l'analyse a été faite sur des sérums frais.¦Cette divergence ne semble pas non plus être due aux différents antigènes utilisés par les trois méthodes. EIA et BBA utilisent le même antigène recombinant EBNA-1, alors que l'IF utilise des "cellules lymphoïdes choisies pour leur production sélective d'antigènes EBNA". Ces cellules sont probablement des cellules infectées par EBV qui devraient exprimer plus d'antigènes de latence que seul EBNA-1. Cette différence devrait donc plutôt en principe résulter en une meilleure sensibilité de l'IF par rapport aux deux autres méthodes.¦Les anti-EBNA IgG peuvent disparaître chez les patients immunocompromis chez qui se produit une réactivation d'EBV. Nous avons donc recherché le status immunitaire des patients du groupe dont les sérums étaient négatifs pour anti-EBNA IgG en IF et positifs par les autres méthodes: seulement 28 des 70 patients étaient immunocompromis.¦Par conséquent, il est probable que dans la majorité de ces résultats discordants, les anticorps anti-EBNA IgG détectés par BBA et EIA sont de vrais positifs non décelés par l'IF.¦En conclusion, BBA est meilleur que la méthode de référance qu'est l'IF, et est égal à EIA en ce qui concerne la performance diagnostique. En outre, ces deux nouvelles méthodes offrent une économie de temps en raison de manipulations moindres, et ne requièrent aucune formation en microscopie à fluorescence. Elles sont également plus économes en échantillons que IF. BBA a l'avantage de n'avoir besoin que de deux analyses pour donner un diagnostique, alors que IF et EIA ont en besoin d'une par anticorps. Enfin, BBA dispose de contrôles internes permettant de reconnaître les liaisons non antigène-spécifiques des anticorps. Par contre, BBA nécessite l'achat d'un lecteur par cytométrie de flux assez coûteux.

Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitary functional and nonfunctional macroadenoma.

Purpose: To evaluate the efficacy and toxicity of stereotactic fractionated radiotherapy (SFRT) for patients with pituitary macroadenoma (PMA).Methods and Materials: Between March 2000 and March 2009, 27 patients (male to female ratio, 1.25) with PMA underwent SFRT (median dose, 50.4 Gy). Mean age of the patients was 56.5 years (range, 20.3 - 77.4). In all but one patient, SFRT was administered for salvage treatment after surgical resection (transphenoidal resection in 23, transphenoidal resection followed by craniotomy in 2 and multiple transphenoidal resections in another patient). In 10 (37%) patients, the PMAs were functional (3 ACTH-secreting, 3 prolactinomas, 2 growth hormone-secreting and 2 multiple hormone-secretion). Three (11.1%) and 9 (33.3%) patients had PMA abutting and compressing the optic chiasm, respectively. Mean tumor volume was 2.9 +/- 4.6 cm(3). Eighteen (66.7%) patients had hypopituitarism prior to SFRT. The mean follow-up period after SFRT was 72.4 +/- 37.2 months.Results: Tumor size decreased for 6 (22.2%) patients and remained unchanged for 19 (70.4%) other patients. Two (7.4%) patients had tumor growth inside the prescribed treatment volume. The estimated 5-year tumor growth control was 95.5% after SFRT. Biochemical remission occurred in 3 (30%) patients with functional PMA. Two patients with normal anterior pituitary function before SFRT developed new deficits 25 and 65 months after treatment. The 5-year survival without new anterior pituitary deficit was thus 95.8%. Five patients with visual field defect had improved visual function and 1 patient with no visual defect prior to SFRT, but an optic chiasm abutting tumor, had a decline in visual function. The estimated 5-year vision and pituitary function preservation rates were 93.2% and 95.8%, respectively.Conclusions: SFRT is a safe and effective treatment for patients with PMA, although longer follow-up is needed to evaluate long-term outcomes. In this study, approximately 1 patient with visual field defect out of two had an improved visual.

Confirmation of functional zones within the human subthalamic nucleus: patterns of connectivity and sub-parcellation using diffusion weighted imaging.

The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinson's disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery.

Scores de mesure fonctionnelle articulaire pour le praticien [Joint functional outcome score for the clinician].

The sports clinician faces multiple treatment options when dealing with overload injuries, and it is important to evaluate their outcomes. Multiple scores exist, some clincian rated (CRO), others patient rated (PRO), the latter being currently favoured. This review presents some of these scores and we selected the ones we feel are the most appropriate for a sports clinician. We considered these common problems: tennis elbow, rotator cuff issues, groin pain, patellofemoral pain syndrome, achilles tendinopathy and ankle instability. In addition, an activity level score is useful to weigh the result in the context of return to performance. These scores help to create a common language between therapists and to evaluate treatments objectively.

Early functional differentiation in the chick embryonic disc: interaction between mechanical activity and extracellular matrix

The mechanical behaviour of ectodermal cells in the area opaca and the supracellular organization of fibronectin in the adjacent extracellular matrix were studied in whole chick blastoderms developing in vitro. The pattern of spontaneous mechanical activity and its modification by immunoglobulins against fibronectin were determined using a real-time image-analysis system. The pattern of fibronectin was studied using immunocytochemical techniques. It was found that the ectodermal cells in the area opaca actively develop a radially oriented contraction, which leads to a distension of the area pellucida from which the embryo develops. Abnormally increased tension resulted in perturbations of gastrulation and neurulation. An optimized mechanical equilibrium within the blastoderm seems to be necessary for normal development. Anti-fibronectin antibodies applied to the basal side of the blastoderm led rapidly and reversibly to an increase of tension in the contracted cells. This observation indicates that modifications of the extracellular matrix can be transmitted to cytoskeletal elements within adjacent cells. The extracellular matrix of the area opaca contains fibronectin arranged in radially oriented fibrils. This orientation corresponds to the direction of migration of the mesodermal cells. Interestingly, the radial pattern of fibronectin is found in the regions where the ectodermal cells are contracted and develop radially oriented forces. This observation suggests that the supracellular assembly of the extracellular materials could be influenced by the mechanical activity of adjacent cells. Possible modulations of the supracellular organization of extracellular matrix by other factors, e.g. diffusible metabolites, is also discussed. The presence of characteristically organized extracellular matrix components, of spatially differentiated cell activities and of reciprocal interactions between them makes the young chick blastoderm an excellent system for physiological studies of the coordinated cellular activities that lead to changes in form, complexity and function.

Analysis of functional and anatomical success following endonasal dacryocystorhinostomy

RésuméLes sténoses des voies lacrymales sont fréquentes surtout chez les patients âgés et provoquent en général un epiphora avec parfois des dacryocystites aiguës ou chroniques. La dacryocystorhinostomie par voie externe (DCREX) a été la technique de choix pour traiter les sténoses post-canaliculaires au XXe siècle. Avec l'avènement de l'endoscopie nasale, l'abord endonasal est devenu facilement accessible et depuis une dizaine d'années, la dacryocystorhinostomie par voie endonasale (DCREN) est en train de supplanter la DCREX dans la majorité des cas.Le but de ce travail est de déterminer les étiologies des sténoses des voies lacrimales, d'évaluer le taux de succès et les complications de la DCREN et de détailler les gestes associés peropératoires.Cette étude rétrospective porte sur 98 patients ayant subi 104 DCREN entre janvier 1994 et février 2006. 78 patients (53 femmes et 25 hommes) présentant 84 sténoses post- canaliculaires remplissent les critères d'inclusion de l'étude. L'âge moyen est de 59 ans (4 - 89 ans).Les résultats obtenus montrent un taux de succès fonctionnel de 94.9% après une première intervention (59/84 DCREN) et de 63.6% pour les DCREN secondaires qui nous ont été référées après d'autres interventions des voies lacrymales (25/84 DCREN). Le suivi postopératoire est de 36,8 mois (12-77 mois). On dénombre 61 gestes rhino-sinusaux associés à la DCREN. Les complications per- et postopératoires sont rares, essentiellement liées aux drains bicanaliculaires. Une étiologie n'a été retrouvée que dans 28% des cas.En conclusion, la DCREN donne d'excellents résultats et peu de complications. En raison des nombreux avantages par rapport à la voie externe et la possibilité du traitement simultané de la pathologie ORL parfois associée, la DCREN est devenue le traitement de premier choix pour les sténoses postcanaliculaires. Le principal défi, quelque soit le type de DCR, est de poser la bonne indication opératoire et en cas d'échec opératoire savoir méticuleusement analyser ses causes

Avian erythrocytes have functional mitochondria, opening novel perspectives for birds as animal models in the study of ageing.

BACKGROUND: In contrast to mammalian erythrocytes, which have lost their nucleus and mitochondria during maturation, the erythrocytes of almost all other vertebrate species are nucleated throughout their lifespan. Little research has been done however to test for the presence and functionality of mitochondria in these cells, especially for birds. Here, we investigated those two points in erythrocytes of one common avian model: the zebra finch (Taeniopygia guttata). RESULTS: Transmission electron microscopy showed the presence of mitochondria in erythrocytes of this small passerine bird, especially after removal of haemoglobin interferences. High-resolution respirometry revealed increased or decreased rates of oxygen consumption by erythrocytes in response to the addition of respiratory chain substrates or inhibitors, respectively. Fluorometric assays confirmed the production of mitochondrial superoxide by avian erythrocytes. Interestingly, measurements of plasmatic oxidative markers indicated lower oxidative stress in blood of the zebra finch compared to a size-matched mammalian model, the mouse. CONCLUSIONS: Altogether, those findings demonstrate that avian erythrocytes possess functional mitochondria in terms of respiratory activities and reactive oxygen species (ROS) production. Interestingly, since blood oxidative stress was lower for our avian model compared to a size-matched mammalian, our results also challenge the idea that mitochondrial ROS production could have been one actor leading to this loss during the course of evolution. Opportunities to assess mitochondrial functioning in avian erythrocytes open new perspectives in the use of birds as models for longitudinal studies of ageing via lifelong blood sampling of the same subjects.

High proportion of wrongly identified methicillin-resistant Staphylococcus aureus carriers by use of a rapid commercial PCR assay due to presence of staphylococcal cassette chromosome element lacking the mecA gene.

During a 9-month period, 217 patients were newly diagnosed as methicillin-resistant Staphylococcus aureus (MRSA) carriers by using a commercial rapid PCR-based test (GeneXpert). However, no MRSA was recovered by culturing the second swab in 61 of these patients. Further analyses showed that 28 (12.9%) of the patients harbored S. aureus isolates with a staphylococcal cassette chromosome element lacking the mecA gene and were thus incorrectly determined to be MRSA carriers.

Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent.

Clinically, heart failure is an age-dependent pathological phenomenon and displays sex-specific characteristics. The renin-angiotensin system mediates cardiac pathology in heart failure. This study investigated the sexually dimorphic functional effects of ageing combined with angiotensin II (AngII) on cardiac muscle cell function, twitch and Ca(2+)-handling characteristics of isolated cardiomyocytes from young (~13 weeks) and aged (~87 weeks) adult wild type (WT) and AngII-transgenic (TG) mice. We hypothesised that AngII-induced contractile impairment would be exacerbated in aged female cardiomyocytes and linked to Ca(2+)-handling disturbances. AngII-induced cardiomyocyte hypertrophy was evident in young adult mice of both sexes and accentuated by age (aged adult ~21-23 % increases in cell length relative to WT). In female AngII-TG mice, ageing was associated with suppressed cardiomyocyte contractility (% shortening, maximum rate of shortening, maximum rate of relaxation). This was associated with delayed cytosolic Ca(2+) removal during twitch relaxation (Tau ~20 % increase relative to young adult female WT), and myofilament responsiveness to Ca(2+) was maintained. In contrast, aged AngII-TG male cardiomyocytes exhibited peak shortening equivalent to young TG; yet, myofilament Ca(2+) responsiveness was profoundly reduced with ageing. Increased pro-arrhythmogenic spontaneous activity was evident with age and cardiac AngII overexpression in male mice (42-55 % of myocytes) but relatively suppressed in female aged transgenic mice. Female myocytes with elevated AngII appear more susceptible to an age-related contractile deficit, whereas male AngII-TG myocytes preserve contractile function with age but exhibit desensitisation of myofilaments to Ca(2+) and a heightened vulnerability to arrhythmic activity. These findings support the contention that sex-specific therapies are required for the treatment of age-progressive heart failure.

Diffusion spectrum imaging shows the structural basis of functional cerebellar circuits in the human cerebellum in vivo.

BACKGROUND: The cerebellum is a complex structure that can be affected by several congenital and acquired diseases leading to alteration of its function and neuronal circuits. Identifying the structural bases of cerebellar neuronal networks in humans in vivo may provide biomarkers for diagnosis and management of cerebellar diseases. OBJECTIVES: To define the anatomy of intrinsic and extrinsic cerebellar circuits using high-angular resolution diffusion spectrum imaging (DSI). METHODS: We acquired high-resolution structural MRI and DSI of the cerebellum in four healthy female subjects at 3T. DSI tractography based on a streamline algorithm was performed to identify the circuits connecting the cerebellar cortex with the deep cerebellar nuclei, selected brainstem nuclei, and the thalamus. RESULTS: Using in-vivo DSI in humans we were able to demonstrate the structure of the following cerebellar neuronal circuits: (1) connections of the inferior olivary nucleus with the cerebellar cortex, and with the deep cerebellar nuclei (2) connections between the cerebellar cortex and the deep cerebellar nuclei, (3) connections of the deep cerebellar nuclei conveyed in the superior (SCP), middle (MCP) and inferior (ICP) cerebellar peduncles, (4) complex intersections of fibers in the SCP, MCP and ICP, and (5) connections between the deep cerebellar nuclei and the red nucleus and the thalamus. CONCLUSION: For the first time, we show that DSI tractography in humans in vivo is capable of revealing the structural bases of complex cerebellar networks. DSI thus appears to be a promising imaging method for characterizing anatomical disruptions that occur in cerebellar diseases, and for monitoring response to therapeutic interventions.

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.