Local shockwave-application prevents flap necrosis

Objective: Local shockwave-application (SW) has shown to improve healing of various tissues and decrease necrosis of flaps. Though, there is no data about the optimal time-point of SW-application with regard to induction of ischemia (i.e. flap elevation) and subsequent effect on flap survival. Therefore we compared 2 shock-wave protocols in a model of persistent ischemia and investigated underlying mechanisms. Methods: 18 C57BL/6-mice equipped with a skinfold chamber containing a musculocutaneous flap were assigned to 3 experimental groups: 1. One session of 500 SWimpulses at 0·15 mJ/mm2 applied 24 hrs before (preconditioning) or 2. Applied 30 min after flap elevation (treatment). 3. Untreated flaps (control). Tissue necrosis,microhemodynamics, inflammation, apoptosis and angiogenesis were assessed by intravital epi-fluorescence microscopy over 10 days. Results: SW significantly reduced flap necrosis independent from the application time-point (preconditioning: 29 ± 7%; treatment: 25 ± 7% vs. control: 47 ± 2%; d10, p<0·05). This was associated with an early increase of functional capillary density (preconditioning: 236 ± 39 cm/cm2; treatment: 211 ± 33 cm/cm2 vs. control: 141 ± 7 cm/cm2; day1, p<0·05). Arteriolar diameter, red blood cell velocity and blood flow were comparable between the 3 experimental groups. SW-application significantly decreased the ischemiainduced inflammatory response (apoptotic cell death and leukocyte-endothelial interaction: (p<0·05)). Sprouts indicating angiogenesis were observed from day 7 only after SW-application. Conclusions: SW protects ischemically challenged musculocutaneous tissue. Interestingly, postoperative SW-application is as efficient as preoperative SWapplication. The protective effect induced by mechanical stress might be based on an early recruitment of ''sleeping capillaries'' maintaining nutritive perfusion and an anti-inflammatory effect within the ischemically jeopardized tissue. SWapplication provides a non-invasive alternative to local thermic and systemic pre-treatment of endangered tissues.

Predicting Non Return to Work after Orthopaedic Trauma: The Wallis Occupational Rehabilitation RisK (WORRK) Model.

BACKGROUND: Workers with persistent disabilities after orthopaedic trauma may need occupational rehabilitation. Despite various risk profiles for non-return-to-work (non-RTW), there is no available predictive model. Moreover, injured workers may have various origins (immigrant workers), which may either affect their return to work or their eligibility for research purposes. The aim of this study was to develop and validate a predictive model that estimates the likelihood of non-RTW after occupational rehabilitation using predictors which do not rely on the worker's background. METHODS: Prospective cohort study (3177 participants, native (51%) and immigrant workers (49%)) with two samples: a) Development sample with patients from 2004 to 2007 with Full and Reduced Models, b) External validation of the Reduced Model with patients from 2008 to March 2010. We collected patients' data and biopsychosocial complexity with an observer rated interview (INTERMED). Non-RTW was assessed two years after discharge from the rehabilitation. Discrimination was assessed by the area under the receiver operating curve (AUC) and calibration was evaluated with a calibration plot. The model was reduced with random forests. RESULTS: At 2 years, the non-RTW status was known for 2462 patients (77.5% of the total sample). The prevalence of non-RTW was 50%. The full model (36 items) and the reduced model (19 items) had acceptable discrimination performance (AUC 0.75, 95% CI 0.72 to 0.78 and 0.74, 95% CI 0.71 to 0.76, respectively) and good calibration. For the validation model, the discrimination performance was acceptable (AUC 0.73; 95% CI 0.70 to 0.77) and calibration was also adequate. CONCLUSIONS: Non-RTW may be predicted with a simple model constructed with variables independent of the patient's education and language fluency. This model is useful for all kinds of trauma in order to adjust for case mix and it is applicable to vulnerable populations like immigrant workers.

Single breath-hold 3D measurement of left atrial volume using compressed sensing cardiovascular magnetic resonance and a non-model-based reconstruction approach.

BACKGROUND: Left atrial (LA) dilatation is associated with a large variety of cardiac diseases. Current cardiovascular magnetic resonance (CMR) strategies to measure LA volumes are based on multi-breath-hold multi-slice acquisitions, which are time-consuming and susceptible to misregistration. AIM: To develop a time-efficient single breath-hold 3D CMR acquisition and reconstruction method to precisely measure LA volumes and function. METHODS: A highly accelerated compressed-sensing multi-slice cine sequence (CS-cineCMR) was combined with a non-model-based 3D reconstruction method to measure LA volumes with high temporal and spatial resolution during a single breath-hold. This approach was validated in LA phantoms of different shapes and applied in 3 patients. In addition, the influence of slice orientations on accuracy was evaluated in the LA phantoms for the new approach in comparison with a conventional model-based biplane area-length reconstruction. As a reference in patients, a self-navigated high-resolution whole-heart 3D dataset (3D-HR-CMR) was acquired during mid-diastole to yield accurate LA volumes. RESULTS: Phantom studies. LA volumes were accurately measured by CS-cineCMR with a mean difference of -4.73 ± 1.75 ml (-8.67 ± 3.54%, r2 = 0.94). For the new method the calculated volumes were not significantly different when different orientations of the CS-cineCMR slices were applied to cover the LA phantoms. Long-axis "aligned" vs "not aligned" with the phantom long-axis yielded similar differences vs the reference volume (-4.87 ± 1.73 ml vs. -4.45 ± 1.97 ml, p = 0.67) and short-axis "perpendicular" vs. "not-perpendicular" with the LA long-axis (-4.72 ± 1.66 ml vs. -4.75 ± 2.13 ml; p = 0.98). The conventional bi-plane area-length method was susceptible for slice orientations (p = 0.0085 for the interaction of "slice orientation" and "reconstruction technique", 2-way ANOVA for repeated measures). To use the 3D-HR-CMR as the reference for LA volumes in patients, it was validated in the LA phantoms (mean difference: -1.37 ± 1.35 ml, -2.38 ± 2.44%, r2 = 0.97). Patient study: The CS-cineCMR LA volumes of the mid-diastolic frame matched closely with the reference LA volume (measured by 3D-HR-CMR) with a difference of -2.66 ± 6.5 ml (3.0% underestimation; true LA volumes: 63 ml, 62 ml, and 395 ml). Finally, a high intra- and inter-observer agreement for maximal and minimal LA volume measurement is also shown. CONCLUSIONS: The proposed method combines a highly accelerated single-breathhold compressed-sensing multi-slice CMR technique with a non-model-based 3D reconstruction to accurately and reproducibly measure LA volumes and function.

Data Envelopment Analysis and non-discretionary inputs : How to select the most suitable model using multi-criteria decision analysis

Within Data Envelopment Analysis, several alternative models allow for an environmental adjustment. The majority of them deliver divergent results. Decision makers face the difficult task of selecting the most suitable model. This study is performed to overcome this difficulty. By doing so, it fills a research gap. First, a two-step web-based survey is conducted. It aims (1) to identify the selection criteria, (2) to prioritize and weight the selection criteria with respect to the goal of selecting the most suitable model and (3) to collect the preferences about which model is preferable to fulfil each selection criterion. Second, Analytic Hierarchy Process is used to quantify the preferences expressed in the survey. Results show that the understandability, the applicability and the acceptability of the alternative models are valid selection criteria. The selection of the most suitable model depends on the preferences of the decision makers with regards to these criteria.

Local Salmonella immunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor.

NlmCategory="UNASSIGNED">The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cervical cancer in an animal model. Non muscle-invasive bladder cancer is another disease that is easily amenable to local therapies. In contrast to data obtained in the GM, in this study we show that intravesical (IVES) instillation of synthetic toll-like receptor (TLR) agonists only modestly induced recruitment of CD8 T cells to the bladder. However, IVES administration of Ty21a, a live bacterial vaccine against typhoid fever, was much more effective and increased the number of total and vaccine-specific CD8 T cells in the bladder approximately 10 fold. Comparison of chemokines induced in the bladder by either CpG (a TLR-9 agonist) or Ty21a highlighted the preferential increase in complement component 5a, CXCL5, CXCL2, CCL8, and CCL5 by Ty21a, suggesting their involvement in the attraction of T cells to the bladder. IVES treatment with Ty21a after vaccination also significantly increased tumor regression compared to vaccination alone, resulting in 90% survival in an orthotopic murine model of bladder cancer expressing a prototype tumor antigen. Our data demonstrate that combining vaccination with local immunostimulation may be an effective treatment strategy for different types of cancer and also highlight the great potential of the Ty21a vaccine, which is routinely used worldwide, in such combinatorial therapies.

Traditional local medicines in the republic of Palau and non-communicable diseases (NCD), signs of effectiveness.

ETHNOPHARMACOLOGICAL RELEVANCE: The aim of this survey was to describe which traditional medicines (TM) are most commonly used for non-communicable diseases (NCD - diabetes, hypertension related to excess weight and obesity) in Pacific islands and with what perceived effectiveness. NCD, especially prevalent in the Pacific, have been subject to many public health interventions, often with rather disappointing results. Innovative interventions are required; one hypothesis is that some local, traditional approaches may have been overlooked. MATERIALS AND METHODS: The method used was a retrospective treatment-outcome study in a nation-wide representative sample of the adult population (about 15,000 individuals) of the Republic of Palau, an archipelago of Micronesia. RESULTS: From 188 respondents (61% female, age 16-87, median 48,), 30 different plants were used, mostly self-prepared (69%), or from a traditional healer (18%). For excess weight, when comparing the two most frequent plants, Morinda citrifolia L. was associated with more adequate outcome than Phaleria nishidae Kaneh. (P=0.05). In case of diabetes, when comparing Phaleria nishidae (=Phaleria nisidai) and Morinda citrifolia, the former was statistically more often associated with the reported outcome "lower blood sugar" (P=0.01). CONCLUSIONS: Statistical association between a plant used and reported outcome is not a proof of effectiveness or safety, but it can help select plants of interest for further studies, e.g. through a reverse pharmacology process, in search of local products which may have a positive impact on population health.

Targeting iron-mediated retinal degeneration by local delivery of transferrin.

Iron is essential for retinal function but contributes to oxidative stress-mediated degeneration. Iron retinal homeostasis is highly regulated and transferrin (Tf), a potent iron chelator, is endogenously secreted by retinal cells. In this study, therapeutic potential of a local Tf delivery was evaluated in animal models of retinal degeneration. After intravitreal injection, Tf spread rapidly within the retina and accumulated in photoreceptors and retinal pigment epithelium, before reaching the blood circulation. Tf injected in the vitreous prior and, to a lesser extent, after light-induced retinal degeneration, efficiently protected the retina histology and function. We found an association between Tf treatment and the modulation of iron homeostasis resulting in a decrease of iron content and oxidative stress marker. The immunomodulation function of Tf could be seen through a reduction in macrophage/microglial activation as well as modulated inflammation responses. In a mouse model of hemochromatosis, Tf had the capacity to clear abnormal iron accumulation from retinas. And in the slow P23H rat model of retinal degeneration, a sustained release of Tf in the vitreous via non-viral gene therapy efficently slowed-down the photoreceptors death and preserved their function. These results clearly demonstrate the synergistic neuroprotective roles of Tf against retinal degeneration and allow identify Tf as an innovative and not toxic therapy for retinal diseases associated with oxidative stress.

Properties of functional brain networks correlate with frequency of psychogenic non-epileptic seizures.

Abnormalities in the topology of brain networks may be an important feature and etiological factor for psychogenic non-epileptic seizures (PNES). To explore this possibility, we applied a graph theoretical approach to functional networks based on resting state EEGs from 13 PNES patients and 13 age- and gender-matched controls. The networks were extracted from Laplacian-transformed time-series by a cross-correlation method. PNES patients showed close to normal local and global connectivity and small-world structure, estimated with clustering coefficient, modularity, global efficiency, and small-worldness (SW) metrics, respectively. Yet the number of PNES attacks per month correlated with a weakness of local connectedness and a skewed balance between local and global connectedness quantified with SW, all in EEG alpha band. In beta band, patients demonstrated above-normal resiliency, measured with assortativity coefficient, which also correlated with the frequency of PNES attacks. This interictal EEG phenotype may help improve differentiation between PNES and epilepsy. The results also suggest that local connectivity could be a target for therapeutic interventions in PNES. Selective modulation (strengthening) of local connectivity might improve the skewed balance between local and global connectivity and so prevent PNES events.

Family relationships and learning experiences in anxious vs. non-anxious families: Are there differences ?

L'objectif principal de ce travail était d'explorer les relations parent-enfant et les processus d'apprentissage familiaux associés aux troubles anxieux. A cet effet, des familles ayant un membre anxieux (la mère ou l'enfant) ont été comparées avec des familles n'ayant aucun membre anxieux. Dans une première étude, l'observation de l'interaction mère-enfant, pendant une situation standardisée de jeu, a révélé que les mères présentant un trouble panique étaient plus susceptibles de se montrer verbalement contrôlantes, critiques et moins sensibles aux besoins de l'enfant, que les mères qui ne présentaient pas de trouble panique. Une deuxième étude a examiné les perceptions des différents membres de la famille quant aux relations au sein de la famille et a indiqué que, par comparaison aux adolescents non-anxieux, les adolescents anxieux étaient plus enclins à éprouver un sentiment d'autonomie individuelle diminué par rapport à leurs parents. Finalement, une troisième étude s'est intéressée à déterminer l'impact d'expériences d'apprentissage moins directes dans l'étiologie de l'anxiété. Les résultats ont indiqué que les mères présentant un trouble panique étaient plus enclines à s'engager dans des comportements qui maintiennent la panique et à impliquer leurs enfants dans ces comportements, que les mères ne présentant pas de trouble panique. En se basant sur des recherches antérieures qui ont établi une relation entre le contrôle parental, la perception de contrôle chez l'enfant et les troubles anxieux, le présent travail non seulement confirme ce lien mais propose également un modèle pour résumer l'état actuel des connaissances concernant les processus familiaux et le développement des troubles anxieux. Deux routes ont été suggérées par lesquelles l'anxiété pourrait être transmise de manière intergénérationnelle. Chacune de ces routes attribue un rôle important à la perception de contrôle chez l'enfant. L'idée est que lorsque les enfants présentent une prédisposition à interpréter le comportement de leurs parents comme hors de leur contrôle, ils seraient plus enclins à développer de l'anxiété. A ce titre, la perception du contrôle représenterait un tampon entre le comportement de contrôle/surprotection des parents et le trouble anxieux chez l'enfant. - The principal objective of the present work was to explore parent-child relationships and family learning processes associated with anxiety disorders. To this purpose, families with and without an anxious family member (mother or child) were compared. In a first study, observation of mother-child interaction, during a standard play situation, revealed that mothers with panic disorder were more likely to display verbal control and criticism, and less likely to display sensitivity toward their children than mothers without panic disorder. A second study examined family members' perceptions of family relationships and indicated that compared to non-anxious adolescents, anxious adolescents were more prone to experience a diminished sense of individual autonomy in relation to their parents. Finally a third study was interested in determining the effect of less direct learning experiences in the aetiology of anxiety. Results indicated that mothers with panic disorder were more likely to engage in panic-maintaining behaviour and to involve their children in this behaviour than mothers without panic disorder. Based on previous research showing a relationship between parental control, children's perception of control, and anxiety disorders, the present work not only further adds evidence to support this link but also proposes a model summarizing the current knowledge concerning family processes and the development of anxiety disorders. Two pathways have been suggested through which anxiety may be intergenerationally transmitted. Both pathways assign an important role to children's perception of control. The idea is that whenever children have a predisposition towards interpreting their parents' behaviour as beyond of their control, they may be more prone to develop anxiety. As such, perceived control may represent a buffer between parental overcontrolling/overprotective behaviours and childhood anxiety disorder.

Structural analysis of Turtle mountain (Alberta) using digital elevation model: Toward a progressive failure

In 1903, the eastern slope of Turtle Mountain (Alberta) was affected by a 30 M m3-rockslide named Frank Slide that resulted in more than 70 casualties. Assuming that the main discontinuity sets, including bedding, control part of the slope morphology, the structural features of Turtle Mountain were investigated using a digital elevation model (DEM). Using new landscape analysis techniques, we have identified three main joint and fault sets. These results are in agreement with those sets identified through field observations. Landscape analysis techniques, using a DEM, confirm and refine the most recent geology model of the Frank Slide. The rockslide was initiated along bedding and a fault at the base of the slope and propagated up slope by a regressive process following a surface composed of pre-existing discontinuities. The DEM analysis also permits the identification of important geological structures along the 1903 slide scar. Based on the so called Sloping Local Base Level (SLBL) an estimation was made of the present unstable volumes in the main scar delimited by the cracks, and around the south area of the scar (South Peak). The SLBL is a method permitting a geometric interpretation of the failure surface based on a DEM. Finally we propose a failure mechanism permitting the progressive failure of the rock mass that considers gentle dipping wedges (30°). The prisms or wedges defined by two discontinuity sets permit the creation of a failure surface by progressive failure. Such structures are more commonly observed in recent rockslides. This method is efficient and is recommended as a preliminary analysis prior to field investigation.

Modeling resting-state functional networks when the cortex falls asleep: local and global changes.

The transition from wakefulness to sleep represents the most conspicuous change in behavior and the level of consciousness occurring in the healthy brain. It is accompanied by similarly conspicuous changes in neural dynamics, traditionally exemplified by the change from "desynchronized" electroencephalogram activity in wake to globally synchronized slow wave activity of early sleep. However, unit and local field recordings indicate that the transition is more gradual than it might appear: On one hand, local slow waves already appear during wake; on the other hand, slow sleep waves are only rarely global. Studies with functional magnetic resonance imaging also reveal changes in resting-state functional connectivity (FC) between wake and slow wave sleep. However, it remains unclear how resting-state networks may change during this transition period. Here, we employ large-scale modeling of the human cortico-cortical anatomical connectivity to evaluate changes in resting-state FC when the model "falls asleep" due to the progressive decrease in arousal-promoting neuromodulation. When cholinergic neuromodulation is parametrically decreased, local slow waves appear, while the overall organization of resting-state networks does not change. Furthermore, we show that these local slow waves are structured macroscopically in networks that resemble the resting-state networks. In contrast, when the neuromodulator decrease further to very low levels, slow waves become global and resting-state networks merge into a single undifferentiated, broadly synchronized network.

NEUROPATHOPHYSIOLOGICAL MECHANISMS IN GLUTARIC ACIDURIA TYPE I: 3-HYDROXYGLUTARIC ACID LEADS TO AMMONIA INCREASE AND NON-APOPTOTIC CELL DEATH

A 3D in vitro model of rat organotypic brain cell cultures in aggregates was used to investigate neurotoxicity mechanisms in glutaric aciduria type I (GA-I). 1 mM glutarate (GA) or 3-hydroxyglutarate (3OHGA) were repeatedly added to the culture media at two different time points. In cultures treated with 3OHGA, we observed an increase in lactate in the medium, pointing to a possible inhibition of Krebs cycle and respiratory chain. We further observed that 3OHGA and to a lesser extend GA induced an increase in ammonia production with concomitant decrease of glutamine concentrations, which may suggest an inhibition of the astrocytic enzyme glutamine synthetase. These previously unreported findings may uncover a pathogenic mechanism in this disease which has deleterious effects on early stages of brain development. By immunohistochemistry we showed that 3OHGA increased non-apoptotic cell death. On the cellular level, 3OHGA and to a lesser extend GA led to cell swelling and loss of astrocytic fibers whereas a loss of oligodendrocytes was only observed for 3OHGA. We conclude that 3OHGAwas the most toxic metabolite in our model for GA-I. 3OHGA induced deleterious effects on glial cells, an increase of ammonia production, and resulted in accentuated cell death of non-apoptotic origin.

A musculoskeletal shoulder model based on pseudo-inverse and null-space optimization.

The goal of the present work was assess the feasibility of using a pseudo-inverse and null-space optimization approach in the modeling of the shoulder biomechanics. The method was applied to a simplified musculoskeletal shoulder model. The mechanical system consisted in the arm, and the external forces were the arm weight, 6 scapulo-humeral muscles and the reaction at the glenohumeral joint, which was considered as a spherical joint. The muscle wrapping was considered around the humeral head assumed spherical. The dynamical equations were solved in a Lagrangian approach. The mathematical redundancy of the mechanical system was solved in two steps: a pseudo-inverse optimization to minimize the square of the muscle stress and a null-space optimization to restrict the muscle force to physiological limits. Several movements were simulated. The mathematical and numerical aspects of the constrained redundancy problem were efficiently solved by the proposed method. The prediction of muscle moment arms was consistent with cadaveric measurements and the joint reaction force was consistent with in vivo measurements. This preliminary work demonstrated that the developed algorithm has a great potential for more complex musculoskeletal modeling of the shoulder joint. In particular it could be further applied to a non-spherical joint model, allowing for the natural translation of the humeral head in the glenoid fossa.

Sex biased spatial strategies relying on the integration of multimodal cues in a rat model of schizophrenia: impairment in predicting future context?

Male and female Wistar rats were treated postnatally (PND 5-16) with BSO (l-buthionine-(S,R)-sulfoximine) to provide a rat model of schizophrenia based on transient glutathione deficit. In the watermaze, BSO-treated male rats perform very efficiently in conditions where a diversity of visual information is continuously available during orientation trajectories [1]. Our hypothesis is that the treatment impairs proactive strategies anticipating future sensory information, while supporting a tight visual adjustment on memorized snapshots, i.e. compensatory reactive strategies. To test this hypothesis, BSO rats' performance was assessed in two conditions using an 8-arm radial maze task: a semi-transparent maze with no available view on the environment from maze centre [2], and a modified 2-parallel maze known to induce a neglect of the parallel pair in normal rats [3-5]. Male rats, but not females, were affected by the BSO treatment. In the semi-transparent maze, BSO males expressed a higher error rate, especially in completing the maze after an interruption. In the 2-parallel maze shape, BSO males, unlike controls, expressed no neglect of the parallel arms. This second result was in accord with a reactive strategy using accurate memory images of the contextual environment instead of a representation based on integrating relative directions. These results are coherent with a treatment-induced deficit in proactive decision strategy based on multimodal cognitive maps, compensated by accurate reactive adaptations based on the memory of local configurations. Control females did not express an efficient proactive capacity in the semi-transparent maze, neither did they show the significant neglect of the parallel arms, which might have masked the BSO induced effect. Their reduced sensitivity to BSO treatment is discussed with regard to a sex biased basal cognitive style.