Distal locking of femoral nails: evaluation of a new radiation-independent targeting system.

OBJECTIVES: The purpose of this study was to assess the effectiveness of a novel radiation-independent aiming device for distal locking of intramedullary nails in a human cadaver model. METHODS: A new targeting system was used in 25 intact human cadaver femora for the distal locking procedure after insertion of an intramedullary nail. The number of successful screw placements and the time needed for this locking procedure were recorded. The accuracy of the aiming process was evaluated by computed tomography. RESULTS: The duration of the distal locking process was 8.0 ± 1.8 minutes (mean ± SD; range, 4-11 minutes). None of the screw placements required fluoroscopic guidance. Computed tomography revealed high accuracy of the locking process. The incidence angle (α) of the locking screws through the distal locking holes of the nail was 86.8° ± 5.0° (mean ± SD; range, 80°-96°). Targeting failed in 1 static locking screw because of a material defect in the drilling sleeve. CONCLUSIONS: This cadaver study indicated that an aiming arm-based targeting device is highly reliable and accurate. The promising results suggest that it will help to decrease radiation exposure compared with the traditional "free-hand technique."

Targeting burn prevention in the pediatric population : a prospective study of children's burns in the Lausanne area

Rapport de synthèse : But de l'étude : Les accidents domestiques représentent un problème significatif en médecine pédiatrique. Le but de cette étude est de mieux comprendre les mécanismes et causes des brûlures afin de pouvoir cibler la prévention. Méthode : Il s'agit d'une étude prospective d'une durée d'une année, d'Août 2004 à Août 2005. Les patients ayant consulté pour des brûlures à l'Hôpital de l'Enfance de Lausanne (HEL) ou au CHUV ont été répertoriés. Le mécanisme et les circonstances des brûlures ont été analysées, de même que l'environnement et les données psycho-sociales. Résultats : huitante-neuf patients ont été inclus dans l'étude, âgés de 2 mois à 15 ans. Septante-huit pour cent des patients avaient moins de 5 ans. Plus de la moitié étaient des garçons. Les brûlures par échaudement prédominaient. Nous n'avons pas pu mettre en évidence d'incidence augmentée de brûlures chez des patients de familles immigrées ou de niveau social bas. Dans la majorité des cas, un adulte était présent au moment de l'accident. Conclusion : Si l'on devait établir un profil type de l'enfant à risque de se brûler dans notre région, il s'agirait d'un garçon âgé de 15 mois-5ans, se brûlant en se versant une tasse de liquide chaud sur la main, à son domicile, en présence de l'un ou de ses deux parents. Le message de prévention devrait donc s'adresser directement aux parents, toutes nationalités et niveau social confondus afin de leur expliquer les dangers de brûlures présents au quotidien à leur domicile. A chaque contrôle, les pédiatres devraient parler des accidents domestiques aux parents. En insistant sur les dangers que représentent les tasses de café, la porte du four et la plaque de la cuisinière, qui sont des éléments du quotidien et qui méritent une attention à chaque utilisation. Les brûlures chez le petit enfant pourraient ainsi être fortement réduites.

Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody

S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.

Targeting IL-1β and IL-17A driven inflammation during influenza-induced exacerbations of chronic lung inflammation.

For patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. Although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. In this study, we report that interleukin-1β (IL-1β) and interleukin-17A (IL-17A) are key mediators of neutrophilic inflammation in influenza-induced exacerbations of chronic lung inflammation. Using a mouse model of disease, our data shows a role for IL-1β in mediating lung dysfunction, and in driving neutrophilic inflammation during the whole phase of viral infection. We further report a role for IL-17A as a mediator of IL-1β induced neutrophilia at early time points during influenza-induced exacerbations. Blocking of IL-17A or IL-1 resulted in a significant abrogation of neutrophil recruitment to the airways in the initial phase of infection or at the peak of viral replication, respectively. Therefore, IL-17A and IL-1β are potential targets for therapeutic treatment of viral exacerbations of chronic lung inflammation.

The deubiquitinating enzyme AMSH3 is required for intracellular trafficking and vacuole biogenesis in Arabidopsis thaliana.

Ubiquitination, deubiquitination, and the formation of specific ubiquitin chain topologies have been implicated in various cellular processes. Little is known, however, about the role of ubiquitin in the development of cellular organelles. Here, we identify and characterize the deubiquitinating enzyme AMSH3 from Arabidopsis thaliana. AMSH3 hydrolyzes K48- and K63-linked ubiquitin chains in vitro and accumulates both ubiquitin chain types in vivo. amsh3 mutants fail to form a central lytic vacuole, accumulate autophagosomes, and mis-sort vacuolar protein cargo to the intercellular space. Furthermore, AMSH3 is required for efficient endocytosis of the styryl dye FM4-64 and the auxin efflux facilitator PIN2. We thus present evidence for a role of deubiquitination in intracellular trafficking and vacuole biogenesis.

Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.

Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.

In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption.

We previously demonstrated the synergistic therapeutic effect of the cetuximab (anti-epidermal growth factor receptor [EGFR] monoclonal antibody, mAb)-trastuzumab (anti-HER2 mAb) combination (2mAbs therapy) in HER2(low) human pancreatic carcinoma xenografts. Here, we compared the 2mAbs therapy, the erlotinib (EGFR tyrosine kinase inhibitor [TKI])-trastuzumab combination and lapatinib alone (dual HER2/EGFR TKI) and explored their possible mechanisms of action. The effects on tumor growth and animal survival of the three therapies were assessed in nude mice xenografted with the human pancreatic carcinoma cell lines Capan-1 and BxPC-3. After therapy, EGFR and HER2 expression and AKT phosphorylation in tumor cells were analyzed by Western blot analysis. EGFR/HER2 heterodimerization was quantified in BxPC-3 cells by time-resolved FRET. In K-ras-mutated Capan-1 xenografts, the 2mAbs therapy gave significantly higher inhibition of tumor growth than the erlotinib/trastuzumab combination, whereas in BxPC-3 (wild-type K-ras) xenografts, the erlotinib/trastuzumab combination showed similar growth inhibition but fewer tumor-free mice. Lapatinib showed no antitumor effect in both types of xenografts. The efficacy of the 2mAbs therapy was partly Fc-independent because F(ab')(2) fragments of the two mAbs significantly inhibited BxPC-3 growth, although with a time-limited therapeutic effect. The 2mAbs therapy was associated with a reduction of EGFR and HER2 expression and AKT phosphorylation. BxPC-3 cells preincubated with the two mAbs showed 50% less EGFR/HER2 heterodimers than controls. In pancreatic carcinoma xenografts, the 2mAbs therapy is more effective than treatments involving dual EGFR/HER2 TKIs. The mechanism of action may involve decreased AKT phosphorylation and/or disruption of EGFR/HER2 heterodimerization.

Differential pattern of glycogen accumulation after protein phosphatase 1 glycogen-targeting subunit PPP1R6 overexpression, compared to PPP1R3C and PPP1R3A, in skeletal muscle cells

Background PPP1R6 is a protein phosphatase 1 glycogen-targeting subunit (PP1-GTS) abundant in skeletal muscle with an undefined metabolic control role. Here PPP1R6 effects on myotube glycogen metabolism, particle size and subcellular distribution are examined and compared with PPP1R3C/PTG and PPP1R3A/GM. Results PPP1R6 overexpression activates glycogen synthase (GS), reduces its phosphorylation at Ser-641/0 and increases the extracted and cytochemically-stained glycogen content, less than PTG but more than GM. PPP1R6 does not change glycogen phosphorylase activity. All tested PP1-GTS-cells have more glycogen particles than controls as found by electron microscopy of myotube sections. Glycogen particle size is distributed for all cell-types in a continuous range, but PPP1R6 forms smaller particles (mean diameter 14.4 nm) than PTG (36.9 nm) and GM (28.3 nm) or those in control cells (29.2 nm). Both PPP1R6- and GM-derived glycogen particles are in cytosol associated with cellular structures; PTG-derived glycogen is found in membrane- and organelle-devoid cytosolic glycogen-rich areas; and glycogen particles are dispersed in the cytosol in control cells. A tagged PPP1R6 protein at the C-terminus with EGFP shows a diffuse cytosol pattern in glucose-replete and -depleted cells and a punctuate pattern surrounding the nucleus in glucose-depleted cells, which colocates with RFP tagged with the Golgi targeting domain of β-1,4-galactosyltransferase, according to a computational prediction for PPP1R6 Golgi location. Conclusions PPP1R6 exerts a powerful glycogenic effect in cultured muscle cells, more than GM and less than PTG. PPP1R6 protein translocates from a Golgi to cytosolic location in response to glucose. The molecular size and subcellular location of myotube glycogen particles is determined by the PPP1R6, PTG and GM scaffolding.

Partisan targeting of inter-governmental transfers & state interference in local elections: evidence from Spain

[spa] En este trabajo examinamos si, en la asignación de transferencias, los gobernantes regionales discriminan a favor de los gobiernos locales controlados por el mismo partido político, y si las perspectivas electorales de los gobiernos locales mejoran si están políticamente alineados con el gobierno regional. Con una nueva base de datos que considera 3.000 municipios españoles durante el período 2000-07 y un diseño de discontinuidad en la regresión, documentamos un efecto robusto de importante magnitud: en elecciones ajustadas, los municipios alineados con el gobierno regional reciben, en media, un 83% más de transferencias per cápita y su gobernante obtiene un 10% más de votos en las elecciones locales. También demostramos que el efecto de la alineación política es mayor: (i) si las elecciones regionales y locales se celebran el mismo día, (ii) en regiones donde las elecciones regionales son menos competidas, y (iii) en regiones con más recursos presupuestarios.

Partisan targeting of inter-governmental transfers & state interference in local elections: evidence from Spain

[spa] En este trabajo examinamos si, en la asignación de transferencias, los gobernantes regionales discriminan a favor de los gobiernos locales controlados por el mismo partido político, y si las perspectivas electorales de los gobiernos locales mejoran si están políticamente alineados con el gobierno regional. Con una nueva base de datos que considera 3.000 municipios españoles durante el período 2000-07 y un diseño de discontinuidad en la regresión, documentamos un efecto robusto de importante magnitud: en elecciones ajustadas, los municipios alineados con el gobierno regional reciben, en media, un 83% más de transferencias per cápita y su gobernante obtiene un 10% más de votos en las elecciones locales. También demostramos que el efecto de la alineación política es mayor: (i) si las elecciones regionales y locales se celebran el mismo día, (ii) en regiones donde las elecciones regionales son menos competidas, y (iii) en regiones con más recursos presupuestarios.

Targeting microglial KATP channels to treat neurodegenerative diseases: a mitochondrial issue

Neurodegeneration is a complex process involving different cell types and neurotransmitters. A common characteristic of neurodegenerative disorders is the occurrence of a neuroinflammatory reaction in which cellular processes involving glial cells, mainly microglia and astrocytes, are activated in response to neuronal death. Microglia do not constitute a unique cell population but rather present a range of phenotypes closely related to the evolution of neurodegeneration. In a dynamic equilibrium with the lesion microenvironment, microglia phenotypes cover from a proinflammatory activation state to a neurotrophic one directly involved in cell repair and extracellular matrix remodeling. At each moment, the microglial phenotype is likely to depend on the diversity of signals from the environment and of its response capacity. As a consequence, microglia present a high energy demand, for which the mitochondria activity determines the microglia participation in the neurodegenerative process. As such, modulation of microglia activity by controlling microglia mitochondrial activity constitutes an innovative approach to interfere in the neurodegenerative process. In this review, we discuss the mitochondrial KATP channel as a new target to control microglia activity, avoid its toxic phenotype, and facilitate a positive disease outcome.