Análisis del comportamiento táctico ofensivo en momentos críticos de juego en el alto rendimiento en balonmano: Un estudio Mixed Methods

El objetivo del artículo es analizar las variables que influyen enlas fases ofensivas críticas del balonmano de alto rendimiento desde unaperspectiva dinámica ecológica y con un planteamiento Mixed Methods.Evaluamos los diferentes sistemas tácticos ofensivos en ataque posicionaly en contraataque de las últimas diez posesiones del balón y acciones ofensivasde partidos de balonmano de élite mediante un análisis observacionalen dos etapas. Una primera etapa CUALI, materializada en forma de registrodescriptivo, que permitieron la construcción de un sistema de observación(SOCTO); y una segunda etapa CUANTI con la que obtuvimosun registro sistematizado posterior mediante las siguientes dimensiones: elmarcador, el tipo de defensa, la simetría numérica, la zona de finalizacióny el tipo de finalización. Utilizando el software de registro LINCE, se observaron19 partidos de las fases finales masculinas del Campeonato delMundo 2011, Campeonato de Europa 2012 y Juegos Olímpicos 2012. Elanálisis descriptivo inicial realizada por entrenadores expertos se ha complementadocon un análisis de T-patterns. Los resultados reafirman que enlos momentos críticos y de desigualdad del final de los partidos los equiposperdedores utilizan en la fase ofensiva las zonas de finalización más alejadasde la portería contraria (zona de 9 metros) y los equipos ganadores utilizanen la fase ofensiva las zonas de finalización intermedias (entre 6 y 9 metros)aumentando así su eficacia

Timing of adjuvant chemotherapy after limb amputation and effect on outcome in dogs with appendicular osteosarcoma without distant metastases

Objective: To determine an optimal time interval between amputation and initiation of adjuvant chemotherapy (TIamp-chemo) in dogs with appendicular osteosarcoma without distant metastases and whether TIamp-chemo was associated with outcome. Animals: 168 client-owned dogs treated at 9 veterinary oncology centers. Procedures: Data were collected from the dogs' medical records concerning potential prognostic variables and outcomes. Dogs were grouped as to whether they received chemotherapy within 3, 5, 7, 10, 15, 20, 30, or > 30 days after amputation of the affected limb. Analyses were performed to identify variables associated with time to tumor progression and survival time after limb amputation and to determine an optimal TIamp-chemo. Results: Median TIamp-chemo was 14 days (range, 1 to 210 days). Median time to tumor progression for dogs with a TIamp-chemo ≤ 5 days (375 days; 95% CI, 162 to 588 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (202 days; 95% CI, 146 to 257 days). Median overall survival time for dogs with a TIamp-chemo ≤ 5 days (445 days; 95% CI, 345 to 545 days) was significantly longer than that for dogs with a TIamp-chemo > 5 days (239 days; 95% CI, 186 to 291 days). Conclusions and clinical relevance: Findings indicated that early (within 5 days) initiation of adjuvant chemotherapy after limb amputation was associated with a significant and clinically relevant survival benefit for dogs with appendicular osteosarcoma without distant metastases. These results suggested that the timing of chemotherapy may be an important prognostic variabl

Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia

Objective: Myotonia congenita (MC) is a rare muscle disease characterized by sarcolemma over-excitability inducing skeletal muscle stiffness. It can be inherited either as an autosomal dominant (Thomsen's disease) or an autosomal recessive (Becker's disease) trait. Both types are caused by loss-of-function mutations in the CLCN1 gene, encoding for ClC-1 chloride channel. We found a ClC-1 mutation, p.G411C, identified in Russian patients who suffered from a severe form of Becker's disease. The purpose of this study was to provide a solid correlation between G411C dysfunction and clinical symptoms in the affected patient. Methods: We provide clinical and genetic information of the proband kindred. Functional studies include patch-clamp electrophysiology, biotinylation assay, western blot analysis, and confocal imaging of G411C and wild-type ClC-1 channels expressed in HEK293T cells. Results: The G411C mutation dramatically abolished chloride currents in transfected HEK cells. Biochemical experiments revealed that the majority of G411C mutant channels did not reach the plasma membrane but remained trapped in the cytoplasm. Treatment with the proteasome inhibitor MG132 reduced the degradation rate of G411C mutant channels, leading to their expression at the plasma membrane. However, despite an increase in cell surface expression, no significant chloride current was recorded in the G411C-transfected cell treated with MG132, suggesting that this mutation produces non-functional ClC-1 chloride channels. Conclusion: These results suggest that the molecular pathophysiology of G411C is linked to a reduced plasma membrane expression and biophysical dysfunction of mutant channels, likely due to a misfolding defect. Chloride current abolition confirms that the mutation is responsible for the clinical phenotype

ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation

Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function

Protein kinase C theta (PKCθ) modulates the ClC-1 chloride channel activity and skeletal muscle phenotype: a biophysical and gene expression study in mouse models lacking the PKCθ

In skeletal muscle, the resting chloride conductance (gCl), due to the ClC-1 chloride channel, controls the sarcolemma electrical stability. Indeed, loss-of-function mutations in ClC-1 gene are responsible of myotonia congenita. The ClC-1 channel can be phosphorylated and inactivated by protein kinases C (PKC), but the relative contribution of each PKC isoforms is unknown. Here, we investigated on the role of PKCθ in the regulation of ClC-1 channel expression and activity in fast- and slow-twitch muscles of mouse models lacking PKCθ. Electrophysiological studies showed an increase of gCl in the PKCθ-null mice with respect to wild type. Muscle excitability was reduced accordingly. However, the expression of the ClC-1 channel, evaluated by qRT-PCR, was not modified in PKCθ-null muscles suggesting that PKCθ affects the ClC-1 activity. Pharmacological studies demonstrated that although PKCθ appreciably modulates gCl, other isoforms are still active and concur to this role. The modification of gCl in PKCθ-null muscles has caused adaptation of the expression of phenotype-specific genes, such as calcineurin and myocyte enhancer factor-2, supporting the role of PKCθ also in the settings of muscle phenotype. Importantly, the lack of PKCθ has prevented the aging-related reduction of gCl, suggesting that its modulation may represent a new strategy to contrast the aging process

Difference in outcome between curative intent vs marginal excision as a first treatment in dogs with oral malignant melanoma and the impact of adjuvant CSPG4-DNA electrovaccination: A retrospective study on 155 cases

Canine oral malignant melanoma is locally invasive and highly metastatic. At present, the best option for local control is en bloc excision followed by radiation if excision margins are incomplete. Adjuvantly, the role of chemotherapy is dubious while immunotherapy appears encouraging. This retrospective study evaluated 155 dogs with oral malignant melanomas (24 stage I, 54 stage II, 66 stage III and 11 stage IV) managed in a single institution. The aim was to evaluate the differences in median survival time (MST) and disease‐free interval (DFI) between dogs which, at presentation, were treated surgically with a curative intent (group 1) vs those marginally excised only (group 2). MST in group 1 was longer than in group 2 (594 vs 458 days), but no significant difference was found (P = .57); a statistical difference was, however, found for DFI (232 vs 183 days, P = .008). In the subpopulation of vaccinated dogs, the impact of adjuvant anti‐CSPG4 DNA electrovaccination was then evaluated (curative intent, group 3, vs marginal, group 4); a significant difference for both MST (1333 vs 470 days, respectively, P = .03) and DFI (324 vs 184 days, respectively, P = .008) was found. Progressive disease was significantly more common in dogs undergoing marginal excision than curative intent excision for both the overall population (P = .03) and the vaccinated dogs (P = .02). This study pointed out that, after staging, wide excision together with adjuvant immunotherapy was an effective approach for canine oral malignant melanoma

Renal and Neurologic Effects of Cadmium, Lead, Mercury, and Arsenic in Children: Evidence of Early Effects and Multiple Interactions at Environmental Exposure Levels

Lead, cadmium, mercury, and arsenic are common environmental pollutants in industrialized countries, but their combined impact on children’s health is little known. We studied their effects on two main targets, the renal and dopaminergic systems, in > 800 children during a cross-sectional European survey. Control and exposed children were recruited from those living around historical nonferrous smelters in France, the Czech Republic, and Poland. Children provided blood and urine samples for the determination of the metals and sensitive renal or neurologic biomarkers. Serum concentrations of creatinine, cystatin C, and β(2)-microglobulin were negatively correlated with blood lead levels (PbB), suggesting an early renal hyperfiltration that averaged 7% in the upper quartile of PbB levels (> 55 μg/L; mean, 78.4 μg/L). The urinary excretion of retinol-binding protein, Clara cell protein, and N-acetyl-β-d-glucosaminidase was associated mainly with cadmium levels in blood or urine and with urinary mercury. All four metals influenced the dopaminergic markers serum prolactin and urinary homovanillic acid, with complex interactions brought to light. Heavy metals polluting the environment can cause subtle effects on children’s renal and dopaminergic systems without clear evidence of a threshold, which reinforces the need to control and regulate potential sources of contamination by heavy metals