ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma

Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-d-aspartate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-d-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans.

Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients.

The cellular mechanisms responsible for enhanced muscle protein breakdown in hospitalized patients, which frequently results in lean body wasting, are unknown. To determine whether the lysosomal, Ca2+-activated, and ubiquitin-proteasome proteolytic pathways are activated, we measured mRNA levels for components of these processes in muscle biopsies from severe head trauma patients. These patients exhibited negative nitrogen balance and increased rates of whole-body protein breakdown (assessed by [13C]leucine infusion) and of myofibrillar protein breakdown (assessed by 3-methylhistidine urinary excretion). Increased muscle mRNA levels for cathepsin D, m-calpain, and critical components of the ubiquitin proteolytic pathway (i.e., ubiquitin, the 14-kDa ubiquitin-conjugating enzyme E2, and proteasome subunits) paralleled these metabolic adaptations. The data clearly support a role for multiple proteolytic processes in increased muscle proteolysis. The ubiquitin proteolytic pathway could be activated by altered glucocorticoid production and/or increased circulating levels of interleukin 1beta and interleukin 6 observed in head trauma patients and account for the breakdown of myofibrillar proteins, as was recently reported in animal studies.

Adaptación psicométrica de los cuestionarios "Trauma Symptom Checklist for Children" (TSCC) y "Trauma Symptom Checklist for Young Children" (TSCYC) en una muestra española de víctimas de abuso sexual infantil

El maltrato infantil y el abuso sexual, como tipo de maltrato en la infancia, supone un problema social que ha estado presente a lo largo de la historia, en todos los países, culturas, estratos sociales. El abuso sexual infantil ha presentado dificultades para su definición al no existir un acuerdo único y darse diferencias sobre los criterios definitorios. Las definiciones propuestas han sido múltiples, algunas son más restrictivas, mientras que otras tienen una perspectiva más amplia. Una de las definiciones más ampliamente usada y aceptada internacionalmente ha sido la propuesta por la OMS (2001), al incorporar los criterios de que el menor se encuentra inmerso en actividades o comportamientos para los que no se encuentra preparado ni física ni psicológicamente, sin disponer de la capacidad de consentimiento, transgrediendo la legislación vigente en cada país (Stoltenborgh, Van Ijendoorn, Euser y Bakermans-Kranenbirg, 2011, en Amado, Arce y Herraiz, 2015). En el campo de la investigación social, la mayoría de profesionales hacen uso de los criterios propuestos por Finkelhor y Hotaling (1984), ratificados en España por López (1994). Dichos conceptos han sido el de coerción y la asimetría de edad o diferencias a nivel madurativo, lo que conlleva a una incapacidad a una libre decisión. Dado que el abuso sexual se suele dar en la más estricta intimidad, resulta realmente complicado cuantificar y estimar su prevalencia e incidencia, dada la denominada “cifra negra” de este tipo de situaciones, puesto que parte de los casos no se han denunciado o ni siquiera se han notificado. A pesar de ello, algunos estudios, como el meta-analítico realizado por Pereda, Guilera, Forns y Gómez-Benito (2009), han notificado una prevalencia de entre 7,4% en el caso de los niños y del 19,2% en las niñas...

Avaliação da capacidade funcional de pacientes vítimas de trauma um ano após alta hospitalar

Objetivos: Avaliar a capacidade funcional de pacientes vítimas de trauma um ano após alta hospitalar e verificar associação da capacidade funcional com fatores relacionados ao trauma e à internação hospitalar. Metodologia: Estudo de coorte prospectivo, com pacientes vítimas de trauma grave (Injury Severity Score - ISS >=16), internados entre Junho e Setembro de 2010 em unidade de terapia intensiva (UTI) cirúrgica especializada em paciente politraumatizado de um hospital público de grande porte na cidade de São Paulo, Brasil. Variáveis de interesse como idade, sexo, escore de Glasgow, Acute Physiology and Chronic Health Disease Classification System II (APACHE II), mecanismos de trauma, número de lesões, região corpórea afetada, número de cirurgias, duração da ventilação mecânica (VM) e tempo de internação hospitalar foram coletadas dos prontuários médicos. A capacidade funcional foi avaliada um ano após alta hospitalar utilizando as escalas Glasgow Outcome Scale (GOS) e Escala de Atividades Instrumentais de Vida Diária de Lawton (AIVDL). Os pacientes também foram questionados se haviam retornado ao trabalho ou estudo. Resultados: O seguimento um ano após trauma foi completo em 49 indivíduos, a maioria composta por jovens (36±11 anos), do sexo masculino (81,6%) e vítimas de acidentes de trânsito (71,5%). Cada indivíduo sofreu aproximadamente 4 lesões corporais, acarretando uma média no ISS de 31 ± 14,4. O traumatismo cranioencefálico foi o tipo de lesão mais comum (65,3%). De acordo com a GOS, a maioria dos pacientes apresentou disfunção moderada (43%) ou disfunção leve ou ausente (37%) um ano após o trauma. A escala AIVDL apresentou pontuação média de 12±4 com aproximadamente 60- 70% dos indivíduos capazes de realizar de forma independente a maioria das atividades avaliadas. Escore de Glasgow, APACHE II, duração da VM e tempo de internação hospitalar foram associadas com a capacidade funcional um ano após lesão. A regressão linear múltipla considerando todas as variáveis significativas revelou associação entre a pontuação da escala AIVDL e o tempo de internação hospitalar. Apenas 32,6% dos indivíduos retornaram ao trabalho ou estudo. Conclusões: A maioria dos pacientes vítimas de trauma grave foi capaz de realizar as atividades avaliadas com independência; apenas um terço deles retornou ao trabalho e/ou estudo um ano após alta hospitalar. O tempo de internação hospitalar foi revelado como preditor significativo para a recuperação da capacidade funcional um ano após lesão grave

Interpersonal Trauma, Posttraumatic Stress and Depression

Dating aggression is common among emerging adults, and women who experience aggression from a dating partner are at risk for elevated depression and posttraumatic stress (Dutton et al., 2006). Although some women end their relationships as a result of aggression, other women remain committed to their partner, and aggression tends to escalate over time. The current study explored the role that depression and posttraumatic stress play in ending aggressive dating relationships as well as changes in these symptoms after ending such a relationship. The current study also sought to identify factors predictive of individual differences in emerging adults' commitment to their aggressive dating relationships. A sample of 148 emerging adult women currently in an aggressive dating relationship completed questionnaires about themselves and their relationship; measures of rejection sensitivity, self-worth, and romantic relational style were included as predictors of the Investment Model variables (e.g., investment, satisfaction, quality of alternatives, and commitment; Rusbult, 1980). Two assessments were completed six months apart. Neither depression nor posttraumatic stress predicted ending an aggressive relationship. However, ending an aggressive relationship was associated with experiencing less physical aggression, which mediated reductions in posttraumatic stress. A more avoidant romantic style indirectly predicted commitment through relationship satisfaction and investment. Both commitment and rejection sensitivity significantly predicted continuing an aggressive relationship six months later.

Trauma Treatment in Forensic Settings: Clinicians' Perspectives, Barriers to Effective Treatment, and Suggestions for Clinical Practice

Between 30% and 90% of the prison population is estimated to have survived traumatic experiences such as sexual, emotional, and physical abuse prior to incarceration (Anonymous, 1999; Fondacaro, Holt, & Powell, 1999; Messina & Grella, 2006; Pollard & Baker, 2000; Veysey, De Cou, & Prescott, 1998). Similarly, information from the Bureau of Justice Statistics (as reported in Warren, 2001) estimated that more than half of the women in state prisons have experienced past physical and sexual abuse. Thus, given the astonishing number of inmates who appear to be victims of some kind of trauma, it seems likely that those who work with these inmates (e.g., prison staff, guards, and treatment providers) will in some way encounter challenges related to the inmates' trauma history. These difficulties may appear in any number of forms including inmates' behavioral outbursts, increased emotionality, sensitivity to triggering situations, and chronic physical or mental health needs (Veysey, et al., 1998). It is also likely that these individuals with trauma histories would benefit greatly from treatment while incarcerated. This treatment could be utilized to minimize symptoms of posttraumatic stress, decrease behavioral problems, and help the inmate function more effectively in society when released from incarceration (Kokorowski & Freng, 2001; Tucker, Cosio, Meshreki, 2003). Few studies have explored the types of trauma treatment that are effective with inmate populations or made specific suggestions for clinicians working in forensic settings (Kokorowski & Freng, 2001). Essentially, there appears to be a large gap in terms of the need for trauma treatment for inmates and the lack of literature addressing what to do about it. However, clinicians across the country seem to be quietly attempting to fulfill this need for trauma treatment with incarcerated populations. They are providing this greatly needed treatment every day. in the face of enormous challenges and often without recognition or the opportunity to share their valuable work with the larger community.

On the Edge of the World: Trauma and Twinship Selfobject Needs in Mrs. Dalloway

Alienation and aloneness appear as common themes in the experience of those impacted by trauma. Self psychology theorists, including contemporary proponents of intersubjectivity theory, have also discussed the ways in which alienation and disconnection from others permeate the experience of post-traumatic stress disorder. This discussion has highlighted the importance and centrality of twinship selfobject needs in providing a relational home for the emotional pain associated with trauma. These phenomena are especially apparent when one encounters the experiences of those combat veterans who have attempted to readjust to society upon returning home from military service. Using self psychology and intersubjectivity theory, this paper explores the ways that fiction, specifically Virginia Woolf's Mrs. Dalloway, can illuminate the ways that trauma negatively impacts twinship selfobject needs in combat veterans. In examining the character of Septimus Smith, this paper illustrates the estrangement, singularity, and alienation associated with post-traumatic stress, and how this state of being can collude with societal misunderstanding and repression to shatter the self's sense of belongingness with and connection to others.

From The Holding Cell to the Holding Environment: Applying an Intersubjective Approach into Trauma Treatment with Women in the Correctional Setting

Abstract This paper investigates themes and parallels related to the traumatic experiences women face within the correctional setting and how these experiences influence women's behavior choices that increase their risk of recidivism. Intersubjective Systems Theory is used to conceptualize the distinct dynamics and impact of trauma with this particular population. Intersubjectivity also informs the changes needed to create an environment that would help women in correctional settings to heal, avoid recidivism, and foster successful community reintegration. Principles from Intersubjective Systems Theory are reviewed in this paper to demonstrate: (a) how developmental trauma impacts the lives of incarcerated women, (b) how these women's attempts at self-healing are often maladaptive and lead to arrests, (c) how the current climate in corrections leads to retraumatization and promotes later recidivism, and (d) what changes in the corrections system would promote optimal healing and better outcomes for incarcerated women. Improved outcomes are defined as healthy boundaries, empowerment in choice of relationships, improvement of social support and occupational skills, and reduction of relapse and recidivism.

De fosses i fantasmes. Memòria, trauma i identitat en l’escena catalana actual

La investigació s’ha elaborat en el marc del projecte emergent “Història i poètiques de la memòria: La violència política en la representació del franquisme (1977-2007)”, (Universitat d’Alacant, GRE13-29).

Racionalización cultural de adicciones mediante representación narrativa del trauma poscolonial en reservas indígenas canadienses

Este artículo examina cómo discursos de salud mental, producidos dentro de un movimiento social de revitalización indígena, proporcionan una racionalidad cultural para la construcción contemporánea de la identidad. El diseño de la investigación ha sido cualitativo, realizándose un estudio de caso etnográfico y utilizando un muestreo intencional. Para la recolección del material empírico se utilizaron técnicas basadas en la entrevista y observación participante. Estrategias de análisis del contenido y del discurso han coadyuvado en la obtención de unos resultados que revelan cómo la concepción de la salud mental en reservas indígenas ha llegado a ser un dominio simbólico para crear y recrear la noción del yo indígena y para afrontar su posición marginal en el contexto poscolonial y sociopolítico canadiense. Las conclusiones de este estudio señalan cómo los problemas psicosociales en el contexto de las reservas indígenas trascienden el fenómeno epidemiológico para convertirlo en un fenómeno político, reflexivo y moral.