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Importance: Posttraumatic stress disorder (PTSD) is a prevalent and serious mental health problem. Although there are effective psychotherapies for PTSD, there is little information about their comparative effectiveness. Objective: To compare the effectiveness of prolonged exposure (PE) vs cognitive processing therapy (CPT) for treating PTSD in veterans. Design, Setting, and Participants: This randomized clinical trial assessed the comparative effectiveness of PE vs CPT among veterans with military-related PTSD recruited from outpatient mental health clinics at 17 Department of Veterans Affairs medical centers across the US from October 31, 2014, to February 1, 2018, with follow-up through February 1, 2019. The primary outcome was assessed using centralized masking. Tested hypotheses were prespecified before trial initiation. Data were analyzed from October 5, 2020, to May 5, 2021. Interventions: Participants were randomized to 1 of 2 individual cognitive-behavioral therapies, PE or CPT, delivered according to a flexible protocol of 10 to 14 sessions. Main Outcomes and Measures: The primary outcome was change in PTSD symptom severity on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from before treatment to the mean after treatment across posttreatment and 3- and 6-month follow-ups. Secondary outcomes included other symptoms, functioning, and quality of life. Results: Analyses were based on all 916 randomized participants (730 [79.7%] men and 186 [20.3%] women; mean [range] age 45.2 [21-80] years), with 455 participants randomized to PE (mean CAPS-5 score at baseline, 39.9 [95% CI, 39.1-40.7] points) and 461 participants randomized to CPT (mean CAPS-5 score at baseline, 40.3 [95% CI, 39.5-41.1] points). PTSD severity on the CAPS-5 improved substantially in both PE (standardized mean difference [SMD], 0.99 [95% CI, 0.89-1.08]) and CPT (SMD, 0.71 [95% CI, 0.61-0.80]) groups from before to after treatment. Mean improvement was greater in PE than CPT (least square mean, 2.42 [95% CI, 0.53-4.31]; P = .01), but the difference was not clinically significant (SMD, 0.17). Results for self-reported PTSD symptoms were comparable with CAPS-5 findings. The PE group had higher odds of response (odds ratio [OR], 1.32 [95% CI, 1.00-1.65]; P < .001), loss of diagnosis (OR, 1.43 [95% CI, 1.12-1.74]; P < .001), and remission (OR, 1.62 [95% CI, 1.24-2.00]; P < .001) compared with the CPT group. Groups did not differ on other outcomes. Treatment dropout was higher in PE (254 participants [55.8%]) than in CPT (215 participants [46.6%]; P < .01). Three participants in the PE group and 1 participant in the CPT group were withdrawn from treatment, and 3 participants in each treatment dropped out owing to serious adverse events. Conclusions and Relevance: This randomized clinical trial found that although PE was statistically more effective than CPT, the difference was not clinically significant, and improvements in PTSD were meaningful in both treatment groups. These findings highlight the importance of shared decision-making to help patients understand the evidence and select their preferred treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01928732.
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Terapia Cognitivo-Conductual , Terapia Implosiva , Trastornos por Estrés Postraumático/terapia , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Estados Unidos , VeteranosRESUMEN
Veterans with posttraumatic stress disorder (PTSD) report more aggression than civilians with PTSD. Because emotion regulation difficulties mediated the relationship between PTSD symptoms and impulsive aggression in veterans, we developed an intervention to increase emotion regulation skills. This pilot study tested the feasibility and acceptability of a three-session treatment, Manage Emotions to Reduce Aggression (MERA), and examined its effectiveness at reducing aggression and emotion dysregulation. Male combat veterans with PTSD and impulsive aggression completed assessments before and 4 weeks after MERA. Overt Aggression Scale measured frequency of aggression; Difficulties in Emotion Regulation Scale assessed emotion dysregulation. Most veterans (95%) who completed MERA and the posttreatment assessment (n = 20) reported MERA was helpful. Veterans in the intent-to-treat sample demonstrated a significant decrease in their frequency of aggression (Cohen's d = -0.55) and emotion dysregulation (Cohen's d = -0.55). MERA may be an innovative treatment that helps veterans reduce aggression.
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Agresión , Regulación Emocional , Trastornos por Estrés Postraumático/terapia , Veteranos/psicología , Adulto , Humanos , Conducta Impulsiva , Masculino , Persona de Mediana Edad , Proyectos Piloto , Trastornos por Estrés Postraumático/psicologíaRESUMEN
BACKGROUND: Resilience represents the capacity to adapt to adversity. Resilience can improve following behavioral interventions. We examined lung transplant candidates' resilience as a novel predictor using the Connor-Davidson Resilience Scale (RISC-10). METHODS: Waitlisted candidates at six centers were mailed questionnaires from 9/16/2015 to 10/1/2019. Follow-up surveys were collected annually and post-transplant. Outcomes were recorded through February 17, 2020. Primary outcome was pre-transplant death/delisting. Analyses included t test or chi-square for group comparisons, Pearson's correlation coefficients for strength of relationships, and Cox proportional-hazard models to evaluate associations with outcomes, adjusting for age, sex, and mood. RESULTS: Participation was 55.3% (N = 199). Baseline RISC-10 averaged 32.0 ± 5.6 and did not differ by demographics, primary transplant diagnosis, or disease severity markers. RISC-10 did not correlate to the commonly utilized Psychosocial Assessment of Candidates for Transplant [PACT] or Stanford Integrated Psychosocial Assessment for Transplantation [SIPAT] tools. Scores < 26.3 (representing > 1 standard deviation below population average) occurred in 16% and were associated with pre-transplant death or delisting, adjusted Hazard Ratio of 2.60 (95% Confidence Interval 1.23-5.77; P = .01). CONCLUSION: One in six lung candidates had low resilience, predicting increased pre-transplant death/delisting. RISC-10 did not correlate with PACT or SIPAT; resilience may represent a novel risk factor.
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Trasplante de Pulmón , Humanos , Modelos de Riesgos Proporcionales , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
BACKGROUND: Frailty and decreased functional status are risk factors for adverse kidney transplant (KT) outcomes. Our objective was to examine the efficacy of an exercise intervention on frailty and decreased functional status in a cohort of patients with advanced chronic kidney disease (CKD). METHODS: We conducted a prospective study involving 21 adults with ≥stage 4 CKD who were (a) frail or pre-frail by Fried phenotype and/or (b) had lower extremity impairment [short physical performance battery score ≤10]. The intervention consisted of two supervised outpatient exercise sessions per week for 8 weeks. RESULTS: Among our cohort, median participant age was 62 years (interquartile range, 53-67) and 85.7% had been evaluated for KT. Following the study, participants reported satisfaction with the intervention and multiple frailty parameters improved significantly, including fatigue, physical activity, walking time, and grip strength. Lower extremity impairment also improved (90.5%-61.9%, P = .03). No study-related adverse events occurred. CONCLUSIONS: Preliminary data from this study suggest that a supervised, outpatient exercise intervention is safe, acceptable, feasible, and associated with improved frailty parameters, and lower extremity function, in patients with advanced CKD. Further studies are needed to confirm these findings and determine whether this prehabilitation strategy improves KT outcomes.
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Fragilidad , Trasplante de Riñón , Adulto , Ejercicio Físico , Humanos , Extremidad Inferior , Persona de Mediana Edad , Ejercicio Preoperatorio , Estudios ProspectivosRESUMEN
BACKGROUND: We examined the association of adult lung transplant candidates' self-reported affect with transplant-related outcomes, evaluating whether a positive (vs negative) frame of mind might be protective. METHOD: Consenting waitlisted candidates from 6 centers completed the questionnaires including the Positive and Negative Affect Schedule annually and posttransplant. Univariate logistic regression analysis was performed to determine the association of baseline affect with outcomes of death or delisting. Models were subsequently adjusted for age, marital status, and education. RESULTS: Questionnaires were completed by 169 candidates (77.9% participation). Mean positive affect, negative affect, and positive-to-negative affect ratio (positivity ratio) were similar to expected norms. The scores of the questionnaire did not change significantly over time. Fifteen (8.9%) waitlisted participants died. Candidates who died while waiting had lower positivity ratios compared to those who survived (1.82 vs 2.45; P = .02). A more negative affect was associated with increased death on the waiting list (adjusted odds ratio [OR] 1.10; P = .021). Conversely, a higher positivity ratio was associated with decreased death while waiting (adjusted OR: 0.45; P = .027). CONCLUSION: Negative affect may represent a novel risk factor for death on the waitlist. Enhancing positive affect may represent a useful target for psychological optimization in lung transplant candidates.
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Trasplante de Pulmón/psicología , Calidad de Vida , Obtención de Tejidos y Órganos , Listas de Espera , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Trauma-focused psychotherapies, such as prolonged exposure and cognitive processing therapy, are the most effective forms of treatment for posttraumatic stress disorder. These treatments are commonly delivered in the Veterans Health Administration; however, dropout means that some veterans fail to benefit. Ending treatment prematurely is a common problem across psychotherapies, with on average, 20% to 25% of patients dropping out. The purpose of this study was to examine veterans' self-reported reasons for dropping out of prolonged exposure or cognitive processing therapy. Veterans who dropped out from prolonged exposure or cognitive processing therapy (N = 28) completed qualitative interviews about their experiences. Interviews were coded by 2 coders using grounded theory. Therapy-related barriers were the largest category reported, and included lack of buy-in to the rationale or specific therapy tasks, believing that treatment was not working, alliance issues, or switching to a different treatment. Practical barriers and finding treatment "too stressful" were also common reasons for dropout. This research provides information that can shape how PTSD treatments are delivered in health care settings. Therapy-related barriers were the largest group, suggesting that providers may need to find more effective ways to communicate the rationale for these therapies or to tailor them to individual patients' needs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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Terapia Cognitivo-Conductual , Terapia Implosiva , Pacientes Desistentes del Tratamiento/psicología , Satisfacción del Paciente , Trastornos por Estrés Postraumático/terapia , Veteranos/psicología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Investigación Cualitativa , Estados Unidos , United States Department of Veterans AffairsRESUMEN
The growth factor-like lipid mediator, lysophosphatidic acid (LPA), is a potent signaling molecule that influences numerous physiologic and pathologic processes. Manipulation of LPA signaling is of growing pharmacotherapeutic interest, especially because LPA resembles compounds with drug-like features. The action of LPA is mediated through activation of multiple types of molecular targets, including six G protein-coupled receptors that are clear targets for drug development. However, the LPA signaling has been linked to pathological responses that include promotion of fibrosis, atherogenesis, tumorigenesis, and metastasis. Thus, a question arises: Can we harness, in an LPA-like drug, the many beneficial activities of this lipid without eliciting its dreadful actions? We developed octadecyl thiophosphate (OTP; subsequently licensed as Rx100), an LPA mimic with higher stability in vivo than LPA. This article highlights progress made toward developing analogs like OTP and exploring prosurvival and regenerative LPA signaling. We determined that LPA prevents cell death triggered by various cellular stresses, including genotoxic stressors, and rescues cells condemned to apoptosis. LPA2 agonists provide a new treatment option for secretory diarrhea and reduce gastric erosion caused by nonsteroidal anti-inflammatory drugs. The potential uses of LPA2 agonists like OTP and sulfamoyl benzoic acid-based radioprotectins must be further explored for therapeutic uses.
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Descubrimiento de Drogas/métodos , Receptores del Ácido Lisofosfatídico/agonistas , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Humanos , Receptores del Ácido Lisofosfatídico/química , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Background: The Veterans Health Administration (VHA) has pioneered the implementation of video to home (VTH) technology to increase access to mental health treatments for Veterans facing barriers to receiving in-person care, particularly for posttraumatic stress disorder (PTSD). Randomized controlled trials have established the noninferiority of evidence-based psychotherapies (EBPs) for PTSD delivered through VTH, compared to in-person delivery. Less is known about the use of VTH to deliver EBPs for PTSD in routine clinical practice. Objective: We examined the provision of EBPs for PTSD delivered via VTH at a large Southwestern VHA PTSD outpatient clinic. Methods: Data were obtained from chart review of the electronic medical records of Veterans receiving at least one session of Cognitive Processing Therapy or Prolonged Exposure via VTH in the VHA PTSD clinic during the study time frame. Results: Fourteen providers (including six psychology trainees) delivered EBPs for PTSD via VTH between 2016 and 2018. Providers treated 74 Veterans (33.8% women) from diverse sociocultural backgrounds who ranged in age from 25 to 79. Each provider treated about 3.08 (± 2.18) Veterans using VTH, not including one provider who saw more than 30. A hybrid approach, in which VTH-delivery was coupled with in-person delivery, was used with 70.3% of Veterans across treatment (including sessions completed before initiation and after termination of the EBP). This demonstrates the versatility of VTH for meeting individual patient needs. Most EBP sessions (85.4%) were conducted over VTH. Despite Veterans attending an average of 6.85 (± 4.88) EBP sessions, 50% terminated before session 7. This dropout rate is consistent with national and local EBP completion averages within the VHA. Veterans receiving Cognitive Processing Therapy via VTH were more likely to complete treatment than those receiving Prolonged Exposure. No other patient factors predicted attrition. Conclusions: This study highlights the use of VTH as "tool in the toolbox" that expands the scope of practice for providers and increases opportunities for Veterans to receive EBPs for PTSD. We describe other potential advantages of using VTH to deliver EBPs for PTSD.
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IMPACT STATEMENT: A critical barrier in treating diarrheal disease is easy-to-use effective treatments. Rx100 is a first in class, novel small molecule that has shown efficacy after both subcutaneous and oral administration in a mouse cholera-toxin- and Citrobacter rodentium infection-induced diarrhea models. Our findings indicate that Rx100 a metabolically stable analog of the lipid mediator lysophosphatidic acid blocks activation of CFTR-mediated secretion responsible for fluid discharge in secretory diarrhea. Rx100 represents a new treatment modality which does not directly block CFTR but attenuates its activation by bacterial toxins. Our results provide proof-of-principle that Rx100 can be developed for use as an effective oral or injectable easy-to-use drug for secretory diarrhea which could significantly improve care by eliminating the need for severely ill patients to regularly consume large quantities of oral rehydration therapies and offering options for pediatric patients.
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Toxinas Bacterianas/toxicidad , Toxina del Cólera/toxicidad , Diarrea/tratamiento farmacológico , Diarrea/prevención & control , Lisofosfolípidos/farmacología , Animales , Diarrea/inducido químicamente , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , RatonesRESUMEN
Introduction It is estimated that 70% of patients with posttraumatic stress disorder (PTSD) have chronic insomnia. A recent meta-analysis examined cognitive-behavioural therapy for insomnia (CBT-I) in veterans with and without PTSD, and suggested that most studies had questionable methodology, but generally supported its effectiveness in this population. Further, while CBT-I via telehealth (i.e. using telecommunication and information technology to deliver health services) has shown effectiveness for primary insomnia, it has not been applied to PTSD-related insomnia. Methods Veterans with insomnia who were diagnosed with PTSD ( n = 12) or having significant subthreshold PTSD symptoms ( n = 6) on the Clinician Administered PTSD Scale were randomly assigned to receive CBT-I in-person ( n = 7) or by telephone ( n = 11), to pilot test the potential effectiveness, acceptability, and feasibility of administering CBT-I in rural veterans. A six-week CBT-I protocol was delivered, and the veteran's insomnia was assessed at post-treatment and follow-up. Results Given the small sample size, Cohen's d was used to detect group differences, finding large effect sizes favouring the in-person delivery, until three-months post-treatment when this difference diminished. Most veterans found the treatment acceptable, regardless of mode of delivery. Based on the results, a larger project is feasible. Feasibility for a larger project is favourable. Discussion In summary, our findings uphold and extend previous research. Specifically, current pilot data suggest that telephone-delivered CBT-I may be able to reduce trauma-related insomnia symptoms. Future trials are needed to assess the effectiveness of CBT-I delivered to rural veterans with posttraumatic insomnia.
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Terapia Cognitivo-Conductual/organización & administración , Servicios de Salud Rural/organización & administración , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Trastornos por Estrés Postraumático/terapia , Teléfono , Veteranos , Adulto , Análisis de Varianza , Cognición , Terapia Cognitivo-Conductual/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Población Rural , Telemedicina/métodosRESUMEN
Prior single-site and regional studies have documented difficulties in implementing prolonged exposure (PE) and cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) into practice in Veterans Affairs (VA) Medical Centers, estimating that between 6% and 13% of VA patients with PTSD receive PE or CPT (Lu, Plagge, Marsiglio, & Dobscha, 2016; Mott et al., 2014; Shiner et al., 2013). However, these studies examined data from fiscal years 2008-2012, and therefore may not reflect more recent utilization patterns. Beginning in 2007, the VA invested heavily in increasing implementation of PE and CPT, including nationwide training rollouts and consultation. Given the length of time required for successful implementation of new practices, it is important to evaluate use of PE and CPT over time. We examined current use of PE and CPT at 1 VA medical center PTSD specialty clinic and compared this to prior rates for the same clinic. Chart reviews for all patients receiving a PTSD clinic initial evaluation between January 1, 2015, and May 31, 2015, indicated that 52% of patients began a course of PE or CPT within the 1-year follow-up period, representing a 5-fold increase from 2008 to 2012. We discuss changes in clinic structure, processes, training, and clinician support that might account for the successful implementation of PE and CPT in this clinic. We also present data on alternative referrals provided to patients not engaging in PE and CPT, and predictors of engagement in PE and CPT. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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Terapia Cognitivo-Conductual/estadística & datos numéricos , Terapia Implosiva/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Trastornos por Estrés Postraumático/terapia , United States Department of Veterans Affairs/estadística & datos numéricos , Veteranos/estadística & datos numéricos , Adulto , Instituciones de Atención Ambulatoria/estadística & datos numéricos , Femenino , Humanos , Masculino , Servicios de Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Estados UnidosRESUMEN
Traumatic brain injury (TBI) and mental health (MH) disorders are prevalent in combat veterans returning from Afghanistan and/or Iraq (hereafter referred to as returning veterans). Accurate estimates of service utilization for veterans with and without TBI exposure (referred to as TBI history) are imperative in order to provide high quality healthcare to returning veterans. We examined associations between TBI history and MH service utilization in a subsample of returning veterans who were newly diagnosed with posttraumatic stress disorder (PTSD), depression, and/or anxiety in the 2010 fiscal year (N = 55,458). Data were extracted from the Veterans Health Administration (VHA) National Patient Care Database. Veterans with MH diagnoses and TBI histories attended significantly more psychotherapy visits, (M = 8.32 visits, SD = 17.15) and were more likely to attend at least 8 psychotherapy visits, (15.7%) than veterans with MH diagnoses but no TBI history (M = 6.48 visits, SD = 12.12; 10.1% attended at least 8 sessions). PTSD and TBI history, but not depression or anxiety, were associated with a greater number of psychotherapy visits when controlling for demographic and clinical variables. PTSD, anxiety, depression, and TBI history were associated with number of psychotropic medication-management visits. TBI history was related to greater MH service utilization, independent of MH diagnoses. Future research should examine what MH services are being utilized and if these services are helping veterans recover from their disorders.
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Lesiones Traumáticas del Encéfalo/complicaciones , Trastornos Mentales/etiología , Trastornos Mentales/terapia , Servicios de Salud Mental , Psicoterapia , Veteranos/psicología , Trastornos de Ansiedad/etiología , Trastornos de Ansiedad/terapia , Comorbilidad , Depresión/diagnóstico , Depresión/etiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Trastornos Mentales/diagnóstico , Visita a Consultorio Médico , Estudios Retrospectivos , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/terapia , Salud de los VeteranosRESUMEN
Posttraumatic stress disorder (PTSD) is common among returning veterans, and aggression frequently co-occurs with PTSD. Veterans with PTSD most commonly engage in impulsive aggression, or aggression that is emotionally charged, unplanned, and uncontrolled, rather than premeditated aggression, which is planned and controlled. Previous research demonstrated a variety of emotions can result in aggression, rather than the traditional conceptualization that only anger leads to aggression. In a veteran sample, deficiencies in the ability to regulate emotions (emotion dysregulation) mediated the relationship between PTSD and impulsive aggression. These results suggest that teaching veterans with PTSD and impulsive aggression how to regulate emotions may decrease aggression. The cases presented illustrate the use of an innovative, single-session emotion regulation treatment for combat veterans with PTSD. Two cases are presented to generate hypotheses on who might benefit from this treatment in the future. The two male veterans treated with this protocol differed in how frequently they used the emotion regulation skills after the treatment and in their treatment outcomes. Teaching veterans how to regulate their emotions in a condensed time frame may be beneficial for certain veterans, and further research on this brief treatment is warranted. (PsycINFO Database Record
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Agresión/psicología , Trastornos de Combate/terapia , Emociones/fisiología , Conducta Impulsiva/fisiología , Psicoterapia/métodos , Autocontrol/psicología , Trastornos por Estrés Postraumático/terapia , Veteranos/psicología , Adulto , Trastornos de Combate/fisiopatología , Humanos , Masculino , Trastornos por Estrés Postraumático/fisiopatologíaRESUMEN
OBJECTIVE: The Department of Veterans Affairs (VA) has promoted large-scale dissemination efforts of evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD). In spite of efforts to make gold-standard treatments available to veterans, few veterans with PTSD receive a full course of psychotherapy. It is unclear if type of trauma experienced is related to treatment initiation and completion. This study aimed to identify patient factors, including experiencing childhood trauma that related to treatment preferences and dropout in a real-world VA PTSD clinic. METHOD: A chart review was conducted for veterans who were referred for individual EBPs for PTSD (N = 199). Extracted variables included demographics, PTSD symptoms, treatment preferences, and treatment completion/dropout. RESULTS: Veterans choose to engage in individual EBP (48%), group treatment (11%), nontrauma focused psychotherapy (15%), or no psychotherapy (26%). Slightly over half of the veterans who began individual EBP completed it, with no statistical differences in completion rates for prolonged exposure and cognitive processing therapy. Childhood trauma was the second-most common type of trauma experienced, next to combat exposure. Those who completed EBP had higher rates of combat trauma (88%) than noncompleters (70%), and noncompleters (50%) had higher rates of childhood trauma than completers (29%). Regardless of trauma experienced, those who completed an EBP experienced substantial reductions in PTSD symptoms. CONCLUSIONS: Assessing veterans for childhood trauma and emotion regulation difficulties may be beneficial even in VA clinics where treatment is most often focused on combat trauma. (PsycINFO Database Record
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Adultos Sobrevivientes de Eventos Adversos Infantiles/estadística & datos numéricos , Trastornos de Combate/epidemiología , Trastornos de Combate/terapia , Cooperación del Paciente/estadística & datos numéricos , Prioridad del Paciente/estadística & datos numéricos , Psicoterapia/estadística & datos numéricos , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/terapia , Adulto , Práctica Clínica Basada en la Evidencia/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos , United States Department of Veterans Affairs/estadística & datos numéricosRESUMEN
We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy γ radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from -24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from -12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by ≥34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4-8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome.
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Síndrome de Radiación Aguda/prevención & control , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de la radiación , Hematopoyesis/efectos de los fármacos , Hematopoyesis/efectos de la radiación , Lisofosfolípidos/metabolismo , Compuestos Organofosforados/farmacología , ATPasas Asociadas con Actividades Celulares Diversas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antígenos CD34/metabolismo , Transporte Biológico/efectos de los fármacos , Transporte Biológico/efectos de la radiación , Materiales Biomiméticos/efectos adversos , Materiales Biomiméticos/farmacocinética , Materiales Biomiméticos/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células Clonales/citología , Células Clonales/efectos de los fármacos , Células Clonales/efectos de la radiación , Relación Dosis-Respuesta a Droga , Femenino , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/microbiología , Glucosa/metabolismo , Células HEK293 , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de la radiación , Humanos , Proteínas con Dominio LIM/metabolismo , Recuento de Leucocitos , Ratones , Ratones Endogámicos C57BL , Compuestos Organofosforados/efectos adversos , Compuestos Organofosforados/farmacocinética , Fosfoproteínas/metabolismo , Recuento de Plaquetas , Complejo de la Endopetidasa Proteasomal , Protectores contra Radiación/efectos adversos , Protectores contra Radiación/farmacocinética , Protectores contra Radiación/farmacología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Factores de Transcripción/metabolismo , Irradiación Corporal Total/efectos adversosRESUMEN
Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.
Asunto(s)
Apoptosis/efectos de los fármacos , Lisofosfolípidos/farmacología , Naftalimidas/farmacología , Receptores del Ácido Lisofosfatídico/agonistas , Sulfonamidas/farmacología , Síndrome de Radiación Aguda/metabolismo , Síndrome de Radiación Aguda/patología , Síndrome de Radiación Aguda/prevención & control , Animales , Apoptosis/efectos de la radiación , Sitios de Unión , Caspasa 8/metabolismo , Línea Celular , Fragmentación del ADN/efectos de los fármacos , Fragmentación del ADN/efectos de la radiación , Rayos gamma , Histonas/metabolismo , Humanos , Lisofosfolípidos/química , Lisofosfolípidos/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Simulación del Acoplamiento Molecular , Naftalimidas/química , Naftalimidas/uso terapéutico , Estructura Terciaria de Proteína , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Sulfonamidas/química , Sulfonamidas/uso terapéuticoRESUMEN
Acute radiation syndrome is induced when a significant portion of the body receives high-dose, as well as high-dose rate, radiation. We have previously identified a quinic acid-based derivative, KZ-41, that protects from radiation injury. Further preclinical efficacy studies were conducted to determine the radiomitigating activity of KZ-41. C57BL/6 mice received total body irradiation (TBI-LD80/30, ¹³7Cs; â¼2 min) followed by either normal saline or KZ-41 (100 mg/kg sc â¼26 h post-TBI). KZ-41 increased 30-day survival by approximately 45% compared with vehicle controls (P < 0.05). To further investigate the potential radiomodulating mechanisms of KZ-41, we developed a combined radiation and vascular injury model. C57BL/6 mice surgically fixed with dorsal windows for dermal vasculature imaging received either sham or TBI (¹³7Cs; 6 Gray). Postcapillary venule injury was induced (24, 48, 72, and 96 h post-TBI) followed by imaging at 5 min and 24 h to assess clot formation and blood flow. Impairment in flow (P < 0.05) and clot formation (P < 0.05) were observed as early as 48 and 72 h, respectively. Thus, vascular injury 72 h post-TBI was used to evaluate intervention (KZ-41; 100 mg/kg i.p. at 12, 36, and 60 h post-TBI) on radiation-induced changes in both flow and clot formation. KZ-41, although not improving flow, increased clot formation (P < 0.05). Platelet counts were lower in both irradiated groups compared with sham controls (P < 0.05). In summary, KZ-41 exerts radiomitigating activity in lethally irradiated mice. Imaging results suggest KZ-41 exerts radiomitigating activity through mechanisms involving promotion of initial clot formation and vascular flow restoration. The imaging model described herein is useful for further examination of radiation-induced vascular injury repair mechanisms.
Asunto(s)
Ácido Quínico/análogos & derivados , Protectores contra Radiación/administración & dosificación , Lesiones del Sistema Vascular/patología , Vénulas/efectos de los fármacos , Vénulas/lesiones , Animales , Células Sanguíneas/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Ratones , Ratones Endogámicos C57BL , Ácido Quínico/administración & dosificación , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/patología , Factor de Necrosis Tumoral alfa/metabolismo , Lesiones del Sistema Vascular/tratamiento farmacológicoRESUMEN
Due to its antiapoptotic action, derivatives of the lipid mediator lysophosphatidic acid (LPA) provide potential therapeutic utility in diseases associated with programmed cell death. Apoptosis is one of the major pathophysiological processes elicited by radiation injury to the organism. Consequently, therapeutic explorations applying compounds that mimic the antiapoptotic action of LPA have begun. Here we present a brief account of our decade-long drug discovery effort aimed at developing LPA mimics with a special focus on specific agonists of the LPA(2) receptor subtype, which was found to be highly effective in protecting cells from apoptosis. We describe new evidence that 2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), a prototypic nonlipid agonist specific to the LPA(2) receptor subtype, rescues apoptotically condemned cells in vitro and in vivo from injury caused by high-dose γ-irradiation. GRI977143 shows the features of a radiomitigator because it is effective in rescuing the lives of mice from deadly levels of radiation when administered 24h after radiation exposure. Our findings suggest that by specifically activating LPA(2) receptors GRI977143 activates the ERK1/2 prosurvival pathway, effectively reduces Bax translocation to the mitochondrion, attenuates the activation of initiator and effector caspases, reduces DNA fragmentation, and inhibits PARP-1 cleavage associated with γ-irradiation-induced apoptosis. GRI977143 also inhibits bystander apoptosis elicited by soluble proapoptotic mediators produced by irradiated cells. Thus, GRI977143 can serve as a prototype scaffold for lead optimization paving the way to more potent analogs amenable for therapeutic exploration. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
Asunto(s)
Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/prevención & control , Receptores del Ácido Lisofosfatídico/metabolismo , Síndrome de Radiación Aguda/tratamiento farmacológico , Síndrome de Radiación Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Efecto Espectador/efectos de los fármacos , Efecto Espectador/efectos de la radiación , Inhibidores de Caspasas/farmacología , Caspasas/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/efectos de la radiación , Citoprotección/efectos de los fármacos , Citoprotección/efectos de la radiación , Fragmentación del ADN/efectos de los fármacos , Fragmentación del ADN/efectos de la radiación , Embrión de Mamíferos/citología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/efectos de la radiación , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Rayos gamma , Lisofosfolípidos/química , Lisofosfolípidos/metabolismo , Lisofosfolípidos/farmacología , Ratones , Ratones Noqueados , Compuestos Organofosforados/farmacología , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Traumatismos por Radiación/patología , Análisis de SupervivenciaRESUMEN
Purpose. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. Methods. To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC. Results. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. Conclusions. These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies.
Asunto(s)
Antineoplásicos Alquilantes/toxicidad , Células Endoteliales/efectos de los fármacos , Melfalán/toxicidad , Arteria Oftálmica/efectos de los fármacos , Animales , Antineoplásicos/toxicidad , Carboplatino/toxicidad , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-8/metabolismo , Macaca mulatta , Neutrófilos/metabolismo , ARN Mensajero/metabolismoRESUMEN
Both hyperoxia and mechanical ventilation can independently cause lung injury. In combination, these insults produce accelerated and severe lung injury. We recently reported that pre-exposure to hyperoxia for 12 hours, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone. We also reported that such injury and apoptosis are inhibited by antioxidant treatment. In this study, we hypothesized that apoptosis signal-regulating kinase-1 (ASK-1), a redox-sensitive, mitogen-activated protein kinase kinase kinase, plays a role in lung injury and apoptosis in this model. To determine the role of ASK-1 in lung injury, the release of inflammatory mediators and apoptosis, attributable to 12 hours of hyperoxia, were followed by large tidal volume mechanical ventilation with hyperoxia. Wild-type and ASK-1 knockout mice were subjected to hyperoxia (Fi(O(2)) = 0.9) for 12 hours before 4 hours of large tidal mechanical ventilation (tidal volume = 25 µl/g) with hyperoxia, and were compared with nonventilated control mice. Lung injury, apoptosis, and cytokine release were measured. The deletion of ASK-1 significantly inhibited lung injury and apoptosis, but did not affect the release of inflammatory mediators, compared with the wild-type mice. ASK-1 is an important regulator of lung injury and apoptosis in this model. Further study is needed to determine the mechanism of lung injury and apoptosis by ASK-1 and its downstream mediators in the lung.