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Despite recent evidence of improved graft outcomes and safety, the high incidence of early acute cellular rejection with belatacept, a high-affinity CTLA4-Ig, has limited its use in clinical transplantation. Here we define how the incomplete control of endogenous donor-reactive memory T cells results in belatacept-resistant rejection in an experimental model of BALB/c.2W-OVA donor heart transplantation into C57BL/6 recipients presensitized to donor splenocytes. These sensitized mice harbored modestly elevated numbers of endogenous donor-specific memory T cells and alloantibodies compared with naive recipients. Continuous CTLA4-Ig treatment was unexpectedly efficacious at inhibiting endogenous graft-reactive T cell expansion but was unable to inhibit late CD4+ and CD8+ T cell infiltration into the allografts, and rejection was observed in 50% of recipients by day 35 after transplantation. When CTLA4-Ig was combined with the sphingosine 1-phosphate receptor-1 (S1PR1) functional antagonist FTY720, alloantibody production was inhibited and donor-specific IFN-γ-producing T cells were reduced to levels approaching nonsensitized tolerant recipients. Late T cell recruitment into the graft was also restrained, and graft survival improved with this combination therapy. These observations suggest that a rational strategy consisting of inhibiting memory T cell expansion and trafficking into the allograft with CTLA4-Ig and FTY720 can promote allograft survival in allosensitized recipients.

Objective: Childhood trauma is associated with a variety of risky, unhealthy, or problem behaviors. The current study aimed to explore experiential avoidance and mindfulness processes as mechanisms through which childhood trauma and problem behavior are linked in a college sample. Participants: The sample consisted of college-aged young adults recruited November-December, 2016 (N = 414). Methods: Participants completed self-report measures of childhood trauma, current problem behavior, experiential avoidance, and mindfulness processes. Bootstrapped mediation analyses examined the mechanistic associations of interest. Results: Mediation analyses indicated that experiential avoidance was a significant mediator of the association between childhood trauma and problem behavior. Additionally, multiple mediation analyses indicated that specific mindfulness facets--act with awareness and nonjudgment of inner experience--significantly mediated the same association. Conclusions: Interventions for college students who have experienced childhood trauma might profitably target mechanisms such as avoidance and mindfulness in order to minimize engagement in problem behavior.

BackgroundExercise influences drug craving and consumption in humans and drug self-administration in laboratory animals, but the effects can be variable. Improved understanding of how exercise affects drug intake or craving would enhance applications of exercise programs to human drug users attempting cessation.MethodsRats were trained in the intravenous self-administration (IVSA) of D-methamphetamine (METH; 0.05 mg/kg/inf), 3,4-methylenedioxymethamphetamine (MDMA; 0.5 mg/kg/inf) or methylone (0.5 mg/kg/inf). Once IVSA was established, the effect of ∼ 22 h of wheel access in the home cage on subsequent drug taking was assessed in a two cohort crossover design.ResultsProvision of home cage wheel access during the day prior to IVSA sessions significantly decreased the self-administration of METH, MDMA and methylone. At the individual level, there was no correlation between the amount a rat used the wheel and the size of the individual's decrease in drug intake.ConclusionsWheel access can reduce self-administration of a variety of psychomotor stimulants. It does so immediately, i.e., without a need for weeks of exercise prior to drug access. This study therefore indicates that future mechanistic investigations should focus on acute effects of exercise. In sum, the results predict that exercise programs can be used to decrease stimulant drug use in individuals even with no exercise history and an established drug taking pattern.

The perinatal period is marked by a higher risk of experiencing depressive, anxiety, and/or trauma-related symptoms, a phenomenon that affects millions of individuals each year. Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) symptoms commonly co-occur but have rarely been examined together beyond prevalence estimates in the perinatal period. Our study aimed to explore patterns of associations among OCD and PTSD symptoms to elucidate within- and between-person effects and how these effects may change over time. Participants (N = 270) were recruited during pregnancy from an academic medical center affiliated with a midwestern university. PTSD, OCD, and depressive symptoms were assessed at pregnancy, 4, 8, and 12 weeks postpartum. A panel graphical vector autoregression model was used to estimate networks. The temporal network provided information regarding directed predictive effects between symptoms, and hyperarousal, neutralizing, and ordering were the most stable and predictive symptoms across time. The contemporaneous network, which yields undirected partial correlations between symptoms at a given moment, indicated that there were positive associations between intrusions and avoidance, hyperarousal and negative alterations in cognitions and mood, as well as between hyperarousal and dysphoria. This study identified hyperarousal and neutralizing as the PTSD and OCD symptoms with the strongest stability, predictive power, and association with other symptoms. Clinically, this indicates that screening for hyperarousal and neutralizing symptoms may identify individuals who could maximally benefit from treatment in the perinatal period. General Scientific Summary: This study elucidates the posttraumatic stress disorder and obsessive-compulsive disorder symptoms most important to assess during pregnancy and the postpartum period. Network analysis determined that negative alterations in cognitions and mood, obsessing, checking, and avoidance symptoms as the symptoms with the highest relative importance in the between-person network, while hyperarousal, neutralizing, and ordering symptoms were the most stable and predictive symptoms across time. Posttraumatic stress disorder and obsessive-compulsive disorder symptoms are not routinely assessed by health care professionals, yet results suggest identified symptoms warrant closer attention in clinical and obstetric settings. [ABSTRACT FROM AUTHOR]

In a community sample of trauma‐exposed postpartum individuals (N = 167; mean age = 30, 90% White; 61.7% completed bachelor's degree or higher) longitudinally completed self‐report measures on PTSD, depressive, and Obsessive‐compulsive disorder (OCD) symptoms (specifically checking, ordering, washing, and obsessing symptoms), preoccupation with intrusive postpartum thoughts/neutralising strategies, and trauma exposure at 4 and 12 weeks postpartum. PTSD symptoms were strongly associated with all OCD symptoms (r = 0.32‐ 0.49, p < 0.001), preoccupation with postpartum‐specific intrusive thoughts (r = 0.32−0.45, p < 0.001), and preoccupation with neutralising strategies (r = 0.21−0.29, p < 0.05) at both time points. PTSD symptoms were also predictive of checking and obsessing symptoms. This study identified PTSD symptoms as a new correlate for preoccupation with postpartum‐specific intrusive thoughts and neutralising strategies in the postpartum period in a community sample. These findings add to the evidence suggesting a strong association between PTSD and OCD symptoms across the lifespan, including in non‐clinical samples. Future research should examine best practices to assess and treat a variety of postpartum psychopathology symptoms, not just depression. [ABSTRACT FROM AUTHOR]