The differential effects of PTSD, MDD, and dissociation on CRP in trauma-exposed women.

OBJECTIVE: C-reactive protein (CRP), a marker of systemic inflammation, has been associated with psychiatric disorders including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Some research suggests that exposure to trauma can trigger increased activity in the inflammatory system. Dissociation is associated with chronic trauma exposure and may be an important factor in understanding the risk for psychiatric outcomes associated with inflammation. The main objective of the current study was to understand how CRP was related to trauma, dissociation, PTSD and MDD in a sample of 55 traumatized African American women with type 2 diabetes mellitus recruited from an urban hospital. METHOD: High sensitivity CRP (hsCRP) was assayed through blood samples; psychiatric disorders were assessed with structured clinical interviews, dissociation was assessed with the Multiscale Dissociation Inventory, and exposure to trauma in childhood and adulthood was assessed with the Childhood Trauma Questionnaire and the Traumatic Events Inventory, respectively. RESULTS: Correlational results showed a significant association between higher concentrations of hsCRP and child abuse (p < 0.05), overall dissociation severity (p < 0.001), and PTSD symptoms (p < 0.01). ANOVA results showed significantly higher levels of hsCRP in those with current MDD, current PTSD, and remitted PTSD. A hierarchical linear regression model demonstrated a significant association between dissociation symptoms and greater hsCRP levels independent of childhood abuse, PTSD, and MDD (R2∆ = 0.11, p = 0.001) and independent of emotion dysregulation (p < 0.05). CONCLUSION: These findings suggest that dissociation symptoms among those with a history of trauma may be particularly associated with higher levels of inflammation.

The Mechanics of Single Cell and Collective Migration of Tumor Cells.

Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.

The role of negative affect in the association between attention bias to threat and posttraumatic stress: An eye-tracking study.

Biased processing of threatening stimuli, including attention toward and away from threat, has been implicated in the development and maintenance of PTSD symptoms. Research examining theoretically-derived mechanisms through which dysregulated processing of threat may be associated with PTSD is scarce. Negative affect, a transdiagnostic risk factor for many types of psychopathology, is one potential mechanism that has yet to be examined. Thus, the present study (n = 92) tested the indirect effect of attention bias on PTSD via negative affect using rigorous eye-tracking methodology in a sample of urban-dwelling, trauma-exposed African-American women. We found support for the hypothesis that attention bias toward threat was indirectly associated with PTSD symptoms through increased negative affect. These results suggest that negative affect may be an important etiological process through which attention bias patterns could impact PTSD symptom severity. Implications for psychological and pharmacological therapeutic interventions targeting threat-related attention biases and negative affect are discussed.

Trauma exposure and stress-related disorders in African-American women with diabetes mellitus.

OBJECTIVE: The purpose of the study was to assess demographic features, rates of trauma exposure, prevalence of post-traumatic stress and depressive symptoms in a group of urban, low-income, African-American women with type 1 or type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: We conducted a survey of (n = 290) low-income, African-American women seeking care in the diabetes clinic of an urban hospital and collected data on the demographic characteristics, childhood and nonchildhood abuse trauma exposure, and the severity of post-traumatic stress and depressive symptoms using the Post-traumatic Stress Disorder (PTSD) Symptom Scale (PSS) and the Beck Depression Inventory (BDI). In a subset of women with type 2 diabetes (n = 96), we assessed haemoglobin A1c to examine the relationship between psychopathology and glycaemic control. RESULTS: Of the overall sample, 61.7% reported exposure to trauma in their lifetime, and 30.4% and 29.3% had current PTSD and MDD, respectively. Exposure to both childhood and nonchildhood abuse trauma was associated with an increased PTSD and depressive symptom severity (P's < .05). PTSD diagnosis, but not depression, was associated with increased haemoglobin A1c (P = .002). CONCLUSIONS: These data document high levels of trauma exposure, PTSD and depressive symptoms in diabetic African-American women treated in a specialty clinic of an urban hospital setting. Furthermore, these data indicate that the presence of PTSD is negatively associated with glycaemic control.

Emotion dysregulation is associated with increased prospective risk for chronic PTSD development.

While emotion dysregulation is associated with many psychological disorders, including posttraumatic stress disorder (PTSD), it remains uncertain whether pre-existing emotion dysregulation increases individual risk for prospectively developing PTSD in the aftermath of trauma exposure. Thus, the objective of the current study was to determine whether emotion dysregulation could prospectively predict the development of chronic PTSD symptoms following a traumatic event above and beyond other known associated factors, including depressive symptoms, baseline PTSD symptoms, total traumas experienced, and exposure to interpersonal trauma. Participants (N = 135) were recruited from the emergency department (ED) at Grady Memorial Hospital in Atlanta and follow-up assessments were conducted at 1-, 3-, 6-, and 12-months following trauma exposure. Latent Growth Mixture Modeling was used to identify PTSD symptom trajectories based on symptoms assessed at 1, 3, 6, and 12 months; three trajectories emerged: "chronic", "recovery", and "resilient". For the present study, probability of chronic PTSD symptoms was used as the outcome variable of interest. Linear regression modeling showed that emotion dysregulation was significantly associated with probability of developing chronic PTSD symptoms (p = 0.001) and accounted for an additional 7% of unique predictive variance when controlling for trauma exposure, baseline PTSD, and depressive symptoms. Our findings suggest that emotion dysregulation can be used as both a predictor of chronic PTSD and as a treatment target. Thus, identifying individuals with high levels of emotion dysregulation at the time of trauma and implementing treatments designed to improve emotion regulation could aid in decreasing the development of chronic PTSD among these at-risk individuals.

Fiber alignment drives changes in architectural and mechanical features in collagen matrices.

Aligned collagen architecture is a characteristic feature of the tumor extracellular matrix (ECM) and has been shown to facilitate cancer metastasis using 3D in vitro models. Additional features of the ECM, such as pore size and stiffness, have also been shown to influence cellular behavior and are implicated in cancer progression. While there are several methods to produce aligned matrices to study the effect on cell behavior in vitro, it is unclear how the alignment itself may alter these other important features of the matrix. In this study, we have generated aligned collagen matrices and characterized their pore sizes and mechanical properties at the micro- and macro-scale. Our results indicate that collagen alignment can alter pore-size of matrices depending on the polymerization temperature of the collagen. Furthermore, alignment does not affect the macro-scale stiffness but alters the micro-scale stiffness in a temperature independent manner. Overall, these results describe the manifestation of confounding variables that arise due to alignment and the importance of fully characterizing biomaterials at both micro- and macro-scales.

Degradable acetalated dextran microparticles for tunable release of an engineered hepatocyte growth factor fragment.

Injectable biomaterials are promising as new therapies to treat myocardial infarction (MI). One useful property of biomaterials is the ability to protect and sustain release of therapeutic payloads. In order to create a platform for optimizing the release rate of cardioprotective molecules we utilized the tunable degradation of acetalated dextran (AcDex). We created microparticles with three distinct degradation profiles and showed that the consequent protein release profiles could be modulated within the infarcted heart. This enabled us to determine how delivery rate impacted the efficacy of a model therapeutic, an engineered hepatocyte growth factor fragment (HGF-f). Our results showed that the cardioprotective efficacy of HGF-f was optimal when delivered over three days post-intramyocardial injection, yielding the largest arterioles, fewest apoptotic cardiomyocytes bordering the infarct and the smallest infarcts compared to empty particle treatment four weeks after injection. This work demonstrates the potential of using AcDex particles as a delivery platform to optimize the time frame for delivering therapeutic proteins to the heart.

Poly-L-arginine based materials as instructive substrates for fibroblast synthesis of collagen.

The interactions of cells and surrounding tissues with biomaterials used in tissue engineering, wound healing, and artificial organs ultimately determine their fate in vivo. We have demonstrated the ability to tune fibroblast responses with the use of varied material chemistries. In particular, we examined cell morphology, cytokine production, and collagen fiber deposition angles in response to a library of arginine-based polymeric materials. The data presented here shows a large range of vascular endothelial growth factor (VEGF) secretion (0.637 ng/10(6) cells/day to 3.25 ng/10(6) cells/day), cell migration (∼15 min < persistence time < 120 min, 0.11 µm/min < speed < 0.23 µm/min), and cell morphology (0.039 < form factor (FF) < 0.107). Collagen orientation, quantified by shape descriptor (D) values that ranges from 0 to 1, representing completely random (D = 0) to aligned (D = 1) fibers, exhibited large variation both in vitro and in vivo (0.167 < D < 0.36 and 0.17 < D < 0.52, respectively). These findings demonstrate the ability to exert a certain level of control over cellular responses with biomaterials and the potential to attain a desired cellular response such as, increased VEGF production or isotropic collagen deposition upon exposure to these materials in wound healing and tissue engineering applications.

Intramyocardial injection of hydrogel with high interstitial spread does not impact action potential propagation.

Injectable biomaterials have been evaluated as potential new therapies for myocardial infarction (MI) and heart failure. These materials have improved left ventricular (LV) geometry and ejection fraction, yet there remain concerns that biomaterial injection may create a substrate for arrhythmia. Since studies of this risk are lacking, we utilized optical mapping to assess the effects of biomaterial injection and interstitial spread on cardiac electrophysiology. Healthy and infarcted rat hearts were injected with a model poly(ethylene glycol) hydrogel with varying degrees of interstitial spread. Activation maps demonstrated delayed propagation of action potentials across the LV epicardium in the hydrogel-injected group when compared to saline and no-injection groups. However, the degree of the electrophysiological changes depended on the spread characteristics of the hydrogel, such that hearts injected with highly spread hydrogels showed no conduction abnormalities. Conversely, the results of this study indicate that injection of a hydrogel exhibiting minimal interstitial spread may create a substrate for arrhythmia shortly after injection by causing LV activation delays and reducing gap junction density at the site of injection. Thus, this work establishes site of delivery and interstitial spread characteristics as important factors in the future design and use of biomaterial therapies for MI treatment. STATEMENT OF SIGNIFICANCE: Biomaterials for treating myocardial infarction have become an increasingly popular area of research. Within the past few years, this work has transitioned to some large animals models, and Phase I & II clinical trials. While these materials have preserved/improved cardiac function the effect of these materials on arrhythmogenesis, which is of considerable concern when injecting anything into the heart, has yet to be understood. Our manuscript is therefore a first of its kind in that it directly examines the potential of an injectable material to create a substrate for arrhythmias. This work suggests that site of delivery and distribution in the tissue are important criteria in the design and development of future biomaterial therapies for myocardial infarction treatment.

Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction.

Hepatocyte growth factor (HGF) has been shown to have anti-fibrotic, pro-angiogenic, and cardioprotective effects; however, it is highly unstable and expensive to manufacture, hindering its clinical translation. Recently, a HGF fragment (HGF-f), an alternative c-MET agonist, was engineered to possess increased stability and recombinant expression yields. In this study, we assessed the potential of HGF-f, delivered in an extracellular matrix (ECM)-derived hydrogel, as a potential treatment for myocardial infarction (MI). HGF-f protected cardiomyocytes from serum-starvation and induced down-regulation of fibrotic markers in whole cardiac cell isolate compared to the untreated control. The ECM hydrogel prolonged release of HGF-f compared to collagen gels, and in vivo delivery of HGF-f from ECM hydrogels mitigated negative left ventricular (LV) remodeling, improved fractional area change (FAC), and increased arteriole density in a rat myocardial infarction model. These results indicate that HGF-f may be a viable alternative to using recombinant HGF, and that an ECM hydrogel can be employed to increase growth factor retention and efficacy.