High molar ratios of tumor necrosis factor α (TNF α) soluble receptors I and II to the TNF ligand in human plasma from male veterans with comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI)

Background and Objectives Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with chronic inflammation, as inferred from increased, but variable, peripheral levels of cytokines. We sought proof of concept for the notion that peripheral cytokine binding proteins and/or soluble receptors can confound measures of cytokines in those with a history of physical and psychological traumatic exposures. Efforts were focused on one of the major cytokines involved in inflammation, tumor necrosis factor-α (TNF- α). Methods We examined blood plasma concentrations of TNF-α, its soluble receptors (TNF-soluble receptors (sR) I and TNFsRII), and C-reactive protein (CRP-1) in a cohort of US Veterans. In a previous study, CRP-1 was shown to be reduced by probiotic anti-inflammatory treatment in this patient cohort. All participants (n = 22) were diagnosed with PTSD and had a history of mild TBI with persistent post-concussive symptoms. Exclusion criteria included medications directly targeting inflammation. Results Molar concentrations of soluble TNFsRI and II exceeded concentrations of the TNF-α ligand. TNFsRI, but not TNFsRII, was significantly associated with CRP-1 (Spearman Rho correlations = 0.518; p=.016 and 0.365; p = .104, respectively). Conclusions TNF soluble receptors may bind to and sequester free TNF-α, suggesting that only measuring ligand concentrations may not provide a fully comprehensive view of inflammation, and potentially lead to inaccurate conclusions. TNFsRI concentration may provide a better estimate of inflammation than TNF-α for those with PTSD and post-acute mTBI with post-concussive symptoms, a hypothesis that invites further testing in larger studies. (AU)

High molar ratios of tumor necrosis factor α (TNF α) soluble receptors I and II to the TNF ligand in human plasma from male veterans with comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI).

Background and Objectives: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with chronic inflammation, as inferred from increased, but variable, peripheral levels of cytokines. We sought proof of concept for the notion that peripheral cytokine binding proteins and/or soluble receptors can confound measures of cytokines in those with a history of physical and psychological traumatic exposures. Efforts were focused on one of the major cytokines involved in inflammation, tumor necrosis factor-α (TNF-α). Methods: We examined blood plasma concentrations of TNF-α, its soluble receptors (TNF-soluble receptors (sR) I and TNFsRII), and C-reactive protein (CRP-1) in a cohort of US Veterans. In a previous study, CRP-1 was shown to be reduced by probiotic anti-inflammatory treatment in this patient cohort. All participants (n = 22) were diagnosed with PTSD and had a history of mild TBI with persistent post-concussive symptoms. Exclusion criteria included medications directly targeting inflammation. Results: Molar concentrations of soluble TNFsRI and II exceeded concentrations of the TNF-α ligand. TNFsRI, but not TNFsRII, was significantly associated with CRP-1 (Spearman Rho correlations = 0.518; p=.016 and 0.365; p = .104, respectively). Conclusions: TNF soluble receptors may bind to and sequester free TNF-α, suggesting that only measuring ligand concentrations may not provide a fully comprehensive view of inflammation, and potentially lead to inaccurate conclusions. TNFsRI concentration may provide a better estimate of inflammation than TNF-α for those with PTSD and post-acute mTBI with post-concussive symptoms, a hypothesis that invites further testing in larger studies.

Interactions of Glutamate and Gamma Amino Butyric Acid with the insulin-like growth factor system in traumatic brain injury (TBI) and/or cardiovascular accidents (CVA or stroke): A systematic review.

The brain maintains homeostasis of neural excitation in part through the receptor-mediated signaling of Glutamate (Glu) and Gamma Amino Butyric Acid (GABA), but localized injuries cause cellular release of excess Glu leading to neurotoxicity. The literature strongly supports the role of Insulin-like growth factor-1 (IGF-1) in adult brain neuroprotection and repair, and research supporting the existence of molecular interactions between Glu, GABA, and IGF-1 in vitro and in normal animals raises the question of whether and/or how the Glu/GABA system interacts with IGF-1 post-injury. This systematic review was undertaken to explore works addressing this question among adults with a history of traumatic brain injury (TBI) and/or cerebrovascular accident (CVA; stroke). The literature was searched for human and animal studies and only four animal papers met inclusion criteria. The SYRCLE criteria was used to evaluate risk of bias; results varied between categories and papers. All the included studies, one on TBI and three on stroke, supported the molecular relationship between the excitatory and IGF-1 systems; two studies provided direct, detailed molecular evidence. The results point to the importance of research on the role of this protective system in pathological brain injury; a hypothetical proposal for future studies is presented.

Association of plasma nitrite levels with obesity and metabolic syndrome in the Old Order Amish.

OBJECTIVES: Plasma nitrite is a metabolite of nitric oxide and reflects endogenous nitric oxide synthase (NOS) activity. Although plasma nitrites were previously linked with obesity and metabolic syndrome (MetS), the direction of association remains inconsistent, possibly due to sample heterogeneity. In a relatively homogeneous population, we hypothesized that nitrite levels will be positively associated with overweight/obesity and MetS. METHODS: Fasting nitrite levels were measured in 116 Old Order Amish (78% women). We performed age-and-sex-adjusted ancovas to compare nitrite levels between three groups (a) overweight/obese(-)MetS(-), (b) overweight/obese(+)MetS(-) and (c) overweight/obese(+)MetS)(+). Multivariate linear regressions were conducted on nitrite associations with continuous metabolic variables, with successive adjustments for demographics, body mass index, C-reactive protein and neopterin. RESULTS: Nitrite levels were higher in the obese/overweight(+)MetS(+) group than in the other two groups (p < 0.001). Nitrites were positively associated with levels of triglycerides (p < 0.0001), total cholesterol (p = 0.048), high-density lipoprotein/cholesterol ratio (p < 0.0001) and fasting glucose (p < 0.0001), and negatively correlated with high-density lipoprotein-cholesterol (p < 0.0001). These associations were robust to adjustments for body mass index and inflammatory markers. CONCLUSION: Further investigation of the connection between obesity/MetS and plasma nitrite levels may lead to novel dietary and pharmacological approaches that ultimately may contribute to reducing the increasing burden of obesity, MetS and cardiovascular morbidity and mortality.

Animal models to improve our understanding and treatment of suicidal behavior.

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.

Using patient self-reports to study heterogeneity of treatment effects in major depressive disorder.

BACKGROUNDS: Clinicians need guidance to address the heterogeneity of treatment responses of patients with major depressive disorder (MDD). While prediction schemes based on symptom clustering and biomarkers have so far not yielded results of sufficient strength to inform clinical decision-making, prediction schemes based on big data predictive analytic models might be more practically useful. METHOD: We review evidence suggesting that prediction equations based on symptoms and other easily-assessed clinical features found in previous research to predict MDD treatment outcomes might provide a foundation for developing predictive analytic clinical decision support models that could help clinicians select optimal (personalised) MDD treatments. These methods could also be useful in targeting patient subsamples for more expensive biomarker assessments. RESULTS: Approximately two dozen baseline variables obtained from medical records or patient reports have been found repeatedly in MDD treatment trials to predict overall treatment outcomes (i.e., intervention v. control) or differential treatment outcomes (i.e., intervention A v. intervention B). Similar evidence has been found in observational studies of MDD persistence-severity. However, no treatment studies have yet attempted to develop treatment outcome equations using the full set of these predictors. Promising preliminary empirical results coupled with recent developments in statistical methodology suggest that models could be developed to provide useful clinical decision support in personalised treatment selection. These tools could also provide a strong foundation to increase statistical power in focused studies of biomarkers and MDD heterogeneity of treatment response in subsequent controlled trials. CONCLUSIONS: Coordinated efforts are needed to develop a protocol for systematically collecting information about established predictors of heterogeneity of MDD treatment response in large observational treatment studies, applying and refining these models in subsequent pragmatic trials, carrying out pooled secondary analyses to extract the maximum amount of information from these coordinated studies, and using this information to focus future discovery efforts in the segment of the patient population in which continued uncertainty about treatment response exists.

The Microbiome of the Built Environment and Human Behavior: Implications for Emotional Health and Well-Being in Postmodern Western Societies.

It is increasingly evident that inflammation is an important determinant of cognitive function and emotional behaviors that are dysregulated in stress-related psychiatric disorders, such as anxiety and affective disorders. Inflammatory responses to physical or psychological stressors are dependent on immunoregulation, which is indicated by a balanced expansion of effector T-cell populations and regulatory T cells. This balance is in part driven by microbial signals. The hygiene or "old friends" hypothesis posits that exposure to immunoregulation-inducing microorganisms is reduced in modern urban societies, leading to an epidemic of inflammatory disease and increased vulnerability to stress-related psychiatric disorders. With the global trend toward urbanization, humans are progressively spending more time in built environments, thereby, experiencing limited exposures to these immunoregulatory "old friends." Here, we evaluate the implications of the global trend toward urbanization, and how this transition may affect human microbial exposures and human behavior.

Testing a machine-learning algorithm to predict the persistence and severity of major depressive disorder from baseline self-reports.

Heterogeneity of major depressive disorder (MDD) illness course complicates clinical decision-making. Although efforts to use symptom profiles or biomarkers to develop clinically useful prognostic subtypes have had limited success, a recent report showed that machine-learning (ML) models developed from self-reports about incident episode characteristics and comorbidities among respondents with lifetime MDD in the World Health Organization World Mental Health (WMH) Surveys predicted MDD persistence, chronicity and severity with good accuracy. We report results of model validation in an independent prospective national household sample of 1056 respondents with lifetime MDD at baseline. The WMH ML models were applied to these baseline data to generate predicted outcome scores that were compared with observed scores assessed 10-12 years after baseline. ML model prediction accuracy was also compared with that of conventional logistic regression models. Area under the receiver operating characteristic curve based on ML (0.63 for high chronicity and 0.71-0.76 for the other prospective outcomes) was consistently higher than for the logistic models (0.62-0.70) despite the latter models including more predictors. A total of 34.6-38.1% of respondents with subsequent high persistence chronicity and 40.8-55.8% with the severity indicators were in the top 20% of the baseline ML-predicted risk distribution, while only 0.9% of respondents with subsequent hospitalizations and 1.5% with suicide attempts were in the lowest 20% of the ML-predicted risk distribution. These results confirm that clinically useful MDD risk-stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models.

Reduced amygdala volume is associated with deficits in inhibitory control: a voxel- and surface-based morphometric analysis of comorbid PTSD/mild TBI.

A significant portion of previously deployed combat Veterans from Operation Enduring Freedom and Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) are affected by comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Despite this fact, neuroimaging studies investigating the neural correlates of cognitive dysfunction within this population are almost nonexistent, with the exception of research examining the neural correlates of diagnostic PTSD or TBI. The current study used both voxel-based and surface-based morphometry to determine whether comorbid PTSD/mTBI is characterized by altered brain structure in the same regions as observed in singular diagnostic PTSD or TBI. Furthermore, we assessed whether alterations in brain structures in these regions were associated with behavioral measures related to inhibitory control, as assessed by the Go/No-go task, self-reports of impulsivity, and/or PTSD or mTBI symptoms. Results indicate volumetric reductions in the bilateral anterior amygdala in our comorbid PTSD/mTBI sample as compared to a control sample of OEF/OIF Veterans with no history of mTBI and/or PTSD. Moreover, increased volume reduction in the amygdala predicted poorer inhibitory control as measured by performance on the Go/No-go task, increased self-reported impulsivity, and greater symptoms associated with PTSD. These findings suggest that alterations in brain anatomy in OEF/OIF/OND Veterans with comorbid PTSD/mTBI are associated with both cognitive deficits and trauma symptoms related to PTSD.

Hypogonadism on admission to acute rehabilitation is correlated with lower functional status at admission and discharge.

PRIMARY OBJECTIVE: To investigate the association between hormone levels and functional status during acute TBI rehabilitation. RESEARCH DESIGN: Retrospective cohort study of 43 men with moderate-to-severe TBI admitted to an acute rehabilitation unit during a 1 year period. METHODS AND PROCEDURES: Labs were drawn on admission, including total and free testosterone (T), prolactin, adrenocorticotropin hormone (ACTH), cortisol, thyroid stimulating hormone (TSH), free thyroxine (fT4) and insulin-like growth factor (IGF-1). Functional Independence Measure (FIM) scores were obtained at admission and discharge. MAIN OUTCOME AND RESULTS: Associations between admission hormone levels and the main outcomes, admission and discharge FIM scores, were assessed using linear regression. Lower total and free T-levels at admission were associated with lower total FIM scores at admission (p < 0.038) and discharge (p < 0.046). Higher cortisol levels at admission were significantly associated with lower admission (p = 0.012) and discharge (p = 0.036) scores on the cognitive-FIM. Prolactin, TSH, fT4 and IGF-1 were not correlated with functional status. CONCLUSIONS: In men, lower total and free T-levels at admission to acute rehabilitation correlate with lower admission and discharge FIM scores. These data support the need for studies to investigate the impact of physiological testosterone therapy on outcomes during and post-rehabilitation.

Use of electrostimulation in the treatment of diabetic neuroarthropathy.

Charcot's joint is a difficult and sometimes frustrating condition to treat, for both the patient and the physician. The authors give a brief overview of Charcot's joint and the treatment options available. They discuss the use of bone stimulators and how electrostimulation may be used to help arrest the progression of Charcot's deformity. To the authors' knowledge, the use of electrostimulation for the treatment of Charcot's joint has been described only once in the literature; three patients were evaluated in that study. In the current study, 11 patients were evaluated, with promising results obtained, thus supporting the findings of the previous study.

Subjective probability of disjunctive hypotheses: local-weight models for decomposition of evidential support.

When the probability of a single member of a set of mutually exclusive and exhaustive possibilities is judged, its alternatives are evaluated as a composite "residual" hypothesis. Support theory (Rottenstreich & Tversky, 1997; Tversky & Koehler, 1994) implies that the process of packing alternatives together in the residual reduces the perceived evidential support for the set of alternatives and consequently inflates the judged probability of the focal hypothesis. Previous work has investigated the global weights that determine the extent to which the overall evidential support for the alternatives is discounted by this packing operation (Koehler, Brenner, & Tversky, 1997). In the present investigation, we analyze this issue in greater detail, examining the local weights that measure the specific contribution of each component hypothesis included implicitly in the residual. We describe a procedure for estimating local weights and introduce a set of plausible properties that impose systematic ordinal relationships among local weights. Results from four experiments testing these properties are reported, and a local-weight model is developed that accounts for nearly all of the variance in the probability judgments in these empirical tests. Local weights appear to be sensitive both to the individual component with which they are associated and to the residual hypothesis in which the component resides.

Intracerebroventricular cholecystokinin A-receptor antagonist does not reduce satiation by endogenous CCK.

Suppression of sham feeding by exogenous CCK-8 or intraintestinal oleate infusion is attenuated by peripheral administration of the CCK-A receptor antagonist, devazepide, but not by the CCK-B antagonist, L365260. Likewise, systemically administered devazepide increases food intake by real feeding rats. These results suggest that endogenous CCK participates in the reduction of food intake by intestinal oleate and ingested food. Although originally categorized as a "peripheral" receptor subtype, the CCK-A receptor is also present in the brain. In an effort to examine whether devazepide acts in the brain or in the periphery to attenuate suppression of food intake by intraintestinal oleate, we injected devazepide into the lateral or fourth cerebral ventricles of intraintestinally infused, sham-fed rats. We also compared the ability of intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) devazepide to elicit increased food intake in real feeding rats. Doses of devazepide that were sufficient to attenuate or abolish oleate-induced suppression of sham feeding, when administered i.p., failed to attenuate suppression of intake when administered i.c.v., i.p. devazepide also was more effective than i.c.v. devazepide for attenuation of the suppression of sham feeding by i.p. injection of exogenous CCK-8. Finally, i.c.v. devazepide was ineffective for increasing real food intake, whereas the same dose administered i.p. significantly increased food intake. Our results do not support participation of brain CCK-A receptors in the suppression of food intake by exogenous CCK, or by endogenous CCK released after intraintestinal oleate infusion, or food intake.

Type A CCK receptors mediate satiety effects of intestinal nutrients.

Previous work indicates that endogenous CCK mediates suppression of sham feeding by some intraintestinal nutrients. To test whether the mechanism involved is dependent upon action at type A or type B CCK receptors, we examined the ability of CCKA (devazepide) and CCKB (L-365,260) receptor antagonists to attenuate the suppression of sham feeding by intraintestinal oleic acid, maltotriose, or L-phenylalanine. Suppression by oleic acid or maltotriose was dose dependently attenuated by intraperitoneal administration of the CCKA receptor antagonist, as was suppression by exogenous CCK. The CCKB receptor antagonist failed to attenuate the suppression of sham feeding by these nutrients. Neither receptor antagonist attenuated the suppression of sham feeding induced by intraintestinal L-phenylalanine. These results suggest that suppression of sham feeding by intestinally infused oleic acid and maltotriose is mediated by endogenous CCK acting at CCKA receptors.

Confidence and accuracy in trait inference: judgment by similarity.

We examined the confidence and accuracy with which people make personality trait inferences and investigate some consequences of the hypothesis that such judgments are based on similarity or conceptual relatedness. Given information concerning a target person's standing on three global personality dimensions, American and Israeli subjects were asked to estimate the target's self-ratings of 50 trait adjectives and to express their confidence by setting a 90 percent uncertainty range around each estimate. The estimates were positively correlated with the actual ratings obtained from subjects who had evaluated themselves in terms of the 50 traits, but were far too extreme. Furthermore, confidence was negatively correlated with accuracy: People's estimates were most inaccurate and made with greatest certainty when the trait in question was highly similar to the information provided as a basic for judgment. We suggest that intuitive personality judgments overestimate the coherence of the structure underlying trait constructs.

Improving text memory by organizing interfering text at retrieval.

We provide evidence that information that organizes interfering text after learning improves recall of original text to which the organizing information does not pertain. Subjects learned two text passages. The second passage was difficult to understand without the aid of a picture that provided the necessary clarifying context. Using the picture as an organizing cue for the second passage (just before retrieval of the first passage) improved recall of the first passage. We address and rule out an alternate explanation that is based on the difficulty of the task immediately preceding recall. These results contradict several traditional hypotheses about interference, and they are difficult to explain with several current models of memory. Implications for learning are discussed.