Laboratory assessment of aggression: The Taylor Aggression Paradigm in adults with and without a disorder of impulsive aggression.

INTRODUCTION: The modified Taylor Aggression Paradigm (TAP) has been used to study impulsive aggression in experimental designs and has been relatively successful in addressing critiques of aggression paradigms; however, little has been done to examine the potential of using the TAP as a direct measure of aggression. This study aimed to explore the psychometric properties of the TAP behavioral indexes as measures of aggression. METHODS: A community sample of 962 adults were divided into three groups based on diagnostic assessments: Intermittent Explosive Disorder; Non-Aggressive Psychiatric Disorder; or healthy controls. Participants then completed the TAP and self-report measures to assess construct validity. A subset of 47 participants completed a second TAP within one year to assess reliability. TAP indexes were based on number of "extreme" shocks selected (high shock index), average shock levels selected (mean shock index), and shocks levels selected without provocation (unprovoked aggression). RESULTS: Overall, TAP indexes were consistent and reliable. IED participants had the highest high shock and mean shock indexes of all groups (X2 = 49.93, p < 0.001). High shock index was related to trait aggression (ß = 0.184, p < 0.001) after including covariates; mean shock index had a trending association with trait anger (ß = 0.102, p = 0.059). CONCLUSION: TAP behavioral indexes demonstrated promising psychometrics as a measure of aggression. High shock index appears to be more strongly associated with aggressive behavior; mean shock index may better measure general hostile responding. Future research might include comparisons specifically with impulse control disorders.

Salivary cortisol awakening levels are reduced in human subjects with intermittent explosive disorder compared with controls.

BACKGROUND: The role of the hypothalamic-pituitary-adrenal (HPA) axis in human aggressive behavior is poorly characterized, though some studies report that, unlike depression, circulating or salivary levels of cortisol are low compared with controls. METHODS: In this study, we collected three salivary cortisol levels (two in the morning and one in the evening) on three separate days in 78 adult study participants with (n = 28) and without (n = 52) prominent histories of impulsive aggressive behavior. Plasma C-Reactive Protein (CRP) and Interleukin-6 (IL-6) were also collected in most study participants. Aggressive study participants meet DSM-5 criteria for Intermittent Explosive Disorder (IED) while non-aggressive participants either had a history of a psychiatric disorder or no such history (Controls). RESULTS: Morning, but not evening, salivary cortisol levels were significantly lower in IED (p < 0.05), compared with control, study participants. In addition, salivary cortisol levels correlated with measures of trait anger (partial r = -0.26, p < 0.05) and aggression (partial r = -0.25, p < 0.05) but not with measures of impulsivity, psychopathy, depression, history of childhood maltreatment, or other tested variables that often differ in individuals with IED. Finally, plasma CRP levels correlated inversely with morning salivary cortisol levels (partial r = -0.28, p < 0.05); plasma IL-6 levels showed a similar, though not statistically significant (rp = -0.20, p = 0.12) relationship with morning salivary cortisol levels. CONCLUSION: The cortisol awakening response appears to be lower in individuals with IED compared with controls. In all study participants, morning salivary cortisol levels correlated inversely with trait anger, trait aggression, and plasma CRP, a marker of systemic inflammation. This suggests the present of a complex interaction between chronic-low level inflammation, the HPA axis, and IED that warrants further investigation.

Childhood and parental characteristics of adults with DSM-5 intermittent explosive disorder compared with healthy and psychiatric controls.

BACKGROUND: Intermittent Explosive Disorder (IED) is a disorder primarily of aggression, defined by recurrent behavioral outbursts out of proportion to provocations or stressors. IED first appears in childhood and adolescence. This study examines the underlying childhood environment of those with IED, particularly familial and school-related factors. METHODS: Adult participants from a larger study completed diagnostic assessments and a battery of self-report measures. Group assignment was based on the assessment: 1) IED diagnosis; 2) non-IED psychiatric diagnosis; and 3) no significant psychiatric history. Groups were compared on factors of parental demographics, intrafamilial aggression, lifetime syndromal and personality diagnoses, neurodevelopmental and learning difficulties, childhood peer relationships, and juvenile legal issues. RESULTS: Significant patterns emerged specific to IED for not being raised by both parents, greater physical aggression to participant, and greater degree of fighting with peers by age ten. LIMITATIONS: The retrospective, and cross-sectional, nature of the study, which prevent the making of causal inferences, and the basic nature of the questions asked of participants which limit a more nuanced interpretation of the data. A further limitation is bias associated with self-reported responses. CONCLUSIONS: Results suggest the prevalence childhood adversaries may be linked with IED; the childhood environment of those with IED likely is substantially more tumultuous than individuals with or without other psychiatric disorders.

Life history of experienced and witnessed aggression: Development of a new assessment instrument.

A Lifetime History of Experienced Aggression and a Lifetime History of Witnessed Aggression assessment was developed and its psychometric properties examined in a modest sample of individuals with and without history of psychopathology. Following this, the two assessments were administered to 400 subjects with or without histories of major psychiatric and personality disorders. These studies demonstrated good to excellent psychometric properties as well as evidence of convergent and divergent validity. Since both assessments quantify the occurrence of aggressive behaviors directed at a person and the occurrence of aggressive behaviors witnessed, the researchers propose that these assessments represents a needed modular assessment of aggression in the environment for behavioral science research.

High non-adherence rates to secondary prevention by chemical adherence testing in patients with TIA.

INTRODUCTION: Transient ischaemic attack (TIA) clinics are important for secondary prevention of fatal or disabling stroke. Non-adherence to prescribed medications is an important reason for treatment failure but difficult to diagnose. This study ascertained the utility of a novel biochemical tool in the objective biochemical diagnosis of non-adherence. METHODS: One-hundred consecutive urine samples collected from patients attending the TIA clinic, at a tertiary centre, were analysed for presence or absence of prescribed cardiovascular medications using liquid chromatography-mass spectrometry (LC-MS/MS). Patients were classified as adherent or non-adherent, respectively. Demographic and clinical characteristics were compared between the two cohorts. Univariate regression analyses were performed for individual variables and model fitting was undertaken for significant variables. RESULTS: The mean duration of follow-up from the index event was 31 days [standard deviation (SD): 18.9]. The overall rate of non-adherence for at least one medication was 24%. In univariate analysis, the number of comorbidities [3.4 (SD: 1.9) vs. 2.5 (1.9), P = 0.032] and total number of all prescribed medications [6.0 (3.3) vs 4.4 (2.1), P = 0.032] were higher in the non-adherent group. On multivariate analysis, the total number of medications prescribed correlated with increased non-adherence (odds ratio: 1.27, 95% Confidence Intervals: 1.1-1.5, P = 0.01). CONCLUSIONS: LC-MS/MS is a clinically useful tool for the diagnosis of non-adherence. Nearly a quarter of TIA patients were non-adherent to their cardiovascular medications Addressing non-adherence early may reduce the risk of future disabling cardiovascular events.

Transforming Growth Factor-Beta Orchestrates Tumour and Bystander Cells in B-Cell Non-Hodgkin Lymphoma.

Transforming growth factor-beta (TGFB) is a critical regulator of normal haematopoiesis. Dysregulation of the TGFB pathway is associated with numerous haematological malignancies including myelofibrosis, acute myeloid leukaemia, and lymphoid disorders. TGFB has classically been seen as a negative regulator of proliferation in haematopoiesis whilst stimulating differentiation and apoptosis, as required to maintain homeostasis. Tumours frequently develop intrinsic resistant mechanisms to homeostatic TGFB signalling to antagonise its tumour-suppressive functions. Furthermore, elevated levels of TGFB enhance pathogenesis through modulation of the immune system and tumour microenvironment. Here, we review recent advances in the understanding of TGFB signalling in B-cell malignancies with a focus on the tumour microenvironment. Malignant B-cells harbour subtype-specific alterations in TGFB signalling elements including downregulation of surface receptors, modulation of SMAD signalling proteins, as well as genetic and epigenetic aberrations. Microenvironmental TGFB generates a protumoural niche reprogramming stromal, natural killer (NK), and T-cells. Increasingly, evidence points to complex bi-directional cross-talk between cells of the microenvironment and malignant B-cells. A greater understanding of intercellular communication and the context-specific nature of TGFB signalling may provide further insight into disease pathogenesis and future therapeutic strategies.

Analgesic Effect of Alcohol Mediates the Association between Alcohol Intoxication and Deliberate Self-Harm.

We examined whether the analgesic effect of alcohol mediates the association between alcohol and deliberate self-harm (DSH) using data from a larger study on alcohol effects. Men (n = 106) and women (n = 104) low-risk alcohol drinkers (ages M = 26.00, SD = 6.98) recruited from the community who had no suicide attempt or episode of deliberate self-harm within the past year were randomly assigned to either a placebo drink condition or a drink calibrated to reach approximately .050%, .075%, or .100% blood alcohol concentration. Notable within-condition BAC variability, as well as overlap between conditions, suggested that BAC would be a more accurate indicator of intoxication compared to condition assignment. Pain tolerance was assessed by increasingly intense 1-s shocks delivered via fingertip electrodes. Self-reported pain associated with the pain tolerance index was also examined. A laboratory task of DSH, the Self-Aggression Paradigm, was then completed, with DSH operationalized as the number of self-administered shocks the participant was led to believe were twice the intensity of his or her pain tolerance and could cause "minor tissue damage that would quickly heal." A negative binomial parallel mediational model for count data revealed that pain tolerance, but not self-report pain, mediated the effect of alcohol on DSH. As such, the current study provides preliminary experimental evidence that the analgesic effect of alcohol is partially responsible for link between alcohol intoxication and deliberate self-harm.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: an analysis of toxicity and impact on R-CHOP delivery.

High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post-R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.

The new biology of PTCL-NOS and AITL: current status and future clinical impact.

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. Angioimmunoblastic T-cell lymphoma (AITL) and some peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have similarities to normal CD4+ T-cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL-NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T-cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL-NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1-like origin) and GATA3 (Th2-like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T-cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.

Does State Dissociation Mediate the Relation Between Alcohol Intoxication and Deliberate Self-Harm?

Research supports the notion that alcohol intoxication is a risk factor for deliberate self-harm (DSH). However, the underlying mechanisms for this relationship are poorly understood. We aimed to determine whether alcohol-induced dissociation mediated alcohol's effects on DSH. We used data from a dose-response study of alcohol intoxication and DSH to test the proposed model. Participants were assigned to reach target blood alcohol concentrations (BAC) ranging from 0.00% through 0.10% and then completed a behavioral measure of DSH. Dissociation was assessed using the Alcohol Dissociative Experiences Scale. BAC predicted both dissociation and DSH, but dissociation did not predict DSH. Although research on clinical populations suggests dissociation is related to DSH, our findings suggest dissociation does not mediate the effects of alcohol on self-harm.

Malignant hyperthermia testing in probands without adverse anesthetic reaction.

BACKGROUND: Malignant hyperthermia (MH) is triggered by reactions to anesthetics. Reports link nonanesthetic-induced MH-like reactions to a variety of disorders. The objective of the authors was to retrospectively investigate the reasons for referrals for MH testing in nonanesthetic cases and assess their phenotype. In addition, the response to the administration of oral dantrolene in nonanesthetic probands with positive caffeine-halothane contracture test (CHCT) was investigated. METHODS: Following institutional research ethics board approval, probands without reaction to anesthesia, who underwent CHCT, were selected. Clinical details and response to dantrolene were analyzed. RESULTS: In total, 87 of 136 (64%) patients referred for nonanesthetic indications tested positive to the CHCT. Of these, 47 with a high creatine kinase (CK), 9 with exercise-induced rhabdomyolysis and/or exercise intolerance, 2 with high CK and exercise-induced rhabdomyolysis and/or exercise intolerance, 15 with postviral chronic fatigue, and 14 with muscle weakness of unknown etiology had a positive CHCT. These patients had a higher CK compared with those with negative CHCT. Oral dantrolene improved the musculoskeletal symptoms in 28 of 34 (82%) CHCT-positive patients. Response to treatment was associated with a significantly higher pretreatment CK and a greater posttreatment CK reduction. CONCLUSIONS: A positive CHCT may represent more than simply an anesthetic-related disorder. Individuals with positive CHCTs may exhibit muscle symptoms without exposure to MH-triggering anesthetics. Oral dantrolene may be useful in alleviating these symptoms.