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Psychoactive medications are increasingly used to treat children and youth with mental health conditions, but individual variations in response highlight the need for precision medicine. Pharmacogenetic (PGx) testing is a key component of precision medicine. The number of commercial pharmacogenetic testing companies promoting PGx, with the promise of achieving individualized and effective treatment of mental health conditions, has grown exponentially in recent years. Scientific evidence supporting the use of PGx to manage mental health conditions is limited, especially for paediatric populations. This practice point outlines steps guiding the use and interpretation of PGx testing for psychoactive medications in clinical settings, along with key supportive resources. Practice guidelines have been developed for variants in pharmacogenes encoding cytochrome P450 drug-metabolizing enzymes (e.g., CYP2C19 , CYP2D6 , CYP2C9 ) as one determinant of drug concentrations in blood, which can support both drug choice and dosing strategy for certain anti-psychotics, anti-depressants, and anti-epileptics. Adverse drug reactions to some anti-epileptic drugs (e.g., carbamazepine and phenytoin) have been associated with certain human leukocyte antigen types and variants in DNA polymerase gamma ( POLG ; valproic acid). Evidence remains limited for genetic variants of drug target proteins, making it challenging to identify patients with altered treatment responses at a therapeutic blood concentration., Competing Interests: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© Canadian Paediatric Society 2024. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Les médicaments psychoactifs sont de plus en plus utilisés pour traiter les enfants et les adolescents ayant des troubles de santé mentale, mais la variabilité des réponses individuelles fait ressortir l'importance d'une médecine personnalisée. Les tests pharmacogénétiques sont un volet important d'un tel type de médecine. Le nombre d'entreprises de tests pharmacogénétiques commerciaux qui font la promotion de tests de ce genre et promettent un traitement efficace et individualisé des troubles de santé mentale se multiplie depuis quelques années. Les preuves scientifiques en appui à l'utilisation de la pharmacogénétique sont limitées, particulièrement dans les populations pédiatriques. Le présent point de pratique souligne les étapes qui orientent le recours à ces tests pour la prise de médicaments psychoactifs en milieu clinique et présente des ressources de soutien importantes. Il existe des directives cliniques sur les variants des pharmacogènes qui encodent les enzymes de métabolisation du cytochrome P450 (p. ex., CYP2C19 , CYP2D6 , CYP2C9 ), lesquels sont l'un des déterminants des concentrations pharmacologiques dans le sang et peuvent appuyer à la fois le choix du médicament et la stratégie posologique de certains antipsychotiques, antidépresseurs et antiépileptiques. Les effets indésirables de certains médicaments antiépileptiques (p. ex., la carbamazépine et la phénytoïne) sont associés à certains types d'antigènes d'histocompatibilité humaine et à des variants de l'ADN polymérase gamma ( POLG ; acide valproïque). Les données probantes sont limitées à l'égard des variants génétiques des protéines qui ciblent les médicaments, et c'est pourquoi il est difficile de déterminer quels patients présenteraient une réponse altérée au traitement à une concentration sanguine thérapeutique., (© Société canadienne de pédiatrie 2024. Publié par Oxford University Press pour le compte de la Société canadienne de pédiatrie. Tous droits réservés. Pour en faire une réutilisation commerciale, veuillez écrire à reprints@oup.com afin d’obtenir les droits de réimpression et de traduction. Toutes les autres autorisations peuvent être obtenues auprès du service RightsLink accessible par le lien Permissions sur la page de l’article affichée dans notre site. Pour obtenir plus d’information, écrivez à journals.permissions@oup.com.)

Introduction Mass casualty incident (MCI) simulation and triage are educational methods used to provide high fidelity training to first response teams. Simulation and triage need to be as effective as possible to train professionals for true emergencies involving mass casualty. Although MCI simulation and triage have been used in the pre-professional setting (i.e. medical school, nursing school, etc.), more data is required regarding quality improvement of these simulations. This study focuses on quality improvement of MCI simulation and triage in the pre-professional training. In order to evaluate simulation quality to optimize future triage simulations, this study had three specific aims: (1) assess participant accuracy of triage after training in Sort, Assess, Life-Saving Interventions, Triage/Transport (SALT); (2) evaluate the role of stress and confidence in participants of triage simulation; (3) determine trainees' perception of unmanned aerial vehicles (drones) in the setting of mass casualty simulation. Methods A total of 44 attendees of the University of Central Florida (UCF) College of Medicine Global Health Conference participated in this study across three groups. Each group was provided a 15-minute lecture on SALT protocol. After the training, the participants continued to a 30-minute simulation in which they were asked to accurately triage up to 46 patient-actors. Each participants' triage designations were compared to the previously assigned designations of each patient-actor. Pre- and post-simulation surveys were collected and analyzed using Statistical Package for the Social Sciences (SPSS) (IBM Corp., Chicago, IL). All other data were analyzed using descriptive statistics.  Results Qualitative and Likert data for the simulation were collected from 44 participants. Given a total of 1,113 triage scores (average of 25.29 triage designations per person), there was data to support that novice learners in this study tended to under-triage using the SALT protocol after 15-minute SALT training, with an overall accuracy of 52.43%. Survey data showed that confidence in mass casualty triage improved post-simulation, improving from median 3/10 to 5/10. Most participants were unaware of the use of unmanned aerial vehicles in MCI but most had positive opinions of their usefulness in MCI after the simulation, with a median score of 8/10. Conclusions Participant accuracy of triage after undergoing a 15-minute training in SALT triage was 52.43%, with a non-statistically significant tendency to under-triage. This accuracy level is consistent with other studies of SALT triage in MCI, but the tendency to undertriage requires further study for validation. Stress levels during the simulation were significantly elevated, while post-simulation confidence increased significantly from pre-simulation. The perception of drone utility in MCI was favorable among participants in this study, indicating drones may be useful for first response teams in future mass casualty simulations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Hartman et al.)

Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder. Three position statements have been developed by the Canadian Paediatric Society, following systematic literature reviews. Statement objectives are to: 1) Summarize the current clinical evidence regarding ADHD,2) Establish a standard for ADHD care, and3) Assist Canadian clinicians in making well-informed, evidence-based decisions to enhance care of children and youth with this condition. Specific topics reviewed in Part 2, which focuses on treatment, include: evidence and context for a range of clinical approaches, combining behavioural and pharmacological interventions to address impairment more effectively, the role of parent and teacher (or other caregiver) training, the use of stimulant and nonstimulant medications, with effects and risks, and dosing and monitoring protocols. Treatment recommendations are based on current guidelines, evidence from the literature, and expert consensus.

Crosstalk between growth factors (GFs) and steroid hormones recurs in embryogenesis and is co-opted in pathology, but underlying mechanisms remain elusive. Our data from mammary cells imply that the crosstalk between the epidermal GF and glucocorticoids (GCs) involves transcription factors like p53 and NF-κB, along with reduced pausing and traveling of RNA polymerase II (RNAPII) at both promoters and bodies of GF-inducible genes. Essentially, GCs inhibit positive feedback loops activated by GFs and stimulate the reciprocal inhibitory loops. As expected, no alterations in DNA methylation accompany the transcriptional events instigated by either stimulus, but forced demethylation of regulatory regions broadened the repertoire of GF-inducible genes. We report that enhancers, like some promoters, are poised for activation by GFs and GCs. In addition, within the cooperative interface of the crosstalk, GFs enhance binding of the GC receptor to DNA and, in synergy with GCs, promote productive RNAPII elongation. Reciprocally, within the antagonistic interface GFs hyper-acetylate chromatin at unmethylated promoters and enhancers of genes involved in motility, but GCs hypoacetylate the corresponding regions. In conclusion, unmethylated genomic regions that encode feedback regulatory modules and differentially recruit RNAPII and acetylases/deacetylases underlie the crosstalk between GFs and a steroid hormone., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Circular RNAs (circRNAs) are widespread circles of non-coding RNAs with largely unknown function. Because stimulation of mammary cells with the epidermal growth factor (EGF) leads to dynamic changes in the abundance of coding and non-coding RNA molecules, and culminates in the acquisition of a robust migratory phenotype, this cellular model might disclose functions of circRNAs. Here we show that circRNAs of EGF-stimulated mammary cells are stably expressed, while mRNAs and microRNAs change within minutes. In general, the circRNAs we detected are relatively long-lived and weakly expressed. Interestingly, they are almost ubiquitously co-expressed with the corresponding linear transcripts, and the respective, shared promoter regions are more active compared to genes producing linear isoforms with no detectable circRNAs. These findings imply that altered abundance of circRNAs, unlike changes in the levels of other RNAs, might not play critical roles in signaling cascades and downstream transcriptional networks that rapidly commit cells to specific outcomes., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Tumor progression can be understood as a collaborative effort of mutations and growth factors, which propels cell proliferation and matrix invasion, and also enables evasion of drug-induced apoptosis. Concentrating on EGFR, we discuss downstream signaling and the initiation of transcriptional events in response to growth factors. Specifically, we portray a wave-like program, which initiates by rapid disappearance of two-dozen microRNAs, followed by an abrupt rise of immediate early genes (IEGs), relatively short transcripts encoding transcriptional regulators. Concurrent with the fall of IEGs, some 30-60 min after stimulation, a larger group, the delayed early genes, is up-regulated and its own fall overlaps the rise of the final wave of late response genes. This late wave persists and determines long-term phenotype acquisition, such as invasiveness. Key regulatory steps in the orderly response to growth factors provide a trove of potential oncogenes and tumor suppressors., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

ATP-competitive mammalian target of rapamycin (mTOR) inhibitors are in early phase clinical trials. These novel targeted agents, including PP242, are mechanistically distinct from the allosteric, partial mTOR inhibitor, rapamycin. The goal of this study was to evaluate how PP242 best combines with standard chemotherapies for colorectal cancer (CRC), and which subsets of patients are most likely to benefit. The combination index for PP242 plus 5-fluorouracil, oxaliplatin, or irinotecan was determined in CRC cell lines with different mutational backgrounds. In KRAS mutant CRC cell lines, sensitivity to PP242 increases with co-mutation of PIK3CA. Mutation of p53 predicts resistance to chemotherapy, but not PP242. Efficacy of PP242 was comparable to that of standard chemotherapies over the dose range tested. Sensitivity or resistance to PP242 dictates relative synergy or antagonism, respectively, when PP242 is combined with 5-fluorouracil. The same trend exists for PP242 + oxaliplatin, but with a narrower dynamic range. Conversely potency of PP242 and the combination index for PP242 + irinotecan were unrelated, but synergy exists across all dose levels in PP242 and irinotecan sensitive, p53 wild-type cell lines. Overall, our in vitro analysis predicts that mutational status can be used to rank sensitivity to PP242 and standard chemotherapies. Single agent potency can in turn be used to predict the combination index in a drug-specific manner. Our data suggest a clinical trial to determine whether ATP-competitive mTOR inhibitors provide benefit in combination with standard chemotherapies for patients with PIK3CA mutant metastatic CRC, stratified by the presence or absence of KRAS co-mutation.

The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.

All viruses require cellular ribosomes to translate their mRNAs. Viruses producing methyl-7 (m⁷) GTP-capped mRNAs, like Herpes Simplex Virus-1 (HSV-1), stimulate cap-dependent translation by activating mTORC1 to inhibit the translational repressor 4E-binding protein 1 (4E-BP1). Here, we establish that the HSV-1 kinase Us3 masquerades as Akt to activate mTORC1. Remarkably, Us3 displays no sequence homology with the cellular kinase Akt, yet directly phosphorylates tuberous sclerosis complex 2 (TSC2) on the same sites as Akt. TSC2 depletion rescued Us3-deficient virus replication, establishing that Us3 enhances replication by phosphorylating TSC2 to constitutively activate mTORC1, effectively bypassing S6K-mediated feedback inhibition. Moreover, Us3 stimulated Akt substrate phosphorylation in infected cells, including FOXO1 and GSK3. Thus, HSV-1 encodes an Akt surrogate with overlapping substrate specificity to activate mTORC1, stimulating translation and virus replication. This establishes Us3 as a unique viral kinase with promising drug development potential.

The serum- and glucocorticoid-induced kinase 1 (SGK1) plays a central role in hormone regulation of epithelial sodium (Na+) channel (ENaC)-dependent Na+ transport in the distal nephron. Phosphorylation within a carboxy-terminal domain, designated the hydrophobic motif (HM), determines the activity of SGK1, but the identity of the HM kinase is unknown. Here, we show that the highly conserved serine-threonine kinase mammalian target of rapamycin (mTOR) is essential for the phosphorylation of the HM of SGK1 and the activation of ENaC. We observed that mTOR, in conjunction with rictor (mTORC2), phosphorylated SGK1 and stimulated ENaC. In contrast, when mTOR assembled with raptor in the rapamycin-inhibited complex (mTORC1), it did not phosphorylate SGK1 or stimulate ENaC. Inhibition of mTOR blocked both SGK1 phosphorylation and ENaC-mediated Na+ transport, whereas specific inhibition of mTORC1 had no effect. Similarly, small hairpin RNA-mediated knockdown of rictor inhibited SGK1 phosphorylation and Na+ current, whereas knockdown of raptor had no effect. Finally, in co-immunoprecipitation experiments, SGK1 interacted selectively with rictor but not with raptor, suggesting selective recruitment of SGK1 to mTORC2. We conclude that mTOR, specifically mTORC2, is the HM kinase for SGK1 and is required for ENaC-mediated Na+ transport, thereby extending our understanding of the molecular mechanisms underlying Na+ balance.

We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers., (Copyright 2010 Elsevier Inc. All rights reserved.)

mTOR (mammalian Target of Rapamycin) is the hub of the phosphoinositide 3-Kinase (PI3-K)→Akt→mTOR pathway, which is one of the most commonly mutated pathways in cancer. PI3-Ks and mTOR are related kinases which share an evolutionarily related kinase domain, although the former is a lipid kinase and the latter is a protein kinase. As a result of their similar ATP sites, the prototypical PI3-K inhibitors LY294002 and wortmannin inhibit both kinases, although the compounds have been primarily thought of as inhibitors of PI3-Ks. The widespread use of these reagents to understand PI3-K signaling and the likelihood that many of their effects are confounded by dual inhibition of PI3-K and mTOR make it essential to develop selective mTOR inhibitors in part to understand the unique cellular effects of inhibition of this key downstream component in the growth factor pathway. Rapamycin has historically provided a means for selective mTOR inhibition, yet it is not a typical ATP competitive inhibitor, making its effects difficult to reconcile with LY294002 and wortmannin. Several groups have recently reported pharmacological agents which inhibit mTOR but not PI3-K, providing a new pharmacological approach to selective mTOR inhibition. The TOR kinase domain inhibitors of mTOR have been termed TORKinibs to distinguish their mode of action from rapamycin and its analogs (rapalogs). These inhibitors bind to the ATP binding site of the kinase domain of mTOR and as a result inhibit both mTOR complexes, TORC1 (rapamycin sensitive) and TORC2 (rapamycin resistant). These molecules have allowed a reinvestigation of mTOR and in particular a reinvestigation of the mechanistic basis for incomplete proliferative arrest of cells by Rapamycin. A consensus has quickly emerged from the study of various TORKinibs that Rapamycin is ineffective at blocking cell proliferation because it only partially inhibits the activity of mTORC1. The profound anti-proliferative effect of TORKinibs suggests that as the molecules enter the clinic they may be successful in the treatment of cancers where rapamycin has failed.

Blood vessels form de novo (vasculogenesis) or upon sprouting of capillaries from preexisting vessels (angiogenesis). With high-resolution imaging of zebrafish vascular development, we uncovered a third mode of blood vessel formation whereby the first embryonic artery and vein, two unconnected blood vessels, arise from a common precursor vessel. The first embryonic vein formed by selective sprouting of progenitor cells from the precursor vessel, followed by vessel segregation. These processes were regulated by the ligand EphrinB2 and its receptor EphB4, which are expressed in arterial-fated and venous-fated progenitors, respectively, and interact to orient the direction of progenitor migration. Thus, directional control of progenitor migration drives arterial-venous segregation and generation of separate parallel vessels from a single precursor vessel, a process essential for vascular development.

This is a case of an otherwise asymptomatic Meckel's diverticulum, which became fibrously adherent to a previous umbilical laparoscopic port site, causing volvulus and small bowel obstruction in a pediatric patient. The diverticulum was diagnosed and resected laparoscopically, remaining bowel viability was maintained, and the child recovered without further sequelae. This complication, though rare, should be considered in the differential diagnosis when a child presents with abdominal pain after undergoing previous laparoscopic surgery. More important, this supports the consideration for the resection of asymptomatic Meckel's diverticulm when discovered incidentally, which is currently a controversial topic.

Gram-negative bacterial infections, unlike viral infections, do not typically protect against subsequent viral infections. This is puzzling given that lipopolysaccharide (LPS) and double-stranded (ds) RNA both activate the TIR domain-containing adaptor-inducing interferon beta (TRIF) pathway and, thus, are both capable of eliciting an antiviral response by stimulating type I interferon (IFN) production. We demonstrate herein that SH2-containing inositol-5'-phosphatase (SHIP) protein levels are dramatically increased in murine macrophages via the MyD88-dependent pathway, by up-regulating autocrine-acting transforming growth factor-beta (TGFbeta). The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, cytosine-phosphate-guanosine (CPG)- and LPS-induced tolerance and cross-tolerance and restrains IFN-beta production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform-specific PI3K inhibitors, that LPS- or cytosine-phosphate-guanosine-induced interleukin-6 (IL-6) is positively regulated by p110alpha, -gamma, and -delta but negatively regulated by p110beta. This may explain some of the controversy concerning the role of PI3K in Toll-like receptor-induced cytokine production. Consistent with our in vitro findings, SHIP(-/-) mice overproduce IFN-beta in response to LPS, and this leads to antiviral hypothermia. Thus, up-regulation of SHIP in response to Gram-negative bacterial infections probably explains the inability of such infections to protect against subsequent viral infections.

The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease., Competing Interests: Competing interests. MEF, BA, ZAK, and KMS are inventors on patent applications owned by UCSF related to PP242 and licensed to Intellikine. ZAK and KMS are consultants to Intellikine.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.

Phosphoinositide kinases such as PI3-kinase synthesize lipid second messengers that control diverse cellular processes. Recently, these enzymes have emerged as an important class of drug targets, and there is significant interest in discovering new lipid kinase inhibitors. We describe here a procedure for the high-throughput determination of lipid kinase inhibitor IC50 values. This assay exploits the fact that phosphoinositides, but not nucleotides such as ATP, bind irreversibly to nitrocellulose membranes. As a result, the radiolabeled lipids from a kinase assay can be isolated by spotting the crude reaction on a nitrocellulose membrane and then washing. We show that diverse phosphoinositide kinases can be assayed using this approach and outline how to perform the assay in 96-well plates. We also describe a MATLAB script that automates the data analysis. The complete procedure requires 3-4 h.

Objective: This study examined whether trauma exposure before, during, and/or after military service contributed to current levels of post-traumatic stress disorder (PTSD) and adjustment. Further, we investigated whether trauma exposure before military service was mediated or moderated by military trauma in its effects on current PTSD and adjustment., Method: In this retrospective study, archival data from the medical records of 422 male veterans diagnosed with PTSD between December 2001 and July 2004 at a Veterans Administration Medical Center PTSD clinic were analyzed. Measures included the Clinician-Administered PTSD Scale interview as well as self-report measures assessing trauma history, health problems, and general psychopathology (including PTSD)., Results: Findings indicated that nonmilitary-related trauma was prevalent in this sample (90%). Regression analyses for PTSD symptom severity revealed that age, greater combat exposure, and a history of physical assault after military service were significantly associated with more severe PTSD symptoms. Childhood physical abuse, adult sexual trauma, and a history of being physically assaulted during military service were also significantly associated with PTSD symptom severity. Mediational analyses indicated that childhood trauma was associated with both adult trauma and increased symptomatology on various outcome measures. Moderational analyses indicated that adult trauma exposure moderated the effect of childhood trauma exposure on health complaints., Conclusions: Results suggest that several variables, including age, greater combat exposure, and premilitary and postmilitary traumas, are associated with increased PTSD symptomatology. This finding underscores the importance of conducting a thorough assessment of trauma when diagnosing PTSD.

Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.

Background: The relationship between posttraumatic stress disorder (PTSD) and parasympathetic nervous system (PNS) functioning was investigated using baroreflex sensitivity (BRS). We hypothesized that individuals with PTSD would exhibit lower BRS than those without PTSD., Methods: Participants were 80 PTSD patients and 50 controls aged 18-68 years. All participants were smokers, many were veterans (55%), and 60 were women. Beat-to-beat BP was collected during a 5-min baseline rest periods from which estimates of BRS were derived using the sequence method., Results: Women with PTSD exhibited lower BRS (M = 10.5, S.D. = 5.1) than women without PTSD (M = 14.6, S.D. = 10.7). For men, PTSD diagnosis was not associated with BRS, p > .05., Conclusions: Among women, PTSD was associated with reduced PNS functioning. Men with PTSD did not have attenuated BRS, which may be due to sample characteristics, such as age and combat veteran status. Reduced PNS activity may predispose women with PTSD to poorer cardiovascular health.

Using ambulatory methods for 1 day of monitoring, the authors of this study investigated the association between smoking and situational cues in 63 smokers with posttraumatic stress disorder (PTSD) and 32 smokers without PTSD. Generalized estimating equations contrasted 682 smoking and 444 nonsmoking situations by group status. Smoking was strongly related to craving, positive and negative affect, PTSD symptoms, restlessness, and several situational variables among PTSD smokers. For non-PTSD smokers, the only significant antecedent variables for smoking were craving, drinking coffee, being alone, not being with family, not working, and being around others who were smoking. These results are consistent with previous ambulatory findings regarding mood in smokers but also underscore that, in certain populations, mood and symptom variables may be significantly associated with ad lib smoking., (((c) 2005 APA, all rights reserved).)

Smoking topography was measured in trauma survivors with and without posttraumatic stress disorder (PTSD) after recalling trauma-related and neutral experiences. Analysis of covariance was performed on puff topography and mood measures using nicotine dependence scores and current major depressive disorder as covariates. Puff volumes were higher in the PTSD group than in the non-PTSD group. The PTSD group exhibited stable puff onset intervals while the non-PTSD group exhibited significantly shorter intervals following trauma recall. These findings support a "ceiling effect" hypothesis in which individuals with PTSD perpetually smoke in such a way as to maximize nicotine delivery, possibly reducing the potentially reinforcing effects of increased smoke delivery in negative affect-inducing situations.

This study investigated the association among cigarette smoking, posttraumatic stress disorder (PTSD), and ambulatory cardiovascular and mood monitoring in 117 male Vietnam combat veterans (61 with PTSD and 56 without PTSD). Positive smoking status was associated with higher systolic blood pressure (SBP) and heart rate (HR), as well as greater diastolic blood pressure (DBP) variability. Compared to individuals without PTSD, PTSD patients had higher HR, anger/hostility ratings, and depression/anxiety ratings. Significant diagnosis by smoking status interactions were found indicating that compared to nonsmokers with PTSD, smokers with PTSD had higher DBP, mean arterial pressure (MAP), and positive affect. Ad lib cigarette smoking during the previous 30 min did not have a significant effect on mood or cardiovascular parameters, except in non-PTSD smokers who reported lower depression/anxiety ratings after smoking. Findings suggest that the effect of smoking on cardiovascular parameters may be amplified in smokers in PTSD. Findings suggest that the interrelationships among cardiovascular parameters, cigarette smoking, and PTSD deserve more research attention.

This study assessed mental and physical health correlates of dispositional forgiveness and religious coping responses in 213 help-seeking veterans diagnosed with PTSD. Controlling for age, socioeconomic status, ethnicity, combat exposure, and hostility, the results indicated that difficulty forgiving oneself and negative religious coping were related to depression, anxiety, and PTSD symptom severity. Difficulty forgiving others was associated with depression and PTSD symptom severity, but not anxiety. Positive religious coping was associated with PTSD symptom severity in this sample. Further investigations that delineate the relevance of forgiveness and religious coping in PTSD may enhance current clinical assessment and treatment approaches.

Genetically encoded signaling proteins provide remarkable opportunities to design and target the expression of molecules that can be used to report critical cellular events in vivo, thereby markedly extending the scope and physiological relevance of studies of cell function. Here we report the development of a transgenic mouse expressing such a reporter and its use to examine postsynaptic signaling in smooth muscle. The circularly permutated, Ca2+-sensing molecule G-CaMP (Nakai, J., Ohkura, M., and Imoto, K. (2001) Nat. Biotechnol. 19, 137-141) was expressed in vascular and non-vascular smooth muscle and functioned as a lineage-specific intracellular Ca2+ reporter. Detrusor tissue from these mice was used to identify two separate types of postsynaptic Ca2+ signals, mediated by distinct neurotransmitters. Intrinsic nerve stimulation evoked rapid, whole-cell Ca2+ transients, or "Ca2+ flashes," and slowly propagating Ca2+ waves. We show that Ca2+ flashes occur through P2X receptor stimulation and ryanodine receptor-mediated Ca2+ release, whereas Ca2+ waves arise from muscarinic receptor stimulation and inositol trisphosphate-mediated Ca2+ release. The distinct ionotropic and metabotropic postsynaptic Ca2+ signals are related at the level of Ca2+ release. Importantly, individual myocytes are capable of both postsynaptic responses, and a transition between Ca2+ -induced Ca2+ release and inositol trisphosphate waves occurs at higher synaptic inputs. Ca2+ signaling mice should provide significant advantages in the study of processive biological signaling.

Calcium release through ryanodine receptors (RYR) activates calcium-dependent membrane conductances and plays an important role in excitation-contraction coupling in smooth muscle. The specific RYR isoforms associated with this release in smooth muscle, and the role of RYR-associated proteins such as FK506 binding proteins (FKBPs), has not been clearly established, however. FKBP12.6 proteins interact with RYR2 Ca(2+) release channels and the absence of these proteins predictably alters the amplitude and kinetics of RYR2 unitary Ca(2+) release events (Ca(2+) sparks). To evaluate the role of specific RYR2 and FBKP12.6 proteins in Ca(2+) release processes in smooth muscle, we compared spontaneous transient outward currents (STOCs), Ca(2+) sparks, Ca(2+)-induced Ca(2+) release, and Ca(2+) waves in smooth muscle cells freshly isolated from wild-type, FKBP12.6(-/-), and RYR3(-/-) mouse bladders. Consistent with a role of FKBP12.6 and RYR2 proteins in spontaneous Ca(2+) sparks, we show that the frequency, amplitude, and kinetics of spontaneous, transient outward currents (STOCs) and spontaneous Ca(2+) sparks are altered in FKBP12.6 deficient myocytes relative to wild-type and RYR3 null cells, which were not significantly different from each other. Ca(2+) -induced Ca(2+) release was similarly augmented in FKBP12.6(-/-), but not in RYR3 null cells relative to wild-type. Finally, Ca(2+) wave speed evoked by CICR was not different in RYR3 cells relative to control, indicating that these proteins are not necessary for normal Ca(2+) wave propagation. The effect of FKBP12.6 deletion on the frequency, amplitude, and kinetics of spontaneous and evoked Ca(2+) sparks in smooth muscle, and the finding of normal Ca(2+) sparks and CICR in RYR3 null mice, indicate that Ca(2+) release through RYR2 molecules contributes to the formation of spontaneous and evoked Ca(2+) sparks, and associated STOCs, in smooth muscle.

This study investigated the associations among PTSD, ambulatory cardiovascular monitoring, and physical health self-reports in 117 male Vietnam combat veterans (61 with PTSD and 56 without PTSD). PTSD was associated with health symptoms and number of current health conditions beyond the influence of several covariates. PTSD was associated with greater systolic blood pressure variability, and an elevated percentage of heart rate and systolic blood pressure readings above baseline. Higher mean heart rate and an elevated percentage of heart rate above baseline were associated with physical health symptoms. None of the ambulatory monitoring variables mediated the association between PTSD and physical health outcomes. Findings suggest that the interrelationships among ambulatory autonomic responses, PTSD, and physical health deserve more research attention.

Researchers have identified difficulties associated with the use of traditional Minnesota Multiphasic Personality Inventory-2 (MMPI-2; Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) validity scales with survivors of traumatic events. A new scale, the Infrequency-Posttraumatic Stress Disorder scale (Fptsd), was created from MMPI-2 items that were infrequently endorsed by 940 male combat veterans presenting for treatment at the posttraumatic stress disorder (PTSD) clinics of 2 Veterans Affairs Medical Centers. A variety of statistical methods were implemented that preliminarily established Fptsd's validity with a validation sample of 323 additional PTSD-diagnosed combat veterans. Results indicate that, relative to previously established validity and overreporting scales (F, Fb, and Fp), Fptsd was significantly less related to psychopathology and distress and better at discriminating simulated from genuinely reported PTSD. Clinical implications are discussed concerning the use of Fptsd to assess disability-seeking veterans suspected of overreporting PTSD symptoms.

Multiyear (37-51 months) follow-up data was obtained on patients who had participated in an open label trial of nefazodone that originally showed nefazodone may be useful for symptom management in posttraumatic stress disorder (PTSD) patients. Ten patients with combat-related DSM-IV posttraumatic stress disorder (PTSD) entered an open-label 12-week trial of nefazodone, beginning with 100 mg/day and increasing as necessary to achieve a maximal response or until reaching a maximum dosage of 600 mg/day. All 10 patients were followed for over 3-4 years and used nefazodone with dosages of 400-600 mg a day. The entire dosagewas shifted to bedtime to facilitate sleep in 7 patients. Data on PTSD symptoms, depression, sleep, and anger were examined. Nefazodone was well tolerated and no significant changes in sexual function were reported. All participants reported compliance with the prescribed nefazodone over 3-4 years. Nine patients reported that it remained effective, and expressed a desire to remain on the medication. On the basis of clinician global impression ratings (compared to baseline), 10 patients were rated as much improved at 12 weeks. Seven of the 10 patients continued to be much improved, 2 were minimally improved, and 1 was rated as worse (compared to baseline assessment) on 3-4-year follow-up. At 3-4-year follow-up, improvements in PTSD symptoms, sleep, and anger were maintained. These improvements were statistically significant with moderate-to-large effect sizes. These data suggest that clinical improvement in PTSD patients administered nefazodone may be maintained with continued treatment. The medication was tolerated well in long-term treatment, compliance was high, and improvement was maintained over several years. Length of treatment, appropriate dose, long-term efficacy, and compliance are all clinically significant issues with little guiding data available. Controlled studies are needed to (a) further investigate the long-term efficacy of nefazodone in the treatment of PTSD; (b) provide information for length of treatment guidelines; and (c) document if discontinuation is possible and efficacious.

This study investigated whether a subgroup of veterans with malignant posttraumatic stress syndrome, as described by Rosenheck (1985) and Lambert et al. (1996), could be identified via cluster analysis within two samples of Vietnam veterans with combat-related posttraumatic stress disorder (PTSD). In the initial subsample (n = 157), four clusters were identified, including a subgroup that scored consistently higher on measures of interpersonal violence and current physical problems. Similar results were found in the cross-validation subsample (n = 156). These results provide support for the theoretical concept of malignant PTSD and suggest that veterans with chronic PTSD are not homogenous. Whereas some manifest extreme levels of both functional impairment and PTSD symptomatology, others exhibit markedly less functional impairment despite manifesting clinically significant levels of PTSD. Clinicians can consider this heterogeneity in their treatment decisions., (Copyright 2002 Wiley Periodicals, Inc.)

Perhaps synaptic vesicles can recycle so rapidly because they avoid complete exocytosis, and release transmitter through a fusion pore that opens transiently. This view emerges from imaging whole terminals where the fluorescent lipid FM1-43 seems unable to leave vesicles during transmitter release. Here we imaged single, FM1-43-stained synaptic vesicles by evanescent field fluorescence microscopy, and tracked the escape of dye from single vesicles by watching the increase in fluorescence after exocytosis. Dye left rapidly and completely during most or all exocytic events. We conclude that vesicles at this terminal allow lipid exchange soon after exocytosis, and lose their dye even if they connected with the plasma membrane only briefly. At the level of single vesicles, therefore, observations with FM1-43 provide no evidence that exocytosis of synaptic vesicles is incomplete.

As a final step in endocytosis, clathrin-coated pits must separate from the plasma membrane and move into the cytosol as a coated vesicle. Because these events involve minute movements that conventional light microscopy cannot resolve, they have not been observed directly and their dynamics remain unexplored. Here, we used evanescent field (EF) microscopy to observe single clathrin-coated pits or vesicles as they draw inwards from the plasma membrane and finally lose their coats. This inward movement occurred immediately after a brief burst of dynamin recruitment and was accompanied by transient actin assembly. Therefore, dynamin may provide the trigger and actin may provide the force for movement into the cytosol.

The current study provides a portrait of emotional-behavioral functioning within a small sample of Vietnam veterans with combat-related posttraumatic stress disorder (PTSD), their partners, and older adolescent and adult children. Veterans, their partners and children reported moderate-low to moderate-high levels of violent behavior. In addition, partner and veteran hostility scores were elevated relative to gender and age matched norms. Partners also reported heightened levels of psychological maltreatment by veterans. Veterans' combat exposure was positively correlated with hostility and violent behavior among children but unrelated to partner variables. Veterans' reports of PTSD symptoms were positively associated with reports of hostility and violence among children, and hostility and general psychological distress among partners. Veterans' violent behavior was also positively correlated with children's violent behavior, but did not yield significant correlations with other child or partner variables. Findings are discussed in relation to prior work and directions for future research are addressed.

Smooth muscle cells undergo substantial increases in length, passively stretching during increases in intraluminal pressure in vessels and hollow organs. Active contractile responses to counteract increased transmural pressure were first described almost a century ago (Bayliss, 1902) and several mechanisms have been advanced to explain this phenomenon. We report here that elongation of smooth muscle cells results in ryanodine receptor-mediated Ca(2+) release in individual myocytes. Mechanical elongation of isolated, single urinary bladder myocytes to approximately 120% of slack length (DeltaL = 20) evoked Ca(2+) release from intracellular stores in the form of single Ca(2+) sparks and propagated Ca(2+) waves. Ca(2+) release was not due to calcium-induced calcium release, as release was observed in Ca(2+)-free extracellular solution and when free Ca(2+) ions in the cytosol were strongly buffered to prevent increases in [Ca(2+)](i). Stretch-induced calcium release (SICR) was not affected by inhibition of InsP(3)R-mediated Ca(2+) release, but was completely blocked by ryanodine. Release occurred in the absence of previously reported stretch-activated currents; however, SICR evoked calcium-activated chloride currents in the form of transient inward currents, suggesting a regulatory mechanism for the generation of spontaneous currents in smooth muscle. SICR was also observed in individual myocytes during stretch of intact urinary bladder smooth muscle segments. Thus, longitudinal stretch of smooth muscle cells induces Ca(2+) release through gating of RYR. SICR may be an important component of the physiological response to increases in luminal pressure in smooth muscle tissues.

Spouse reports may serve as an important source of collateral information in the assessment of posttraumatic stress disorder (PTSD) and associated behavioral problems. This study examined the concordance of anger reports among 94 combat veterans and their partners. Veterans' scores on subscales of the Multidimensional Anger Inventory were compared with scores on a parallel version completed by partners to assess veterans' anger symptomatology. The study examined whether the concordance between veteran and partner-reported anger is moderated by whether the veteran suffers from PTSD. There was moderate agreement between veterans and their partners on reports of anger and little evidence to suggest that PTSD diagnosis affected the convergence between partner and veteran scores.

The current study examined service era differences in a sample of 172 Gulf and Vietnam outpatient veterans with combat-related posttraumatic stress disorder (PTSD). Participants completed the MMPI-2 and several additional self-report measures of symptom severity (PTSD, depression, anxiety, hostility, and health complaints). Results indicated that MMPI-2 profiles differed significantly according to service era with Vietnam veterans scoring higher on scales 2, 8, and 0 and lower on scale 9 than did Gulf veterans. Examination of group means derived from parametric analysis of MMPI-2 data suggested a mean two-point code type of 2-8/8-2 for Vietnam veterans and 1-8/8-1 for Gulf veterans. In contrast, when the data were examined using descriptive techniques based on frequency counts of individual MMPI-2 profiles, the most frequently occurring two-point codetype was 7-8/8-7 for Vietnam veterans, and 6-8/8-6 for Gulf veterans. In addition, Gulf veterans reported a greater number of total health complaints than Vietnam veterans, whereas Vietnam veterans reported a greater number of physician-diagnosed physical conditions. Potential advantages of incorporating descriptive approaches versus parametric methods when examining profile data are also presented., (Copyright 2002 Wiley Periodicals, Inc.)

This study investigated the cardiovascular responses to a relived anger task in 118 male Vietnam combat veterans (62 with posttraumatic stress disorder [PTSD] and 56 without PTSD). Participants completed standardized diagnostic measures, hostility measures, and a laboratory session in which they relived a self-chosen anger memory while heart rate (HR), systolic blood pressure, and diastolic blood pressure (DBP) were measured continuously using an Ohmeda Finapres monitor. Compared with veterans without PTSD, PTSD veterans took less time to feel anger, had greater mean HR and DBP response during relived anger, and reported greater anger and anxiety during the task. There was a significant relationship between covert hostility and anger response, during and after the anger task only in participants with PTSD.

This study was conducted to evaluate the effect of bupropion sustained-release (SR) on smoking cessation in patients with chronic posttraumatic stress disorder (PTSD). Fifteen veterans with chronic PTSD who desired to stop smoking enrolled in a 12-week double-blind evaluation of bupropion SR and placebo. Patients were randomly assigned in a 2:1 ratio to receive either bupropion SR or placebo. Bupropion SR was initiated at 150 mg daily for 3 or 4 days and increased to a final dose of 150 mg twice daily (300 mg daily total). Ten patients received bupropion SR and five received placebo. Nine of the patients who received bupropion SR were already being treated with at least one other psychotropic medication. One of the ten patients did not complete the study because of medication side effects. Eighty percent of patients receiving bupropion SR successfully stopped smoking by the end of week 2, and 6 (60%) of these 10 maintained smoking cessation at the study endpoint (week 12). At the 6-month follow-up, 40% of the patients (4 of 10) who received bupropion SR maintained smoking cessation. One (20%) of the five patients who received placebo stopped smoking and maintained smoking cessation at the 6-month follow-up. Bupropion SR was generally well-tolerated in combination with other psychotropic medications. Bupropion SR may be effective in helping patients who desire to quit smoking and who also have a concomitant anxiety disorder, such as PTSD.

The present study assessed drug use and the validity of self-reports of substance use among help-seeking veterans referred to a specialty clinic for the assessment of posttraumatic stress disorder (PTSD). Patients (n = 341) were asked to provide a urine sample for use in drug screening as part of an evaluation of PTSD. Self-reports of substance use were compared with same-day supervised urine samples for 317 patients who volunteered to participate in a drug screening. Results suggested that self-reports were generally quite valid. Only 8% of the cases involved patients not reporting substance use detected by urine screens. A total of 42% of the participants were identified as using drugs of abuse (excluding alcohol) through self-report and urine drug screens. Among participants using drugs, PTSD diagnosis was significantly associated with greater marijuana and depressant use as compared with stimulant (cocaine and amphetamines) use.

This study investigated hostility and functional health status in 90 women veterans with and without PTSD. Compared to women without PTSD, women veterans with PTSD reported significantly higher levels of hostility. Minority status was associated with increased hostility. Compared to a national sample, hostility scores for women with PTSD were greater by a factor of 1.5 PTSD diagnosis was also associated with poorer functioning on all SF-36 Health Survey scales. Controlling for age and education, hostility was related to all SF-36 Health Survey scales in the women with PTSD.

Background: Fluoxetine and placebo were studied in a population of combat veterans with severe, chronic PTSD., Methods: Twelve male veterans with PTSD were enrolled in a 12 week double-blind evaluation of fluoxetine and placebo. Mean fluoxetine dose at endpoint (week 12) was 48 mg/day with a range of 10 mg to 60 mg., Results: One fluoxetine patient responded (17%) and two of the six placebo patients responded (33%)., Conclusions: Fluoxetine patients did not show a greater response than placebo patients in this small sample of male combat veterans with severe, chronic PTSD. Fluoxetine has displayed an efficacious response in controlled studies of patients with PTSD who were predominantly female, suffered civilian (noncombat) traumas, and were overall experiencing less severe PTSD. The reasons for the low response rate to fluoxetine in our study is unknown and will await further study examining variables other than symptoms that might influence outcome, such as gender, comorbidity, prior treatment history, trauma type, severity and chronicity.

The present study investigated the relationship between daily diary affect ratings and ambulatory cardiovascular activity in 117 male Vietnam combat veterans (61 with posttraumatic stress disorder [PTSD] and 56 without PTSD). Participants completed 12-14 hr of ambulatory monitoring and daily diary affect ratings. Compared with veterans without PTSD, veterans with PTSD reported higher negative affect and lower positive affect in daily diary ratings. No differences were detected for mean laboratory initial recordings or mean ambulatory heart rate (HR), systolic blood pressure (SBP), or diastolic blood pressure (DBP). However, compared with veterans without PTSD, veterans with PTSD demonstrated higher SBP and DBP variability and a higher proportion of HR activity (compared with initial recording values) during daily activity. There was a significant Time of Day x Group interaction for mean HR, with a trend for PTSD participants to maintain HR levels during evening hours.

Background: The anticonvulsant, lamotrigine, may be useful for symptom management in PTSD., Methods: Subjects enrolled in a 12-week double-blind evaluation of lamotrigine and placebo. Patients were randomized 2:1 to either lamotrigine or placebo. Lamotrigine was initiated at 25 mg/day and slowly titrated every 1 to 2 weeks over 8 weeks to a maximum dosage of 500 mg/day if tolerated., Results: Fifteen subjects entered treatment, fourteen of whom returned for subsequent visits. Of 10 patients who received lamotrigine, 5 (50%) responded according to the DGRP, compared to 1 of 4 (25%) who received placebo. Lamotrigine patients showed improvement on reexperiencing and avoidance/numbing symptoms compared to placebo patients. Treatments were generally well tolerated., Conclusions: Lamotrigine may be effective as a primary psychopharmacologic treatment in both combat and civilian PTSD and could also be considered as an adjunct to antidepressant therapy used in the treatment of PTSD. These promising results warrant further large sample double-blind, placebo-controlled trials.

Objective: A two-part study was conducted to examine the health status of Vietnam veterans with posttraumatic stress disorder (PTSD). In part 1, veterans with and without PTSD were compared on health behaviors and on self-reported and physician-rated health problems. Consistency of self-report with physician rating for health problems across the two groups was compared. In part 2, the association between health status and PTSD symptom severity, depression, somatization, and health behaviors in PTSD patients was evaluated., Method: In part 1, 276 combat veterans (225 with PTSD and 51 without PTSD) provided health status information, and medical records were reviewed. In part 2, 225 PTSD patients completed standardized PTSD severity, somatization, and depression measures., Results: When analyses controlled for age, socioeconomic status, minority status, combat exposure, alcohol use, and pack-year history, veterans with PTSD reported and were rated as having a greater number of health problems than veterans without PTSD. Agreement between self-report and physician ratings for both groups ranged from low to moderate. Level of agreement between patient and physician was similar across groups. In the analysis of veterans with PTSD, somatization and PTSD symptom severity were significantly related to self-report of health problems, whereas only PTSD symptom severity was related to physician-rated health. Pack-year history was significantly related to self-reported health status in both groups., Conclusions: The presence and severity of PTSD in veterans were associated with greater physical health problems and conditions. Psychological variables (e.g., PTSD status, PTSD severity, somatization) and a behavioral variable (pack-year history) were related to health status.

The present study investigated variables associated with performance on the Trail Making Test from the Halstead-Reitan neuropsychological test battery in Vietnam combat veterans. There was a significant difference in performance between veterans with and without PTSD on both parts of the Trail Making Test. In subgroup analyses excluding participants on medications (antianxiety, antidepressant, and cardiac), comorbid diagnoses (history of alcohol or substance abuse, history of major depression and comorbid anxiety disorder) and compensation-seeking status, the group difference on Trails B remained significant. However, subgroup analyses suggested that poorer performance on Trails A was influenced by antianxiety and cardiac medications, as well as heavy combat exposure status.

Vietnam combat veterans (N = 151) with chronic posttraumatic stress disorder (PTSD) completed measures of atrocities exposure, combat exposure, PTSD symptom severity, guilt and interpersonal violence. PTSD symptom severity, guilt and interpersonal violence rates were similar to previously reported studies that examined treatment seeking combat veterans with PTSD. Controlling for combat exposure, endorsement of atrocities exposure was related to PTSD symptom severity, PTSD B (reexperiencing) symptoms, Global Guilt, Guilt Cognitions, and cognitive subscales of Hindsight-Bias/Responsibility and Wrongdoing. These results are discussed in the context of previous research conducted regarding atrocities exposure and PTSD.