Inhalation of environmental particulate matter (PM) is correlated with adverse health effects in humans, but gene products that couple detection with cellular responses, and the specific properties of PM that target different pathways, have not been fully elucidated. TRPA1 and V1 are two cation channels expressed by sensory neurons and non-neuronal cells of the respiratory tract that have been implicated as possible mediators of PM toxicity. The goals of this research were to determine if environmental PM preferentially activated TRPA1 and to elucidate the criteria responsible for selectivity. Quantification of TRPA1 activation by 4 model PM revealed that diesel exhaust PM (DEP) and coal fly ash PM (CFA1) were TRPA1 agonists at concentrations >0.077 mg/ml. DEP was more potent and approximately 97% of the activity of DEP was recovered by serial extraction of the solid DEP with ethanol and hexane:n-butyl chloride. Modification of the electrophile/agonist binding sites on TRPA1 (C621, C641, C665 and K710) to non-nucleophilic residues reduced TRPA1 activation by DEP and abolished activation by DEP extracts as well as multiple individual electrophilic chemical components of DEP. However, responses to CFA1 and DEP solids were not affected by these mutations. Activity-guided fractionation of DEP and high resolution mass spectroscopy identified several new DEP-derived TRPA1 agonists and activation of mouse dorsal root ganglion neurons demonstrated TRPA1 is a primary target for DEP in a heterogeneous population of primary sensory nerves. It is concluded that TRPA1 is a specific target for electrophilic chemical components of DEP and proposed that activation of TRPA1 in the respiratory tract is likely to be an important mechanism for DEP pneumotoxicity.

Cigarette smoke, diesel exhaust, and other combustion-derived particles activate the calcium channel transient receptor potential ankyrin-1 (TRPA1), causing irritation and inflammation in the respiratory tract. It was hypothesized that wood smoke particulate and select chemical constituents thereof would also activate TRPA1 in lung cells, potentially explaining the adverse effects of wood and other forms of biomass smoke on the respiratory system. TRPA1 activation was assessed using calcium imaging assays in TRPA1-overexpressing HEK-293 cells, mouse primary trigeminal neurons, and human adenocarcinoma (A549) lung cells. Particles from pine and mesquite smoke were less potent agonists of TRPA1 than an equivalent mass concentration of an ethanol extract of diesel exhaust particles; pine particles were comparable in potency to cigarette smoke condensate, and mesquite particles were the least potent. The fine particulate (PM<2.5 μm) of wood smoke were the most potent TRPA1 agonists and several chemical constituents of wood smoke particulate: 3,5-ditert-butylphenol, coniferaldehyde, formaldehyde, perinaphthenone, agathic acid, and isocupressic acid were TRPA1 agonists. Pine particulate activated TRPA1 in mouse trigeminal neurons and A549 cells in a concentration-dependent manner, which was inhibited by the TRPA1 antagonist HC-030031. TRPA1 activation by wood smoke particles occurred through the electrophile/oxidant-sensing domain (i.e., C621/C641/C665/K710), based on the inhibition of cellular responses when the particles were pre-treated with glutathione; a role for the menthol-binding site of TRPA1 (S873/T874) was demonstrated for 3,5-ditert-butylphenol. This study demonstrated that TRPA1 is a molecular sensor for wood smoke particulate and several chemical constituents thereof, in sensory neurons and A549 cells, suggesting that TRPA1 may mediate some of the adverse effects of wood smoke in humans.

Environmental particulate matter (PM) pollutants adversely affect human health, but the molecular basis is poorly understood. The ion channel transient receptor potential vanilloid-1 (TRPV1) has been implicated as a sensor for environmental PM and a mediator of adverse events in the respiratory tract. The objectives of this study were to determine whether TRPV1 can distinguish chemically and physically unique PM that represents important sources of air pollution; to elucidate the molecular basis of TRPV1 activation by PM; and to ascertain the contributions of TRPV1 to human lung cell and mouse lung tissue responses exposed to an insoluble PM agonist, coal fly ash (CFA1). The major findings of this study are that TRPV1 is activated by some, but not all of the prototype PM materials evaluated, with rank-ordered responses of CFA1 Ͼ diesel exhaust PM Ͼ crystalline silica; TRP melastatin-8 is also robustly activated by CFA1, whereas other TRP channels expressed by airway sensory neurons and lung epithelial cells that may also be activated by CFA1, including TRPs ankyrin 1 (A1), canonical 4␣ (C4␣), M2, V2, V3, and V4, were either slightly (TRPA1) or not activated by CFA1; activation of TRPV1 by CFA1 occurs via cell surface interactions between the solid components of CFA1 and specific amino acid residues of TRPV1 that are localized in the putative pore-loop region; and activation of TRPV1 by CFA1 is not exclusive in mouse lungs but represents a pathway by which CFA1 affects the expression of selected genes in lung epithelial cells and airway tissue.

Objective This manuscript examines the prevalence of childhood maltreatment and the relationship between childhood maltreatment and current psychiatric disorder in detained youths. Methods Clinical research interviewers assessed history of childhood maltreatment with the Child Maltreatment Assessment Profile and psychiatric diagnosis with the Diagnostic Interview Schedule for Children version 2.3 in a stratified, random sample of 1829 detained youths at the Cook Country Juvenile Temporary Detention Center; final n=1735. History of maltreatment was also ascertained from records from the Cook County Court Child Protection Division. Results Over three-quarters of females and over two-thirds of males had a history of physical abuse (moderate or severe). More than 40% of females and 10% of males had a history of sexual abuse. Females and non-Hispanic whites had the highest prevalence rates of childhood maltreatment. Among females, sexual abuse was associated with every type of psychiatric disorder. For example, females who experienced abuse were 2.6 to 10.7 times more likely to have any disorder compared with females who had no maltreatment. Among males, maltreatment was associated with every disorder except anxiety disorders (odds ratios ranged from 1.9–7.9). Among those who were sexually abused, abuse with force was associated with anxiety and affective disorders for females and attention-deficit/hyperactivity (ADHD)/disruptive behavior and substance use disorders for males. Conclusions Psychiatrists and other mental health specialists must screen delinquent youth, not only for psychiatric disorders but also for past and ongoing maltreatment. Discharge planning should include protective and therapeutic services. Trauma-related mental health services should be available during incarceration.

Objective-. To examine the prevalence, development, and persistence of sex and drug behaviors that place delinquent youth at risk for human immunodeficiency virus and other sexually transmitted infections (HIV/STI).Methods-At the baseline interview, HIV/STI drug and sex risk behaviors were assessed in a stratified random sample of 800 juvenile detainees, aged 10 to 18 years. Participants were reinterviewed approximately 3 years later (mean [SD] follow-up, 3.2 [0.3] years; median follow-up, 3.1 years). The final sample in these analyses (n = 724) includes 316 females and 408 males, 393 African Americans, 198 Hispanics, 131 non-Hispanic whites, and 2 participants who self-identified as "other."Results-Nearly three quarters of youth engaged in one or more unprotected sexual risk behaviors at follow-up. Over 60% had engaged in 10 or more risk behaviors at their baseline interview, and nearly two thirds of them persisted in 10 or more risk behaviors at follow-up. Among youth living in the community, many behaviors were more prevalent at follow-up than at baseline. Among incarcerated youth, the opposite pattern prevailed. Development and persistence of HIV/STI risk behaviors differed by gender, race/ethnicity, and age, even after adjusting for incarceration status. Compared with females, males had higher prevalence rates of many HIV/STI risk behaviors and were more likely to persist in some behaviors and develop new ones. Yet, injection risk behaviors were more prevalent among females than males and were also more likely to develop and persist. Compared with persons younger than 18, persons 18 and older had higher prevalence rates of many HIV/STI risk behaviors at follow-up. Overall, there were few racial and ethnic differences in patterns of HIV/STI risk behaviors; most involved the initiation and persistence of substance use among nonHispanic whites and Hispanics.Conclusions-Because detained youth have a median stay of only 2 weeks, HIV/STI risk behaviors in delinquent youth are a community public health problem, not just a problem for the juvenile justice system. Improving the coordination among systems that provide HIV/STI interventions to youth -primary care, education, mental health, and juvenile justice -can reduce the prevalence of risk behaviors and substantially reduce the spread of HIV/STI in young people.Corresponding Author: Linda A. Teplin, PhD, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 710 N. Lakeshore Drive, Suite 900, Chicago, IL 60611. . psycholegal@northwestern.edu. NIH Public Access Author ManuscriptPediatrics. Author manuscript; available in PMC 2010 January 29. Published in final edited form as:Pediatrics. 10-14Minorities are also overrepresented in the juvenile justice system, where HIV/STI risk behaviors are prevalent. 15-20 Detained youth report more risk behaviors and initiate them at younger ages than do youth in the community.21 Detained youth are likely to be at continued risk for HIV infection as they age. Adults in p...

Antisocial personality disorder (APD) is a serious public and mental health concern. Understanding how well conduct disorder (CD) and other mental disorders predict the development of APD among youth involved in the juvenile justice system is critical for prevention. This study used a stratified random sample of 1112 detained youth to examine the development of APD at a three-year followup interview. Nearly one fifth of male juvenile detainees later developed APD; approximately one quarter of male juvenile detainees with CD at baseline later developed APD. Significantly more males than females developed APD; no differences were found by race/ethnicity. Having five or more symptoms of CD, dysthymia, alcohol use disorder, or generalized anxiety disorder was significantly associated with developing modified APD (M-APD; APD without the CD requirement). Some disorders were strong predictors of APD; however, none were adequate screeners for identifying which detainees would later develop M-APD. The findings of this study have implications for interventions and further research in developmental psychopathology. Keywords conduct disorder; antisocial personality disorder; mental disorder; detained youth; longitudinal Persistent antisocial behavior places a heavy burden on the community, the justice system, and the public health system (Miller, Cohen, & Wiersema, 1996). Adults with antisocial personality disorder (APD) are likely to experience a range of problematic behaviors and outcomes: criminal and violent behavior, substance use, early death, divorce, unemployment, and homelessness (Black, Baumgard, Bell, & Kao, 1996;Hodgins & Cote, 1993;Jainchill, Hawke, & Yagelka, 2000;Robins, Tipp, & Przybeck, 1991;Westermeyer & Thuras, 2005).Corresponding Author: Jason J. Washburn, PhD, ABPP, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 710 N. Lakeshore Drive, Suite 900, Chicago, IL 60611. Phone: 312-503-3500. Fax: 312-503-3535. j-washburn@northwestern.edu. Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/journals/ccp. Considering the high social and financial costs associated with APD, identifying youth at risk for this disorder is critical for prevention (Loeber, Green, & Lahey, 2003;Offord, 2000). NIH Public AccessAmong many of the factors hypothesized to affect the development of APD are mental disorders in childhood and adolescence. Conduct disorder (CD) in childhood and adolescence is the factor most often associated with the development of APD (Abramowitz, Kosson, & Seiden...

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.

Objective-To examine the prevalence of posttraumatic stress disorder (PTSD) and comorbid psychiatric disorders among juvenile detainees.Methods-Participants were a stratified random sample of 898 youth (10-18 years of age) arrested and detained in Chicago.Results-Among participants with PTSD, 93% had at least 1 comorbid psychiatric disorder compared with 64% without PTSD. Over half of participants with PTSD had 2 or more types of comorbid disorders (i.e., affective, anxiety, behavioral, and substance use disorders), and 11% had all 4 types of comorbid disorders. Among males, having any psychiatric diagnosis significantly increased the odds of having comorbid PTSD. Among females, alcohol use disorder and comorbid alcohol and drug use disorder significantly increased the odds of having PTSD. No significant difference in prevalence rates of PTSD was found between males and females with specific psychiatric disorders.Conclusions-High rates of PTSD and comorbid disorders among detainees argue for improved screening in detention centers. Implications for services are discussed in light of the clinical challenges of treating persons with comorbid disorders.Most youth in detention have 1 or more psychiatric disorders (1). Posttraumatic stress disorder (PTSD) is one of the more prevalent disorders in detention, affecting at least 1 in 10 youth (2-4). One of the more debilitating aspects of PTSD is its tendency to co-occur with other psychiatric disorders (5-7). In a community sample, Giaconia and colleagues (8) found that nearly four-fifths of those with lifetime PTSD also had one or more additional disorders. Studies of detained adolescent males in Russia (9) and detained adolescent females in Australia (10) found that all of the detainees with PTSD had at least 1 comorbid disorder.It is unclear if PTSD increases the vulnerability to other disorders or if there are common genetic or environmental factors underlying the disorders (5,11). Researchers agree, however, that comorbid disorders have an adverse impact on the prognosis and treatment of individuals with PTSD. Youth with PTSD and comorbid disorders have significantly more behavioral and health problems and more impaired interpersonal relationships than those without comorbid disorders (5).Send correspondence to Dr. Teplin at the Department of Psychiatry and Behavioral Sciences, Northwestern University Medical School, 710 North Lake Shore Dr., Suite 900, Chicago, IL 60611 (l-teplin@northwestern.edu).. An earlier version of this article was presented at the annual meeting of the Midwestern Psychological Association, Chicago, May, 2006. Effective treatment planning for detained youth with PTSD requires epidemiologic data on patterns of prevalence and comorbidity. Yet, to our knowledge, no epidemiologic study of detainees in the US has examined PTSD and comorbid psychiatric disorders. In this paper, we administered standardized diagnostic measures to a large, stratified random sample of detained youth to: (a) compare the prevalence of psychiatric disorders amo...