Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Drug metabolizing enzyme systems in the houbara bustard (Chlamydotis undulata)

This study compared catalytic and immunochemical properties of drug metabolizing phase I and II enzyme systems in houbara bustard (Chlamydotis undulata) liver and kidney and rat liver. P450 content in bustard liver (0.34 +/- 0.03 nmol mg(-1) protein) was 50% lower than that of rat liver (0.70+/-0.02 nmol mg(-1) protein). With the exception of aniline hydroxylase activity, monooxygenase activities using aminopyrine, ethoxyresorufin and ethoxycoumarin as substrates were all significantly lower than corresponding rat liver enzymes. As found in mammalian systems the P450 activities in the bird liver were higher than in the kidney. Immunohistochemical analysis of microsomes using antibodies to rat hepatic P450 demonstrated that bustard liver and kidney express P4502Cl1 homologous protein; no appreciable cross-reactivity was observed in bustards using antibodies to P4502E1, 1A1 or 1A2 isoenzymes. Glutathione content and glutathione S-transferase (GST) activity in bustard liver were comparable with those of rat liver. GST activity in the kidney was 65% lower than the liver. Western blotting of liver and kidney cytosol with human GST isoenzyme-specific antibodies revealed that the expression of alpha-class of antibodies exceeds mu in the bustard. In contrast, the pi-class of GST was not detected in the bustard liver. This data demonstrates that hepatic and renal microsomes from the bustard have multiple forms of phase I and phase II enzymes. The multiplicity and tissue specific expression of xenobiotic metabolizing enzymes in bustards may play a significant role in determining the pharmacokinetics of drugs and susceptibility of the birds to various environmental pollutants and toxic insults

Changes in secondary outcomes associated with brief interventions for problem gambling in methadone patients

BackgroundPatients in methadone maintenance treatment (MMT) with problem gambling (PG) experience worse psychosocial outcomes than their non-PG counterparts. Interventions targeting PG in MMT may enhance psychosocial functioning beyond gambling reduction and abstinence. The present study was a secondary data analysis that examined the trajectories of non-gambling outcomes of three brief PG interventions (i.e., brief psychoeducation, brief advice, motivational enhancement therapy plus cognitive-behavioral therapy [MET + CBT]) among MMT patients.MethodsParticipants (N = 109) were engaged in substance use disorder treatment, met criteria for PG, and had a current or lifetime history of MMT. Latent growth curve models examined outcome trajectories of psychiatric, medical, legal, employment, and social problems, as well as psychological distress and quality of life. Follow-up analyses examined clinically significant change.ResultsMET + CBT patients reported lower medical problems at baseline and over time than the brief interventions. There was no evidence of differences between interventions on the other outcomes. Psychiatric problems and psychological distress decreased over time for the entire sample, regardless of the PG intervention. About 24% and 13% of the sample demonstrated clinically significant improvements in psychological distress from baseline to 5 months, and 5 months to 12 months, respectively. Nearly 21% of the sample showed clinically significant improvements in psychiatric problems from 5 months to 12 months. Among all patients, men and those with more severe opioid dependence symptoms demonstrated the greatest psychological improvements.ConclusionsMany patients in MMT with PG experience improvements in psychological problems, including long-term improvement, regardless of the PG intervention offered

Distracted Driving in Teens With and Without Attention-Deficit/Hyperactivity Disorder

OBJECTIVE: This study is among the first to examine the effect of talking on a cell phone or text messaging while driving in teens with and without Attention Deficit/Hyperactivity Disorder (ADHD). METHOD: Teens (average age 17 years) with a diagnosis of ADHD (N=16) were matched with typically developing controls (N=18). All participants operated a driving simulator while (1) conversing on a cell phone, (2) text messaging, and (3) with no distraction during a baseline condition. Six indicators of driving performance were recorded: (a) time to complete the drive; (b) lane deviations; (c) variability in lane position (i.e., Root Mean Square [RMS]); (d) reaction time; (e) motor vehicle collisions; and, (f) speed fluctuation. RESULTS: Significantly greater variation in lane position occurred in the texting task compared to no task and the cell phone task. While texting, in particular, teens with ADHD took significantly less time to complete the scenario. No significant main effects of group were found. CONCLUSIONS: Generally, those with ADHD did not differ in regard to driving performance, when compared to controls, with the exception of one outcome: time to complete scenario. These findings suggest that distracted driving impairs driving performance of teen drivers, regardless of ADHD status. Texting while driving had the greatest negative impact on driving performance, particularly with regard to variability in lane position (i.e., RMS). This study sheds light on key issues regarding injury prevention, with the intent of providing pediatric care providers with the knowledge to inform teen drivers of risks associated with distracted driving which will ultimately result in reduced rates of motor vehicle crashes and concomitant injuries

Effects of Childhood and Adult Persistent Attention-Deficit/Hyperactivity Disorder on Risk of Motor Vehicle Crashes: Results From the Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder

ObjectiveTo determine motor vehicle crash (MVC) risk in adults with a history of childhood attention-deficit/hyperactivity disorder (ADHD) and persistent ADHD symptoms.MethodParticipants with (n = 441) and without (n = 239; local normative comparison group) childhood ADHD from the Multimodal Treatment of Attention-Deficit/Hyperactivity Disorder (MTA) Study were included. Participants provided self-reports on total number of MVCs they had been involved in and the time of licensure. Driving experience was estimated as the number of months since licensure. Total number of MVCs by adulthood was regressed on baseline ADHD status adjusting for sex, age at follow-up, driving experience, baseline oppositional defiant disorder/conduct disorder comorbidity, baseline household income level, adult oppositional defiant disorder/conduct disorder symptoms, adolescent and adult substance use, and adult antisocial personality disorder symptoms. We repeated the analysis using adult ADHD status (persistent versus desistant versus local normative comparison group) and symptom level as the predictor variables. Results are presented as incidence rate ratio (IRR) and CI.ResultsChildhood ADHD was associated with a higher number of MVCs (IRR = 1.45, CI = 1.15-1.82), and adult ADHD symptom persistence was associated with more MVCs than desistance (IRR = 1.46, CI = 1.14-1.86). ADHD desistance was not associated with a significantly increased risk for MVCs compared with the local normative comparison group (IRR = 1.24, CI = 0.96-1.61). Concurrent symptoms of inattention and hyperactivity/impulsivity predicted MVC risk.ConclusionPersistence of ADHD into adulthood is a stronger predictor of MVC risk than childhood-limited ADHD.Clinical trial registration informationMultimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) Study; https://clinicaltrials.gov; NCT00000388

Impact of Distracted Driving on Safety and Traffic Flow

Studies have documented a link between distracted driving and diminished safety; however, an association between distracted driving and traffic congestion has not been investigated in depth. The present study examined the behavior of teens and young adults operating a driving simulator while engaged in various distractions (i.e., cell phone, texting, and undistracted) and driving conditions (i.e., free flow, stable flow, and oversaturation). Seventy five participants 16 to 25 years of age (split into 2 groups: novice drivers and young adults) drove a STISIM simulator three times, each time with one of three randomly presented distractions. Each drive was designed to represent daytime scenery on a 4 lane divided roadway and included three equal roadway portions representing Levels of Service (LOS) A, C, and E as defined in the 2000 Highway Capacity Manual. Participants also completed questionnaires documenting demographics and driving history. Both safety and traffic flow related driving outcomes were considered. A Repeated Measures Multivariate Analysis of Variance was employed to analyze continuous outcome variables and a Generalized Estimate Equation (GEE) poisson model was used to analyze count variables. Results revealed that, in general more lane deviations and crashes occurred during texting. Distraction (in most cases, text messaging) had a significantly negative impact on traffic flow, such that participants exhibited greater fluctuation in speed, changed lanes significantly fewer times, and took longer to complete the scenario. In turn, more simulated vehicles passed the participant drivers while they were texting or talking on a cell phone than while undistracted. The results indicate that distracted driving, particularly texting, may lead to reduced safety and traffic flow, thus having a negative impact on traffic operations. No significant differences were detected between age groups, suggesting that all drivers, regardless of age, may drive in a manner that impacts safety and traffic flow negatively when distracted