Human severe sepsis cytokine mixture increases β2-integrin-dependent polymorphonuclear leukocyte adhesion to cerebral microvascular endothelial cells in vitro.

INTRODUCTION: Sepsis-associated encephalopathy (SAE) is a state of acute brain dysfunction in response to a systemic infection. We propose that systemic inflammation during sepsis causes increased adhesion of leukocytes to the brain microvasculature, resulting in blood-brain barrier dysfunction. Thus, our objectives were to measure inflammatory analytes in plasma of severe sepsis patients to create an experimental cytokine mixture (CM), and to use this CM to investigate the activation and interactions of polymorphonuclear leukocytes (PMN) and human cerebrovascular endothelial cells (hCMEC/D3) in vitro. METHODS: The concentrations of 41 inflammatory analytes were quantified in plasma obtained from 20 severe sepsis patients and 20 age- and sex-matched healthy controls employing an antibody microarray. Two CMs were prepared to mimic severe sepsis (SSCM) and control (CCM), and these CMs were then used for PMN and hCMEC/D3 stimulation in vitro. PMN adhesion to hCMEC/D3 was assessed under conditions of flow (shear stress 0.7 dyn/cm(2)). RESULTS: Eight inflammatory analytes elevated in plasma obtained from severe sepsis patients were used to prepare SSCM and CCM. Stimulation of PMN with SSCM led to a marked increase in PMN adhesion to hCMEC/D3, as compared to CCM. PMN adhesion was abolished with neutralizing antibodies to either β2 (CD18), αL/β2 (CD11α/CD18; LFA-1) or αM/β2 (CD11β/CD18; Mac-1) integrins. In addition, immune-neutralization of the endothelial (hCMEC/D3) cell adhesion molecule, ICAM-1 (CD54) also suppressed PMN adhesion. CONCLUSIONS: Human SSCM up-regulates PMN pro-adhesive phenotype and promotes PMN adhesion to cerebrovascular endothelial cells through a β2-integrin-ICAM-1-dependent mechanism. PMN adhesion to the brain microvasculature may contribute to SAE

Human severe sepsis cytokine mixture increases beta 2-integrin-dependent polymorphonuclear leukocyte adhesion to cerebral microvascular endothelial cells in vitro

Introduction: Sepsis-associated encephalopathy (SAE) is a state of acute brain dysfunction in response to a systemic infection. We propose that systemic inflammation during sepsis causes increased adhesion of leukocytes to the brain microvasculature, resulting in blood-brain barrier dysfunction. Thus, our objectives were to measure inflammatory analytes in plasma of severe sepsis patients to create an experimental cytokine mixture (CM), and to use this CM to investigate the activation and interactions of polymorphonuclear leukocytes (PMN) and human cerebrovascular endothelial cells (hCMEC/D3) in vitro. Methods: The concentrations of 41 inflammatory analytes were quantified in plasma obtained from 20 severe sepsis patients and 20 age- and sex-matched healthy controls employing an antibody microarray. Two CMs were prepared to mimic severe sepsis (SSCM) and control (CCM), and these CMs were then used for PMN and hCMEC/D3 stimulation in vitro. PMN adhesion to hCMEC/D3 was assessed under conditions of flow (shear stress 0.7 dyn/cm(2)). Results: Eight inflammatory analytes elevated in plasma obtained from severe sepsis patients were used to prepare SSCM and CCM. Stimulation of PMN with SSCM led to a marked increase in PMN adhesion to hCMEC/D3, as compared to CCM. PMN adhesion was abolished with neutralizing antibodies to either beta 2 (CD18), alpha(L)/beta(2) (CD11 alpha/CD18; LFA-1) or alpha(M)/beta(2) (CD11 beta/CD18; Mac-1) integrins. In addition, immune-neutralization of the endothelial (hCMEC/D3) cell adhesion molecule, ICAM-1 (CD54) also suppressed PMN adhesion. Conclusions: Human SSCM up-regulates PMN pro-adhesive phenotype and promotes PMN adhesion to cerebrovascular endothelial cells through a beta 2-integrin-ICAM-1-dependent mechanism. PMN adhesion to the brain microvasculature may contribute to SAE

Cocaine's fall and marijuana's rise: questions and insights based on new estimates of consumption and expenditures in US drug markets

ABSTRACT Aims Drug policy strategies and discussions often use prevalence of drug use as a primary performance indicator. However, three other indicators are at least as relevant: the number of heavy users, total expenditures and total amount consumed. This paper stems from our efforts to develop annual estimates of these three measures for cocaine (including crack), heroin, marijuana and methamphetamine in the United States. Methods The estimates exploit complementary strengths of a general population survey (National Survey on Drug Use and Health) and both survey and urinalysis test result data for arrestees (Arrestee Drug Abuse Monitoring Program), supplemented by many other data sources. Results Throughout the 2000s US drug users spent in the order of $100 billion annually on these drugs, although the spending distribution and use patterns changed dramatically. From 2006 to 2010, the amount of marijuana consumed in the United States probably increased by more than 30%, while the amount of cocaine consumed in the United States fell by approximately 50%. These figures are consistent with supply-side indicators, such as seizures and production estimates. For all the drugs, total consumption and expenditures are driven by the minority of users who consume on 21 or more days each month. Conclusions Even for established drugs, consumption can change rapidly. The halving of the cocaine market in five years and the parallel (but independent) large rise in daily/near-daily marijuana use are major events that were not anticipated by the expert community and raise important theoretical, research, and policy issues

Cocaine's fall and marijuana's rise: questions and insights based on new estimates of consumption and expenditures in US drug markets

ABSTRACT Aims Drug policy strategies and discussions often use prevalence of drug use as a primary performance indicator. However, three other indicators are at least as relevant: the number of heavy users, total expenditures and total amount consumed. This paper stems from our efforts to develop annual estimates of these three measures for cocaine (including crack), heroin, marijuana and methamphetamine in the United States. Methods The estimates exploit complementary strengths of a general population survey (National Survey on Drug Use and Health) and both survey and urinalysis test result data for arrestees (Arrestee Drug Abuse Monitoring Program), supplemented by many other data sources. Results Throughout the 2000s US drug users spent in the order of $100 billion annually on these drugs, although the spending distribution and use patterns changed dramatically. From 2006 to 2010, the amount of marijuana consumed in the United States probably increased by more than 30%, while the amount of cocaine consumed in the United States fell by approximately 50%. These figures are consistent with supply-side indicators, such as seizures and production estimates. For all the drugs, total consumption and expenditures are driven by the minority of users who consume on 21 or more days each month. Conclusions Even for established drugs, consumption can change rapidly. The halving of the cocaine market in five years and the parallel (but independent) large rise in daily/near-daily marijuana use are major events that were not anticipated by the expert community and raise important theoretical, research, and policy issues

A Natural Experiment to Test the Effect of Sanction Certainty and Celerity on Substance-Impaired Driving: North Dakota’s 24/7 Sobriety Program

Objectives Evaluate the deterrent effect of a program that increases the certainty and celerity of sanction for arrestees ordered to abstain from alcohol and other drugs on substance-impaired driving arrests. Methods We examine participant compliance with orders to abstain from alcohol and other drug use via breathalyzer, body-worn continuous alcohol monitoring devices, transdermal drug patches, and urinalyses. We then evaluate the impact of the 24/7 Sobriety program on substance-impaired driving arrests. Using variation across counties in the timing of program implementation in North Dakota as a natural experiment, we use difference-in-differences fixed effects Poisson regressions to measure the program’s effect on county-level arrests for substance-impaired driving. Results Over half of participants ordered to abstain from substance use complete 24/7 Sobriety without a detected substance use event. At the county level, the program is associated with a 9% reduction in substance-impaired driving arrests after accounting for the impact of oil exploration in the Bakken region, law enforcement intensity, alcohol availability, whether the state’s large universities were in session, and socio-demographic characteristics. We find that the Bakken oil boom is associated with a 22% increase in substance-impaired driving arrests. Conclusions The results suggest frequent monitoring combined with increased sanction celerity deters substance use-involved crime. While the results are generally consistent with an earlier study of 24/7 Sobriety in another state, differences in the study outcome measures implementation choices across states make direct comparisons difficult. More can be learned by conducting randomized controlled trials that vary time on program, testing technology, and/or level of sanction

Efficacy of Frequent Monitoring With Swift, Certain, and Modest Sanctions for Violations: Insights From South Dakota’s 24/7 Sobriety Project

Objectives. We examined the public health impact of South Dakota’s 24/7 Sobriety Project, an innovative program requiring individuals arrested for or convicted of alcohol-involved offenses to submit to breathalyzer tests twice per day or wear a continuous alcohol monitoring bracelet. Those testing positive are subject to swift, certain, and modest sanctions. Methods. We conducted differences-in-differences analyses comparing changes in arrests for driving while under the influence of alcohol (DUI), arrests for domestic violence, and traffic crashes in counties to the program with counties without the program. Results. Between 2005 and 2010, more than 17 000 residents of South Dakota—including more than 10% of men aged 18 to 40 years in some counties—had participated in the 24/7 program. At the county level, we documented a 12% reduction in repeat DUI arrests (P = .023) and a 9% reduction in domestic violence arrests (P = .035) following adoption of the program. Evidence for traffic crashes was mixed. Conclusions. In community supervision settings, frequent alcohol testing with swift, certain, and modest sanctions for violations can reduce problem drinking and improve public health outcomes