Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers.

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. CLINICALTRIALS.GOV: NCT02039349. This article is part of the special issue on 'Neuropeptides'.

The alcohol-intoxicated trauma patient: impact on imaging and radiation exposure.

INTRODUCTION: The purpose of this study was to investigate the effects of alcohol intoxication in trauma patients in regard to its impact on application of computed tomography (CT) and associated radiation exposure. METHODS: We conducted a retrospective study from a continuous patient cohort. INCLUSION CRITERIA: admission to the emergency room of an urban Level 1 trauma center with trauma team activation during a 12-month period (Jan 1st-Dec 31st 2012). Patients with incomplete data, age ≤ 12 years and with neurological diseases were excluded. Demographics, mechanisms, severity and patterns of injury (Abbreviated Injury Scale, Injury Severity Score, Glasgow Coma Scale), blood alcohol concentration (BAC, in permille, ‰), imaging studies (head/whole body CT), radiation exposure, and hospital length of stay, surgical procedures and mortality were evaluated with SPSS statistics (Version 25, IBM Inc., Armonk, New York). RESULTS: A positive BAC (mean 1.80 ± 0.767) was reported in 19.2% (n = 41/214) of the cohort. Alcohol intoxication was associated with higher utilization of head CT (65.9 vs. 46.8%, p = 0.017) and radiation exposure (231.75 vs. 151.25 mAS, p = 0.045; dose-length product, 583.03 vs. 391.04, p = 0.006). In general, the presence of alcohol was associated with over-triage (p = 0.001), despite minor injury severity (ISS < 9) and a comparable rate of head injuries (p = 0.275). Head injury (AIS ≥ 3) and positive BAC (OR 2.34, 95% CI 1.096-5.001) were identified as strongest independent predictors for head CT. CONCLUSION: Alcohol intoxication is a common finding in trauma patients, and the rate of moderate and serious head injuries seems to be comparable to a more severely injured control group. Furthermore, head CT utilization in intoxicated patients is associated with significant radiation exposure, despite poor image quality, due to motion artifacts (27%). Future strategies are required to exclude head injuries safely, while reducing the rate of head CT and associated radiation exposure in intoxicated patients.

Analysis of BMSCs-intervened viscoelasticity of sciatic nerve in rats with chronic alcoholic intoxication 1.

PURPOSE: To investigate the impact of bone mesenchymal stem cells (BMSCs) intervention on the viscoelasticity of sciatic nerve in rats with chronic alcohol intoxication (CAI). METHODS: The CAI rat models were prepared, divided into model groups, and treated with either BMSCs or basic fibroblast growth factor (bFGF). Then the rats underwent electrophysiological test and the serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and metallothionein (MT) were measured. Histological observation, stress relaxation test, and creep test were performed for the sciatic nerve of the CAI model in each group. RESULTS: The MDA level of group BMSC was significantly lower (p<0.05) than that of groups MOD (the CIA model) and bFGF. The SOD and MT levels were higher in group BMSC than in groups MOD and bFGF (p<0.05). The motor nerve conduction velocity and amplitude were higher in group BMSC than in groups MOD and bFGF (p<0.05). The amounts of 7200s stress reduction and 7200 s strain increase of the sciatic nerve in group BMSC were greater than those in groups bFGF and MOD (p<0.05). CONCLUSION: Bone mesenchymal stem cells can improve the metabolism of free radicals, restore the tissue morphology and viscoelasticity of the chronic alcohol intoxication animal model, and positively affect the repairing of the injured sciatic nerve.

Analysis of BMSCs-intervened viscoelasticity of sciatic nerve in rats with chronic alcoholic intoxication

Abstract Purpose: To investigate the impact of bone mesenchymal stem cells (BMSCs) intervention on the viscoelasticity of sciatic nerve in rats with chronic alcohol intoxication (CAI). Methods: The CAI rat models were prepared, divided into model groups, and treated with either BMSCs or basic fibroblast growth factor (bFGF). Then the rats underwent electrophysiological test and the serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and metallothionein (MT) were measured. Histological observation, stress relaxation test, and creep test were performed for the sciatic nerve of the CAI model in each group. Results: The MDA level of group BMSC was significantly lower (p<0.05) than that of groups MOD (the CIA model) and bFGF. The SOD and MT levels were higher in group BMSC than in groups MOD and bFGF (p<0.05). The motor nerve conduction velocity and amplitude were higher in group BMSC than in groups MOD and bFGF (p<0.05). The amounts of 7200s stress reduction and 7200 s strain increase of the sciatic nerve in group BMSC were greater than those in groups bFGF and MOD (p<0.05). Conclusion: Bone mesenchymal stem cells can improve the metabolism of free radicals, restore the tissue morphology and viscoelasticity of the chronic alcohol intoxication animal model, and positively affect the repairing of the injured sciatic nerve.

Effects of acute ethanol intoxication in an ovine peritonitis model.

BACKGROUND: Acute ethanol intoxication has been shown to have contrasting effects on outcomes in sepsis. The aim of this study was to explore the effects of acute ethanol intoxication on hemodynamics, renal function, brain perfusion and lactate/pyruvate in an ovine sepsis model. METHODS: Anesthetized, mechanically ventilated female sheep were randomized to an ethanol group (n = 7), which received 1 g/kg ethanol diluted in intravenous (i.v.) saline infusion or a control group (n = 7), which received the same volume of i.v. saline. Both groups received the treatment for a period of 2 h prior to induction of sepsis by intraperitoneal injection of feces. Other treatment included fluid resuscitation but no vasopressors or antibiotics. Global hemodynamics, renal blood flow, brain cortex laser Doppler flowmetry and microdialysis analyses were recorded hourly. RESULTS: In the ethanol group, blood ethanol concentrations were 137 ± 29 mg/dL at the time of feces injection and decreased to become undetectable by 12 h. Arterial hypotension occurred earlier in the ethanol than in the control group (8 [7-12] vs. 14 [11-20] hours, p = 0.03). Lactate levels increased to > 2 mmol/L earlier in the ethanol group. Renal dysfunction (9 [6-13] vs. 13 [12-15] hours, p = 0.05) and oliguria (urine output < 0.5 mL/kg/h; 10 [7-12] vs. 13 [12, 13] hours, p = 0.01) developed earlier in the ethanol than in the control group. Brain blood flow and lactate/pyruvate were unaffected. There was no significant difference in survival time. CONCLUSIONS: Acute ethanol intoxication in this model of peritonitis resulted in earlier development of shock and renal dysfunction but did not alter brain perfusion and metabolism or short-term survival.

Perception of intoxication in a field study of the night-time economy: Blood alcohol concentration, patron characteristics, and event-level predictors.

OBJECTIVE: Determine the relationship of subjective intoxication to blood alcohol concentration (BAC) and examine whether patron and event-level characteristics modify the relationship of BAC to subjective intoxication. METHODS: An in-situ systematic random sample of alcohol consumers attending night-time entertainment districts between 10pm and 3am on Friday and Saturday nights in five Australian cities completed a brief interview (n=4628). Participants reported age, sex, and pre-drinking, energy drink, tobacco, illicit stimulant and other illicit drug use that night, and their subjective intoxication and BAC were assessed. RESULTS: Male and female drinkers displayed equally low sensitivity to the impact of alcohol consumption when self-assessing their intoxication (BAC only explained 19% of variance). The marginal effect of BAC was not constant. At low BAC, participants were somewhat sensitive to increases in alcohol consumption, but at higher BAC levels that modest sensitivity dissipated (actual BAC had less impact on self-assessed intoxication). The slope ultimately leveled out to be non-responsive to additional alcohol intake. Staying out late, pre-drinking, and being young introduced biases resulting in higher self-assessed intoxication regardless of actual BAC. Further, both energy drinks and stimulant use modified the association between BAC and perceived intoxication, resulting in more compressed changes in self-assessment as BAC varies up or down, indicating less ability to perceive differences in BAC level. CONCLUSIONS: The ability of intoxicated patrons to detect further intoxication is impaired. Co-consumption of energy drinks and/or stimulant drugs is associated with impaired intoxication judgment, creating an additional challenge for the responsible service and consumption of alcohol.

Urinary bladder volume measured in whole-body CT scans is a useful marker for alcohol intoxication.

PURPOSE: The aim of this study was to investigate whether urinary bladder volume (UBV) and blood alcohol concentration (BAC) correlate in a cohort of emergency trauma patients. Furthermore, the feasibility of semi-automated 3D-CT volumetry for urinary bladder volumetry calculations in whole-body CT examinations was elucidated. MATERIAL AND METHODS: Whole-body CT scans of 831 individuals treated in the emergency department with suspected multiple injuries were included. Manual 3D-CT volumetry of the urinary bladder was performed and the mechanism of injury, patient demographics, BAC, serum creatinine, and hematocrit were retrospectively analyzed. Semi-automated calculation of UBV was performed in 30 patients. Statistical analysis included ROC analysis to calculate cut-off values, sensitivity, and specificity. The Mann-Whitney test and Spearman's correlation coefficient were used to detect significant correlations between UBV and BAC. RESULTS: Manual 3D-CT volumetry showed maximum sensitivity and specificity with a cut-off value for urinary bladder volume of 416.3 mL (sensitivity 50.9%; specificity 76.3%; AUC 0.678). With a cut-off value of 4.2 mL/µmol for the creatinine quotient (quotient of serum creatinine and UBV), the sensitivity was 64.2% (specificity 67.0%; AUC 0.681). Semi-automated 3D-CT volumetry resulted in lower UBV values compared to those obtained with manual 3D-CT volumetry. CONCLUSION: Semi-automated 3D-CT volumetry is a reliable method to quantify UBV. UBV correlates with positive BAC results. A UBV above 416 mL seen on an initial whole-body CT must raise suspicion of alcohol intoxication. The creatinine quotient is an even more sensitive and specific parameter for the detection of alcohol intoxication.

Acute ethanol intoxication suppresses pentraxin 3 expression in a mouse sepsis model involving cecal ligation and puncture.

Acute ethanol intoxication impairs immunological reactions and increases the risk of sepsis; however, the underlying mechanism remains unclear. Pentraxin (PTX) 3 is a humoral pattern recognition receptor whose levels rapidly increase in response to inflammation. PTX3 production is triggered by tumor necrosis factor (TNF)-α and is mediated by c-Jun N-terminal kinase (JNK). As PTX3 exerts protective effects against sepsis as well as acute lung injury, we investigated whether acute ethanol exposure exacerbates sepsis by altering PTX3 expression. Sepsis was induced in C57/BL6 mice by cecal ligation and puncture (CLP) after ethanol/saline administration. Survival rates were significantly lower in ethanol-treated than in saline-treated mice. Increased vascular permeability and attenuation of PTX3 expression were observed in the lungs of ethanol-treated mice 4 h after CLP. Concomitant with a delayed increase of plasma TNF-α in ethanol-treated mice, plasma PTX3 was also suppressed in the early phase of sepsis. Although TNF-α level in ethanol-treated mice exceeded that in saline-treated mice 16 h after CLP, PTX3 levels were still suppressed in the former group. JNK phosphorylation in lung tissue was suppressed in both groups 4 and 16 h after CLP. Furthermore, JNK phosphorylation in ethanol-treated human umbilical vein endothelial cells was suppressed even in the presence of exogenous TNF-α, resulting in inhibition of PTX3 mRNA and protein expression. Our results suggest that ethanol suppresses de novo PTX3 synthesis via two mechanisms - i.e., suppression of TNF-α production and inhibition of JNK phosphorylation. PTX3 suppression may therefore contribute to exacerbation of sepsis in acute ethanol intoxication.

Alcohol Intoxication Reduces Systemic Interleukin-6 Levels and Leukocyte Counts After Severe TBI Compared With Not Intoxicated TBI Patients.

BACKGROUND: The effect of alcohol consumption on inflammatory state and outcome in brain-injured patients remains controversial. We analyzed the influence of positive blood alcohol concentration (BAC) on inflammatory changes, inhospital complications, and mortality in traumatic brain injury (TBI) patients. PATIENTS AND METHODS: Patients with an Injury Severity Score (ISS) at least 16 and Abbreviated Injury Scale of head (AIS-head) at least 3 were included upon arrival in the emergency room and grouped according to positive BAC (>0.5‰, BAC) vs. less than 0.5‰ alcohol (no BAC). Injury severity, vital signs, complications, mortality, and systemic interleukin (IL)-6 levels were prospectively determined, and BAC was quantified. According to ISS, AIS-head, age, and sex, we performed matched-pair analysis. RESULTS: A total of 101 TBI patients were included. Of them 74 patients were dedicated to no BAC group and 27 to BAC group. ISS was significantly higher in the no BAC group. Positive BAC group required significantly less packed red blood cells and fresh frozen plasma (P < 0.05). Shorter ICU stays were found in BAC-positive patients. Inhospital complications, including single/multiple organ failure, systemic inflammatory response syndrome, sepsis, pneumonia, and acute respiratory distress syndrome, showed no significant differences. Systemic IL-6 levels and leukocyte counts (IL-6: 65.0 ±â€Š8.0 vs. 151.8 ±â€Š22.3; leukocytes: 10.2 ±â€Š0.9 vs. 13.2 ±â€Š0.8, both P < 0.05) were significantly lower in BAC-positive patients. Matched-pair analysis was performed with 27 pairs. No significant differences in transfusions were monitored after matching. However, lowered systemic IL-6 levels and leukocyte counts in the BAC group were also detected after matching, indicating that this effect is ISS-independent. CONCLUSIONS: This study shows that positive BAC in TBI patients is associated with lower systemic IL-6 levels and leukocyte numbers, indicating that positive BAC may have immunosuppressive effects in this cohort of patients compared with TBI patients who were not alcohol intoxicated.

The prevalence of alcohol-related trauma recidivism: A systematic review.

OBJECTIVE: Recurrent admission to a hospital or trauma centre for separate incidents of traumatic injury is known as trauma recidivism. Although use of alcohol is a known risk factor for injury and associated with trauma recidivism, the scale of alcohol-related trauma recidivism has not been well described. The purpose of this review was to search the published literature for studies that evaluated the prevalence of alcohol use among trauma recidivists. Our primary objective was to determine the proportion of trauma recidivism related to alcohol use. The association between alcohol and trauma recidivism was evaluated as a secondary objective. METHODS: Four electronic databases (MEDLINE, Embase, CINAHL, Web of Science) were searched from inception until December 2015 for all articles that might provide evidence on the proportion of trauma recidivism related to use of alcohol. After removal of duplicates, the search strategy yielded 2470 records for screening. Only primary studies that reported on repeated admissions to a hospital or trauma centre for traumatic injuries specifically related to alcohol use were included. Descriptive statistics were used to assess study characteristics and the prevalence of trauma recidivism related to alcohol use. An aggregate weighted estimate of alcohol-related trauma recidivism was calculated. RESULTS: A total of 12 studies met all inclusion criteria. Studies were published between 1989 and 2014. Overall, there were 3386 trauma recidivists among included studies. The proportion of trauma recidivists with evidence of alcohol use on admission ranged from 26.7% to 76.9% (median 46.4%). The aggregated sample produced a weighted estimate of 41.0% (1388/3386) for alcohol-related trauma recidivism. In four studies, the association between alcohol and trauma recidivism was examined; all four found a positive association between alcohol use and repeated admission for traumatic injury. Studies varied considerably in design, trauma populations, periods for evaluating recidivism, definitions for positive alcohol on admission, and methods used to determine alcohol use. CONCLUSION: Evidence from current literature suggests that 41.0% of trauma recidivism is related to use of alcohol. Due to methodological limitations among the studies included for review, this may underestimate the actual prevalence of alcohol-related trauma recidivism.

Acute alcohol intoxication and bispectral index monitoring.

BACKGROUND: Bispectral index (BIS) monitoring is commonly used to decrease the risk of awareness during anaesthesia. We aimed to determine the relationship between blood alcohol concentration and brain function (as measured by BIS) in healthy adults. METHODS: In this prospective observational study, 21 anaesthetic registrars self-regulated alcohol consumption over a 3-h period. Expired alcohol concentration (breathalyser) and BIS measurements were performed hourly for 4 h. A venous blood alcohol sample was taken at the conclusion of the study period. RESULTS: The main outcome measures were the correlation between blood alcohol and brain function as measured by BIS and the change in BIS from baseline (∆BIS) at 4 h. The median number of standard drinks consumed was 9.1 (IQR 7.7-12.3), range 5.4-17. At 4 h, there was a moderate inverse correlation between BIS and blood alcohol (r = -0.49, P = 0.029) and between ∆BIS and blood alcohol (r = -0.46, P =0.043). CONCLUSION: In healthy young adults, we found a moderate correlation between venous blood alcohol concentration and BIS. This suggests that acute alcohol consumption can decrease BIS. This information may be relevant when providing anaesthesia to intoxicated patients who require urgent or time-critical surgery, although certain limitations of this study should be kept in mind.

Chemical composition, antioxidant properties and hepatoprotective effects of chamomile (Matricaria recutita L.) decoction extract against alcohol-induced oxidative stress in rat.

The present study assessed the chemical composition, antioxidant properties, and hepatoprotective effects of subacute pre-treatment with chamomile (Matricaria recutita L.) decoction extract (CDE) against ethanol (EtOH)-induced oxidative stress in rats. The colorimetric analysis demonstrated that the CDE is rich in total polyphenols, total flavonoids and condensed tannins, and exhibited an important in vitro antioxidant activity. The use of LC/MS technique allowed us to identify 10 phenolic compounds in CDE. We found that CDE pretreatment, in vivo, protected against EtOH-induced liver injury evident by plasma transaminases activity and preservation of the hepatic tissue structure. The CDE counteracted EtOH-induced liver lipoperoxidation, preserved thiol -SH groups and prevented the depletion of antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). We also showed that acute alcohol administration increased tissue and plasma hydrogen peroxide (H(2)O(2)), calcium and free iron levels. More importantly, CDE pre-treatment reversed all EtOH-induced disturbances in intracellular mediators. In conclusion, our data suggest that CDE exerted a potential hepatoprotective effect against EtOH-induced oxidative stress in rat, at least in part, by negatively regulating Fenton reaction components such as H(2)O(2) and free iron, which are known to lead to cytotoxicity mediated by intracellular calcium deregulation.

Adverse effects of admission blood alcohol on long-term cognitive function in patients with traumatic brain injury.

BACKGROUND: Alcohol is known to be protective in patients with traumatic brain injury (TBI); however, its impact on the long-term cognitive function is unknown. We hypothesize that intoxication at the time of injury is associated with adverse long-term cognitive function in patients sustaining TBI. METHODS: We performed a 2-year retrospective study of all trauma patients with isolated TBI presenting to our Level I trauma center and discharged to a single rehabilitation facility. Patients with moderate-to-severe TBI (head Abbreviated Injury Scale [AIS] score ≥ 3), measured admission blood alcohol concentration, and measured cognitive function on hospital discharge and rehabilitation center discharge were included. Cognitive function was assessed using Functional Independence Measure (FIM) scores. Delta cognitive FIM was defined as the difference between rehabilitation center discharge and hospital discharge cognitive FIM scores. Multivariate linear regression was performed. RESULTS: A total of 64 patients were included. Mean (SD) age was 51.8 (23) years, median head AIS score was 3 (IQR, 3-5), and median Glasgow Coma Scale (GCS) score was 11 (IQR, 3-15). Mean (SD) cognitive FIM score on hospital discharge was 17 (6), and mean (SD) cognitive improvement was 8.6 (4.7). Sixty percent (n = 39) were under the influence of alcohol on admission, and the mean (SD) admission blood alcohol concentration was 132 (102).On multivariate linear regression analysis, admission blood alcohol concentration (ß = -0.4; 95% confidence interval, -6.7 to -0.8; p = 0.01) and age (ß = -0.13; 95% confidence interval, -0.2 to -0.04; p = 0.04) were negatively associated with improvement in long-term cognitive function. CONCLUSION: Alcohol intoxication at the time of injury is associated with lower improvement in long-term cognitive function. Older intoxicated patients are likely to have a lower cognitive improvement. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.

Alcohol and tobacco cue effects on craving in non-daily smokers.

Non-daily smokers commonly smoke cigarettes following the consumption of alcohol, yet the reason(s) for this remains poorly understood. The present study examined the impact of alcohol consumption on responses in tobacco salient cues 49 male and 50 female non-daily smokers. After the administration of an alcohol, placebo, or control beverage, participants were exposed to series neutral video clips and tobacco smoking salient video clips, and their subjective states and heart rates were monitored. The timing of the exposure to the tobacco smoking clips was randomly determined to coincide with the timing of either the ascending limb or the descending limb of the blood alcohol concentration (BAC) curve of the alcohol beverage condition. The tobacco smoking clips were found to increase cigarette craving regardless of beverage condition or timing of exposure (p = .002). Alcohol consumption was associated with increased ratings of intoxication (p < .001), increased heart rate across participants (p < .001), and increased cigarette craving in female participants specifically (p = .017). Alcohol did not influence responses to the smoking videos. These results suggest that smoking salient cues and alcohol may impact cigarette craving in non-daily smokers through independent processes.

Driving intoxicated: is hospital admission protective against legal ramifications?

BACKGROUND: According to the US National Highway Traffic Safety Administration, in 2010, 10,228 people were killed in alcohol-impaired driving crashes. Daily, intoxicated drivers are seen in trauma centers across the country. At our trauma center, we sought to determine the number of drivers who had a documented elevation in their blood alcohol content (BAC) and compare this with county police records to evaluate how many charges for driving while intoxicated (DWI) were issued. METHODS: A retrospective chart review was performed for trauma admissions during a 3-year period. Patients with a BAC of less than 0.08 g/dL were excluded. Only documented drivers were included. This group of intoxicated drivers was then compared against public records from the Dallas County for any record of a charge of DWI. RESULTS: During a 3-year period, from 2009 to 2011, 118 drivers had a confirmed BAC above the legal limit of 0.08 g/dL. Average BAC level was 0.218 g/dL. Injuries varied widely between patients with an average Injury Severity Score (ISS) of 11. Extremity fractures were seen in 27%, facial fractures were seen in 16%, and intracranial hemorrhage was seen in 7%. Forty-eight percent of the patients were admitted to the intensive care unit initially, with an average length of intensive care unit stay of 1.5 days (range, 0-25 days). Only 18% of our patients (21) received a charge of DWI. Four patients were charge with related offenses. CONCLUSION: A motor vehicle accident may be protective against the legal ramifications of drinking and driving. Less than 20% of patients who were driving under the influence incurred any legal repercussion. Deterrents that prevent law enforcement from being able to obtain evidence needed for prosecution should be eliminated. Health care providers and law enforcement agencies should work as a team to help mitigate the incidence of drunk driving and its burden on society. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Angiotensin (1-7) contributes to nitric oxide tonic inhibition of vasopressin release during hemorrhagic shock in acute ethanol intoxicated rodents.

AIMS: Acute ethanol intoxication (AEI) attenuates the arginine vasopressin (AVP) response to hemorrhage leading to impaired hemodynamic counter-regulation and accentuated hemodynamic stability. Previously we identified that the ethanol-induced impairment of circulating AVP concentrations in response to hemorrhage was the result of augmented central nitric oxide (NO) inhibition. The aim of the current study was to examine the mechanisms underlying ethanol-induced up-regulation of paraventricular nucleus (PVN) NO concentration. Angiotensin (ANG) (1-7) is an important mediator of NO production through activation of the Mas receptor. We hypothesized that Mas receptor inhibition would decrease central NO concentration and thus restore the rise in circulating AVP levels during hemorrhagic shock in AEI rats. MAIN METHODS: Conscious male Sprague-Dawley rats (300-325 g) received a 15 h intra-gastric infusion of ethanol (2.5 g/kg+300 mg/kg/h) or dextrose prior to a fixed-pressure (~40 mm Hg) 60 min hemorrhage. The Mas receptor antagonist A-779 was injected through an intracerebroventricular (ICV) cannula 15 min prior to hemorrhage. KEY FINDINGS: PVN NOS activity and NO were significantly higher in AEI compared to DEX-treated controls at the completion of hemorrhage. ICV A-779 administration decreased NOS activity and NO concentration, partially restoring the rise in circulating AVP level at completion of hemorrhage in AEI rats. SIGNIFICANCE: These results suggest that Mas receptor activation contributes to the NO-mediated inhibitory tone of AVP release in the ethanol-intoxicated hemorrhaged host.

Risk of severe driver injury by driving with psychoactive substances.

Driving with alcohol and other psychoactive substances imposes an increased risk of severe injury accidents. In a population-based case-control design, the relative risks of severe driver injury (MAIS≥2) by driving with ten substance groups were approximated by odds ratios (alcohol, amphetamines, benzoylecgonine, cocaine, cannabis, illicit opiates, benzodiazepines and Z-drugs, i.e. zolpidem and zopiclone, medicinal opioids, alcohol-drug combinations and drug-drug combinations). Data from six countries were included in the study: Belgium, Denmark, Finland, Italy, Lithuania and the Netherlands. Case samples (N=2490) were collected from severely injured drivers of passenger cars or vans in selected hospitals in various regions of the countries. Control samples (N=15,832) were sampled in a uniform sampling scheme stratified according to country, time, road type and season. Relative risks were approximated by odds ratios and calculated by logistic regression. The estimates were adjusted for age, gender and country. The highest risk of the driver being severely injured was associated with driving positive for high concentrations of alcohol (≥0.8 g/L), alone or in combination with other psychoactive substances. For alcohol, risk increased exponentially with blood alcohol concentration (BAC). The second most risky category contained various drug-drug combinations, amphetamines and medicinal opioids. Medium increased risk was associated with medium sized BACs (at or above 0.5 g/L, below 0.8 g/L) and benzoylecgonine. The least risky drug seemed to be cannabis and benzodiazepines and Z-drugs. For male drivers, the risk of being severely injured by driving with any of the psychoactive substances was about 65% of that of female drivers. For each of the substance groups there was a decrease in the risk of severe driver injury with increasing age. It is concluded that among psychoactive substances alcohol still poses the largest problem in terms of driver risk of getting injured.

Support for blood alcohol screening in pediatric trauma.

BACKGROUND: Alcohol intoxication in pediatric trauma is underappreciated. The aim of this study was to characterize alcohol screening rates in pediatric trauma. METHODS: The Los Angeles County Trauma System Database was queried for all patients aged ≤ 18 years who required admission between 2003 and 2008. Patients were compared by age and gender. RESULTS: A total of 18,598 patients met the inclusion criteria; 4,899 (26.3%) underwent blood alcohol screening, and 2,797 (57.1%) of those screened positive. Screening increased with age (3.3% for 0-9 years, 15.1% for 10-14 years, and 45.4% for 15-18 years; P < .01), as did alcohol intoxication (1.9% for 0-9 years, 5.8% 10-14 years, and 27.3% for 15-18 years; P < .01). Male gender predicted higher mortality in those aged 15 to 18 years (adjusted odds ratio, 1.7; P < .01), while alcohol intoxication did not (adjusted odds ratio, .97; P = .84). CONCLUSIONS: Alcohol intoxication is common in adolescent trauma patients. Screening is encouraged for pediatric trauma patients aged ≥10 years who require admission.