Pharmacokinetics, safety and preliminary pharmacodynamic evaluation of DARE-VVA1: a soft gelatin capsule containing tamoxifen for the treatment of vulvovaginal atrophy.

OBJECTIVE: This study aimed to measure safety, systemic pharmacokinetics and preliminary efficacy of a vaginal tamoxifen capsule (DARE-VVA1) among postmenopausal women with moderate-to-severe vulvovaginal atrophy. METHODS: This was a randomized, placebo-controlled, double-blind, phase 1/2 study of DARE-VVA1, in four doses (1, 5, 10 and 20 mg). RESULTS: Seventeen women were enrolled and 14 completed the 8-week treatment. DARE-VVA1 was safe. All adverse events were of mild or moderate severity and distributed similarly among active and placebo groups. Plasma tamoxifen concentrations were highest among women using DARE-VVA1 20 mg, but the maximum mean (standard deviation) plasma tamoxifen concentrations on day 1 (2.66 ± 0.85 ng/ml) and day 56 (5.69 ± 1.87 ng/ml) were <14% of those measured after one oral tamoxifen dose. Active study product users had significant decreases from pre-treatment baseline in vaginal pH and proportion of vaginal parabasal cells (p = 0.04 for both endpoints), with women randomized to the 10 mg or 20 mg dose experiencing the largest treatment impact. The severity of vaginal dryness and dyspareunia decreased significantly from baseline with active study product use (p = 0.02 for both endpoints). CONCLUSIONS: DARE-VVA1 is safe and results in minimal systemic exposure to tamoxifen. Preliminary efficacy data support further development of this product.

Pre-service Military-related and Mental Disorder Factors Associated with Leaving the UK Armed Forces.

Background: The UK Armed Forces (UKAF) have a substantial manning deficit as more personnel leave than join. This article identified pre-service, military, and mental health factors giving rise to leaving the UKAF and estimated the contributions to leaving of those factors which are potentially amenable to modification. Methods: This study utilized data from a three-phase cohort study (2004-2006, 2007-2009 and 2014-2016), commencing while respondents were serving in the UKAF (n = 10,836; 6,046 (55.8%) had left service). Associations between leaving the services and socio-demographics, military career and experiences, and mental health were determined using Cox regression. Contribution to leaving was based on population attributable fractions (PAF) from Cox regression. Analyses were stratified by rank due to the different career structures of Commissioned Officers and enlisted personnel. Results: Leaving the UKAF was associated with joining when older, being a woman with a child/children, Army service, combat role, lower education level, and poor mental health. Factors contributing a significant proportion of leaving among enlisted personnel were joining over the age of 17, history of externalizing behavior, being female, common mental disorders, and alcohol misuse. Among Commissioned Officers only age at joining and sex contributed significant proportions to leaving. Conclusions: The key factors for leaving are education and higher age at recruitment. These are not amenable to intervention, for policy, equity, and legal reasons. Heavy drinking and common mental disorder symptoms may be more amenable to modification and hence reduce rates of leaving the UKAF. Women are more likely to leave due to childbearing.

Case-matched Comparison of Postoperative Outcomes Following Surgery for Inflammatory Bowel Disease After Exposure to Vedolizumab vs Other Biologics.

BACKGROUND AND AIM: The effects of vedolizumab [VEDO] exposure on perioperative outcomes following surgery for inflammatory bowel disease [IBD] remain controversial. The aim of our study was to compare postoperative morbidity of IBD surgery following treatment with VEDO vs other biologics or no biologics. METHODS: An institutional review board-approved, prospectively collected database was queried to identify all patients undergoing abdominal surgery for IBD between August 2012 and May 2017. The impact of VEDO within 12 weeks preoperatively on postoperative morbidity was initially assessed with univariate and multivariable analyses on all patients. A case-matched analysis was then carried out comparing patients exposed to VEDO vs other biologic agents, based on gender, age ± 5 years, diagnosis, date of surgery ± 2 years, and surgical procedure. RESULTS: Out of 980 patients, 141 received VEDO. The majority of patients [59%] underwent surgery involving end or diverting ostomy creation. The initial multivariate analysis conducted on all patients indicated that VEDO use was independently associated with increased overall morbidity [p <0.001], but not infectious morbidity [p = 0.30]. However, the case-matched comparison of 95 VEDO-treated patients vs 95 patients treated with adalimumab or infliximab did not indicate any difference in overall morbidity [p = 0.32], infectious complications [p = 0.15], or surgical site infections [p = 0.12]. CONCLUSIONS: In a study population having a high rate of surgery involving ostomy creation, the exposure to preoperative VEDO was not associated with an increased morbidity rate when compared with other biologics.

Accurate measurement of androgen after androgen esters: problems created by ex vivo esterase effects and LC-MS/MS interference.

BACKGROUND: Ex vivo androgen prodrug conversion by blood esterases after oral androgen ester administration may result in an overestimation of the measured blood androgens. OBJECTIVE: We investigated whether blood collection tubes with esterase inhibitors decreased the conversion of testosterone undecanoate (TU) and dimethandrolone undecanoate (DMAU) to their active metabolites, testosterone (T), and dimethandrolone (DMA), providing a more accurate assessment of circulating T/DMA levels. METHODS: Blood was collected in tubes with/without esterase inhibitors from: (i) four healthy and four hypogonadal men receiving no androgens and spiked ex vivo with TU/DMAU; (ii) four men taking oral TU (Andriol® ); and (iii) eight hypogonadal men dosed with oral 316 mg TU and 15 healthy men with 200 mg DMAU. T/DMA levels were measured by LC-MS/MS. RESULTS: Sodium fluoride (NaF, an esterase inhibitor) decreased measured T levels by 14.2% in men not receiving TU. Increasing amounts of TU/DMAU added to blood collected into plain tubes resulted in a concentration-dependent overestimation of T/DMA that was reduced by collecting blood into NaF tubes (by 30-85%), and keeping samples at 4 °C and minimizing time prior to centrifugation. After oral TU/DMAU administration to men, when TU/DMAU levels were >15/10 ng/mL, respectively, blood collected in NaF tubes yielded lower measured T concentrations by 15-30% and DMA by 22% due to an additional inhibitory effect of NaF on blood esterases. CONCLUSION: NaF directly lowers plasma T/DMA levels measured by LC-MS/MS and also inhibits blood esterase activity. Overestimation of T/DMA in blood collected in tubes without NaF after oral TU/DMAU administration is important for pharmacokinetics studies in drug development clinical trials but may have limited impact in clinical practice/utilization because the differences between measured and true androgen values are modest and the wide therapeutic androgen efficacy ranges obviate the need for highly accurate androgen measurements during therapy.

Preventing secondary exposure to women from men applying a novel nestorone/testosterone contraceptive gel.

BACKGROUND: Testosterone (T)/Nestorone (NES) combination gel is a potential transdermal male contraceptive that suppresses gonadotropins and spermatogenesis. Transfer of transdermal T from men to women can be prevented by washing or covering application sites with clothing. OBJECTIVES: We hypothesized that showering or wearing a shirt over gel application sites would prevent secondary exposure of T and NES to a woman after close skin contact. MATERIALS AND METHODS: Twelve healthy male and 12 healthy female participants were recruited. Men applied T/NES 62 mg/8 mg gel to their shoulders and upper arms. Two hours after application, female partners rubbed the application site for 15 min. Exposure in the female partner was assessed under three conditions: a shirt covered the application site; the man showered prior to skin contact; or without intervention to reduce transfer. Serum T and NES concentrations were measured by LC-MS/MS in serial blood samples for 24 h after gel exposure. MAIN OUTCOMES: Change in female serum T and NES levels as measured by average concentration over 24 h (Cavg ). RESULTS: Median female serum T Cavg was 23.9 ng/dL (interquartile range, 19.3, 33.9) with the shirt barrier and 26.7 ng/dL (20.7, 33.9) after showering, which was higher than baseline 20.9 ng/dL (16.7, 25.0), both p < 0.03) but lower than without intervention (58.2 ng/dL [30.9, 89.1], both p < 0.01). Female serum NES Cavg and maximum concentration were below the lower limit of quantification with the shirt barrier and after showering, but increased without intervention in six of 12 women (maximum concentration <60 pg/mL). Men had lower average serum NES levels after showering (47 pg/ml [20, 94] compared to no intervention (153.3 pg/mL [51, 241], p < 0.02). CONCLUSION: Secondary transfer of T and NES occurs after intensive skin contact with the gel application site. Secondary transfer is decreased by a shirt barrier or showering before contact.

Trajectories of alcohol use in the UK military and associations with mental health.

INTRODUCTION: There are higher levels of alcohol misuse in the military compared to the general population. Yet there is a dearth of research in military populations on the longitudinal patterns of alcohol use. This study aims to identify group trajectories of alcohol consumption in the UK military and to identify associations with childhood adversity, deployment history and mental disorder. METHODS: Data on weekly alcohol consumption across an eight year period and three phases of a UK military cohort study (n=667) were examined using growth mixture modelling. RESULTS: Five alcohol trajectory classes were identified: mid-average drinkers (55%), abstainers (4%), low level drinkers (19%), decreasing drinkers (3%) and heavy drinkers (19%). Alcohol consumption remained stable over the three periods in all classes, other than in the small decreasing trajectory class. Individuals in the heavy drinking class were more likely to have deployed to Iraq. Abstainers and heavy drinkers were more likely to report post-traumatic stress disorders at baseline compared to average drinkers. CONCLUSIONS: Heavy drinkers in the UK military did not change their drinking pattern over a period of eight years. This highlights the need to develop effective preventive programmes to lessen the physical and psychological consequences of long-term heavy alcohol use. Individuals with a mental health problem appeared more likely to either be drinking at a high level or to be abstaining from use.

Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive.

Dimethandrolone (DMA, 7α,11ß-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be advantageous for the application of DMAU as a male contraceptive.

Content Validation and Evaluation of an Endovascular Teamwork Assessment Tool.

OBJECTIVE/BACKGROUND: To modify, content validate, and evaluate a teamwork assessment tool for use in endovascular surgery. METHODS: A multistage, multimethod study was conducted. Stage 1 included expert review and modification of the existing Observational Teamwork Assessment for Surgery (OTAS) tool. Stage 2 included identification of additional exemplar behaviours contributing to effective teamwork and enhanced patient safety in endovascular surgery (using real-time observation, focus groups, and semistructured interviews of multidisciplinary teams). Stage 3 included content validation of exemplar behaviours using expert consensus according to established psychometric recommendations and evaluation of structure, content, feasibility, and usability of the Endovascular Observational Teamwork Assessment Tool (Endo-OTAS) by an expert multidisciplinary panel. Stage 4 included final team expert review of exemplars. RESULTS: OTAS core team behaviours were maintained (communication, coordination, cooperation, leadership team monitoring). Of the 114 OTAS behavioural exemplars, 19 were modified, four removed, and 39 additional endovascular-specific behaviours identified. Content validation of these 153 exemplar behaviours showed that 113/153 (73.9%) reached the predetermined Item-Content Validity Index rating for teamwork and/or patient safety. After expert team review, 140/153 (91.5%) exemplars were deemed to warrant inclusion in the tool. More than 90% of the expert panel agreed that Endo-OTAS is an appropriate teamwork assessment tool with observable behaviours. Some concerns were noted about the time required to conduct observations and provide performance feedback. CONCLUSION: Endo-OTAS is a novel teamwork assessment tool, with evidence for content validity and relevance to endovascular teams. Endo-OTAS enables systematic objective assessment of the quality of team performance during endovascular procedures.

Are common mental disorders more prevalent in the UK serving military compared to the general working population?

BACKGROUND: Although the military is considered to be a stressful occupation, there are remarkably few studies that compare the prevalence of common mental disorder (CMD) between the military and the general population. This study examined the prevalence of probable CMD in a serving UK military sample compared to a general population sample of employed individuals. METHOD: Data for the general population was from the 2003 and 2008 collections for the Health Survey for England (HSE) and for the serving military from phases 1 (2004-2006) and 2 (2007-2009) of the King's Centre for Military Health Research (KCMHR) cohort study. Probable CMD was assessed by the General Health Questionnaire (GHQ-12). The datasets were appended to calculate the odds of CMD in the military compared to the general population. RESULTS: The odds of probable CMD was approximately double in the military, when comparing phase 1 of the military study to the 2003 HSE [odds ratio (OR) 2.4, 95% confidence interval (CI) 2.1-2.7], and phase 2 to the 2008 HSE (OR 2.3, 95% CI 2.0-2.6) after adjustment for sex, age, social class, education and marital status. CONCLUSIONS: Serving military personnel are more likely to endorse symptoms of CMD compared to those selected from a general population study as employed in other occupations, even after accounting for demographic characteristics. This difference may be partly explained by the context of the military study, with evidence from previous research for higher reports of symptoms from the GHQ in occupational compared to population studies, in addition to the role of predisposing characteristics.

Highlights of recent developments and trends in cancer nanotechnology research--view from NCI Alliance for Nanotechnology in Cancer.

Although the incidence of cancer and cancer related deaths in the United States has decreased over the past two decades due to improvements in early detection and treatment, cancer still is responsible for a quarter of the deaths in this country. There is much room for improvement on the standard treatments currently available and the National Cancer Institute (NCI) has recognized the potential for nanotechnology and nanomaterials in this area. The NCI Alliance for Nanotechnology in Cancer was formed in 2004 to support multidisciplinary researchers in the application of nanotechnology to cancer diagnosis and treatment. The researchers in the Alliance have been productive in generating innovative solutions to some of the central issues of cancer treatment including how to detect tumors earlier, how to target cancer cells specifically, and how to improve the therapeutic index of existing chemotherapies and radiotherapy treatments. Highly creative ideas are being pursued where novelty in nanomaterial development enables new modalities of detection or therapy. This review highlights some of the innovative materials approaches being pursued by researchers funded by the NCI Alliance. Their discoveries to improve the functionality of nanoparticles for medical applications includes the generation of new platforms, improvements in the manufacturing of nanoparticles and determining the underlying reasons for the movement of nanoparticles in the blood.

Reversal of morphine analgesic tolerance by ethanol in the mouse.

The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)(B) receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABA(A) antagonist bicuculline but not by the GABA(B) antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment.

What explains post-traumatic stress disorder (PTSD) in UK service personnel: deployment or something else?

BACKGROUND: In previous studies an association between deployment to Iraq or Afghanistan and an overall increased risk for post-traumatic stress disorder (PTSD) in UK armed forces has not been found. The lack of a deployment effect might be explained by including, in the comparison group, personnel deployed on other operations or who have experienced traumatic stressors unrelated to deployment. METHODS: The sample comprised 8261 regular UK armed forces personnel who deployed to Iraq, Afghanistan or other operational areas or were not deployed. Participants completed the PTSD CheckList-Civilian Version (PCL-C) and provided information about deployment history, demographic and service factors, serious accidents and childhood experiences. RESULTS: Deployment to Iraq or Afghanistan [odds ratio (OR) 1.2, 95% confidence interval (CI) 0.6-2.2] or elsewhere (OR 1.1, 95% CI 0.6-2.0) was unrelated to PTSD although holding a combat role was associated with PTSD if deployed to Iraq or Afghanistan (OR 2.7, 95% CI 1.9-3.9). Childhood adversity (OR 3.3, 95% CI 2.1-5.0), having left service (OR 2.7, 95% CI 1.9-4.0) and serious accident (OR 2.1, 95% CI 1.4-3.0) were associated with PTSD whereas higher rank was protective (OR 0.3, 95% CI 0.12-0.76). CONCLUSIONS: For the majority of UK armed forces personnel, deployment whether to Iraq, Afghanistan or elsewhere confers no greater risk for PTSD than service in the armed forces per se but holding a combat role in those deployed to Iraq or Afghanistan is associated with PTSD. Vulnerability factors such as lower rank, childhood adversity and leaving service, and having had a serious accident, may be at least as important as holding a combat role in predicting PTSD in UK armed forces personnel.

Improving patient safety in the operating theatre and perioperative care: obstacles, interventions, and priorities for accelerating progress.

The publication of To Err Is Human in the USA and An Organisation with a Memory in the UK more than a decade ago put patient safety firmly on the clinical and policy agenda. To date, however, progress in improving safety and outcomes of hospitalized patients has been slower than the authors of these reports had envisaged. Here, we first review and analyse some of the reasons for the lack of evident progress in improving patient safety across healthcare specialities. We then focus on what we believe is a critical part of the healthcare system that can contribute to safety but also to error-healthcare teams. Finally, we review team training interventions and tools available for the assessment and improvement of team performance and we offer recommendations based on the existing evidence-base that have potential to improve patient safety and outcomes in the coming decade.

Violent behaviour in U.K. military personnel returning home after deployment.

BACKGROUND: There is growing concern about an alleged rise in violent behaviour amongst military personnel returning from deployment to Iraq and Afghanistan. The aims of this study were to determine the prevalence of violence in a sample of U.K. military personnel following homecoming from deployment in Iraq and to examine the impact of deployment-related experiences, such as combat trauma, on violence, and the role of sociodemographics and pre-enlistment antisocial behaviour. METHOD: This study used baseline data from a cohort study of a large randomly selected sample of U.K. Armed Forces personnel in service at the time of the Iraq war (2003). Regular personnel (n=4928) who had been deployed to Iraq were included. Data, collected by questionnaire, included information on deployment experiences, sociodemographic and military characteristics, pre-enlistment antisocial behaviour, post-deployment health outcomes and a self-report measure of physical violence in the weeks following return from deployment. RESULTS: Prevalence of violence was 12.6%. This was strongly associated with pre-enlistment antisocial behaviour [adjusted odds ratio (aOR) 3.6, 95% confidence interval (CI) 2.9-4.4]. After controlling for pre-enlistment antisocial behaviour, sociodemographics and military factors, violence was still strongly associated with holding a combat role (aOR 2.0, 95% CI 1.6-2.5) and having experienced multiple traumatic events on deployment (aOR for four or more traumatic events 3.7, 95% CI 2.5-5.5). Violence on homecoming was also associated with mental health problems such as post-traumatic stress disorder (aOR 4.8, 95% CI 3.2-7.2) and alcohol misuse (aOR 3.1, 95% CI 2.5-3.9). CONCLUSIONS: Experiences of combat and trauma during deployment were significantly associated with violent behaviour following homecoming in U.K. military personnel. Post-deployment mental health problems and alcohol misuse are also associated with increased violence.

Steady-state pharmacokinetics of oral testosterone undecanoate with concomitant inhibition of 5α-reductase by finasteride.

Oral testosterone undecanoate (TU) is used to treat testosterone deficiency; however, oral TU treatment elevates dihydrotestosterone (DHT), which may be associated with an increased risk of acne, male pattern baldness and prostate hyperplasia. Co-administration of 5α-reductase inhibitors with other formulations of oral testosterone suppresses DHT production and increases serum testosterone. We hypothesized that finasteride would increase serum testosterone and lower DHT during treatment with oral TU. Therefore, we studied the steady-state pharmacokinetics of oral TU, 200 mg equivalents of testosterone twice daily for 7 days, alone and with finasteride 0.5 and 1.0 mg po twice daily in an open-label, three-way crossover study in 11 young men with experimentally induced hypogonadism. On the seventh day of each dosing period, serum testosterone, DHT and oestradiol were measured at baseline and 1, 2, 4, 8, 12, 13, 14, 16, 20 and 24 h after the morning dose. Serum testosterone and DHT were significantly increased into and above their normal ranges similarly by all three treatments. Co-administration of finasteride at 0.5 and 1.0 mg po twice daily had no significant effect on either serum testosterone or DHT. Oral TU differs from other formulations of oral testosterone in its response to concomitant inhibition of 5α-reductase, perhaps because of its unique lymphatic route of absorption.

Smoking among males in the UK Armed Forces: changes over a seven year period.

OBJECTIVES: We assessed socio-demographic and military factors associated with smoking among males in the UK Armed Forces; made comparisons with the general population; and, tested the hypothesis that smoking has declined in the Armed Forces. METHODS: Using data from two cross-sectional studies (conducted in 1998 and 2004), we examined the patterns of smoking among regular male UK Service personnel aged 20-49 years and made comparisons with general population data from England, Scotland and Wales. RESULTS: In 2004, the prevalence of smoking among military males aged 20-49 years was 30% (n=2276), compared to 33% within the general population. Among current smokers, the mean number of cigarettes smoked per day was 15 for the military and 14 for the general population. The prevalence of smoking has decreased in lower ranks between 1998 and 2004 by 5.1% in 20-24 year olds to 6.3% in 35-49 year olds. These decreases are similar to those seen within those in the routine, manual or intermediate socio-economic group. CONCLUSIONS: Smoking among males in the UK military is associated with similar factors to those in the general population. As these factors are clustered in younger personnel, policies to decrease smoking should be targeted at younger recruits.

The effect of protein kinase C and G protein-coupled receptor kinase inhibition on tolerance induced by mu-opioid agonists of different efficacy.

Differences in the mechanisms underlying tolerance and mu-opioid receptor desensitization resulting from exposure to opioid agonists of different efficacy have been suggested previously. The objective of this study was to determine the effects of protein kinase C (PKC) and G protein-coupled receptor kinase (GRK) inhibition on antinociceptive tolerance in vivo to opioid agonists of different efficacy. A rapid (8-h) tolerance-induction model was used where each opioid was repeatedly administered to naive mice. Animals were then challenged with the opioid after injection of a kinase inhibitor to determine its effects on the level of tolerance. Tolerance to meperidine, morphine, or fentanyl was fully reversed by the PKC inhibitor 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)carbazole (Gö6976). However, in vivo tolerance to [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) was not reversed by PKC inhibition. The novel small-molecule GRK inhibitors beta-adrenergic receptor kinase 1 inhibitor and 2-(8-[(dimethylamino) methyl]-6,7,8,9-tetrahydropyridol[1,2-a]indol-3-yl)-3-(1-methylindol-3-yl)maleimide (Ro 32-0432) did not reverse the tolerance to meperidine, fentanyl, or morphine but did reverse the tolerance to DAMGO. To correlate GRK-dependent DAMGO-induced tolerance with mu-opioid receptor desensitization, we used in vitro whole-cell patch-clamp recording from mouse locus coeruleus neurons and observed that the GRK inhibitors reduced DAMGO-induced desensitization of mu-opioid receptors, whereas the PKC inhibitor had no effect. These results suggest that tolerance induced by low- and moderate-efficacy mu-opioid receptor agonists is dependent on PKC, whereas tolerance induced by the high-efficacy agonist DAMGO is dependent on GRK.

Symptoms of post-concussional syndrome are non-specifically related to mild traumatic brain injury in UK Armed Forces personnel on return from deployment in Iraq: an analysis of self-reported data.

BACKGROUND: Mild traumatic brain injury (mTBI) is being claimed as the 'signature' injury of the Iraq war, and is believed to be the cause of long-term symptomatic ill health (post-concussional syndrome; PCS) in an unknown proportion of military personnel. METHOD: We analysed cross-sectional data from a large, randomly selected cohort of UK military personnel deployed to Iraq (n=5869). Two markers of PCS were generated: 'PCS symptoms' (indicating the presence of mTBI-related symptoms: none, 1-2, 3+) and 'PCS symptom severity' (indicating the presence of mTBI-related symptoms at either a moderate or severe level of severity: none, 1-2, 3+). RESULTS: PCS symptoms and PCS symptom severity were associated with self-reported exposure to blast whilst in a combat zone. However, the same symptoms were also associated with other in-theatre exposures such as potential exposure to depleted uranium and aiding the wounded. Strong associations were apparent between having PCS symptoms and other health outcomes, in particular being a post-traumatic stress disorder or General Health Questionnaire case. CONCLUSIONS: PCS symptoms are common and some are related to exposures such as blast injury. However, this association is not specific, and the same symptom complex is also related to numerous other risk factors and exposures. Post-deployment screening for PCS and/or mTBI in the absence of contemporaneous recording of exposure is likely to be fraught with hazards.

How do experiences in Iraq affect alcohol use among male UK armed forces personnel?

OBJECTIVES: This paper reports on a statistically significant association between alcohol use and deployment to the 2003 Iraq War. It assesses the occupational factors and deployment experiences associated with heavy drinking in regular UK servicemen deployed to Iraq in the first phase of the 2003 Iraq War (Operation TELIC 1, the military codename for the conflict in Iraq). METHODS: A random representative sample of 3578 regular male UK Armed Forces personnel who were deployed to Iraq during Operation TELIC 1 participated in a cross-sectional postal questionnaire study (response rate 61%). Participants completed a questionnaire, between June 2004 and March 2006 (ie, after deployment), about their health, including a measure of alcohol use (Alcohol Use Disorders Identification Test, AUDIT) and questions about their experiences on deployment to Iraq. Heavy drinkers were identified as those scoring 16 or above on the AUDIT. RESULTS: After adjustment for sociodemographic and military factors, and the presence of psychological distress, heavy drinkers were more likely to have had major problems at home during (odds ratio (OR) 1.33, 95% confidence interval (CI) 1.04 to 1.70) and following their deployment (OR 1.68, 95% CI 1.32 to 2.14). Being deployed with their parent unit (OR 1.28, 95% CI 1.02 to 1.61), medium to high in-theatre unit comradeship (medium: OR 1.35, 95% CI 1.04 to 1.77; high: OR 1.35, 95% CI 1.02 to 1.79) and poor unit leadership (OR 1.78, 95% CI 1.37 to 2.31) were also associated with heavy drinking. CONCLUSIONS: Deployment experiences and problems at home during and following deployment, as well as the occupational milieu of the unit, influence personnel's risk of heavy drinking.