Predictors of attempted suicide among Swiss patients with alcohol-use disorders

Objective: Suicide attempts are common in patients being treated for alcohol-use disorders (AUDs). However, clinical assessment of suicide risk is difficult. In this Swiss multisite study, we propose a decision tree to facilitate identification of profiles of AUD patients at high risk for suicidal behavior. Method: In this retrospective study, we used a sample of 700 patients (243 female), attending 1 of 12 treatment programs for AUDs in the German-speaking part of Switzerland. Sixty-nine patients who reported a suicide attempt in the 3 months before the index treatment were compared using risk factors with 631 patients without a suicide attempt. Receiver operating characteristic (ROC) analyses were used to identify patients at risk of having had a suicide attempt in the previous 3 months. Results: Consistent with previous empirical findings in AUD patients, a prior history of attempted suicide and severe symptoms of depression and aggression considerably increased the risk of a suicide attempt and, in combination, raised the likelihood of a prior suicide attempt to 52%. In addition, one third of AUD patients who had a history of suicide attempts and previous inpatient psychiatric treatment, or who were male and had previous inpatient psychiatric treatment, also reported a suicide attempt. Conclusions: The empirically supported decision tree helps to identify profiles of suicidal AUD patients in Switzerland and supplements clinicians' judgments in making triage decisions for suicide management.

Bone-marrow derived progenitor cells are associated with psychosocial determinants of health after controlling for classical biological and behavioral cardiovascular risk factors

BACKGROUND: Circulating progenitor cells have been implicated with maintaining vascular integrity. Low counts are found in adults with high cardiovascular risk and are associated with impaired endothelial function. It remains unknown whether psychosocial risk factors are independently related to counts of circulating progenitor cells. METHODS: We investigated a random sample of 468 adult industrial employees (mean age 41.2 years, 89% men) of Caucasian origin. Cardiovascular risk factors (blood pressure, LDL, HDL and C-reactive protein), health behavior (smoking, alcohol and physical exercise), psychological variables (effort-reward imbalance social support, negative affectivity) and interaction terms served as predictors of circulating progenitor cells (CD34+ CD31dim) as enumerated by flow-cytometry. FINDINGS: Psychosocial variables were independently associated with progenitor cell counts. The association with risk factors increased with age (explained variance in 18-36 year olds R(2)=0.17, p=0.55; age 36.1-46 R(2)=0.32, p=0.001; age>46 R(2)=0.27, p<0.001). Data revealed a shift from a larger association between behavioral and psychosocial variables and cell counts to a stronger association between biological variables and cell counts in older individuals. A significant interaction was observed between smoking and effort-reward imbalance in middle-aged subjects, those with both risk factors present had lower cell counts. In older employees, the interaction between biological risk factors and smoking was related to lower cell counts. INTERPRETATION: In working middle-aged and older men, psychosocial risk factors were related to circulating counts of progenitor cells. Smoking interacted negatively with psychosocial risk factors (middle-aged men) or with biological risk factors (older employees).

Variability in the prevalence of adult ADHD in treatment seeking substance use disorder patients: results from an international multi-center study exploring DSM-IV and DSM-5 criteria

Background: Available studies vary in their estimated prevalence of attention deficit/hyperactivity disor-der (ADHD) in substance use disorder (SUD) patients, ranging from 2 to 83%. A better understanding ofthe possible reasons for this variability and the effect of the change from DSM-IV to DSM-5 is needed.Methods: A two stage international multi-center, cross-sectional study in 10 countries, among patientsform inpatient and outpatient addiction treatment centers for alcohol and/or drug use disorder patients. Atotal of 3558 treatment seeking SUD patients were screened for adult ADHD. A subsample of 1276 subjects,both screen positive and screen negative patients, participated in a structured diagnostic interview. 5AdultsResults: Prevalence of DSM-IV and DSM-5 adult ADHD varied for DSM-IV from 5.4% (CI 95%: 2.4–8.3) forHungary to 31.3% (CI 95%:25.2–37.5) for Norway and for DSM-5 from 7.6% (CI 95%: 4.1–11.1) for Hungary to32.6% (CI 95%: 26.4–38.8) for Norway. Using the same assessment procedures in all countries and centersresulted in substantial reduction of the variability in the prevalence of adult ADHD reported in previousstudies among SUD patients (2–83% → 5.4–31.3%). The remaining variability was partly explained byprimary substance of abuse and by country (Nordic versus non-Nordic countries). Prevalence estimatesfor DSM-5 were slightly higher than for DSM-IV.Conclusions: Given the generally high prevalence of adult ADHD, all treatment seeking SUD patientsshould be screened and, after a confirmed diagnosis, treated for ADHD since the literature indicates poorprognoses of SUD in treatment seeking SUD patients with ADHD.

Homicide-suicides compared to homicides and suicides: systematic review and meta-analysis.

Homicide-suicides, the murder of one or several individuals followed by the suicide of the perpetrator, are rare but have devastating effects on families and communities. We did a systematic review and meta-analysis of studies comparing perpetrators of homicide-suicides with perpetrators of simple homicides and suicides and examined the proportion of firearm use and its correlation with firearm availability. We searched Medline and Embase from inception to July 2012 and identified 27 eligible studies. Perpetrators of homicide-suicides were older and more likely to be male and married to or separated from their victims than perpetrator of simple homicides or suicides. Influence of alcohol and a history of domestic violence or unemployment were less prevalent in homicide-suicides than in homicides. The proportion of firearm use in homicide-suicides varied across countries and was highest in the USA, Switzerland and South Africa, followed by Australia, Canada, The Netherlands and England and Wales, with a strong correlation between the use of firearms and the level of civilian gun ownership in the country. Our results indicate that homicide-suicides represent a distinct entity, with characteristics distinguishing them both from homicides and suicides.

Equine cytochrome P450 2B6--genomic identification, expression and functional characterization with ketamine

Ketamine is an anesthetic and analgesic regularly used in veterinary patients. As ketamine is almost always administered in combination with other drugs, interactions between ketamine and other drugs bear the risk of either adverse effects or diminished efficacy. Since cytochrome P450 enzymes (CYPs) play a pivotal role in the phase I metabolism of the majority of all marketed drugs, drug-drug interactions often occur at the active site of these enzymes. CYPs have been thoroughly examined in humans and laboratory animals, but little is known about equine CYPs. The characterization of equine CYPs is essential for a better understanding of drug metabolism in horses. We report annotation, cloning and heterologous expression of the equine CYP2B6 in V79 Chinese hamster fibroblasts. After computational annotation of all CYP2B genes, the coding sequence (CDS) of equine CYP2B6 was amplified by RT-PCR from horse liver total RNA and revealed an amino acid sequence identity of 77% and a similarity of 93.7% to its human ortholog. A non-synonymous variant c.226G>A in exon 2 of the equine CYP2B6 was detected in 97 horses. The mutant A-allele showed an allele frequency of 82%. Two further variants in exon 3 were detected in one and two horses of this group, respectively. Transfected V79 cells were incubated with racemic ketamine and norketamine as probe substrates to determine metabolic activity. The recombinant equine CYP2B6 N-demethylated ketamine to norketamine and produced metabolites of norketamine, such as hydroxylated norketamines and 5,6-dehydronorketamine. V(max) for S-/and R-norketamine formation was 0.49 and 0.45nmol/h/mg cellular protein and K(m) was 3.41 and 2.66μM, respectively. The N-demethylation of S-/R-ketamine was inhibited concentration-dependently with clopidogrel showing an IC(50) of 5.63 and 6.26μM, respectively. The functional importance of the recorded genetic variants remains to be explored. Equine CYP2B6 was determined to be a CYP enzyme involved in ketamine and norketamine metabolism, thus confirming results from inhibition studies with horse liver microsomes. Clopidogrel seems to be a feasible inhibitor for equine CYP2B6. The specificity still needs to be established with other single equine CYPs. Heterologous expression of single equine CYP enzymes opens new possibilities to substantially improve the understanding of drug metabolism and drug interactions in horses.

2-methiopropamine, a thiopene analogue of metamphetamine: studies on its metabolism abt detectability in the rat and human using

2-Methiopropamine [1-(thiophen-2-yl)-2-methylaminopropane, 2-MPA], a thiophene analogue of methamphetamine, is available from online vendors selling "Research chemicals." The first samples were seized by the German police in 2011. As it is a recreational stimulant, its inclusion in routine drug screening protocols should be required. The aims of this study were to identify the phase I and II metabolites of 2-MPA in rat and human urine and to identify the human cytochrome-P450 (CYP) isoenzymes involved in its phase I metabolism. In addition, the detectability of 2-MPA in urine samples using the authors' well-established gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-linear ion trap-mass spectrometry (LC-MS(n)) screening protocols was also evaluated. The metabolites were isolated from rat and human urine samples by solid-Phase extraction without or following enzymatic cleavage of conjugates. The phase I metabolites, following acetylation, were separated and identified by GC-MS and/or liquid chromatography-high-resolution linear ion trap mass spectrometry (LC-HR-MS(n)) and the phase II metabolites by LC-HR-MS(n). The following Major metabolic pathways were proposed: N-demethylation, hydroxylation at the side chain and at the thiophene ring, and combination of these transformations followed by glucuronidation and/or sulfation. CYP1A2, CYP2C19, CYP2D6, and CYP3A4 were identified as the major phase I metabolizing enzymes. They were also involved in the N-demethylation of the analogue methamphetamine and CYP2C19, CYP2D6, and CYP3A4 in its ring hydroxylation. Following the administration of a typical user's dose, 2-MPA and its metabolites were identified in rat urine using the authors' GC-MS and the LC-MS(n) screening approaches. Ingestion of 2-MPA could also be detected by both protocols in an authentic human urine sample.

Patterns of care and outcomes for pregnant inmates and their infants in Texas state prisons: Epidemiologic and ethnographic analyses

Female inmates make up the fastest growing segment in our criminal justice system today. The rapidly increasing trend for female prisoners calls for enhanced efforts to strategically plan the correctional facilities that address the needs of this growing population, and to work with communities to prevent crime in women. The incarcerated women in the U.S. have an estimated 145,000 minor children who are predisposed to unique psychosocial problems as a result of parental incarceration.^ This study examined the patterns of care and outcomes for pregnant inmates and their infants in Texas state prisons between 1994 and 1996. The study population consists of 202 pregnant inmates who delivered in a 2-year period, and a randomly sampled comparison cohort of 804 women from general Texas population, matched on race and educational levels. Both quantitative and qualitative data were used to elucidate the inmates' risk-factor profile, delivery/birth outcomes, and the patterns of care during pregnancy. The continuity-of-care issues for this population were also explored.^ Epidemiologic data were derived from multiple record systems to establish the comparison between two cohorts. A significantly great proportion of the inmates have prior lifestyle risk-factors (smoking, alcohol, and illicit drug abuse), poorer health status, and worse medical history. However, most of these existing risk-factors seem to show little manifestation in their current pregnancy. On the basis of maternal labor/delivery outcome and a number of neonatal indicators, this study found some evidence of a better pregnancy outcome for the inmate cohort when compared to the comparison group. Some possible explanations of this paradox were discussed. Seventeen percent of inmates gave birth to infants with suspected congenital syphilis. The placement patterns for the infants' care immediately after birth were elucidated.^ In addition to the quantitative data, an ethnographic approach was used to collect qualitative data from a subset of the inmate cohort (n = 20) and 12 care providers. The qualitative data were analyzed for their contents and themes, giving rise to a detailed description of the inmates' pregnancy experience. Eleven themes emerged from the study's thematic analysis, which provides the context for interpreting the epidemiologic data.^ Meaningful findings in this study were presented in a three-dimensional matrix to shed light on the apparent relationship between outcome indicators and their potential determinants. The suspected "linkages" between the outcome and their determinants can be used to generate hypotheses for future studies. ^

The relationship of maternal low birthweight and infant low birthweight among African-American women at term delivery: Findings from the 1988 National Maternal and Infant Health Survey

A cohort study study design was used to study the relationship of maternal low birthweight and infant low birthweight among African American women delivering full term infants. The cohort consisted of 3,157 mother-infant pairs drawn from the 1988 National Maternal and Infant Health Survey conducted by the National Center for Health Statistics. The objectives of the study were (1) to determine if low birthweight, African American mothers delivering term infants experienced higher rates of infant low birthweight and (2) to examine the role of selected contributory variables in the relationship of maternal low birthweight and infant low birthweight. Contributory risk factors examined included maternal marital status, maternal age, maternal education, maternal height, maternal prepregnant weight, birth order, history of a prior low birthweight delivery, timing of prenatal care, number of prenatal visits, gestational length, infant gender, and behavioral factors of smoking, alcohol, and illicit drug use during pregnancy.^ Using logistic regression analysis, risk of infant low birthweight among maternal low birthweight mothers increased after controlling for less than a high school education, less than 20 years of age, prepregnant weight less than 100 lbs, history of a prior low birthweight delivery, birth order, smoking during pregnancy, and use of alcohol and illicit drugs during pregnancy, but was not statistically significant. Loss of statistical significance was attributed to a large reduction in cases available for analysis after including illicit drug use in the model.^ This study demonstrated a consistent pattern of increased rates of infant low birthweight among low birthweight mothers. The force of history remains, hence women with this trait should be carefully monitored and advised during pregnancy to decrease risk of a low birthweight infant, in order to decrease the chain of events leading to future generations of low birthweight mothers. ^

Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum

Trichloroethylene (TCE)-induced liver toxicity and carcinogenesis is believed to be mediated in part by activation of the peroxisome proliferator-activated receptor α (PPARα). However, the contribution of the two TCE metabolites, dichloroacetate (DCA) and trichloroacetate (TCA) to the toxicity of TCE, remains unclear. The aim of the present study was to determine the metabolite profiles in serum and urine upon exposure of mice to TCE, to aid in determining the metabolic response to TCE exposure and the contribution of DCA and TCA to TCE toxicity. C57BL/6 mice were administered TCE, TCA, or DCA, and urine and serum subjected to ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based global metabolomics analysis. The ions were identified through searching metabolomics databases and by comparison with authentic standards, and quantitated using multiple reactions monitoring. Quantitative polymerase chain reaction of mRNA, biochemical analysis, and liver histology were also performed. TCE exposure resulted in a decrease in urine of metabolites involved in fatty acid metabolism, resulting from altered expression of PPARα target genes. TCE treatment also induced altered phospholipid homeostasis in serum, as revealed by increased serum lysophosphatidylcholine 18:0 and 18:1, and phosphatidylcholine metabolites. TCA administration revealed similar metabolite profiles in urine and serum upon TCE exposure, which correlated with a more robust induction of PPARα target gene expression associated with TCA than DCA treatment. These data show the metabolic response to TCE exposure and demonstrate that TCA is the major contributor to TCE-induced metabolite alterations observed in urine and serum.

The composition and timing of flower odour emission by wild Petunia axillaris coincide with the antennal perception and nocturnal activity of the pollinator Manduca sexta

In the genus Petunia, distinct pollination syndromes may have evolved in association with bee-visitation (P. integrifolia spp.) or hawk moth-visitation (P. axillaris spp). We investigated the extent of congruence between floral fragrance and olfactory perception of the hawk moth Manduca sexta. Hawk moth pollinated P. axillaris releases high levels of several compounds compared to the bee-pollinated P. integrifolia that releases benzaldehyde almost exclusively. The three dominating compounds in P. axillaris were benzaldehyde, benzyl alcohol and methyl benzoate. In P. axillaris, benzenoids showed a circadian rhythm with an emission peak at night, which was absent from P. integrifolia. These characters were highly conserved among different P. axillaris subspecies and P. axillaris accessions, with some differences in fragrance composition. Electroantennogram (EAG) recordings using flower-blends of different wild Petunia species on female M. sexta antennae showed that P. axillaris odours elicited stronger responses than P. integrifolia odours. EAG responses were highest to the three dominating compounds in the P. axillaris flower odours. Further, EAG responses to odour-samples collected from P. axillaris flowers confirmed that odours collected at night evoked stronger responses from M. sexta than odours collected during the day. These results show that timing of odour emissions by P. axillaris is in tune with nocturnal hawk moth activity and that flower-volatile composition is adapted to the antennal perception of these pollinators.

Determination of Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A) in whole blood and plasma by LC–MS/MS and application in authentic samples from drivers suspected of driving under the influence of cannabis

Delta-9-tetrahydrocannabinolic acid A (THCA-A) is the biosynthetic precursor of delta-9-tetrahydrocannabinol (THC) in cannabis plants, and has no psychotropic effects. THCA-A can be detected in blood and urine, and several metabolites have been identified. THCA-A was also shown to be incorporated in hair by side stream smoke to a minor extent, but incorporation via blood stream or sweat seems unlikely. The detection of THCA-A in biological fluids may serve as a marker for differentiating between the intake of prescribed THC medication – containing only pure THC – and cannabis products containing THC besides THC-acid A and other cannabinoids. However, the knowledge about its usefulness in forensic cases is very limited. The aim of the present work was the development of a reliable method for THCA-A determination in human blood or plasma using LC–MS/MS and application to cases of driving under the influence of drugs. Fifty eight (58) authentic whole blood and the respective plasma samples were collected from drivers suspected of driving under the influence of cannabis from the region of Bern (Switzerland). Samples were first tested for THC, 11-OH-THC and THC-COOH, and then additionally for THCA-A. For this purpose, the existing LC–MS/MS method was modified and validated, and found to be selective and linear over a range of 1.0 to 200 ng/mL (the correlation coefficients were above 0.9980 in all validation runs). Limit of detection (LOD) and limit of quantification (LOQ) were 0.3 ng/mL and 1.0 ng/mL respectively. Intra- and inter-assay accuracy were equal or better than 90% and intra- and inter-assay precision were equal or better than 11.1%. The mean extraction efficiencies were satisfactory being equal or higher than 85.4%. THCA-A was stable in whole blood samples after 3 freeze/thaw cycles and storage at 4 °C for 7 days. Re-injection (autosampler) stability was also satisfactory. THC was present in all blood samples with levels ranging from 0.7 to 51 ng/mL. THCA-A concentrations ranged from 1.0 to 496 ng/mL in blood samples and from 1.4 to 824 ng/mL in plasma samples. The plasma:blood partition coefficient had a mean value of 1.7 (±0.21, SD). No correlation was found between the degree of intoxication or impairment stated in the police protocols or reports of medical examinations and the detected THCA-A-concentration in blood.

Fluorescence-encoded gold nanoparticles: library design and modulation of cellular uptake into dendritic cells.

In order to harness the unique properties of nanoparticles for novel clinical applications and to modulate their uptake into specific immune cells we designed a new library of homo- and hetero-functional fluorescence-encoded gold nanoparticles (Au-NPs) using different poly(vinyl alcohol) and poly(ethylene glycol)-based polymers for particle coating and stabilization. The encoded particles were fully characterized by UV-Vis and fluorescence spectroscopy, zeta potential and dynamic light scattering. The uptake by human monocyte derived dendritic cells in vitro was studied by confocal laser scanning microscopy and quantified by fluorescence-activated cell sorting and inductively coupled plasma atomic emission spectroscopy. We show how the chemical modification of particle surfaces, for instance by attaching fluorescent dyes, can conceal fundamental particle properties and modulate cellular uptake. In order to mask the influence of fluorescent dyes on cellular uptake while still exploiting its fluorescence for detection, we have created hetero-functionalized Au-NPs, which again show typical particle dependent cellular interactions. Our study clearly prove that the thorough characterization of nanoparticles at each modification step in the engineering process is absolutely essential and that it can be necessary to make substantial adjustments of the particles in order to obtain reliable cellular uptake data, which truly reflects particle properties.

Efficacy of motivational enhancement therapy on alcohol use disorders in patients with chronic hepatitis C: a randomized controlled trial

AIMS: To determine the efficacy of motivational enhancement therapy (MET) on alcohol use in patients with the hepatitis C virus (HCV) and an alcohol use disorder (AUD). DESIGN: Randomized, single-blind, controlled trial comparing MET to a control education condition with 6-month follow-up. SETTING: Patients were recruited from hepatitis clinics at the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care Systems, USA. PARTICIPANTS AND INTERVENTION: Patients with HCV, an AUD and continued alcohol use (n = 139) were randomized to receive either MET (n = 70) or a control education condition (n = 69) over 3 months. MEASUREMENTS: Data were self-reported percentage of days abstinent from alcohol and number of standard alcohol drinks per week 6 months after randomization. FINDINGS: At baseline, subjects in MET had 34.98% days abstinent, which increased to 73.15% at 6 months compared to 34.63 and 59.49% for the control condition. Multi-level models examined changes in alcohol consumption between MET and control groups. Results showed a significant increase in percentage of days abstinent overall (F(1120.4)  = 28.04, P < 0.001) and a significant group × time effect (F(1119.9)  = 5.23, P = 0.024) with the MET group showing a greater increase in percentage of days abstinent at 6 months compared with the education control condition. There were no significant differences between groups for drinks per week. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. CONCLUSION: Motivational enhancement therapy (MET) appears to increase the percentage of days abstinent in patients with chronic hepatitis C, alcohol use disorders and ongoing alcohol use. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

The impact of testosterone, tibolone and black cohosh on purified mammary and placental 17β-hydroxysteroid dehydrogenase type 1

Abstract Context: Mammary and placental 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1). Objective: To assess the impact of testosterone, tibolone, and black cohosh on purified mammary and placental 17βHSD1. Materials and methods: 17βHSD1 was purified from human mammary gland and placenta by column chromatography, its activity was monitored by a radioactive activity assay, and the degree of purification was determined by gel electrophoresis. Photometric cofactor transformation analysis was performed to assess 17βHSD1 activity without or in presence of testosterone, tibolone and black cohosh. Results: 17βHSD1 from both sources displayed a comparable basal activity. Testosterone and tibolone metabolites inhibited purified mammary and placental 17βHSD1 activity to a different extent, whereas black cohosh had no impact. Discussion: Studies on purified enzymes reveal the individual action of drugs on local regulatory mechanisms thus helping to develop more targeted therapeutic intervention. Conclusion: Testosterone, tibolone and black cohosh display a beneficial effect on local mammary estrogen metabolism by not affecting or decreasing local estradiol exposure.

The role of glucosinolates and the jasmonic acid pathway in resistance of Arabidopsis thaliana against molluscan herbivores

Although slugs and snails play important roles in terrestrial ecosystems and cause considerable damage on a variety of crop plants, knowledge about the mechanisms of plant immunity to molluscs is limited. We found slugs to be natural herbivores of Arabidopsis thaliana and therefore investigated possible resistance mechanisms of this species against several molluscan herbivores. Treating wounded leaves with the mucus residue (‘slime trail’) of the Spanish slug Arion lusitanicus increased wound-induced jasmonate levels, suggesting the presence of defence elicitors in the mucus. Plants deficient in jasmonate biosynthesis and signalling suffered more damage by molluscan herbivores in the laboratory and in the field, demonstrating that JA-mediated defences protect A. thaliana against slugs and snails. Furthermore, experiments using A. thaliana mutants with altered levels of specific glucosinolate classes revealed the importance of aliphatic glucosinolates in defending leaves and reproductive structures against molluscs. The presence in mollusc faeces of known and novel metabolites arising from glutathione conjugation with glucosinolate hydrolysis products suggests that molluscan herbivores actively detoxify glucosinolates. Higher levels of aliphatic glucosinolates were found in plants during the night compared to the day, which correlated well with the nocturnal activity rhythms of slugs and snails. Our data highlight the function of well-known antiherbivore defence pathways in resistance against slugs and snails and suggest an important role for the diurnal regulation of defence metabolites against nocturnal molluscan herbivores.