Risk Pathways Contributing to the Alcohol Harm Paradox: Socioeconomic Deprivation Confers Susceptibility to Alcohol Dependence via Greater Exposure to Aversive Experience, Internalizing Symptoms and Drinking to Cope

This is the final version. Available on open access from Frontiers MediaData Availability Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Socioeconomic deprivation is associated with greater alcohol problems despite lower alcohol consumption, but the mechanisms underpinning this alcohol harm paradox remain obscure. Fragmented published evidence collectively supports a multistage causal risk pathway wherein socioeconomic deprivation increases the probability of exposure to aversive experience, which promotes internalizing symptoms (depression and anxiety), which promotes drinking alcohol to cope with negative affect, which in turn accelerates the transition from alcohol use to dependence. To evaluate this proposed risk pathway, 219 hazardous drinkers from an undergraduate population completed questionnaires assessing these constructs in a single, cross sectional, online survey. Partial correlation coefficients revealed that each variable showed the strongest unique association with the next variable in the proposed multistage model, when adjusting for the other variables. Bootstrapped serial mediation analysis revealed that the indirect pathway linking all the variables in the proposed serial order was significant, while all other permutations were non-significant. Network centrality analysis corroborated the serial order of this indirect path. Finally, risk ratios estimated by categorizing the variables suggested that socioeconomic deprivation increased the risk of aversive experience by 32%, which increased the risk of internalizing symptoms by 180%, which increased the risk of drinking to cope by 64%, which increased susceptibility to alcohol dependence by 59%. These preliminary findings need to be corroborated by future research, nevertheless, they call for prevention strategies founded on social justice and the minimization of aversive experience in socially deprived individuals to mitigate mental health problems, maladaptive coping and addiction.Alcohol Research UKMedical Research Council (MRC

The direct effect of drinking to cope on alcohol problems is not mediated by alcohol consumption: Invariance across gender and countries

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: Data will be made available on request.BACKGROUND: Drinking to cope with negative affect confers a direct risk of alcohol problems independently of greater alcohol consumption (i.e., confers susceptibility to the alcohol harm paradox). However, it remains unclear whether this risk is common across gender and countries. METHODS: The current study applied path analysis to two cross-sectional samples of 18-25-year-old undergraduate hazardous drinking students recruited from the UK (Study 1; N = 873) and internationally (Study 2; N = 4064 recruited in Argentina, Canada, South Africa, Spain, Uruguay, USA, and England). The Drinking Motives Questionnaire (DMQ) measured drinking to cope with negative affect and drinking to enhance positive affect (i.e., enhancement motives). The Alcohol Use Disorders Identification Test (AUDIT) measured alcohol consumption and problems. RESULTS: In both studies, drinking to cope with negative affect had a direct effect on alcohol problems (S1: β = 0.259, SE = 0.031, p <.001; S2: β = 0.255, SE = 0.017, p <.001), and only a negligible proportion of this effect was mediated by alcohol consumption (S1: 2.58 %, p =.550; S2: 0.79 %, p=.538). By contrast, drinking to enhance positive affect had a smaller direct effect on alcohol problems (S1: β = 0.000, SE = 0.033, p =.989; S2: β = 0.044, SE = 0.017, p =.009), and a substantial proportion of this effect was mediated by greater alcohol consumption (S1: 99.76 %, p <.001; S2: 60.36 %, p <.001). Crucially, in both studies, the direct effect of drinking to cope on alcohol problems was invariant across gender and countries. CONCLUSIONS: These findings suggest that individuals who endorse drinking to cope with negative affect are uniquely susceptible to the alcohol harm paradox, that is, greater alcohol problems which cannot be explained by greater alcohol consumption, and this susceptibility is common across gender and countries.Alcohol Change UKMedical Research Council (MRC

Does Preexisting Antiplatelet Treatment Influence Postthrombolysis Intracranial Hemorrhage in Community‐treated Ischemic Stroke Patients? An Observational Study

Objectives Intracranial hemorrhage ( ICH ) after acute stroke thrombolysis is associated with poor outcomes. Previous investigations of the relationship between preexisting antiplatelet use and the safety of intravenous ( IV ) thrombolysis have been limited by low event rates. The objective of this study was to determine whether preexisting antiplatelet therapy increased the risk of ICH following acute stroke thrombolysis. The primary hypothesis was that antiplatelet use would not be associated with radiographic evidence of ICH after controlling for relevant confounders. Methods Consecutive cases of thrombolysis patients treated in the emergency department (ED) were identified using multiple methods. Retrospective data were collected from four hospitals from 1996 to 2004 and 24 other hospitals from 2007 to 2010 as part of a cluster‐randomized trial. The same chart abstraction tool was used during both time periods, and data were subjected to numerous quality control checks. Hemorrhages were classified using a prespecified methodology: ICH was defined as presence of hemorrhage in radiographic interpretations of follow‐up imaging (primary outcome). Symptomatic ICH ( sICH ) was defined as radiographic ICH with associated clinical worsening. A multivariable logistic regression model was constructed to adjust for clinical factors previously identified to be related to postthrombolysis ICH. Sensitivity analyses were conducted where the unadjusted and adjusted results from this study were combined with those of previously published external studies on this topic via meta‐analytic techniques. Results There were 830 patients included, with 47% having documented preexisting antiplatelet treatment. The mean (± standard deviation [SD]) age was 69 (±15) years, and the cohort was 53% male. The unadjusted proportion of patients with any ICH was 15.1% without antiplatelet use and 19.3% with antiplatelet use (absolute risk difference = 4.2%, 95% confidence interval [CI] = −1.2% to 9.6%); for sICH this was 6.1% without antiplatelet use and 9% with antiplatelet use (absolute risk difference = 3.1%, 95% CI = −1% to 6.7%). After adjusting for confounders, antiplatelet use was not significantly associated with radiographic ICH (odds ratio [OR] = 1.1, 95% CI = 0.8 to 1.7) or sICH (OR = 1.3, 95% CI = 0.7 to 2.2). In patients 81 years and older, there was a higher risk of radiographic ICH (absolute risk difference = 11.9%, 95% CI = 0.1% to 23.6%). The meta‐analyses combined the findings of this investigation with previous similar work and found increased unadjusted risks of radiographic ICH (absolute risk difference = 4.9%, 95% CI = 0.7% to 9%) and sICH (absolute risk difference = 4%, 95% CI = 2.3% to 5.6%). The meta‐analytic adjusted OR of sICH for antiplatelet use was 1.6 (95% CI = 1.1 to 2.4). Conclusions The authors did not find that preexisting antiplatelet use was associated with postthrombolysis ICH or sICH in this cohort of community treated patients. Preexisting tobacco use, younger age, and lower severity were associated with lower odds of sICH . The meta‐analyses demonstrated small, but statistically significant increases in the absolute risk of radiographic ICH and sICH , along with increased odds of sICH in patients with preexisting antiplatelet use. Resumen ¿Influye el Tratamiento Antiagregante Previo en la Hemorragia Intracraneal tras la Trombolisis en los Pacientes con Ictus Isquémicos Tratados en la Comunidad? Un Estudio Observacional Objetivos La hemorragia intracraneal ( HIC ) tras la trombolisis de un ictus agudo se asocia con malos resultados. Los estudios previos de la relación entre el uso de antiagregantes y la seguridad de la trombolisis intravenosa ( IV ) han estado limitados por los porcentajes bajos de sucesos. El objetivo de este estudio fue determinar si el tratamiento antiagregante previo está asociado con la evidencia radiológica de HIC tras el control por los factores de confusión relevantes. Metodología Se identificaron los casos consecutivos de pacientes tratados con trombolisis en el SU de múltiples formas. Se recogieron los datos de forma retrospectiva de cuatro hospitales de 1996 a 2004 y de 24 hospitales distintos de 2007 a 2010 como parte de un ensayo clínico aleatorizado en racimos. Se utilizó la misma tabla resumen de historia clínica durante ambos periodos de tiempo y los datos fueron sometidos a numerosos controles de calidad. Las hemorragias se clasificaron siguiendo una metodología preestablecida: la HIC se definió como la presencia de hemorragia en las interpretaciones radiológicas de las imágenes de seguimiento (resultado primario); y la HIC sintomática ( HIC s) se definió como la HIC radiológica asociada con un empeoramiento clínico. Se construyó un modelo multivariable de regresión logística para ajustar los factores clínicos previamente identificados como relacionados con un la HIC tras la trombolisis. Los análisis de sensibilidad se realizaron mediante técnicas de metanálisis y se combinaron los resultados ajustados y no ajustados de esta investigación con los estudios externos previamente publicados en este tema. Resultados Se incluyeron 830 pacientes, de los cuales el 47% tenía documentado tratamiento antiagregante previo. La media de edad fue de 69 años, y el 53% eran varones. La proporción no ajustada de pacientes con cualquier tipo de HIC fue del 15,1% sin toma de antiagregante y del 19,3% con la toma de antiagregante (diferencia del riesgo absoluto 4,2%, IC 95% = −1,2% a 9,6%); y para las HIC s fue del 6,1% sin toma de antiagregantes y del 9% con la toma de antiagregantes (diferencia absoluta del riesgo 3,1%, IC 95% = −1% a 6,7%). Tras ajustar por los factores de confusión, la toma de antiagregantes no se asoció de forma significativa con la HIC radiológica ( OR 1,1, IC 95% = 0,8 a 1,7]) o HIC s ( OR 1,3, IC 95% = 0,7 a 2,2). En los pacientes de 81 años o más, hubo mayor riesgo de HIC radiológica (diferencia de riesgo absoluta 11,9%, IC 95% = 0,1% a 23,6%). El metanálisis que combinó los hallazgos de esta investigación con los trabajos similares previos encontró un riesgo no ajustado incrementado para la HIC radiológica (diferencia absoluta del riesgo 4,9%, IC 95% = 0,7% a 9%) y de HIC s (diferencia absoluta del riesgo 4%, IC 95% = 2,3% a 5,6%). La odds ratio ajustada del metanálisis de HIC s para los pacientes con tratamiento de antigregantes fue de 1,6 ( IC 95% = 1,1 a 2,4). Conclusiones Los autores no encontraron que la toma previa de antigregantes se asocie con la HIC o la HIC s tras la trombolisis en esta cohorte de pacientes tratados en la comunidad. El consumo previo de tabaco, la edad más joven y la menor gravedad se asociaron con odds ratio menores de HIC s. El metanálisis demostró un incremento bajo, aunque estadísticamente significativo, de riesgo absoluto de HIC radiológica o de HIC s, con una odds ratio aumentada de HIC s en los pacientes con toma previa de antiagregantes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96759/1/acem12077.pd

Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force

BackgroundNeuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma.MethodsThe International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force.ResultsGuidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation.ConclusionsMetaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy

General practitioner advice on physical activity: Analyses in a cohort of older primary health care patients (getABI)

<p>Abstract</p> <p>Background</p> <p>Although the benefits of physical activity for health and functioning are recognized to extend throughout life, the physical activity level of most older people is insufficient with respect to current guidelines. The primary health care setting may offer an opportunity to influence and to support older people to become physically active on a regular basis. Currently, there is a lack of data concerning general practitioner (GP) advice on physical activity in Germany. Therefore, the aim of this study was to evaluate the rate and characteristics of older patients receiving advice on physical activity from their GP.</p> <p>Methods</p> <p>This is a cross-sectional study using data collected at 7 years of follow-up of a prospective cohort study (German epidemiological trial on ankle brachial index, getABI). 6,880 unselected patients aged 65 years and above in the primary health care setting in Germany were followed up since October 2001. During the 7-year follow-up telephone interview, 1,937 patients were asked whether their GP had advised them to get regular physical activity within the preceding 12 months. The interview also included questions on socio-demographic and lifestyle variables, medical conditions, and physical activity. Logistic regression analysis (unadjusted and adjusted for all covariables) was used to examine factors associated with receiving advice. Analyses comprised only complete cases with regard to the analysed variables. Results are expressed as odds ratios (ORs) with 95% confidence intervals (95% CI).</p> <p>Results</p> <p>Of the 1,627 analysed patients (median age 77; range 72-93 years; 52.5% women), 534 (32.8%) stated that they had been advised to get regular physical activity. In the adjusted model, those more likely to receive GP advice on physical activity were men (OR [95% CI] 1.34 [1.06-1.70]), patients suffering from pain (1.43 [1.13-1.81]), coronary heart disease and/or myocardial infarction (1.56 [1.21-2.01]), diabetes mellitus (1.79 [1.39-2.30]) or arthritis (1.37 [1.08-1.73]), and patients taking a high (> 5) number of medications (1.41 [1.11-1.80]).</p> <p>Conclusions</p> <p>The study revealed a relatively low rate of older primary health care patients receiving GP advice on physical activity. GPs appeared to focus their advice on patients with chronic medical conditions. However, there are likely to be many more patients who would benefit from advice.</p

An N-methyl-d-aspartate receptor agonist facilitates sleep-independent synaptic plasticity associated with working memory capacity enhancement

Working memory (WM) capacity improvement is impacted by sleep, and possibly by N-methyl-D-aspartate (NMDA) agonists such as D-cycloserine (DCS), which also affects procedural skill performance. However, the mechanisms behind these relationships are not well understood. In order to investigate the neural basis underlying relationships between WM skill learning and sleep, DCS, and both sleep and DCS together, we evaluated training-retest performances in the n-back task among healthy subjects who were given either a placebo or DCS before the task training, and then followed task training sessions either with wakefulness or sleep. DCS facilitated WM capacity enhancement only occurring after a period of wakefulness, rather than sleep, indicating that WM capacity enhancement is affected by a cellular heterogeneity in synaptic plasticity between time spent awake and time spent asleep. These findings may contribute to development, anti-aging processes, and rehabilitation of higher cognition

The Regulation of MS-KIF18A Expression and Cross Talk with Estrogen Receptor

This study provides a novel view on the interactions between the MS-KIF18A, a kinesin protein, and estrogen receptor alpha (ERα) which were studied in vivo and in vitro. Additionally, the regulation of MS-KIF18A expression by estrogen was investigated at the gene and protein levels. An association between recombinant proteins; ERα and MS-KIF18A was demonstrated in vitro in a pull down assay. Such interactions were proven also for endogenous proteins in MBA-15 cells were detected prominently in the cytoplasm and are up-regulated by estrogen. Additionally, an association between these proteins and the transcription factor NF-κB was identified. MS-KIF18A mRNA expression was measured in vivo in relation to age and estrogen level in mice and rats models. A decrease in MS-KIF18A mRNA level was measured in old and in OVX-estrogen depleted rats as compared to young animals. The low MS-KIF18A mRNA expression in OVX rats was restored by estrogen treatment. We studied the regulation of MS-KIF18A transcription by estrogen using the luciferase reporter gene and chromatin immuno-percipitation (ChIP) assays. The luciferase reporter gene assay demonstrated an increase in MS-KIF18A promoter activity in response to 10−8 M estrogen and 10−7M ICI-182,780. Complimentary, the ChIP assay quantified the binding of ERα and pcJun to the MS-KIF18A promoter that was enhanced in cells treated by estrogen and ICI-182,780. In addition, cells treated by estrogen expressed higher levels of MS-KIF18A mRNA and protein and the protein turnover in MBA-15 cells was accelerated. Presented data demonstrated that ERα is a defined cargo of MS-KIF18A and added novel insight on the role of estrogen in regulation of MS-KIF18A expression both in vivo and in vitro

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging