Prazosin Reduces Alcohol Intake in an Animal Model of Alcohol Relapse

BACKGROUND: Many alcoholics and heavy drinkers undergo repeated cycles of alcohol abstinence followed by relapse to alcohol drinking; a pattern that contributes to escalated alcohol intake over time. In rodents, alcohol drinking that is interspersed with periods of alcohol deprivation (imposed abstinence) increases alcohol intake during reaccess to alcohol. This is termed the "alcohol deprivation effect" or "ADE" and is a model of alcohol relapse in humans. We have previously reported that prazosin reduces alcohol drinking during both brief and prolonged treatment in rats selectively bred for alcohol preference ("P" rats). This study explores whether prazosin prevents alcohol "relapse" in P rats, as reflected by a reduced or abolished ADE. METHODS: Adult male P rats were given 24-hour access to food and water and scheduled access to alcohol (15 and 30% v/v solutions presented concurrently) for 2 h/d. After 5 weeks, rats underwent imposed alcohol deprivation for 2 weeks, followed by alcohol reaccess for 2 weeks, and this pattern was repeated for a total of 3 cycles. Rats were injected with prazosin (0, 0.5, 1.0, or 2.0 mg/kg body weight, intraperitoneally) once a day for the first 5 days of each alcohol reaccess cycle. RESULTS: Alcohol intake increased on the first day of each alcohol reaccess cycle, demonstrating the formation of an ADE. The ADE was short-lived, lasting only 1 day, during each of the 3 cycles. Prazosin, in all doses tested, prevented the expression of an ADE in all 3 alcohol reaccess cycles. CONCLUSIONS: Prazosin decreases alcohol intake in P rats even in a situation that would be expected to increase alcohol drinking, namely following periods of alcohol deprivation. This suggests that prazosin may be effective in reducing alcohol relapse that often occurs during attempts to achieve permanent alcohol abstinence in treatment-seeking alcoholics and heavy drinkers

Genome Diversification in Phylogenetic Lineages I and II of \u3ci\u3eListeria monocytogenes\u3c/i\u3e: Identification of Segments Unique to Lineage II Populations

Thirteen different serotypes of Listeria monocytogenes can be distinguished on the basis of variation in somatic and flagellar antigens. Although the known virulence genes are present in all serotypes, greater than 90% of human cases of listeriosis are caused by serotypes 1/2a, 1/2b, and 4b and nearly all outbreaks of food-borne listeriosis have been caused by serotype 4b strains. Phylogenetic analysis of these three common clinical serotypes places them into two different lineages, with serotypes 1/2b and 4b belonging to lineage I and 1/2a belonging to lineage II. To begin examining evolution of the genome in these serotypes, DNA microarray analysis was used to identify lineage-specific and serotype-specific differences in genome content. A set of 44 strains representing serotypes 1/2a, 1/2b, and 4b was probed with a shotgun DNA microarray constructed from the serotype 1/2a strain 10403s. Clones spanning 47 different genes in 16 different contiguous segments relative to the lineage II 1/2a genome were found to be absent in all lineage I strains tested (serotype 4b and 1/2b) and an additional nine were altered exclusively in 4b strains. Southern hybridization confirmed that conserved alterations were, in all but two loci, due to absence of the segments from the genome. Genes within these contiguous segments comprise five functional categories, including genes involved in synthesis of cell surface molecules and regulation of virulence gene expression. Phylogenetic reconstruction and examination of compositional bias in the regions of difference are consistent with a model in which the ancestor of the two lineages had the 1/2 somatic serotype and the regions absent in the lineage I genome arose by loss of ancestral sequences

A Standardized Patient Counseling Rubric for a Pharmaceutical Care and Communications Course

Objective. To restructure a required pharmaceutical care and communications course to place greater emphasis on communication skills and include a high-stakes assessment. Design. A standardized counseling rubric was developed for use throughout the pharmacy curriculum and the counseling laboratory practicals were changed to high-stakes assessments. Assessment. An annual mid-semester and end-of-semester high-stakes patient-counseling objective structured clinical examination (OSCE) conducted prior to and after revision of the course and counseling rubric documented improvements in students’ scores. Performance on the post-course annual assessment patient counseling OSCE improved compared to that on the pre-course (p,0.001). Conclusion. The 2010 course revision improved students’ medication counseling abilities and readiness to practice. Major course revisions should be undertaken only after input from all stakeholders and with data to support the need for change

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

MotivationMultiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.ResultsWe performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementationDatasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary informationSupplementary data are available at Bioinformatics online

Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4(+) BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

Social work and gender::An argument for practical accounts

This article contributes to the debate on gender and social work by examining dominant approaches within the field. Anti-discriminatory, woman-centered and intersectional accounts are critiqued for reliance upon both reification and isolation of gender. Via examination of poststructural, queer and trans theories within social work, the author then presents accounts based upon structural/materialist, ethnomethodological and discursive theories, in order to open up debates about conceptualization of gender. These are used to suggest that social work should adopt a focus on gender as a practical accomplishment that occurs within various settings or contexts

Migraine headaches in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>Headaches are more frequent in Chronic Fatigue Syndrome (CFS) than healthy control (HC) subjects. The 2004 International Headache Society (IHS) criteria were used to define CFS headache phenotypes.</p> <p>Methods</p> <p>Subjects in Cohort 1 (HC = 368; CFS = 203) completed questionnaires about many diverse symptoms by giving nominal (yes/no) answers. Cohort 2 (HC = 21; CFS = 67) had more focused evaluations. They scored symptom severities on 0 to 4 anchored ordinal scales, and had structured headache evaluations. All subjects had history and physical examinations; assessments for exclusion criteria; questionnaires about CFS related symptoms (0 to 4 scale), Multidimensional Fatigue Inventory (MFI) and Medical Outcome Survey Short Form 36 (MOS SF-36).</p> <p>Results</p> <p>Demographics, trends for the number of diffuse "functional" symptoms present, and severity of CFS case designation criteria symptoms were equivalent between CFS subjects in Cohorts 1 and 2. HC had significantly fewer symptoms, lower MFI and higher SF-36 domain scores than CFS in both cohorts. Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC. The CFS group had migraine without aura (60%; MO; CFS+MO), with aura (24%; CFS+MA), tension headaches only (12%), or no headaches (4%). Co-morbid tension and migraine headaches were found in 67% of CFS. CFS+MA had higher severity scores than CFS+MO for the sum of scores for poor memory, dizziness, balance, and numbness ("Neuro-construct", p = 0.002) and perceived heart rhythm disturbances, palpitations and noncardiac chest pain ("Cardio-construct"; p = 0.045, t-tests after Bonferroni corrections). CFS+MO subjects had lower pressure-induced pain thresholds (2.36 kg [1.95-2.78; 95% C.I.] n = 40) and a higher prevalence of fibromyalgia (47%; 1990 criteria) compared to HC (5.23 kg [3.95-6.52] n = 20; and 0%, respectively). Sumatriptan was beneficial for 13 out of 14 newly diagnosed CFS migraine subjects.</p> <p>Conclusions</p> <p>CFS subjects had higher prevalences of MO and MA than HC, suggesting that mechanisms of migraine pathogenesis such as central sensitization may contribute to CFS pathophysiology.</p> <p>Clinical Trial Registration</p> <p>Georgetown University IRB # 2006-481</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00810329">NCT00810329</a></p

AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder:COORDINATE-MDD consortium design and rationale

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project