Ethanol Oxidation and Toxicity: Role of Alcohol P-450 Oxygenase

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66172/1/j.1530-0277.1986.tb05179.x.pd

Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort

Background Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. Methods This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Results Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Conclusions Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population

The Relationship Between Homework Compliance and Therapy Outcomes: An Updated Meta-Analysis

The current study was an updated meta-analysis of manuscripts since the year 2000 examining the effects of homework compliance on treatment outcome. A total of 23 studies encompassing 2,183 subjects were included. Results indicated a significant relationship between homework compliance and treatment outcome suggesting a small to medium effect (r = .26; 95% CI = .19–.33). Moderator analyses were conducted to determine the differential effect size of homework on treatment outcome by target symptoms (e.g., depression; anxiety), source of homework rating (e.g., client; therapist), timing of homework rating (e.g., retroactive vs. contemporaneous), and type of homework rating (e.g., Likert; total homeworks completed). Results indicated that effect sizes were robust across target symptoms, but differed by source of homework rating, timing of homework rating, and type of homework rating. Specifically, studies utilizing combined client and therapist ratings of compliance had significantly higher mean effect size relative to those using therapist only assessments and those using objective assessments. Further, studies that rated the percentage of homeworks completed had a significantly lower mean effect size compared to studies using Likert ratings, and retroactive assessments had higher effect size than contemporaneous assessments

Metabolic control in a nationally representative diabetic elderly sample in Costa Rica: patients at community health centers vs. patients at other health care settings

<p>Abstract</p> <p>Background</p> <p>Costa Rica, like other developing countries, is experiencing an increasing burden of chronic conditions such as diabetes mellitus (DM), especially among its elderly population. This article has two goals: (1) to assess the level of metabolic control among the diabetic population age ≥ 60 years old in Costa Rica, and (2) to test whether diabetic elderly patients of community health centers differ from patients in other health care settings in terms of the level of metabolic control.</p> <p>Methods</p> <p>Data come from the project CRELES, a nationally representative study of people aged 60 and over in Costa Rica. This article analyzes a subsample of 542 participants in CRELES with self-reported diagnosis of diabetes mellitus. Odds ratios of poor levels of metabolic control at different health care settings are computed using logistic regressions.</p> <p>Results</p> <p>Lack of metabolic control among elderly diabetic population in Costa Rica is described as follows: 37% have glycated hemoglobin ≥ 7%; 78% have systolic blood pressure ≥ 130 mmHg; 66% have diastolic blood pressure ≥ 80 mmHg; 48% have triglycerides ≥ 150 mg/dl; 78% have LDL ≥ 100 mg/dl; 70% have HDL ≤ 40 mg/dl. Elevated levels of triglycerides and LDL were higher in patients of community health centers than in patients of other clinical settings. There were no statistical differences in the other metabolic control indicators across health care settings.</p> <p>Conclusion</p> <p>Levels of metabolic control among elderly population with DM in Costa Rica are not that different from those observed in industrialized countries. Elevated levels of triglycerides and LDL at community health centers may indicate problems of dyslipidemia treatment among diabetic patients; these problems are not observed in other health care settings. The Costa Rican health care system should address this problem, given that community health centers constitute a means of democratizing access to primary health care to underserved and poor areas.</p

Comparison of Handaxes from Bose Basin (China) and the Western Acheulean Indicates Convergence of Form, Not Cognitive Differences

Alleged differences between Palaeolithic assemblages from eastern Asia and the west have been the focus of controversial discussion for over half a century, most famously in terms of the so-called ‘Movius Line’. Recent discussion has centered on issues of comparability between handaxes from eastern Asian and ‘Acheulean’ examples from western portions of the Old World. Here, we present a multivariate morphometric analysis in order to more fully document how Mid-Pleistocene (i.e. ∼803 Kyr) handaxes from Bose Basin, China compare to examples from the west, as well as with additional (Mode 1) cores from across the Old World. Results show that handaxes from both the western Old World and Bose are significantly different from the Mode 1 cores, suggesting a gross comparability with regard to functionally-related form. Results also demonstrate overlap between the ranges of shape variation in Acheulean handaxes and those from Bose, demonstrating that neither raw material nor cognitive factors were an absolute impediment to Bose hominins in making comparable handaxe forms to their hominin kin west of the Movius Line. However, the shapes of western handaxes are different from the Bose examples to a statistically significant degree. Moreover, the handaxe assemblages from the western Old World are all more similar to each other than any individual assemblage is to the Bose handaxes. Variation in handaxe form is also comparatively high for the Bose material, consistent with suggestions that they represent an emergent, convergent instance of handaxe technology authored by Pleistocene hominins with cognitive capacities directly comparable to those of ‘Acheulean’ hominins

Effects of Alcohol on the Acquisition and Expression of Fear Potentiated Startle in Mouse Lines Selectively Bred for High and Low Alcohol Preference

Rationale: Anxiety disorders and alcohol-use disorders frequently co-occur in humans perhaps because alcohol relieves anxiety. Studies in humans and rats indicate that alcohol may have greater anxiolytic effects in organisms with increased genetic propensity for high alcohol consumption. Objectives and Methods: The purpose of this study was to investigate the effects of moderate doses of alcohol (0.5, 1.0, 1.5 g/kg) on the acquisition and expression of anxiety-related behavior using a fear-potentiated startle (FPS) procedure. Experiments were conducted in two replicate pairs of mouse lines selectively bred for high- (HAP1 and HAP2) and low- (LAP1 and LAP2) alcohol preference; these lines have previously shown a genetic correlation between alcohol preference and FPS (HAP\u3eLAP; Barrenha and Chester 2007). In a control experiment, the effect of diazepam (4.0 mg/kg) on the expression of FPS was tested in HAP2 and LAP2 mice. Results: The 1.5 g/kg alcohol dose moderately decreased the expression of FPS in both HAP lines but not LAP lines. Alcohol had no effect on the acquisition of FPS in any line. Diazepam reduced FPS to a similar extent in both HAP2 and LAP2 mice. Conclusions: HAP mice may be more sensitive to the anxiolytic effects of alcohol than LAP mice when alcohol is given prior to the expression of FPS. These data collected in two pairs of HAP/LAP mouse lines suggest that the anxiolytic response to alcohol in HAP mice may be genetically correlated with their propensity toward high alcohol preference and robust FPS

Estrogenic botanical supplements, health-related quality of life, fatigue, and hormone-related symptoms in breast cancer survivors: a HEAL study report

<p>Abstract</p> <p>Background</p> <p>It remains unclear whether estrogenic botanical supplement (EBS) use influences breast cancer survivors' health-related outcomes.</p> <p>Methods</p> <p>We examined the associations of EBS use with health-related quality of life (HRQOL), with fatigue, and with 15 hormone-related symptoms such as hot flashes and night sweats among 767 breast cancer survivors participating in the Health, Eating, Activity, and Lifestyle (HEAL) Study. HRQOL was measured by the Medical Outcomes Study short form-36 physical and mental component scale summary score. Fatigue was measured by the Revised-Piper Fatigue Scale score.</p> <p>Results</p> <p>Neither overall EBS use nor the number of EBS types used was associated with HRQOL, fatigue, or hormone-related symptoms. However, comparisons of those using each specific type of EBS with non-EBS users revealed the following associations. Soy supplements users were more likely to have a better physical health summary score (odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.02-2.70). Flaxseed oil users were more likely to have a better mental health summary score (OR = 1.76, 95% CI = 1.05-2.94). Ginseng users were more likely to report severe fatigue and several hormone-related symptoms (all ORs ≥ 1.7 and all 95% CIs exclude 1). Red clover users were less likely to report weight gain, night sweats, and difficulty concentrating (all OR approximately 0.4 and all 95% CIs exclude 1). Alfalfa users were less likely to experience sleep interruption (OR = 0.28, 95% CI = 0.12-0.68). Dehydroepiandrosterone users were less likely to have hot flashes (OR = 0.33, 95% CI = 0.14-0.82).</p> <p>Conclusions</p> <p>Our findings indicate that several specific types of EBS might have important influences on a woman's various aspects of quality of life, but further verification is necessary.</p

Lysophosphatidic Acid Acyltransferase β (LPAATβ) Promotes the Tumor Growth of Human Osteosarcoma

Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways