bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of human copy number variation on a new era of genetic testing
Authors: Choy KW , Setlur SR , Lee C , Lau TK 
Published: January 2010

Please cite this paper as: Choy K, Setlur S, Lee C, Lau T. The impact of human copy number variation on a new era of genetic testing. BJOG 2010;117:391–397.Cytogenetic studies have demonstrated that duplications or deletions of entire chromosomes or microscopically visible aberrations are associated with specific congenital disorders. The subsequent development and application of microarray‐based assays have established the importance of copy number variants (CNV) as a substantial source of genetic diversity in the human genome. Pathogenic CNVs are associated not only with birth defects and cancers, but also with neurodevelopmental disorders at birth or neurodegenerative diseases in adulthood. Unfortunately, the limited knowledge of the phenotypic effects of most CNVs has led to the classification of many CNVs as genomic imbalances of unknown clinical significance. This has caused many clinicians to resist the introduction of microarray technologies in detecting CNVs in a genome‐wide manner for prenatal applications. This review summarises our current understanding of CNVs, the common detection methods, and the implications for human health and prenatal diagnosis.
Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one‐step and two‐step methods
Authors: Meltzer SJ , Snyder J , Penrod JR , Nudi M , Morin L 
Published: January 2010

Please cite this paper as: Meltzer S, Snyder J, Penrod J, Nudi M, Morin L. Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one‐step and two‐step methods. BJOG 2010;117:407–415.Objective  To conduct a cost minimisation analysis of three methods of gestational diabetes mellitus (GDM) screening and diagnosis.Design  Prospective randomised controlled trial.Setting  University teaching hospital.Population  Pregnant women (n = 1594) presenting for GDM screening.Methods  Women presenting for GDM screening, who consented to participate, were randomised to GR1 [1‐hour, 50‐g glucose screen (GS) ± 3‐hour, 100‐g oral glucose tolerance test (OGTT)], GR2 (50‐g GS ± 2‐hour, 75‐g OGTT) or GR3 (2‐hour, 75‐g OGTT). Demographics, health and time/travel cost information were assessed for each glucose testing visit.Main outcome measures  Costs (direct and indirect) and prevalence of GDM diagnosis.Results  The direct sampling costs of the glucose tests per woman were as follows: GS, CAN$12.57; 75‐g OGTT, $36.10; 100‐g OGTT, CAN$48.13. Among women in the two‐step method groups diagnosed with GDM, 39% of the GR1 and 61% of the GR2 groups were diagnosed at the first step by GS ≥ 10.3 mmol/l, according to the Canadian Diabetes Association recommendations, contributing to a lower total cost in these groups. The total costs per woman screened were as follows: GR1, CAN$91.61; GR2, CAN$89.03; GR3, CAN$108.38. The GDM prevalence was similar (3.7%, 3.7% and 3.6%, respectively). The higher costs of GR3 were related to more blood draws and the time required for all women to undergo the 2‐hour OGTT.Conclusions  Careful consideration should be given to an internationally recommended method of universal screening for GDM which minimises the burden and cost for individual women and the healthcare system, yet provides diagnostic efficacy. The two‐step method (GS ± OGTT) accomplished this better than the one‐step method (75‐g OGTT).
Activation of presynaptic α7 nicotinic receptors evokes an excitatory response in hippocampal CA3 neurones in anaesthetized rats: anin vivoiontophoretic study
Authors: Huang Lan‐Ting , Sherwood John L , Sun Ya‐Jie , Lodge David , Wang Yun 
Published: January 2010

Background and purpose: α7 Nicotinic receptors have been suggested to play an important role in hippocampal learning and memory. However, the direct action of this receptor subtype on hippocampal pyramidal neuronesin vivohas not yet been fully investigated. The availability of selective agonists for α7 receptors [AR‐R17779 and (R)‐(‐)‐5′‐phenylspiro[1‐azabicyclo[2.2.2] octane‐3,2′‐(3′H)furo[2,3‐b]pyridine (PSAB‐OFP)] has now allowed this role to be investigated.Experimental approach: Single‐cell extracellular recordings were made from hippocampal CA3 pyramidal neurones in anaesthetized rats. The effects of nicotine, AR‐R17779 and PSAB‐OFP, applied either systemically or iontophoretically, were studied on the activity of these neurones.Key results: Intravenous injection of cumulative doses of nicotine and PSAB‐OFP induced dose‐related, significant increases in neuronal firing in the majority of neurones tested. This excitation could be inhibited by intravenous administration of methyllycaconitine (MLA), a selective α7 nicotinic receptor antagonist. Furthermore, iontophoretic application of nicotine, AR‐R17779 and PSAB‐OFP each evoked current‐dependent excitation of most CA3 pyramidal neurones studied, and this excitation was antagonized by co‐iontophoretic application of MLA. In addition, the excitation induced by iontophoretic application of nicotine, AR‐R17779 or PSAB‐OFP was also blocked by co‐iontophoretic application of either 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX) or D(2)‐2‐amino‐5‐phosphonopentanoate (D‐AP5), selective N‐methyl‐D‐aspartic acid (NMDA) and non‐NMDA receptor antagonists respectively.Conclusions and implications: CA3 pyramidal neurones are modulated by activation of presynaptic α7 nicotinic receptors, which, at least in part, enhances glutamate release onto post‐synaptic (RS)‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole proprionic acid and NMDA receptors on these CA3 neurones. This mechanism probably contributes to the effects of nicotine on hippocampal learning and memory.
Ethanol Modulates Corticotropin Releasing Hormone Release From the Rat Hypothalamus: Does Acetaldehyde Play a Role?
Authors: Cannizzaro Carla , La Barbera Marco , Plescia Fulvio , Cacace Silvana , Tringali Giuseppe 
Published: January 2010

Background and Methods: Ethanol (EtOH) activates hypothalamic–pituitary–adrenal (HPA) axis, resulting in adrenocorticotropin hormone, glucocorticoid release, and in modifications of the response of the axis to other stressors. The initial site of EtOH action within the HPA system seems to be the hypothalamus. Thus, to determine the mechanisms responsible for these effects, we investigated: (i) whether EtOH was able to release corticotrophic releasing hormone (CRH) from incubated hypothalamic explants; (ii) whether acetaldehyde (ACD), its first metabolite formed in the brain by catalase activity, might play a role in EtOH activity. To this aim, rat hypothalamic explants were incubated with: (i) medium containing EtOH at 32.6 × 103 μM; (ii) different concentration of ACD (1, 3, 10, and 30 μM); (iii) EtOH plus 3amino‐1,2,4‐triazole (3AT, 32 × 103 μM) an inhibitor of cerebral catalase; (iv) ACD plus D‐penicillamine (DP, 50.3 × 103 μM) an ACD‐trapping agent. CRH levels were evaluated by a radioimmunoassay.Results: Incubation with EtOH induced a 7‐fold increase in CRH secretion, with respect to basal levels; ACD was able to stimulate CRH release in a dose‐dependent manner; the inhibition of cerebral catalase by 3AT blocked EtOH‐induced CRH outflow; the inactivation of ACD by DP reverted the ACD‐stimulating effect on CRH secretion.Conclusions: These data show that both EtOH and acetaldehyde are able to increase hypothalamic CRH release from the rat hypothalamus and that acetaldehyde itself appears to be the mediator of EtOH activity.
An Event‐Related Potential Study of Response Inhibition in ADHD With and Without Prenatal Alcohol Exposure
Authors: Burden Matthew J. , Jacobson Joseph L. , Westerlund Alissa , Lundahl Leslie H. , Morrison Audrey , Dodge Neil C. , Klorman Rafael , Nelson Charles A. , Avison Malcolm J. , Jacobson Sandra W. 
Published: January 2010

Background:  The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes.Methods:  We recorded event‐related potentials (ERPs) during a Go/No‐go response inhibition task in young adults with prospectively obtained histories of prenatal alcohol exposure and childhood ADHD.Results:  Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No‐go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level.Conclusion:  This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD.
Event‐Related Oscillations Versus Event‐Related Potentials in a P300 Task as Biomarkers for Alcoholism
Authors: Andrew Colin , Fein George 
Published: January 2010

Objective:  It has been proposed that event‐related oscillation (ERO) measures of EEG activity recorded in P300 tasks provide more powerful biomarkers of alcoholism than event‐related potential (ERP) measures. This study examines this question in a group of long‐term abstinent alcoholics (LTAAs).Methods:  EEGs were recorded on 48 LTAAs and 48 age and gender‐matched nonalcoholic controls (NACs) during the performance of a 3‐condition visual target detection task. The event‐related data were analyzed to extract ERP amplitude measures and total and evoked ERO power measures. Data were analyzed using multivariate analysis of covariance to determine the contributions of ERO versus ERP measures to discriminate between the LTAA versus NAC groups.Results:  The LTAA group showed significantly lower evoked δ ERO power and total δ and θ ERO power compared to the control group. The evoked and total ERO power measures provide an alternative (but not more powerful) representation of the group difference than does P3b amplitude. There was a weak suggestion that nonphase‐locked θ ERO power (which contributes to total ERO power) might provide independent discriminatory information.Conclusions:  Reduced evoked ERO power in the response to target stimuli provided an alternative and comparable representation of the reduced P3b amplitude in LTAA. This is not surprising as the evoked ERO power measures are derived from time‐frequency representations of the ERP waveform. Induced theta oscillations might provide independent discriminatory information beyond ERP amplitude measures, but separate analysis of the event‐related nonphase‐locked activity is required to investigate this further.
Ethanol‐Induced Increase of Agouti‐Related Protein (AgRP) Immunoreactivity in the Arcuate Nucleus of the Hypothalamus of C57BL/6J, but not 129/SvJ, Inbred Mice
Authors: Cubero Inmaculada , Navarro Montserrat , Carvajal Francisca , Lerma‐Cabrera Jose Manuel , Thiele Todd E. 
Published: January 2010

Background: The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor, pro‐opiomelanocortin (POMC). Previous research has shown that MC receptor (MCR) agonists reduce, and MCR antagonists increase, ethanol consumption in rats and mice. Consistently, genetic deletion of the endogenous MCR antagonist, agouti‐related protein (AgRP), causes reductions of ethanol‐reinforced lever pressing and binge‐like ethanol drinking in C57BL/6J mice. Ethanol also has direct effects on the central MC system, as chronic exposure to an ethanol‐containing diet causes significant reductions of α‐melanocyte stimulating hormone (α‐MSH) immunoreactivity in specific brain regions of Sprague‐Dawley rats. Together, these observations suggest that the central MC system modulates neurobiological responses to ethanol. To further characterize the role of the MC system in responses to ethanol, here we compared AgRP and α‐MSH immunoreactivity in response to an acute injection of saline or ethanol between high ethanol drinking C57BL/6J mice and moderate ethanol drinking 129/SvJ mice.Methods: Mice received an intraperitoneal (i.p.) injection of ethanol (1.5 g/kg or 3.5 g/kg; mixed in 0.9% saline) or an equivolume of 0.9% saline. Two hours after injection, animals were sacrificed and their brains were processed for AgRP and α‐MSH immunoreactivity.Results: Results indicated that acute ethanol administration triggered a dose‐dependent increase in AgRP immunoreactivity in the arcuate (ARC) of C57BL/6J mice, an effect that was not evident in the 129/SvJ strain. Although acute administration of ethanol did not influence α‐MSH immunoreactivity, C57BL/6J mice had significantly greater overall α‐MSH immunoreactivity in the ARC, dorsomedial, and lateral regions of the hypothalamus relative to the 129/SvJ strain. In contrast, C57BL/6J mice displayed significantly lower α‐MSH immunoreactivity in the medial amygdala.Conclusions: The results show that acute ethanol exposure has direct effects on endogenous AgRP activity in ethanol preferring C57BL/6J mice. It is suggested that ethanol‐induced increases in AgRP may be part of a positive feedback system that stimulates excessive binge‐like ethanol drinking in C57BL/6J mice. Inherent differences in α‐MSH immunoreactivity may contribute to differences in neurobiological responses to ethanol that are characteristically observed between the C57BL/6J and 129/SvJ inbred strains of mice.
NeoHepatocytes From Alcoholics and Controls Express Hepatocyte Markers and Display Reduced Fibrogenic TGF‐β/Smad3 Signaling: Advantage for Cell Transplantation?
Authors: Ehnert Sabrina , Knobeloch Daniel , Blankenstein Antje , Müller Alexandra , Böcker Ulrich , Gillen Sonja , Friess Helmut , Thasler Wolfgang E. , Dooley Steven , Nussler Andreas K. 
Published: January 2010

Background:  Liver transplantation is the only definitive treatment for end stage liver disease. Donor organ scarcity raises a growing interest in new therapeutic options. Recently, we have shown that injection of monocyte‐derived NeoHepatocytes can increase survival in rats with extended liver resection. In order to apply this technology in humans with chronic liver diseases in an autologous setting, we generated NeoHepatocytes from patients with alcoholic liver disease and healthy controls and compared those to human hepatocytes.Methods:  We generated NeoHepatocytes from alcoholics with Child A and B cirrhosis and healthy controls. Hepatocytes marker expression and transforming growth factor (TGF)‐β signaling was investigated by RT‐PCR, Western blot, immunofluorescent staining, and adenoviral reporter assays. Glucose and urea was measured photometrically. Phase I and II enzyme activities were measured using fluorogenic substrates. Neutral lipids were visualized by Oil Red O staining.Results:  There was no significant difference in generation and yield of NeoHepatocytes from alcoholics and controls. Hepatocyte markers, e.g., cytokeratin18 and alcohol dehydrogenase 1, increased significantly throughout differentiation. Glucose and urea production did not differ between alcoholics and controls and was comparable to human hepatocytes. During differentiation, phase I and II enzyme activities increased, however remained significantly lower than in human hepatocytes. Fat accumulation was induced by treatment with insulin, TGF‐β and ethanol only in differentiated cells and hepatocytes. TGF‐β signaling, via Smad transcription factors, critically required for progression of chronic liver disease, was comparable among the investigated cell types, merely expression of Smad1 and ‐3 was reduced (∼30 and ∼60%) in monocytes, programmable cells of monocytic origin, and NeoHepatocytes. Subsequently, expression of TGF‐β regulated pro‐fibrogenic genes, e.g., connective tissue growth factor and fibronectin was reduced.Conclusions:  Generation of NeoHepatocytes from alcoholics, displaying several features of human hepatocytes, offers new perspectives for cell therapeutic approaches, as cells can be obtained repeatedly in a noninvasive manner. Furthermore, the autologous setting reduces the need for immunosuppressants, which may support recovery of patients which are declined for liver transplantation.
Effects of Straight Chain Alcohols on Specific Isoforms of Adenylyl Cyclase
Authors: Hasanuzzaman Mohammad , Yoshimura Masami 
Published: January 2010

Background:  Our previous studies showed that the activity of adenylyl cyclase (AC) was enhanced by pharmacologically relevant concentrations of ethanol, that this enhancing effect of ethanol on AC activity was AC isoform specific, and that the alcohol cutoff effect for n‐alkanol potentiation of AC activity was also AC isoform specific. Therefore, we hypothesized that within the cyclic AMP‐generating system, AC is the target of ethanol’s action and that alcohols interact directly with the AC molecules. To characterize the interaction between alcohols and AC proteins, the effects of a series of straight chain alcohols would be very valuable in understanding alcohol action at the molecular level. To our knowledge, straight chain alcohols other than n‐alkanols and 1,Ω‐diols have not been used extensively to study alcohol effects on the activity of AC or other proteins important in the alcohol research field.Methods:  The effects of a series of straight chain alcohols on D1A dopamine receptor‐stimulated activity of AC isoforms type 6, 7, and 9 (AC6, AC7, and AC9) were examined in transfected Hela cells by a cAMP accumulation assay.Results:  In general, all 3 AC isoforms responded to a series of straight chain alcohols in a similar manner. The order of responsiveness is as follows: monoalcohol > diol > triol and tetraol. Within monoalcohols, 1‐alcohols had larger effects than 2‐alcohols. Two of 3 stereoisomers of 2,3‐butanediol, [D‐(‐)‐2,3‐butanediol and meso‐2,3‐butanediol] showed similar enhancing effects on all 3 AC isoforms. However, the third stereoisomer, L‐(+)‐2,3‐butanediol, inhibited AC7 activity, while it stimulated AC6 and AC9.Conclusion:  The number and the position of hydroxyl groups in straight chain alcohols play an important role in the magnitude of the enhancement on AC activity. Regardless of AC isoforms, the most effective of the straight chain alcohols seems to be the 1‐alcohol (n‐alkanol) for a given chain length. We found that one of the stereoisomers of 2,3‐butanediol had opposite effects on AC activity depending on the AC isoform. Overall, the results are consistent with the hypotheses and demonstrate that a series of straight chain alcohols can be a valuable tool to study AC‐alcohol interactions.
Life Cycle Cost Disclosure, Consumer Behavior, and Business Implications
Authors: Deutsch Matthias 
Published: January 2010

SummaryComprehensive assessments of final consumption have identified “housing” as a major contributor to total environmental impacts. Within this category, electrical‐energy‐using products are important. Do consumers opt for more energy‐efficient household appliances if they are provided with life cycle cost (LCC)—that is, the sum of purchase price and operating cost estimated over the life span of the appliance? And what consequences does LCC disclosure have for business? Physical energy figures shown on appliance labels may be cognitively demanding for consumers, whereas monetary information promises to simplify the decision problem. Despite the rising interest in monetary cost disclosure, its effectiveness relative to physical cost disclosure has not been rigorously evaluated. This research approached the question of effectiveness with an online field experiment for washing machines. Customers of a commercially operating online shop were randomly assigned to two groups. The control group was provided with regular product price information; the treatment group received additional LCC information. A total of 2,065 clicks were recorded and analyzed with multiple regression that controlled for several product characteristics. The evidence suggests that LCC disclosure decreases the mean specific energy use of chosen washing machines by 0.8% (p < 0.01) and their mean specific water use by 0.7% (p < 0.05). As to business implications, LCC disclosure had no effect on the indicator of retail volume, which makes it unattractive for retailers to provide LCC on their own initiative.
Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort Cognitive Study
Authors: Yaffe Kristine , Ackerson Lynn , Tamura Manjula Kurella , Le Blanc Patti , Kusek John W. , Sehgal Ashwini R. , Cohen Debbie , Anderson Cheryl , Appel Lawrence , DeSalvo Karen , Ojo Akinlolu , Seliger Stephen , Robinson Nancy , Makos Gail , Go Alan S. ,   for the Chronic Renal Insufficiency Cohort Investigators
Published: January 2010

OBJECTIVES: To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors.DESIGN: Cross‐sectional.SETTING: Chronic Renal Insufficiency Cohort Study.PARTICIPANTS: Eight hundred twenty‐five adults aged 55 and older with CKD.MEASUREMENTS: Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m2) was estimated using the four‐variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score ≤1 standard deviations from the mean).RESULTS: Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1–3.9), naming (AOR=1.9, 95% CI=1.0–3.3), attention (AOR=2.4, 95% CI=1.3–4.5), executive function (AOR=2.5, 95% CI=1.9–4.4), and delayed memory (AOR=1.5, 95% CI=0.9–2.6) but not on category fluency (AOR=1.1, 95% CI=0.6–2.0) than those with mild to moderate CKD (eGFR 45–59).CONCLUSION: In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.