Splanchnic Artery Stenosis and Abdominal Complaints: Clinical History Is of Limited Value in Detection of Gastrointestinal Ischemia

BACKGROUND: Splanchnic artery stenosis is common and mostly asymptomatic and may lead to gastrointestinal ischemia (chronic splanchnic syndrome, CSS). This study was designed to assess risk factors for CSS in the medical history of patients with splanchnic artery stenosis and whether these risk factors can be used to identify patients with high and low risk of CSS. METHODS: All patients referred for suspected CSS underwent a standardized workup, including a medical history with questionnaire, duplex ultrasound, gastrointestinal tonometry, and angiography. Definitive diagnosis and treatment advice was made in a multidisciplinary team. Patients with confirmed CSS were compared with no-CSS patients. RESULTS: A total of 270 patients (102 M, 168 F; mean age, 53 years) with splanchnic artery stenosis were analyzed, of whom 109 (40%) had CSS and 161 no CSS. CSS-patients more often reported postprandial pain (87% vs. 72%, p = 0.007), weight loss (85% vs. 70%, p = 0.006), adapted eating pattern (90% vs. 79%, p = 0.005) and diarrhea (35% vs. 22%, p = 0.023). If none of these risk factors were present, the probability of CSS was 13%; if all were present, the probability was 60%. Adapted eating pattern (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.08-8.88) and diarrhea (OR 2.6; 95% CI 1.31-5.3) were statistically significant in multivariate analysis. CONCLUSIONS: In patients with splanchnic artery stenosis, the clinical history is of limited value for detection of CSS. A diagnostic test to detect ischemia is indispensable for proper selection of patients with splanchnic artery stenosis who might benefit from treatment

Public understandings of addiction: where do neurobiological explanations fit?

Developments in the field of neuroscience, according to its proponents, offer the prospect of an enhanced understanding and treatment of addicted persons. Consequently, its advocates consider that improving public understanding of addiction neuroscience is a desirable aim. Those critical of neuroscientific approaches, however, charge that it is a totalising, reductive perspective–one that ignores other known causes in favour of neurobiological explanations. Sociologist Nikolas Rose has argued that neuroscience, and its associated technologies, are coming to dominate cultural models to the extent that 'we' increasingly understand ourselves as 'neurochemical selves'. Drawing on 55 qualitative interviews conducted with members of the Australian public residing in the Greater Brisbane area, we challenge both the 'expectational discourses' of neuroscientists and the criticisms of its detractors. Members of the public accepted multiple perspectives on the causes of addiction, including some elements of neurobiological explanations. Their discussions of addiction drew upon a broad range of philosophical, sociological, anthropological, psychological and neurobiological vocabularies, suggesting that they synthesised newer technical understandings, such as that offered by neuroscience, with older ones. Holding conceptual models that acknowledge the complexity of addiction aetiology into which new information is incorporated suggests that the impact of neuroscientific discourse in directing the public's beliefs about addiction is likely to be more limited than proponents or opponents of neuroscience expect

Physician Attitudes towards Pharmacological Cognitive Enhancement: Safety Concerns Are Paramount

The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between safety and benefit in consideration of pharmacological cognitive enhancement

Testing the role of predicted gene knockouts in human anthropometric trait variation

National Heart, Lung, and Blood Institute (NHLBI) S.L. is funded by a Canadian Institutes of Health Research Banting doctoral scholarship. G.L. is funded by Genome Canada and Génome Québec; the Canada Research Chairs program; and the Montreal Heart Institute Foundation. C.M.L. is supported by Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A); and the Li Ka Shing Foundation. N.S. is funded by National Institutes of Health (grant numbers HL088456, HL111089, HL116747). The Mount Sinai BioMe Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. GO ESP is supported by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO, RC2 HL-102924 to WHISP). The ESP exome sequencing was performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL- 102926 to SeattleGO). EGCUT work was supported through the Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education (grant number SF0180142s08); the Development Fund of the University of Tartu (grant number SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and through FP7 (grant number 313010). EGCUT were further supported by the US National Institute of Health (grant number R01DK075787). A.K.M. was supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship (#7-12-MN- 02). The BioVU dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access publication charges for this article was provided by a block grant from Research Councils UK to the University of Cambridge

Testing the role of predicted gene knockouts in human anthropometric trait variation

National Heart, Lung, and Blood Institute (NHLBI) S.L. is funded by a Canadian Institutes of Health Research Banting doctoral scholarship. G.L. is funded by Genome Canada and Génome Québec; the Canada Research Chairs program; and the Montreal Heart Institute Foundation. C.M.L. is supported by Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A); and the Li Ka Shing Foundation. N.S. is funded by National Institutes of Health (grant numbers HL088456, HL111089, HL116747). The Mount Sinai BioMe Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. GO ESP is supported by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO, RC2 HL-102924 to WHISP). The ESP exome sequencing was performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL- 102926 to SeattleGO). EGCUT work was supported through the Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education (grant number SF0180142s08); the Development Fund of the University of Tartu (grant number SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and through FP7 (grant number 313010). EGCUT were further supported by the US National Institute of Health (grant number R01DK075787). A.K.M. was supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship (#7-12-MN- 02). The BioVU dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access publication charges for this article was provided by a block grant from Research Councils UK to the University of Cambridge

Testing the role of predicted gene knockouts in human anthropometric trait variation

National Heart, Lung, and Blood Institute (NHLBI) S.L. is funded by a Canadian Institutes of Health Research Banting doctoral scholarship. G.L. is funded by Genome Canada and Génome Québec; the Canada Research Chairs program; and the Montreal Heart Institute Foundation. C.M.L. is supported by Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A); and the Li Ka Shing Foundation. N.S. is funded by National Institutes of Health (grant numbers HL088456, HL111089, HL116747). The Mount Sinai BioMe Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. GO ESP is supported by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO, RC2 HL-102924 to WHISP). The ESP exome sequencing was performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL- 102926 to SeattleGO). EGCUT work was supported through the Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education (grant number SF0180142s08); the Development Fund of the University of Tartu (grant number SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and through FP7 (grant number 313010). EGCUT were further supported by the US National Institute of Health (grant number R01DK075787). A.K.M. was supported by an American Diabetes Association Mentor-Based Postdoctoral Fellowship (#7-12-MN- 02). The BioVU dataset used in the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Genome-wide genotyping was funded by NIH grants RC2GM092618 from NIGMS/OD and U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access publication charges for this article was provided by a block grant from Research Councils UK to the University of Cambridge

Reduced global longitudinal strain in association to increased left ventricular mass in patients with aortic valve stenosis and normal ejection fraction: a hybrid study combining echocardiography and magnetic resonance imaging

<p>Abstract</p> <p>Background</p> <p>Increased muscle mass index of the left ventricle (LVMi) is an independent predictor for the development of symptoms in patients with asymptomatic aortic stenosis (AS). While the onset of clinical symptoms and left ventricular systolic dysfunction determines a poor prognosis, the standard echocardiographic evaluation of LV dysfunction, only based on measurements of the LV ejection fraction (EF), may be insufficient for an early assessment of imminent heart failure. Contrary, 2-dimensional speckle tracking (2DS) seems to be superior in detecting subtle changes in myocardial function. The aim of the study was to assess these LV function deteriorations with global longitudinal strain (GLS) analysis and the relations to LVMi in patients with AS and normal EF.</p> <p>Methods</p> <p>50 patients with moderate to severe AS and 31 controls were enrolled. All patients underwent echocardiography, including 2DS imaging. LVMi measures were performed with magnetic resonance imaging in 38 patients with AS and indexed for body surface area.</p> <p>Results</p> <p>The total group of patients with AST showed a GLS of -15,2 ± 3,6% while the control group reached -19,5 ± 2,7% (p < 0,001). By splitting the group with AS in normal, moderate and severe increased LVMi, the GLS was -17,0 ± 2,6%, -13,2 ± 3,8% and -12,4 ± 2,9%, respectively (p = 0,001), where LVMi and GLS showed a significant correlation (r = 0,6, p < 0,001).</p> <p>Conclusions</p> <p>In conclusion, increased LVMi is reflected in abnormalities of GLS and the proportion of GLS impairment depends on the extent of LV hypertrophy. Therefore, simultaneous measurement of LVMi and GLS might be useful to identify patients at high risk for transition into heart failure who would benefit from aortic valve replacement irrespectively of LV EF.</p

Patterns of wood carbon dioxide efflux across a 2,000-m elevation transect in an Andean moist forest

During a 1-year measurement period, we recorded the CO2 efflux from stems (RS) and coarse woody roots (RR) of 13–20 common tree species at three study sites at 1,050, 1,890 and 3,050 m a.s.l. in an Andean moist forest. The objective of this work was to study elevation changes of woody tissue CO2 efflux and the relationship to climate variation, site characteristics and growth. Furthermore, we aim to provide insights into important respiration–productivity relationships of a little studied tropical vegetation type. We expected RS and RR to vary with dry and humid season conditions. We further expected RS to vary more than RR due to a more stable soil than air temperature regime. Seasonal variation in woody tissue CO2 efflux was indeed mainly attributable to stems. At the same time, temperature played only a small role in triggering variations in RS. At stand level, the ratio of C release (g C m−2 ground area year−1) between stems and roots varied from 4:1 at 1,050 m to 1:1 at 3,050 m, indicating the increasing prevalence of root activity at high elevations. The fraction of growth respiration from total respiration varied between 10 (3,050 m) and 14% (1,050 m) for stems and between 5 (1,050 m) and 30% (3,050 m) for roots. Our results show that respiratory activity and hence productivity is not driven by low temperatures towards higher elevations in this tropical montane forest. We suggest that future studies should examine the limitation of carbohydrate supply from leaves as a driver for the changes in respiratory activity with elevation

Gene Expression Responses Linked to Reproduction Effect Concentrations (EC10,20,50,90) of Dimethoate, Atrazine and Carbendazim, in Enchytraeus albidus

BACKGROUND: Molecular mechanisms of response to pesticides are scarce and information on such responses from soil invertebrates is almost inexistent. Enchytraeus albidus (Oligochaeta) is a standard soil ecotoxicology model species for which effects of many pesticides are known on survival, reproduction and avoidance behaviour. With the recent microarray development additional information can be retrieved on the molecular effects. METHODOLOGY/PRINCIPAL FINDINGS: Experiments were performed to investigate the transcription responses of E. albidus when exposed to three pesticides - dimethoate (insecticide), atrazine (herbicide) and carbendazim (fungicide) - in a range of concentrations that inhibited reproduction by 10%, 20%, 50% and 90% (EC(10), EC(20), EC(50) and EC(90), respectively). The goal of this study was to further identify key biological processes affected by each compound and if dose-related. All three pesticides significantly affected biological processes like translation, regulation of the cell cycle or general response to stress. Intracellular signalling and microtubule-based movement were affected by dimethoate and carbendazim whereas atrazine affected lipid and steroid metabolism (also by dimethoate) or carbohydrate metabolism (also by carbendazim). Response to DNA damage/DNA repair was exclusively affected by carbendazim. CONCLUSIONS: Changes in gene expression were significantly altered after 2 days of exposure in a dose-related manner. The mechanisms of response were comparable with the ones for mammals, suggesting across species conserved modes of action. The present results indicate the potential of using gene expression in risk assessment and the advantage as early markers

Restoration of IFNγR Subunit Assembly, IFNγ Signaling and Parasite Clearance in Leishmania donovani Infected Macrophages: Role of Membrane Cholesterol

Despite the presence of significant levels of systemic Interferon gamma (IFNγ), the host protective cytokine, Kala-azar patients display high parasite load with downregulated IFNγ signaling in Leishmania donovani (LD) infected macrophages (LD-MØs); the cause of such aberrant phenomenon is unknown. Here we reveal for the first time the mechanistic basis of impaired IFNγ signaling in parasitized murine macrophages. Our study clearly shows that in LD-MØs IFNγ receptor (IFNγR) expression and their ligand-affinity remained unaltered. The intracellular parasites did not pose any generalized defect in LD-MØs as IL-10 mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation remained unaltered with respect to normal. Previously, we showed that LD-MØs are more fluid than normal MØs due to quenching of membrane cholesterol. The decreased rigidity in LD-MØs was not due to parasite derived lipophosphoglycan (LPG) because purified LPG failed to alter fluidity in normal MØs. IFNγR subunit 1 (IFNγR1) and subunit 2 (IFNγR2) colocalize in raft upon IFNγ stimulation of normal MØs, but this was absent in LD-MØs. Oddly enough, such association of IFNγR1 and IFNγR2 could be restored upon liposomal delivery of cholesterol as evident from the fluorescence resonance energy transfer (FRET) experiment and co-immunoprecipitation studies. Furthermore, liposomal cholesterol treatment together with IFNγ allowed reassociation of signaling assembly (phospho-JAK1, JAK2 and STAT1) in LD-MØs, appropriate signaling, and subsequent parasite killing. This effect was cholesterol specific because cholesterol analogue 4-cholestene-3-one failed to restore the response. The presence of cholesterol binding motifs [(L/V)-X1–5-Y-X1–5-(R/K)] in the transmembrane domain of IFNγR1 was also noted. The interaction of peptides representing this motif of IFNγR1 was studied with cholesterol-liposome and analogue-liposome with difference of two orders of magnitude in respective affinity (KD: 4.27×10−9 M versus 2.69×10−7 M). These observations reinforce the importance of cholesterol in the regulation of function of IFNγR1 proteins. This study clearly demonstrates that during its intracellular life-cycle LD perturbs IFNγR1 and IFNγR2 assembly and subsequent ligand driven signaling by quenching MØ membrane cholesterol