tbuckley/cabot-search huggingface dataset:
Interacting Effects of Genetic Predisposition and Depression on Adolescent Smoking Progression
Authors: Janet Audrain-McGovern, Caryn Lerman, E. Paul Wileyto, Daniel Rodriguez, Peter G. Shields
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The goal of the present study was to identify specific genetic associations with smoking progression in adolescents and to determine whether these genetic effects on smoking practices are potentiated by depression symptoms. METHOD: Effects of dopamine transporter (SLC6A3) and dopamine receptor (DRD2) genetic variants on smoking progression were evaluated in a cohort of 615 adolescents, including those who had never smoked, and in a subgroup including only adolescents who had been exposed to nicotine (i.e., smoked at least a puff of a cigarette) (N=292). These adolescents were followed from 9th to 11th grade. Depression symptoms were also assessed. RESULTS: In the model of adolescents with a previous smoking experience, the likelihood of progressing to a higher level of smoking by the 11th grade increased almost twofold with each additional DRD2 A1 allele. The likelihood of smoking progression with each additional A1 allele was more pronounced among adolescents with substantial depression symptoms. The model including never-smokers revealed no significant genetic effects. Neither model revealed effects of SLC6A3. CONCLUSIONS: These results provide the first evidence, to the authors' knowledge, for an association of the DRD2 A1 allele with smoking progression among adolescents. This effect is potentiated by depression symptoms. These effects appear to be specific to adolescents who have had at least some nicotine exposure (i.e., at least a puff of a cigarette).
Clear Differences in Levels of a Formaldehyde-DNA Adduct in Leukocytes of Smokers and Nonsmokers
Authors: Mingyao Wang, Guang Cheng, Silvia Balbo, Steven G. Carmella, Peter W. Villalta, Stephen S. Hecht
Journal: Cancer Research (2009)

Formaldehyde is considered carcinogenic to humans by the IARC, but there are no previous reports of formaldehyde-DNA adducts in humans. In this study, we used liquid chromatography-electrospray ionization-tandem mass spectrometry to quantify the formaldehyde-DNA adduct N(6)-hydroxymethyldeoxyadenosine (N(6)-HOMe-dAdo) in leukocyte DNA samples from 32 smokers of >or=10 cigarettes per day and 30 nonsmokers. Clear peaks coeluting with the internal standard in two different systems were seen in samples from smokers but rarely in nonsmokers. N(6)-HOMe-dAdo was detected in 29 of 32 smoker samples (mean +/- SD, 179 +/- 205 fmol/micromol dAdo). In contrast, it was detected in only 7 of 30 nonsmoker samples (15.5 +/- 33.8 fmol/micromol dAdo; P < 0.001). The results of this study show remarkable differences between smokers and nonsmokers in levels of a leukocyte formaldehyde-DNA adduct, suggesting a potentially important and previously unrecognized role for formaldehyde as a cause of cancer induced by cigarette smoking.
Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives
Authors: P. Lévy, J-L. Pépin, C. Arnaud, R. Tamisier, J-C. Borel, M. Dematteis, D. Godin-Ribuot, C. Ribuot
Journal: European Respiratory Journal (2008)

There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), Cheyne–Stokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown. In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials. Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality. Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.
So much easier to attack straw men
Authors: Richard W. Byrne
Journal: Behavioral and Brain Sciences (1998)

Rather than dealing with the important issues in the interpretation of behavioural data, Heyes seems only to reiterate lessons well-learned before she first reviewed the topic of primate deception. She also appears to misrepresent a series of published analyses. Despite her emphatic denials, the commonsense view is the best: informed observations and experiments can both provide evidence of theory of mind.
Sugar-Sweetened Beverages and Genetic Risk of Obesity
Authors: Qibin Qi, Audrey Y. Chu, Jae H. Kang, Majken K. Jensen, Gary C. Curhan, Louis R. Pasquale, Paul M. Ridker, David J. Hunter, Walter C. Willett, Eric B. Rimm, Daniel I. Chasman, Frank B. Hu, Lu Qi
Journal: New England Journal of Medicine (2012)

Temporal increases in the consumption of sugar-sweetened beverages have paralleled the rise in obesity prevalence, but whether the intake of such beverages interacts with the genetic predisposition to adiposity is unknown.We analyzed the interaction between genetic predisposition and the intake of sugar-sweetened beverages in relation to body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and obesity risk in 6934 women from the Nurses' Health Study (NHS) and in 4423 men from the Health Professionals Follow-up Study (HPFS) and also in a replication cohort of 21,740 women from the Women's Genome Health Study (WGHS). The genetic-predisposition score was calculated on the basis of 32 BMI-associated loci. The intake of sugar-sweetened beverages was examined prospectively in relation to BMI.In the NHS and HPFS cohorts, the genetic association with BMI was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake. In the combined cohorts, the increases in BMI per increment of 10 risk alleles were 1.00 for an intake of less than one serving per month, 1.12 for one to four servings per month, 1.38 for two to six servings per week, and 1.78 for one or more servings per day (P<0.001 for interaction). For the same categories of intake, the relative risks of incident obesity per increment of 10 risk alleles were 1.19 (95% confidence interval [CI], 0.90 to 1.59), 1.67 (95% CI, 1.28 to 2.16), 1.58 (95% CI, 1.01 to 2.47), and 5.06 (95% CI, 1.66 to 15.5) (P=0.02 for interaction). In the WGHS cohort, the increases in BMI per increment of 10 risk alleles were 1.39, 1.64, 1.90, and 2.53 across the four categories of intake (P=0.001 for interaction); the relative risks for incident obesity were 1.40 (95% CI, 1.19 to 1.64), 1.50 (95% CI, 1.16 to 1.93), 1.54 (95% CI, 1.21 to 1.94), and 3.16 (95% CI, 2.03 to 4.92), respectively (P=0.007 for interaction).The genetic association with adiposity appeared to be more pronounced with greater intake of sugar-sweetened beverages. (Funded by the National Institutes of Health and others.).
Molecular Risk Stratification of Medulloblastoma Patients Based on Immunohistochemical Analysis of MYC, LDHB, and CCNB1 Expression
Authors: Talitha de Haas, Nancy Hasselt, Dirk Troost, Huib Caron, Mara Popovic, Lorna Zadravec-Zaletel, Wieslawa Grajkowska, Marta Perek, Maria-Chiara Osterheld, David Ellison, Frank Baas, Rogier Versteeg, Marcel Kool
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Medulloblastoma is the most common malignant embryonal brain tumor in children. The current clinical risk stratification to select treatment modalities is not optimal because it does not identify the standard-risk patients with resistant disease or the unknown number of high-risk patients who might be overtreated with current protocols. The aim of this study is to improve the risk stratification of medulloblastoma patients by using the expression of multiple prognostic markers in combination with current clinical parameters. Experimental Design: Candidate prognostic markers were selected from literature or from medulloblastoma expression data. Selected genes were immunohistochemically analyzed for their prognostic value using medulloblastoma tissue arrays containing 124 well-characterized patient samples. Results: Protein expression analyses showed that the combined expression of three genes was able to predict survival in medulloblastoma patients. Low MYC expression identified medulloblastoma patients with a very good outcome. In contrast, concomitant expression of LDHB and CCNB1 characterized patients with a very poor outcome. Multivariate analyses showed that both expression of MYC and the LDHB/CCNB1 gene signature were strong prognostic markers independent of the clinical parameters metastasis and residual disease. Combined analysis of clinical and molecular markers enabled greater resolution of disease risk than clinical factors alone. Conclusions: A molecular risk stratification model for medulloblastoma patients is proposed based on the signature of MYC, LDHB, and CCNB1 expression. Combined with clinical variables, the model may provide a more accurate basis for targeting therapy in children with this disease.
Formation of Endogenous “Antiinflammatory” Lipid Mediators by Transcellular Biosynthesis
Authors: CHARLES N. SERHAN, TOMOKO TAKANO, NAN CHIANG, KARSTEN GRONERT, CLARY B. CLISH
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Neutrophil-dependent vascular injury gives rise to increased vascular permeability, edema, and further release of chemoattractants. Leukotriene B 4  (LTB 4 ) is among the most potent neutrophil stimuli and thus participates in tissue injury via recruiting neutrophils (PMNs, polymorphonuclear leukocytes) in pathophysiologic scenarios (1). Lipoxins are trihydroxytetraene-containing eicosanoids that are, among other in vivo sites, also generated within vascular lumen primarily by platelet-leukocyte interactions by pathways (Figure 1) that are activated during multicellular responses such as inflammation, atherosclerosis, and thrombosis (for a review, see Reference 2). In addition, aspirin has been found to trigger the transcellular biosynthesis of a new group of compounds termed 15-epi-lipoxins (15-epi-LXs) or aspirin-triggered lipoxins, which are likely to contribute to some of the beneficial actions ascribed to aspirin by serving as local endogenous antiinflammatory lipid mediators (2). Thus, these LX branches illustrated in Figure 1 involve cell-cell interactions that appear to produce endogenous stop signals or antiinflammatory compounds, while the 5-lipoxygenase pathway generates leukotrienes that evoke cellular events that are considered to be proinflammatory.
Generation of a Mouse Model of Von Hippel–Lindau Kidney Disease Leading to Renal Cancers by Expression of a Constitutively Active Mutant of <i>HIF1α</i>
Authors: Leiping Fu, Gang Wang, Maria M. Shevchuk, David M. Nanus, Lorraine J. Gudas
Journal: Cancer Research (2011)

Renal cancers are highly aggressive and clinically challenging, but a transgenic mouse model to promote pathologic studies and therapeutic advances has yet to be established. Here, we report the generation of a transgenic mouse model of von Hippel-Lindau (VHL) renal cancer termed the TRACK model (transgenic model of cancer of the kidney). TRACK mice specifically express a mutated, constitutively active HIF1α in kidney proximal tubule (PT) cells. Kidney histologies displayed by TRACK mice are highly similar to histologies seen in patients with VHL disease, including areas of distorted tubular structure, cells with clear cytoplasm and increased glycogen and lipid deposition, multiple renal cysts, and early onset of clear cell renal cell carcinoma (ccRCC). Distorted tubules in TRACK mice exhibit higher levels of CA-IX, Glut1, and VEGF than tubules in nontransgenic control mice. Furthermore, these tubules exhibit increased numbers of endothelial cells, increased cell proliferation, and increased expression of the human ccRCC marker CD70(TNFSF7). Moreover, PT cells in kidney tubules from TRACK mice exhibit increased genomic instability, as monitored by elevated levels of γH2AX. Our findings establish that activated HIF1α in murine kidney PT cells is sufficient to promote cell proliferation, angiogenesis, genomic instability, and other phenotypic alterations characteristic of human VHL kidney disease, establishing the TRACK mouse as a valid preclinical model of human renal cell carcinoma.
Growing old(er) with postinfectious bronchiolitis obliterans
Authors: Paul Cullinan, Andrew Bush
Journal: Thorax (2014)

Most healthy children shrug off viral respiratory tract infections with little difficulty or assistance and a full recovery is the norm. A small minority, in contrast, are left with serious consequences. Important among these is postinfectious bronchiolitis obliterans (pBO) characterised by persistent—and sometimes severe—airway obstruction with functional and radiological evidence of small airway involvement that is generally unresponsive to bronchodilator or steroid treatment. Diagnosis is usually confirmed by high resolution computed tomography scanning although the images can be confused with asthma1 and clinical context is everything. Lung biopsy is rarely needed, but if it is done, fibrosis and obliteration of the distal airways are the cardinal features. Treatment options are limited and proof of their effectiveness largely anecdotal; there are no relevant randomised controlled trials but asthma therapies, including bronchodilators, and long term azithromycin are often used. Supportive care should be offered, with oxygen as needed, avoidance of indoor and outdoor pollution, especially tobacco smoke, immunisations including pneumococcal and influenza, and good nutrition.

In most settings, pBO is undoubtedly rare but in the absence of systematic case registration its incidence is unmeasured. While cases have been reported in many different countries, there has been, for around 30 years, a striking preponderance from the southern ‘cone’ of South America (Chile, Argentina and southern Brazil) where the condition seems to have been more common than elsewhere. For example, 28% of 415 children admitted with an acute lower respiratory infection over a 17-year period to a hospital in Buenos Aires developed pBO (a further 15% died) over an unquantified period of observation. …
Simvastatin Improves Disturbed Endothelial Barrier Function
Authors: Geerten P. van Nieuw Amerongen, Mario A. Vermeer, Pascale Nègre-Aminou, Jan Lankelma, Jef J. Emeis, Victor W. M. van Hinsbergh
Journal: Circulation (2000)

Background —Recent clinical trials have established that inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce the risk of acute coronary events. These effects of statins cannot be fully explained by their lipid-lowering potential. Improved endothelial function may contribute to the positive effects of statin treatment. Methods and Results —In the present study, we report that simvastatin reduces endothelial barrier dysfunction, which is associated with the development of atherosclerosis. Treatment of human umbilical vein endothelial cells for 24 hours with 5 μmol/L simvastatin reduced the thrombin-induced endothelial barrier dysfunction in vitro by 55±3%, as assessed by the passage of peroxidase through human umbilical vein endothelial cell monolayers. Similar effects were found on the thrombin-induced passage of 125 I-LDL through human aortic endothelial cell monolayers. This reduction in barrier dysfunction by simvastatin was both dose and time dependent and was accompanied by a reduction in the thrombin-induced formation of stress fibers and focal adhesions and membrane association of RhoA. Simvastatin treatment had no effect on intracellular cAMP levels. In Watanabe heritable hyperlipidemic rabbits, treatment for 1 month with 15 mg/kg simvastatin reduced vascular leakage in both the thoracic and abdominal part of the aorta, as evidenced by the Evans blue dye exclusion test. The decreased permeability was not accompanied by a reduction of oil red O–stainable atherosclerotic lesions. Conclusions —These data show that simvastatin, in a relatively high concentration, improves disturbed endothelial barrier function both in vitro and in vivo. The data also support the beneficial effects of simvastatin in acute coronary events by mechanisms other than its lipid-lowering effect .
Metaplastic (hyperplastic) polyps of the large bowel: benign neoplasms after all?
Authors: G T Williams
Journal: Gut (1997)

Commentary __~~~~~~M etaplastic (hyperplastic) polyps of the large bowel: benign neoplasms after all?What are metaplastic, or as they are now more commonly called, hyperplastic, polyps of the large bowel?Commonest of all colorectal polyps, and frequently having a tantalising
Role of Stromal-Derived Factor-1α in the Induction of Circulating CD34+CXCR4+ Progenitor Cells After Cardiac Surgery
Authors: Shigetoshi Mieno, Basel Ramlawi, Munir Boodhwani, Richard T. Clements, Keisuke Minamimura, Takashi Maki, Shu-Hua Xu, Cesario Bianchi, Jian Li, Frank W. Sellke
Journal: Circulation (2006)

Background— Cardioplegia and cardiopulmonary bypass (CP/CPB) leads to an increase in circulating progenitor cells. The role of stromal-derived factor-1α (SDF-1α), a key regulator of progenitor cell mobilization, and other cytokines in this process is not clear. Methods and Results— Peripheral blood (n=24), atrial and skeletal tissue (n=6) samples were taken from patients undergoing CP/CPB before (pre-CP/CPB), 4 hours (post-CP/CPB), and 4 days (POD4) after CP/CPB. The number of circulating CD34+CXCR4+ cells increased post-CP/CPB (442±53 versus 286±27; P =0.04 versus pre-CP/CPB), but not at POD4 (382±50; P =0.28 versus pre-CP/CPB). Plasma levels of SDF-1α increased post-CP/CPB as compared with pre-CP/CPB (3325±325 versus 2911±165 pg/mL; P =0.046) but returned to baseline at POD4 (2838±224 pg/mL; P =0.90). Plasma levels of vascular endothelial growth factor were similar post-CP/CPB ( P =0.90 versus pre-CP/CPB) but increased at POD4 (220±40 pg/mL versus 134±26 pg/mL; P =0.04 versus pre-CP/CPB). Serum levels of granulocyte-colony stimulating factor (G-CSF) increased early after CP/CPB as compared with pre-CP/CPB (265.0±41.7 versus 11.1±1.1 pg/mL; P &lt;0.001) and returned to baseline at POD4 ( P =0.84 versus pre-CP/CPB). The circulating CD34+CXCR4+ cells were positively correlated with plasma levels of SDF-1α early after CP/CPB ( r =0.56, P &lt;0.01), but not at other times. Protein expression of SDF-1α was elevated in the atrial myocardium after CP/CPB (9.4-fold; P =0.03). Conclusions— Exposure to CP/CPB leads to an increase in circulating CD34+CXCR4+ progenitor cells, which is associated with increased myocardial SDF-1α expression. The numbers of CD34+CXCR4+ progenitor cells positively correlate with the plasma levels of SDF-1α post-CP/CPB, suggesting an important role of SDF-1α in progenitor cell mobilization.
Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)
Authors: Hervé Avet-Loiseau, Xavier Leleu, Murielle Roussel, Philippe Moreau, Catherine Guerin-Charbonnel, Denis Caillot, Gérald Marit, Lotfi Benboubker, Laurent Voillat, Claire Mathiot, Brigitte Kolb, Margaret Macro, Loïc Campion, Marc Wetterwald, Anne-Marie Stoppa, Cyrille Hulin, Thierry Facon, Michel Attal, Stéphane Minvielle, Jean-Luc Harousseau
Journal: Journal of Clinical Oncology (2010)

Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters.A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p).We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients.Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.
Surgery for disc disease
Authors: J N Alastair Gibson
Journal: BMJ (2007)

<h3>Background:</h3> Chronic abdominal pain (CAP) is common among schoolchildren, but risk factors for its onset are still largely unknown. <h3>Aims:</h3> To determine the frequency of onset of CAP in schoolchildren and investigate risk factors for its development. <h3>Methods:</h3> 1411 schoolchildren aged 11–14 years were recruited from schools in North West England. Information was collected on recent pain symptoms and potential risk factors for developing CAP. Participants were followed up 1 and 4 years later and new episodes of CAP were identified. <h3>Results:</h3> 22% reported new-onset abdominal pain at 1-year follow-up which persisted at 4-year follow-up (CAP). CAP was almost three times higher in girls than boys (34% vs 13%; χ<sup>2</sup>: 26.0; p&lt;0.001). In girls, reporting headache at baseline was the only predictive factor for CAP onset: those reporting headaches experienced a doubling in the risk of symptom onset (relative risk: 2.1; 95% confidence interval: 0.95 to 4.7). In contrast, in boys, development of CAP was independently predicted by daytime tiredness (3.0; 1.2 to 7.6), lack of school enjoyment (2.0; 0.95 to 4.2), adverse psychosocial exposures (2.3; 1.2 to 4.5) and taller stature (1.9; 0.8 to 4.5). <h3>Conclusion:</h3> Our results suggest that over 20% of adolescent schoolchildren experience new-onset non-self-limiting abdominal pain over a 1-year period. Future abdominal pain is predicted by previous somatic symptom reporting in girls and both somatic symptom reporting and psychosocial factors in boys. These risk factors indicate a possible mechanism for understanding the development of CAP, and might have important implications for both primary and secondary preventive strategies.