tbuckley/cabot-search huggingface dataset:
A Novel Approach to Detecting and Measuring Recombination: New Insights into Evolution in Viruses, Bacteria, and Mitochondria
Authors: Michael Worobey
Journal: Molecular Biology and Evolution (2001)

An accurate estimate of the extent of recombination is important whenever phylogenetic methods are applied to potentially recombining nucleotide sequences. Here, data sets from viruses, bacteria, and mitochondria were examined for deviations from clonality using a new approach for detecting and measuring recombination. The apparent rate heterogeneity (ARH) among sites in a sequence alignment can be inflated as an artifact of recombination. However, the composition of polymorphic sites will differ in a data set with recombination-generated ARH versus a clonal data set that exhibits the equivalent degree of rate heterogeneity. This is because recombinant data sets, encompassing regions of conflicting phylogenetic history, tend to yield "starlike" trees that are superficially similar to those inferred from clonal data sets with weak phylogenetic signal throughout. Specifically, a recombinant data set will be unexpectedly rich in conflicting phylogenetic information compared with clonally generated data sets supporting the same tree shape. Its value of q—defined as the proportion of two-state parsimony-informative sites to all polymorphic sites—will be greater than that expected for nonrecombinant data. The method proposed here, the informative-sites test, compares the value of q against a null distribution of values found using Monte Carlo–simulated data evolved under the null hypothesis of clonality. A significant excess of q indicates that the assumption of clonality is not valid and hence that the ARH in the data is at least partly an artifact of recombination. Investigations of the procedure using simulated sequences indicated that it can successfully detect and measure recombination and that it is unlikely to produce "false positives." Simulations also showed that for recombinant data, naïve use of maximum-likelihood models incorporating rate heterogeneity can lead to overestimation of the time to the most recent common ancestor. Application of the test to real data revealed for the first time that populations of viruses, like those of bacteria, can be brought close to complete linkage equilibrium by pervasive recombination. On the other hand, the test did not reject the hypothesis of clonality when applied to a data set from the coding region of human mitochondrial DNA, despite its high level of ARH and homoplasy.
Neurobiology of the structure of personality: Dopamine, facilitation of incentive motivation, and extraversion
Authors: Richard A. Depue, Paul F. Collins
Journal: Behavioral and Brain Sciences (1999)

Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, “experience-expectant,” and “experience-dependent.” Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive context and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.
Studies of hematopoietic stem cells spared by 5-fluorouracil.
Authors: G Van Zant
Journal: The Journal of Experimental Medicine (1984)

Mouse marrow cells were exposed to 5-fluorouracil (FU) either in vivo or in vitro and the effects on the hematopoietic stem cell compartment were studied. The drug was highly toxic to bone marrow cells including the spleen colony-forming unit (CFU-S) population. The small population of stem cells surviving FU, however, caused a different pattern of spleen colony growth when injected into lethally irradiated mice. Whereas numbers of spleen colonies caused by normal marrow cells remained constant during an 8-14 d period after transplantation, spleen colonies derived from FU-treated marrow cells increased by as much as 100-fold during this time. This effect on stem cells was dose dependent both in vitro and in vivo. When FU was given in vivo, the day 14/day 8 ratio of colonies was greatest 1 d after injection and, over the next 7 d, returned to a near-normal value, that is, unity. A number of studies have shown that the stem cell compartment is heterogeneous with respect to self-replicative capacity and developmental potential. An age structure for the stem cell compartment has been proposed wherein cells with a short mitotic history are more likely to self-replicate than they are to differentiate; hence they are more primitive. 'Older' stem cells with a longer mitotic history are, according to the hypothesis, more likely to differentiate. 5-fluorouracil may be toxic to the older stem cells and selectively spare the more primitive subpopulation. Although the surviving cells may not themselves be able to form spleen colonies, they may give rise to an older cohort of cells more likely to differentiate and form spleen colonies. It is the requisite developmental maturation within the stem cell compartment that may be responsible for the delay in appearance of spleen colonies derived from FU-treated marrow. Our results support this explanation and identify the locus of at least part of this activity as the bone marrow. We found that the FU-treated marrow did not cause an increase in spleen colony numbers between 8 and 14 d in hosts with a long-standing marrow aplasia, due to the incorporation of 89Sr into bone. I propose that the delayed spleen colony appearance in normal hosts is the result of developmental maturation of the primitive stem cell compartment that survives FU and is responsible for spleen colonies arising around day 14. This maturation, at least initially, occurs in the marrow and leads to the replenishment of the more differentiated CFU-S subsets ablated by FU, which are normally responsible for spleen colonies appearing earlier after transplantation.
Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: A multicenter survey on safety and efficacy
Authors: Wim Laleman, Macarena Simon-Talero, Geert Maleux, Mercedes Perez, Koen Ameloot, German Soriano, Jordi Villalba, Juan-Carlos Garcia-Pagan, Marta Barrufet, Rajiv Jalan, Jocelyn Brookes, Evangelos Thalassinos, Andrew K. Burroughs, Juan Cordoba, Frederik Nevens
Journal: Hepatology (2013)

Abstract Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy-refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6-C13, MELD [Model of Endstage Liver Disease] 5-28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short-term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE ( P &lt; 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE-free over a mean follow-up period of 697 ± 157 days ( P &lt; 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three-quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure-related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites. Conclusion : This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve.
Effect of autoimmune diseases on risk and survival in histology-specific lung cancer
Authors: Kari Hemminki, Xiangdong Liu, Jianguang Ji, Jan Sundquist, Kristina Sundquist
Journal: European Respiratory Journal (2012)

Patients with autoimmune diseases are at an increased risk of cancer due to underlying dysregulation of the immune system or treatment. Data on cancer incidence, mortality and survival after autoimmune diseases would provide further information on the clinical implications. We systematically analysed data on lung cancer in patients diagnosed with 33 different autoimmune diseases. Standardised incidence ratios (SIRs), standardised mortality ratios (SMRs) and hazard ratios (HRs) were calculated for subsequent incident lung cancers or lung cancer deaths up to 2008 in patients hospitalised for autoimmune disease after 1964. Increased risks of lung cancer were recorded for SIRs after 12 autoimmune diseases, SMRs after 11 autoimmune diseases and HRs after two autoimmune diseases. The highest SIRs and SMRs, respectively, were seen after discoid lupus erythematosus (4.71 and 4.80), polymyosistis/dermatomyositis (4.20 and 4.17), systemic lupus erythematosus (2.47 and 2.69), rheumatic fever (2.07 and 2.07) and systemic sclerosis (2.19 and 1.98). Autoimmune disease did not influence survival overall but some autoimmune diseases appeared to impair survival in small cell carcinoma. All autoimmune diseases that had an SIR &gt;2.0 are known to present with lung manifestations, suggesting that the autoimmune process contributes to lung cancer susceptibility. The data on survival are reassuring that autoimmune diseases do not influence prognosis in lung cancer.
Vitamin D Gene Pathway Polymorphisms and Risk of Colorectal, Breast, and Prostate Cancer
Authors: Marjorie L. McCullough, Roberd M. Bostick, Tinisha L. Mayo
Journal: Annual Review of Nutrition (2009)

Higher vitamin D exposure is hypothesized to prevent several cancers, possibly through genomic effects modulated by the vitamin D receptor (VDR), and autocrine/paracrine metabolism of the VDR's ligand, 1α,25-(OH) 2 -vitamin D. Herein we review the background and evidence to date on associations between polymorphisms in VDR and selected genes in the vitamin D pathway in relation to colorectal, breast, and prostate cancer. Although most studies to date have examined only a few VDR polymorphisms, more are beginning to comprehensively investigate polymorphisms in the VDR as well as in other vitamin D pathway genes, such as the vitamin D–binding protein gene (Gc) and CYP27B1 and CYP24A1, which code for enzymes that, respectively, synthesize and degrade 1α,25-(OH) 2 -vitamin D. Currently, there is no strong, consistent epidemiologic evidence for substantial influences of single variants in vitamin D pathway genes on risk for colorectal, breast, or prostate cancer, but promising leads are developing.
A Polyepitope DNA Vaccine Targeted to Her-2/ErbB-2 Elicits a Broad Range of Human and Murine CTL Effectors to Protect against Tumor Challenge
Authors: Antonio Scardino, Maurizio Alimandi, Pierpaolo Correale, Steven G. Smith, Roberto Bei, Hüseyin Firat, Maria Grazia Cusi, Olivier Faure, Stephanie Graf-Dubois, Giulia Cencioni, Jordan Marrocco, Salem Chouaib, François A. Lemonnier, Andrew Michael Jackson, Kostas Kosmatopoulos
Journal: Cancer Research (2007)

Abstract A cDNA vaccine (pVax1/pet-neu) was designed to encode 12 different Her-2/ErbB-2–derived, HLA-A*0201–restricted dominant and high-affinity heteroclitic cryptic epitopes. Vaccination with pVax1/pet-neu triggered multiple and ErbB-2–specific CTL responses in HLA-A*0201 transgenic HHD mice and in HLA-A*0201 healthy donors in vitro. Human and murine CTL specific for each one of the 12 ErbB-2 peptides recognized in vitro both human and murine tumor cells overexpressing endogenous ErbB-2. Furthermore, vaccination of HHD mice with pVax1/pet-neu significantly delayed the in vivo growth of challenged ErbB-2–expressing tumor (EL4/HHD/neu murine thymoma) more actively when compared with vaccination with the empty vector (pVax1) or vehicle alone. These data indicate that the pVax1/pet-neu cDNA vaccine coding for a poly-ErbB-2 epitope is able to generate simultaneous ErbB-2–specific antitumor responses against dominant and cryptic multiple epitopes. [Cancer Res 2007;67(14):7028–36]
Chlorhexidine Bathing and Health Care–Associated Infections
Authors: Michael J. Noto, Henry J. Domenico, Daniel W. Byrne, Tom Talbot, Todd W. Rice, Gordon R. Bernard, Arthur P. Wheeler
Journal: JAMA (2015)

Daily bathing of critically ill patients with the broad-spectrum, topical antimicrobial agent chlorhexidine is widely performed and may reduce health care-associated infections.To determine if daily bathing of critically ill patients with chlorhexidine decreases the incidence of health care-associated infections.A pragmatic cluster randomized, crossover study of 9340 patients admitted to 5 adult intensive care units of a tertiary medical center in Nashville, Tennessee, from July 2012 through July 2013.Units performed once-daily bathing of all patients with disposable cloths impregnated with 2% chlorhexidine or nonantimicrobial cloths as a control. Bathing treatments were performed for a 10-week period followed by a 2-week washout period during which patients were bathed with nonantimicrobial disposable cloths, before crossover to the alternate bathing treatment for 10 weeks. Each unit crossed over between bathing assignments 3 times during the study.The primary prespecified outcome was a composite of central line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), ventilator-associated pneumonia (VAP), and Clostridium difficile infections. Secondary outcomes included rates of clinical cultures that tested positive for multidrug-resistant organisms, blood culture contamination, health care-associated bloodstream infections, and rates of the primary outcome by ICU.During the chlorhexidine bathing period, 55 infections occurred: 4 CLABSI, 21 CAUTI, 17 VAP, and 13 C difficile. During the control bathing period, 60 infections occurred: 4 CLABSI, 32 CAUTI, 8 VAP, and 16 C difficile. The primary outcome rate was 2.86 per 1000 patient-days during the chlorhexidine and 2.90 per 1000 patient-days during the control bathing periods (rate difference, -0.04; 95% CI, -1.10 to 1.01; P = .95). After adjusting for baseline variables, no difference between groups in the rate of the primary outcome was detected. Chlorhexidine bathing did not change rates of infection-related secondary outcomes including hospital-acquired bloodstream infections, blood culture contamination, or clinical cultures yielding multidrug-resistant organisms. In a prespecified subgroup analysis, no difference in the primary outcome was detected in any individual intensive care unit.In this pragmatic trial, daily bathing with chlorhexidine did not reduce the incidence of health care-associated infections including CLABSIs, CAUTIs, VAP, or C difficile. These findings do not support daily bathing of critically ill patients with chlorhexidine.clinicaltrials.gov Identifier: NCT02033187.
Therapeutic regimens in interstitial lung disease guided by genetic screening: fact or fiction?
Authors: J. A. Bakker, J. Bierau, M. Drent
Journal: European Respiratory Journal (2007)

Drug-induced pulmonary toxicity is a serious and expanding problem 1, 2. Since the mid 1980s, the understanding of the metabolism of pharmaceuticals has increased substantially. Not least because of the introduction of molecular biological techniques, defects in drug-metabolising pathways have been elucidated. Nowadays, pharmacogenetics can guide the clinician in the choice of the best therapeutic regimen, resulting in “personalised medicine” 3.

A decreased drug efficacy and unexpected and serious adverse drug reactions (ADR) are major threats to patients and occur more frequently than expected. Considerable efforts are needed to treat these ADR 4. Therefore, prevention of ADR is of utmost importance for the patient and the clinician. ADR can be due to inherited defects in drug activation, which mostly lead to decreased efficacy of the treatment, or to defects in drug-metabolising enzymes; the …
Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome
Authors: Fadi J Charchar, Lisa DS Bloomer, Timothy A Barnes, Mark J Cowley, Christopher P Nelson, Yanzhong Wang, Matthew Denniff, Radoslaw Debiec, Paraskevi Christofidou, Scott Nankervis, Anna F Dominiczak, Ahmed Bani-Mustafa, Anthony J Balmforth, Alistair S Hall, Jeanette Erdmann, Francois Cambien, Panos Deloukas, Christian Hengstenberg, Chris Packard, Heribert Schunkert, Willem H Ouwehand, Ian Ford, Alison H Goodall, Mark A Jobling, Nilesh J Samani, Maciej Tomaszewski
Journal: The Lancet (2012)
Prevalence of sleep-disordered breathing related symptoms and results from an objective vigilance test in patients with chronic heart failure
Authors: Tanja Geib, Andrea Hetzenecker, Nina Plappert, Wibke Reinhard, Günter Riegger, Michael Pfeifer, Michael Arzt
Journal: European Respiratory Journal (2013)

Background: The Epworth Sleepiness Scale (ESS) has been shown to be unreliable in predicting sleep-disordered breathing (SDB) in patients with chronic heart failure (CHF).  Objectives: to assess the prevalence of diverse SDB-related symptoms and objective vigilance in CHF patients according to SDB severity.  Methods: 222 consecutive CHF patients (age 62±10 y, LVEF 34%) underwent polysomnography (1/2002-10/2011. Patients were stratified in those with no (apnoea-hypopnoea index, AHI  Results: While in the groups with no, moderate and severe SDB the ESS scores were similar and in the normal range (6.9±4, 7.4±4 and 8.0±5, p=0.452, respectively), several symptoms were more often reported in CHF patients with more severe SDB: e.g. daytime fatigue (no, moderate and severe SDB: 53, 69 and 80%, p=0.005), unintentional sleep (9, 5 and 32%, p=0.004), nocturia (66, 89 and 85%, p=0.011), nocturnal dyspnea (11, 13 and 25%, 0.071) as well as xerostomia (52, 49 and 70%, p=0.018). In addition, CHF patients with increasing degree of SDB had significantly less right responses in the vigilance test (99±1, 95±7 and 87±20, p=0.027).  Conclusions: Considering the full spectrum of SDB-related symptoms and objective vigilance testing, most CHF patients with moderate or severe SDB have at least one related symptom or functional impairment as a potential treatment target.
Triage of Patients with Acute Chest Pain and Possible Cardiac Ischemia: The Elusive Search for Diagnostic Perfection
Authors: Lee Goldman, Ajay J. Kirtane
Journal: Annals of Internal Medicine (2003)

Few diagnostic decisions in medicine have been more heavily researched than the approach to the patient with acute chest pain. Despite the advances in both diagnosing and treating patients presenting with this symptom, cases of missed myocardial infarctions still cause substantial morbidity and mortality. This article examines a case in which a patient was sent home from the emergency department after presenting with chest pain and was subsequently found to have a myocardial infarction. In the context of the case, the article discusses clinical decision making about the diagnosis and triage of patients presenting with acute chest pain or with symptoms consistent with possible cardiac ischemia. A standardized approach to addressing the management of these patients is essential, given the adverse consequences of missing a life-threatening condition. For a list of questions and answers from the Quality Grand Rounds conference, see the Appendix.
Complication Rates of Tension-Free Midurethral Slings in the Treatment of Female Stress Urinary Incontinence: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Comparing Tension-Free Midurethral Tapes to Other Surgical Procedures and Different Devices
Authors: Giacomo Novara, Antonio Galfano, Rafael Boscolo-Berto, Silvia Secco, Stefano Cavalleri, Vincenzo Ficarra, Walter Artibani
Journal: European Urology (2007)
Methylation of the <i>DPYD</i> Promoter: An Alternative Mechanism for Dihydropyrimidine Dehydrogenase Deficiency in Cancer Patients
Authors: Hany H. Ezzeldin, Adam M. Lee, Lori K. Mattison, Robert B. Diasio
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency, a known pharmacogenetic syndrome associated with 5-fluorouracil (5-FU) toxicity, has been detected in 3% to 5% of the population. Genotypic studies have identified &amp;gt;32 sequence variants in the DPYD gene; however, in a number of cases, sequence variants could not explain the molecular basis of DPD deficiency. Recent studies in cell lines indicate that hypermethylation of the DPYD promoter might down-egulate DPD expression. The current study investigates the role of methylation in cancer patients with an unexplained molecular basis of DPD deficiency. Experimental Design: DPD deficiency was identified phenotypically by both enzyme assay and uracil breath test, and genotypically by denaturing high-performance liquid chromatography. The methylation status was evaluated in PCR products (209 bp) of bisulfite-modified DPYD promoter, using a novel denaturing high-performance liquid chromatography method that distinguishes between methylated and unmethylated alleles. Clinical samples included five volunteers with normal DPD enzyme activity, five DPD-deficient volunteers, and five DPD-deficient cancer patients with a history of 5-FU toxicity. Results: No evidence of methylation was detected in samples from volunteers with normal DPD. Methylation was detected in five of five DPD-deficient volunteers and in three of five of the DPD-deficient cancer patient samples. Of note, one of the two samples from patients with DPD-deficient cancer with no evidence of methylation had the mutation DPYD*2A, whereas the other had DPYD*13. Discussion: Methylation of the DPYD promoter region is associated with down-regulation of DPD activity in clinical samples and should be considered as a potentially important regulatory mechanism of DPD activity and basis for 5-FU toxicity in cancer patients.