tbuckley/cabot-search huggingface dataset:
Patterns of Bacterial Gene Movement
Authors: W. Hao
Journal: Molecular Biology and Evolution (2004)

Lateral gene transfer has emerged as an important force in bacterial evolution. A substantial number of genes can be inserted into or deleted from genomes through the process of lateral transfer. In this study, we looked for atypical occurrence of genes among related organisms to detect laterally transferred genes. We have analyzed 50 bacterial complete genomes from nine groups. For each group we use a 16s rRNA phylogeny and a comparison of protein similarity to map gene insertions/deletions onto their species phylogeny. The results reveal that there is poor correlation of genes inserted, deleted, and duplicated with evolutionary branch length. In addition, the numbers of genes inserted, deleted, or duplicated within the same branch are not always correlated with each other. Nor is there any similarity within groups. For example, in the Rhizobiales group, the ratio of insertions to deletions in the evolutionary branch leading to Agrobacterium tumefaciens str. C58 (Cereon) is 0.52, but it is 39.52 for Mesorhizobium loti. Most strikingly, the number of insertions of foreign genes is much larger in the external branches of the trees. These insertions also greatly outnumber the occurrence of deletions, and yet the genome sizes of these bacteria remain roughly constant. This indicates that many of the insertions are specific to each organism and are lost before related species can evolve. Simulations of the process of insertion and deletion, tailored to each phylogeny, support this conclusion.
PTU-104 Outcomes Of Increased Dose Of Allopurinol In Ibd Patients Who Developed Hepatotoxicity On Low Azathioprine And Allopurinol Co-therapy Treatment
Authors: M Pericleous, A Abdulrehman, C Bull, G Mackenzie, J Stenner, M Cowan, G Hillman, A Ansari
Journal: Gut (2014)

<h3>Introduction</h3> The thiopurines (azathioprine (AZA) and metcaptopurine (6MP)) are established first line therapies for inflammatory bowel disease (IBD). However, when these agents are used at their target dose side effects are common, gastrointestinal intolerance (10–20%) and hepatotoxicity (&gt;10%).<sup>1</sup> These side effects can often be bypassed by using low dose AZA and allopurinol (ALLO) co-therapy (LDAA). The current opinion is that hepatotoxicity is secondary to high red cell methylated metabolites (MMPR/MMP). However, many patients develop hepatotoxicity without high MMP levels<sup>.2</sup> We report a series of patients who regardless of low MMP developed hepatotoxicity whilst on allopurinol co-therapy, 3 of which were TPMT heterozygotes. <h3>Aim</h3> to determine outcomes of increasing the dose of Allopurinol from 100 to 200 mg in patients with hepatotoxicity to LDAA. <h3>Methods</h3> Patient records and our IBD database were searched for patients on LDAA who developed hepatotoxicity whilst on LDAA (100 mg of ALLO). Liver function tests (LFTs), liver screen, ultrasound results and clinical outcomes were determined. <h3>Results</h3> From the 2500 patients with IBD locally, 600 were exposed to thiopurines and 300 were on LDAA. Nine patients had sustained hepatotoxicity, 3 were TPMT heterozygotes. Seven of these patients responded fully to increased dose of ALLO to 200mg. Two had a suboptimal response (1 had PSC as a potential cause). All patients had asymptomatic abnormalities of LFTS, negative chronic liver screen apart from 2 who had ultrasound proven fatty liver disease without abnormal LFTs prior to LDAA. We observed that all patients had improvements in their LFTs, whilst 7 had complete correction of abnormal AST, ALP and bilirubin. Median time for treatment was 24 months (range 12–48 months), with full response to therapy in all 7 patients. <h3>Conclusion</h3> This is the first series which reports improvement of LFTs by increasing ALLO dose for patients on LDAA. This subgroup of patients were unlikely to have high MMPR as 3 of them were TPMT heterozygotes and all were on LDAA therapy, therefore a different mechanism, of hepatotoxicity is proposed (Figure 1). It is possible that reactive oxygen species generated from the oxidation of metcaptopurine are responsible, and this can be further improved by adjusting the dose of ALLO. Further studies are required. <h3>References</h3> Bastida G, Nos P, Aguas M, <i>et al</i>. Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease. <i>Aliment Pharmacol Ther</i> 2005;22:775–82 Shaye OA, Yadegari M, Abreu MT, <i>et al. </i>Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients.<i> Am J Gastroenterol</i> 2007;102:2488–94 <h3>Disclosure of Interest</h3> None Declared.
Central flow tilting disc valve for aortic valve replacement
Authors: V. O. Bjork
Journal: Thorax (1970)

A new central flow tilting disc valve has been introduced. The clinical experience from the first 50 patients treated with aortic valve replacement and followed up for 12 months is reported. The results obtained are so encouraging that the tilting disc valve is at present preferred for all aortic valve replacements in this institution.
X-linked Disorder Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (ipex) In Brazilian Twins Brothers - A Report
Authors: J. Tanno, A.M. Castro, V. Oliveira, A.C. Pastorino, A. Fomin, J. Oliveira, M. Carneiro Sampaio, T. Dela Mana, V.H. Koch, C.M. Jacob
Journal: Journal of Allergy and Clinical Immunology (2009)
Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus
Authors: None AMAGAI, None KOMAI, None HASHIMOTO, None SHIRAKATA, None HASHIMOTO, None YAMADA, None KITAJIMA, None OHYA, None IWANAMI, None NISHIKAWA
Journal: British Journal of Dermatology (1999)

Pemphigus is an autoimmune blistering disease with two major subtypes, pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Patients with pemphigus have circulating antidesmoglein (Dsg)1 and/or anti-Dsg3 IgG autoantibodies. We have previously developed enzyme-linked immunosorbent assays (ELISAs) using recombinant Dsg1 and Dsg3 expressed by baculovirus as a diagnostic tool for pemphigus. The purpose of this study was to evaluate the practical application of these ELISAs for clinical use with a large number of serum samples. We used 81 PV sera, 48 PF sera, 114 bullous pemphigoid (BP) sera, 124 collagen disease sera, nine sera of other non-pemphigus bullous diseases and 179 normal control sera. A cut-off value was determined by receiver-operating-characteristic plots. Forty-seven of 48 PF sera (97.9%) were positive in the Dsg1 ELISA and 79 of 81 PV sera (97.5%) were positive in the Dsg3 ELISA, while only two (1.1%) and four (2.2%) of 179 normal sera were positive in Dsg1 and Dsg3 ELISAs, respectively. However, some disease control sera of BP and collagen diseases exceeded the cut-off value. Introduction of a grey zone helped to decrease the number of these false-positive sera. Furthermore, in three patients studied, the respective Dsg1 and Dsg3 ELISA scores showed parallel fluctuation with the disease activity along the time course. We conclude that Dsg1 and Dsg3 ELISAs provide a simple, sensitive and highly specific assay for the diagnosis of patients with PV and PF and that these ELISAs may be a valuable tool to monitor the disease activity. We also propose diagnostic criteria for pemphigus based on ELISA reactivity: if a serum is positive against Dsg3 it indicates a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, it indicates a diagnosis of PF.
Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Nian Liu, Barbara Colombi, Mirella Memmi, Spyros Zissimopoulos, Nicoletta Rizzi, Sara Negri, Marcello Imbriani, Carlo Napolitano, F. Anthony Lai, Silvia G. Priori
Journal: Circulation Research (2006)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2 R4496C+/− ). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (n=20) in WT but induced DADs in 21 of 33 (63%) RyR2 R4496C+/− myocytes ( P =0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2 R4496C+/− myocytes ( P =0.001). DADs and triggered activity were abolished by ryanodine (10 μmol/L) but not by K201 (1 μmol/L or 10 μmol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2 R4496C+/− mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2–FKBP12.6 interaction both in WT and RyR2 R4496C+/− either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2 R4496C+/− myocytes and ventricular arrhythmias in RyR2 R4496C+/− mice; and (3) RyR2–FKBP12.6 interaction in RyR2 R4496C+/− is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex.
Corticosteroid therapy increases membrane‐tethered while decreases secreted mucin expression in nasal polyps
Authors: A. Martínez‐Antón, C. De Bolós, I. Alobid, P. Benítez, J. Roca‐Ferrer, C. Picado, J. Mullol
Journal: Allergy (2008)

Mucus hypersecretion is a hallmark of nasal polyposis (NP). Corticosteroids (CS) are first-line treatment for NP, decreasing their size and inflammatory component. However, their effect on mucin production is not well-understood. The aim of this (pilot) study was to investigate CS effect on mucin expression in NP.Patients were randomized in control (n = 9) and treatment (oral prednisone for 2 weeks and intranasal budesonide for 12 weeks; n = 23) groups. Nasal polyposis from nonasthmatic (NP; n = 13), aspirin-tolerant (NP-ATA; n = 11) and aspirin-intolerant (NP-AIA; n = 8) asthmatics were studied. Nasal polyposis biopsies were obtained before (w0) and after 2 (w2) and 12 (w12) weeks of CS treatment. Secreted (MUC5AC, MUC5B and MUC8) and membrane-tethered (MUC1, MUC4) mucins (immunohistochemistry) and goblet cells (Alcian blue-periodic acid Schiff) were quantified in both epithelium and glands. Rhinorrea and nasal obstruction were also assessed.At w2, steroids increased MUC1 (from 70 to 97.5) and MUC4 (from 80 to 100) in NP-ATA patients' epithelium compared with baseline (w0). At w12, steroids decreased MUC5AC (from 40 to 5) and MUC5B (from 45 to 2.5) in NP-ATA patients' epithelium and glands, respectively, compared with baseline. No mucin presented significant changes in NP-AIA patients. MUC5AC and MUC5B expression correlated with goblet and mucous cell numbers, respectively, and MUC5AC also with rhinorrea score.These results suggest: (i) CS up-regulate membrane (MUC1, MUC4) while down-regulate secreted (MUC5AC, MUC5B) mucins; (ii) there exists a link between secreted mucin expression and goblet cell hyperplasia; and (iii) NP from AIA may develop resistance to CS treatment.
PAML 4: Phylogenetic Analysis by Maximum Likelihood
Authors: Z. Yang
Journal: Molecular Biology and Evolution (2007)

PAML, currently in version 4, is a package of programs for phylogenetic analyses of DNA and protein sequences using maximum likelihood (ML). The programs may be used to compare and test phylogenetic trees, but their main strengths lie in the rich repertoire of evolutionary models implemented, which can be used to estimate parameters in models of sequence evolution and to test interesting biological hypotheses. Uses of the programs include estimation of synonymous and nonsynonymous rates (dN and dS) between two protein-coding DNA sequences, inference of positive Darwinian selection through phylogenetic comparison of protein-coding genes, reconstruction of ancestral genes and proteins for molecular restoration studies of extinct life forms, combined analysis of heterogeneous data sets from multiple gene loci, and estimation of species divergence times incorporating uncertainties in fossil calibrations. This note discusses some of the major applications of the package, which includes example data sets to demonstrate their use. The package is written in ANSI C, and runs under Windows, Mac OSX, and UNIX systems. It is available at http://abacus.gene.ucl.ac.uk/software/paml.html.
Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population
Authors: Barbara A. Piasecki, James D. Lewis, Rajender K. Reddy, Scarlett L. Bellamy, Steven B. Porter, Robert M. Weinrieb, Donald D. Stieritz, Kyong-Mi Chang
Journal: Hepatology (2004)

Hepatitis C virus (HCV) is spontaneously cleared in 15% to 45% of individuals during primary infection. To define the role of alcohol, race, and HBV or HIV coinfections in natural HCV clearance, we examined these parameters in 203 spontaneously HCV-recovered subjects (HCV Ab +/RNA - subjects without prior antiviral therapy) and 293 chronically HCV-infected patients (HCV Ab +/RNA +). Subjects were identified from 1,454 HCV antibody-seropositive US veterans tested for HCV RNA between January 2000 and July 2002 at the Philadelphia Veterans Affairs Medical Center. In univariate analysis, alcohol use disorder (odds ratio [OR] 0.52; 95% CI, 0.31-0.85; P = .006) and black race (OR 0.65; 95% CI, 0.44-0.96; P = .024) were both associated with decreased likelihood of spontaneous HCV clearance. In multivariate analyses adjusting for race, HIV infection, age, and alcohol use disorder, alcohol remained strongly associated with reduced HCV clearance (OR 0.49; 95% CI, 0.30-0.81; P = 0.005). In contrast, the association between black race and viral clearance was no longer statistically significant (adjusted OR 0.72; 95% CI, 0.48-1.09; P = .125). HIV coinfection was negatively associated with HCV clearance (OR 0.37; 95% CI, 0.16-0.83; P = .016), while HBV coinfection was positively associated with HCV clearance (unadjusted OR 5.0; 95% CI, 1.26-28.6; P = .008). In conclusion, the likelihood of spontaneous clearance of HCV may be influenced by alcohol and viral coinfections. (Hepatology 2004;40:892-899).
An aneurysm is born
Authors: K. Niijima
Journal: Journal of the Royal Society of Medicine (2003)

is often quoted. The clinical diagnosis of botulism is confirmed by injection of the patient’s serum into a laboratory animal, which then shows signs of neurotoxicity. Seven serotypes of the toxin are known, but only types A, B and E have been consistently responsible for botulism in man and trivalent antitoxin directed at these is the treatment of choice. Prompt treatment is crucial since, once the toxin has blocked neurotransmission at a synapse, antitoxin will have no effect on that synapse. Even a suspicion of botulism demands treatment with antitoxin, without waiting for a laboratory test. Recovery from the neurotoxic injury depends on the regeneration of neuromuscular junctions, which may take many months and is often incomplete. The implementation of ventilatory support has reduced the mortality from 60‐70% in the early twentieth century to around 20% more recently. 5 Even with the diagnosis of botulism, our patient’s progression within 45 minutes from an alert ambulatory state to respiratory arrest is hard to explain. We suspect that his earlier symptoms of weakness and somnolence reflected increasing compromise of his tidal exchange, culminating in the hypoxia/hypercardia that precipitated the arrest. Previously unseen and unpredicted routes of infection with botulinal toxin have emerged. Intravenous and nasal routes from recreational drugs ‘cut’ with contaminated soil particles and ‘inadvertent’ botulism in patients being treated with botulinal toxin for dystonias and cosmetic procedures 8 have been reported. The possibility of the use of C. botulinum and its toxin as a weapon for bio-terrorism is considered both ‘real and frightening’.2,9
Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis
Authors: Shaolin Shi, Liping Yu, Celine Chiu, Yezhou Sun, Jin Chen, Greg Khitrov, Matthias Merkenschlager, Lawrence B. Holzman, Weijia Zhang, Peter Mundel, Erwin P. Bottinger
Journal: Journal of the American Society of Nephrology (2008)

Dicer is an enzyme that generates microRNA (miRNA), which are small, noncoding RNA that function as important regulators of gene and protein expression. For exploration of the functional roles of miRNA in glomerular biology, Dicer was inactivated selectively in mouse podocytes. Mutant mice developed proteinuria 4 to 5 weeks after birth and died several weeks later, presumably from kidney failure. Multiple abnormalities were observed in glomeruli of mutant mice, including foot process effacement, irregular and split areas of the glomerular basement membrane, podocyte apoptosis and depletion, mesangial expansion, capillary dilation, and glomerulosclerosis. Gene profiling revealed upregulation of 190 genes in glomeruli isolated from mutant mice at the onset of proteinuria compared with control littermates. Target sequences for 16 miRNA were significantly enriched in the 3′-untranslated regions of the 190 upregulated genes. Further suggesting validity of the <i>in silico</i> analysis, six of the eight top-candidate miRNA were identified in miRNA libraries generated from podocyte cultures; these included four members of the mir-30 miRNA family, which are known to degrade target transcripts directly. Among 15 upregulated target genes of the mir-30 miRNA, four genes known to be expressed and/or functional in podocytes were identified, including receptor for advanced glycation end product, vimentin, heat-shock protein 20, and immediate early response 3. Receptor for advanced glycation end product and immediate early response 3 are known to mediate podocyte apoptosis, whereas vimentin and heat-shock protein-20 are involved in cytoskeletal structure. Taken together, these results provide a knowledge base for ongoing investigations to validate functional roles for the mir-30 miRNA family in podocyte homeostasis and podocytopathies.
Relationship between changes in left ventricular bipolar electrograms and regional myocardial blood flow during acute coronary artery occlusion in the dog.
Authors: R Ruffy, D E Lovelace, T M Mueller, S B Knoebel, D P Zipes
Journal: Circulation Research (1979)

The purpose of this study was to determine whether a quantitative relationship existed between a reduction in regional myocardial blood flow, measured by radiolabeled microspheres, and the degree and type of changes in myocardial activation recorded in bipolar left ventricular subepicardial and subendocardial electrograms, in open-chest dogs following acute coronary artery occlusion. We found that the degree of regional myocardial ischemia was related quantitatively to the reduction in amplitude recorded with bipolar electrograms in the subepicardium and subendocardium, and to the increase in duration of subepicardial electrograms. Other characteristics measured in electrograms did not relate to the degree of ischemia. Despite a comparable reduction in regional myocardial blood flow, subepicardial conduction delay exceeded that recorded in the subendocardium, which often exhibited accelerated conduction.
Quality of Informed Consent: a New Measure of Understanding Among Research Subjects
Authors: S. Joffe, E. F. Cook, P. D. Cleary, J. W. Clark, J. C. Weeks
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: The informed consent of participants is ethically and legally required for most research involving human subjects. However, standardized methods for assessing the adequacy of informed consent to research are lacking. Methods and Results: We designed a brief questionnaire, the Quality of Informed Consent (QuIC), to measure subjects' actual (objective) and perceived (subjective) understanding of cancer clinical trials. The QuIC incorporates the basic elements of informed consent specified in federal regulations, assesses the therapeutic misconception (the belief that all aspects of a clinical trial are designed to directly benefit the subject), and employs the language and structure of the new National Cancer Institute template for informed consent documents. We modified the QuIC after receiving feedback from pilot tests with cancer research subjects, as well as validation from two independent expert panels. We then sent the QuIC to 287 adult cancer patients enrolled on phase I, II, or III clinical trials. Two hundred seven subjects (72%) completed the QuIC. To assess test–retest reliability, a random sample of 32 respondents was selected, of whom 17 (53%) completed the questionnaire a second time. The test–retest reliability was good with intraclass correlation coefficients of .66 for tests of objective understanding and .77 for tests of subjective understanding. The current version of the QuIC, which consists of 20 questions for objective understanding and 14 questions for subjective understanding, was tested for time and ease of administration in a sample of nine adult cancer patients. The QuIC required an average of 7.2 minutes to complete. Conclusions: The QuIC is a brief, reliable, and valid questionnaire that holds promise as a standardized way to assess the outcome of the informed consent process in cancer clinical trials.
Nosocomial tracheobronchitis in mechanically ventilated patients: incidence, aetiology and outcome
Authors: S. Nseir, C. Di Pompeo, P. Pronnier, S. Beague, T. Onimus, F. Saulnier, B. Grandbastien, D. Mathieu, M. Delvallez-Roussel, A. Durocher
Journal: European Respiratory Journal (2002)

The aim of this study was to determine the incidence, the organisms responsible for and the impact on outcome of nosocomial tracheobronchitis (NTB) in the intensive care unit (ICU). This prospective observational cohort study was conducted in a 30-bed medical/surgical ICU over a period of 6.5 yrs. All patients ventilated for >48 h were eligible. Patients with nosocomial pneumonia (NP) without prior NTB were excluded. Patients with first episodes of NTB were compared with those without NTB by univariate analysis. The study diagnosed 201 (10.6%) cases of NTB. Pseudomonas aeruginosa was the most common bacteria. NP rates were similar in patients with NTB compared with patients without NTB. Even in the absence of subsequent NP, NTB was associated with a significantly higher length of ICU stay and duration of mechanical ventilation in both surgical and medical populations. Mortality rates were similar in NTB patients without subsequent NP compared with patients without NTB. Antimicrobial treatment in NTB patients was associated with a trend to a better outcome. Nosocomial tracheobronchitis is common in mechanically ventilated intensive care unit patients. In this population, nosocomial tracheobronchitis was associated with longer durations of intensive care unit stay and mechanical ventilation. Further studies are needed to determine the impact of antibiotics on outcomes of patients with nosocomial tracheobronchitis.
Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma
Authors: B. Esmaeli, P. McLaughlin, B. Pro, F. Samaniego, I. Gayed, F. Hagemeister, J. Romaguera, F. Cabanillas, S.S. Neelapu, R. Banay, L. Fayad, M. Wayne Saville, L.W. Kwak
Journal: Annals of Oncology (2009)