tbuckley/cabot-search huggingface dataset:
A metagenomic insight into our gut's microbiome
Authors: Patricia Lepage, Marion C Leclerc, Marie Joossens, Stanislas Mondot, Hervé M Blottière, Jeroen Raes, Dusko Ehrlich, Joel Doré
Journal: Gut (2012)

Advances in sequencing technology and the development of metagenomic and bioinformatics methods have opened up new ways to investigate the 10<sup>14</sup> microorganisms inhabiting the human gut. The gene composition of human gut microbiome in a large and deeply sequenced cohort highlighted an overall non-redundant genome size 150 times larger than the human genome. The <i>in silico</i> predictions based on metagenomic sequencing are now actively followed, compared and challenged using additional 'omics' technologies. Interactions between the microbiota and its host are of key interest in several pathologies and applying meta-omics to describe the human gut microbiome will give a better understanding of this crucial crosstalk at mucosal interfaces. Adding to the growing appreciation of the importance of the microbiome is the discovery that numerous phages, that is, viruses of prokaryotes infecting bacteria (bacteriophages) or archaea with a high host specificity, inhabit the human gut and impact microbial activity. In addition, gene exchanges within the gut microbiota have proved to be more frequent than anticipated. Taken together, these innovative exploratory technologies are expected to unravel new information networks critical for gut homeostasis and human health. Among the challenges faced, the <i>in vivo</i> validation of these networks, together with their integration into the prediction and prognosis of disease, may require further working hypothesis and collaborative efforts.
Pre–B-Cell Colony–Enhancing Factor Regulates NAD <sup>+</sup> -Dependent Protein Deacetylase Activity and Promotes Vascular Smooth Muscle Cell Maturation
Authors: Eric van der Veer, Zengxuan Nong, Caroline O’Neil, Brad Urquhart, David Freeman, J. Geoffrey Pickering
Journal: Circulation Research (2005)

Conversion of vascular smooth muscle cells (SMCs) from a proliferative state to a nonproliferative, contractile state confers vasomotor function to developing and remodeling blood vessels. Using a maturation-competent human SMC line, we determined that this shift in phenotype was accompanied by upregulation of pre–B-cell colony–enhancing factor (PBEF), a protein proposed to be a cytokine. Knockdown of endogenous PBEF increased SMC apoptosis and reduced the capacity of synthetic SMCs to mature to a contractile state. In keeping with these findings, human SMCs transduced with the PBEF gene had enhanced survival, an elongated bipolar morphology, and increased levels of h-caldesmon, smoothelin-A, smoothelin-B, and metavinculin. Notwithstanding some prior reports, PBEF did not have attributes of a cytokine but instead imparted the cell with increased nicotinamide phosphoribosyltransferase activity. Intracellular nicotinamide adenine dinucleotide (NAD + ) content was increased in PBEF-overexpressing SMCs and decreased in PBEF-knockdown SMCs. Furthermore, NAD + -dependent protein deacetylase activity was found to be essential for SMC maturation and was increased by PBEF. Xenotransplantation of human SMCs into immunodeficient mice revealed an increased capacity for PBEF-overexpressing SMCs to mature and intimately invest nascent endothelial channels. This microvessel chimerism and maturation process was perturbed when SMC PBEF expression was lowered. These findings identify PBEF as a regulator of NAD + -dependent reactions in SMCs, reactions that promote, among other potential processes, the acquisition of a mature SMC phenotype.
Results of a Phase II Study of High-Dose Thoracic Radiation Therapy With Concurrent Cisplatin and Etoposide in Limited-Stage Small-Cell Lung Cancer (NCCTG 95-20-53)
Authors: Steven E. Schild, James A. Bonner, Shauna Hillman, Timothy F. Kozelsky, Antonio P.G. Vigliotti, Randolph S. Marks, David L. Graham, Gamini S. Soori, John W. Kugler, Richard C. Tenglin, Donald B. Wender, Alex Adjei
Journal: Journal of Clinical Oncology (2007)

Purpose To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). Patients and Methods A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). Results Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. Conclusion This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.
Practice-Based Evidence in Public Health: Improving Reach, Relevance, and Results
Authors: Alice Ammerman, Tosha Woods Smith, Larissa Calancie
Journal: Annual Review of Public Health (2014)

The most threatening public health challenges today are chronic and complex and require joint effort from academic researchers in partnership with clinical and public health practitioners to identify and implement sustainable solutions that work in the real world. Practice-based research offers researchers and practitioners an underutilized way forward, an opportunity to work together to design and test feasible, evidence-based programs to address our greatest challenges. In this article, we outline the need for practice-based evidence, tools, and strategies that investigators can use to generate practice-based evidence, describe approaches to translating practice-based evidence into practice, and offer recommendations for making practice-based research the norm in public health.
Determinants of the Cardiomyopathic Phenotype in Chimeric Mice Overexpressing Cardiac Gsα
Authors: Dorothy E. Vatner, Gui-Ping Yang, Yong-Jian Geng, Kuniya Asai, Jeung S. Yun, Thomas E. Wagner, Yoshihiro Ishikawa, Sanford P. Bishop, Charles J. Homcy, Stephen F. Vatner
Journal: Circulation Research (2000)

Abstract —Mice with overexpressed cardiac Gsα develop cardiomyopathy, characterized by myocyte hypertrophy and extensive myocardial fibrosis. The cardiomyopathy likely involves chronically enhanced β-adrenergic signaling, because it can be blocked with long-term propranolol treatment. It remains unknown whether the genotype of the myocyte is solely responsible for the progressive pathological changes. A chimeric population in the heart should answer this question. Accordingly, we developed a chimeric animal, which combined cells from a transgenic overexpressed Gsα parent and a Rosa mouse containing the LacZ reporter gene, facilitating identification of the non–Gsα cells, which express a blue color with exposure to β-galactosidase. We studied these animals at 14 to 17 months of age (when cardiomyopathy should have been present), with the proportion of Gsα cells in the myocardium ranging from 5% to 88%. β-Galactosidase staining of the hearts demonstrated Gsα and Rosa cells, exhibiting a mosaic pattern. The fibrosis and hypertrophy, characteristic of the cardiomyopathy, were not distributed randomly. There was a direct correlation ( r =0.85) between the extent of myocyte hypertrophy (determined by computer imaging) and the quantity of Gsα cells. The fibrosis, determined by picric acid Sirius red, was also more prominent in areas with the greatest Gsα cell density, with a correlation of r =0.88. Thus, the overexpressed Gsα can exert its action over the life of the animal, resulting in a local picture of cardiomyopathic damage in discrete regions of the heart, where clusters of the overexpressed Gsα cells reside, sparing the clusters of normal cells derived from the normal Rosa parent.
Eosinophilic Bronchitis Is an Important Cause of Chronic Cough
Authors: CHRISTOPHER E. BRIGHTLING, RICHARD WARD, KAH LAY GOH, ANDREW J. WARDLAW, IAN D. PAVORD
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Eosinophilic bronchitis presents with chronic cough and sputum eosinophilia, but without the abnormalities of airway function seen in asthma. It is important to know how commonly eosinophilic bronchitis causes cough, since in contrast to cough in patients without sputum eosinophilia, the cough responds to inhaled corticosteroids. We investigated patients referred over a 2-yr period with chronic cough, using a well-established protocol with the addition of induced sputum in selected cases. Eosinophilic bronchitis was diagnosed if patients had no symptoms suggesting variable airflow obstruction, and had normal spirometric values, normal peak expiratory flow variability, no airway hyperresponsiveness (provocative concentration of methacholine producing a 20% decrease in FEV(1) ([PC(20)] > 8 mg/ml), and sputum eosinophilia (> 3%). Ninety-one patients with chronic cough were identified among 856 referrals. The primary diagnosis was eosinophilic bronchitis in 12 patients, rhinitis in 20, asthma in 16, post-viral-infection status in 12, and gastroesophageal reflux in seven. In a further 18 patients a diagnosis was established. The cause of chronic cough remained unexplained in six patients. In all 12 patients with eosinophilic bronchitis, the cough improved after treatment with inhaled budesonide 400 micrograms twice daily, and in eight of these patients who had a follow-up sputum analysis, the eosinophil count decreased significantly, from 16.8% to 1.6%. We conclude that eosinophilic bronchitis is a common cause of chronic cough, and that sputum induction is important in the investigation of cough.
Enhanced Effect of Combining Human Cardiac Stem Cells and Bone Marrow Mesenchymal Stem Cells to Reduce Infarct Size and to Restore Cardiac Function After Myocardial Infarction
Authors: Adam R. Williams, Konstantinos E. Hatzistergos, Benjamin Addicott, Fred McCall, Decio Carvalho, Viky Suncion, Azorides R. Morales, Jose Da Silva, Mark A. Sussman, Alan W. Heldman, Joshua M. Hare
Journal: Circulation (2012)

Background— Because mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit + cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h) MSCs with c-kit + hCSCs produces greater infarct size reduction compared with either cell administered alone after myocardial infarction (MI). Methods and Results— Yorkshire swine underwent balloon occlusion of the left anterior descending coronary artery followed by reperfusion and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial combination hCSCs/hMSCs (1 million cells/200 million cells, n=5), hCSCs alone (1 million cells, n=5), hMSCs alone (200 million cells, n=5), or placebo (phosphate-buffered saline; n=5) was injected into the infarct border zones at 14 days after MI. Phenotypic response to cell therapy was assessed by cardiac magnetic resonance imaging and micromanometer conductance catheterization hemodynamics. Although each cell therapy group had reduced MI size relative to placebo ( P &lt;0.05), the MI size reduction was 2-fold greater in combination versus either cell therapy alone ( P &lt;0.05). Accompanying enhanced MI size reduction were substantial improvement in left ventricular chamber compliance (end-diastolic pressure-volume relationship; P &lt;0.01) and contractility (preload recruitable stroke work and dP/dtmax; P &lt;0.05) in combination-treated swine. Ejection fraction was restored to baseline in cell-treated pigs, whereas placebo pigs had persistently depressed left ventricular function ( P &lt;0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group versus either cell type alone ( P &lt;0.001). Conclusions— Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction and restores diastolic and systolic function toward normal after MI. Taken together, these findings illustrate important biological interactions between c-kit + CSCs and MSCs that enhance cell-based therapeutic responses.
Correspondence on the paper by Bridevaux<i>et al</i>
Authors: Carl M Preiksaitis, Ajit P Limaye
Journal: Thorax (2013)

We read with interest the important prospective natural history study of respiratory virus infections (RVI) in lung transplant recipients by Bridevaux et al. 1 Although the authors were unable to find an association between acute rejection and RVI, they acknowledge the possibility that RVI might predispose to chronic rejection, bronchiolitis obliterans syndrome (BOS).The association between BOS and RVI has been highly discussed in the literature, but a recent meta-analysis by Vu et al 2 remained inconclusive on the connection.In view of this, we wonder whether the authors have analysed the association of incident RVI with BOS in their cohort.We were surprised at the authors' conclusion that "… asymptomatic carriage is rare" for several reasons.First, the frequency of surveillance testing did not appear to be frequent enough to exclude a high rate of self-resolving infections (ie, infections may have occurred between screening tests).Second, we note that RVI were detected in 14% of routine screening/surveillance visits.And finally, the proportion of positive viral tests was 10% at screening visits even among those without any symptoms.These data all suggest that RVI might be substantially more common than previously recognised and not necessarily predicted by symptomatology.It was unclear from the Methods section whether bronchoscopies were performed for surveillance or only for cause.It would be of interest if the authors could clarify this issue and provide positivity rates of bronchoalveolar lavage done for surveillance versus for cause.Future studies will be needed to define any significance (or not) of asymptomatic versus symptomatic RVI in terms of clinically relevant outcomes (risk for subsequent bacterial/fungal superinfection, chronic allograft injury/dysfunction, etc).An additional point of interest is the connection between viral infection of the upper and lower respiratory tracts.We wonder whether the authors could supply any data to support the assumption that infections are first identifiable in the upper airways before progressing to the lungs.We thank the authors for their continued investigation of this important topic and informative paper.
Evidence for decreased coronary flow reserve in viable postischemic myocardium.
Authors: J Vanhaecke, W Flameng, M Borgers, I K Jang, F Van de Werf, H De Geest
Journal: Circulation Research (1990)

To try to unravel the complexity and heterogeneity of the "no-reflow" phenomenon and its underlying mechanisms, we studied tissue perfusion in reperfused heart muscle by using tracer microspheres in an anesthetized dog model of 90-minute coronary occlusion followed by reperfusion for 2 1/2 hours, 24 hours, or 1 week. Regional myocardial blood flow was determined both in basal flow conditions and during reactive hyperemia. The effect of intracoronary adenosine administration was examined, and the ultrastructure of postischemic myocardium was analyzed. In viable reperfused tissue (as delineated by triphenyltetrazolium chloride staining), reflow in basal conditions is unimpaired. Coronary flow reserve (as approximated by peak reactive hyperemic flow) is intact at the start of reperfusion, decreases by more than half after 2 1/2 hours, and recovers completely within 1 week. This impairment of coronary reserve can be relieved by intracoronary adenosine administration. On ultrastructural examination, the capillaries are patent. On the other hand, in irreversibly damaged myocardium, both the basal reflow impairment and the decrease in coronary flow reserve are severe and permanent. Coronary flow reserve is already decreased at the start of reperfusion, and the pharmacological intervention has no beneficial effect. Ultrastructurally, extracellular and intracellular edema invariably are present, whereas the vascular endothelium is damaged and the capillaries are packed with red blood cells. We conclude that the no-reflow phenomenon (i.e., mechanical obstruction to blood flow) is limited to infarcted tissue. In viable myocardium, however, coronary flow reserve is transiently diminished, probably because of washout and subsequent insufficient availability of the chemical mediator adenosine after breakdown and slow recovery of the precursor ATP pool.
Paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation in locally advanced nasopharyngeal carcinoma
Authors: A.S.C. Wong, R.A. Soo, J.J. Lu, K.S. Loh, K.S. Tan, W.S. Hsieh, T.P. Shakespeare, E.T. Chua, H.L. Lim, B.C. Goh
Journal: Annals of Oncology (2006)
Cytosine arabinoside transport and metabolism in acute leukemias and T cell lymphoblastic lymphoma.
Authors: J S Wiley, J Taupin, G P Jamieson, M Snook, W H Sawyer, L R Finch
Journal: Journal of Clinical Investigation (1985)

Cytosine arabinoside (araC) has proven efficacy in acute myeloid leukemia (AML), but its place in the treatment of acute lymphoblastic leukemia (ALL) and T lymphoblastic lymphoma is uncertain. The therapeutic potential of araC has been assessed in patients with AML, ALL, and T lymphoblastic lymphoma by measuring the conversion of araC to its active metabolite, the 5'-triphosphate of araC (araCTP), in purified blasts from patients as well as in normal polymorphs and lymphocytes. In all leukemias, araCTP was the major intracellular metabolite of araC. The highest araCTP formation was in blasts from T lymphoblastic lymphoma, which formed threefold more nucleotide than myeloblasts, and in turn myeloblasts formed twofold more araCTP than lymphoblasts from ALL. The mean araCTP formation in myeloblasts was sixfold greater than polymorphs, but in contrast, lymphoblasts and lymphocytes formed low and similar amounts of this nucleotide. Reasons for the sixfold range in araCTP accumulation in the various leukemic blasts were studied. The mean size of myeloblasts was 35-70% larger than lymphoblasts when compared on the basis of protein or intracellular water content, but T lymphoblastic lymphoma blasts and lymphoblasts were the same size. Activities of deoxycytidine kinase, deoxycytidylate deaminase, and pyrimidine nucleoside monophosphate kinase were not different between any of the leukemic cell types. The number of nucleoside transport sites on blasts was estimated by measuring the equilibrium binding of [3H]nitrobenzylthioinosine (NBMPR), which binds with high affinity to the transporter. Scatchard analysis yielded mean values of 27,500 sites/cell for T lymphoblastic lymphoma blasts, 10,000 sites/cell for myeloblasts, and 2,300 sites/cell for lymphoblasts. Our previous work has shown that araC influx correlates with the maximum number of 3H-NBMPR binding sites in leukemic and normal white cells. A strong correlation was observed between the number of nucleoside transport sites per leukemic blast cell and the accumulation of intracellular araCTP from extracellular araC at 1 microM. Membrane transport of araC at the low concentrations (approximately 1 microM), which are achieved therapeutically, is a major rate-limiting step in its conversion to araCTP by leukemic blast cells. Myeloblasts form more araCTP than lymphoblasts because of both higher nucleoside transport capacity and larger cell size. The highest nucleoside transport capacity and largest conversion of araC to araCTP is in T lymphoblastic lymphoma, which suggests that araC may be effective in the treatment of this disease.
Time Course for Antipsychotic Treatment Response in First-Episode Schizophrenia
Authors: Robin Emsley
Journal: American Journal of Psychiatry (2006)

Objective: The authors examined early onset of antipsychotic action and early prediction of nonresponse to antipsychotics in patients with first-episode schizophrenia. Method: Time to clinical response (≥20% improvement in total score on the Positive and Negative Syndrome Scale [PANSS]) was determined in 522 participants in a randomized, controlled trial comparing risperidone and haloperidol. Median treatment length was 206 days. Results: Clinical response was achieved in 77% (N=400) of subjects. Among these patients, clinical response was achieved in 23.3%, 23.3%, 18.5%, and 12.5% at weeks 1, 2, 3, and 4, respectively, after treatment initiation. However, in 22.5% of patients, response was not achieved until after 4 weeks, and in 11.2%, it was not achieved until after 8 weeks. In 45% of patients, response was achieved with a dose of 1–2 mg/day, in 27% with 3 mg/day, in 17% with 4 mg/day, and in the remaining 11% with higher doses. Improvement in the PANSS total score of at least 30%, 40%, and 50%, respectively, were achieved by 63.0%, 44.8%, and 27.5% of patients. Conclusions: Time to antipsychotic response varied widely, suggesting that, in first-episode schizophrenia, longer treatment trials may be necessary.
Preservatives in Insulin Preparations Impair Leukocyte Function: In vitro study
Authors: Ineke van Faassen, A Marian JJ Verweij-van Vught, Mary Z Lomecky-Janousek, Peter PA Razenberg, Eduard A van der Veen
Journal: Diabetes Care (1990)

m-Cresol and methyl p-hydroxybenzoate are preservatives in insulin preparations. As previously reported, in diabetic patients on continuous subcutaneous insulin infusion, users of insulin-containing m-cresol had significantly more inflamed infusion sites than users of insulin with methyl p-hydroxybenzoate. This study assessed the influence of insulin with and without these preservatives on leukocyte function. Leukocyte function was investigated in a killing experiment, expressed as the percentage of bacteria killed after 60 min incubation of bacteria (Staphylococcus aureus), polymorphonuclear leukocytes, serum, and insulin preparations. Because preservative is retained by the infusion device, insulin with preservative was tested before and after 1 and 4 days perfusion with a PVC pump catheter. After perfusion, the amount of preservative was reduced (percentage of original concentration after 1 and 4 days 8 and 30% m-cresol and 42 and 72% methyl p-hydroxybenzoate, respectively). The killing percentage in insulin with m-cresol reduced compared with insulin without preservative (mean ± SE 95.4 ± 0.8%) and the control without insulin (95.8 ± 0.8%), both before and after 1 and 4 days perfusion (74.8 ± 0.7, 80.2 ± 2.8, and 80.6 ± 1.6%, respectively; P &amp;lt; 0.01). The same occurred in insulin with methyl p-hydroxybenzoate (85.0 ± 0.9% before and 88.4 ± 0.9 and 86.2 ± 0.8% after 1 and 4 days perfusion; P &amp;lt; 0.05). All insulin preparations with m-cresol caused lower killing percentages than corresponding insulin preparations with methyl p-hydroxybenzoate (P &amp;lt; 0.05). These results demonstrate that both preservatives impaired leukocyte function, but m-cresol was the most noxious in this respect. This indicates that preservatives in insulin preparations are possibly implicated in the pathogenesis of local infections in continuous subcutaneous insulin infusion.