tbuckley/cabot-search huggingface dataset:
Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition
Authors: Mihai Pop, Alan W Walker, Joseph Paulson, Brianna Lindsay, Martin Antonio, M Anowar Hossain, Joseph Oundo, Boubou Tamboura, Volker Mai, Irina Astrovskaya, Hector Corrada Bravo, Richard Rance, Mark Stares, Myron M Levine, Sandra Panchalingam, Karen Kotloff, Usman N Ikumapayi, Chinelo Ebruke, Mitchell Adeyemi, Dilruba Ahmed, Firoz Ahmed, Meer Taifur Alam, Ruhul Amin, Sabbir Siddiqui, John B Ochieng, Emmanuel Ouma, Jane Juma, Euince Mailu, Richard Omore, J Glenn Morris, Robert F Breiman, Debasish Saha, Julian Parkhill, James P Nataro, O Colin Stine
Journal: Genome biology (2014)

Abstract Background Diarrheal diseases continue to contribute significantly to morbidity and mortality in infants and young children in developing countries. There is an urgent need to better understand the contributions of novel, potentially uncultured, diarrheal pathogens to severe diarrheal disease, as well as distortions in normal gut microbiota composition that might facilitate severe disease. Results We use high throughput 16S rRNA gene sequencing to compare fecal microbiota composition in children under five years of age who have been diagnosed with moderate to severe diarrhea (MSD) with the microbiota from diarrhea-free controls. Our study includes 992 children from four low-income countries in West and East Africa, and Southeast Asia. Known pathogens, as well as bacteria currently not considered as important diarrhea-causing pathogens, are positively associated with MSD, and these include Escherichia/Shigella , and Granulicatella species, and Streptococcus mitis/pneumoniae groups. In both cases and controls, there tend to be distinct negative correlations between facultative anaerobic lineages and obligate anaerobic lineages. Overall genus-level microbiota composition exhibit a shift in controls from low to high levels of Prevotella and in MSD cases from high to low levels of Escherichia/Shigella in younger versus older children; however, there was significant variation among many genera by both site and age. Conclusions Our findings expand the current understanding of microbiota-associated diarrhea pathogenicity in young children from developing countries. Our findings are necessarily based on correlative analyses and must be further validated through epidemiological and molecular techniques.
Stand during working day to prevent health risks of sedentary jobs, says guidance
Authors: S. Mayor
Journal: BMJ (2015)

People whose jobs are predominantly desk based should be encouraged to stand up and walk about for at least two hours during each working day, says the first UK guidance developed to reduce the health risks of prolonged sitting at work.1

Growing evidence has shown links between a sedentary lifestyle and an increased risk of cardiovascular disease, diabetes, and some cancers. To help reduce this risk Public Health England and a UK community …
Treatment of Philadelphia Chromosome-Positive Early Chronic Phase Chronic Myelogenous Leukemia With Daily Doses of Interferon Alpha and Low-Dose Cytarabine
Authors: Hagop M. Kantarjian, Susan O'Brien, Terry L. Smith, Mary Beth Rios, Jorge Cortes, Miloslav Beran, Charles Koller, Francis J. Giles, Michael Andreeff, Steven Kornblau, Sergio Giralt, Michael J. Keating, Moshe Talpaz
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN-α) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN-α and ara-C induce cytogenetic responses as single-agent therapy in CML. PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN-α 5 megaunits/m 2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN-α with or without intermittent ara-C (7 days/mo). RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive &lt; 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rate was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN-α was 3.7 megaunits/m 2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN-α plus ara-C combination. The incidence of CHR was higher with IFN-α plus daily ara-C compared with IFN-α plus intermittent ara-C and IFN-α alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN-α regimens (7 v 10 v 12 months; P &lt; .01). However, with the present follow-up, the survival and time to blastic transformation were similar. CONCLUSION: The combination of IFN-α plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN-α compared with our previous studies.
Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart
Authors: Ian G. Webb, Yasuhiro Nishino, James E. Clark, Colin Murdoch, Simon J. Walker, Marcus R. Makowski, Rene M. Botnar, Simon R. Redwood, Ajay M. Shah, Michael S. Marber
Journal: Cardiovascular Research (2010)

Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3alpha and 9 of GSK-3beta respectively, required for inactivation by upstream kinases.Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts.Expression of inactivation-resistant GSK-3alpha/beta does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3alpha/beta, may enable a sustained cardiac response to chronic beta-agonist stimulation while preventing pathological remodelling.
Hallmarks of the ageing lung
Authors: Silke Meiners, Oliver Eickelberg, Melanie Königshoff
Journal: European Respiratory Journal (2015)

Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, “dysregulation of the extracellular matrix”, which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases.
In vivo NIRF and MR dual-modality imaging using glycol chitosan nanoparticles
Authors: Jaehong Key, Christy Cooper, Ah Young Kim, Deepika Dhawan, Deborah W. Knapp, Kwangmeyung Kim, Jae Hyung Park, Kuiwon Choi, Ick Chan Kwon, Kinam Park, James F. Leary
Journal: Journal of Controlled Release (2012)
Randomized Phase III Trial of Maintenance Bevacizumab With or Without Pemetrexed After First-Line Induction With Bevacizumab, Cisplatin, and Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: AVAPERL (MO22089)
Authors: Fabrice Barlesi, Arnaud Scherpereel, Achim Rittmeyer, Antonio Pazzola, Neus Ferrer Tur, Joo-Hang Kim, Myung-Ju Ahn, Joachim G.J.V. Aerts, Vera Gorbunova, Anders Vikström, Elaine K. Wong, Pablo Perez-Moreno, Lada Mitchell, Harry J.M. Groen
Journal: Journal of Clinical Oncology (2013)

Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment.Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m(2), and pemetrexed 500 mg/m(2) once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment.In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed.In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.
Nomogram to Predict the Benefit of Radiation for Older Patients With Breast Cancer Treated With Conservative Surgery
Authors: Jeffrey M. Albert, Diane D. Liu, Yu Shen, I-Wen Pan, Ya-Chen Tina Shih, Karen E. Hoffman, Thomas A. Buchholz, Sharon H. Giordano, Benjamin D. Smith
Journal: Journal of Clinical Oncology (2012)

Purpose The role of radiation therapy (RT) after conservative surgery (CS) remains controversial for older patients with breast cancer. Guidelines based on recent clinical trials have suggested that RT may be omitted in selected patients with favorable disease. However, it is not known whether this recommendation should extend to other older women. Accordingly, we developed a nomogram to predict the likelihood of long-term breast preservation with and without RT. Methods We used Surveillance, Epidemiology, and End Results–Medicare data to identify 16,092 women age 66 to 79 years treated with CS between 1992 and 2002, using claims to identify receipt of RT and subsequent mastectomy. Time to mastectomy was estimated using the Kaplan-Meier method. Cox proportional hazards models determined the effect of covariates on mastectomy-free survival (MFS). A nomogram was developed to predict 5- and 10-year MFS, given associated risk factors, and bootstrap validation was performed. Results With a median follow-up of 7.2 years, the overall 5- and 10-year MFS rates were 98.1% (95% CI, 97.8% to 98.3%) and 95.4% (95% CI, 94.9% to 95.8%), respectively. In multivariate analysis, age, race, tumor size, estrogen receptor status, and receipt of RT were predictive of time to mastectomy and were incorporated into the nomogram. Nodal status was also included given a significant interaction with RT. The resulting nomogram demonstrated good accuracy in predicting MFS, with a bootstrap-corrected concordance index of 0.66. Conclusion This clinically useful tool predicts 5- and 10-year MFS among older women with early breast cancer using readily available clinicopathologic factors and can aid individualized clinical decision making by estimating predicted benefit from RT.
Validation of a Type 2 Diabetes Screening Tool in Rural Honduras
Authors: Evan C. Milton, William H. Herman, Allison E. Aiello, Kris R. Danielson, Milton O. Mendoza-Avelarez, John D. Piette
Journal: Diabetes Care (2009)

OBJECTIVE To validate a low-cost tool for identifying diabetic patients in rural areas of Latin America. RESEARCH DESIGN AND METHODS A regression equation incorporating postprandial time and a random plasma glucose was used to screen 800 adults in Honduras. Patients with a probability of diabetes of ≥20% were asked to return for a fasting plasma glucose (FPG). A random fifth of those with a screener-based probability of diabetes &amp;lt;20% were also asked to return for follow-up. The gold standard was an FPG ≥126 mg/dl. RESULTS The screener had very good test characteristics (area under the receiver operating characteristic curve = 0.89). Using the screening criterion of ≥0.42, the equation had a sensitivity of 74.1% and specificity of 97.2%. CONCLUSIONS This screener is a valid measure of diabetes risk in Honduras and could be used to identify diabetic patients in poor clinics in Latin America.
Force-feeding prisoners and the role of physicians
Authors: George J Annas
Journal: The Lancet (2009)

In his Sept 29 address to the United Nations General Assembly, President Barack Obama told the world that for those "who question the character and cause of my nation" two "concrete actions" should be taken as proof that the USA really has changed: the prohibition, "without exception or equivocation" of the use of torture and ordering the prison at Guantanamo Bay to be closed. Both are critical steps for my country to try to regain its position in the world as a human rights leader.
The Serine Repeat Antigen (SERA) Gene Family Phylogeny in Plasmodium: The Impact of GC Content and Reconciliation of Gene and Species Trees
Authors: Richard Bourgon, Mauro Delorenzi, Tobias Sargeant, Anthony N. Hodder, Brendan S. Crabb, Terence P. Speed
Journal: Molecular Biology and Evolution (2004)

Plasmodium falciparum is the parasite responsible for the most acute form of malaria in humans. Recently, the serine repeat antigen (SERA) in P. falciparum has attracted attention as a potential vaccine and drug target, and it has been shown to be a member of a large gene family. To clarify the relationships among the numerous P. falciparum SERAs and to identify orthologs to SERA5 and SERA6 in Plasmodium species affecting rodents, gene trees were inferred from nucleotide and amino acid sequence data for 33 putative SERA homologs in seven different species. (A distance method for nucleotide sequences that is specifically designed to accommodate differing GC content yielded results that were largely compatible with the amino acid tree. Standard-distance and maximum-likelihood methods for nucleotide sequences, on the other hand, yielded gene trees that differed in important respects.) To infer the pattern of duplication, speciation, and gene loss events in the SERA gene family history, the resulting gene trees were then "reconciled" with two competing Plasmodium species tree topologies that have been identified by previous phylogenetic studies. Parsimony of reconciliation was used as a criterion for selecting a gene tree/species tree pair and provided (1) support for one of the two species trees and for the core topology of the amino acid-derived gene tree, (2) a basis for critiquing fine detail in a poorly resolved region of the gene tree, (3) a set of predicted "missing genes" in some species, (4) clarification of the relationship among the P. falciparum SERA, and (5) some information about SERA5 and SERA6 orthologs in the rodent malaria parasites. Parsimony of reconciliation and a second criterion--implied mutational pattern at two key active sites in the SERA proteins-were also seen to be useful supplements to standard "bootstrap" analysis for inferred topologies.
A Bony Fish Immunological Receptor of the NITR Multigene Family Mediates Allogeneic Recognition
Authors: John P. Cannon, Robert N. Haire, Andrew T. Magis, Donna D. Eason, Kelley N. Winfrey, Jose A. Hernandez Prada, Kate M. Bailey, Jean Jakoncic, Gary W. Litman, David A. Ostrov
Journal: Immunity (2008)
Identification of Anaplastic Lymphoma Kinase as a Potential Therapeutic Target in Ovarian Cancer
Authors: Hong Ren, Zhi-Ping Tan, Xin Zhu, Katherine Crosby, Herbert Haack, Jian-Min Ren, Sean Beausoleil, Albrecht Moritz, Gregory Innocenti, John Rush, Yi Zhang, Xin-Min Zhou, Ting-Lei Gu, Yi-Feng Yang, Michael J. Comb
Journal: Cancer Research (2012)

Ovarian cancer is the leading cause of death from gynecologic cancer. Improvement in the clinical outcome of patients is likely to be achieved by the identification of molecular events that underlie the oncogenesis of ovarian cancer. Here we show that the anaplastic lymphoma kinase (ALK) is aberrantly activated in ovarian cancer. Using an unbiased and global phosphoproteomic approach, we profiled 69 Chinese primary ovarian tumor tissues and found ALK to be aberrantly expressed and phosphorylated in 4 tumors. Genetic characterization of these ALK-positive tumors indicated that full-length ALK expression in two serous carcinoma patients is consistent with ALK gene copy number gain, whereas a stromal sarcoma patient carries a novel transmembrane ALK fusion gene: FN1-ALK. Biochemical and functional analysis showed that both full-length ALK and FN1-ALK are oncogenic, and tumors expressing ALK or FN1-ALK are sensitive to ALK kinase inhibitors. Furthermore, immunohistochemical analysis of ovarian tumor tissue microarray detected aberrant ALK expression in 2% to 4% serous carcinoma patients. Our findings provide new insights into the pathogenesis of ovarian cancer and identify ALK as a potential therapeutic target in a subset of serous ovarian carcinoma and stromal sarcoma patients.
Distribution of coronary artery flow to the canine right atrium and sinoatrial node.
Authors: C W White, M L Marcus, F M Abboud
Journal: Circulation Research (1977)

We assessed segmental distribution of blood flow to the right atrium and the region of the sinoatrial node using micropheres (7-10 mum) in 20 anesthetized dogs. Mean right atrial flow averaged 83+/-7 (SE) ml/min X 100 g, which was 56% of the left ventricular blood flow. The distribution of right atrial flow was not homogeneous. For example, flow to anterior right atriaater (105+/-8 ml/min X 100 g) than mean right atrial flow. Following ligation of the sinus node artery, perfusion of the segment containing the sinus node decreased by only 36%. Relative preservation of perfusion to the sinus node following sinus node artery ligation may explain why ligation of the sinus node artery does not alter heart rate. Furthermore, we also found that cannulation and pump perfusion of the sinus node artery at pressures 10 and 50 mm Hg greater than systolic pressure did not alter the distribution of right atrial flow. Thus, because cannulation and perfusion of the sinus node artery do not artifactually distort regional right atrial blood flow, we conclude that this should be a useful method for evaluating responsiveness of the sinus node to various interventions.
Post-mortem shrinkage of homograft aortic valves
Authors: F. Dexter, R. J. Donnelly, P. B. Deverall, D. A. Watson
Journal: Thorax (1972)

Experience has shown that some frame-mounted homograft aortic valves, although competent immediately after mounting, are incompetent when subsequently presented for surgical use. Retraction and shrinkage of the cusps appears to be the cause of this change. Clinical and experimental studies have shown that shrinkage of homograft aortic valves occurs over an approximately five-day period after death of the donor and it is recommended that this period should elapse before mounting homograft aortic valves on to support frames.
Determination of Right Ventricular Structure and Function in Normoxic and Hypoxic Mice
Authors: Marielle Scherrer-Crosbie, Wolfgang Steudel, Patrick R. Hunziker, Gary P. Foster, Leoncio Garrido, Noah Liel-Cohen, Warren M. Zapol, Michael H. Picard
Journal: Circulation (1998)

Background —Noninvasive cardiac evaluation is of great importance in transgenic mice. Transthoracic echocardiography can visualize the left ventricle well but has not been as successful for the right ventricle (RV). We developed a method of transesophageal echocardiography (TEE) to evaluate murine RV size and function. Methods and Results —Normoxic and chronically hypoxic mice (F io 2 =0.11, 3 weeks) and agarose RV casts were scanned with a rotating 3.5F/30-MHz intravascular ultrasound probe. In vivo, the probe was inserted in the mouse esophagus and withdrawn to obtain contiguous horizontal planes at 1-mm intervals. In vitro, the probe was withdrawn along the left ventricular posterior wall of excised hearts. The borders of the RV were traced on each plane, allowing calculation of diastolic and systolic volumes, RV mass, RV ejection fraction, stroke volume, and cardiac output. RV wall thickness was measured. Echo volumes obtained in vitro were compared with cast volumes. Echo-derived cardiac output was compared with measurements of an ascending aortic Doppler flow probe. Echo-derived RV free wall mass was compared with true RV free wall weight. There was excellent agreement between cast and TEE volumes ( y =0.82 x +6.03, r =0.88, P &lt;0.01) and flow-probe and echo cardiac output ( y =1.00 x +0.45, r =0.99, P &lt;0.0001). Although echo-derived RV mass and wall thickness were well correlated with true RV weight, echo-derived RV mass underestimated true weight ( y =0.53 x +2.29, r =0.81, P &lt;0.0001). RV mass and wall thickness were greater in hypoxic mice than in normoxic mice (0.78±0.19 versus 0.51±0.14 mg/g, P &lt;0.03, 0.50±0.03 versus 0.38±0.03 mm, P &lt;0.04). Conclusions —TEE with an intravascular ultrasound catheter is a simple, accurate, and reproducible method to study RV size and function in mice.