tbuckley/cabot-search huggingface dataset:
KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity
Authors: Mojca Skoberne, Alice Yewdall, Keith S. Bahjat, Emmanuelle Godefroy, Peter Lauer, Edward Lemmens, Weiqun Liu, Will Luckett, Meredith Leong, Thomas W. Dubensky, Dirk G. Brockstedt, Nina Bhardwaj
Journal: Journal of Clinical Investigation (2008)

Vaccine strategies that utilize human DCs to enhance antitumor immunity have yet to realize their full potential. Approaches that optimally target a spectrum of antigens to DCs are urgently needed. Here we report the development of a platform for loading DCs with antigen. It is based on killed but metabolically active (KBMA) recombinant Listeria monocytogenes and facilitates both antigen delivery and maturation of human DCs. Highly attenuated KBMA L. monocytogenes were engineered to express an epitope of the melanoma-associated antigen MelanA/Mart-1 that is recognized by human CD8+ T cells when presented by the MHC class I molecule HLA-A*0201. The engineered KBMA L. monocytogenes induced human DC upregulation of costimulatory molecules and secretion of pro-Th1 cytokines and type I interferons, leading to effective priming of Mart-1–specific human CD8+ T cells and lysis of patient-derived melanoma cells. KBMA L. monocytogenes expressing full-length NY-ESO-1 protein, another melanoma-associated antigen, delivered the antigen for presentation by MHC class I and class II molecules independent of the MHC haplotype of the DC donor. A mouse therapeutic tumor model was used to show that KBMA L. monocytogenes efficiently targeted APCs in vivo to induce protective antitumor responses. Together, our data demonstrate that KBMA L. monocytogenes may be a powerful platform that can both deliver recombinant antigen to DCs for presentation and provide a potent DC-maturation stimulus, making it a potential cancer vaccine candidate.
A role for cigarette fumes in the development of emphysema through reduced alveolar cell proliferation and upregulation of apoptosis
Authors: M. East
Journal: Thorax (2010)

This paper describes a molecular mechanism for the loss of alveolar tissue in cigarette smoke-induced lung injury. Under the influence of adverse environmental conditions including hypoxia, the intracellular stress protein Rtp801 is transcribed. This study sought to demonstrate that Rtp801 downregulates the kinase mammalian target of …
Familial proptosis and obesity in the Ptolemies
Authors: H. Ashrafian
Journal: Journal of the Royal Society of Medicine (2005)

Dr McNaught is right to point out examples of racism in the NHS (December 2004 JRSM 1 ).But what to do about it?Maybe we can learn some lessons from the past.Today there is an over-representation of black people in the mental health system but in the 1960s Irish people were over-represented. 2 Psychiatrists thought that the prevalence of schizophrenia was high in people from the west of Ireland and invented a new syndrome 'western seaboard psychosis'. 3 Anthropologists descended on the unsuspecting immigrants to ask them if their Catholic faith caused their minds to unbalance and psychiatrists followed to dole out antipsychotics.But then some proper research was done and it showed no excess of schizophrenia in Irish immigrants. 4 The methods of case collection in the early studies were poor and cross-cultural comparisons were not properly thought through. 3 Today Irish people are no more likely to be diagnosed with schizophrenia than anyone else.How did this happen?I would love to say that it was because of the new research or because of government initiatives.The research helped a bit but the main cures for anti-Irish discrimination were that the new immigrants were richer, better educated, better informed and more questioning.They would not be fobbed off with a misdiagnosis.An increasing understanding and appreciation of Irish culture also helped reduce anti-Irish discrimination generally.The most effective cure of all was time.A cynic would add that, nowadays, people have a new batch of immigrants (such as asylum seekers) to discriminate against.So we need fewer new policy drives and more changes of heart.These will only come from changes in society.Blaming individuals or even the NHS will not help.
Probabilistic Characterization of R-R Intervals
Authors: M. ten Hoopen, J. P. M. Bongaarts
Journal: Cardiovascular Research (1969)

Statistical methods are applied in order to characterize R–R interval sequences of the ECG. By way of example, the interval distribution and the joint probability density function of pairs of adjacent intervals are treated in detail for data on one normal testee and three patients. The results are compared with the properties of the respective cardiotachograms. These methods of display, if used with discretion, provide a compact overall view of the degree of irregularity of intervals, and of the form of interdependency between the durations of successive intervals.
Overexpression of Placenta Growth Factor Contributes to the Pathogenesis of Pulmonary Emphysema
Authors: Po-Nien Tsao, Yi-Ning Su, Hung Li, Pei-Hsin Huang, Chiang-Ting Chien, Yih-Loong Lai, Chien-Nan Lee, Chi-An Chen, Wen-Fang Cheng, Shu-Chen Wei, Chong-Jen Yu, Fon-Jou Hsieh, Su-Ming Hsu
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

To examine the role of placenta growth factor (PlGF) in the pathogenesis of pulmonary emphysema, we generated PlGF-transgenic (TG) mice using a phosphoglycerate kinase promoter. This resulted in constitutive overexpression of PlGF. In these TG mice, pulmonary emphysema, with enlarged air spaces and enhanced pulmonary compliance, first appeared at 6 months of age and became prominent at 12 months. Increased alveolar septal cell apoptosis was noted in their lungs. Fluorescence-activated cell sorter analysis suggests that these apoptotic septal cells are type II pneumocytes. At the same time, the messenger RNA of vascular endothelial growth factor and platelet-endothelial cell adhesion molecule-1, an endothelial cell marker, were downregulated indicating a reduced number of endothelial cells and its survival factor VEGF. In vitro, exogenous PlGF can inhibit the proliferation and promote the cell death of mouse type II pneumocytes. In normal newborn mice, abundant expression of PlGF messenger RNA was detected in the lungs during saccular division but was rapidly downregulated after alveolarization was complete. Thus, a persistently elevated PlGF was detrimental to the developed lung and causes the emphysematous change seen in our TG mice. Our study suggests that PlGF plays an important role in the pathogenesis of pulmonary emphysema via its action on type II pneumocytes.
Increased Expression of Germinal Center–Associated Nuclear Protein RNA-Primase Is Associated with Lymphomagenesis
Authors: Satoru Fujimura, Yan Xing, Motohiro Takeya, Yasuyuki Yamashita, Koichi Ohshima, Kazuhiko Kuwahara, Nobuo Sakaguchi
Journal: Cancer Research (2005)

Abstract Lymphomas arise containing abnormalities of various differentiation stage-specific molecules. In the study reported here, we have shown abnormal up-regulation of germinal center B cell–associated GANP in various human lymphomas including mantle cell, diffuse large B cell, and Hodgkin lymphoma, by immunohistochemical analysis. To study the role of GANP in lymphomagenesis, we generated mutant mice (ganp-Tg) that express the transgenic ganp gene under immunoglobulin enhancer and promoter control. Ganp-Tg mice showed a high incidence of lymphomagenesis (29.5%) after aging with a non-B/non-T cell surface phenotype having slight CD45R/B220 expression and Ig transcripts of rearranged VH-DH-JH IgH loci. Lymphomas generated in ganp-Tg mice displayed similar pathologic characteristics to mouse reticulum cell neoplasm or Hodgkin lymphoma–like lesions. The VH sequences of individual mice showed that the tumors proliferated from a single clone or oligoclones, as is found in human diffuse large B-cell lymphomas and Hodgkin lymphoma. These results suggest that GANP overexpression is a causative factor in the generation of B lymphomas.
Use of linezolid in complex MDR-TB cases
Authors: Yi-Wen Huang, Hsin-Chieh Tsai, Ching-Nien Chang, Wen-Ta Yang
Journal: European Respiratory Journal (2012)

Introduction   The control of tuberculosis is facing challenges with the development of drug resistance as more drugs are used. Complex MDR-TB has recently emerged as a global public health issue. In Taiwan, there are around 600-800 MDR-TB cases with 1.0% new TB cases, 6.2% retreatment cases and 10.0% XDR-TB. Treating MDR-TB has become much more difficult, a new treatment regimen is mandatory.   Aims   Our aim is to investigate the use of linezolid in treating complex MDR-TB.   Methods   For subjects with persistent positive sputa after a prolonged use of 2 nd  line drugs or resistance to more than 7 medications, linezolid was utilized. Clinical, epidemiological and microbiological characteristics of all subjects were collected. Drug tolerance, side effects and treatment outcomes of linezolid were also recorded.   Results   Nine MDR-TB patients (6 men and 3 women with a median age of 47 years) received linezolid. The  M. tuberculosis  strains were resistant to a median of 7 drugs. Culture conversion occurred in 5 cases at a median of 21 days. Six out of 9 (69%) cases had side effects including mild to moderate-severe anemia, thrombocytopenia, optic neuropathy, and peripheral neuropathy. Most side effects resolved after linezolid was reduced or ceased. Linezolid was tolerated well by most patients. However, one patient stopped due to severe side effects and one died from non-TB caused co-morbidity.   Conclusions   Treatment for complex MDR-TB is complicated and time-consuming, linezoid has appeared to be a potential drug with a high sputum conversion rate and good tolerance. However, further study is required to determine the effect of linezolid in MDR-TB since the present study is limited by its small size.
Loss of Two Introns from the Magnolia tripetala Mitochondrial cox2 Gene Implicates Horizontal Gene Transfer and Gene Conversion as a Novel Mechanism of Intron Loss
Authors: N. J. Hepburn, D. W. Schmidt, J. P. Mower
Journal: Molecular Biology and Evolution (2012)

Intron loss is often thought to occur through retroprocessing, which is the reverse transcription and genomic integration of a spliced transcript.In plant mitochondria, several unambiguous examples of retroprocessing are supported by the parallel loss of an intron and numerous adjacent RNA edit sites, but in most cases, the evidence for intron loss via retroprocessing is weak or lacking entirely.To evaluate mechanisms of intron loss, we designed a polymerase chain reaction (PCR)-based assay to detect recent intron losses from the mitochondrial cox2 gene within genus Magnolia, which was previously suggested to have variability in cox2 intron content.Our assay showed that all 22 examined species have a cox2 gene with two introns.However, one species, Magnolia tripetala, contains an additional cox2 gene that lacks both introns.Quantitative PCR showed that both M. tripetala cox2 genes are present in the mitochondrial genome.Although the intronless gene has lost several ancestral RNA edit sites, their distribution is inconsistent with retroprocessing models.Instead, phylogenetic and gene conversion analyses indicate that the intronless gene was horizontally acquired from a eudicot and then underwent gene conversion with the native intron-containing gene.The models are presented to summarize the roles of horizontal gene transfer and gene conversion as a novel mechanism of intron loss.
A Family of Selfish Minicircular Chromosomes with Jumbled Chloroplast Gene Fragments from a Dinoflagellate
Authors: Zhaoduo Zhang, T. Cavalier-Smith, B. R. Green
Journal: Molecular Biology and Evolution (2001)

Chloroplast genes of several dinoflagellate species are located on unigenic DNA minicircular chromosomes. We have now completely sequenced five aberrant minicircular chromosomes from the dinoflagellate Heterocapsa triquetra. These probably nonfunctional DNA circles lack complete genes, with each being composed of several short fragments of two or three different chloroplast genes and a common conserved region with a tripartite 9G-9A-9G core like the putative replicon origin of functional single-gene circular chloroplast chromosomes. Their sequences imply that all five circles evolved by differential deletions and duplications from common ancestral circles bearing fragments of four genes: psbA, psbC, 16S rRNA, and 23S rRNA. It appears that recombination between separate unigenic chromosomes initially gave intermediate heterodimers, which were subsequently stabilized by deletions that included part or all of one putative replicon origin. We suggest that homologous recombination at the 9G-9A-9G core regions produced a psbA/psbC heterodimer which generated two distinct chimeric circles by differential deletions and duplications. A 23S/16S rRNA heterodimer more likely formed by illegitimate recombination between 16S and 23S rRNA genes. Homologous recombination between the 9G-9A-9G core regions of both heterodimers and additional differential deletions and duplications could then have yielded the other three circles. Near identity of the gene fragments and 9G-9A-9G cores, despite diverging adjacent regions, may be maintained by gene conversion. The conserved organization of the 9G-9A-9G cores alone favors the idea that they are replicon origins and suggests that they may enable the aberrant minicircles to parasitize the chloroplast's replication machinery as selfish circles.
Increased hepatic stiffness as consequence of high hepatic afterload in the fontan circulation: A vascular doppler and elastography study
Authors: Shaija S. Kutty, Qinghai Peng, David A. Danford, Scott E. Fletcher, Deborah Perry, Geoffrey A. Talmon, Cynthia Scott, John D. Kugler, Kim F. Duncan, Ruben E. Quiros-Tejeira, Shelby Kutty
Journal: Hepatology (2013)

Hepatic dysfunction is a recognized complication after Fontan palliation of congenital heart disease. We sought to quantitatively measure hepatic stiffness and vascular Doppler indices using ultrasound (US) and shear wave elastography (SWE) in a Fontan cohort. Subjects were prospectively recruited for echocardiography and real-time hepatic duplex US with SWE for hepatic stiffness (kPa). Doppler peak velocities, velocity time integral, resistive, pulsatility, acceleration indices (RI, PI, AI), and flow volume were measured in celiac artery, superior mesenteric artery, and main portal vein (MPV). A subset underwent cardiac catheterizations with liver biopsy. Correlations were explored between SWE, duplex, hemodynamic, and histopathologic data. In all, 106 subjects were studied including 41 patients with Fontan physiology (age 13.8 ± 6 years, weight 45.4 ± 23 kg) and 65 controls (age 15.0 ± 8.4 years, weight 47.9 ± 22 kg). Patients with Fontan physiology had significantly higher hepatic stiffness (15.6 versus 5.5 kPa, P < 0.0001), higher celiac RI (0.78 versus 0.73, P = 0.04) superior mesenteric artery RI (0.89 versus 0.84, P = 0.005), and celiac PI (1.87 versus 1.6, P = 0.034); while MPV flow volume (287 versus 420 mL/min in controls, P = 0.007) and SMA AI (829 versus 1100, P = 0.002) were lower. Significant correlation was seen for stiffness with ventricular end-diastolic pressure (P = 0.001) and pulmonary artery wedge pressure (P = 0.009). Greater stiffness correlated with greater degrees of histopathologic fibrosis. No significant change was seen in stiffness or other duplex indices with age, gender, time since Fontan, or ventricular morphology.Elevated hepatic afterload in Fontan, manifested by high ventricular end-diastolic pressures and pulmonary arterial wedge pressures, is associated with remarkably increased hepatic stiffness, abnormal vascular flow patterns, and fibrotic histologic changes. The MPV is dilated and carries decreased flow volume, while the celiac and superior mesenteric arterial RI is increased. SWE is feasible in this population and shows promise as a means for predicting disease severity on liver biopsy.
True dedication to clinical research: the Clinical Center of the National Institutes of Health receives the 2011 Mary Woodard Lasker Award for Public Service
Authors: Karen Honey
Journal: Journal of Clinical Investigation (2011)

The Holy Grail for the majority of physician-scientists is for their work to translate into something beneficial for human health. As the largest hospital in the United States devoted entirely to clinical research, the Clinical Center of the NIH (Figure ​(Figure1)1) is the place where many have reached this goal. The Albert and Mary Lasker Foundation is honoring the Clinical Center of the NIH with the 2011 Mary Woodard Lasker Award for Public Service for its many years of service as a model research hospital that provides high-quality patient care; enables rapid translation of laboratory observations into new, innovative approaches for diagnosing, treating, and preventing disease; and trains thousands of physician-scientists who lead the way in translational biomedical research. 



Figure 1

The Mark O. Hatfield Clinical Research Center, the newest addition to the Clinical Center of the NIH, which is being honored with the 2011 Mary Woodard Lasker Award for Public Service for providing innovative therapy and high-quality patient care, treating ...
British Journal of Sports Medicine in the digital age
Authors: D Mitchell
Journal: British Journal of Sports Medicine (2006)

water, and swimming lead to abnormal remodelling of the left ventricle, but it does indicate that care should be taken when prescribing aqua exercises and swimming.(1) Decompensated heart failure is an absolute contraindication to immersion and swimming.(2) Patients with severe MI and/or CHF who tolerate sleeping in a flat position can bathe in a tub-that is, balneotherapeutic baths-in a half sitting position-that is, immersed no deeper than up to the xiphoid.(3) Therapeutic water exercises in a pool-for example, for orthopaedic reasons-can be allowed for patients with severe MI and severe CHF provided that they are in an upright position and immersed no deeper than the xiphoid.(4) Whether swimming is appropriate, and truly safe in the long term, in patients with severe MI and severe CHF needs to be investigated in a study of patients in a swimming programme and compared with non-swimming patients with CHF of similar aetiology and severity of disease.
The influence of growing up on a farm on adult allergy, asthma and lung function
Authors: Brittany Campbell, Cecilie Svanes, Chantal Raherison, Bénédicte Leynaert, Caroline Lodge, Adrian Lowe, Thorarinn Gislason, Joachim Heinrich, Jordi Sunyer, Francisco Gómez Real, Dan Norbäck, Melanie Matheson, Matthias Wjst, Julia Dratva, Roberto de Marco, Christer Janson, Shyamali Dharmage
Journal: European Respiratory Journal (2014)

Aim : Investigate the impact of early-life farm exposure on objective measures of adult sensitization, asthma and lung function.   Background : Early life farming exposure may protect against asthma and allergies, but no study has investigated this effect on measures of lung function.   Methods : The ECRHS II recorded living environment (farm, rural environment, inner city) in the first 5 years of life for ∼10,000 26-54 year old participants from 14 countries. Outcomes assessed were: bronchial hyperreactivity (BHR, a fall of >= 20% in FEV1 after methacholine challenge test), current asthma (BHR + wheezing or use of asthma medications in past 12 months), and sensitization. Regression techniques investigated the associations between all outcomes and early childhood environment for any 9farming effect9.   Results : Compared to those who grew up in a city, a significantly lower odds of sensitization was observed in those who grew up in a farm (aOR 0.46 95% CI 0.37-0.58) and rural environment (aOR 0.83 95% CI 0.73-0 .94). However, the protective effect for those who grew up on a farm was significantly higher than for a rural environment, which was consistent across all participating countries. Early-life on a farm was also associated with less asthma, BHR and rhinitis, but only in the presence of atopy. Also, women with early-life farm exposure had significantly increased FEV1, independent of both atopy and asthma.   Conclusions : The protective effect of farming on asthma, BHR, and rhinitis are driven by atopy. However, farming seems to have an independent beneficial effect on FEV1 among females, which is a novel finding. The protective 9farm-effect9 appears to be stronger than the protective 9rural effect9.
A pathway for entry of reoviruses into the host through M cells of the respiratory tract.
Authors: M J Morin, A Warner, B N Fields
Journal: The Journal of Experimental Medicine (1994)

Many microorganisms gain access to the systemic circulation after entering the respiratory tract. The precise pathways used to cross the mucosal barriers of the lungs have not been clearly described. We have used the mammalian reoviruses in order to determine the pathway that a systemic virus uses to penetrate the mucosal barrier and enter the systemic circulation after entering the airways of the lungs. Reoviruses enter through pulmonary M cells, which overlie bronchus-associated lymphoid tissue, and subsequently spread to regional lymph nodes. Thus, the pathway through M cells represents a strategy by which viruses and probably other microorganisms can penetrate the mucosal surface of the respiratory tract and thereby enter the systemic circulation.
Circadian Control of Epigenetic Modifications Modulates Metabolism
Authors: Hélène Duez, Bart Staels
Journal: Circulation Research (2011)

A new study in reveals how circadian epigenetic modification of DNA drives diurnal gene expression in mouse liver and is Science required for the maintenance of lipid homeostasis.Numerous physiological processes (including sleep/wake cycles, body temperature, blood pressure, hormone secretion, metabolic pathways, etc display diurnal variations.These circadian rhythms are programmed centrally by light, allowing alignment to seasonal variations of night/day cycles, and peripherally by food availability.Disruption of these circadian rhythms (due to frequent jetlag, sleep restriction or rotating shift work) predisposes to metabolic disorders and cardiovascular diseases .Genome-wide studies indicate that the 1 expression of 10 15 of genes cycles in many organs involved in metabolic control, such as the liver, and cardiovascular function, such as -%
Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats.
Authors: D L Greiner, J P Mordes, E S Handler, M Angelillo, N Nakamura, A A Rossini
Journal: The Journal of Experimental Medicine (1987)

To investigate the role of RT6+ T cells in the pathogenesis of diabetes in BB/W rats, we treated animals from the diabetes-resistant (DR) subline with anti-RT6.1 lymphocytotoxic mAb. This depleted greater than 95% of peripheral RT6+ T cells but did not substantially reduce levels of circulating T cells or the in vitro response of spleen cells to mitogen. Treatment of 30-d-old DR BB/W rats in this way: induced insulitis and diabetes, rendered nondiabetic RT6-depleted DR rats susceptible to the adoptive transfer of diabetes by spleen cells from acutely diabetic BB/W rats, and yielded DR spleen cell populations capable of the adoptive transfer of diabetes to diabetes-prone (DP) or DR recipients. Treatment of DR rats beginning at 60 d of age failed to produce these effects. These results suggest that both susceptibility and resistance to diabetes in the BB/W rat are in part regulated by the RT6+ T cell subset and provide evidence for the importance of regulatory T lymphocytes in the pathogenesis of autoimmunity and diabetes in BB/W rats.