tbuckley/cabot-search huggingface dataset:
Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock
Authors: Julia V. Busik, Maria Tikhonenko, Ashay Bhatwadekar, Madalina Opreanu, Nafissa Yakubova, Sergio Caballero, Danny Player, Takahiko Nakagawa, Aqeela Afzal, Jennifer Kielczewski, Andrew Sochacki, Stephanie Hasty, Sergio Li Calzi, Sungjin Kim, Shane K. Duclas, Mark S. Segal, Dennis L. Guberski, Walter J. Esselman, Michael E. Boulton, Maria B. Grant
Journal: The Journal of Experimental Medicine (2009)

The present epidemic of diabetes is resulting in a worldwide increase in cardiovascular and microvascular complications including retinopathy. Current thinking has focused on local influences in the retina as being responsible for development of this diabetic complication. However, the contribution of circulating cells in maintenance, repair, and dysfunction of the vasculature is now becoming appreciated. Diabetic individuals have fewer endothelial progenitor cells (EPCs) in their circulation and these cells have diminished migratory potential, which contributes to their decreased reparative capacity. Using a rat model of type 2 diabetes, we show that the decrease in EPC release from diabetic bone marrow is caused by bone marrow neuropathy and that these changes precede the development of diabetic retinopathy. In rats that had diabetes for 4 mo, we observed a dramatic reduction in the number of nerve terminal endings in the bone marrow. Denervation was accompanied by increased numbers of EPCs within the bone marrow but decreased numbers in circulation. Furthermore, denervation was accompanied by a loss of circadian release of EPCs and a marked reduction in clock gene expression in the retina and in EPCs themselves. This reduction in the circadian peak of EPC release led to diminished reparative capacity, resulting in the development of the hallmark feature of diabetic retinopathy, acellular retinal capillaries. Thus, for the first time, diabetic retinopathy is related to neuropathy of the bone marrow. This novel finding shows that bone marrow denervation represents a new therapeutic target for treatment of diabetic vascular complications.
Molecular testing for antibiotic resistance in Helicobacter pylori
Authors: R J Owen
Journal: Gut (2002)

<h3>Abstract</h3> Both environmental differences and geographic distances may contribute to the genetic differentiation of populations on the landscape. Understanding the relative importance of these drivers is of particular interest in the context of geographic range limits, as both swamping gene flow and lack of genetic diversity are hypothesized causes of range limits. We investigated the landscape genetic structure of 32 populations of the annual wildflower <i>Clarkia pulchella</i> from across the species' geographic range in the interior Pacific North-west. We tested whether climatic differences between populations influenced the magnitude of their genetic differentiation. We also investigated patterns of population structure and geographic gradients in genetic diversity. Contrary to our expectations, we found an increase in genetic diversity near the species' northern range edge. We found no notable contribution of climatic differences to genetic differentiation, indicating that any processes that might operate to differentiate populations based on temperature or precipitation are not affecting the putatively neutral loci in these analyses. Rather, these results support seed and pollen movement at limited distances relative to the species' range and that this movement and the subsequent incorporation of immigrants into the local gene pool are not influenced by temperature or precipitation similarities among populations. We found that populations in the northern and southern parts of the range tended to belong to distinct genetic groups and that central and eastern populations were admixed between these two groups. This pattern could be the result of a past or current geographic barrier associated with the Columbia Plateau, or it could be the result of spread from separate sets of refugia after the last glacial maximum.
Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial
Authors: Jesus San Miguel, Katja Weisel, Philippe Moreau, Martha Lacy, Kevin Song, Michel Delforge, Lionel Karlin, Hartmut Goldschmidt, Anne Banos, Albert Oriol, Adrian Alegre, Christine Chen, Michele Cavo, Laurent Garderet, Valentina Ivanova, Joaquin Martinez-Lopez, Andrew Belch, Antonio Palumbo, Stephen Schey, Pieter Sonneveld, Xin Yu, Lars Sternas, Christian Jacques, Mohamed Zaki, Meletios Dimopoulos
Journal: The Lancet Oncology (2013)
Sword swallowing and its side effects
Authors: Brian Witcombe, Dan Meyer
Journal: BMJ (2006)

<b>Objective</b> To evaluate information on the practice and associated ill effects of sword swallowing. <b>Design</b> Letters sent to sword swallowers requesting information on technique and complications. <b>Setting</b> Membership lists of the Sword Swallowers9 Association International. <b>Participants</b> 110 sword swallowers from 16 countries. <b>Results</b> We had information from 46 sword swallowers. Major complications are more likely when the swallower is distracted or swallows multiple or unusual swords or when previous injury is present. Perforations mainly involve the oesophagus and usually have a good prognosis. Sore throats are common, particularly while the skill is being learnt or when performances are too frequent. Major gastrointestinal bleeding sometimes occurs, and occasional chest pains tend to be treated without medical advice. Sword swallowers without healthcare coverage expose themselves to financial as well as physical risk. <b>Conclusions</b> Sword swallowers run a higher risk of injury when they are distracted or adding embellishments to their performance, but injured performers have a better prognosis than patients who suffer iatrogenic perforation.
Patient Race/Ethnicity and Patient-Physician Race/Ethnicity Concordance in the Management of Cardiovascular Disease Risk Factors for Patients With Diabetes
Authors: Ana H. Traylor, Usha Subramanian, Connie S. Uratsu, Carol M. Mangione, Joe V. Selby, Julie A. Schmittdiel
Journal: Diabetes Care (2009)

OBJECTIVE Patient-physician race/ethnicity concordance can improve care for minority patients. However, its effect on cardiovascular disease (CVD) care and prevention is unknown. We examined associations of patient race/ethnicity and patient-physician race/ethnicity concordance on CVD risk factor levels and appropriate modification of treatment in response to high risk factor values (treatment intensification) in a large cohort of diabetic patients. RESEARCH DESIGN AND METHODS The study population included 108,555 adult diabetic patients in Kaiser Permanente Northern California in 2005. Probit models assessed the effect of patient race/ethnicity on risk factor control and treatment intensification after adjusting for patient and physician-level characteristics. RESULTS African American patients were less likely than whites to have A1C &amp;lt;8.0% (64 vs. 69%, P &amp;lt; 0.0001), LDL cholesterol &amp;lt;100 mg/dl (40 vs. 47%, P &amp;lt; 0.0001), and systolic blood pressure (SBP) &amp;lt;140 mmHg (70 vs. 78%, P &amp;lt; 0.0001). Hispanic patients were less likely than whites to have A1C &amp;lt;8% (62 vs. 69%, P &amp;lt; 0.0001). African American patients were less likely than whites to have A1C treatment intensification (73 vs. 77%, P &amp;lt; 0.0001; odds ratio [OR] 0.8 [95% CI 0.7–0.9]) but more likely to receive treatment intensification for SBP (78 vs. 71%, P &amp;lt; 0.0001; 1.5 [1.3–1.7]). Hispanic patients were more likely to have LDL cholesterol treatment intensification (47 vs. 45%, P &amp;lt; 0.05; 1.1 [1.0–1.2]). Patient-physician race/ethnicity concordance was not significantly associated with risk factor control or treatment intensification. CONCLUSIONS Patient race/ethnicity is associated with risk factor control and treatment intensification, but patient-physician race/ethnicity concordance was not. Further research should investigate other potential drivers of disparities in CVD care.
Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure
Authors: Karl Swedberg, James B. Young, Inder S. Anand, Sunfa Cheng, Akshay S. Desai, Rafael Diaz, Aldo P. Maggioni, John J.V. McMurray, Christopher O'Connor, Marc A. Pfeffer, Scott D. Solomon, Yan Sun, Michal Tendera, Dirk J. van Veldhuisen
Journal: New England Journal of Medicine (2013)

Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia.
The Direct Binding of a p58 Killer Cell Inhibitory Receptor to Human Histocompatibility Leukocyte Antigen (HLA)-Cw4 Exhibits Peptide Selectivity
Authors: Sumati Rajagopalan, Eric O. Long
Journal: The Journal of Experimental Medicine (1997)

Natural killer (NK) cells in mice and humans express a number of structurally diverse receptors that inhibit target cell lysis upon recognition of major histocompatibility complex (MHC) class I molecules expressed on targets. The contribution of peptide to the structural features of class I required for NK cell inhibition appears to vary depending on the type of receptor engaged. Thus, while there is no peptide specificity in NK inhibition mediated by Ly-49A in the mouse, human histocompatibility antigen (HLA)-B*2705-specific NK clones displayed selectivity for peptides. In this report, we examine the role of peptide in the recognition of HLA-C by the defined killer cell inhibitory receptor (KIR) cl42 with established specificity for HLA-Cw4. Binding of soluble KIR cl42 molecules to HLA-Cw4 expressed on transporter associated with antigen presentation (TAP)-deficient RMA-S cells occurred only upon exogenous peptide loading. Moreover, there was peptide selectivity in that certain substitutions at positions 7 and 8 of the nonamer peptide QYDDAVYKL abolished Cw4 interaction with KIR cl42 despite similar surface expression of HLA-C. The specificity of this direct interaction between peptide-loaded HLA-Cw4 on RMA-S cells and soluble KIR cl42 correlated with recognition by NK clones in that they were inhibited only by HLA-Cw4 loaded with the appropriate peptides.
Tumor Karyotype Predicts Clinical Outcome in Colorectal Cancer Patients
Authors: Georgia Bardi, Claus Fenger, Bertil Johansson, Felix Mitelman, Sverre Heim
Journal: Journal of Clinical Oncology (2004)

To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC).Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates.In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patients with stage I and II carcinomas, none of the clinicopathologic variables could independently predict patient survival, whereas the presence of structural chromosomal aberrations was the only independent predictor of poor prognosis. In the subset of patients with stage III carcinomas, the presence of structural changes of chromosome 8 was a stronger independent predictor of prognosis than was tumor grade.Cytogenetic tumor features are valuable predictors of prognosis in CRC patients. The tumor karyotype should therefore be taken into account in the clinical management of patients with this disease, especially for patients having cancers of the early or intermediate stages I, II, and III.
Mutation of Succinate Dehydrogenase Subunit C Results in Increased O2·−, Oxidative Stress, and Genomic Instability
Authors: Benjamin G. Slane, Nùkhet Aykin-Burns, Brian J. Smith, Amanda L. Kalen, Prabhat C. Goswami, Frederick E. Domann, Douglas R. Spitz
Journal: Cancer Research (2006)

Abstract Mutations in genes coding for succinate dehydrogenase (SDH) subunits are believed to contribute to cancer and aging, but the mechanism for this is unclear. Hamster fibroblasts expressing a mutation in SDH subunit C (SDHC; B9) showed 3-fold increases in dihydroethidine and dichlorodihydrofluorescein (CDCFH2) oxidation indicative of increased steady-state levels of O2·− and H2O2, increases in glutathione/glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental B1 cells. B9 cells also showed characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation–induced cytotoxicity. Expression of wild-type (WT) human SDHC in B9 cells caused prooxidant production, glucose consumption, sensitivity to glucose deprivation–induced cytotoxicity, and aneuploidy to revert to the WT phenotype. These data show that SDHC mutations cause increased O2·− production, metabolic oxidative stress, and genomic instability and that mutations in genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer cells. These results also allow for the speculation that DNA damage to genes coding for electron transport chain proteins could result in a “mutator phenotype” by increasing steady-state levels of O2·− and H2O2. (Cancer Res 2006; 66(15): 7615-20)
Alternative multiple breath washout outcomes for clinical trials in cystic fibrosis
Authors: Felix Ratjen, Juliana Salazar, Renee Jensen, Reshma Amin, Per Gustafsson, Sanja Stanojevic, Padmaja Subbarao
Journal: European Respiratory Journal (2012)

The Lung Clearance Index (LCI) is a sensitive marker of early lung disease. and LCI, but not spirometry, was able to detect treatment effects of hypertonic saline in CF patients with mild disease (Amin et al; Thorax 2010). We used data from this interventional trial to investigate whether any other outcomes of the multiple breath washout could detect treatment effects similar to LCI. Using a cross-over design, patients were randomized to either hypertonic saline or isotonic saline in a randomized sequence, separated by a 4 week washout period. MBW was measured in triplicate by mass spectrometry (AMIS 2000; Innovision A/S, Odense, Denmark) using a gas mixture containing 4% SF 6 , 4% He, 21% O 2  and balanced N 2 . The current analysis includes 15 subjects for whom the following additional outcome measures could be assessed: normalized concentration of end tidal tracer gas (Cnet) at 6 turnovers (6T0), moment ratios (M1M0, M2M0) and LCI measured by helium. No significant treatment effects were observed for LCI measured with helium as a tracer gas. For SF 6,  unlike the LCI, Cnet at 6TO was not able to detect a treatment effect of hypertonic saline. Moment ratios showed different results depending on the ratio chosen; M1M0 was significantly lower for hypertonic saline at 1/40 th  the starting SF 6  concentration, whereas both M1M0 and M2M0 demonstrated a significant treatment effect when 6TO was used as the washout end point. These findings suggest that moment ratios, which may be less sensitive to variations in respiratory rate and tidal volume, may provide a complementary outcome to the LCI in clinical trials.  Supported by the Sellers Chair for Cystic Fibrosis.
A virtual world of paleontology
Authors: John A Cunningham, Imran A Rahman, Stephan Lautenschlager, Emily J Rayfield, Philip C J Donoghue
Journal: Trends in Ecology & Evolution (2014)

Computer-aided visualization and analysis of fossils has revolutionized the study of extinct organisms. Novel techniques allow fossils to be characterized in three dimensions and in unprecedented detail. This has enabled paleontologists to gain important insights into their anatomy, development, and preservation. New protocols allow more objective reconstructions of fossil organisms, including soft tissues, from incomplete remains. The resulting digital reconstructions can be used in functional analyses, rigorously testing long-standing hypotheses regarding the paleobiology of extinct organisms. These approaches are transforming our understanding of long-studied fossil groups, and of the narratives of organismal and ecological evolution that have been built upon them.
Cell Type–Specific Targeted Mutations of <i>Kras</i> and <i>Pten</i> Document Proliferation Arrest in Granulosa Cells versus Oncogenic Insult to Ovarian Surface Epithelial Cells
Authors: Heng-Yu Fan, Zhilin Liu, Marilene Paquet, Jinrong Wang, John P. Lydon, Francesco J. DeMayo, JoAnne S. Richards
Journal: Cancer Research (2009)

Abstract The small G-protein KRAS is crucial for mediating gonadotropin-induced events associated with ovulation. However, constitutive expression of KrasG12D in granulosa cells disrupted normal follicle development leading to the persistence of abnormal follicle-like structures containing nonmitotic cells. To determine what factors mediate this potent effect of KrasG12D, gene profiling analyses were done. We also analyzed KrasG12D;Cyp19-Cre and KrasG12;Pgr-Cre mutant mouse models that express Cre prior to or after the initiation of granulosa cell differentiation, respectively. KrasG12D induced cell cycle arrest in granulosa cells of the KrasG12D;Cyp19-Cre mice but not in the KrasG12D;Pgr-Cre mice, documenting the cell context–specific effect of KrasG12D. Expression of KrasG12D silenced the Kras gene, reduced cell cycle activator genes, and impaired the expression of granulosa cell and oocyte-specific genes. Conversely, levels of PTEN and phosphorylated p38 mitogen-activated protein kinase (MAPK) increased markedly in the mutant granulosa cells. Because disrupting Pten in granulosa cells leads to increased proliferation and survival, Pten was disrupted in the KrasG12D mutant mice. The Pten/Kras mutant mice were infertile but lacked granulosa cell tumors. By contrast, the Ptenfl/fl;KrasG12D;Amhr2-Cre mice developed aggressive ovarian surface epithelial cell tumors that did not occur in the Ptenfl/fl;KrasG12D;Cyp19-Cre or Ptenfl/fl;KrasG12D;Pgr-Cre mouse strains. These data document unequivocally that Amhr2-Cre is expressed in and mediates allelic recombination of oncogenic genes in ovarian surface epithelial cells. That KrasG12D/Pten mutant granulosa cells do not transform but rather undergo cell cycle arrest indicates that they resist the oncogenic insults of Kras/Pten by robust self-protecting mechanisms that silence the Kras gene and elevate PTEN and phosphorylated p38 MAPK. [Cancer Res 2009;69(16):6463–72]
Contribution of Small GTPase Rho and Its Target Protein ROCK in a Murine Model of Lung Fibrosis
Authors: YASUO SHIMIZU, KUNIO DOBASHI, KUNIHIKO IIZUKA, TAKEO HORIE, KOUKI SUZUKI, HIDEO TUKAGOSHI, TUGIO NAKAZAWA, YOICHI NAKAZATO, MASATOMO MORI
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Excess fibroblasts and inflammatory cells may play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The small GTPase, Rho, and its target protein, Rho-associated coiled-coil-forming protein kinase (ROCK), have been recognized to be major regulators of cell locomotion mediated by reorganization of the actin cytoskelton. Activated ROCK inhibits myosin phosphatase, and this in turn induces phosphorylation of the myosin light chain (MLC). To determine the mechanisms underlying the deterioration process of IPF, we investigated the effect of Y-27632, a selective ROCK inhibitor, in a murine model of bleomycin (BLM)-induced lung fibrosis. The Aschcroft score and hydroxyproline content of the BLM-treated mouse lung decreased in response to Y-27632 treatment. The number of broncoalveolar cells was decreased by Y-27632, and migration of macrophages, neutrophils, and fibroblasts in vitro was inhibited by Y-27632 regardless of various stimuli. Although expression of ROCK-II mRNA in the lung homogenates of the BLM-treated mice was increased approximately 9-fold, expression of ROCK-II protein showed only a slight tendency to increase. BLM elevated MLC phosphorylation levels, and Y-27632 inhibited BLM response. These findings indicate that the Rho/ROCK-mediated pathway plays an important role in IPF, and that blocking of this pathway leads to inhibition of IPF development.
Immunogenicity of recombinant hepatitis B vaccine (rHBV) in recipients of unrelated or related allogeneic hematopoietic cell (HC) transplants
Authors: Dana Jaffe, Esperanza B. Papadopoulos, James W. Young, Richard J. O'Reilly, Susan Prockop, Nancy A. Kernan, Ann Jakubowski, Farid Boulad, Miguel-Angel Perales, Hugo Castro-Malaspina, Trudy N. Small
Journal: Blood (2006)
Inflammation in pulmonary arterial hypertension: is it time to quell the fire?
Authors: Paul M. Hassoun
Journal: European Respiratory Journal (2014)

Two new studies demonstrate an association between circulating inflammatory mediators and mortality in PAH http://ow.ly/szrQoInflammare, or to set ablaze, is the Latin origin of the word inflammation, a physical condition that was undoubtedly already familiar to the ancient Egyptians and Greeks.It is, however, the Roman Aulus Celsus who is credited with describing, in the first century AD, the four cardinal signs of inflammation consisting of rubor et tumor cum calore et dolore (redness and swelling with heat and pain).Two centuries later, Galen promoted the humoral view of inflammation as a potential part of the healing process rather than a pure pathological process, and may have proposed the fifth cardinal sign (functio laesa or loss of function) [1], although this is also attributed to Virchow in the 19th century [2].And while we now know that, in many pathologies characterised by inflammation, the initial four cardinal signs can be subclinical and silent, it is clear that for Virchow inflammation was ultimately pathologic since it lead to loss of function.