tbuckley/cabot-search huggingface dataset:
The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain
Authors: Daniel R. Beisner, Petra Langerak, Albert E. Parker, Carol Dahlberg, Francella J. Otero, Sue E. Sutton, Laurent Poirot, Whitney Barnes, Michael A. Young, Sherry Niessen, Tim Wiltshire, Ursula Bodendorf, Bruno Martoglio, Benjamin Cravatt, Michael P. Cooke
Journal: The Journal of Experimental Medicine (2012)

B cell development requires tight regulation to allow for the generation of a diverse repertoire while preventing the development of autoreactive cells. We report, using N-ethyl-N-nitrosourea (ENU)–induced mutagenesis, the identification of a mutant mouse (chompB) with a block in early B cell development. The blockade occurs after the transitional 1 (T1) stage and leads to a decrease in mature B cell subsets and deficits in T cell–dependent antibody responses. Additionally, chompB mice have decreases in myeloid dendritic cells (DCs). The mutation was mapped to the intramembrane protease signal peptide peptidase-like 2a (Sppl2a), a gene not previously implicated in immune cell development. Proteomic analysis identified the invariant chain (CD74) as a key substrate of Sppl2a and suggests that regulated intramembrane proteolysis of CD74 by Sppl2a contributes to B cell and DC survival. Moreover, these data suggest that modulation of Sppl2a may be a useful therapeutic strategy for treatment of B cell dependent autoimmune disorders.
Diurnal ventilation via mouthpiece: survival in end-stage Duchenne patients
Authors: M. Toussaint, M. Steens, G. Wasteels, P. Soudon
Journal: European Respiratory Journal (2006)

The present study aimed to assess the impact of diurnal mouthpiece intermittent positive pressure ventilation (MIPPV) as the extension of the nasal intermittent positive pressure ventilation (NIPPV) in Duchenne muscular dystrophy (DMD). In total, 42 DMD patients aged 15–33 yrs, normocapnic at night with NIPPV and receiving MIPPV since end-diurnal hypercapnia, were studied. Transcutaneous CO 2 tension ( P t,CO 2 ) was prospectively monitored at the end of the day, before and after MIPPV initiation. Vital capacity (VC), breathing pattern and maximal inspiratory strength were measured. Patients were asked to score the presence (1 point) or absence (0 point) of seven respiratory-linked symptoms before and after MIPPV establishment. Survival rates reached 88, 77, 58 and 51% after 1, 3, 5 and 7 yrs, respectively. The mean survival rate was 31 yrs. VC stabilised during 5 yrs with MIPPV. Symptom scores significantly decreased and P t,CO 2 normalised during the day (8.17±2.22 to 5.78±0.73 kPa). No accident and minor side-effects were observed in this 184 cumulated patient-yrs study. In conclusion, daytime mouthpiece ventilation is safe, prolongs survival and stabilises vital capacity in Duchenne muscular dystrophy patients. It is recommended on the condition that patients are equipped with a self-supporting harness.
Phenylbutyrate Therapy for Pyruvate Dehydrogenase Complex Deficiency and Lactic Acidosis
Authors: Rosa Ferriero, Giuseppe Manco, Eleonora Lamantea, Edoardo Nusco, Maria I. Ferrante, Paolo Sordino, Peter W. Stacpoole, Brendan Lee, Massimo Zeviani, Nicola Brunetti-Pierri
Journal: Science Translational Medicine (2013)

Phenylbutyrate enhances pyruvate dehydrogenase enzyme complex (PDHC) activity through inhibition of PDHC kinase, rescues the severe phenotype of a zebrafish model of PDHC deficiency, and prevents systemic lactic acidosis.
A4.8 The oxidative burst mediates resolution of inflammation and bone homeostasis in gout
Authors: C Schauer, C Czegley, R Billyy, J Hahn, J Rech, L Munoz, G Schett, M Herrmann, MH Hoffmann
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> The production of reactive oxygen species (ROS) during the oxidative burst is of crucial importance for the regulation of inflammation and the prevention of autoimmunity. Diminished ROS-production was reported to cause aggravation of disease in animal models of arthritis, multiple sclerosis, and psoriasis. In a murine gout model, ROS-deficient animals exhibit exacerbated and chronic inflammation and excessive new bone formation. The aim of this project is to characterise this phenotype and to elucidate its implications for human individuals with gout. <h3>Methods</h3> Experimental gouty arthritis was induced by intraosseal injection of monosodium urate crystals (MSU) into the foot pads of wild type and Ncf1** mice that have a defective ROS-formation from phagocytes due to a mutation in a subunit of the NADPH oxidase complex 2. Paws were taken at different time points after injection and were subjected to histopathological and micro-computed tomography analyses. The role of different cell types (neutrophil granulocytes, inflammatory monocytes) and key cytokines of inflammation (IL-1, IL-6, TNF) was determined by blockade with antibodies, anakinra, or etanercept, respectively, <i>in vivo</i>. Human individuals with acute and chronic gout were analysed by dual energy computer tomography (DECT) for deposition of MSU and bone remodelling. Furthermore, their blood was analysed for their capacity to undergo oxidative burst and formation of neutrophil extracellular traps (NETs). <h3>Results</h3> MSU-injected Ncf1** mice exhibited exacerbated and chronic paw inflammation with dramatic bone turnover: while on the ipsilateral site of the injection, osteolysis was predominant, large osteophytes were building on the contralateral side. In contrast, the transient inflammation developing after MSU-injection in wild type animals did not cause major changes in bone homeostasis. Depletion of neutrophils ameliorated inflammation in Ncf1** mice, but lead to chronification of arthritis in wild type mice, arguing for a role of these cells in the resolution of inflammation. Blockade on TNF, IL-1, and IL-6 all significantly dampened inflammation. In human individuals with gout, lesions and bony spurs reminiscent of those in mice could be found by DECT. <h3>Conclusion</h3> Upon ROS-deficiency in mice, dysregulated neutrophil function and production of inflammatory cytokines results in chronic inflammation and massive bone remodelling in gouty arthritis. The pattern of bone destruction and new bone formation found in human gout suggests that similar mechanisms could be at work.
Allergic rhinitis is a risk factor for traffic safety
Authors: E. F. P. M. Vuurman, L. L. Vuurman, I. Lutgens, B. Kremer
Journal: Allergy (2014)

Abstract Background Allergic rhinitis ( AR ) affects up to 30% of the adult population and symptomatic patients continue to engage in daily life activities, including car driving. Previous studies have shown that AR can impair cognitive functions, especially during longer‐lasting tasks. Other reports suggest negative effects on psychomotor functions such as driving, but no clear evidence has been presented yet. Objectives Primary objective was to determine the effect of AR per se on actual driving performance and compare it with the effects of treated AR . Methods Nineteen patients with documented AR history underwent a unique and validated 1‐h on‐the‐road driving test outside the pollen season. In a 4‐leg repeated measures design, patients underwent a nasal provocation test with either pollen or inactive control prior to the driving test. In the three conditions with pollen provocation, patients were pretreated with either cetirizine 10 mg, fluticasone furoate 27.5 μg, or placebo to alleviate the provoked AR symptoms. Results The driving performance of patients when symptomatic and not treated was significantly impaired compared to the placebo condition. When engaging in a secondary memory task during driving, their performance deteriorated further. The magnitude of impairment was relevant and comparable to that seen at a blood alcohol level of 0.05%, the legal limit in many countries. Treatment of AR symptoms partially counteracted the effect of AR on driving. Conclusions Untreated AR can impair driving ability and put patients at risk. Drug therapy reduces this impairment, and AR patients should therefore be advised to always treat their condition.
A case of Marfan's syndrome with absent right coronary artery complicated by aortic dissection and right ventricular infarction.
Authors: A G Leitch, P K Caves
Journal: Thorax (1975)

The first patient to be reported with Marfan9s syndrome and an absent right coronary artery is described. Dissection of the ascending aorta was associated with right ventricular infarction which was probably due to the coronary artery anomaly and caused his death.
One-Year Health Assessment of Adult Survivors of &lt;EMPH TYPE="ITAL"&gt;Bacillus anthracis&lt;/EMPH&gt; Infection
Authors: Dori B Reissman, Ellen A S Whitney, Thomas H Taylor, James A Hayslett, Peter M Dull, Ileana Arias, David A Ashford, Eddy A Bresnitz, Christina Tan, Nancy Rosenstein, Bradley A Perkins
Journal: JAMA (2004)

Little is known about potential long-term health effects of bioterrorism-related Bacillus anthracis infection.To describe the relationship between anthrax infection and persistent somatic symptoms among adults surviving bioterrorism-related anthrax disease approximately 1 year after illness onset in 2001.Cross-sectional study of 15 of 16 adult survivors from September through December 2002 using a clinical interview, a medical review-of-system questionnaire, 2 standardized self-administered questionnaires, and a review of available medical records.Health complaints summarized by the body system affected and by symptom categories; psychological distress measured by the Revised 90-Item Symptom Checklist; and health-related quality-of-life indices by the Medical Outcomes Study 36-Item Short-Form Health Survey (version 2).The anthrax survivors reported symptoms affecting multiple body systems, significantly greater overall psychological distress (P<.001), and significantly reduced health-related quality-of-life indices compared with US referent populations. Eight survivors (53%) had not returned to work since their infection. Comparing disease manifestations, inhalational survivors reported significantly lower overall physical health than cutaneous survivors (mean scores, 30 vs 41; P =.02). Available medical records could not explain the persisting health complaints.The anthrax survivors continued to report significant health problems and poor life adjustment 1 year after onset of bioterrorism-related anthrax disease.
Empirically Establishing Blood Glucose Targets to Achieve HbA1c Goals
Authors: Nancy Wei, Hui Zheng, David M. Nathan
Journal: Diabetes Care (2014)

OBJECTIVE To determine the average fasting, postprandial, and bedtime self-monitored blood glucose (SMBG) concentrations associated with specified HbA1c levels using data from the A1c-Derived Average Glucose (ADAG) study. RESEARCH DESIGN AND METHODS The ADAG study was a multicenter observational study that used continuous glucose monitoring and SMBG testing to determine the relationship between mean average glucose and HbA1c. We used the SMBG data from 470 of the ADAG study participants (237 with type 1 diabetes and 147 with type 2 diabetes) to determine the average fasting, premeal, 90-min postmeal, and bedtime blood glucose (BG) for predefined target HbA1c groups between 5.5 and 8.5% (37–69 mmol/mol). t Tests were used to compare mean BG values between type 1 and type 2 diabetes groups. RESULTS The average fasting BG needed to achieve predefined HbA1c target levels of 5.5–6.49% (37–47 mmol/mol), 6.5–6.99% (48–52 mmol/mol), 7.0–7.49% (52–58 mmol/mol), 7.5–7.99% (58–64 mmol/mol), and 8.0–8.5% (64–69 mmol/mol) were 122 mg/dL with 95% CI 117–127, 142 mg/dL (135–150), 152 mg/dL (143–162), 167 mg/dL (157–177), and 178 mg/dL (164–192), respectively. Postmeal BG to achieve the HbA1c level of 6.5–6.99% (48–52 mmol/mol) and 7.0–7.49% (52–58 mmol/mol) were 164 mg/dL (159–169) and 176 mg/dL (170–183), respectively. Bedtime BG was 153 mg/dL (145–161) and 177 mg/dL (166–188), respectively. CONCLUSIONS We have determined the average BG at premeal, postmeal, and bedtime to achieve a variety of HbA1c targets. These results, based on empirical data, will help patients and providers set realistic day-to-day SMBG targets to achieve individualized HbA1c goals.
Use of long sequence alignments to study the evolution and regulation of mammalian globin gene clusters.
Authors: R Hardison, W Miller
Journal: Molecular Biology and Evolution (1993)

The determination of long segments of DNA sequences encompassing the beta- and alpha-globin gene clusters has provided an unprecedented data base for analysis of genome evolution and regulation of gene clusters. A newly developed computer tool kit generates local alignments between such long sequences in a space-efficient manner, helps the user analyze the alignments effectively, and finds consistently aligning blocks of sequences in multiple pairwise comparisons. Such sequence analyses among the beta-like globin gene clusters of human, galago, rabbit, and mouse have revealed the general patterns of evolution of this gene cluster. Alignments in the flanking regions are very useful in assigning orthologous relationships. Investigation of such matches between the mouse and human beta-like globin gene clusters has led to a reassessment of some orthologous assignments in mouse and to a revision of the proposed pathway for evolution of this gene cluster. In general, the interspersed repetitive elements have inserted independently, presumably via a retrotransposition mechanism, in the different mammalian lineages. However, some examples of ancient L1 repeats are found, including one between the epsilon- and gamma-globin genes that appears to have been in the ancestral eutherian gene cluster. Prominent matching sequences are found in a long region 5' to the epsilon-globin gene, the locus control region (LCR) that is a positive regulator of the entire gene cluster. Three-way alignments among the human, goat, and rabbit sequences can extend for > or = 3 kb in part of the LCR (DNase hypersensitive site 3), indicating that the cis-acting components of this complex regulatory region cover a long segment of DNA. In contrast to the beta-like globin gene clusters, the alpha-like globin gene clusters of many mammals occur in very G+C-rich isochores and contain prominent CpG islands. The regions between the alpha-like globin genes are evolving faster than the intergenic regions of the beta-like globin gene clusters. The contrasts between the two gene clusters can be attributed to differences in DNA metabolism in the isochore. The proximal control elements of the rabbit alpha-globin gene are located both 5' to and within the gene. All of this region is part of a prominent CpG island that may be acting as an extended, enhancer-independent promoter. One can hypothesize that the analogue to the LCR in the alpha-globin gene cluster may interface with the distinctive alpha-globin promoter in ways different from the interaction between the beta LCR and the promoters of beta-like globin genes.(ABSTRACT TRUNCATED AT 400 WORDS)
Cigarette Smoking and the Risk of Colorectal Cancer in Women
Authors: R. S. Sandler, D. P. Sandler, G. W. Comstock, K. J. Helsing, D. L. Shore
Journal: JNCI Journal of the National Cancer Institute (1988)

Colorectal cancer incidence rates for smokers, nonsmokers living with smokers (i.e., passive smokers), and nonsmokers in smoke-free households were compared in a 12-year prospective study of 25,369 women who participated in a private census conducted in Washington County, MD, in 1963. Women who smoked had a decreased relative risk of colorectal cancer compared with the risk for nonsmokers (age-adjusted relative risk, 0.76; 95% confidence interval, 0.52-1.10). The risk for passive smokers was similar to that for smokers. The relative risks were significantly reduced for older women; relative risks were 0.42 for smokers and 0.66 for passive smokers over age 65. The data suggest that older women who smoke have a lower risk of colorectal cancer than nonsmokers. The effect may be mediated by an antiestrogenic effect of smoking.
(8) Malignant lymphoma of the skin treated with bleomycin
Authors: Michael R. Klaber, Dowling D. Munro
Journal: British Journal of Dermatology (1974)

Journal Article (8) Malignant lymphoma of the skin treated with bleomycin Get access Michael R. Klaber, Michael R. Klaber Department of Dermatology, St Bartholomew's Hospital, London, E.C.1 Search for other works by this author on: Oxford Academic Google Scholar Dowling D. Munro Dowling D. Munro Department of Dermatology, St Bartholomew's Hospital, London, E.C.1 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue s10, 1 July 1974, Pages 48–51, https://doi.org/10.1111/j.1365-2133.1974.tb12511.x Published: 01 July 1974
Overview of an interlaboratory collaboration on evaluating the effects of model hepatotoxicants on hepatic gene expression.
Authors: Roger G Ulrich, John C Rockett, G Gordon Gibson, Syril D Pettit
Journal: Environmental Health Perspectives (2004)

DNA microarrays and related tools offer promise for identification of pathways involved in toxic responses to xenobiotics. To be useful for risk assessment, experimental data must be challenged for reliability and interlaboratory reproducibility. Toward this goal, the Hepatotoxicity Working Group of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Technical Committee on Application of Genomics to Mechanism-Based Risk Assessment evaluated and compared biological and gene expression responses in rats exposed to two model hepatotoxins--clofibrate and methapyrilene. This collaborative effort provided an unprecedented opportunity for the working group to evaluate and compare multiple biological, genomic, and toxicological parameters across different laboratories and microarray platforms. Many of the results from this collaboration are presented in accompanying articles in this mini-monograph, whereas others have been published previously. (Italic)In vivo(/Italic) studies for both compounds were conducted in two laboratories using a standard experimental protocol, and RNA samples were distributed to 16 laboratories for analysis on six microarray platforms. Histopathology, clinical chemistry, and organ weight changes were consistent with reported effects. Gene expression results demonstrated reasonable agreement between laboratories and across platforms. Discrepancies in expression profiles of some individual genes were largely due to platform differences and approaches to data analysis rather than to biological or interlaboratory variability. Despite these discrepancies there was overall agreement in the biological pathways affected by these compounds, demonstrating that transcriptional profiling is reproducible between laboratories and can reliably identify affected pathways necessary to provide mechanistic insight. This effort represents an important first step toward the use of transcriptional profiling in risk assessment.
ANTIGENIC DIFFERENCES BETWEEN MATT HEMOLYTIC STREPTOCOCCI AND THEIR GLOSSY VARIANTS
Authors: R. C. Lancefield, E. W. Todd
Journal: The Journal of Experimental Medicine (1928)

The matt and the glossy forms of four strains of hemolytic streptococci were used to immunize rabbits. Precipitin tests showed that rabbit sera prepared against matt organisms, whether virulent or avirulent for mice, contained type-specific antibody while sera prepared against completely degraded glossy organisms contained no type-specific antibody. Type-specific antibody was removed from the sera by absorption with homologous matt organisms but was unaffected by absorption with homologous glossy organisms. Passive protection experiments on mice showed that anti-matt sera were protective and anti-glossy sera non-protective against infection with homologous virulent organisms. Vaccination of mice with matt organisms rendered them immune to subsequent infection with homologous virulent cultures; but vaccination with glossy organisms established no active immunity.
Inhibition of Prostate Cancer Growth by Muscadine Grape Skin Extract and Resveratrol through Distinct Mechanisms
Authors: Tamaro S. Hudson, Diane K. Hartle, Stephen D. Hursting, Nomeli P. Nunez, Thomas T.Y. Wang, Heather A. Young, Praveen Arany, Jeffrey E. Green
Journal: Cancer Research (2007)

Abstract The phytochemical resveratrol contained in red grapes has been shown to inhibit prostate cancer cell growth, in part, through its antioxidant activity. Muscadine grapes contain unique phytochemical constituents compared with other grapes and are potentially a source for novel compounds with antitumor activities. We compared the antitumor activities of muscadine grape skin extract (MSKE), which we show contains no resveratrol, with that of resveratrol using primary cultures of normal prostate epithelial cells (PrEC) and the prostate cancer cell lines RWPE-1, WPE1-NA22, WPE1-NB14, and WPE1-NB26, representing different stages of prostate cancer progression. MSKE significantly inhibited tumor cell growth in all transformed prostate cancer cell lines but not PrEC cells. Prostate tumor cell lines, but not PrEC cells, exhibited high rates of apoptosis in response to MSKE through targeting of the phosphatidylinositol 3-kinase–Akt and mitogen-activated protein kinase survival pathways. The reduction in Akt activity by MSKE is mediated through a reduction in Akt transcription, enhanced proteosome degradation of Akt, and altered levels of DJ-1, a known regulator of PTEN. In contrast to MSKE, resveratrol did not induce apoptosis in this model but arrested cells at the G1-S phase transition of the cell cycle associated with increased expression of p21 and decreased expression of cyclin D1 and cyclin-dependent kinase 4 proteins. These results show that MSKE and resveratrol target distinct pathways to inhibit prostate cancer cell growth in this system and that the unique properties of MSKE suggest that it may be an important source for further development of chemopreventive or therapeutic agents against prostate cancer. [Cancer Res 2007;67(17):8396–405]
Tumor Susceptibility and Apoptosis Defect in a Mouse Strain Expressing a Human p53 Transgene
Authors: Crissy Dudgeon, Calvina Kek, Oleg N. Demidov, Shin-ichi Saito, Kenneth Fernandes, Alexandra Diot, Jean-Christophe Bourdon, David P. Lane, Ettore Appella, Albert J. Fornace, Dmitry V. Bulavin
Journal: Cancer Research (2006)

Abstract Activation of apoptosis is believed to be critical for the role of p53 as a tumor suppressor. Here, we report a new mouse strain carrying a human p53 transgene in the mouse p53-null background. Expression of human p53 in these mice was comparable with wild-type murine p53; however, transactivation, induction of apoptosis, and G1-S checkpoint, but not transrepression or regulation of a centrosomal checkpoint, were deregulated. Although multiple functions of p53 were abrogated, mice carrying the human p53 transgene did not show early onset of tumors as typically seen for p53-null mice. In contrast, human p53 in the p53-null background did not prevent accelerated tumor development after genotoxic or oncogenic stress. Such behavior of human p53 expressed at physiologic levels in transgenic cells could be explained by unexpectedly high binding with Mdm2. By using Nutlin-3a, an inhibitor of the interaction between Mdm2 and p53, we were able to partially reconstitute p53 transactivation and apoptosis in transgenic cells. Our findings indicate that the interaction between p53 and Mdm2 controls p53 transcriptional activity in homeostatic tissues and regulates DNA damage– and oncogene-induced, but not spontaneous, tumorigenesis.(Cancer Res 2006; 66(6): 2928-36)