tbuckley/cabot-search huggingface dataset:
T1 Hypoxia-Inducible Factor 2α Regulates Neutrophilic Inflammation in Humans, Mice and Zebrafish
Authors: AAR Thompson, PM Elks, HM Marriott, KR Higgins, S Parmar, G Shaw, S Eamsamarng, EE McGrath, F Formenti, FJ Van Eeden, VL Kinnula, CW Pugh, I Sabroe, DH Dockrell, ER Chilvers, PA Robbins, MC Simon, RS Johnson, SA Renshaw, MKB Whyte, SR Walmsley
Journal: Thorax (2012)

Neutrophilic inflammation plays an important role in inflammatory lung diseases but therapeutic targeting of neutrophil (PMN) persistence is lacking. PMN lifespan and function is regulated by hypoxia, a characteristic feature of inflamed tissues, via the HIF/VHL/hydroxylase pathway, specifically hypoxia inducible factor-1α (HIF-1α) and prolyl hydroxylase-3 (PHD3). Targeting HIF-1α in myeloid cells impaired immune function, but PHD3 regulated PMN lifespan without affecting function. Given that PHD3 preferentially regulates HIF-2α, we investigated the role of HIF-2α in PMN-mediated inflammation. Peripheral blood PMNs isolated from healthy volunteers and mice expressed HIF-2α and expression was enhanced by heat-killed bacteria. Using PMNs isolated from patients with active inflammatory arthritis (IA) we demonstrated significant upregulation of <i>HIF2A</i> mRNA (IA 92.9±30.3 vs. control 4.3±0.9 AU relative to <i>ACTB</i>, <i>P</i>&lt;0.05) and protein (IA 0.26±0.05 vs. control 0.01±0.01 OD relative to P38, <i>P</i>&lt;0.01) in circulating inflammatory PMNs. PMNs recruited to the airways of patients with COPD also displayed strong HIF-2α staining. The consequences of HIF-2α upregulation were examined using human PMNs from patients with gain-of-function mutations in the <i>HIF2A</i> gene. Neutrophils isolated from these patients had reduced rates of constitutive apoptosis. Recapitulation of the human <i>HIF2A</i> mutations in the orthologous <i>HIF2A</i> gene, <i>epas1a</i>, in zebrafish delayed resolution of inflammation in a tail injury model (24 hrs post injury, <i>epas1a</i> 12.7±1.4 vs. ctrl 5.2±0.5 PMNs, p&lt;0.001) with an associated reduction in PMN apoptosis (<i>epas1a</i> 1.0% vs. ctrl 1.6%, p&lt;0.05). Mice with myeloid-specific deletion of <i>Hif2a</i> had normal PMN survival in response to hypoxia and the cells showed no functional defect <i>in vitro</i>. Importantly, in a PMN-mediated acute lung injury model, myeloid-specific deficiency of HIF-2α markedly enhanced resolution of inflammation (BAL PMN count 48 hours following nebulised LPS, WT<i></i> 2.13×10<sup>6</sup>±0.08 vs. KO 1.39×10<sup>6</sup>±0.24, p&lt;0.05) and reduced lung injury (BAL IgM at 48 hours, WT 211±22.8 vs. KO 74.7±27.2 ng/ml), implicating HIF-2α in PMN persistence in inflamed lung tissue. These data support a critical and selective role for HIF-2α in the resolution of inflammation through the maintenance of PMN survival, and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.
Younger Age at Onset of Type 1 Diabetes in Concordant Sibling Pairs Is Associated With Increased Risk for Autoimmune Thyroid Disease
Authors: Gregory Goodwin, Lisa K. Volkening, Lori M.B. Laffel
Journal: Diabetes Care (2006)

Individuals with type 1 diabetes are at increased risk for the development of additional autoimmune disorders compared with the general population (1–11). Autoimmune thyroiditis (AIT) and celiac disease are relatively common among patients with type 1 diabetes, with prevalence rates of ∼17 and 6%, respectively (4). We sought to examine the relationship between age at onset of type 1 diabetes and prevalence of additional autoimmune disorders in a sample of sibling pairs concordant for type 1 diabetes.

Sibling pairs concordant for type 1 diabetes who visited the Joslin Diabetes Center’s Pediatric, Adolescent, and Young Adult Section between June 2002 and March 2005 were identified via a search of the electronic patient database. All identified patients were insulin dependent since diagnosis and showed no evidence of insulin resistance. Monozygotic twin pairs were excluded from the study. Charts were analyzed for evidence of additional autoimmune disorders. The institutional review board approved the study protocol.

Sibling pairs were classified according to age at type 1 diabetes diagnosis. Group 1 was composed of pairs in which both proband and sibling were diagnosed at <10 years of age. Group 2 was composed of all other pairs (i.e., at least one sibling diagnosed at 10–18 years). Screening for thyroid dysfunction was performed by obtaining thyroxine (T4 and T3RU) and/or serum thyrotropin (TSH).

At least one screening was performed every 2 years in 90% of the patients. Screening for celiac disease was obtained on any patient with symptoms …
Cord-Blood Engraftment with Ex Vivo Mesenchymal-Cell Coculture
Authors: Marcos de Lima, Ian McNiece, Simon N. Robinson, Mark Munsell, Mary Eapen, Mary Horowitz, Amin Alousi, Rima Saliba, John D. McMannis, Indreshpal Kaur, Partow Kebriaei, Simrit Parmar, Uday Popat, Chitra Hosing, Richard Champlin, Catherine Bollard, Jeffrey J. Molldrem, Roy B. Jones, Yago Nieto, Borje S. Andersson, Nina Shah, Betul Oran, Laurence J.N. Cooper, Laura Worth, Muzaffar H. Qazilbash, Martin Korbling, Gabriela Rondon, Stefan Ciurea, Doyle Bosque, Ila Maewal, Paul J. Simmons, Elizabeth J. Shpall
Journal: New England Journal of Medicine (2012)

Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.
Sports medicine? The ultimate folly
Authors: P Marfleet
Journal: British Journal of Sports Medicine (2000)

“Sports medicine? I suppose that means treating frisbee injuries.” I am told that this comment was made with a slight sneer and a snort of derision by a consultant orthopaedic surgeon. It reminds me of a similar incident about 12 years ago when I was attending a GP refresher course, and a consultant rheumatologist informed his audience that “there is no such thing as a sports injury”.

I find such comments sad and not a little frightening. Sad, because they reveal a lack of knowledge, understanding, and a suspiciously closed mind. Frightening because a statement made by an “expert” in this way is taken at face value by the trusting recipients, who, in …
Addition of PNU-100480 to First-Line Drugs Shortens the Time Needed to Cure Murine Tuberculosis
Authors: Kathy N. Williams, Steven J. Brickner, Charles K. Stover, Tong Zhu, Adam Ogden, Rokeya Tasneen, Sandeep Tyagi, Jacques H. Grosset, Eric L. Nuermberger
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

We recently reported strong bactericidal activity of the oxazolidinone PNU-100480 and its ability to increase the initial bactericidal effect of various combinations of first-line tuberculosis drugs and moxifloxacin in a murine model.To investigate whether the addition of PNU-100480 to the standard first-line regimen of rifampin, isoniazid, and pyrazinamide could shorten the duration of treatment necessary to prevent relapse after treatment discontinuation.Following aerosol infection with Mycobacterium tuberculosis H37Rv and a 13-day incubation period, control mice were treated with the first-line regimen while test mice received the same regimen with PNU-100480 or linezolid added for the first 2 or 4 months. Efficacy was assessed on the basis of quantitative cultures of lung homogenates performed monthly during treatment and 3 months after completion of 3, 4, 5, or 6 months of treatment to determine the relapse rate.After 2 months of treatment, mice receiving PNU-100480 in addition to the first-line regimen had lung CFU counts two orders of magnitude lower than control mice receiving the first-line regimen alone. Relapse rates after 4 months of treatment were 90, 35, and 5% when PNU-100480 was added to the first-line regimen for 0, 2, and 4 months, respectively. When the total treatment duration was 3 months, relapse rates were 85 and 35 to 45% when mice received PNU-100480 for 2 and 3 months, respectively; all control mice remained culture positive at the time of treatment completion with 17 to 72 CFU per lung. Addition of linezolid to the first-line regimen had an antagonistic effect resulting in higher CFU counts and failure to render mice culture-negative in 4 months of treatment.Together with previous findings, these results confirm that PNU-100480, which is now in Phase I clinical testing, has sterilizing activity in the murine model and suggest that it may be capable of shortening treatment duration for drug-susceptible as well as drug-resistant tuberculosis in humans.
Thymic hyperplasia in patients with Graves' disease. Identification of thyrotropin receptors in human thymus.
Authors: M Murakami, Y Hosoi, T Negishi, Y Kamiya, K Miyashita, M Yamada, T Iriuchijima, H Yokoo, I Yoshida, Y Tsushima, M Mori
Journal: Journal of Clinical Investigation (1996)

Thymic size and density were studied in 23 untreated patients with Graves' disease and 38 control subjects using computed tomography. Both thymic size and density were higher in untreated patients with Graves' disease than in control subjects in the age-matched group. After treatment with antithyroid drugs, both thymic size and density were significantly reduced, with a concomitant decrease in thyrotropin receptor antibodies. PCR of human thymic cDNA using primers for human thyrotropin receptor amplified a fragment in a size expected for the receptor, and its nucleotide sequence was identical to human thyrotropin receptor cDNA in the thyroid. Northern blot analysis of human thymic poly(A)+ RNA demonstrated the presence of the full length form of thyrotropin receptor mRNA. Western blot analysis of human thymic membrane using anti-thyrotropin receptor peptide antibodies demonstrated a band of 100 kD that was also observed in the thyroid membrane. Immunohistochemistry of thymic tissue using mouse antihuman thyrotropin receptor monoclonal antibodies demonstrated the immunostaining of epithelial cells. These results indicate that thymic hyperplasia is apparently associated with Graves' disease and suggest that thymic thyrotropin receptor may act as an autoantigen that may be involved in the pathophysiology of development of Graves' disease.
Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia.
Authors: M L Christensen, G K Rivera, W R Crom, M L Hancock, W E Evans
Journal: Journal of Clinical Oncology (1988)

Hydration and urinary alkalinization are used with high-dose methotrexate (HDMTX) to minimize renal toxicity resulting from methotrexate (MTX) precipitation in the kidney tubules. The effect of two hydration and alkalinization schedules on MTX plasma concentrations were evaluated in 100 children with acute lymphocytic leukemia (ALL) following two courses of MTX, 2 g/m2. The mean 21- and 44-hour MTX plasma concentrations were significantly lower in the group receiving the greater hydration and alkalinization schedule: 0.79 (0.90 SD) v 1.39 (1.99 SD) mumol/L for 21-hour MTX plasma concentrations, P = .01; and 0.18 (0.38 SD) v 0.25 (0.50 SD) mumol/L for 44-hour MTX plasma concentrations, P = .01. Although the overall incidence of toxic events was similar in both groups, the incidence of severe toxicity was reduced in the group that received the greater hydration and alkalinization, 6% v 16%. This study demonstrated that the amount of hydration and alkalinization can affect MTX plasma concentrations. Optimizing the hydration and alkalinization schedule is important for minimizing the incidence of severe toxicity associated with HDMTX.
Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2–dependent fibrinolysis
Authors: Andrew T. Jacovina, Arunkumar B. Deora, Qi Ling, M. Johan Broekman, Dena Almeida, Caroline B. Greenberg, Aaron J. Marcus, Jonathan D. Smith, Katherine A. Hajjar
Journal: Journal of Clinical Investigation (2009)

When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 muM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed "A2") is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the "tail" domain of A2. We also demonstrated that fibrinolysis and angiogenesis are severely impaired in A2-deficient mice. We now report here that, although hyperhomocysteinemic mice had a normal coagulation profile and normal platelet function, fibrin accumulated in their tissues due to reduced perivascular fibrinolytic activity and angiogenesis was impaired. A2 isolated from hyperhomocysteinemic mice failed to fully support TPA-dependent plasmin activation. However, infusion of hyperhomocysteinemic mice with fresh recombinant A2, which localized to neoangiogenic endothelial cells, resulted in normalization of angiogenesis and disappearance of peri- and intravascular fibrin. We therefore conclude that hyperhomocysteinemia impairs postnatal angiogenesis by derivatizing A2, preventing perivascular fibrinolysis, and inhibiting directed endothelial cell migration. These findings provide a mechanistic explanation for microvascular dysfunction and macrovascular occlusion in individuals with hyperhomocysteinemia.
Microduplications of 16p11.2 are associated with schizophrenia
Authors: Shane E McCarthy, Vladimir Makarov, George Kirov, Anjene M Addington, Jon McClellan, Seungtai Yoon, Diana O Perkins, Diane E Dickel, Mary Kusenda, Olga Krastoshevsky, Verena Krause, Ravinesh A Kumar, Detelina Grozeva, Dheeraj Malhotra, Tom Walsh, Elaine H Zackai, Paige Kaplan, Jaya Ganesh, Ian D Krantz, Nancy B Spinner, Patricia Roccanova, Abhishek Bhandari, Kevin Pavon, B Lakshmi, Anthony Leotta, Jude Kendall, Yoon-ha Lee, Vladimir Vacic, Sydney Gary, Lilia M Iakoucheva, Timothy J Crow, Susan L Christian, Jeffrey A Lieberman, T Scott Stroup, Terho Lehtimäki, Kaija Puura, Chad Haldeman-Englert, Justin Pearl, Meredith Goodell, Virginia L Willour, Pamela DeRosse, Jo Steele, Layla Kassem, Jessica Wolff, Nisha Chitkara, Francis J McMahon, Anil K Malhotra, James B Potash, Thomas G Schulze, Markus M Nöthen, Sven Cichon, Marcella Rietschel, Ellen Leibenluft, Vlad Kustanovich, Clara M Lajonchere, James S Sutcliffe, David Skuse, Michael Gill, Louise Gallagher, Nancy R Mendell, Nick Craddock, Michael J Owen, Michael C O'Donovan, Tamim H Shaikh, Ezra Susser, Lynn E DeLisi, Patrick F Sullivan, Curtis K Deutsch, Judith Rapoport, Deborah L Levy, Mary-Claire King, Jonathan Sebat
Journal: Nature Genetics (2009)
Prevention of Hyaline Membrane Disease With Plasminogen
Authors: Clara M. Ambrus
Journal: JAMA (1977)

In a double-blind, randomized study, 500 premature infants were treated with plasminogen or placebo intravenously within 60 minutes of birth. There was a substantial decrease in severe clinical respiratory distress, death caused by hyaline membrane disease, and total mortality in the plasminogen-treated infants as compared to the controls.
Immunodepressive Effect of 3-Methylcholanthrene. Antibody Formation at the Cellular Level and Reaction Against Weak Antigenic Homografts&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Jan Stjernswärd
Journal: JNCI Journal of the National Cancer Institute (1965)

3-Methyldiolanthrene (MCA) administered to mice reduced the number of antibody-producing spleen cells after immunization with sheep erythrocytes measured at a single cellular level. The immuno-depression was rapid and long. Even 2 days after MCA exposure, when test antigen was given, the number of plaque-forming spleen cells (PFC) decreased more than 50 percent. After a single exposure to MCA, the PFC remained depressed for a period corresponding to the latency period prior to the appearance of the MCA-induced sarcomas. This depression of PFC was studied in groups of mice at different intervals between 1 and 20 weeks after MCA administration. Spleen weight and total spleen cell number were reduced, and there was a specific reduction of PFC when expressed as a fraction of the total number of spleen cells. The depression of the cellular immune response was compared with the humoral hemolysing and hemagglutinating antibody response toward a heterologous test antigen, sheep erythrocytes. Impairment of the graft rejection after MCA exposure, tested across a monospecific weak histocompatibility barrier (H-1) by skin grafting, was first demonstrable at the time of tumor appearance. Skingraft survival was not affected during the earlier part of the tumor latency period. The findings are discussed in relation to an earlier suggestion of Prehn and Main that MCA inhibits immunological responses and thereby allows the outgrowth of antigenic neoplastic cells.
Alum with Interleukin-12 Augments Immunity to a Melanoma Peptide Vaccine: Correlation with Time to Relapse in Patients with Resected High-Risk Disease
Authors: Omid Hamid, Jolie C. Solomon, Ronald Scotland, Marile Garcia, Shirley Sian, Wei Ye, Susan L. Groshen, Jeff S. Weber
Journal: Clinical Cancer Research (2007)

We attempted to augment immunity to melanoma antigens using interleukin-12 (IL-12) with aluminum hydroxide (alum) for sustained release or granulocyte macrophage colony-stimulating factor (GM-CSF) added to a multipeptide vaccine.Sixty patients with high-risk resected melanoma were randomized to receive melanoma peptides gp100(209-217) (210M), MART-1(26-35) (27L), and tyrosinase(368-376) (370D) with adjuvant Montanide ISA 51 and either IL-12 at 30 ng/kg with alum (group A), IL-12 at 100 ng/kg with alum (group B), or IL-12 at 30 ng/kg with 250 mug GM-CSF (group C).Three patients had stage IIC (5%), 50 had stage III (83%), and 7 had stage IV (12%) melanoma. Most toxicities were grade 1/2 and resolved rapidly. Significant toxicity included grade 3 colitis and visual changes and grade 3 headache resolving after stopping IL-12 but continuing peptide vaccine. A higher rate of post-vaccine 6-month immune response to gp100 and MART-1 was observed in group A (15 of 19) or B (19 of 20) that received IL-12 plus alum versus group C with IL-12/GM-CSF (4 of 21; P < 0.001). Post-vaccine enzyme-linked immunospot response rates to peptide analogues in group B were higher than group A (P = 0.031 for gp100 and P = 0.010 for MART-1); both were higher than group C (P < 0.001 for gp100 and P < 0.026 for MART-1). With a median of 24 months of follow-up, 23 patients have relapsed. Post-vaccine immune response to MART-1 was associated with relapse-free survival (P = 0.012).IL-12 with alum augmented an immune response to melanoma antigens compared with IL-12 with GM-CSF. Immune response was associated with time to relapse.
Evaluation of Blood Volume Measurement Techniques
Authors: JOHN W. REMINGTON, CARLETON H. BAKER
Journal: Circulation Research (1961)

To assess the ability of an injection of Cr 51 -tagged red cells and one of T 1824 to measure a standard part of the total blood volume, two types of experiments have been done. First, three or four successive injections were made, separated by the sampling period of 80 minutes, in both intact and splenectomized dogs under different anesthetic regimes. The tagged cells gave total cell volumes showing no trend away from the expected value, based on the first determination and the cells lost in the sample taken, and the standard deviation was but 3.0 per cent. There was no real difference in this error depending upon the anesthesia. The T 1824 measured plasma volume tended to become progressively greater than the expected value with each injection. This trend could not be corrected out on the basis of either a plasma specific gravity or a hematocrit change. The standard deviation was three times larger than for the cell volume. Part of this variability might be related to fluctuations in dye concentration away from the bestfit slope, as were quite common at various times during the sampling period. Yet, plasma volumes based on the concentration shown at any particular time (e.g., 10 minutes) gave slightly worse agreement with the expected. The second experiment involved measurements of cell and plasma volume after three successive bleedings. Here both volumes were greater than the expected, with the standard deviation of the cell volume still less than that of the plasma volume. Curiously enough, T 1824 could follow the changes in plasma volume in these bleeding experiments a little better than it could reproduce the same volume in essentially normovolemic dogs.
Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation
Authors: Akira Abe, Susan Gregory, Lihsueh Lee, Paul D. Killen, Roscoe O. Brady, Ashok Kulkarni, James A. Shayman
Journal: Journal of Clinical Investigation (2000)

We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in alpha-galactosidase A (alpha-gal A) knockout mice, a model of Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidi no-propanol (D-t-EtDO-P4) showed a concentration-dependent decrement in glucosylceramide levels in kidney, liver, and spleen. A single intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide metabolism. A concentration-dependent decrement in renal and hepatic globotriaosylceramide levels was observed in alpha-Gal A(-) males treated for 4 weeks with D-t-EtDO-P4. When 8-week-old alpha-Gal A(-) males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an alpha-galactosidase A-independent salvage pathway for globotriaosylceramide degradation. Complications observed with another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, including weight loss and acellularity of lymphatic organs, were not observed with D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to substrate deprivation therapy.
CONSEQUENT INTRAFAMILIAL IMMUNIZATION FOR DL-A HAPLOTYPING IN CANINES
Authors: J. A. van der Does, J. J. van Rood, W. S. Walker, R. B. Epstein
Journal: The Journal of Experimental Medicine (1973)

A procedure of intrafamilial immunization is described for production of antisera recognizing DL-A haplotypes. In a colony consisting of 1 sire, 6 bitches, and 67 offspring all haplotypes could be accurately allocated. In the colony the observed reaction frequencies of the antisera are in agreement with mendelian codominant inheritance. Mixed lymphocyte culture tests confirmed the accuracy of the serologic typing and the presence of homozygous individuals within the colony. Further evidence is presented supporting the presence of two or more subloci within the DL-A system. Colonies of canines such as the one described should provide a sensitive system for evaluating interaction between serologic DL-A typing, MLC reactivity, and immune response genetics in a nonrodent species which is not highly inbred.