tbuckley/cabot-search huggingface dataset:
Flushing out neutrophils
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

d > < d o c t o p i c > N e w s < / d o c t o p i c > Flushing out neutrophilsActivated neutrophils that infiltrate the liver during severe sepsis lodge themselves in the liver's tiniest blood vessels and cause organ damage.On page < a d d a r t t y p e = " r e l " d o i = " 1 0 . 1 0 8 4 / j e m . 2 0 0 7 1 7 6 5 " > 915< / a d d a r t > , McDonald et al. examine how neutrophils burrow into the liver and suggest a way to pry them out.Neutrophil recruitment in response to sepsis-triggering bacterial toxins such as LPS unfolds in several stages.In most places in the body, adhesion molecules called selectins initially snare neutrophils and help them tether to and roll along blood vessel walls.The cells subsequently adhere more firmly through integrins.But because neutrophils do not seem to need these molecules to stick to the blood capillaries in the liver, researchers suspected that the narrowness of these vessels instead physically traps the neutrophils.McDonald et al. now provide evidence against this entrapment model by showing that neutrophils are snagged by a different adhesion molecule, hyaluronan (HA), which they found at high levels in liver vessels.When mice were injected with LPS, neutrophil adhesion levels increased 14 fold, although HA levels did not change.The increased adhesiveness may be due to an HA-associated protein called SHAP, which increases HA's affinity for its neutrophil cell surface ligand, CD44.SHAP levels on the liver's capillary walls were increased by LPS treatments.Disrupting the interaction between CD44 and HA might potentially reverse sepsis; injecting LPS-treated mice with an anti-CD44 antibody rapidly detached neutrophils from the liver capillary walls and decreased liver damage.
Hyperhomocysteinemia, a Cardiac Metabolic Disease
Authors: Justin S. Becker, Alexandra Adler, Aaron Schneeberger, Harer Huang, Zipping Wang, Erin Walsh, Akos Koller, Thomas H. Hintze
Journal: Circulation (2005)

Hyperhomocysteinemia (HHcy) is a reliable indicator of cardiovascular disease, in part because of the production of superoxide and scavenging of nitric oxide (NO). The present study assessed the impact of HHcy on the NO-dependent control of cardiac O2 consumption and examined enzymatic sources of superoxide.Rats and mice were fed methionine in drinking water for 5 to 9 weeks to increase plasma homocysteine, a process that did not cause significant changes in hemodynamic function. The ability of the NO agonists bradykinin and carbachol to reduce myocardial O2 consumption in vitro was impaired by approximately 40% in methionine-fed rats, and this impairment was proportional to their individual plasma homocysteine concentration. However, responses were restored in the presence of ascorbic acid, tempol, and apocynin, which inhibits NADPH oxidase assembly. Western blots showed no difference in Cu/Zn or Mn superoxide dismutase, endothelial NO synthase, or inducible NO synthase protein, but HHcy caused a 100% increase in the p22phox subunit of NADPH oxidase. Western blots with plasma membrane-enriched fractions of cell lysate detected elevated levels of p22phox, p67phox, and rac-1, which indicates increased oxidase assembly. Finally, mice lacking a functional gp91phox subunit of NADPH oxidase demonstrated normal NO-dependent regulation of myocardial O2 consumption after methionine feeding.In HHcy, superoxide produced by NADPH oxidase reduces the ability of NO to regulate mitochondrial function in the myocardium. The severity of this effect is proportional to the increase in homocysteine.
Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124
Authors: Primo N. Lara, Ronald Natale, John Crowley, Heinz Josef Lenz, Mary W. Redman, Jane E. Carleton, James Jett, Corey J. Langer, J. Philip Kuebler, Shaker R. Dakhil, Kari Chansky, David R. Gandara
Journal: Journal of Clinical Oncology (2009)

Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients.Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.
Transglutaminases: new target molecules for inflammatory bowel disease?
Authors: B Siegmund
Journal: Gut (2005)

Transglutaminases may be involved in intestinal inflammation and may even represent therapeutic targets for ulcerative colitis

The family of transglutaminases (TG) includes the plasma form factor XIIIa as well as the tissue transglutaminase (tTG) and keratinocyte transglutaminase (TGk). In particular, tTG reminds every gastroenterologist primarily of coeliac disease where tTG represents the key autoantigen.1 Disease induction is confined to tTG, a ubiquitous enzyme which is released from fibroblasts, endothelial, and inflammatory cells during mechanical irritation or inflammation. At acidic pH, which occurs with inflammation, tTG can, apart from its physiological function described in more detail below, also simply deamidate some of the glutamine residues of the gluten peptides. In coeliac disease, deamidation introduces a negative charge into the gluten peptides which can increase the binding affinity to HLA-DQ2 or HLA-DQ8, the primary HLA association in coeliac disease. Binding of gluten peptide to either HLA-DQ2 or HLA-DQ8 results in an increase in their capacity to stimulate T cells, thus inducing intestinal inflammation.2,3

As indicated in this issue of Gut by D’Argenio and colleagues,4 TG may be involved in intestinal inflammation in a completely different way and may even represent a therapeutic target (see page 496) . But how can the physiological function of TG be defined? TG are enzymes catalysing the covalent cross linking between proteins by forming e(γ-glutamyl)-lysine isopeptide bonds. These bonds are formed between glutaminase and lysine residues thus stabilising intra- and extracellular proteins, a process which is required for a variety of essential physiological purposes such as barrier function in epithelia, apoptosis, and extracellular matrix formation.5 Substrates include intracellular (actin cytoskeleton, histones) as well as extracellular (collagen, vitronectin, fibronectin) …
Elevated Maternal Interleukin-8 Levels and Risk of Schizophrenia in Adult Offspring
Authors: Alan S Brown, Jonathan Hooton, Catherine A Schaefer, Haiying Zhang, Eva Petkova, Vicki Babulas, Megan Perrin, Jack M Gorman, Ezra S Susser
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Many studies have implicated prenatal infection in the etiology of schizophrenia. Cytokines, a family of soluble polypeptides, are critically important in the immune response to infection and in other inflammatory processes. The goal of this study was to determine whether second-trimester levels of four cytokines—interleukin-8 (IL-8), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)—are higher in the mothers of offspring who later developed schizophrenia spectrum disorders than in matched comparison subjects. METHOD: The authors conducted a nested case-control study of maternal serum cytokine levels in a large birth cohort, born 1959–1967. Cases (N=59) were subjects diagnosed with schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder) who had available second-trimester maternal serum samples. Comparison subjects (N=105) were members of the birth cohort, had not been diagnosed with a schizophrenia spectrum disorder or major affective disorder, and were matched to subjects with schizophrenia for date of birth, gender, length of time in the cohort, and availability of maternal sera. Maternal second-trimester serum levels of IL-8, IL-1β, IL-6, and TNF-α were determined by sandwich enzyme-linked immunosorbent assay. RESULTS: The second-trimester IL-8 levels in mothers of offspring with schizophrenia spectrum disorders were significantly higher than those of the mothers of comparison subjects. There were no differences between subjects with schizophrenia and comparison subjects with respect to maternal levels of IL-1β, IL-6, or TNF-α. CONCLUSIONS: Using prospectively collected prenatal sera in a large and well-characterized birth cohort, the authors have documented a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring. These findings provide further support for a substantive role of in utero infection or inflammation in the etiology of schizophrenia. Moreover, these results may have important implications for elucidating the mechanisms by which disrupted fetal development raises the risk of this disorder.
Augmentation of chemically induced pancreatic and bronchial cancers by epidermal growth factor.
Authors: R A Malt, J F Chester, H A Gaissert, J S Ross
Journal: Gut (1987)

The incidence of Syrian golden hamsters with pancreatic cancer induced by subcutaneous injections of N-nitroso-bis(2-oxopropyl)amine for 19 weeks (each 10 mg/kg) increased from 44% to 75% (p=0.016) when epidermal growth factor was also administered from week 5 through week 8 (5 mug energy three days for injections). Epidermal growth factor increased pancreatic weight and body weight. The incidence of animals with bronchial cancer doubled. Epidermal growth factor could be a cocarcinogen as a result of its mitogenic activity.
Hormones and breast and endometrial cancers: preventive strategies and future research.
Authors: B S Hulka, L A Brinton
Journal: Environmental Health Perspectives (1995)

A number of hormonal approaches for prevention of endometrial and breast cancers have been proposed. Because of the hormonal responsiveness of both tumors, much attention has focused on effects of exogenous hormone use. Although estrogens in hormone replacement therapy increase the risk of endometrial cancer, the disease is substantially reduced by long-term use of oral contraceptives. The issues with breast cancer are more complex, mainly because of a variety of unresolved effects. Long-term estrogen use is associated with some increase in breast cancer risk, and certain patterns of oral contraceptives appear to predispose to early-onset disease. With respect to estrogens, preventive approaches for both tumors would include use for as limited periods of time as possible. Addition of a progestin appears to lower estrogen-associated endometrial disease, but its effect on breast cancer risk remains less clear. Additional studies on effects of detailed usage parameters should provide useful insights into etiologic mechanisms. Other preventive approaches for endometrial cancer that may work through hormonal mechanisms include staying thin, being physically active, and maintaining a vegetarian diet. Breast cancer risk may possibly be reduced by extended periods of breastfeeding, restriction of intake of alcoholic beverages, remaining thin later in life, and being physically active. Additional research is needed to clarify the biologic mechanisms of these associations. The bridging of epidemiology with the biologic sciences should clarify many unresolved issues and lead to better preventive approaches.
SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation
Authors: N. Uza, H. Nakase, S. Yamamoto, T. Yoshino, Y. Takeda, S. Ueno, S. Inoue, S. Mikami, M. Matsuura, T. Shimaoka, N. Kume, M. Minami, S. Yonehara, H. Ikeuchi, T. Chiba
Journal: Gut (2011)

<h3>Background and aims</h3> Inflammatory bowel disease (IBD) is initiated and perpetuated by a dysregulated immune response to unknown environmental antigens such as luminal bacteria in genetically susceptible hosts. SR-PSOX/CXCL16, a scavenger receptor that binds phosphatidylserine and oxidised lipoprotein, has both phagocytic activity and chemotactic properties. The aim of this study was to investigate the role of SR-PSOX/CXCL16 in patients with IBD and experimental murine colitis. <h3>Methods</h3> The serum levels of SR-PSOX/CXCL16 were measured in patients with IBD. The roles of SR-PSOX/CXCL16 in phagocytosis of bacterial components and cytokine production by macrophages from wild-type (WT) and SR-PSOX/CXCL16 knockout (KO) mice were assessed. Colitis was induced by administering dextran sulfate sodium (DSS) to WT and SR-PSOX/CXCL16 KO mice. Colonic inflammation was analysed by clinical, histological and immunological parameters. Finally, the effect of a monoclonal antibody (mAb) to SR-PSOX/CXCL16 on DSS-induced colitis and trinitrobenzene sulfonic acid-induced colitis models was evaluated. <h3>Results</h3> Serum levels of SR-PSOX/CXCL16 correlated significantly with the disease activity of patients with IBD. Ex vivo experiments showed that SR-PSOX/CXCL16 was involved in both phagocytosis of bacterial antigens and the T helper 1 immune response through the production of interleukin 12 and interferon γ. In vivo murine experiments demonstrated the upregulated gene expression of SR-PSOX/CXCL16 in inflamed colonic tissues and the predominant expression of SR-PSOX/CXCL16 on macrophages. SR-PSOX/CXCL16 KO mice were less susceptible to colonic inflammation than were their WT littermates. Administration of SR-PSOX/CXCL16 mAb ameliorated the condition in the two different experimental colitis models. <h3>Conclusions</h3> SR-PSOX/CXCL16 plays a critical role in colonic inflammation and could be a potential therapeutic target for patients with IBD.
Estimating Risk of Circulatory Disease: Little et al. Respond
Authors: Mark P. Little, Dimitry Bazyka, Simon D. Bouffler, John D. Harrison, Elisabeth Cardis, Francis A. Cucinotta, Michaela Kreuzer, Olivier Laurent, Soile Tapio, Richard Wakeford, Lydia Zablotska, Steven E. Lipshultz
Journal: Environmental Health Perspectives (2012)
Ampicillin Therapy for Pharyngeal Gonorrhea
Authors: Joseph M. Di Caprio
Journal: JAMA (1978)

Single-dose oral ampicillin trihydrate is ineffective for the treatment of pharyngeal gonorrhea. An evaluation was made of the efficacy of extended oral ampicillin therapy. The regimen consisted of a single oral 3.5-g dose of ampicillin trihydrate and 1.0 g of probenecid on the first day, followed by 500 mg of ampicillin trihydrate four times a day for each of the succeeding two days, for a total ampicillin trihydrate dose of 7.5 g. One or two follow-up cultures taken within 35 days of completion of therapy were obtained in 77 of the 101 patients treated. Positive test-of-cure cultures were reported in three persons, two of whom may have been reinfected. The failure rate was calculated to range between 1.3% (1/77) to 3.9% (3/77). This compares favorably with current recommended modes of therapy. (<i>JAMA</i>239:1631-1633, 1978)
Dissociation between the electrophysiological properties and total tissue cyclic guanosine monophosphate content of guinea pig atria.
Authors: M J Mirro, J C Bailey, A M Watanabe
Journal: Circulation Research (1979)

The purpose of this study was to investigate the role of cyclic guanosine monophosphate (cyclic GMP) in mediating the direct electrophysiological effects of acetylcholine in guinea pig atria. Acetylcholine significantly diminished spontaneous rate of right atria without increasing cyclic GMP content. Reductions in rate following acetylcholine were augmented by pretreatment with physostigmine, but cyclic GMP levels remained unchanged. In left atria, acetylcholine significantly shortened action potential duration within 5 seconds (both with and without physostigmine pretreatment), but cyclic GMP content was not significantly elevated. Cyclic GMP levels in right atria were significantly increased in response to acetylcholine when the Ca2+ content of the buffer was elevated from 1.25 mM TO 2.5 MM; however, reductions in automaticity in the right atria were not augmented in the high Ca2+ buffer. Marked increases in cyclic GMP content were produced by Na nitroprusside superfusion without changing automaticity of right atria or action potential duration of left atria. Finally, both right and left atria were superfused with cyclic GMP analogs (8-bromo cyclic GMP and dibutyryl cyclic GMP) at high concentrations (10(-4)) for 15 minutes without producing significant effects on spontaneous rate or action potential duration. These results failed to show a correlation between total tissue cyclic GMP content and the electrophysiological effects of acetylcholine on guinea pig atria. The reasons for this are either that cyclic GMP does not mediate directly the electrophysiological effects of acetylcholine, or that small changes in cyclic GMP concentrations, undetectable when total tissue nucleotide levels are measured, occur in discrete effector pools of the cardiac cell to mediate the intracellular effects of the choline ester.
Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells
Authors: Hans-Jürgen Gober, Magdalena Kistowska, Lena Angman, Paul Jenö, Lucia Mori, Gennaro De Libero
Journal: The Journal of Experimental Medicine (2003)

T lymphocytes expressing the T cell receptor (TCR)-gammadelta recognize unknown antigens on tumor cells. Here we identify metabolites of the mevalonate pathway as the tumor ligands that activate TCR-gammadelta cells. In tumor cells, blockade of hydroxy-methylglutaryl-CoA reductase (HMGR), the rate limiting enzyme of the mevalonate pathway, prevents both accumulation of mevalonate metabolites and recognition by TCR-gammadelta cells. When metabolite accumulation is induced by overexpressing HMGR or by treatment with nitrogen-containing bisphosphonate drugs, tumor cells derived from many tissues acquire the capacity to stimulate the same TCR-gammadelta population. Accumulation of mevalonate metabolites in tumor cells is a powerful danger signal that activates the immune response and may represent a novel target of tumor immunotherapy.
Differences in recommendations between the Allergic Rhinitis and its Impact on Asthma Update 2010 and US Rhinitis Practice Parameters
Authors: Bradley Chipps, Sheldon Spector, Judith Farrar, Warner Carr, Eli Meltzer, William Storms, Michael Kaliner, Allan Luskin, Donald Bukstein, John Oppenheimer, Brian Smart, Jenifer Derebery, Julia Harder, Mark Dykewicz, Michael Benninger
Journal: Journal of Allergy and Clinical Immunology (2011)
Association of reduced total iron binding capacity and fungal infections in leukemic granulocytopenic patients.
Authors: J E Karp, W G Merz
Journal: Journal of Clinical Oncology (1986)

Serum total iron-binding capacity (TIBC) was measured serially on 70 patients with acute leukemia throughout the period of chemotherapy-induced granulocytopenia. Fungal infections were documented in 13 of these patients (18.6%), while 41 patients (58.6%) had clinically suspected fungal infections and 16 (22.9%) had no evidence of fungal infections during the granulocytopenia. Documented fungal infection occurred in patients with the greatest reduction in TIBC (P less than .015). Early reduction in TIBC also correlated with a greater risk for occurrence of fungal infection, and the earliest institution of amphotericin B (Amp-B) (P less than .004). Effective antifungal therapy was further associated with a return of TIBC levels toward normal. These data demonstrate that altered iron metabolism during granulocytopenia is associated with the development of fungal infections in compromised patients. Serial monitoring of TIBC, along with other clinical and mycologic findings, may prove useful in developing strategies for predicting patients at risk for developing a fungal infection and directing the appropriate use of empiric therapy with Amp-B.
A potential pitfall in the use of the Disease Activity Score (DAS28) as the main response criterion in treatment guidelines for patients with rheumatoid arthritis
Authors: P V Gardiner
Journal: Annals of the Rheumatic Diseases (2004)

The Disease Activity Score1 is widely used to quantify disease activity and gauge response to treatment. A rather complex calculation conceals the relative contribution of each measure to the composite score. The 28 joint version (DAS28) is used in the British Society for Rheumatology guidelines to determine response to anti-tumour necrosis factor α (anti-TNFα) treatment.2 A reduction in DAS28 of ⩾1.2 is considered significant improvement, as is a reduction in DAS28 score to <3.2. These figures are important, as under current guidelines clinicians are advised to discontinue anti-TNF treatment if either of these criteria is not achieved at 3 months. …
Hepatocarcinogenic Activities of Hydroxymethyl Derivatives of 4-(&lt;italic&gt;N,N&lt;/italic&gt;-Dimethylamino)azobenzene in ACI/N Rats
Authors: H Mori, T Tanaka, S Sugie, T Kuniyasu, H Iwata, H Ni-i, A Nishiwaki, Y Mori
Journal: JNCI Journal of the National Cancer Institute (1987)

The hepatocarcinogenic potencies of three newly identified hydroxymethyl derivatives of 4-(N,N-dimethylamino)azobenzene [(DAB) CAS: 60-11-7], i.e., 2'-CH2OH-DAB, 3'-CH2OH-DAB, and 4'-CH2OH-DAB, were strictly evaluated in a long-term test (400 days) and compared to the potency of 3'-CH3-DAB. ACI/N rats, known to be less sensitive to azo dye carcinogenesis, were given one of these compounds in their diets for 120 days. The incidence of hepatocellular carcinoma in group 2 (20/20), which was given 3'-CH2OH-DAB, was much higher than that in any of the other groups: group 1 (2'-CH2OH-DAB; 4/19), group 3 (4'-CH2OH-DAB; 1/25), or group 4 (3'-CH3-DAB; 3/24). These data suggest that 3'-CH2OH-DAB is the most potent hepatocarcinogen in the series of azo dyes. Possible reasons for the potency of the chemical are discussed.