tbuckley/cabot-search huggingface dataset:
ENDOTOXIN FEVER IN GRANULOCYTOPENIC ANIMALS
Authors: John C. Herion, Richard I. Walker, Jeffress G. Palmer
Journal: The Journal of Experimental Medicine (1961)

The febrile response to bacterial endotoxin was measured in rabbits made leukopenic with nitrogen mustard. A striking increase in susceptibility to the lethal effects of endotoxin occurred in severely leukopenic animals. Animals without circulating granulocytes, or with only basophils, developed no significant fever after endotoxin injection. Animals with circulating granulocytes other than basophils exhibited a biphasic febrile response to endotoxin; this response was significantly less in magnitude than that of control animals. Control animals, severely granulocytopenic animals, and animals with no circulating granulocytes other than basophils showed comparable febrile responses to serum pyrogen. These results suggest that granulocytes inactivate endotoxin in vivo and support the hypothesis that leukocyte pyrogen is a necessary intermediate in endotoxin fever. Basophils do not appear to participate in this process. These observations also contradict previous studies that were taken to indicate a normal febrile response to endotoxin in leukopenic animals and suggest that those results are related to the persistence of granulocytes.
Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming
Authors: Anne E. Powell, Eric C. Anderson, Paige S. Davies, Alain D. Silk, Carl Pelz, Soren Impey, Melissa H. Wong
Journal: Cancer Research (2011)

The most deadly phase in cancer progression is attributed to the inappropriate acquisition of molecular machinery leading to metastatic transformation and spread of disease to distant organs. Although it is appreciated that metastasis involves epithelial-mesenchymal interplay, the underlying mechanism defining this process is poorly understood. Specifically, how cancer cells evade immune surveillance and gain the ability to navigate the circulatory system remains a focus. One possible mechanism underlying metastatic conversion is fusion between blood-derived immune cells and cancer cells. While this notion is a century old, in vivo evidence that cell fusion occurs within tumors and imparts genetic or physiologic changes remains controversial. We have previously demonstrated in vivo cell fusion between blood cells and intestinal epithelial cells in an injury setting. Here, we hypothesize that immune cells, such as macrophages, fuse with tumor cells imparting metastatic capabilities by transferring their cellular identity. We used parabiosis to introduce fluorescent-labeled bone marrow-derived cells to mice with intestinal tumors, finding that fusion between circulating blood-derived cells and tumor epithelium occurs during the natural course of tumorigenesis. Moreover, we identify the macrophage as a key cellular partner for this process. Interestingly, cell fusion hybrids retain a transcriptome identity characteristic of both parental derivatives, while also expressing a unique subset of transcripts. Our data supports the novel possibility that tumorigenic cell fusion may impart physical behavior attributed to migratory macrophages, including navigation of circulation and immune evasion. As such, cell fusion may represent a promising novel mechanism underlying the metastatic conversion of cancer cells.
Relationship Between Patient Medication Adherence and Subsequent Clinical Inertia in Type 2 Diabetes Glycemic Management
Authors: Richard Grant, Alyce S. Adams, Connie Mah Trinacty, Fang Zhang, Ken Kleinman, Stephen B. Soumerai, James B. Meigs, Dennis Ross-Degnan
Journal: Diabetes Care (2007)

Clinical inertia has been identified as a critical barrier to glycemic control in type 2 diabetes. We assessed the relationship between patients' initial medication adherence and subsequent regimen intensification among patients with persistently elevated A1C levels.We analyzed an inception cohort of 2,065 insured patients with type 2 diabetes who were newly started on hypoglycemic therapy and were followed for at least 3 years between 1992 and 2001. Medication adherence was assessed by taking the ratio of medication days dispensed (from pharmacy records) to medication days prescribed (as documented in the medical record) for the first prescribed hypoglycemic drug. Adherence was measured for the period between medication initiation and the next elevated A1C result measured at least 3 months later; intensification was defined as a dose increase or the addition of a second hypoglycemic agent.Patients were aged (mean +/- SD) 55.4 +/- 12.2 years; 53% were men, and 19% were black. Baseline medication adherence was 79.8 +/- 19.3%. Patients in the lowest quartile of adherence were significantly less likely to have their regimens increased within 12 months of their first elevated A1C compared with patients in the highest quartile (27 vs. 37%, respectively, with increased regimens if A1C is elevated, P < 0.001). In multivariate models adjusting for patient demographic and treatment factors, patients in the highest adherence quartile had 53% greater odds of medication intensification after an elevated A1C (95% CI 1.11-1.93, P = 0.01).Among insured diabetic patients with elevated A1C, level of medication adherence predicted subsequent medication intensification. Poor patient self-management behavior increases therapeutic clinical inertia.
Nasal epithelial cells express IL‐10 at levels that negatively correlate with clinical symptoms in patients with house dust mite allergy
Authors: B. Muller, E. J. J. De Groot, I. J. M. Kortekaas, W. J. Fokkens, C. M. Van Drunen
Journal: Allergy (2007)

Background: Despite constant exposure to micro‐organisms and other immunogenic environmental factors, relatively very few immunological responses are initiated in the nasal mucosa. Although several mechanisms could play a role in maintaining this immune suppressive milieu, none of them have been validated. Previous data from our group suggested that locally produced interleukin (IL)‐10 could be involved in maintaining local homeostasis. Methods: To investigate the role of epithelial IL‐10 expression in the manifestation of allergic symptoms, we used immunohistochemistry to study the expression of IL‐10 in the nasal epithelium of healthy individuals and house dust mite allergic patients. In the allergic patients, we determined potential correlations of epithelial expression with allergic symptoms, both at baseline and after allergen provocation. Results: IL‐10 is expressed in the basal and differentiated epithelial cells of both healthy individuals and allergic rhinitis patients. In the allergic individuals, there is a strong negative correlation at baseline between the epithelial expression level of IL‐10 and rhinorrhoea and sneezing, but not between that expression level and nasal blockage or peak nasal inspiratory flow (PNIF). This correlation disappears with steroid treatment or after allergen provocation, although the expression at baseline seems to predict PNIF scores after provocation. Conclusions: Our data not only reveals IL‐10 expression by human nasal epithelial cells, but also suggests that nasal epithelial IL‐10 regulates allergic symptoms. Targeting the regulation mechanisms affecting IL‐10 or targeting the regulation mechanism affected by IL‐10 could constitute new options for the treatment of allergic disease.
Gonadal Function in Males After Chemotherapy for Early-Stage Hodgkin's Lymphoma Treated in Four Subsequent Trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Étude des Lymphomes de l'Adulte
Authors: Marleen A.E. van der Kaaij, Natacha Heutte, Nolwenn Le Stang, John M.M. Raemaekers, Arnold H.M. Simons, Patrice Carde, Evert M. Noordijk, Christophe Fermé, José Thomas, Houchingue Eghbali, Hanneke C. Kluin-Nelemans, Michel Henry-Amar
Journal: Journal of Clinical Oncology (2007)

To analyze fertility in male patients treated with various combinations of radiotherapy and chemotherapy, with or without alkylating agents, or with radiotherapy alone for Hodgkin's lymphoma.Follicle-stimulating hormone (FSH) levels were measured in patients with early-stage upper-diaphragmatic disease enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) trials (H6-H9). Median follow-up after therapy was 32 months. Patients with FSH measurement at least 12 months after end of treatment (n = 355) were selected to assess post-treatment fertility. Patients with FSH measurement 0 to 9 months after therapy (n = 349) were selected to analyze fertility recovery; of these, patients with elevated FSH (> 10 U/L; n = 101) were followed until recovery. Factors predictive for therapy-related infertility were assessed by logistic regression.The proportion of elevated FSH was 3% and 8% in patients treated with radiotherapy only or with nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], epirubicin, bleomycin, vinblastine, prednisone [EBVP]); it was 60% (P < .001) after chemotherapy containing alkylating agents (mechlorethamine, vincristine, procarbazine, prednisone [MOPP], MOPP/doxorubicin, bleomycin, vinblastine [ABV], bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone [BEACOPP]). After a median time of 19 months, recovery of fertility occurred in 82% of patients treated without alkylating chemotherapy. This proportion was 30%, statistically (P < .001) lower in those treated with alkylating chemotherapy, and median time to recovery was 27 months. The post-treatment proportion of elevated FSH increased significantly (P < .001) with the dose of alkylating chemotherapy administered, and recovery was less frequent and slower after higher doses. Age more than 50 years and stage II disease also contributed to poor outcome.Fertility can be secured after nonalkylating chemotherapy for Hodgkin's lymphoma. In contrast, alkylating chemotherapy has a dismal effect, even after a limited number of cycles.
Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa
Authors: Michael C. Campbell, Alessia Ranciaro, Daniel Zinshteyn, Renata Rawlings-Goss, Jibril Hirbo, Simon Thompson, Dawit Woldemeskel, Alain Froment, Joseph B. Rucker, Sabah A. Omar, Jean-Marie Bodo, Thomas Nyambo, Gurja Belay, Dennis Drayna, Paul A.S. Breslin, Sarah A. Tishkoff
Journal: Molecular Biology and Evolution (2013)

Bitter taste perception influences human nutrition and health, and the genetic variation underlying this trait may play a role in disease susceptibility. To better understand the genetic architecture and patterns of phenotypic variability of bitter taste perception, we sequenced a 996 bp region, encompassing the coding exon of TAS2R16, a bitter taste receptor gene, in 595 individuals from 74 African populations and in 94 non-Africans from 11 populations. We also performed genotype–phenotype association analyses of threshold levels of sensitivity to salicin, a bitter anti-inflammatory compound, in 296 individuals from Central and East Africa. In addition, we characterized TAS2R16 mutants in vitro to investigate the effects of polymorphic loci identified at this locus on receptor function. Here, we report striking signatures of positive selection, including significant Fay and Wu’s H statistics predominantly in East Africa, indicating strong local adaptation and greater genetic structure among African populations than expected under neutrality. Furthermore, we observed a “star-like” phylogeny for haplotypes with the derived allele at polymorphic site 516 associated with increased bitter taste perception that is consistent with a model of selection for “high-sensitivity” variation. In contrast, haplotypes carrying the “low-sensitivity” ancestral allele at site 516 showed evidence of strong purifying selection. We also demonstrated, for the first time, the functional effect of nonsynonymous variation at site 516 on salicin phenotypic variance in vivo in diverse Africans and showed that most other nonsynonymous substitutions have weak or no effect on cell surface expression in vitro, suggesting that one main polymorphism at TAS2R16 influences salicin recognition. Additionally, we detected geographic differences in levels of bitter taste perception in Africa not previously reported and infer an East African origin for high salicin sensitivity in human populations.
Brief Chemotherapy and Involved-Region Irradiation for Limited-Stage Diffuse Large-Cell Lymphoma: An 18-Year Experience From the British Columbia Cancer Agency
Authors: Tamara N. Shenkier, Nicholas Voss, Randall Fairey, Randy D. Gascoyne, Paul Hoskins, Richard Klasa, Paul Klimo, Susan E. O’Reilly, Simon Sutcliffe, Joseph M. Connors
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate clinical outcome of patients with limited-stage diffuse large-cell lymphoma (DLCL) treated with three cycles of chemotherapy followed by involved-region irradiation (IRRT). PATIENTS AND METHODS: Adults with limited-stage DLCL were treated with brief doxorubicin-containing chemotherapy regimens between 1980 and 1998. IRRT was administered 3 to 4 weeks after the third chemotherapy treatment in a dose equivalent to 30 Gy in 10 fractions. RESULTS: Three hundred and eight patients (median age, 64 years) were included, and 299 experienced complete remission. After a median follow-up of 86 months, 64 patients developed progressive disease, and 104 patients died (43 from lymphoma, three from toxicity, and 58 from other causes). Actuarial overall and progression-free survival (PFS) rates were, respectively, 80% and 81% at 5 years and 63% and 74% at 10 years. For subgroups identified using the Miller modification of the International Prognostic Index (IPI), the overall survival rates at 5 and 10 years were, respectively, 97% and 89% (no factors), 77% and 56% (one or two factors), and 58% and 48% (three or four factors), and the 5-year and 10-year PFS rates were, respectively, 94% and 89% (no factors), 79% and 73% (one or two factors), and 60% and 50% (three or four factors). Men with testicular presentation, had a definitely inferior outcome. CONCLUSION: Long-term outcome with three cycles of doxorubicin-based chemotherapy and IRRT confirms that this is a successful approach for the majority of patients with limited-stage DLCL. Subgroups with worse prognoses can be identified, and these patients should be offered alternative treatment approaches.
Molecular imaging of αvβ3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA†
Authors: Carmen Burtea, Sophie Laurent, Oltea Murariu, Dirk Rattat, Gérard Toubeau, Alfons Verbruggen, David Vansthertem, Luce Vander Elst, Robert N. Muller
Journal: Cardiovascular Research (2008)

AimsThe integrin αvβ3 is highly expressed in atherosclerotic plaques by medial and intimal smooth muscle cells and by endothelial cells of angiogenic microvessels. In this study, we have assessed non-invasive molecular magnetic resonance imaging (MRI) of plaque-associated αvβ3 integrin expression on transgenic ApoE−/− mice with a low molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD). The analogous compound Eu-DTPA-g-mimRGD was employed for an in vivo competition experiment and to confirm the molecular targeting. The specific interaction of mimRGD conjugated to Gd-DTPA or to 99mTc-DTPA with αvβ3 integrin was furthermore confirmed on Jurkat T lymphocytes.
Increased Amygdala and Insula Activation During Emotion Processing in Anxiety-Prone Subjects
Authors: Murray B. Stein, Alan N. Simmons, Justin S. Feinstein, Martin P. Paulus
Journal: American Journal of Psychiatry (2007)

Increased amygdala reactivity during processing of certain types of emotional stimuli (e.g., fear, anger) has been observed in patients with anxiety disorders such as social phobia and posttraumatic stress disorder (PTSD). It is uncertain whether this heightened amygdala reactivity is specific to treatment-seeking patients with anxiety disorders or is a general feature of individuals with increased anxiety-related temperamental traits.Thirty-two physically healthy subjects 18-21 years old were recruited from a large pool of college students. Of these, 16 were chosen on the basis of scoring in the upper-15th percentile on a measure of trait anxiety (anxiety-prone group), and 16 were chosen on the basis of scoring in the normative range (40th-60th percentile). Subjects participated in functional magnetic resonance imaging (fMRI) during an emotion face assessment task that has been shown to reliably engage amygdala and associated limbic structures.Anxiety-prone subjects had significantly greater bilateral amygdala and insula activation to emotional faces than did the anxiety-normative comparison subjects. Higher scores on several measures assessing anxiety proneness (e.g., neuroticism, trait anxiety, and anxiety sensitivity) were associated with greater activation of the amygdala (predominantly left-sided) and the anterior insula (bilateral).Increased amygdala and insula reactivity to certain types of emotional processing is seen in young adults with increased anxiety-related temperamental traits. Therefore, this brain emotion-processing profile may be a functional endophenotype for proneness to (certain kinds of) anxiety disorders.
Visual acuity testing in schools: what needs to be done
Authors: Y F Yang, M Dcole
Journal: BMJ (1996)

almost universally, while others have gained favour in only a few regions.The greatest inconsistency is in pae- diatric life support.Cardiac arrest in children is usually secondary to hypoxia or hypovolaemia' yet some regions teach paediatric defibrillation in preference to airway, ventilatory, and venous access skills.No national stand- ards exist, and we recommend that achieving national uniformity in airway, ventilation, and fluid resuscitation skills should be a priority.Few prehospital skills have been formally evaluated in the United Kingdom in terms of cost and patient outcome, and debate surrounds even basic skills.3Differ- ences between regions could be used to advantage in future studies by providing control groups.The results of such studies could then be used to decide which skills paramedics should be taught.Formal research is needed to evaluate taining costs, retention and use of skills, and patient outcome.More urgently, a national authority is needed to coordinate research and implement the results throughout the paramedic service.
A Patient-Centered Vision of Care for ESRD
Authors: Stefaan J. Vandecasteele, Manjula Kurella Tamura
Journal: Journal of the American Society of Nephrology (2014)

The ESRD population is heterogeneous, including patients without severe comorbidity for whom dialysis is a bridge to transplantation or a long-term maintenance treatment, as well as patients with a limited life expectancy as a result of advanced age or severe comorbidity for whom dialysis will be the final treatment destination. The complex medical and social context of this latter group fits poorly in the homogeneous, disease-centered, and process-driven approach of many clinical practice guidelines for dialysis. In this commentary, we argue that the standards of treatment allocated to each individual patient should be defined not merely by his or her disease state, but also by his or her preferences and prognosis. In this more patient-centered approach, three attainable treatment goals with a corresponding therapeutic approach could be defined: (1) dialysis as bridging or long-term maintenance treatment, (2) dialysis as final treatment destination, and (3) active medical management without dialysis. For patients with a better overall prognosis, this approach will emphasize complication prevention and long-term survival. For patients with a limited overall prognosis, strictly disease-centered interventions often impose a treatment burden that does not translate into a proportional improvement in quantity or quality of life. For these patients, a patient-centered approach will place more emphasis on palliative management strategies that are less disease specific.
The Antiinflammatory Endothelial Tyrosine Kinase Tie2 Interacts With a Novel Nuclear Factor-κB Inhibitor ABIN-2
Authors: David P. Hughes, Marie B. Marron, Nicholas P.J. Brindle
Journal: Circulation Research (2003)

Tie2 is a receptor tyrosine kinase expressed predominantly in endothelial cells and is essential for blood vessel formation and maintenance. The receptor has potent antiinflammatory effects on endothelial cells, suppressing vascular endothelial growth factor– and tumor necrosis factor–induced expression of leukocyte adhesion molecules and procoagulant tissue factor and inhibiting vascular leakage. To delineate the signaling pathways utilized by Tie2, we performed yeast two-hybrid screening of a human endothelial cell cDNA library and identified a novel protein interacting with the intracellular domain of the receptor. This protein was found to be human A20 binding inhibitor of NF-κB activation-2, ABIN-2, an inhibitor of NF-κB–mediated inflammatory gene expression. Coexpression of Tie2 and ABIN-2 in CHO cells confirmed the interaction occurs in mammalian cells. In contrast, Tie1 did not interact with ABIN-2 in the yeast two-hybrid system or mammalian cells. Deletion analysis identified the Tie2 binding motif to be encompassed between residues 171 and 272 in ABIN-2. Interaction was dependent on Tie2 autophosphorylation but ABIN-2 was not tyrosine phosphorylated by Tie2. Furthermore, in endothelial cells the interaction was stimulated by the Tie2 ligand angiopoietin-1. Expression of ABIN-2 deletion mutants in endothelial cells suppressed the ability of angiopoietin-1 to inhibit phorbol ester–stimulated NF-κB–dependent reporter gene activity. These findings provide the first direct link between Tie2 and a key regulator of inflammatory responses in endothelial cells. Interaction between Tie2 and ABIN-2 may be important in the vascular protective antiinflammatory actions of Tie2.
Antibiotic resistant tuberculosis in the United Kingdom: 1993-1999
Authors: T Djuretic
Journal: Thorax (2002)

The re-emergence of tuberculosis as a global health problem over the past two decades, accompanied by an increase in tuberculosis drug resistance, prompted the development of a comprehensive national surveillance system for tuberculosis drug resistance in 1993.The UK Mycobacterial Resistance Network (Mycobnet), which includes all mycobacterial reference and regional laboratories in the UK, collects a minimum dataset on all individuals from whom an initial isolate of Mycobacterium tuberculosis complex has been isolated and submitted by source hospital laboratories. Data sought include susceptibility to first line antibiotics, demographic, geographical, and risk factor information.There were 25 217 reports of initial isolates of M tuberculosis complex in the UK between 1993 and 1999. All were tested for sensitivity to isoniazid, rifampicin, and ethambutol and 12 692 of the isolates were also tested for sensitivity to pyrazinamide and streptomycin. A total of 1523 (6.1%) isolates were resistant to one or more drugs, 1397 isolates (5.6%) were resistant to isoniazid with or without resistance to other drugs, and 299 (1.2%) were multidrug resistant. Although the numbers of drug resistant isolates increased over the period, the proportions remained little changed. Certain groups of people were at a higher risk of acquiring drug resistant tuberculosis including younger men, residents of London, foreign born subjects, patients with a previous history of tuberculosis and those infected with HIV.Although the proportion of drug resistant tuberculosis cases appears to be stable in the UK at present, more than one in 20 patients has drug resistant disease at diagnosis and more than one in 100 has multidrug resistant disease. Tuberculosis control measures should be strengthened to minimise the emergence of drug resistance through rapid diagnosis, rapid identification of drug resistance, supervised treatment, and maintenance of comprehensive surveillance.