tbuckley/cabot-search huggingface dataset:
Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins
Authors: A. Romano, F. Gaeta, R. L. Valluzzi, C. Alonzi, M. Maggioletti, A. Zaffiro, C. Caruso, D. Quaratino
Journal: Allergy (2013)

Studies performed on subjects with IgE-mediated hypersensitivity to penicillins have demonstrated a 1% rate of cross-reactivity between penicillins and both imipenem and meropenem, while a single study found a 5.5% rate of cross-reactivity with imipenem/cilastatin in subjects with T-cell-mediated hypersensitivity to β-lactams, mostly penicillins. We studied 204 consecutive subjects with a well-demonstrated T-cell-mediated hypersensitivity to assess the cross-reactivity with carbapenems and the tolerability of such alternative β-lactams. All 204 subjects underwent skin tests with imipenem/cilastatin and meropenem; 130 of them were skin-tested also with ertapenem. Subjects with negative test results were challenged with these carbapenems. All subjects displayed negative skin tests to carbapenems and tolerated challenges. These data demonstrate the absence of clinically significant T-cell-mediated cross-reactivity between penicillins and carbapenems. Negative delayed-reading skin testing with carbapenems in individuals with documented T-cell-mediated hypersensitivity to penicillins correlates well with subsequent clinical tolerance of therapeutic doses of carbapenems.
When should a long acting agonist be added to an inhaled corticosteroid?
Authors: A E Tattersfield
Journal: Thorax (2005)

Evidence suggests that adding a long acting β agonist provides more clinical benefit than doubling the dose of an inhaled steroid even for relatively low doses of inhaled corticosteroid

Meta-analyses are a mixed blessing; they can be helpful and they can be misleading,1–3 and meta-analyses of studies in asthma are no exception.4 They are misleading when they fail to make clear that the conclusions only pertain to patients fulfilling the inclusion and exclusion criteria for the original studies. To suggest that they either confirm what everyone knows or provide conclusions, from somewhat dubious sources with spurious precision, may be unduly cynical. Nevertheless, it appears to be difficult to identify questions where a meta-analysis is able to provide important new insights into asthma management.

Professor Beasley’s group in New Zealand has used meta-analysis in the past to look at the dose-response relation for inhaled budesonide and fluticasone.5,6 The two meta-analyses included all studies that had assessed at least two doses of the inhaled corticosteroid in addition to placebo. The conclusion of the analyses was that, in …
THE ORIGIN OF HODGKIN AND REED/STERNBERG CELLS IN HODGKIN'S DISEASE
Authors: Ralf Küppers, Klaus Rajewsky
Journal: Annual Review of Immunology (1998)

▪ Abstract One of the characteristic features of Hodgkin's disease (HD) is the presence of a small population of often bizarre-looking large mono- or multinucleated Hodgkin and Reed-Sternberg (HRS) cells within the affected tissue. Recent cytogenetic investigations, studies of Epstein-Barr virus (EBV) genomes present in HRS cells, and analyses of Ig gene rearrangements amplified from single, micromanipulated HRS cells show that these cells largely represent clonal populations. The finding of Ig gene rearrangements in HRS cells in most cases of HD identifies B cells as the precursors of HRS cells in most if not all cases. Furthermore, the presence and pattern of somatic mutations within the rearranged Ig genes show that HRS cells in classical (i.e. nodular sclerosis, mixed cellularity, and lymphocyte depletion HD) as well as lymphocyte predominant (LP) HD originate from germinal center (GC) B cells. Ongoing somatic mutation and evidence for selection link HRS cells from LP HD to a mutating, antigen-selected GC B cell. In classical HD, the finding of “crippling” mutations and lack of stringent selection for antigen receptor expression suggests that in this case HRS cells are derived from a compartment of GC B cells that were destined to die but escaped apoptosis by some transforming event. One candidate for the latter is EBV infection.
Inhibition of inflammatory gene expression by dexamethasone partly depends on the phosphatase, MKP-1 (DUSP1)
Authors: Suharsh Shah, Elizabeth King, Robert Newton
Journal: European Respiratory Journal (2013)

Acting on the glucocorticoid receptor (GR), inhaled glucocorticoids (GCs) are a cornerstone in the treatment of asthma and suppress airway inflammation by reducing inflammatory gene expression. Traditionally, GR was believed to directly repress inflammatory gene transcription (transrepression). However, evidence also suggests that GC-dependent gene expression (transactivation) plays an important repressive role. Since repression of interleukin-8 (IL8) and GM-CSF (CSF2) by dexamethasone (Dex) depends on gene expression, we now examine the repressive role of Dex-induced mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 (DUSP1).

METHODS: Pulmonary A549 epithelial cells were treated with IL-1β (1 ng/ml), with/without Dex (1 µM). Inflammatory gene expression was assessed by real-time PCR and ELISA, and MAPK activation by western blotting. Roles for MAPKs were explored with selective inhibitors and roles for MKP-1 were tested by over-expression and siRNA silencing.

RESULTS: IL-1β rapidly increased inflammatory gene expression and this was MAPK-dependent. MKP-1 over-expression repressed expression of many IL-1β-induced inflammatory genes, including IL8 and CSF2. Inflammatory gene expression was significantly repressed by Dex in a manner that was modestly and transiently reversed by silencing of Dex-induced MKP-1.

Conclusions: The apparently partial and transient role of MKP-1 in the repression of inflammatory gene expression, for example IL8 and CSF2, by Dex suggests that additional GC-induced gene products are also important. This provides a rational for functional screening of GC-inducible genes that may show repressive functions.
Depressive Symptoms in Spouses of Older Patients with Severe Sepsis, Surrogate Decision Makers’ Interpretation of Prognostic Information, and Effect of Estrogen on <i>Pseudomonas</i> in Cystic Fibrosis
Authors: Rita N. Bakhru, Mary McKenzie, Jason B. Turowski
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Critical illness exacts an emotional toll, not only from the patient but also from family members, resulting in depression, anxiety, and posttraumatic stress disorder. This study by Davydow and colleagues evaluates the incidence of depressive symptoms in spouses of elderly patients hospitalized with severe sepsis. The authors used the Health and Retirement Study (HRS)—a United States–based longitudinal study of community-dwelling adults over age 50 years interviewed at 2-year intervals—and linked this to Medicare claims for hospitalizations with severe sepsis. The HRS provided an eight-item depression scale for up to three surveys before a Medicare claim for severe sepsis, followed by up to four subsequent surveys. Among 16,722 HRS respondents linked to Medicare claims, 929 had a spouse hospitalized for severe sepsis, for a total of 1,128 hospitalizations. Hospitalization culminated in survival in 947 of these episodes. The prevalence of depressive symptoms among wives was 20% before the episode of severe sepsis, increasing to 34% (P , 0.001) following the episode. Among husbands, the prevalence increased from 17% before the episode to 25% (P , 0.001) following. In fixed-effects logistic regression, controlling for all spousal characteristics that did not change over time, the increased risk of depression remained significant among wives of patients but not among husbands. The odds of experiencing major depressive symptoms remained elevated (odds ratio, 2.86) even among the wives whose husbands survived the episode of severe sepsis, and the magnitude of this risk tracked with the degree of disability among the survivors. Similar findings among husbands of patients with sepsis were not demonstrated. This study advances our understanding of the association between depression in family members and critically ill patients by demonstrating that the risk of depression is not restricted to wives who lose their spouses but extends to those who provide ongoing care to survivors with residual disability. The findings among husbands of patients with sepsis were equivocal, leaving one to wonder whether this reflects a methodological limitation or a true sex difference. Of note, the mortality rate among elderly, severely septic patients was 21.9% in this study, which is substantially lower than that in other contemporary series. It is possible that the ability to recognize Medicare patients with severe sepsis by the methods employed in the study is biased or that the HRS respondents are not representative of all elderly patients with severe sepsis. Nonetheless, this study prompts medical caregivers to be attuned to the psychological needs of spouses of critically ill patients, most notably those providing care to survivors.
Systemic Spread Is an Early Step in Breast Cancer
Authors: Yves Hüsemann, Jochen B. Geigl, Falk Schubert, Piero Musiani, Manfred Meyer, Elke Burghart, Guido Forni, Roland Eils, Tanja Fehm, Gert Riethmüller, Christoph A. Klein
Journal: Cancer Cell (2008)
Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure
Authors: Yoshiaki Kawase, Hung Q. Ly, Fabrice Prunier, Djamel Lebeche, Yanfen Shi, Hongwei Jin, Lahouaria Hadri, Ryuichi Yoneyama, Kozo Hoshino, Yoshiaki Takewa, Susumu Sakata, Richard Peluso, Krisztina Zsebo, Judith K. Gwathmey, Jean-Claude Tardif, Jean-François Tanguay, Roger J. Hajjar
Journal: Journal of the American College of Cardiology (2008)
Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies
Authors: Rajesh Krishna, Matt S Anderson, Arthur J Bergman, Bo Jin, Marissa Fallon, Josee Cote, Kim Rosko, Cynthia Chavez-Eng, Ryan Lutz, Daniel M Bloomfield, Maria Gutierrez, James Doherty, Fredrick Bieberdorf, Jeffrey Chodakewitz, Keith M Gottesdiener, John A Wagner
Journal: The Lancet (2007)
MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia
Authors: Tomohisa Baba, Kazuhito Naka, Soji Morishita, Norio Komatsu, Atsushi Hirao, Naofumi Mukaida
Journal: The Journal of Experimental Medicine (2013)

In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene–transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL+lineage−c-kit− immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1α/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal.
Need for global action for cancer control
Authors: P. Boyle, B.O. Anderson, L.C. Andersson, Y. Ariyaratne, G.-R. Auleley, M. Barbacid, H. Bartelink, J. Baselga, K. Behbehani, F. Belardelli, A. Berns, J. Bishop, O. Brawley, H. Burns, M. Clanton, B. Cox, D. Currow, J.-M. Dangou, D. de Valeriola, K. Dinshaw, A. Eggermont, J. Fitzpatrick, M. Forstmane, E. Garaci, A.T. Gavin, T. Kakizoe, M. Kasler, N. Keita, D. Kerr, D. Khayat, S. Khleif, T. Khuhaprema, T. Knezevic, R. Kubinova, M. Mallath, J. Martin-Moreno, D. McCance, J.G. McVie, A. Merriman, T. Ngoma, M. Nowacki, J. Orgelbrand, J.-G. Park, M. Pierotti, L.P. Ashton, P. Puska, C.V.R. Escobar, B. Rajan, T. Rajkumar, U. Ringborg, C. Robertson, A. Rodger, L. Roovali, L.A. Santini, M. Sarhan, J. Seffrin, V. Semiglazov, B.M. Shrestha, K.C. Soo, V. Stamenic, C. Tamblyn, R. Thomas, M. Tuncer, T. Tursz, R. Vaitkiene, C. Vallejos, U. Veronesi, A. Wojtyla, D. Yach, K.-Y. Yoo, W. Zatonski, D. Zaridze, Y.-X. Zeng, P. Zhao, T. Zheng
Journal: Annals of Oncology (2008)
Changes in Invasive Pneumococcal Disease among HIV-Infected Adults Living in the Era of Childhood Pneumococcal Immunization
Authors: Brendan Flannery
Journal: Annals of Internal Medicine (2006)

Background: Adults infected with HIV have high rates of invasive pneumococcal disease. Introduction of pneumococcal conjugate vaccine for children could affect disease among HIV-infected adults. Objective: To compare invasive pneumococcal disease among HIV-infected adults before and after the introduction of a pediatric conjugate vaccine. Design: Active laboratory-based surveillance in an adult population of 10.8 million, including 38 314 living with AIDS. Setting: 7 Active Bacterial Core surveillance areas in the United States. Patients: All surveillance-area residents 18 to 64 years of age with Streptococcus pneumoniae isolated from a sterile site between 1998 and 2003. Measurements: Ratio of the number of cases of invasive pneumococcal disease among HIV-infected adults to the estimated number of adults 18 to 64 years of age living with AIDS; serotype-specific subset analyses; and comparison of periods before and after introduction of conjugate vaccine by using exact tests. Results: Of 8582 cases of invasive pneumococcal disease in adults, 2013 (24%) occurred among persons infected with HIV. Between baseline (1998 to 1999) and 2003, the ratio of invasive pneumococcal disease in HIV-infected adults to the number of adults living with AIDS in the surveillance areas decreased from 1127 to 919 cases per 100 000 AIDS population, a reduction of 19% (P = 0.002). Among HIV-infected adults, the ratio for disease caused by pneumococcal serotypes included in the conjugate vaccine decreased 62% (P < 0.001), although the ratio for disease caused by nonvaccine serotypes increased 44% (P < 0.001). Limitations: Ratios are proxy measures of incidence rates. The denominator of surveillance-area residents living with HIV infection was not available. Conclusions: Introduction of the pediatric conjugate vaccine was associated with an overall decrease in invasive pneumococcal disease among HIV-infected adults, despite increased disease caused by nonvaccine serotypes.
Is anorectal endosonography valuable in dyschesia?
Authors: S M Van Outryve
Journal: Gut (2002)

Dyschesia can be provoked by inappropriate defecation movements. The aim of this prospective study was to demonstrate dysfunction of the anal sphincter and/or the musculus (m.) puborectalis in patients with dyschesia using anorectal endosonography.Twenty consecutive patients with a medical history of dyschesia and a control group of 20 healthy subjects underwent linear anorectal endosonography (Toshiba models IUV 5060 and PVL-625 RT). In both groups, the dimensions of the anal sphincter and the m. puborectalis were measured at rest, and during voluntary squeezing and straining. Statistical analysis was performed within and between the two groups.The anal sphincter became paradoxically shorter and/or thicker during straining (versus the resting state) in 85% of patients but in only 35% of control subjects. Changes in sphincter length were statistically significantly different (p<0.01, chi(2) test) in patients compared with control subjects. The m. puborectalis became paradoxically shorter and/or thicker during straining in 80% of patients but in only 30% of controls. Both the changes in length and thickness of the m. puborectalis were significantly different (p<0.01, chi(2) test) in patients versus control subjects.Linear anorectal endosonography demonstrated incomplete or even absent relaxation of the anal sphincter and the m. puborectalis during a defecation movement in the majority of our patients with dyschesia. This study highlights the value of this elegant ultrasonographic technique in the diagnosis of "pelvic floor dyssynergia" or "anismus".
Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial
Authors: Robert A Hauser, C Warren Olanow, Karl D Kieburtz, Emmanuelle Pourcher, Any Docu-Axelerad, Mark Lew, Olexandr Kozyolkin, Ann Neale, Chris Resburg, Uwe Meya, Christopher Kenney, Stephen Bandak
Journal: The Lancet Neurology (2014)
The diagnostic accuracy of clinical examination in hand lacerations
Authors: R. Nassab, K. Kok, J. Constantinides, V. Rajaratnam
Journal: International Journal of Surgery (2006)

Hand injuries account for a significant proportion of emergency department attendance. We investigated the diagnostic accuracy of clinical examination in patients with simple hand lacerations undergoing surgical exploration at our unit. One hundred and sixty-five consecutive patients were identified as undergoing exploration of the hand. Case notes of these patients were reviewed. The clinical findings, made by emergency department doctors (ED) and hand surgeons (HS), were compared with the operative findings. A total of 101 patients were included following exclusion criteria. Both ED and HS correctly identified 68.2% of flexor tendon injuries. Overall, the ED diagnosed accurately significantly fewer extensor tendon injuries (ED 65.6% vs HS 75.0%, p < 0.001). Similarly, HS diagnosed nerve injuries more accurately than ED (ED 54.5% vs HS 78.8%, p < 0.005). Clinical examination forms an important part of the patient assessment, provides the surgeon with an idea of which structures are potentially injured, and its value should never be underestimated. Formal exploration, however, should be undertaken since both ED and HS missed about 30% injuries.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/Refractory Leukemia
Authors: Hiroto Inaba, Jeffrey E. Rubnitz, Elaine Coustan-Smith, Lie Li, Brian D. Furmanski, Gerard P. Mascara, Kenneth M. Heym, Robbin Christensen, Mihaela Onciu, Sheila A. Shurtleff, Stanley B. Pounds, Ching-Hon Pui, Raul C. Ribeiro, Dario Campana, Sharyn D. Baker
Journal: Journal of Clinical Oncology (2011)

To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
EXPERIMENTS ON THE PURIFICATION AND CONCENTRATION OF THE VIRUS OF POLIOMYELITIS
Authors: Albert B. Sabin
Journal: The Journal of Experimental Medicine (1932)

Methods employed by Willstätter and his coworkers in the isolation and purification of enzymes have been applied to the virus of poliomyelitis. Rhoads (6) showed that alumina gel C mixed with poliomyelitis virus in certain proportions at an acid pH resulted in the adsorption and inactivation of the virus. The experiments in this communication confirm Rhoads' observation, and show further that the adsorption as well as the inactivation are reversible; i.e., by changing the pH to the alkaline side with M/15 Na(2)HPO(4) it is possible to free the virus in a state in which it is again capable of producing typical poliomyelitis. These experiments show also that by this process the virus undergoes considerable purification by diminution in the concentration of non-virus-containing substances. Washing the alumina gel C-virus complex with M/5 NaCl-M/15 KH(2)PO(4) apparently dissociates no virus but is capable of freeing a certain amount of extractible organic substances. Furthermore, it is possible to increase the degree of purity and concentration of the virus by distillation in vacuo, and subsequent repeated adsorptions and elutions. By such partial purification and concentration, a virus solution with a minimal effective dose (as regards the production of typical poliomyelitis) of 0.0003 cc. was obtained. This solution had 0.04 mg. N per cc., and gave negative biuret, xanthoproteic, and ninhydrin reactions. These methods offer an opportunity for the preparation of a quantity of sufficiently purified and concentrated poliomyelitis virus to warrant the beginning of a study of its chemical nature; they also offer a means of anchoring the virus to an insoluble, and centrifugable substance (alumina gel C), which promises to facilitate various immunological studies, that might otherwise have been impossible.