tbuckley/cabot-search huggingface dataset:
Adverse Effects of Cytomegalovirus Vaccination in Mice
Authors: M. Colin Jordan
Journal: Journal of Clinical Investigation (1980)

Studies of live attenuated cytomegalovirus (CMV) vaccine have recently been initiated in man. The possibilities of latent infection and disease resulting from reactivation of vaccine virus are major concerns. Because markers for attenuation of tissue culture-passaged mouse CMV (MCMV) exist, studies of potential adverse effects of vaccination were initiated in mice. Plaque-purified MCMV was passed 12 times in cell culture ("vaccine virus") and shown to be attenuated by virtue of loss of lethality and diminished replication in reticuloendothelial organs of normal mice. Although subcutaneous inoculation of 10(5) plaque-forming units of wild virus was lethal for mice immunosuppressed with antilymphocyte serum (18/18 died), "vaccine MCMV" killed only 3/18 (P < 0.05) and was thus shown to be highly attenuated even in immunosuppressed animals. 4 mo after subcutaneous inoculation of vaccine MCMV, no infectious virus was detectable in the tissues of normal C(3)H mice. However, immunosuppression with anti-lymphocyte serum and cortisone caused MCMV reactivation, dissemination, and wide-spread cytomegalic inclusion disease in 19 of 20 animals. Characterization of the reactivating virus recovered from salivary glands indicated that reversion to virulence had occurred. Thus, vaccine MCMV, although markedly attenuated initially, established latent infection, reactivated after immunosuppression, and reverted to virulence, at least in salivary gland tissue. These data from the murine model substantiate the need for careful surveillance and virologic study of patients given experimental CMV vaccine.
Quantitative proteomics on nasal lavage fluid from asthma phenotypes
Authors: Linda Ekerljung, Serena O'Neil, Sara Hansson, Carina Sihlbom, Jan Lötvall, Bo Lundbäck
Journal: European Respiratory Journal (2012)

Asthma is a complex disease composed of many phenotypes with different underlying mechanisms. In line with the united airways concept, identification of proteins in nasal lavage fluid (NLF) could reflect the proteome of the lung. This study aimed to explore differences in mechanisms between asthma phenotypes using quantitative proteomics on NLF.  NLF was collected from 3 groups of asthmatics; aspirin intolerant asthma (AIA, n=9), multi-symptom asthma (MSA, n=9), and MSA with chronic rhinosinusitis (CRS, n=9) and a group of healthy subjects (n=9). Proteins extracted from NLF were quantified using tandem mass tag technology and a nano-LC MS/MS instrument. Pathway analysis was used to identify global proteome differences.  In all, 474 proteins could be identified and quantified in at least 3 samples per group. In total, 93 proteins in AIA, 113 proteins in CRS and 75 proteins in MSA met the fold change cut off of 1.3 compared to healthy. Of these, 21 proteins were found in all asthma phenotypes, which could reflect common processes in asthma, while 33 proteins were unique to AIA, 56 to CRS and 26 to MSA. Analysis of the global proteomes revealed mechanistic differences between the phenotypes. CRS was more associated with epithelial associated conditions than AIA and MSA. AIA was more associated with carbohydrate metabolism than CRS and MSA, which had more proteins associated with cellular movement and signalling.  Evidence of inflammatory processes can be found in different asthma phenotypes compared to healthy individuals. A comparison between asthma phenotypes revealed mechanistic differences. Quantitative proteomic analysis of NLF was thus capable of detecting relevant disease mechanisms in different asthma phenotypes.
Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study
Authors: Mark C Genovese, Patrick Durez, Hanno B Richards, Jerzy Supronik, Eva Dokoupilova, Vadim Mazurov, Jacob A Aelion, Sang-Heon Lee, Christine E Codding, Herbert Kellner, Takashi Ikawa, Sophie Hugot, Shephard Mpofu
Journal: Annals of the Rheumatic Diseases (2012)

Objective To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA). Methods Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16. Results Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25–300 mg was 36.0–53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)–C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75–300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one). Conclusions ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.
Effects of Rhinovirus Infection on Hydrogen Peroxide– induced Alterations of Barrier Function in the Cultured Human Tracheal Epithelium
Authors: TAKASHI OHRUI, MUTSUO YAMAYA, KIYOHISA SEKIZAWA, NORIHIRO YAMADA, TOMOKO SUZUKI, MASANORI TERAJIMA, SHOJI OKINAGA, HIDETADA SASAKI
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

To investigate whether rhinovirus infection impairs epithelial barrier functions, human rhinovirus 14 (HRV-14) was infected to primary cultures of human tracheal epithelial cells and experiments were performed on Day 2 after HRV-14 infection. Hydrogen peroxide (H2O2; 3 x 10(-)4 M) increased electrical conductance (G) across the epithelial cell sheet measured with Ussing's chamber methods. Exposure of the epithelial cells to HRV-14 had no effect on H2O2-induced increases in G and [3H]mannitol flux through the cultured epithelium in the control condition, but it markedly potentiated H2O2- induced increases in both parameters in IL-1beta (100 U/ml) pretreated condition. However, pretreatment with TNF-alpha (100 U/ml) was without effect. IL-1beta enhanced the intercellular adhesion molecule-1 (ICAM-1) expression assessed by immunohistochemical analysis and susceptibility of epithelial cells to HRV-14 infection. An antibody to ICAM-1 inhibited HRV-14 infection of epithelial cells and abolished H2O2-induced increases in G and [3H]mannitol flux in IL-1beta-pretreated epithelial cells with HRV-14 infection. These results suggest that rhinovirus infection may reduce barrier functions in the airway epithelium in association with upregulation of ICAM-1 expression.
Attenuating homologous recombination stimulates an AID-induced antileukemic effect
Authors: Kristin R. Lamont, Muneer G. Hasham, Nina M. Donghia, Jane Branca, Margaret Chavaree, Betsy Chase, Anne Breggia, Jacquelyn Hedlund, Ivette Emery, Francesca Cavallo, Maria Jasin, Jens Rüter, Kevin D. Mills
Journal: The Journal of Experimental Medicine (2013)

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population.
Effectiveness of Medical Resident Education in Mechanical Ventilation
Authors: Christopher E. Cox, Shannon S. Carson, E. Wesley Ely, Joseph A. Govert, Joanne M. Garrett, Roy G. Brower, David G. Morris, Edward Abraham, Vincent Donnabella, Antoinette Spevetz, Jesse B. Hall
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Specific methods of mechanical ventilation management reduce mortality and lower health care costs. However, in the face of a predicted deficit of intensivists, it is unclear whether residency programs are training internists to provide effective care for patients who require mechanical ventilation. To evaluate these educational outcomes, we administered a validated 19-item case-based test and survey to resident physicians at 31 diverse U.S. internal medicine residency programs nationwide. Of 347 senior residents, 259 (75%) responded. The mean test score was 74% correct (SD, 14%; range, 37 to 100%). Important items representing evidence-based standards of critical care answered incorrectly were as follows: use of appropriate tidal volume in the acute respiratory distress syndrome (48% incorrect), identifying a patient ready for a weaning trial (38% incorrect), and recognizing indication for noninvasive ventilation (27% incorrect). Most accurately identified pneumothorax (86% correct) and increased intrathoracic positive end-expiratory pressure (93% correct). Better scores were associated with "closed" versus "open" intensive care unit organization (76 versus 71% correct, p = 0.001), resident perception of greater versus lesser ventilator knowledge (79 versus 71% correct, p = 0.001), and graduation from a U.S. versus international medical school (75 versus 69% correct, p = 0.033). Although overall training satisfaction correlated strongly with program use of learning objectives (r = 0.89, p < 0.0001), only 46% reported being satisfied with their mechanical ventilation training. We conclude that senior residents may not be gaining essential evidence-based knowledge needed to provide effective care for patients who require mechanical ventilation. Residency programs should emphasize evidence-based learning objectives to guide mechanical ventilation instruction.
Clinical Application of Antiangiogenic Therapy: Microvessel Density, What It Does and Doesn't Tell Us
Authors: Lynn Hlatky, Philip Hahnfeldt, Judah Folkman
Journal: JNCI Journal of the National Cancer Institute (2002)

A substantial number of clinical trials using antiangiogenic therapies are ongoing worldwide. How to achieve the maximum benefit from these therapies and how to monitor patient response are of paramount concern to investigators. There are currently no markers of the net angiogenic activity of a tumor available to aid investigators in the design of antiangiogenic treatment schemes. It stands to reason that quantification of various aspects of tumor vasculature might provide an indication of angiogenic activity. One often-quantified aspect of tumor vasculature is microvessel density. Studies over the last decade have demonstrated the value of using tumor microvessel density as a prognostic indicator for a wide range of cancers. In this context, measurement of microvessel density facilitates assessments of disease stage and the likelihood of recurrence and helps guide treatment decisions. Recently, however, it has been assumed by some investigators that measurements of microvessel density may also reveal the degree of angiogenic activity in a tumor. Based on this assumption, quantification of microvessel density is thought to constitute a surrogate marker for the efficacy of antiangiogenic agents as well as a means by which to assess which patients are good candidates for antiangiogenic therapy prior to treatment. Here we contend that, although microvessel density is a useful prognostic marker, it is not, by itself, an indicator of therapeutic efficacy, nor should it be used to guide the stratification of patients for therapeutic trials. In this review, we discuss the evidence for these assertions and what can and cannot be determined from measurements of microvessel density.
Pregnancy: a risk factor for Budd-Chiari syndrome?
Authors: P-E Rautou, A Plessier, J Bernuau, M-H Denninger, R Moucari, D Valla
Journal: Gut (2009)

In a review on Recent Advances in Clinical Practice for Budd–Chiari syndrome (BCS) ( Gut 2008; 57 :1469–78), one of us emphasised that multiple thrombotic risk factors are usually present in patients with BCS. Below, we report recent results from our group which further support this paradigm and extend it to the context of pregnancy.

An influence of female sex hormones on the risk of BCS has long been recognised on the basis of an increased risk of BCS among oral contraceptive users.1 2 However, the role of pregnancy in causing BCS remains unclear: although 6–47% of reported BCS cases encountered in women presented in pregnancy or postpartum (hereafter referred to as time-related to pregnancy), other risk factors for thrombosis were not investigated.3–6

Among 96 patients with primary BCS diagnosed in our centre between January 1995 and December 2005, there were …
Recurrent varicella pneumonia complicating an endogenous reactivation of chickenpox in an HIV-infected adult patient
Authors: P Fraisse, M Faller, D Rey, N Labouret, M Partisani, F Stoll-Keller, JM Lang, E Weitzenblum
Journal: European Respiratory Journal (1998)

We report the case of an adult patient with acquired immune deficiency syndrome (AIDS) presenting with acute dyspnoea and cutaneous disseminated lesions suggestive of an atypical varicella. The chest radiograph and the computed tomography (CT)-scan revealed a miliary pneumonia. On a previous serum sample varicella-zoster (VZV)-specific serum immunoglobulin (Ig)G titre was 1/200. A high dose acyclovir treatment was effective, but recurrences occurred twice when the treatment was discontinued. During the first recurrence the polymerase chain reaction (PCR) detected the presence of VZV in the bronchoalveolar lavage (BAL) sample. These findings confirmed the diagnosis of secondary varicella with pulmonary involvement. Secondary varicella pneumonia has not been reported in a human immunodeficiency virus (HIV)-infected adult until now. The use of PCR on a BAL sample was very useful in this case because viral culture remained negative. Recurrences of the varicella pneumonia suggested that a maintenance treatment was required in this deeply immunocompromised patient.
Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial.
Authors: R Keays, P M Harrison, J A Wendon, A Forbes, C Gove, G J Alexander, R Williams
Journal: BMJ (1991)

OBJECTIVE--To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN--A prospective randomised controlled study. SETTING--The Institute of Liver Studies, King's College Hospital, London. PATIENTS--50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS--Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES--Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS--The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS--Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.
Predicting the Outcome of Salvage Radiation Therapy for Recurrent Prostate Cancer After Radical Prostatectomy
Authors: Andrew J. Stephenson, Peter T. Scardino, Michael W. Kattan, Thomas M. Pisansky, Kevin M. Slawin, Eric A. Klein, Mitchell S. Anscher, Jeff M. Michalski, Howard M. Sandler, Daniel W. Lin, Jeffrey D. Forman, Michael J. Zelefsky, Larry L. Kestin, Claus G. Roehrborn, Charles N. Catton, Theodore L. DeWeese, Stanley L. Liauw, Richard K. Valicenti, Deborah A. Kuban, Alan Pollack
Journal: Journal of Clinical Oncology (2007)

An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence.Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients.The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69.Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.
Determination of the Molecular Relationship Between Multiple Tumors Within One Patient Is of Clinical Importance
Authors: J. R.M. van der Sijp
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the molecular relationship between multiple tumors within one patient and to evaluate the impact of this knowledge on clinical management. PATIENTS AND METHODS: In 25 consecutive patients with multiple tumors, proven by histology and immunohistochemistry to be identical, molecular aberrations were determined. Each patient had at least one lesion in the lung or head and neck region. Loss of heterozygosity (LOH) and p53 aberration analyses were carried out, and similar aberration profiles suggest clonality and metastasis whereas different profiles suggest independent primary tumors. RESULTS: The molecular determinations indicated that 12 patients had a probable second primary tumor and 10 patients had a metastasis of the first lesion. In three patients, both an independent primary tumor and a metastasis were present. The molecular findings determined the course of additional treatment in all 10 patients with metastases, in all three patients with both a second primary tumor and a metastasis, and in seven of 12 patients with a second primary tumor. CONCLUSION: By comparing DNA alterations of multiple tumors within one patient, the relationship between the tumors can be assessed. This study shows that in 20 of 25 patients, knowledge of the nature of both lesions was essential in clinical decision making. Furthermore, after thorough analysis of the five cases where clinical decision making was not influenced, there was in retrospect no clear indication for LOH or p53 analysis. Because these molecular analyses can be performed on routine specimens, they can be applied in almost all patients.
Gene Mutations in Apical Hypertrophic Cardiomyopathy
Authors: Michael Arad, Manual Penas-Lado, Lorenzo Monserrat, Barry J. Maron, Mark Sherrid, Carolyn Y. Ho, Scott Barr, Ahmad Karim, Timothy M. Olson, Mitsohiro Kamisago, J.G. Seidman, Christine E. Seidman
Journal: Circulation (2005)

Background— Nonobstructive hypertrophy localized to the cardiac apex is an uncommon morphological variant of hypertrophic cardiomyopathy (HCM) that often is further distinguished by distinct giant negative T waves and a benign clinical course. The genetic relationship between HCM with typical hypertrophic morphology versus isolated apical hypertrophy is incompletely understood. Methods and Results— Genetic cause was investigated in 15 probands with apical hypertrophy by DNA sequence analyses of 9 sarcomere protein genes and 3 other genes ( GLA , PRKAG2 , and LAMP2 ) implicated in idiopathic cardiac hypertrophy. Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA , PRKAG2 , or LAMP2 . Clinical evaluations demonstrated familial apical HCM in 4 probands, and in 3 probands disease-causing mutations were identified. Two families shared a cardiac actin Glu101Lys missense mutation; all members of both families with clinical manifestations of HCM (n=16) had apical hypertrophy. An essential light chain missense mutation Met149Val caused apical or midventricular segment HCM in another proband and 5 family members, but 6 other affected relatives had typical HCM morphologies. No other sarcomere gene mutations identified in the remaining probands caused apical HCM in other family members. Conclusions— Sarcomere protein gene mutations that cause apical hypertrophy rather than more common HCM morphologies reflect interactions among genetic etiology, background modifier genes, and/or hemodynamic factors. Only a limited number of sarcomere gene defects (eg, cardiac actin Glu101Lys) consistently produce apical HCM.