tbuckley/cabot-search huggingface dataset:
Phase III Prevention Trial of Fenretinide in Patients with Resected Non–Muscle-Invasive Bladder Cancer
Authors: Anita L. Sabichi, Seth P. Lerner, E. Neely Atkinson, H. Barton Grossman, Nancy P. Caraway, Colin P. Dinney, David F. Penson, Surena Matin, Ashish Kamat, Louis L. Pisters, Daniel W. Lin, Ruth L. Katz, Dean E. Brenner, George P. Hemstreet, Mary Wargo, Archie Bleyer, William H. Sanders, John L. Clifford, Howard L. Parnes, Scott M. Lippman
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The study aims to evaluate the efficacy and toxicity of fenretinide in preventing tumor recurrence in patients with transitional cell carcinoma (TCC) of the bladder. Experimental Design: We conducted a multicenter phase III, randomized, placebo-controlled trial of fenretinide (200 mg/day orally for 12 months) in patients with non–muscle-invasive bladder TCC (stages Ta, Tis, or T1) after transurethral resection with or without adjuvant intravesical Bacillus Calmette-Guerin (BCG). Patients received cystoscopic evaluation and bladder cytology every 3 months during the 1-year on study drug and a final evaluation at 15 months. The primary endpoint was time to recurrence. Results: A total of 149 patients were enrolled; 137 were evaluable for recurrence. The risk of recurrence was considered to be “low” in 72% (no prior BCG) and intermediate or high in 32% (prior BCG) of the evaluable patients. Of the lower-risk group, 68% had solitary tumors and 32% had multifocal, low-grade papillary (Ta, grade 1 or grade 2) tumors. The 1-year recurrence rates by Kaplan-Meier estimate were 32.3% (placebo) versus 31.5% (fenretinide; P = 0.88 log-rank test). Fenretinide was well tolerated and had no unexpected toxic effects; only elevated serum triglyceride levels were significantly more frequent on fenretinide (versus placebo). The Data Safety and Monitoring Board recommended study closure at 149 patients (before reaching the accrual goal of 160 patients) because an interim review of the data showed a low likelihood of detecting a difference between the two arms, even if the original accrual goal was met. Conclusions: Although well tolerated, fenretinide did not reduce the time-to-recurrence in patients with Ta, T1, or Tis TCC of the bladder.
Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation
Authors: Michael T. Dill, Zuzanna Makowska, Gaia Trincucci, Andreas J. Gruber, Julia E. Vogt, Magdalena Filipowicz, Diego Calabrese, Ilona Krol, Daryl T. Lau, Luigi Terracciano, Erik van Nimwegen, Volker Roth, Markus H. Heim
Journal: Journal of Clinical Investigation (2014)

The use of pegylated interferon-α (pegIFN-α) has replaced unmodified recombinant IFN-α for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-α is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. Here, we analyzed pegIFN-α–induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-α injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-α in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-α administration. Evaluation of liver biopsies revealed that pegIFN-α induces hundreds of genes that can be classified into four clusters based on different temporal expression profiles. In all clusters, gene transcription was mainly driven by IFN-stimulated gene factor 3 (ISGF3). Compared with conventional IFN-α therapy, pegIFN-α induced a broader spectrum of gene expression, including many genes involved in cellular immunity. IFN-induced secondary transcription factors did not result in additional waves of gene expression. Our data indicate that the superior antiviral efficacy of pegIFN-α is not the result of prolonged Jak/STAT pathway activation in hepatocytes, but rather is due to induction of additional genes that are involved in cellular immune responses.
The Influence of Increased Bronchial Responsiveness, Atopy, and Serum IgE on Decline in FEV<sub>1</sub>: A Longitudinal Study in the Elderly
Authors: M. Tracey A. Villar, Lindsey Dow, David Coggon, Fiona C. Lampe, Stephen T. Holgate
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

We have performed a 4-yr prospective survey of the association of allergen skin test positivity, total serum immunoglobulin E (IgE), and bronchial responsiveness to methacholine, with longitudinal decline in FEV1, in subjects over 65 yr of age. In 1987, 324 subjects completed a respiratory questionnaire, and underwent measurement of FEV1 and FVC, methacholine challenge, skin prick testing (to Dermatophagoides pteronyssinus, cat fur, mixed grasses, and Aspergillus fumigatus) and estimation of total serum IgE. After an interval of 4 yr, 212 subjects were reexamined. The mean annual decline in FEV1 was significantly higher in males than in females, but was not significantly influenced by smoking habits defined at the start of the study. The relation of atopy (skin test reaction to allergen ≥ 3 mm greater than saline control), increased bronchial responsiveness (PD20FEV1 ≤ 6.4 µmoles methacholine) and serum IgE > 80 IU/ml, to annual decline in FEV1 was examined for each risk factor individually with adjustment for age, sex, height, and initial FEV1, by multiple linear regression. Both atopy and bronchial responsiveness were significantly associated with accelerated decline in FEV1. Elevated IgE was correlated with faster FEV1 decline in subjects who were current smokers at the start of the study. In a multiple regression model examining the mutually adjusted associations of all relevant variables with annual decline in FEV1, male sex was the most important predictor (B = 38.6 ml/yr, 95% CI = 4.3, 72.9). Increased bronchial responsiveness also tended to be associated with accelerated decline in FEV1. In further analyses incorporating the same variables, but restricted to specific smoking categories, age was the only significant factor in the never-smokers, whereas both atopy (B = 44.5 ml/yr, 95% CI = 3.8, 85.3) and increased bronchial responsiveness (B = 43.5 ml/yr, 95% CI = 4.6, 82.3) were significant predictors of accelerated FEV1 decline in former and current smokers combined. In conclusion, allergy and increased bronchial responsiveness are risk factors for a more rapid decline in lung function in the elderly, particularly in former and current smokers.
Severe Maternal Sepsis in the UK, 2011–2012: A National Case-Control Study
Authors: Colleen D. Acosta, Jennifer J. Kurinczuk, D. Nuala Lucas, Derek J. Tuffnell, Susan Sellers, Marian Knight
Journal: PLoS Medicine (2014)

Background In light of increasing rates and severity of sepsis worldwide, this study aimed to estimate the incidence of, and describe the causative organisms, sources of infection, and risk factors for, severe maternal sepsis in the UK. Methods and Findings A prospective case-control study included 365 confirmed cases of severe maternal sepsis and 757 controls from all UK obstetrician-led maternity units from June 1, 2011, to May 31, 2012. Incidence of severe sepsis was 4.7 (95% CI 4.2–5.2) per 10,000 maternities; 71 (19.5%) women developed septic shock; and five (1.4%) women died. Genital tract infection (31.0%) and the organism Escherichia coli (21.1%) were most common. Women had significantly increased adjusted odds ratios (aORs) of severe sepsis if they were black or other ethnic minority (aOR = 1.82; 95% CI 1.82–2.51), were primiparous (aOR = 1.60; 95% CI 1.17–2.20), had a pre-existing medical problem (aOR = 1.40; 95% CI 1.01–1.94), had febrile illness or were taking antibiotics in the 2 wk prior to presentation (aOR = 12.07; 95% CI 8.11–17.97), or had an operative vaginal delivery (aOR = 2.49; 95% CI 1.32–4.70), pre-labour cesarean (aOR = 3.83; 95% CI 2.24–6.56), or cesarean after labour onset (aOR = 8.06; 95% CI 4.65–13.97). Median time between delivery and sepsis was 3 d (interquartile range = 1–7 d). Multiple pregnancy (aOR = 5.75; 95% CI 1.54–21.45) and infection with group A streptococcus (aOR = 4.84; 2.17–10.78) were associated with progression to septic shock; for 16 (50%) women with a group A streptococcal infection there was <2 h—and for 24 (75%) women, <9 h—between the first sign of systemic inflammatory response syndrome and a diagnosis of severe sepsis. A limitation of this study was the proportion of women with sepsis without an identified organism or infection source (16.4%). Conclusions For each maternal sepsis death, approximately 50 women have life-threatening morbidity from sepsis. Follow-up to ensure infection is eradicated is important. The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign guideline of early administration of high-dose intravenous antibiotics within 1 h of admission to hospital for anyone with suspected sepsis. Signs of severe sepsis in peripartum women, particularly with confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency. Please see later in the article for the Editors' Summary
Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism
Authors: Sabine Brouxhon, Stephanos Kyrkanides, M. Kerry O'Banion, Renee Johnson, David A. Pearce, Gina M. Centola, Jen-nie H. Miller, Kieran H. McGrath, Brandon Erdle, Glynis Scott, Sandra Schneider, JoAnne VanBuskirk, Alice P. Pentland
Journal: Cancer Research (2007)

Abstract The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin–mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E2 (PGE2) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin–mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E-cadherin. We also show that UV irradiation, via the PGE2-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin–mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE2-EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. [Cancer Res 2007;67(16):7654–64]
Inflammation assessment in patients with arthritis using a novel in vivo fluorescence optical imaging technology
Authors: Stephanie G Werner, Hans-Eckhard Langer, Sarah Ohrndorf, Malte Bahner, Peter Schott, Carsten Schwenke, Michael Schirner, Hans Bastian, Gudrun Lind-Albrecht, Bernward Kurtz, Gerd R Burmester, Marina Backhaus
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Indocyanine green (ICG)-enhanced fluorescence optical imaging (FOI) is an established technology for imaging of inflammation in animal models. In experimental models of arthritis, FOI findings corresponded to histologically proven synovitis. This is the first comparative study of FOI with other imaging modalities in humans with arthritis. <h3>Methods</h3> 252 FOI examinations (Xiralite system, mivenion GmbH, Berlin, Germany; ICG bolus of 0.1 mg/kg/body weight, sequence of 360 images, one image per second) were compared with clinical examination (CE), ultrasonography (US) and MRI of patients with arthritis of the hands. <h3>Results</h3> In an FOI sequence, three phases could be distinguished (P1–P3). With MRI as reference, FOI had a sensitivity of 76% and a specificity of 54%, while the specificity of phase 1 was 94%. FOI had agreement rates up to 88% versus CE, 64% versus greyscale US, 88% versus power Doppler US and 83% versus MRI, depending on the compared phase and parameter. FOI showed a higher rate of positive results compared to CE, US and MRI. In individual patients, FOI correlated significantly (p&lt;0.05) with disease activity (Disease Activity Score 28, r=0.41), US (r=0.40) and RAMRIS (Rheumatoid Arthritis MRI Score) (r=0.56). FOI was normal in 97.8% of joints of controls. <h3>Conclusion</h3> ICG-enhanced FOI is a new technology offering sensitive imaging detection of inflammatory changes in subjects with arthritis. FOI was more sensitive than CE and had good agreement with CE, US in power Doppler mode and MRI, while showing more positive results than these. An adequate interpretation of an FOI sequence requires a separate evaluation of all phases. For the detection of synovitis and tenosynovitis, FOI appears to be as informative as 1.5 T MRI and US.
The Incidence and Prevalence of Systemic Lupus Erythematosus, 2002–2004: The Georgia Lupus Registry
Authors: S. Sam Lim, A. Rana Bayakly, Charles G. Helmick, Caroline Gordon, Kirk A. Easley, Cristina Drenkard
Journal: Arthritis & Rheumatology (2013)

The Georgia Lupus Registry is a population-based registry designed to improve our ability to estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in a large population.Potential cases of SLE were identified from multiple sources during the years 2002 through 2004. Cases were defined according to the American College of Rheumatology (ACR) criteria for SLE or a combined definition. Age-standardized rates were determined and stratified by race and sex. With capture-recapture analyses, we estimated the under-ascertainment of cases.Using the ACR case definition, the overall crude and age-adjusted incidence rate was 5.6 per 100,000, with capture-recapture and combined definition rates being slightly higher. The age-adjusted incidence rate in women was >5 times higher than that for men (9.2 versus 1.8). Black women had an incidence rate nearly 3 times higher than that in white women, with a significantly higher rate in the group ages 30-59 years. The overall crude and age-adjusted prevalence rates were 74.4 and 73 per 100,000, respectively. The age-adjusted prevalence rate in women was nearly 9 times higher than that for men (127.6 versus 14.7). Black women had very high rates (196.2). A striking difference was seen in the proportion of prevalent cases with end-stage renal disease, with 7-fold greater involvement among black patients.With the more complete case-finding methods we used, the incidence and prevalence rates of SLE are among the highest reported in the US. The results continue to underscore striking sex, age, and racial disparities between black patients and white patients with SLE.
The Handbook of Clinical Trials and Other Research: A Earl-Slater. Abingdon, UK: Radcliffe Medical Press Ltd, 2002, pp 352. ISBN 1-85775- 485-9
Authors: P Hungin
Journal: Gut (2003)

Caution with the use of cyclosporin in pregnancyWe read the article by Alstead and Nelson-Piercy with great interest. 1 We report a case (submitted for publication) of a woman with fulminant ulcerative colitis in the 29th week of pregnancy.Her disease was refractory to steroids, but she refused to have cyclosporin whilst pregnant.She therefore underwent an emergency Caesarean section and was given intravenous cyclosporin post-operatively.After 48 hours of treatment she developed severe hypertension with hypertensive encephalopathy and seizures.Although cyclosporin has been considered to be safe for both mother and foetus, we would like to highlight concerns that it is associated with potentially life threatening side effects.As a result, patients must be counselled thoroughly about the potential morbidity associated with this treatment and monitored closely.We agree with Dr Alstead in that cyclosporin should be used with extreme caution in pregnancy and the postnatal period.
Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis
Authors: A Calin, B A C Dijkmans, P Emery, M Hakala, J Kalden, M Leirisalo-Repo, E M Mola, C Salvarani, R Sanmartí, J Sany, J Sibilia, J Sieper, S van der Linden, E Veys, A M Appel, S Fatenejad
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> A double blind, randomised, placebo controlled study to evaluate the safety and efficacy of etanercept to treat adult patients with ankylosing spondylitis (AS). <b>Methods:</b> Adult patients with AS at 14&nbsp;European sites were randomly assigned to 25 mg injections of etanercept or placebo twice weekly for 12 weeks. The primary efficacy end point was an improvement of at least 20% in patient reported symptoms, based on the multicomponent Assessments in Ankylosing Spondylitis (ASAS) response criteria (ASAS 20). Secondary end points included ASAS 50 and ASAS 70 responses and improved scores on individual components of ASAS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), acute phase reactants, and spinal mobility tests. Safety was evaluated during scheduled visits. <b>Results:</b> Of 84 patients enrolled, 45 received etanercept and 39 received placebo. Significantly more etanercept patients than placebo patients responded at the ASAS&nbsp;20 level as early as week&nbsp;2, and sustained differences were evident up to week 12. Significantly more etanercept patients reported ASAS 50 responses at all times and ASAS 70 responses at weeks&nbsp;2, 4, and 8; reported lower composite and fatigue BASDAI scores; had lower acute phase reactant levels; and had improved spinal flexion. Etanercept was well tolerated. Most adverse events were mild to moderate; the only between-group difference was injection site reactions, which occurred significantly more often in etanercept patients. <b>Conclusions:</b> Etanercept is a well tolerated and effective treatment for reducing clinical symptoms and signs of AS.
Left Ventricular Pressure-Volume Relations and Performance as Affected by Sudden Increases in Developed Pressure
Authors: R. G. MONROE, C. G. LA FARGE, W. J. GAMBLE, A. ROSENTHAL, S. HONDA
Journal: Circulation Research (1968)

Left ventricular performance in the isolated dog heart was observed in a preparation in which left ventricular pressure and volume could be monitored continuously while the ventricle contracted isobarically by compressing air into a large chamber. By suddenly reducing the orifice connecting the ventricle to the chamber a constant load was imposed on the ventricle, abruptly forcing it to develop pressure in systole. This pressure increased over the ensuing 3 minutes while both the load and the end-diastolic pressure remained constant, implying that the sudden development of pressure by the ventricle was attended by a positive inotropic effect, otherwise known as homeometric autoregulation. Further studies showed this positive inotropic effect to be a function of the magnitude of the abrupt increase in systolic pressure and the time course of the experiment. β-adrenergic receptor blockade with propranolol decreased but did not abolish this effect. Infusion of norepinephrine did not enhance it. Increases in ventricular compliance that accompanied loading could not fully account for it. Evidence is presented that this positive inotropic effect may in part be mediated through the release of intrinsic catecholamines when the ventricle is forced to increase its systolic pressure.
Fetal and Infant Growth and Asthma Symptoms in Preschool Children
Authors: Agnes M. M. Sonnenschein-van der Voort, Vincent W. V. Jaddoe, Hein Raat, Henriëtte A. Moll, Albert Hofman, Johan C. de Jongste, Liesbeth Duijts
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Low birth weight is associated with an increased risk of wheezing in childhood.Objectives: We examined the associations of longitudinally measured fetal and infant growth patterns with the risks of asthma symptoms in preschool children.Methods: This study was embedded in a population-based prospective cohort study among 5,125 children. Second- and third-trimester fetal growth characteristics (head circumference, femur length, abdominal circumference, and weight) were estimated by repeated ultrasounds. Infant growth (head circumference, length, and weight) was measured at birth and at the ages of 3, 6, and 12 months. Parental report of asthma symptoms until the age of 4 years was yearly obtained by questionnaires.Measurements and Main Results: Both fetal restricted and accelerated growth, defined as a negative or positive change of more than 0.67 standard deviation score, were not associated with asthma symptoms until the age of 4 years. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms (overall odds ratio for wheezing: 1.44 [95% confidence interval: 1.22, 1.70]; shortness of breath: 1.32 [1.12, 1.56]; dry cough: 1.16 [1.01, 1.34]; persistent phlegm: 1.30 [1.07, 1.58]), but not with eczema (0.95 [0.80, 1.14]). These associations were independent of other fetal growth patterns and tended to be stronger for children of atopic mothers than for children of nonatopic mothers.Conclusions: Weight-gain acceleration in early infancy was associated with increased risks of asthma symptoms in preschool children, independent of fetal growth. Early infancy might be a critical period for the development of asthma.
Locally Up-regulated Lymphotoxin α, Not Systemic Tumor Necrosis Factor α, Is the Principle Mediator of Murine Cerebral Malaria
Authors: Christian R. Engwerda, Tracey L. Mynott, Sanjeet Sawhney, J. Brian De Souza, Quentin D. Bickle, Paul M. Kaye
Journal: The Journal of Experimental Medicine (2002)

Cerebral malaria (CM) causes death in children and nonimmune adults. TNF-alpha has been thought to play a key role in the development of CM. In contrast, the role of the related cyto-kine lymphotoxin alpha (LTalpha) in CM has been overlooked. Here we show that LTalpha, not TNFalpha, is the principal mediator of murine CM. Mice deficient in TNFalpha (B6.TNFalpha-/-) were as susceptible to CM caused by Plasmodium berghei (ANKA) as C57BL/6 mice, and died 6 to 8 d after infection after developing neurological signs of CM, associated with perivascular brain hemorrhage. Significantly, the development of CM in B6.TNFalpha-/- mice was not associated with increased intracellular adhesion molecule (ICAM)-1 expression on cerebral vasculature and the intraluminal accumulation of complement receptor 3 (CR3)-positive leukocytes was moderate. In contrast, mice deficient in LTalpha (B6.LTalpha-/-) were completely resistant to CM and died 11 to 14 d after infection with severe anemia and hyperparasitemia. No difference in blood parasite burden was found between C57BL/6, B6.TNFalpha-/-, and B6.LTalpha-/- mice at the onset of CM symptoms in the two susceptible strains. In addition, studies in bone marrow (BM) chimeric mice showed the persistence of cerebral LTalpha mRNA after irradiation and engraftment of LTalpha-deficient BM, indicating that LTalpha originated from a radiation-resistant cell population.