tbuckley/cabot-search huggingface dataset:
Differential Requirement for Mesenchyme in the Proliferation and Maturation of Thymic Epithelial Progenitors
Authors: William E. Jenkinson, Eric J. Jenkinson, Graham Anderson
Journal: The Journal of Experimental Medicine (2003)

Formation of a mature thymic epithelial microenvironment is an essential prerequisite for the generation of a functionally competent T cell pool. It is likely that recently identified thymic epithelial precursors undergo phases of proliferation and differentiation to generate mature cortical and medullary thymic microenvironments. The mechanisms regulating development of immature thymic epithelial cells are unknown. Here we provide evidence that expansion of embryonic thymic epithelium is regulated by the continued presence of mesenchyme. In particular, mesenchymal cells are shown to mediate thymic epithelial cell proliferation through their provision of fibroblast growth factors 7 and 10. In contrast, differentiation of immature thymic epithelial cells, including acquisition of markers of mature cortical and medullary epithelium, occurs in the absence of ongoing mesenchymal support. Collectively, our data define a role for mesenchymal cells in thymus development, and indicate distinct mechanisms regulate proliferation and differentiation of immature thymic epithelial cells. In addition, our findings may aid in studies aimed at developing strategies to enhance thymus reconstitution and functioning in clinical certain contexts where thymic epithelial cell function is perturbed.
Second Malignancy Risks After Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: Differences by Lymphoma Subtype
Authors: Lindsay M. Morton, Rochelle E. Curtis, Martha S. Linet, Elizabeth C. Bluhm, Margaret A. Tucker, Neil Caporaso, Lynn A.G. Ries, Joseph F. Fraumeni
Journal: Journal of Clinical Oncology (2010)

Previous studies have shown increased risks of second malignancies after non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, no earlier investigation has quantified differences in risk of new malignancy by lymphoma subtype.We evaluated second cancer and leukemia risks among 43,145 1-year survivors of CLL/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL) from 11 Surveillance, Epidemiology, and End Results (SEER) population-based registries during 1992 to 2006.Among patients without HIV/AIDS-related lymphoma, lung cancer risks were significantly elevated after CLL/SLL and FL but not after DLBCL (standardized incidence ratio [SIR], CLL/SLL = 1.42, FL = 1.28, DLBCL = 1.00; Poisson regression P for difference among subtypes, P(Diff) = .001). A similar pattern was observed for risk of cutaneous melanoma (SIR: CLL/SLL = 1.92, FL = 1.60, DLBCL = 1.06; P(Diff) = .004). Acute nonlymphocytic leukemia risks were significantly elevated after FL and DLBCL, particularly among patients receiving initial chemotherapy, but not after CLL/SLL (SIR: CLL/SLL = 1.13, FL = 5.96, DLBCL = 4.96; P(Diff) < .001). Patients with HIV/AIDS-related lymphoma (n = 932) were predominantly diagnosed with DLBCL and had significantly and substantially elevated risks for second anal cancer (SIR = 120.50) and Kaposi's sarcoma (SIR = 138.90).Our findings suggest that differing immunologic alterations, treatments (eg, alkylating agent chemotherapy), genetic susceptibilities, and other risk factors (eg, viral infections, tobacco use) among lymphoma subtypes contribute to the patterns of second malignancy risk. Elucidating these patterns may provide etiologic clues to lymphoma as well as to the second malignancies.
First FDA Approval of Neoadjuvant Therapy for Breast Cancer: Pertuzumab for the Treatment of Patients with HER2-Positive Breast Cancer
Authors: Laleh Amiri-Kordestani, Suparna Wedam, Lijun Zhang, Shenghui Tang, Amy Tilley, Amna Ibrahim, Robert Justice, Richard Pazdur, Patricia Cortazar
Journal: Clinical Cancer Research (2014)

Abstract On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab–docetaxel (TD), pertuzumab–trastuzumab–docetaxel (PTD), pertuzumab–trastuzumab, or pertuzumab–docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial. Clin Cancer Res; 20(21); 5359–64. ©2014 AACR.
Treatment of ulcerative reflux oesophagitis with colloidal bismuth subcitrate in combination with cimetidine.
Authors: M V Borkent, J A Beker
Journal: Gut (1988)

Twenty patients took part in a controlled double blind study comparing the efficacy of colloidal bismuth and cimetidine (800 mg at night) with cimetidine alone in the treatment of ulcerative reflux oesophagitis. Colloidal bismuth 120 mg was administered through an intraoesophageal tube four times a day. Cimetidine with colloidal bismuth gives significantly (p less than 0.001) better results than cimetidine alone. Of 10 patients treated with cimetidine and bismuth, seven had no endoscopic signs of oesophagitis after three weeks and three had grade I oesophagitis. Of 10 patients treated with cimetidine alone, one had grade I oesophagitis and three grade II oesophagitis after three weeks. The remaining six still had grade III oesophagitis. This study also shows that in nine of 10 patients reflux oesophagitis was accompanied by infection with campylobacter like organisms (CLO). After treatment the bacteria disappeared promptly in five patients receiving combination therapy and in two of four treated with cimetidine alone. The possible role of CLO in reflux oesophagitis is uncertain.
P1211 HIGH DOSE RIBAVIRIN INFLUENCES EARLY VIRAL KINETICS AND IMPROVES SVR RATES IN CHRONIC HCV PATIENTS WHO ADHERE TO THERAPY (VIRID STUDY)
Authors: L. Koning, J.P.H. Drenth, R. Roomer, J.T. Brouwer, N. Aparicio, J.G. Den Hollander, B.C. Baak, P. Honkoop, M. Klemt-Kropp, H.L.A. Janssen, B.E. Hansen, R.J. de Knegt
Journal: Journal of Hepatology (2014)
HDL and Cardiovascular Risk
Authors: Bernd Hewing, Kathryn J. Moore, Edward A. Fisher
Journal: Circulation Research (2012)

H igh-density lipoprotein cholesterol (HDL-C) has been dubbed the good cholesterol because it is thought to reflect the ability of HDL particles to remove excess cholesterol molecules from peripheral cells (including those in atherosclerotic plaques) for return to the liver.Not surprisingly, then, HDL-C has frequently been assumed to be a biomarker of HDL function, consistent with the inverse relationship in observational studies between plasma levels of HDL-C and risk of coronary artery disease.Recently, Voight et al have challenged this assumption by showing that genetically elevated HDL-C did not protect against myocardial infarction.This finding has fueled a lively discussion in the lay, scientific, and medical press about the relationship between HDL-C and HDL function, and the potential effectiveness of various HDL-C raising strategies.Epidemiological studies clearly show that levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the risk of coronary artery disease and its thrombotic complications. 1 However, in a recent study, Voight et al 2 tested the hypothesis that increased plasma HDL-C is protective for myocardial infarction (MI) by examining the relationship between genetic variations associated with elevated levels of plasma HDL-C and the risk of MI. 2 The major approach used was Mendelian randomization, a method developed to infer disease causality of a genetic variation. 3n the first test of the hypothesis, a loss of function single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser; minor allele frequency 2.6%) that is associated with an elevated mean plasma level of HDL-C (but no change in the
DNA damage and repair in atherosclerosis
Authors: M MAHMOUDI, J MERCER, M BENNETT
Journal: Cardiovascular Research (2006)

There is increasing evidence that human atherosclerosis is associated with damage to the DNA of both circulating cells, and cells of the vessel wall. Reactive oxygen species are the most likely agents inducing DNA damage in atherosclerosis. DNA damage produces a variety of responses, including cell senescence, apoptosis and DNA repair. This review summarises the evidence for DNA damage in atherosclerosis, the cellular responses to damage and the mechanisms of signalling DNA damage.
Safety of thalidomide
Authors: S Asscher
Journal: BMJ (1994)

Calcium, vitamin D, and hip fractures Incidence offalls may have decreased EDITOR,-Marie C Chapuy and colleagues report that treatment with cholecalciferol and calcium prevents non-vertebral fractures in elderly women and suggest that this is due to an improvement in bone metabolism.'As they mentioned in a previous report of this study, however, the result- ing increase in bone density is low.2A more likely explanation for the results might be a decrease in the incidence of falls in the active treatment group.This incidence, however, was not reported.A difference in the incidence of falls between the two groups could be explained by the muscular effects of cholecalciferol treatment.Indeed, apart from its action on bone metabolism, a low vitamin D concentration causes muscular weakness, which can be reversed by substitution.34Chapuy and colleagues mention that the mean serum concentration of 25-hydroxycholecalciferol normalised in the active treatment group but remained low in the controls.In a prospective study that I carried out in 63 elderly women (mean age 82-5 (SD 5 4) years), all living in the community and independent in basic activities of daily living, muscular strength and exercise capacity were related to serum 25hydroxycholecalciferol concentrations (table ).Serum 25-hydroxycholecalciferol concentration and mean (SD) grnp strength for both hands and distance walked in six minute walking test in 63 elderly women 25-Hydroxycholecalciferol* (nmol/l) <40 ¢40 (n=50) (n= 13) P valuet Grip strength (kPa) 45-5±20-0 59-8±26-6 <0 05 Distancewalked(m) 149±111 273±115 <0 01 *Normal value > 40 nmol/l.tStudent's t test.Other recent reports on the treatment of osteo- porosis in elderly people have also failed to mention the incidence of falls.'In general, all studies on osteoporotic fractures should mention this incidence as it is essential to the understanding of the dynamics of the intervention.
ON THE PRESENCE OF THE TYPHOID BACILLUS IN THE URINE
Authors: Mark Wyman Richardson
Journal: The Journal of Experimental Medicine (1898)

(1) Typhoid bacilli were demonstrated in the urines of 9 out of 38 typhoid patients (about 25 per cent). 172 specimens were examined with 44 positive results. (2) The bacilli, when demonstrated, were always present in large numbers and in practically pure culture. (3) The bacilli appeared first in the later stages of the disease and persisted in the great majority of cases far into convalescence. The urines of typhoid patients should, therefore, not only be rigidly disinfected during the disease, but they should also be carefully supervised during convalescence. (4) The typhoid bacilli were practically always associated with albuminuria and the presence of renal casts. On the other hand urines containing considerable amounts of albumin and casts in large numbers often showed no typhoid bacilli. (5) Irrigation of the bladder with antiseptic solutions offers a possible means for removing permanently the bacilli from the urine.
Bacterial confirmation of gonococcal arthritis.
Authors: J M Davis, M M Peel
Journal: Annals of the Rheumatic Diseases (1984)

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at −120 mV (3% inhibition by 100 <i>µ</i>M lacosamide) but greatly enhanced at −80 mV (43% inhibition by 100 <i>µ</i>M lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at −120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at −40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 <i>µ</i>M lidocaine or 300 <i>µ</i>M carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding.
Limitation of myocardial reperfusion injury by intravenous perfluorochemicals. Role of neutrophil activation.
Authors: A K Bajaj, M A Cobb, R Virmani, J C Gay, R T Light, M B Forman
Journal: Circulation (1989)

Neutrophil activation and infiltration into the ischemic myocardium after reperfusion may limit the amount of salvageable myocardium (reperfusion injury). The effects of intravenous perfluorochemicals (Fluosol-DA) on infarct size, ventricular contractility, and neutrophil function were assessed in an occlusion-reperfusion canine model. Closed-chest dogs were subjected to 90 minutes of left anterior descending artery occlusion followed by 24 hours of reperfusion. Animals were randomized to receive either Fluosol-DA (FDA, n = 8) or Ringer's lactate (CONT, n = 10) intravenously over 30 minutes just before left anterior descending artery reperfusion. Neutrophil demargination and infiltration into the myocardium were assessed in vivo with In111. Neutrophil chemotaxis, superoxide radical production, and lysozyme degranulation were evaluated ex vivo at baseline, 1 hour after occlusion, and 1 hour after reperfusion. Perfluorochemicals significantly reduced infarct size expressed as percent of area at risk (FDA, 7 +/- 4%; CONT, 24 +/- 6%; p less than 0.01). This was associated with positive wall motion in the jeopardized zone of Fluosol-DA animals compared with dyskinesis in control animals (FDA, +4.4 +/- 2.1%; CONT, -1.1 +/- 1.5%; p less than 0.05). Electron microscopy showed reduced neutrophil and erythrocyte plugging of capillaries with relative preservation of endothelial cells in the Fluosol-DA animals. Myocardial blood flow was greater in the ischemic endocardium of Fluosol-DA animals 1 hour after reperfusion (FDA, 1.23 +/- 0.21; CONT, 0.62 +/- 0.08 ml/g/min; p less than 0.01). Neutrophil demargination and infiltration into the ischemic myocardium was reduced in the animals treated with Fluosol-DA. (FDA, 2.5 +/- 0.7 x 10(3); CONT, 14.1 +/- 2.7 x 10(3) neutrophils/g; p less than 0.01). Neutrophil chemotaxis and lysozyme release were also markedly suppressed in the Fluosol-DA groups ex vivo. These results show that intravenous Fluosol-DA significantly reduces reperfusion injury with greater salvage of myocardium and improved left ventricular function. The chief mechanism of action of Fluosol-DA appears to be the suppression of neutrophil function.
High-Volume Hemofiltration After Out-of-Hospital Cardiac Arrest
Authors: Ivan Laurent, Christophe Adrie, Christophe Vinsonneau, Alain Cariou, Jean-Daniel Chiche, Alice Ohanessian, Christian Spaulding, Pierre Carli, Jean-François Dhainaut, Mehran Monchi
Journal: Journal of the American College of Cardiology (2005)
Peripheral Vascular Disease and Peripheral Neuropathy in Individuals With Cardiometabolic Clustering and Obesity
Authors: Kelly R. Ylitalo, MaryFran Sowers, Steven Heeringa
Journal: Diabetes Care (2011)

Two lower-extremity diseases (LEDs), including peripheral neuropathy and peripheral vascular disease (PVD), are leading causes of disability in the U.S. Although LEDs can be complications of diabetes, their prevelances and risk factors apart from diabetes are poorly described. This study describes the prevalence of LEDs and examines the association of obesity and cardiometabolic clustering in a population-based sample.Adults aged≥40 years (n=2,514) were evaluated in the 2001-2004 National Health and Nutrition Examination Survey for clustering of two or more cardiometabolic characteristics, including elevated triglycerides or plasma glucose, low HDL cholesterol levels, increased waist circumference, or hypertension. Clustering was combined with BMI (dichotomized at ≥30 kg/m2) to generate three groups: obese (with or without clustering); nonobese with clustering; and nonobese without clustering. Multivariate logistic regression procedures incorporated the complex survey sampling design.Overall, 9.0% of individuals had peripheral neuropathy alone, 8.5% had PVD alone, and 2.4% had both LEDs. The obese group was more likely to have peripheral neuropathy (odds ratio 2.20 [95% CI 1.43-3.39]), PVD (3.10 [1.84-5.22]), and both LEDs (6.91 [2.64-18.06]) compared with nonobese subjects without clustering. Within the nonobese group, clustering increased the odds of peripheral neuropathy (1.50 [1.00-2.25]) and PVD (2.48 [1.38-4.44]) compared with no clustering.Obesity and clustering markedly increased the likelihood of LEDs in this sample and identified a group for whom preventive activities may reduce the risk of future disability.
Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group
Authors: G. Fountzilas, H.P. Kalofonos, U. Dafni, C. Papadimitriou, D. Bafaloukos, P. Papakostas, A. Kalogera-Fountzila, H. Gogas, G. Aravantinos, L.A. Moulopoulos, T. Economopoulos, D. Pectasides, N. Maniadakis, V. Siafaka, E. Briasoulis, C. Christodoulou, D. Tsavdaridis, P. Makrantonakis, E. Razis, P. Kosmidis, D. Skarlos, M.A. Dimopoulos
Journal: Annals of Oncology (2004)
Incidence of viral infections in patients with lung transplantation
Authors: Pierre-Olivier Bridevaux, John-David Aubert, Paola Soccal, Thierry Rochat, Laurent Kaiser
Journal: European Respiratory Journal (2012)

Lung transplant recipients (LTR) are at risk of respiratory viral infection (VI). Our goal was to characterize clinical factors associated with upper or lower respiratory tract VI, as well as the relation between VI and acute graft rejection (AR) in a cohort of LTR patients.  Method  LTR patients (n=112) from Lausanne & Geneva University hospitals had systematic nasopharyngeal swabs (NPS) and when indicated bronchoalveolar lavage (BAL) with transbronchial biopsy (N visits=903). We screened 18 distinct respiratory viruses with rt-PCR during: a) seven 6-week investigator-driven screening period (n=570), b) regular (n=124) and c) emergency visits (n=209).  Results  During follow-up, 172/903 VI (19%) were identified in 68/112 (61%) LTRs with 34/276 infected BAL and VI rate was highest during emergency visits (p  Rhinoviruses were most frequent both in NPS (n=85/138, 65%) and BAL (n=20/34, 59%). New symptoms were reported in 73% of VI. AR was not associated with VI nor initiation of AR therapy up to 3 months (both p=0.5). Association wa unchanged when restricted to VI other than rhinovirus.  Conclusion  Viral infection rate is high among LTR and related to one third of emergency visits. In this study, common viral infection was not associated with acute rejection or initiation of acute rejection therapy within 3 months.
Nephrotoxicity in the Elderly Due to Co-Prescription of Angiotensin Converting Enzyme Inhibitors and Nonsteroidal Anti-Inflammatory Drugs
Authors: Vedamurthy Adhiyaman, Muhammad Asghar, Anthony Oke, Anthony D White, Ikram U Shah
Journal: Journal of the Royal Society of Medicine (2001)

Both angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs can lead to functional renal insufficiency. In an observational study we assessed the frequency of this adverse effect in patients aged over 75 years receiving these drugs in combination. In one year, out of 1500 patients whose records were screened, 12 were prescribed this combination. 2 developed acute renal failure, of whom one died and the other recovered after discontinuation of both drugs. 4 patients showed deterioration in renal function, which returned to normal after one of the drugs was stopped. Renal function remained stable in 6 patients: patients with deterioration in renal function were older and more likely to be on diuretics. This drug combination is commonly nephrotoxic in the elderly and should be avoided, especially in those taking diuretics.
Primary Prevention of Sudden Death With Implantable Defibrillator Therapy in Patients With Cardiac Disease
Authors: Derek V. Exner, George J. Klein, Eric N. Prystowsky
Journal: Circulation (2001)

S udden cardiac death (SCD) is a major public health problem in North America, responsible for approximately 400 000 deaths annually. 1,2Most episodes of SCD in ambulatory populations result from ventricular tachyarrhythmias, 3 whereas bradyarrhythmias may be important in some populations, notably hospitalized patients with advanced heart failure 4 (Figure 1).A prior article in this series by Zipes and Wellens 2 provides a detailed review of the pathogenesis of SCD, its underlying causes, and treatment strategies. ICD TherapyThe availability of a therapy that reliably terminates the vast majority of life-threatening tachyarrhythmic and bradyarrhythmic events has tremendous clinical appeal.The implantable cardioverter defibrillator (ICD) represents such a therapy.Despite its appeal, the ICD is imperfect.Currently, systems are costly, have a limited life expectancy, and are subject to complications in the long term. 5,6Furthermore, many patients at risk for SCD are at risk of dying from causes that the ICD would not alter.The impact of ICD shocks also merits consideration.Evidence links multiple shocks with myocardial injury 7 and fibrosis, 8 and sporadic shocks are associated with significant, independent reductions in quality of life.Compared with patients not having shocks, patients in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial who had Ն1 shocks in the initial year of follow-up had significant declines in self-perceived physical functioning and mental well-being, independent of ejection fraction (EF), social circumstances, and medication use.The reduction in quality of life associated with shocks was of a magnitude similar to clinically important adverse effects from amiodarone. 9 Cost-efficacy is a vital issue in settings of limited or restricted health care resources 6 and is particularly relevant as ICD use is expanded to include patients sharing only some similarity to populations in which it has been demonstrated to be effective, so-called indication creep. 10