tbuckley/cabot-search huggingface dataset:
S137 Vascular Endothelial Growth Factor (vegf) Expression In The Ipf Lung - A Role For Anti-angiogenic Isoforms?
Authors: S. Barratt, T. Blythe, C. Jarrett, G. Welsh, K. Ourradi, C. Scotton, D. Bates, A. Millar
Journal: Thorax (2014)

<h3>Introduction</h3> VEGF has been implicated in the pathogenesis of IPF. Differential splicing of the VEGF gene produces an alternative family of isoforms (VEGF<sub>xxx</sub>b) that have anti-angiogenic properties, in contrast to conventional isoforms (VEGF<sub>xxx</sub>). Currently available literature on the role of VEGF in IPF has not differentiated between these families of isoforms and thus a degree of literature re-appraisal is required. Hypotheses The balance of VEGF<sub>xxx</sub>:VEGF<sub>xxx</sub>b isoforms may be important in IPF pathogenesis VEGF<sub>xxx</sub>b isoforms may abrogate the development of IPF <h3>Methods</h3> Human lung sections and BALF were used to quantify isoform expression in the IPF lung and were compared to controls (ELISA and IHC). Explanted ‘normal’ (NF) and ‘fibrotic’ (FF) fibroblasts were grown in culture with subsequent total RNA and cell lysate extraction (qPCR and WB). Wild-type mice were administered bleomycin (BLM) then received bi-weekly therapeutic intraperitoneal (IP) injections of rhVEGF<sub>165</sub>b (from day 10). Fibrosis was assessed histologically (Masson’s Trichrome and Lung fibrosis score). <h3>Results</h3> In the IPF lung, the alveolar epithelium was the most prominent site for total VEGF (PanVEGF isoforms) but also for VEGF<sub>165</sub>b (n = 10). Addiitonal staining was noted in fibroblasts and lung inflammatory cells. Alveolar and fibrotic cells in the least fibrotic areas of the IPF lung expressed significantly less VEGF<sub>165</sub>b than severely fibrotic areas (p &lt; 0.001, n = 10). Examination of IPF BALF by ELISA revealed that total VEGF expression was significantly lower compared to control (IPF: 18.04 pg/ml +/- 6.13 n = 15, CTRL 85.72 pg/ml +/- 17.08 n = 13), whilst VEGF<sub>165</sub>b could not be detected in identical samples. Explanted NF and FF express comparable quantities of VEGF<sub>xxx</sub> and VEGF<sub>xxx</sub>b isoforms at the mRNA and protein level. Rh VEGF<sub>165</sub> increases the mRNA expression of fibronectin (p &lt; 0.001, n = 4) an effect not seen following the administration of rhVEGF<sub>165</sub>b. Administration of rhVEGF<sub>165</sub>b to mice attenuated the development of BLM-induced pulmonary fibrosis (Masson’s Trichrome (Figure 1) and lung fibrosis score (mean score: BLM alone 41.20 vs VEGF<sub>165</sub>b 30.67, p &lt; 0.01, n = 6 per group)). <h3>Conclusion</h3> Differential expression of VEGF<sub>xxx</sub> and VEGF<sub>xxx</sub>b isoforms occurs in the IPF lung. <i>In vitro</i>, recombinant proteins appear to have differential effects on ECM synthesis and <i>in vivo</i> attenuate the formation of pulmonary fibrosis. A mouse overexpressing VEGF<sub>165</sub>b in the lung has been developed to study this concept in greater detail.
Higher surgical training in the UK
Authors: Arun Kochhar, Stephen French
Journal: Journal of the Royal Society of Medicine (2005)

Ray and co-workers demonstrate the large effect that shortening of higher specialist training might have on operative experience (June 2005 JRSM1). Looking for solutions, they mention a proposal that trainees not wishing to undertake a certain procedure should 'turn over those cases to fellow trainees keen to take up that procedure.' This approach, however, would substantially reduce overall surgical experience, with adverse effects on surgical judgment. They also suggest intensification of training to make up for the shortfall. It is difficult to envisage how this could be achieved with a shift working pattern and the limitation of working hours. Quality of life for junior doctors and continuity of care would also be adversely affected. One proposal is that surgical nurse practitioners could do tasks traditionally performed by junior doctors, leaving the juniors to spend more time in the operating theatre.2 An important consideration is that, when surgical trainees are providing service work at night, they lose training opportunities during the day when operating lists are done. This might be remedied by having specific operating lists run by committed teachers. Surgical training needs to be restructured with an emphasis on quality rather than quantity.
Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium
Authors: Harald Kögler, Heather Fraser, Sylvia McCune, Ruth Altschuld, Eduardo Marbán
Journal: Cardiovascular Research (2003)

Objective: Xanthine oxidase (XO) inhibitors enhance myofilament Ca2+ responsiveness of normal rat myocardium. We examined whether this inotropic action is preserved or magnified in failing rat myocardium and whether the magnitude of this effect correlates with tissue xanthine-oxidoreductase (XOR) activity. Methods: Hearts of 18–20 month-old SHHF (spontaneous hypertensive/heart failure) rats with end-stage heart failure, as well as of normal control rats, were perfused with the XO inhibitor oxypurinol. Afterwards, [Ca2+]i and tension were measured simultaneously in fura-2-loaded intact isolated right ventricular trabeculae. XOR activity was determined fluorometrically in myocardial homogenates. Results: In failing myocardium, 100 μM oxypurinol significantly increased systolic twitch tension (by 87 and 92% at 1.0 and 1.5 mM extracellular [Ca2+], respectively), without altering [Ca2+]i transient amplitude. Oxypurinol did not alter the midpoint or cooperativity of the steady-state tension-[Ca2+]i relationship, but significantly enhanced maximum Ca2+-activated tension by 75% in failing myocardium. Oxypurinol also exerted a positive inotropic effect in failing myocardium, which was, however, of significantly smaller relative magnitude. Failing rat myocardium exhibited higher XOR activity than nonfailing myocardium, and this activity was largely suppressed in oxypurinol-treated preparations. Conclusions: The magnitude of functional improvement with XOR inhibitors depends on the initial level of XOR activity. Specifically, the inotropic actions of oxypurinol are more pronounced in failing rat myocardium, a tissue that exhibits enhanced XOR activity. Our findings rationalize how XO inhibitors boost cardiac contractility and improve mechanoenergetic coupling, and why the effects might be relatively 'selective' for heart failure.
Effects of N-alpha-methyl-histamine on human H2 receptors expressed in CHO cells
Authors: T Saitoh
Journal: Gut (2002)

<b>Background:</b> Production of <i>N</i>-alpha-methyl-histamine (NAMH), a histamine H<sub>3</sub> receptor (H3R) agonist, is reportedly promoted in <i>Helicobacter pylori</i> infected human gastric mucosa. NAMH was suggested to act directly on histamine H<sub>2</sub> receptors (H2Rs) in animals to stimulate acid secretion and to be a H2R agonist. As H2Rs and H3Rs play different roles in gastric acid secretion, it is very important to verify that NAMH is a H2R agonist. <b>Aims:</b> To determine whether NAMH is a H2R agonist, as well as a H3R agonist. <b>Methods:</b> We used a Chinese hamster ovary (CHO) cell line expressing human H2Rs (CHO-H2R) and control CHO cells. Expression of human H2Rs was confirmed by tiotidine binding. cAMP production in CHO-H2R and control cells in response to histamine or NAMH was measured. cAMP production in response to 10<sup>−7</sup> M NAMH was also measured in the presence or absence of the H2R antagonist famotidine and the H3R antagonist thioperamide. <b>Results:</b> NAMH dose dependently stimulated cAMP productions in CHO-H2R cells. This production was inhibited by famotidine but not by thioperamide. Control CHO cells were unresponsive to either histamine or NAMH. In addition, the effect of NAMH, in terms of cAMP production in CHO-H2R cells, was more potent than that of histamine—that is, with a lower EC<sub>50</sub> concentration and higher maximal cAMP production. Both NAMH and histamine, but not <i>R</i>-alpha-methyl-histamine, effectively inhibited [<sup>3</sup>H] tiotidine binding to CHO-H2R cells. <b>Conclusions:</b> NAMH, which is produced in the gastric mucosa by <i>H pylori</i>, is a potent H2R agonist as well as a H3R agonist.
Prevalence of Off-Label Use and Spending in 2010 Among Patent-Protected Chemotherapies in a Population-Based Cohort of Medical Oncologists
Authors: Rena M. Conti, Arielle C. Bernstein, Victoria M. Villaflor, Richard L. Schilsky, Meredith B. Rosenthal, Peter B. Bach
Journal: Journal of Clinical Oncology (2013)

The prevalence of off-label anticancer drug use is not well characterized. The extent of off-label use is a policy concern because the clinical benefits of such use to patients may not outweigh costs or adverse health outcomes.
Lack of clarity and high expectations could lead England's new health regulator to fail
Authors: A. O'Dowd
Journal: BMJ (2011)

England’s health regulator is at high risk of failure because of confusion around its precise role and the extent of its responsibilities, says a report.

Monitor, the regulator for NHS foundation trusts, which is due to become the economic regulator for the whole health service in England under the NHS reforms, could fail in its daunting new role thanks to a combination of too many objectives set for it and not enough of a precise role spelt out.

This conclusion was put forward in a new report Economic regulation in health care: What can we learn from other regulators , published on 3 November by health policy think tank the King’s Fund.

Under the proposals contained in the Health and …
Are randomized trials obsolete or more important than ever in the genomic era?
Authors: John Pa Ioannidis, Muin J Khoury
Journal: Genome Medicine (2013)

Th e genomic era has raised the possibility of major changes in the design, conduct, and even the existence of randomized trials as we know them [13].Randomized trials are often seen as a slow, laborious, expensive, and diffi cult step in the translational process and are associated with a high attrition rate for drugs.Indeed, most tests that are in use for the screening, diagnosis, prognosis, monitoring or management of patients have never been scrutinized by a randomized trial.Th is has largely been due to a failure to realize that tests can do as much harm and as much good as drugs or devices; thus, a rigorous appraisal of their clinical utility, including both the possible benefi ts and the possible harms, is necessary.Moreover, numerous new omicsbased tests are continu ally being proposed, especially in the context of targeted preventive or therapeutic interventions.Given rapid develop ment of these new biomarkers, can we make ran dom ized trials more adaptable to a changing land scape?Furthermore, do we still need randomized trials at all?Our answers to these two questions are: yes, to some extent; and yes, defi nitely.We will explain our reasoning in this article.
Minimal dose of aerosolized interferon-alpha in human subjects: biological consequences and side-effects
Authors: S Giosuè, M Casarini, F Ameglio, L Alemanno, C Saltini, A Bisetti
Journal: European Respiratory Journal (1996)

Interferon-alpha (IFN-alpha) is a leucocyte-derived cytokine with pleiotropic effects on the cells of the immune system, including the ability to promote viral and microbial killing. This study was designed to evaluate the biologically active dosage of aerosolized lymphoblastoid IFN-alpha, in normal subjects and patients with chronic bronchitis, using serum 2'-5' oligoadenylate synthetase (OAS) as a marker of IFN-alpha activity. Three groups of subjects were included: two healthy groups and one of patients with chronic bronchitis. Group A (controls, n = 5) was studied in order to determine the minimal IFN-alpha dose able to induce biological effects without side-effects. IFN-alpha was given in a dose escalation trial including 0, 0.3 x 10(6), 1.0 x 10(6) and 3.0 x 10(6) IU.day-1 (5 day administration). Only the administration of 3.0 x 10(6) IU.day-1 of IFN-alpha induced a significant biological activity, increasing serum levels of OAS. Group B (controls, n = 5) and C (chronic bronchitis, n = 5) were given 3.0 x 10(6) IU.day-1 (10 day administration) in order to study serum, bronchoalveolar lavage fluid (BALF) and BALF cell modifications, after treatment. OAS serum levels and nitroblue tetrazolium (NBT) reduction tests, the latter used as a measure of phagocyte cell activity, increased both in normal subjects and in patients with chronic bronchitis. No significant change of serum IFN-alpha levels was found. It is concluded that aerosolized IFN-alpha administration to the lung is well-tolerated at biologically active doses. The activity can be monitored by quantifying OAS serum levels through a simple blood test.
Beneficial Effect of Pistachio Consumption on Glucose Metabolism, Insulin Resistance, Inflammation, and Related Metabolic Risk Markers: A Randomized Clinical Trial
Authors: Pablo Hernández-Alonso, Jordi Salas-Salvadó, Mònica Baldrich-Mora, Martí Juanola-Falgarona, Mònica Bulló
Journal: Diabetes Care (2014)

OBJECTIVE To examine whether a pistachio-rich diet reduces the prediabetes stage and improves its metabolic risk profile. RESEARCH DESIGN AND METHODS Prediabetic subjects were recruited to participate in this Spanish randomized clinical trial between 20 September 2011 and 4 February 2013. In a crossover manner, 54 subjects consumed two diets, each for 4 months: a pistachio-supplemented diet (PD) and a control diet (CD). A 2-week washout period separated study periods. Diets were isocaloric and matched for protein, fiber, and saturated fatty acids. A total of 55% of the CD calories came from carbohydrates and 30% from fat, whereas for the PD, these percentages were 50 and 35%, respectively (including 57 g/day of pistachios). RESULTS Fasting glucose, insulin, and HOMA of insulin resistance decreased significantly after the PD compared with the CD. Other cardiometabolic risk markers such as fibrinogen, oxidized LDL, and platelet factor 4 significantly decreased under the PD compared with the CD (P &amp;lt; 0.05), whereas glucagon-like peptide-1 increased. Interleukin-6 mRNA and resistin gene expression decreased by 9 and 6%, respectively, in lymphocytes after the pistachio intervention (P &amp;lt; 0.05, for PD vs. CD). SLC2A4 expression increased by 69% in CD (P = 0.03, for PD vs. CD). Cellular glucose uptake by lymphocytes decreased by 78.78% during the PD (P = 0.01, PD vs. CD). CONCLUSIONS Chronic pistachio consumption is emerging as a useful nutritional strategy for the prediabetic state. Data suggest that pistachios have a glucose- and insulin-lowering effect, promote a healthier metabolic profile, and reverse certain metabolic deleterious consequences of prediabetes.
Hormonal contraception without estrogens
Authors: Collins J, Crosignani Pg
Journal: Human Reproduction Update (2003)

The long-term clinical effects of ethinyl estradiol and the impact on environmental safety of the alkylated estrogen components used in combined contraceptive pills remain the subject of debate. The development of improved methods for the use of progestogen-only contraception would represent a viable and desirable option. Several progestogen compounds are not alkylated, and these can be delivered through a variety of routes. Some of the progestogen-only methods are well established in clinical use. Estimates for both perfect and typical effectiveness are less than one pregnancy per 100 woman-years with oral, injectable, implantable and intrauterine methods. In practice, with the oral progestogen-only method, perfect and typical effectiveness range from three to five pregnancies per 100 woman-years. The main side effect with all progestogen-only methods is unpredictable vaginal bleeding during the first months of use, and this may lead to discontinuation. Nevertheless, continuation of use is more frequent if patients are well informed of this side effect before treatment begins. No cardiovascular- and cancer-related side effects have been proven.
Meta-Analysis of Cognitive Functioning in Breast Cancer Survivors Previously Treated With Standard-Dose Chemotherapy
Authors: Heather S.L. Jim, Kristin M. Phillips, Sari Chait, Leigh Anne Faul, Mihaela A. Popa, Yun-Hsiang Lee, Mallory G. Hussin, Paul B. Jacobsen, Brent J. Small
Journal: Journal of Clinical Oncology (2012)

Purpose Evidence is mixed regarding long-term cognitive deficits in patients treated with chemotherapy. Previous meta-analyses have not focused specifically on the postchemotherapy period and have not incorporated several recent studies. The goal of the current study was to conduct a meta-analysis of cognitive functioning in breast cancer survivors who were treated with chemotherapy ≥ 6 months previously. Methods A search of PubMed, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library yielded 2,751 abstracts, which were independently evaluated by pairs of raters. Meta-analysis was conducted on 17 studies of 807 patients previously treated with standard-dose chemotherapy for breast cancer. Neuropsychological tests were categorized according to eight cognitive domains: attention, executive functioning, information processing, motor speed, verbal ability, verbal memory, visual memory, and visuospatial ability. Results Deficits in cognitive functioning were observed in patients treated with chemotherapy relative to controls or prechemotherapy baseline in the domains of verbal ability (g = −0.19; P &lt; .01) and visuospatial ability (g = −0.27; P &lt; .01). Patients treated with chemotherapy performed worse than noncancer controls in verbal ability and worse than patients treated without chemotherapy in visuospatial ability (both P &lt; .01). Age, education, time since treatment, and endocrine therapy did not moderate observed cognitive deficits in verbal ability or visuospatial ability (all P ≥ .51). Conclusion Results indicate that, on average, observed cognitive deficits in patients with breast cancer previously treated with chemotherapy are small in magnitude and limited to the domains of verbal ability and visuospatial ability. This information can be used to inform interventions to educate patients with breast cancer regarding the long-term impact of chemotherapy on cognitive functioning.
Prosthetic Heart Valves
Authors: Philippe Pibarot, Jean G. Dumesnil
Journal: Circulation (2009)

T he introduction of valve replacement surgery in the early 1960s has dramatically improved the outcome of patients with valvular heart disease.Approximately 90 000 valve substitutes are now implanted in the United States and 280 000 worldwide each year; approximately half are mechanical valves and half are bioprosthetic valves.Despite the marked improvements in prosthetic valve design and surgical procedures over the past decades, valve replacement does not provide a definitive cure to the patient.Instead, native valve disease is traded for "prosthetic valve disease," and the outcome of patients undergoing valve replacement is affected by prosthetic valve hemodynamics, durability, and thrombogenicity.Nonetheless, many of the prosthesis-related complications can be prevented or their impact minimized through optimal prosthesis selection in the individual patient and careful medical management and follow-up after implantation.The purpose of this article is to provide an overview of the current state of knowledge and future perspectives with regard to optimal prosthesis selection and clinical management after valve implantation. Types of Prosthetic Heart Valve DesignThe ideal valve substitute should mimic the characteristics of a normal native valve.In particular, it should have excellent hemodynamics, long durability, high thromboresistance, and excellent implantability.Unfortunately, this ideal valve substitute does not exist, and each of the currently available prosthetic valves has inherent limitations. Mechanical ValvesThree basic types of mechanical valve design exist: bileaflet, monoleaflet, and caged ball valves (Figure 1A, 1B, and1C). Caged Ball ValvesCaged ball valves, which consist of a silastic ball with a circular sewing ring and a cage formed by 3 metal arches, are no longer implanted.However, several thousands of patients still have caged ball valves, and these patients require follow-up. Monoleaflet ValvesMonoleaflet valves are composed of a single disk secured by lateral or central metal struts.The opening angle of the disk relative to valve annulus ranges from 60°to 80°, resulting in 2 distinct orifices of different sizes. Bileaflet ValvesBileaflet valves are made of 2 semilunar disks attached to a rigid valve ring by small hinges.The opening angle of the leaflets relative to the annulus plane ranges from 75°to 90°, and the open valve consists of 3 orifices: a small, slit-like central orifice between the 2 open leaflets and 2 larger semicircular orifices laterally.
ABVD versus BEACOPP for Hodgkin's Lymphoma When High-Dose Salvage Is Planned
Authors: Simonetta Viviani, Pier Luigi Zinzani, Alessandro Rambaldi, Ercole Brusamolino, Alessandro Levis, Valeria Bonfante, Umberto Vitolo, Alessandro Pulsoni, Anna Marina Liberati, Giorgina Specchia, Pinuccia Valagussa, Andrea Rossi, Francesco Zaja, Enrico M. Pogliani, Patrizia Pregno, Manuel Gotti, Andrea Gallamini, Delia Rota Scalabrini, Gianni Bonadonna, Alessandro M. Gianni
Journal: New England Journal of Medicine (2011)

BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months.The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group.Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).