tbuckley/cabot-search huggingface dataset:
Role of Nox2-Based NADPH Oxidase in Bone Marrow and Progenitor Cell Function Involved in Neovascularization Induced by Hindlimb Ischemia
Authors: Norifumi Urao, Hyoe Inomata, Masooma Razvi, Ha Won Kim, Kishore Wary, Ronald McKinney, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation Research (2008)

Bone marrow (BM) is the major reservoir for endothelial progenitor cells (EPCs). Postnatal neovascularization depends on not only angiogenesis but also vasculogenesis, which is mediated through mobilization of EPCs from BM and their recruitment to the ischemic sites. Reactive oxygen species (ROS) derived from Nox2-based NADPH oxidase play an important role in postnatal neovascularization; however, their role in BM and EPC function is unknown. Here we show that hindlimb ischemia of mice significantly increases Nox2 expression and ROS production in BM-mononuclear cells (BMCs), which is associated with an increase in circulating EPC-like cells. Mice lacking Nox2 show reduction of ischemia-induced flow recovery, ROS levels in BMCs, as well as EPC mobilization from BM. Transplantation of wild-type (WT)-BM into Nox2-deficient mice rescues the defective neovascularization, whereas WT mice transplanted with Nox2-deficient BM show reduced flow recovery and capillary density compared to WT-BM transplanted control. Intravenous infusion of WT- and Nox2-deficient BMCs into WT mice reveals that neovascularization and homing capacity are impaired in Nox2-deficient BMCs in vivo. In vitro, Nox2-deficient c-kit + Lin − BM stem/progenitor cells show impaired chemotaxis and invasion as well as polarization of actins in response to stromal derived factor (SDF), which is associated with blunted SDF-1–mediated phosphorylation of Akt. In conclusion, Nox2-derived ROS in BM play a critical role in mobilization, homing, and angiogenic capacity of EPCs and BM stem/progenitor cells, thereby promoting revascularization of ischemic tissue. Thus, NADPH oxidase in BM and EPCs is potential therapeutic targets for promoting neovascularization in ischemic cardiovascular diseases.
Lack of Correlation between Epidermal Growth Factor Receptor Status and Response to Panitumumab Monotherapy in Metastatic Colorectal Cancer
Authors: J. Randolph Hecht, Edith Mitchell, Marcus A. Neubauer, Howard A. Burris, Paul Swanson, Timothy Lopez, Glenn Buchanan, Maureen Reiner, Jennifer Gansert, Jordan Berlin
Journal: Clinical Cancer Research (2010)

Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is approved as monotherapy for the treatment of metastatic colorectal cancer. We evaluated the association of tumor EGFR expression levels with outcomes in patients with chemorefractory metastatic colorectal cancer.Two phase II, multicenter, single-arm, open-label studies enrolled chemorefractory patients with tumors expressing low/negative (1-9%/<1%; Low/Negative EGFR study) or high (> or =10%; High EGFR study) levels of EGFR. Patients received panitumumab 6 mg/kg every two weeks until disease progression or intolerance. End points included objective response rate (per response evaluation criteria in solid tumors), progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses by tumor KRAS status were carried out.A total of 203 patients (Low/Negative EGFR) and 185 patients (High EGFR) enrolled in the studies. The overall response rate was 5.7% [95% confidence interval (95% CI), 2.6-10.5] in patients with low/negative EGFR and 4.2% (95% CI, 1.6-9.0) in patients with high EGFR; the response rate at week 16 was 4% in both studies (all partial responses). Median PFS times were 8.1 weeks (95% CI, 7.1-12.6), 8.1 weeks (95% CI, 7.4-11.1), and 7.3 weeks (95% CI, 7.1-7.6) in patients with negative, low, and high levels of EGFR expression, respectively. PFS and OS were longer in patients with wild-type KRAS than those with mutant KRAS. As expected, most adverse events were skin related.These studies confirm previous reports that tumor EGFR expression levels are not associated with efficacy with an anti-EGFR antibody and that anti-EGFR antibody therapy should be limited to those patients whose tumors express wild-type KRAS.
Diffusely Metastatic Digital Papillary Adenocarcinoma 11 Years After Initial Presentation Treated With Palliative Chemotherapy and Radiotherapy
Authors: Joshua A. Jones, Vatsal B. Patel, Benjamin Goldsmith, Ursina Teitelbaum, John P. Plastaras
Journal: Journal of Clinical Oncology (2013)

A 48-year-old man presented in 1999 with a mass on his right thumb.Biopsy revealed aggressive digital papillary adenoma.He underwent partial amputation; pathology revealed a 1.5-cm aggressive digital papillary adenocarcinoma (ADPCa) with widely negative margins.The final pathology was described previously by Jih et al. 1 There was no evidence of metastatic disease on cross-sectional imaging at the time.The patient was followed with routine physical examination and cross-sectional imaging for 5 years without evidence of recurrence or spread.The patient was treated for pneumonia in late 2009.A follow-up computed tomography scan in early 2010 showed a subcentimeter mass in the lingula for which 6-month follow-up was recommended.In June 2010, the patient presented with substernal chest pain and was treated for non-ST elevation myocardial infarction with a bare metal stent in the proximal right circumflex artery.A postprocedure chest x-ray in June 2010 revealed a left lower lobe lung nodule.Subsequent computed tomography imaging of the chest, abdomen, and pelvis revealed a 2.5-cm mass at the left lung base, a 3-cm lingular mass abutting the chest wall, multiple liver hypodensities, a lytic lesion in the left pubic ramus, and several subcutaneous nodules, the largest in the left chest wall measuring 2 cm.There was also stranding with enhancement of the left gluteus and adductor musculature.Magnetic resonance imaging of the brain demonstrated no intracranial pathology.A subcentimeter mass was noted along the right thenar eminence at the base of the right thumb, the site of initial diagnosis.Three biopsies were performed in the following areas: the left chest wall and underlying lingular mass, the left gluteus maximus muscle, and the right thenar eminence.All revealed ADPCa that was consistent with the primary lesion, now presenting as metastatic disease 11 years after initial treatment.The patient reported difficulty walking because of pain in his left buttock that extended into his left thigh.He also reported pain in the right hand that extended from the area of initial amputation of the right thumb to the mass at the base of the first finger.There was exquisite point tenderness in the anterolateral sole of each foot; each was associated with a subcentimeter nodule.These lesions (left buttock, right hand, and bilateral feet) grew rapidly over the course of 2 weeks.The patient had a decreased appetite and lost 20 pounds over 3 months.The patient did not have any medical history of immune deficiency.Medications at the time of referral included aspirin, atorvastatin, clopidogrel, lisinopril, metoprolol, extended-release morphine (15 mg every 8 hours), and hydromorphone (2 mg every 3 hours) as
Remission and relapse of Crohn's disease following autologous haematopoietic stem cell transplantation for non-Hodgkin's lymphoma
Authors: V Anumakonda, B Hayee, G Chung-Faye
Journal: Gut (2007)

allowed to undertake all endoscopic procedures in the field of conventional endoscopy.A recent editorial from Dewitt 1 asks, ''Is there anything now we can't do?'' with double balloon enteroscopy.We would ask, ''Is there anything now we can do''?We encountered the case in our early experience of double balloon enteroscopy, and only a diagnostic endoscope was available in Taiwan.Because of our limited experience in the use of double balloon enteroscopy and the lack of suitable haemostasis equipment, a discussion with the patient was held and it was determined that he preferred the option of surgical resection of the polyp.At present, we are capable of diagnosing various small intestinal diseases with the use of double balloon enteroscopy.However, we still need more experience to improve our technique for treating the lesions found and managing the associated complications.More studies are required to show the effectiveness and safety of therapeutic double balloon enteroscopy compared with traditional methods.
Heparan Sulfate Proteoglycans Initiate Dengue Virus Infection of Hepatocytes
Authors: Philip Hilgard, Richard Stockert
Journal: Hepatology (2000)

Dengue viruses (DEN) cause a broad spectrum of clinical manifestations including potentially life–threatening conditions such as hemorrhagic shock syndrome and less frequently acute hepatitis with liver failure and encephalopathy. In addition, dengue viruses provide a potential model to understand the initiation of hepatocyte infection by the structurally closely related hepatitis C virus (HCV), because this virus at present cannot be grown in cell culture. Although the initial steps of viral infection are a critical determinant of tissue tropism and therefore pathogenesis, little is known about the molecular basis of binding and endocytic trafficking of DEN or of any other flavivirus. Our studies revealed that binding of radiolabeled DEN to the human hepatoma cell line HuH–7 was strictly pH dependent and substantially inhibitable by the glycosaminoglycan heparin. Ligand–blot analysis, performed as a viral overlay assay, showed two heparan sulfate (HS) containing cell–surface binding proteins resolving at 33 and 37 kd. Based on the sensitivity of unprotected virus and the viral binding site on the cell surface to trypsin, viral internalization was quantified as an increase in trypsin protected virus over time. Virus trafficking to the site of degradation was inhibited by pH dissociation of the clathrin coat and dependent on IP 3 –mediated homotypic endosomal fusion. These findings confirm the hypothesis that binding and internalization of DEN by hepatocytes are mediated primarily by HS containing proteoglycans and suggest that flaviviruses traffic the major clathrin–dependent endocytic pathway during infection.
Can Motor Nerve Conduction Velocity Predict Foot Problems in Diabetic Subjects Over a 6-Year Outcome Period?
Authors: Anne L. Carrington, Jonathan E. Shaw, Carine H.M. Van Schie, Caroline A. Abbott, Loretta Vileikyte, Andrew J.M. Boulton
Journal: Diabetes Care (2002)

OBJECTIVE—This study examined motor nerve conduction velocity (MNCV) and other peripheral nerve and vascular tests as predictors for foot ulceration, amputation, and mortality in diabetes over a 6-year follow-up period. RESEARCH DESIGN AND METHODS—We recruited 169 diabetic subjects (without significant peripheral vascular disease with an ankle brachial pressure index [ABPI] ≥0.75) for the study and separated them into groups (to ensure diversity of nerve function). The control group consisted of 22 nondiabetic people. At baseline, all subjects underwent assessment of MNCV; vibration, pressure, and temperature perception thresholds; peripheral vascular function; and other diabetes assessments. RESULTS—Over the 6-year outcome period, 37.3% of the diabetic subjects developed at least one new ulcer, 11.2% had a lower-limb amputation (LLA) (minor or major), and 18.3% died. Using multivariate Cox’s regression analysis (RR [95% CI] and removing previous ulcers as a confounding variable, MNCV was found to be the best predictor of new ulceration (0.90 [0.84–0.96], P = 0.001) and the best predictors of amputation were pressure perception threshold (PPT) (5.18 [1.96–13.68], P = 0.001) and medial arterial calcification (2.88 [1.13–7.35], P = 0.027). Creatinine (1.01 [1.00–1.01], P &amp;lt; 0.001), MNCV (0.84 [0.73–0.97], P = 0.016), and skin oxygen levels (14.32 [3.04–67.52], P = 0.001) were the best predictors of mortality. CONCLUSIONS—This study shows that MNCV, which is often assessed in clinical trials of neuropathy, can predict foot ulceration and death in diabetes. In addition, tests of PPT and medial arterial calcification can be used in the clinic to predict LLA in diabetic subjects.
Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs
Authors: Christina Charles-Schoeman, Gerd Burmester, Peter Nash, Cristiano A F Zerbini, Koshika Soma, Kenneth Kwok, Thijs Hendrikx, Eustratios Bananis, Roy Fleischmann
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). <h3>Methods</h3> Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. <h3>Results</h3> 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). <h3>Conclusions</h3> Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. <h3>Trial registration numbers</h3> (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).
How to evaluate and improve the quality and credibility of an outcomes database: validation and feedback study on the UK Cardiac Surgery Experience
Authors: L. G Fine
Journal: BMJ (2003)

To assess the quality and completeness of a database of clinical outcomes after cardiac surgery and to determine whether a process of validation, monitoring, and feedback could improve the quality of the database.Stratified sampling of retrospective data followed by prospective re-sampling of database after intervention of monitoring, validation, and feedback.Ten tertiary care cardiac surgery centres in the United Kingdom.Validation of data derived from a stratified sample of case notes (recording of deaths cross checked with mortuary records), monitoring of completeness and accuracy of data entry, feedback to local data managers and lead surgeons.Average percentage missing data, average kappa coefficient, and reliability score by centre for 17 variables required for assignment of risk scores. Actual minus risk adjusted mortality in each centre.The database was incomplete, with a mean (SE) of 24.96% (0.09%) of essential data elements missing, whereas only 1.18% (0.06%) were missing in the patient records (P<0.0001). Intervention was associated with (a) significantly less missing data (9.33% (0.08%) P<0.0001); (b) marginal improvement in reliability of data and mean (SE) overall centre reliability score (0.53 (0.15) v 0.44 (0.17)); and (c) improved accuracy of assigned Parsonnet risk scores (kappa 0.84 v 0.70). Mortality scores (actual minus risk adjusted mortality) for all participating centres fell within two standard deviations of the mean score.A short period of independent validation, monitoring, and feedback improved the quality of an outcomes database and improved the process of risk adjustment, but with substantial room for further improvement. Wider application of this approach should increase the credibility of similar databases before their public release.
Tumour suppression induced by the macrophage activating lipopeptide MALP-2 in an ultrasound guided pancreatic carcinoma mouse model
Authors: C Schneider
Journal: Gut (2004)

Carcinoma of the exocrine pancreas has a particularly poor prognosis. Therefore, novel therapeutic strategies such as immunotherapy are required. Here we investigated the immunomodulatory capacity of macrophage activating lipopeptide 2 (MALP-2), which binds to toll-like receptors 2 and 6 and induces activation of nuclear factor kappaB in monocytes. This causes the release of early stage leucocyte attracting chemokines and proinflammatory cytokines.MALP-2 was tested in a new orthotopic ultrasound guided pancreatic cancer mouse model. This model is close to the biological situation and avoids the stress and immunostimulation caused by laparotomy. Cells from the syngeneic, highly aggressive, and metastatic cell line Panc 02 were administered orthotopically, by ultrasound guidance, to C57bl/6 mice. MALP-2 was administered intratumorally or intraperitoneally and tumour growth, immune status, and leucocyte infiltration at the tumour site were determined.We showed a tumour suppressive effect induced by a single injection of MALP-2. Median survival increased from 21 to 30 days (p<0.002). Combining chemotherapy (gemcitabine) with MALP-2 treatment caused further prolonged survival (median survival 27 days with chemotherapy alone v 37 days for combined treatment; p<0.0002). The life prolonging effect was paralleled by a significant increase in cytotoxic T cells, restoration of beta2 integrin expression on lymphocytes, and high expression of CD45RB on T helper cells. Immunohistochemical stains showed strong cytotoxic T lymphocyte and natural killer cell infiltration.In conclusion, in a model of orthotopic pancreatic cancer in mice, we induced a tumour suppressive effect by treatment with a synthetic lipopeptide. Treatment with MALP-2 could be an option for immunotherapy in pancreatic cancer.
Drug use. Data, sources, and limitations
Authors: T. D. Rucker
Journal: JAMA (1974)

It is estimated that 2.8 million prescriptions and drug orders representing an economic value of $11 billion were dispensed in the United States in 1973. There are differences in drug use according to various demographic and socioeconomic characteristics, and to physician prescribing rates and drug product rankings. Current sources of drug data are the manufacturer, prescriber, dispenser, and patient. A model information system for prescription services should be designed primarily to support professional decision-making in treating patients. There are certain specific functions for this system, and the health professions should provide leadership that will facilitate its development and operation. (<i>JAMA</i>230:888-890, 1974)
Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction
Authors: D FRACCAROLLO, P GALUPPO, I SCHMIDT, G ERTL, J BAUERSACHS
Journal: Cardiovascular Research (2005)

The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood.We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats.Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed.Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.
Postgraduate education in Australia and the United Kingdom compared
Authors: R M Clarke, C E Engel
Journal: BMJ (1981)

necessities, however wisely the money was spent.The latter was the poverty of families which were obviously poverty striken although their income was above the poverty line.This was the first attempt to define a poverty line on careful estimates of needs in terms of expenditure on nutrition, clothing, fuel, and other essential items.The level changes with time as other items of modern living are included.We feel it is necessary to define the poverty line in Britain based on an acceptable package of goods, services, amenities, etc, considered as essentials for healthy living in the 'eighties.Correlations based on local authority areas show that the proportion of individuals in social class V is associated with unemployment,