tbuckley/cabot-search huggingface dataset:
Should doctors get CME points for reading?
Authors: H. A. Holm
Journal: BMJ (2000)

See also p 432 

> “To study the phenomenon of disease without books is to sail an uncharted sea, while to study books without patients is not to go sea at all.” William Osler1

Practising medicine without reading is unthinkable, and reading is extensively used in searching for information to solve clinical problems.2 3 Moreover, lack of time for reading is often perceived as a threat to professional practice and has a negative impact on perceived level of coping.4 Yet most programmes of continuing medical education give little credit for reading: what evidence do we have that it is an effective way of learning?

Scanning journals for articles of interest is probably what first comes to mind when thinking of doctors' reading. Reading is also often used for re-examining one's clinical practice (How should I manage patients with osteoporosis?) or finding information to solve more focused problems (What is the best treatment for tick bites?). As computers become part of doctors' office equipment, access to databases should enable doctors quickly to find the most updated and reliable answers to their clinical problems. In essence this is no different from reading journals, books, or self produced notes.

The …
Presence and regulation of Raf-1-K (Kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments.
Authors: Y Terada, T Yamada, M Takayama, H Nonoguchi, S Sasaki, K Tomita, F Marumo
Journal: Journal of the American Society of Nephrology (1995)

Renal nephron segments are heterogeneous, and receptors for endothelin (ET)-1, ET-3, Angiotensin II (AII), epidermal growth factor (EGF), and insulin-like growth factor I distribute differently along the nephron segments. Recently, growth factors and vasoactive substances are reported to stimulate mitogen-activated protein kinase (MAP-K). In this study, we showed that mRNA and proteins of MEK-K, Raf-1-K, MAPK-K, MAP-K (p42 and p44), and S6-K are expressed ubiquitously in intact nephron segment. We demonstrated that four tiers of a cascade composed of the Raf-1-K, MAP-K, MAP-K, and S6-K are stimulated by ET-1 and ET-3 in rat intact glomeruli (Glm) via primarily B-type ET receptors and PKC. The stimulatory effect of EGF and IGF-I to MAP-K activity is inhibited by a tyrosine kinase inhibitor in Glm. IGF-I significantly stimulates MAP-K activity and EGF and All moderately stimulate MAP-K activity in the proximal convoluted tubule (PCT). EGF significantly increased MAP-K cascades and ET-1 and ET-3 slightly increased MAP-K cascades in the medullary thick ascending limb (MTAL). EGF significantly stimulated MAP-K cascades, and ET-1 and ET-3 moderately stimulate MAP-K cascades in the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD). MAPK-K and S6-K are similarly stimulated by these agonists in each segment. This study shows that MAP-K cascades are expressed in every nephron segment. ET-1, ET-3, All, EGF, and IGF-I stimulate MAP-K cascades heterogeneously along the nephron segment. It was concluded that MAP-K cascades play an important role in the regulation of renal function.
Local Delivery of Imatinib Mesylate (STI571)-Incorporated Nanoparticle Ex Vivo Suppresses Vein Graft Neointima Formation
Authors: Satoshi Kimura, Kensuke Egashira, Kaku Nakano, Eiko Iwata, Miho Miyagawa, Hiroyuki Tsujimoto, Kaori Hara, Yoshiaki Kawashima, Ryuji Tominaga, Kenji Sunagawa
Journal: Circulation (2008)

Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure attributable to neointima formation. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of vein graft failure. Therefore, we hypothesized that nanoparticle (NP)-mediated drug delivery system of PDGF-receptor (PDGF-R) tyrosine kinase inhibitor (imatinib mesylate: STI571) could be an innovative therapeutic strategy.Uptake of STI571-NP normalized PDGF-induced cell proliferation and migration. Excised rabbit jugular vein was treated ex vivo with PBS, STI571 only, FITC-NP, or STI571-NP, then interposed back into the carotid artery position. NP was detected in many cells in the neointima and media at 7 and 28 days after grafting. Significant neointima was formed 28 days after grafting in the PBS group; this neointima formation was suppressed in the STI571-NP group. STI571-NP treatment inhibited cell proliferation and phosphorylation of the PDGF-R-beta but did not affect inflammation and endothelial regeneration.STI571-NP-induced suppression of vein graft neointima formation holds promise as a strategy for preventing vein graft failure.
Molecular Pathways: Response and Resistance to BRAF and MEK Inhibitors in BRAFV600E Tumors
Authors: Meghna Das Thakur, Darrin D. Stuart
Journal: Clinical Cancer Research (2013)

The RAS-RAF-MEK (MAP-ERK kinase)-ERK (extracellular signal-regulated kinase) pathway plays a central role in driving proliferation, survival, and metastasis signals in tumor cells, and the prevalence of oncogenic mutations in RAS and BRAF and upstream nodes makes this pathway the focus of significant oncology drug development efforts. This focus has been justified by the recent success of BRAF and MEK inhibitors in prolonging the lives of patients with BRAF(V600E/K)-mutant melanoma. Although it is disappointing that cures are relatively rare, this should not detract from the value of these agents to patients with cancer and the opportunity they provide in allowing us to gain a deeper understanding of drug response and resistance. These insights have already provided the basis for the evaluation of alternative dosing regimens and combination therapies in patients with melanoma.
Expression of interleukin 2 receptors by monocytes from patients with acquired immunodeficiency syndrome and induction of monocyte interleukin 2 receptors by human immunodeficiency virus in vitro.
Authors: J B Allen, N McCartney-Francis, P D Smith, G Simon, S Gartner, L M Wahl, M Popovic, S M Wahl
Journal: Journal of Clinical Investigation (1990)

A population of circulating mononuclear cells from patients with AIDS was identified which expressed interleukin 2 receptors (IL-2R). By dual-fluorescence flow microfluorometry, the patients' IL-2R+ cells were further identified as Leu M3+ monocytes (29.4 +/- 5.2% of the Leu M3+ cells were IL-2R+, n = 15), whereas Leu M3+ monocytes from normal subjects were IL-2R negative (2.0 +/- 0.42%; P less than 0.001). By Northern analysis, monocytes from AIDS patients, but not control subjects, constitutively expressed steady-state levels of IL-2R mRNA. Functionally, the IL-2R+ monocytes were capable of depleting IL-2 from culture supernatants, suggesting a mechanism for the reduced IL-2 levels commonly seen in AIDS patients. IL-2R+ monocytes also expressed increased levels of surface HLA-DR which may favor monocyte T-cell interactions and the transmission of human immunodeficiency virus (HIV). In additional studies, normal monocytes were infected with a macrophage-tropic HIV isolate in vitro and monitored for IL-2R and HLA-DR expression. Within 24-48 h after exposure to HIV in vitro, but before evidence of productive infection, greater than 25% of the monocytes became IL-2R+ with increasing numbers of IL-2R+ cells and HLA-DR levels through day 6. These early signaling effects of HIV could be mimicked by adding purified HIV envelope glycoprotein gp120 to the monocytes. This stimulation of monocytes before or independent of productive infection of the cells by HIV is consistent with in vivo observations of activated and/or abnormal functions by monocytes that do not appear to be infected with HIV in AIDS patients.
Multiple object tracking in molecular bioimaging by Rao-Blackwellized marginal particle filtering
Authors: I. Smal, E. Meijering, K. Draegestein, N. Galjart, I. Grigoriev, A. Akhmanova, M.E. van Royen, A.B. Houtsmuller, W. Niessen
Journal: Medical Image Analysis (2008)
Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience
Authors: Lilyana Angelov, Nancy D. Doolittle, Dale F. Kraemer, Tali Siegal, Gene H. Barnett, David M. Peereboom, Glen Stevens, John McGregor, Kristoph Jahnke, Cynthia A. Lacy, Nancy A. Hedrick, Edna Shalom, Sandra Ference, Susan Bell, Lisa Sorenson, Rose Marie Tyson, Marianne Haluska, Edward A. Neuwelt
Journal: Journal of Clinical Oncology (2009)

Purpose Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. Patients and Methods This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age ≥ 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age &lt; 60 years and KPS ≥ 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. Conclusion This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.
High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin
Authors: Toshihiko Tanno, Natarajan V Bhanu, Patricia A Oneal, Sung-Ho Goh, Pamela Staker, Y Terry Lee, John W Moroney, Christopher H Reed, Naomi LC Luban, Rui-Hong Wang, Thomas E Eling, Richard Childs, Tomas Ganz, Susan F Leitman, Suthat Fucharoen, Jeffery L Miller
Journal: Nature Medicine (2007)
Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis
Authors: Gavin Giovannoni, Stuart Cook, Kottil Rammohan, Peter Rieckmann, Per Soelberg Sørensen, Patrick Vermersch, Anthony Hamlett, Vissia Viglietta, Steven Greenberg
Journal: The Lancet Neurology (2011)
PTU-075 Liver dysfunction after major hepatic resection
Authors: D C Bartlett, E L Neo, G Bonney, R Marudanayagam, D Mirza
Journal: Gut (2012)

<h3>Introduction</h3> Liver failure is a potentially fatal complication following major hepatic resection. This study evaluates the incidence and factors associated with posthepatectomy liver failure (PHLF), as well as the outcomes and survival of these patients. <h3>Methods</h3> All patients who underwent elective major hepatic resection (&gt;4 liver segments) between January 2001 and March 2011 were identified from a prospective database. Patients with bilirubin levels &gt;100 mmol/l or INR &gt;2 on three consecutive days within the first post-operative week were diagnosed with PHLF (n=54). These patients were compared with 654 control patients. <h3>Results</h3> Patients with PHLF had a higher incidence of diabetes mellitus compared to the control group (9.5% vs 3.1%, p=0.05). There was no significant difference in age, pre-operative chemotherapy, weight of resected specimen, use of Pringle manoeuvre, degree of steatosis/fibrosis of background liver, or amount of perioperative blood transfusion. Post-operatively, patients with PHLF were more likely to require n-acetylcysteine (51.4% vs 13.4%, p&lt;0.001) and dialysis (13.2% vs 1.8%, p&lt;0.001), and had longer ITU stay (mean 2.57 days vs 0.84 days, p&lt;0.001). The PHLF group had higher 30-day (22.6% vs 3.1%, p&lt;0.001) and 90-day mortality (41.5% vs 4.7%, p&lt;0.001). Median survival was 9.86 months in the PHLF group and 49.77 months in the control group (p&lt;0.001). <h3>Conclusion</h3> This study over a 10-year period has shown a small risk of PHLF (7.6%) in patients undergoing major hepatic resection. PHLF is associated with significantly increased post-operative morbidity and mortality. <h3>Competing interests</h3> None declared.
Systems Theory, Psychiatry, and School Phobia
Authors: WILLIAM M. BOLMAN
Journal: American Journal of Psychiatry (1970)

In this systems approach to the syndrome of school refusal, the author illustrates how a unifying theory can be applied to a specific clinical problem in psychiatry. The approach allows for an assessment of the contributions by various levels of the system to the production of the school-phobic child: the child himself (including neurological and psychological sublevels), the family, school, community, and broad societal patterns. Following this assessment, the clinician can choose those levels or interfaces that offer the best possibility of leverage for change.
Significance of differential expression of thymidylate synthase in normal and primary tumor tissues from patients with colorectal cancer
Authors: Yanyan Liu, Qingxin Xia, Yanzhao Jia, Hongqiang Guo, Bing Wei, Yawei Hua, Shujun Yang
Journal: Journal of Hematology & Oncology (2011)

The role of thymidylate synthase (TS) is essential as a key rate-limiting enzyme in DNA synthesis. It is the primary target of fluorouracil and its derivates in colorectal cancer. In this study, TS mRNA expression was examined in primary tumor and normal tissues from 76 patients with high- risk stage II/III colorectal cancer by laser capture microdissection and polymerase chain reaction. Thirty (39.47%) patients were found to have higher TS expression in primary tumors with earlier stage (P = 0.018), lower histological grades (P = 0.001) and high frequency microsatellite instability (P = 0.000). Multivariate analysis showed that microsatellite instability, histological grade and number of lymph nodes examined are independent prognostic markers.
Decreased Expression of Tumor Necrosis Factor-α in Failing Human Myocardium After Mechanical Circulatory Support
Authors: Guillermo Torre-Amione, Sonny J. Stetson, Keith A. Youker, Jean-Bernard Durand, Branislav Radovancevic, Reynolds M. Delgado, O. H. Frazier, Mark L. Entman, George P. Noon
Journal: Circulation (1999)

Background —An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-α is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-α expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-α expression in human failing myocardium. Methods and Results —Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-α, and quantitative analysis of the stained area was performed. We found that TNF-α content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-α content were found in patients who were successfully weaned off the LVAD who did not require transplantation. Conclusions —These data show for the first time that chronic mechanical circulatory assistance decreases TNF-α content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.
17% of patients who call an ambulance for an exacerbation of COPD could be treated at home
Authors: Anna Moore, John Martin, John Bowen, Paul Katterhorn, Anthony Davison
Journal: European Respiratory Journal (2011)

Introduction:  COPD is a chronic condition and healthcare policy in almost all countries is to try and deliver as much care for chronic diseases in the community and reduce the reliance and expense of hospital care. The National Clinical Guideline Centre (NICE) guidelines for COPD (2010) (www.nice.org.uk/guidance/CG101) give clear recommendation for factors to consider when deciding to treat a patient at home. The aim of this study was to see what percentages of patients who had an exacerbation of COPD and call an ambulance meet the criteria for home treatment.   Methods:  All 18 patients who had called an ambulance because of an exacerbation of COPD in 17 days were included in the study. The ambulance service recorded the 12 relevant factors from the NICE guideline which should be considered when deciding to treat a patient at home on a proforma over 17 days.   Results:  Saturation was ≤ 87% in 9 patients. 6 were not able to cope at home, 8 had severe breathlessness, 7 had poor general condition, 10 had poor level of activity, none were cyanosed, 4 had worsening peripheral oedema, all had a normal level of consciousness, 6 were receiving LTOT, 7 were living alone or not coping, no patients recorded having acute confusion, 6 had a rapid rate of onset, 5 had significant comorbidities.   Conclusions:  3 of the 18 patients (17%) had no factor that indicated that there was a need to be treated in hospital. The majority of patients who call an ambulance with an exacerbation get taken to hospital. Hospital at home for COPD has been proven to be successful and 17% of patients who call an ambulance could be safely managed in such a scheme. This would avoid them being assessed and admitted to hospital.
Pilot Study of the Mechanism of Action of Preoperative Trastuzumab in Patients with Primary Operable Breast Tumors Overexpressing HER2
Authors: Roberto Gennari, Sylvie Menard, Francesco Fagnoni, Luisa Ponchio, Mario Scelsi, Elda Tagliabue, Fabio Castiglioni, Laura Villani, Cesare Magalotti, Nadia Gibelli, Barbara Oliviero, Bettina Ballardini, Gianantonio Da Prada, Alberto Zambelli, Alberto Costa
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity. Experimental Design: A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies. Result: Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity. Conclusions: The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.
Dating the age of admixture via wavelet transform analysis of genome-wide data
Authors: Irina Pugach, Rostislav Matveyev, Andreas Wollstein, Manfred Kayser, Mark Stoneking
Journal: Genome biology (2011)

We describe a PCA-based genome scan approach to analyze genome-wide admixture structure, and introduce wavelet transform analysis as a method for estimating the time of admixture. We test the wavelet transform method with simulations and apply it to genome-wide SNP data from eight admixed human populations. The wavelet transform method offers better resolution than existing methods for dating admixture, and can be applied to either SNP or sequence data from humans or other species.
Studies on Derivation of Transcobalamin III from Granulocytes ENHANCEMENT BY LITHIUM AND ELIMINATION BY FLUORIDE OF IN VITRO INCREMENTS IN VITAMIN B12-BINDING CAPACITY
Authors: J. M. Scott, F. J. Bloomfield, R. Stebbins, V. Herbert
Journal: Journal of Clinical Investigation (1974)

Unsaturated vitamin B(12)-binding capacity (UBBC) of human serum is not reproducibly measurable because it increases variably in vitro in relation to time, temperature, and, in the case of plasma, anticoagulant present before removal of cells. This variable increase proved to be due to variable release in vitro of transcobalamin III (TC III) from granulocytes. UBBC increase was greatest (up to fourfold normal levels) in the presence of lithium, which is the heparin salt used in many laboratories doing UBBC studies. In vitro increase was least when blood was collected in EDTA at 0 degrees C and immediately centrifuges at 0 degrees C (T(0) sample); results equivalent to T(0) were obtained at room temperature even after several hours delay when 47 mM fluoride was present; either cold temperature or 47 mM fluoride appeared to prevent TC III release from granulocytes. The measured levels of the three transcobalamins with T(0) methods of collection, which presumably reflect most closely the in vivo circulating levels, suggest that TC I and TC III in normal plasms are of the same order of magnitude and together normally comprise less than 10% of the UBBC. Approximately 90% of the UBBC content of sonicates of peripheral blood granulocytes and of bone marrow aspirates of normal individuals appears to be TC III, with the rest being TC I. Thus, normal myelocytes, like normal granulocytes, appear to contain mainly TC III. No TC II was present in any of the sonicates. The general practice in most laboratories has been to determine serum UBBC. Because in vitro increments of up to 119% were found to occur in serum, this practice should be replaced by collection using methods that prevent such increments. Blood collected in EDTA-47 mM NaF had a stable, reproducible UBBC with no significant in vitro increment with time.EDTA-NaF UBBC was 640+/-168 (range 380-921 pg B(12) bound/ml plasma) for 12 normal adult men and 809+/-232 (range 505-1208) for normal adult women. It presumably approximates circulating UBBC and is substantially below the serum UBBC mean of 935+/-262 (range 611-1506 for the same 12 men) and 1273+/-355 (range 811-2306 for the same 10 women).