tbuckley/cabot-search huggingface dataset:
A multicentre national audit of the recording of patients weight: Implications for the prescription of gentamicin and therapeutic-dose low molecular weight heparin
Authors: Jamie Willson, Sebastian Thomas, Jonathan Horsnell, Soumen Sen, Strachan Mackenzie, Arti Patel, William Ratliff, Sabrina Black, Sarasvati Chauhan, Alice Armitage, G.P. Tarr, Kathryn Garnham, Alistair Robb
Journal: International Journal of Surgery (2012)
Mechanical Strain Tightly Controls Fibroblast Growth Factor-2 Release From Cultured Human Vascular Smooth Muscle Cells
Authors: George C. Cheng, William H. Briggs, David S. Gerson, Peter Libby, Alan J. Grodzinsky, Martha L. Gray, Richard T. Lee
Journal: Circulation Research (1997)

Although fibroblast growth factor-2 (FGF-2) participates in the response to vascular injury, the role of cellular deformation in FGF-2 release is incompletely understood. To test the hypothesis that mechanical strain tightly controls FGF-2 release, a novel device was used to impose homogeneous and uniform biaxial strain to human vascular smooth muscle cells. Release of FGF-2 increased with the number of cycles of strain (14%, 1 Hz); 1, 9, and 90 cycles of strain, respectively, released 0.55±0.06%, 2.9±0.3%, and 5.5±1.3% of the total cellular FGF-2 (versus 0.00±0.40% for control, P &lt;.05), but release was not further increased for strain of 90 to 90 000 cycles. Mechanical release of FGF-2 depended on both the frequency and amplitude of deformation. For example, strain (90 cycles, 1 Hz) at 4% amplitude released only 0.1±0.1% of the total FGF-2, but strain at 14% and 33% amplitudes, respectively, released 5.7±0.5% and 19.0±3.0% of the FGF-2 cellular pool ( P &lt;.05), suggesting a strain amplitude threshold for FGF-2 release. Injury to a subpopulation of cells increased with the frequency and amplitude of strain, but cells were not injured by strains below 10% amplitude. Strain following pretreatment with heparin released 12.6±1.6% of the total FGF-2 (versus 15.8±0.9% for strain alone, P &lt;.05), indicating that most FGF-2 was liberated from the nuclear or cytoplasmic pools and not from low-affinity extracellular receptors. Conversely, strain in the presence of heparin released 25.2±3.5% of the total FGF-2 (versus 15.6±2.6% for strain alone, P &lt;.05). Thus, cellular strain closely modulates the release of intracellular FGF-2 from human vascular smooth muscle cells, but FGF-2 release is negligible in response to the smaller strains that occur in the normal artery. In addition, larger mechanical strains lead to transfer of intracellular FGF-2 to the extracellular low-affinity receptors, where FGF-2 may be displaced by heparin. These observations provide insight into the mechanisms by which deforming vascular injury, such as that produced by arterial interventions, may elicit a proliferative response.
Forceps biopsy and suction catheter for sampling in pulmonary nodules and infiltrates
Authors: Antje Peschke, Bärbel Wiedemann, Gert Höffken, Dirk Koschel
Journal: European Respiratory Journal (2011)

Transbronchial lung biopsy with forceps is a standard procedure in bronchoscopic tissue sampling. Suction catheter aspiration is another technique, but it is not widely known and almost no data exist regarding its diagnostic efficiency. 272 patients were included in a prospective and randomised study between February 2007 and October 2009. All were referred for bronchoscopic evaluation of pulmonary nodules/masses or infiltrates. We compared the diagnostic yield of forceps biopsy and suction catheter aspiration for a definite diagnosis and looked at whether such a diagnosis depends on the underlying pulmonary change. All patients underwent bronchoscopy with forceps biopsy and catheter aspiration. A definitive diagnosis was reached in a total of 183 (67.3%) patients, with catheter aspiration in 140 (51.5%) patients and with forceps biopsy in 136 (50.0%) patients. In 90 (33.1%) patients, a definite diagnosis could only be reached with the combination of both techniques. The diagnostic yield of forceps biopsy was better than catheter aspiration in infiltrates (p=0.027), but was no different in nodules or masses (p=0.09). Suction catheter aspiration is a useful technique of bronchoscopic tissue sampling. The combination of catheter aspiration and forceps biopsy results in a higher diagnostic yield than either method used alone.
Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study
Authors: Shigeki Ohtake, Shuichi Miyawaki, Hiroyuki Fujita, Hitoshi Kiyoi, Katsuji Shinagawa, Noriko Usui, Hirokazu Okumura, Koichi Miyamura, Chiaki Nakaseko, Yasushi Miyazaki, Atsushi Fujieda, Tadashi Nagai, Takahisa Yamane, Masafumi Taniwaki, Masatomo Takahashi, Fumiharu Yagasaki, Yukihiko Kimura, Norio Asou, Hisashi Sakamaki, Hiroshi Handa, Sumihisa Honda, Kazunori Ohnishi, Tomoki Naoe, Ryuzo Ohno
Journal: Blood (2010)
Catheter Closure of Moderate- to Large-Sized Patent Ductus Arteriosus Using the New Amplatzer Duct Occluder: Immediate and Short-Term Results
Authors: Jozef Masura, Kevin P Walsh, Basil Thanopoulous, Chen Chan, John Bass, Yousef Goussous, Paul Gavora, Ziyad M Hijazi
Journal: Journal of the American College of Cardiology (1998)
Morphologic and Cytochemical Comparison of Human Lymphoblastoid T-Cell and B-Cell Lines: Light and Electron Microscopy 2
Authors: John W. Parker, Clive R. Taylor, Paul K. Pattengale, Ivor Royston, Barbara H. Tindle, Mary Jo Cain, Robert J. Lukes
Journal: JNCI Journal of the National Cancer Institute (1978)

Human lymphoblastoid cell lines characterized as T- or B-cells by various markers were compared morphologically and cytochemically by light and electron microscopy. Distinct differences in nuclear morphology, amount of cytoplasm, pyroninophilia, and periodic acid-Schiff (PAS) staining enabled us to discriminate between T- and B-cell lines. T-cells had nuclei with an irregular configuration, stippled heterochromatin, and small or absent nucleoli. The scanty cytoplasm of T-cells contained intensely stained, PAS-positive globules and was less pyroninophilic than the cytoplasm of B-cells. B-cells had more rounded, uniform, vesicular nuclei with prominent nucleoli and peripheral heterochromatin. The cytoplasm of B-cells was abundant and strongly pyroninophilic. Transmission electron microscopy generally confirmed these morphologic differences. These findings supported our contention that consistent cytologic features concordant with immunologic markers make it possible to identify certain lymphomas as being of B- or T-cell origin on purely morphologic grounds.
Antiinflammatory Effects of Genistein, a Tyrosine Kinase Inhibitor, on a Guinea Pig Model of Asthma
Authors: Wei Duan, I. Chun Kuo, Sathiyamoorthy Selvarajan, Kaw Yan Chua, Boon Huat Bay, W. S. Fred Wong
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Protein tyrosine kinase signaling cascade plays a pivotal role in the activation of inflammatory cells. The purpose of this study was to investigate the effects of genistein, a broad-spectrum protein tyrosine kinase inhibitor, on airway inflammation in an in vivo guinea pig model of asthma. Guinea pigs were actively sensitized by intraperitoneal injections of ovalbumin. Aerosolized ovalbumin induced acute bronchoconstriction in conscious animals in a dose-dependent manner. Genistein (15 mg/kg given intraperitoneally) markedly inhibited ovalbumin-induced, but not histamine- and methacholine-induced, acute bronchoconstriction. In addition, genistein significantly reduced ovalbumin-induced increases in total cell counts and eosinophils recovered in bronchoalveolar lavage fluid, airway eosinophilia, and eosinophil peroxidase activity in cell-free bronchoalveolar lavage fluid and markedly attenuated ovalbumin-induced airway hyperresponsiveness to inhaled methacholine. Immunoblot analysis of lung lysates isolated from genistein-pretreated animals showed that epidermal growth factor-induced tyrosine phosphorylation in lung tissues was inhibited by genistein. These results implicate that inhibition of tyrosine kinase signaling cascade may have therapeutic potential for allergic airway inflammation.
Clinical impact of the methotrexate resistance-associated genes C-MYC and dihydrofolate reductase (DHFR) in high-grade osteosarcoma
Authors: I Scionti, F Michelacci, M Pasello, C M Hattinger, M Alberghini, M C Manara, G Bacci, S Ferrari, K Scotlandi, P Picci, Massimo Serra
Journal: Annals of Oncology (2008)
Agreement Between Clinician and Patient Ratings of Adaptive Functioning and Developmental History
Authors: Jared A. DeFife, Rebecca Drill, Ora Nakash, Drew Westen
Journal: American Journal of Psychiatry (2010)

Psychiatric researchers rely heavily on patient report data for clinical research. However, patient reports are prone to defensive and self-presentation biases. Recent research using practice networks has relied on clinician reports, and both forensic and personality disorder researchers have recently turned to quantified data from clinically expert observers as well. However, critics have raised legitimate concerns about the reliability and validity of data from clinician informants. The aim of this study was to assess the validity and diagnostic efficiency of clinician reports of their patients' adaptive functioning and developmental histories, using patient reports as the comparative standard traditionally used in psychiatric research.Eighty-four clinicians and their patients completed a clinical data form designed to assess a range of patient functioning, clinical history, and developmental relationship variables used in multiple clinician report studies. The authors correlated clinician and patient reports across a number of clinically relevant adaptive functioning variables and calculated diagnostic efficiency statistics for a range of clinical history variables, including suicide attempts, hospitalizations, arrests, interpersonal conflicts affecting employment, and childhood physical and sexual abuse.Across variables, patient-therapist correlations (0.40-0.66) and overall correct classification statistics (0.74-0.96) were high.The data demonstrate that clinicians' judgments about their patients' functioning and histories agree with patients' self-reports and that in areas of discrepancy, clinicians tend to make appropriately conservative judgments in the absence of clear data. These findings suggest that quantified clinical judgment provides a vast untapped potential for large-sample research on psychopathology and treatment.
Conduction Slowing in Diabetic Sensorimotor Polyneuropathy
Authors: Samantha K. Dunnigan, Hamid Ebadi, Ari Breiner, Hans D. Katzberg, Leif E. Lovblom, Bruce A. Perkins, Vera Bril
Journal: Diabetes Care (2013)

Mild demyelination may contribute more to the pathophysiology of nerve fiber injury in diabetic sensorimotor polyneuropathy (DSP) than previously thought. We investigated the clinical and electrodiagnostic classifications of nerve injury in diabetic patients to detect evidence of conduction slowing in DSP.Type 1 diabetic subjects (n = 62) and type 2 diabetic subjects (n = 111) with a broad spectrum of DSP underwent clinical examination and nerve conduction studies (NCS). Patients were classified as having axonal (group A), conduction slowing (group D), or combined (group C) DSP based on electrodiagnostic criteria. Patients with chronic immune-mediated neuropathies were not included. The groups were compared using ANOVA, contingency tables, and Kruskal-Wallis analyses.Of the 173 type 1 and type 2 diabetic subjects with a mean age of 59.1 ± 13.6 years and hemoglobin A1c (HbA1c) of 8.0 ± 1.8% (64 ± 19.7 mmol/mol), 46% were in group A, 32% were in group D, and 22% were in group C. The severity of DSP increased across groups A, D, and C, respectively, based on clinical and NCS parameters. The mean HbA1c for group D subjects (8.9 ± 2.3% [74 ± 25.1 mmol/mol]) was higher than for group A and group C subjects (7.7 ± 1.4% [61 ± 15.3 mmol/mol] and 7.5 ± 1.3% [58 ± 14.2 mmol/mol]; P = 0.003), and this difference was observed in those with type 1 diabetes.The presence of conduction slowing in patients with suboptimally controlled type 1 diabetes indicates the possibility that this stage of DSP may be amenable to intervention via improved glycemic control.
Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense
Authors: Shida Yousefi, Jeffrey A Gold, Nicola Andina, James J Lee, Ann M Kelly, Evelyne Kozlowski, Inès Schmid, Alex Straumann, Janine Reichenbach, Gerald J Gleich, Hans-Uwe Simon
Journal: Nature Medicine (2008)
Intact Heart Loose Patch Photolysis Reveals Ionic Current Kinetics During Ventricular Action Potentials
Authors: Josefina Ramos-Franco, Yuriana Aguilar-Sanchez, Ariel L. Escobar
Journal: Circulation Research (2015)

Assessing the underlying ionic currents during a triggered action potential (AP) in intact perfused hearts offers the opportunity to link molecular mechanisms with pathophysiological problems in cardiovascular research. The developed loose patch photolysis technique can provide striking new insights into cardiac function at the whole heart level during health and disease.To measure transmembrane ionic currents during an AP to determine how and when surface Ca(2+) influx that triggers Ca(2+)-induced Ca(2+) release occurs and how Ca(2+)-activated conductances can contribute to the genesis of AP phase 2.Loose patch photolysis allows the measurement of transmembrane ionic currents in intact hearts. During a triggered AP, a voltage-dependent Ca(2+) conductance was fractionally activated (dis-inhibited) by rapidly photo-degrading nifedipine, the Ca(2+) channel blocker. The ionic currents during a mouse ventricular AP showed a fast early component and a slower late component. Pharmacological studies established that the molecular basis underlying the early component was driven by an influx of Ca(2+) through the L-type channel, CaV 1.2. The late component was identified as an Na(+)-Ca(2+) exchanger current mediated by Ca(2+) released from the sarcoplasmic reticulum.The novel loose patch photolysis technique allowed the dissection of transmembrane ionic currents in the intact heart. We were able to determine that during an AP, L-type Ca(2+) current contributes to phase 1, whereas Na(+)-Ca(2+) exchanger contributes to phase 2. In addition, loose patch photolysis revealed that the influx of Ca(2+) through L-type Ca(2+) channels terminates because of voltage-dependent deactivation and not by Ca(2+)-dependent inactivation, as commonly believed.
Junior doctor is struck off after prescribing errors and "disgraceful" conduct
Authors: C. Dyer
Journal: BMJ (2015)

A junior doctor who made two “potentially dangerous” prescribing errors within days and then committed a string of petty crimes while excluded from work has been struck off the UK medical register.

Prashen Pillay was a foundation year 1 trainee doing a rotation in geriatric medicine in Sussex when he wrote 250 milligrams instead of 250 micrograms on a digoxin prescription—effectively multiplying the dose by 1000. A nurse, realising that such a dose was impossible, administered 2.5 milligrams, still 10 times the intended dose. The 76 year old patient, Joan Dixon, died of a heart attack within hours.

Pillay had made a similar error two weeks previously, transcribing “4 units” of fast acting insulin as “40 units,” although the 82 year …
Analysis of Potential Predictive Markers of Cetuximab Benefit in BMS099, a Phase III Study of Cetuximab and First-Line Taxane/Carboplatin in Advanced Non–Small-Cell Lung Cancer
Authors: Shirin Khambata-Ford, Christopher T. Harbison, Lowell L. Hart, Melissa Awad, Li-An Xu, Christine E. Horak, Shaker Dakhil, Robert C. Hermann, Thomas J. Lynch, Martin R. Weber
Journal: Journal of Clinical Oncology (2010)

PURPOSE The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is efficacious in multiple tumor types. Patient selection with markers predictive of benefit may enhance its therapeutic index. This retrospective, correlative analysis of the phase III trial BMS099 of cetuximab in advanced non-small-cell lung cancer (NSCLC) was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab. METHODS In BMS099, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC of any histology or EGFR expression status were randomly assigned to taxane/carboplatin (T/C) with or without cetuximab. Biomarkers analyzed included K-Ras and EGFR mutations by direct sequencing, EGFR protein expression by immunohistochemistry (IHC), and EGFR gene copy number by fluorescent in situ hybridization (FISH). Relationships between biomarker status and progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) were assessed by log-rank tests per treatment arm for treatment-specific effects and across the total evaluable population. Results Tumor samples were available from 225 randomly assigned patients. K-Ras mutations were found in 17% of evaluable patients (35 of 202 patients), EGFR mutations were found in 10% (17 of 166 patients), EGFR positivity by IHC was found in 89% (131 of 148 patients), and FISH positivity was found in 52% (54 of 104 patients). No significant associations were found between biomarker status and PFS, OS, and ORR in the treatment-specific analyses. CONCLUSION In contrast with colorectal cancer, and within the limitations of the data set, efficacy parameters did not appear to correlate with K-Ras mutation status or with any of the EGFR-related biomarkers evaluated. Additional exploratory analyses are essential to identify predictive markers and to optimize patient selection for cetuximab therapy in NSCLC.
Effective double whammy targets DNA synthesis in leukemia
Authors: Bruce A. Chabner
Journal: The Journal of Experimental Medicine (2014)

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Insight from Bruce Chabner



Inhibition of DNA synthesis is a keystone of cancer therapy. The purine and pyrimidine precursors of DNA are obtained either by the de novo pathway (DNP) or the nucleotide salvage pathway (NSP). The DNP generates nucleotides that are reduced to the
Free Radicals, Mitochondria, and Oxidized Lipids
Authors: Jessica Gutierrez, Scott W. Ballinger, Victor M. Darley-Usmar, Aimee Landar
Journal: Circulation Research (2006)

Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. It was also recognized early in mitochondrial research that the reduction of oxygen to generate the free radical superoxide occurs at various sites in the respiratory chain and was postulated that this could lead to mitochondrial dysfunction in a variety of disease states. Over recent years, this view has broadened substantially with the discovery that reactive oxygen, nitrogen, and lipid species can also modulate physiological cell function through a process known as redox cell signaling. These redox active second messengers are formed through regulated enzymatic pathways, including those in the mitochondrion, and result in the posttranslational modification of mitochondrial proteins and DNA. In some cases, the signaling pathways lead to cytotoxicity. Under physiological conditions, the same mediators at low concentrations activate the cytoprotective signaling pathways that increase cellular antioxidants. Thus, it is critical to understand the mechanisms by which these pathways are distinguished to develop strategies that will lead to the prevention of cardiovascular disease. In this review, we describe recent evidence that supports the hypothesis that mitochondria have an important role in cell signaling, and so contribute to both the adaptation to oxidative stress and the development of vascular diseases.
Carvedilol for Prevention of Restenosis After Directional Coronary Atherectomy
Authors: Patrick W. Serruys, David P. Foley, Berthold Höfling, Jacques Puel, Helmut D. Glogar, Ricardo Seabra-Gomes, Javier Goicolea, Pierre Coste, Wolfgang Rutsch, Hugo Katus, Hans Bonnier, William Wijns, Amadeo Betriu, Ulrike Hauf-Zachariou, Eline Montauban van Swijndregt, Rein Melkert, Rudiger Simon
Journal: Circulation (2000)

Background —In addition to its known properties as a competitive, nonselective β and α-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis. Methods and Results —In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 hours before scheduled directional coronary atherectomy and continuing for 5 months after a successful procedure. The primary end point was the minimal luminal diameter as determined during follow-up angiography 26±2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 (88.9%), a ≤50% diameter stenosis was achieved without the use of a stent. Evaluable follow-up angiography was available in 292 eligible patients (90%). No differences in minimal luminal diameter (1.99±0.73 mm versus 2.00±0.74 mm), angiographic restenosis rate (23.4% versus 23.9%), target lesion revascularization (16.2 versus 14.5), or event-free survival (79.2% versus 79.7%) between the placebo and carvedilol groups were observed at 7 months. Conclusions —The maximum recommended daily dose of the antioxidant and β-blocker carvedilol failed to reduce restenosis after successful atherectomy. These findings are in contrast to those of the Multivitamins and Probucol Trial, which raises doubts regarding the validity of the interpretation that restenosis reduction by probucol was via antioxidant effects. The relationship between antioxidant agents and restenosis remains to be elucidated.
A phase II study of laquinimod in Crohn's disease
Authors: Geert D'Haens, William J Sandborn, Jean Frederic Colombel, Paul Rutgeerts, Kurt Brown, Hadas Barkay, Anat Sakov, Asi Haviv, Brian G Feagan
Journal: Gut (2014)

<h3>Objective</h3> Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn9s disease (CD), Huntington9s disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD. <h3>Design</h3> Multicentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) &lt;150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF). <h3>Results</h3> 117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses. <h3>Conclusions</h3> Laquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD. <h3>Trial registration number</h3> NCT00737932.