tbuckley/cabot-search huggingface dataset:
Do-not-resuscitate orders. Time for reappraisal in long-term-care institutions
Authors: D. J. Murphy
Journal: JAMA (1988)

Murphy, a physician, proposes a policy under which the attending physician and nurses would consider the resuscitation status of patients after their admission to a long-term-care (LTC) facility and make unilateral decisions about writing do-not-resuscitate (DNR) orders for severely demented patients and for chronically ill patients for whom CPR is believed to be futile. He reasons that the ethical consensus that patient autonomy should prevail in DNR determinations does not apply to the LTC population where medical indications should be given first priority in ethical decision making. Murphy notes that the broad spectrum of cases adjudicated show that, with few exceptions, courts usually rule that withholding or withdrawing therapy in these instances is legally acceptable.
Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma
Authors: H Tilg
Journal: Gut (2002)

Background: Interleukin 10 (IL-10) exerts anti-inflammatory actions by counteracting many biological effects of interferon γ (IFN-γ). Aims: To investigate this in humans, we studied the effects of human recombinant IL-10 administration on IFN-γ production by patient leucocytes. Furthermore, we assessed the IFN-γ inducible molecule neopterin and nitrite/nitrate serum levels, which are indicative of endogenous nitric oxide formation. Methods: As part of two placebo controlled double blind studies, we analysed patients with chronic active Crohn9s disease (CACD) who received either subcutaneous recombinant human IL-10 (n=44) or placebo (n=10) daily for 28 days, and patients with mild to moderate Crohn9s disease (MCD) treated with either subcutaneous IL-10 (n=52) or placebo (n=16) daily for 28 days. Neopterin and nitrite/nitrate concentrations were measured in serum, and ex vivo IFN-γ formation by lipopolysaccharide or phytohaemagglutinin (PHA) stimulated whole blood cells were investigated before, during, and after IL-10 therapy. Results: In patients with CACD, the highest dose of 20 μg/kg IL-10 caused a significant increase in serum neopterin on days +15 and +29 of therapy compared with pretreatment levels. No changes were observed for nitrite/nitrate levels under either condition. In MCD, treatment with 20 μg/kg IL-10 resulted in a significant increase in PHA induced IFN-γ production. Conclusions: High doses of IL-10 upregulate the production of IFN-γ and neopterin. This phenomenon may be responsible for the lack of efficacy of high doses of IL-10 in the treatment of CACD and MCD.
Hedgehog: an Attribute to Tumor Regrowth after Chemoradiotherapy and a Target to Improve Radiation Response
Authors: Jennifer Sims-Mourtada, Julie G. Izzo, Smith Apisarnthanarax, Tsung-Teh Wu, Usha Malhotra, Rajyalashmi Luthra, Zhongxing Liao, Ritsuko Komaki, Albert van der Kogel, Jaffer Ajani, K.S. Clifford Chao
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Despite aggressive chemotherapy, radiotherapy, surgery, or combination approaches, the survival rate of patients with esophageal cancer remains poor. Recent studies have suggested that constitutive activation of the Hedgehog (Hh) pathway in cancers of the digestive tract may contribute to the growth and maintenance of cancer. However, the relationship between Hh signaling and therapeutic response is unknown. Experimental Design: The expression and temporal kinetics of Hh signaling and proliferation biomarkers after chemoradiotherapy were examined in esophageal tumor xenografts. Additionally, immunohistochemical analysis of Sonic Hh (Shh) and Gli-1 expression were done on residual tumors from patients who received neoadjuvant chemoradiotherapy followed by surgery. The ability of Shh signaling to induce proliferation in esophageal cell lines was determined. Expression of cell cycle checkpoint proteins was analyzed in cells in which Hh signaling was activated or inhibited. We further determined the effect of inhibiting Hh signaling in sensitizing esophageal tumors to radiation. Results: We showed that the Shh signaling pathway was extensively activated in esophageal cancer xenografts and residual tumors after chemoradiotherapy and the temporal kinetics of Hh signaling preceded increases in proliferation biomarker expression and tumor size during tumor regrowth. We further showed that Hh pathway activity influences proliferation rates of esophageal cancer cell lines through up-regulation of the G1-cyclin-Rb axis. Additionally, we found that blocking Hh signaling enhanced radiation cytotoxicity of esophageal cancer cells. Conclusions: These results suggest that activation of the Hh pathway may promote tumor repopulation after chemoradiotherapy and contribute to chemoradiation resistance in esophageal cancers.
Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3
Authors: N UEDA, D ZIPES, J WU
Journal: Cardiovascular Research (2004)

Objective: Ventricular tachyarrhythmias (VTs) occur frequently in patients having long QT syndrome (LQTS) or after acute myocardial ischemia. However, the synergistic effects of ischemia and LQTS on arrhythmia development are unclear. We evaluated the contribution of a prior episode of ischemia on the arrhythmogenicity of the LQTS. Methods: Using a 256-channel optical mapping system, we mapped action potentials on the cut-exposed transmural surfaces of perfused and preconditioned muscle wedges isolated from canine left ventricular walls and recorded their transmural electrocardiogram (ECG). Results: We observed that 40 min of global ischemia followed by 60 min of reperfusion, at which time action potential duration (APD) and conduction velocity had recovered, significantly enhanced the APD prolongation produced by 20 nmol/l anemone toxin II (ATX-II). Wedges after the above ischemia, reperfusion, and ATX-II procedures had 100% (8/8) occurrences of early afterdepolarizations (EADs) and 87.5% (7/8) occurrences of spontaneous VTs and reentry. We observed epicardial, midmyocardial, and endocardial occurrences of EADs in one, seven, and four wedges, respectively. Focal EADs and reentry were responsible for 73% and 18% of the repetitive activations in the VTs. In contrast, neither EADs nor VTs occurred in eight control wedges following identical procedures except without ischemia, and VT occurred in 20% wedges (2/10) after ischemia and reperfusion but before ATX-II. Conclusion: A prior episode of acute ischemia, even after apparent electrophysiologic recovery, enhances the arrhythmogenicity of LQTS induced by ATX-II through the development of EADs and reentry.
Expression of Advanced Glycation End Products and Their Cellular Receptor RAGE in Diabetic Nephropathy and Nondiabetic Renal Disease
Authors: NOZOMU TANJI, GLEN S. MARKOWITZ, CAIFENG FU, THOMAS KISLINGER, AKIHIKO TAGUCHI, MONIKA PISCHETSRIEDER, DAVID STERN, ANN MARIE SCHMIDT, VIVETTE D. D'AGATI
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Advanced glycation end products (AGE) contribute to diabetic tissue injury by two major mechanisms, i.e. , the alteration of extracellular matrix architecture through nonenzymatic glycation, with formation of protein crosslinks, and the modulation of cellular functions through interactions with specific cell surface receptors, the best characterized of which is the receptor for AGE (RAGE). Recent evidence suggests that the AGE-RAGE interaction may also be promoted by inflammatory processes and oxidative cellular injury. To characterize the distributions of AGE and RAGE in diabetic kidneys and to determine their specificity for diabetic nephropathy, an immunohistochemical analysis of renal biopsies from patients with diabetic nephropathy ( n = 26), hypertensive nephrosclerosis ( n = 7), idiopathic focal segmental glomerulosclerosis ( n = 11), focal sclerosis secondary to obesity ( n = 7), and lupus nephritis ( n = 11) and from normal control subjects ( n = 2) was performed, using affinity-purified antibodies raised to RAGE and two subclasses of AGE, i.e., Nε -(carboxymethyl)-lysine (CML) and pentosidine (PENT). AGE were detected equally in diffuse and nodular diabetic nephropathy. CML was the major AGE detected in diabetic mesangium (96%), glomerular basement membranes (GBM) (42%), tubular basement membranes (85%), and vessel walls (96%). In diabetic nephropathy, PENT was preferentially located in interstitial collagen (90%) and was less consistently observed in vessel walls (54%), mesangium (77%), GBM (4%), and tubular basement membranes (31%). RAGE was expressed on normal podocytes and was upregulated in diabetic nephropathy. The restriction of RAGE mRNA expression to glomeruli was confirmed by reverse transcription-PCR analysis of microdissected renal tissue compartments. The extent of mesangial and GBM immunoreactivity for CML, but not PENT, was correlated with the severity of diabetic glomerulosclerosis, as assessed pathologically. CML and PENT were also identified in areas of glomerulosclerosis and arteriosclerosis in idiopathic and secondary focal segmental glomerulosclerosis, hypertensive nephrosclerosis, and lupus nephritis. In active lupus nephritis, CML and PENT were detected in the proliferative glomerular tufts and crescents. In conclusion, CML is a major AGE in renal basement membranes in diabetic nephropathy, and its accumulation involves upregulation of RAGE on podocytes. AGE are also accumulated in acute inflammatory glomerulonephritis secondary to systemic lupus erythematosus, possibly via enzymatic oxidation of glomerular matrix proteins.
CELLULAR DIFFERENTIATION OF THE IMMUNE SYSTEM OF MICE
Authors: G. M. Shearer, G. Cudkowicz, R. L. Priore
Journal: The Journal of Experimental Medicine (1969)

Thymocytes and marrow cells of unprimed donor mice were mixed in vitro and transplanted into X-irradiated syngeneic mice. 18 hr later, sheep erythrocytes were injected to induce immune responses. Splenic plaque-forming cells (PFC) secreting IgM (direct PFC) or IgG (indirect PFC) hemolytic antibody were enumerated at the time of peak responses. By transplanting graded and limiting numbers of thymocytes with 4 x 10(7) marrow cells, inocula were found which contained one or a few thymic antigen-reactive cells (ARC) reaching the recipient spleens, interacting with marrow cells, and inducing PFC formation. The frequency values of ARC inferred from direct and indirect plaque assays were very similar, 1 in approximately 10(7) thymocytes. Furthermore, statistical analysis indicated that the formation of direct PFC was not independent of the formation of indirect PFC. This was interpreted to mean that ARC were not specialized themselves and did not determine the molecular class of antibody to be secreted after interaction with marrow cells. Spleens of thymus-marrow grafted mice containing one or two ARC and non-limiting numbers of marrow precursors of PFC (P-PFC), had direct and indirect PFC clustered in several focal areas. Assuming that each focal area represented the progeny of one P-PFC that had interacted with ARC, these results confirmed the statistical evidence for lack of class differentiation in thymic ARC, and also indicated that each ARC or its progeny cells interacted with more than one P-PFC of either class.
Lack of effect of TNF blockade therapy on circulating adiponectin levels in patients with autoimmune disease: results from two independent prospective studies
Authors: M. J. L. Peters, P. Watt, L. Cherry, P. Welsh, E. Henninger, B. A. C. Dijkmans, I. B. McInnes, M. T. Nurmohamed, N. Sattar
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Background</h3> Adiponectin is an anti-inflammatory and potentially antiatherogenic molecule. Some recent reports suggest that tumour necrosis factor α (TNFα) blockade therapy increases circulating adiponectin levels, but data are sparse and inconsistent. <h3>Methods</h3> Data from a double-blind placebo controlled study of onercept in 126 patients with psoriatic arthritis (PsA) and from pre- and post-adalimumab treatment in 171 patients with rheumatoid arthritis (RA) were used to examine the effect of TNFα blockade therapy on adiponectin. <h3>Results</h3> Despite expected associations of adiponectin with gender and baseline high-density lipoprotein cholesterol and triglyceride, adiponectin levels did not change over time with TNFα blockade therapy in either group. The mean±SD absolute change in adiponectin levels was −0.23±4.6 μg/ml in patients with PsA treated with combined onercept 50 mg and onercept 100 mg (vs placebo, p=0.60) and 0.28±3.23 μg/ml in patients with RA treated with adalimumab (vs baseline, p=0.66). <h3>Conclusion</h3> These results do not support a significant effect of TNFα blockade therapy on circulating adiponectin levels in patients with autoimmune disease.
Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production
Authors: Lauren Cohn, Robert J. Homer, Anthony Marinov, John Rankin, Kim Bottomly
Journal: The Journal of Experimental Medicine (1997)

Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased mucus secretion is an important clinical symptom and contributes to airway obstruction in asthma. Activated CD4 Th1 and Th2 cells have both been identified in airway biopsies of asthmatics but their role in mucus production is not clear. Using CD4 T cells from mice transgenic for the OVA-specific TCR, we studied the role of Th1 and Th2 cells in airway inflammation and mucus production. Airway inflammation induced by Th2 cells was comprised of eosinophils and lymphocytes; features found in asthmatic patients. Additionally, there was a marked increase in mucus production in mice that received Th2 cells and inhaled OVA, but not in mice that received Th1 cells. However, OVA-specific Th2 cells from IL-4–deficient mice were not recruited to the lung and did not induce mucus production. When this defect in homing was overcome by administration of TNF-α, IL-4 −/− Th2 cells induced mucus as effectively as IL-4 +/+ Th2 cells. These studies establish a role for Th2 cells in mucus production and dissect the effector functions of IL-4 in these processes. These data suggest that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
STEREOCHEMISTRY AND VITALISM.
Authors: Keith Manchester
Journal: JAMA (1898)

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Location of Cardiac Arrest in a City Center
Authors: Fredrik Folke, Freddy Knudsen Lippert, Søren Loumann Nielsen, Gunnar Hilmar Gislason, Morten Lock Hansen, Tina Ken Schramm, Rikke Sørensen, Emil Loldrup Fosbøl, Søren Skøtt Andersen, Søren Rasmussen, Lars Køber, Christian Torp-Pedersen
Journal: Circulation (2009)

Background— Public-access defibrillation with automated external defibrillators (AEDs) is being implemented in many countries worldwide with considerable financial implications. The potential benefit and economic consequences of focused or unfocused AED deployment are unknown. Methods and Results— All cardiac arrests in public in Copenhagen, Denmark, from 1994 through 2005 were geographically located, as were 104 public AEDs placed by local initiatives. In accordance with European Resuscitation Council and American Heart Association (AHA) guidelines, areas with a high incidence of cardiac arrests were defined as those with 1 cardiac arrest every 2 or 5 years, respectively. There were 1274 cardiac arrests in public locations. According to the European Resuscitation Council or AHA guidelines, AEDs needed to be deployed in 1.2% and 10.6% of the city area, providing coverage for 19.5% (n=249) and 66.8% (n=851) of all cardiac arrests, respectively. The excessive cost of such AED deployments was estimated to be $33 100 or $41 000 per additional quality-adjusted life year, whereas unguided AED placement covering the entire city had an estimated cost of $108 700 per quality-adjusted life year. Areas with major train stations (1.8 arrests every 5 years per area), large public squares, and pedestrianized areas (0.6 arrests every 5 years per area) were main predictors of frequent cardiac arrests. Conclusion— To achieve wide AED coverage, AEDs need to be more widely distributed than recommended by the European Resuscitation Council guidelines but consistent with the American Heart Association guidelines. Strategic placement of AEDs is pivotal for public-access defibrillation, whereas with unguided initiatives, AEDs are likely to be placed inappropriately.
Phase Ib Dose-Escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma
Authors: Ruben Niesvizky, Thomas G. Martin, William I. Bensinger, Melissa Alsina, David S. Siegel, Lori A. Kunkel, Alvin F. Wong, Susan Lee, Robert Z. Orlowski, Michael Wang
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study. Experimental Design: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly. Results: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. Conclusion: The maximum planned CRd dose, carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy. Clin Cancer Res; 19(8); 2248–56. ©2013 AACR.
Computer support for determining drug dose: systematic review and meta-analysis
Authors: R. Walton, S. Dovey, E. Harvey, N. Freemantle
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective</b>: To review the effectiveness of computer support for determining optimum drug dose. <b>Design</b>: Systematic review of comparative studies where computers gave advice to clinicians on the most appropriate drug dose. Search methods used were standard for the Cochrane Collaboration on Effective Professional Practice. <b>Subjects</b>: Comparative studies conducted worldwide and published between 1966 and 1996. <b>Main outcome measures</b>: For qualitative review, relative percentage differences were calculated to compare effects of computer support in different settings. For quantitative data, effect sizes were calculated and combined in meta-analyses. <b>Results</b>: Eighteen studies met the inclusion criteria. The drugs studied were theophylline, warfarin, heparin, aminoglycosides, nitroprusside, lignocaine, oxytocin, fentanyl, and midazolam. The computer programs used individualised pharmacokinetic models to calculate the most appropriate dose. Meta-analysis of data from 671 patients showed higher blood concentrations of drug with computer support (effect size 0.69, 95% confidence interval 0.36 to 1.02) and reduced time to achieve therapeutic control (0.44, 0.17 to 0.71). The total dose of drug used was unchanged, and there were fewer unwanted effects of treatment. Five of six studies measuring outcomes of care showed benefit from computer assistance. <b>Conclusions</b>: This review suggests that using computers to determine the correct dose of certain drugs in acute hospital settings is beneficial. Computers may give doctors the confidence to use higher doses when necessary, adjusting the drug dose more accurately to individual patients. Further research is necessary to evaluate the benefits in general use.
Safety and activity of sunitinib in elderly patients (≥70 years) with metastatic renal cell carcinoma: a multicenter study
Authors: A Brunello, U Basso, C Sacco, T Sava, R De Vivo, A Camerini, C Barile, A Roma, M Maruzzo, C Falci, V Zagonel
Journal: Annals of Oncology (2012)
Dabrafenib and Trametinib, Alone and in Combination for <i>BRAF</i>-Mutant Metastatic Melanoma
Authors: Alexander M. Menzies, Georgina V. Long
Journal: Clinical Cancer Research (2014)

Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF(V600E) metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-naïve patients with BRAF(V600E) or BRAF(V600K) also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma.