tbuckley/cabot-search huggingface dataset:
Mycophenolate mofetil for Crohn's disease Reply
Authors: J C ATHERTON;
Journal: Gut (2000)

Editor,—On the basis of a study reported recently by Neurath et al ( Gut 1999; 44 :625–628), commentaries in Gut 1 and the Lancet 2 suggested that mycophenolate mofetil (MMF) should be used in patients with Crohn's disease who have either not responded to or are intolerant of azathioprine or 6-mercaptopurine. This advice is premature: firstly, because the study was flawed and, secondly, because it examined only management of acute inflammation, not the place of MMF in maintaining remission and in steroid sparing (a fact acknowledged in both commentaries).

The study by Neurath et al compared the effect of MMF 15 mg/kg daily with azathioprine 2.5 mg/kg daily, both with high dose steroids, in the treatment of active chronic Crohn's …
Vagus nerve controls resolution and pro-resolving mediators of inflammation
Authors: Valbona Mirakaj, Jesmond Dalli, Tiago Granja, Peter Rosenberger, Charles N. Serhan
Journal: The Journal of Experimental Medicine (2014)

Resolution of inflammation is now recognized as a biosynthetically active process involving pro-resolving mediators. Here, we show in zymosan-initiated peritoneal inflammation that the vagus nerve regulates local expression of netrin-1, an axonal guidance molecule that activates resolution, and that vagotomy reduced local pro-resolving mediators, thereby delaying resolution. In netrin-1+/− mice, resolvin D1 (RvD1) was less effective in reducing neutrophil influx promoting resolution of peritonitis compared with Ntn1+/+. Netrin-1 shortened the resolution interval, decreasing exudate neutrophils, reducing proinflammatory mediators, and stimulating the production of resolvins, protectins, and lipoxins. Human monocytes incubated with netrin-1 produced proresolving mediators, including resolvins and lipoxins. Netrin-1 and RvD1 displayed bidirectional activation in that they stimulated each other’s expression and enhanced efferocytosis. These results indicate that the vagus nerve regulates both netrin-1 and pro-resolving lipid mediators, which act in a bidirectional fashion to stimulate resolution, and provide evidence for a novel mechanism for local neuronal control of resolution.
Sensitization to Lolium multiflorum, a major Brazilian grass that causes pollinosis in patients living in Southern Brazil
Authors: E.A. Taketomi, M.C. Sopelete, P.F.S. Moreira, D.A.O. Silva, C.M. Santos, A. Sá-Júnior, F.A.M. Vieira, S.J. Sung
Journal: Journal of Allergy and Clinical Immunology (2005)
Refusal of Intensive Care Unit Admission Due to a Full Unit
Authors: René Robert, Jean Reignier, Caroline Tournoux-Facon, Thierry Boulain, Olivier Lesieur, Valérie Gissot, Vincent Souday, Mouldi Hamrouni, Cécile Chapon, Jean-Paul Gouello
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Intensive care unit (ICU) beds are a scarce resource, and patients denied intensive care only because the unit is full may be at increased risk of death.Objective: To compare mortality after first ICU referral in admitted patients and in patients denied admission because the unit was full.Methods: Prospective observational multicenter cohort study of consecutive patients referred for ICU admission during two 45-day periods, conducted in 10 ICUs.Measurements and Main Results: Of 1,762 patients, 430 were excluded from the study, 116 with previously denied admission to another ICU and 270 because they were deemed too sick or too well to benefit from ICU admission. Of the remaining 1,332 patients, 1,139 were admitted, and 193 were denied admission because the unit was full (65 were never admitted, 39 were admitted after bumping of another patient, and 89 were admitted on subsequent referral). Crude Day 28 and Day 60 mortality rates in the nonadmitted and admitted groups were 30.1 versus 24.3% (P = 0.07) and 33.3 versus 27.2% (P = 0.06), respectively. Day 28 mortality adjusted on age, previous disease, Glasgow scale score less than or equal to 8, shock, creatinine level greater than or equal to 250 μmol/L, and prothrombin time greater than or equal to 30 seconds was nonsignificantly higher in patients refused ICU admission only because of a full unit compared with patients admitted immediately. Patients admitted after subsequent referral had higher mortality rates on Day 28 (P = 0.05) and Day 60 (P = 0.04) compared with directly admitted patients.Conclusions: Delayed ICU admission due to a full unit at first referral is associated with increased mortality.
Prevalence of acid reflux in functional dyspepsia and its association with symptom profile
Authors: J Tack
Journal: Gut (2005)

A subset of functional dyspepsia patients respond to acid suppressive therapy, but the prevalence of non-erosive reflux disease in functional dyspepsia and its relevance to symptoms have never been established. The aim of the present study was to study 24 hour pH monitoring in consecutive functional dyspepsia patients.A total of 247 patients with dyspeptic symptoms (166 women, mean age 44 (SEM 1) year), with a negative upper gastrointestinal endoscopy and without dominant symptoms of heartburn participated in the study. In all patients, the severity of dyspeptic symptoms and the presence of heartburn was assessed by a questionnaire and a 24 hour oesophageal pH monitoring study was performed. All patients underwent a gastric emptying breath test and in 113 a gastric barostat study was performed.Abnormal pH monitoring (acid exposure >5% of time) was found in 58 patients (23%). Of 21 patients with a positive heartburn questionnaire, 76% had pathological pH monitoring, while this was the case in only 18.5% of patients with a negative heartburn questionnaire. Demographic characteristics and the prevalence of other pathophysiological mechanisms did not differ between heartburn negative patients with normal or abnormal acid exposure. Pathological acid exposure in heartburn negative patients was associated with the presence of epigastric pain (65 v 84%, p<0.005) and of moderate or severe pain (48 v 69%, p = 0.005).Pathological oesophageal acid exposure is only present in a subset of heartburn negative functional dyspepsia patients, which are characterised by a higher prevalence of epigastric pain.
Postmenopausal estrogen and progestin effects on the serum proteome
Authors: Sharon J Pitteri, Samir M Hanash, Aaron Aragaki, Lynn M Amon, Lin Chen, Tina Busald Buson, Sophie Paczesny, Hiroyuki Katayama, Hong Wang, Melissa M Johnson, Qing Zhang, Martin McIntosh, Pei Wang, Charles Kooperberg, Jacques E Rossouw, Rebecca D Jackson, JoAnn E Manson, Judith Hsia, Simin Liu, Lisa Martin, Ross L Prentice
Journal: Genome Medicine (2009)

Women's Health Initiative randomized trials of postmenopausal hormone therapy reported intervention effects on several clinical outcomes, with some important differences between estrogen alone and estrogen plus progestin. The biologic mechanisms underlying these effects, and these differences, have yet to be fully elucidated.Baseline serum samples were compared with samples drawn 1 year later for 50 women assigned to active hormone therapy in both the estrogen-plus-progestin and estrogen-alone randomized trials, by applying an in-depth proteomic discovery platform to serum pools from 10 women per pool.In total, 378 proteins were quantified in two or more of the 10 pooled serum comparisons, by using strict identification criteria. Of these, 169 (44.7%) showed evidence (nominal P < 0.05) of change in concentration between baseline and 1 year for one or both of estrogen-plus-progestin and estrogen-alone groups. Quantitative changes were highly correlated between the two hormone-therapy preparations. A total of 98 proteins had false discovery rates < 0.05 for change with estrogen plus progestin, compared with 94 for estrogen alone. Of these, 84 had false discovery rates <0.05 for both preparations. The observed changes included multiple proteins relevant to coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors, and osteogenesis. Evidence of differential changes also was noted between the hormone preparations, with the strongest evidence in growth factor and inflammation pathways.Serum proteomic analyses yielded a large number of proteins similarly affected by estrogen plus progestin and by estrogen alone and identified some proteins and pathways that appear to be differentially affected between the two hormone preparations; this may explain their distinct clinical effects.
Linkage of Chromosome 5q and 11q Gene Markers to Asthma-associated Quantitative Traits in Australian Children
Authors: LYLE J. PALMER, SIW E. DANIELS, PETER J. RYE, NEIL A. GIBSON, GUAN K. TAY, WILLIAM O. C. M. COOKSON, JACK GOLDBLATT, PAUL R. BURTON, PETER N. LeSOUËF
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Asthma is a genetically complex disease, and the investigation of putative linkages to candidate loci in independent populations is an important part of the gene discovery process. This study investigated the linkage of microsatellite markers in the 5q and 11q regions to asthma-associated quantitative traits in 121 Australian Caucasian nuclear families. The families were recruited on the basis of a child proband: a cohort of 95 randomly recruited families of unselected probands (n = 442 subjects) and a cohort of 26 families of probands selected on the basis of severe symptomatic asthma (n = 134 subjects). The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts, and the dose–response slope (DRS) of FEV1 to histamine provocation. Multipoint linkage analysis using Haseman-Elston sib-pair methods provided evidence of significant linkage between the chromosome 5q markers and loge total serum IgE levels, specific serum IgE levels, and loge blood eosinophil counts. The chromosome 11q markers showed evidence of significant linkage to specific serum IgE levels. Neither region demonstrated significant linkage to the loge DRS to histamine. Phenotypes were residualized for age and sex. These data are consistent with the existence of loci regulating asthma-associated quantitative traits in both the 5q31–33 and 11q13 chromosomal regions.
Medical Liability Reform
Authors: C. Thomas Yarington
Journal: JAMA (1988)

<h3>To the Editor.—</h3> I write concerning the recent article by Dr Abraham<sup>1</sup>on medical liability reform in the July 1 issue of<i>JAMA</i>. He mentions one-way and two-way fee shifting as mechanisms to limit litigation, but states that two-way fee shifting might reduce access to the courts by less prosperous plaintiffs who have otherwise meritorious claims. I suggest that another mechanism to limit litigation, which apparently has had success elsewhere, is for a system of two-way fee shifting in which a losing defendant pays the costs of the plaintiff, including legal fees (as now exists), but in which a losing plaintiff pays all costs incurred by the victorous defendant, including legal fees. Should the plaintiff be indigent or otherwise unable to pay this cost, the burden would shift to the plaintiff's attorney, and bond would be required prior to litigation to ensure that both parties could meet this potential
Mnt-Deficient Mammary Glands Exhibit Impaired Involution and Tumors with Characteristics of Myc Overexpression
Authors: Kazuhito Toyo-oka, Timothy J. Bowen, Shinji Hirotsune, Zirong Li, Sonia Jain, Sara Ota, Laure Escoubet Lozach, Ivan Garcia Bassett, Jean Lozach, Michael G. Rosenfeld, Christopher K. Glass, Robert Eisenman, Bing Ren, Peter Hurlin, Anthony Wynshaw-Boris
Journal: Cancer Research (2006)

The proto-oncogene c-Myc plays a central role in cell growth and the development of human tumors. c-Myc interacts with Max and Myc-Max complexes bind to E-box and related sequences to activate transcription. Max also interacts with Mnt but Mnt-Max complexes repress transcription when bound to these sequences. MNT maps to human chromosome 17p13.3, a region frequently deleted in various human tumors, including mammary gland tumors. Consistent with the possibility that Mnt functions as a Myc antagonist, Mnt-deficient fibroblasts exhibit many of the hallmark characteristics of cells that overexpress Myc, and conditional (Cre/Lox) inactivation of Mnt in mammary gland epithelium leads to adenocarcinomas. Here, we further characterize mammary gland tissue following conditional deletion of Mnt in the mammary gland. We show that loss of Mnt severely disrupts mammary gland involution and leads to hyperplastic ducts associated with reduced numbers of apoptotic cells. These findings suggest that loss of Mnt in mammary tissue has similarities to Myc overexpression. We tested this directly by using promoter array analysis and mRNA expression analysis by oligonucleotide arrays. We found that Mnt and c-Myc bound to similar promoters in tumors from MMTV-c-Myc transgenic mice, and mRNA expression patterns were similar between mammary tumors from MMTV-Cre/Mnt(KO/CKO) and MMTV-c-Myc transgenic mice. These results reveal an important role for Mnt in pregnancy-associated mammary gland development and suggest that mammary gland tumorigenesis in the absence of Mnt is analogous to that caused by Myc deregulation.
THE EOSINOPHILIC LEUKOCYTE
Authors: Russell Ross, Seymour J. Klebanoff
Journal: The Journal of Experimental Medicine (1966)

This study has presented the fine structure changes in the eosinophilic leukocyte in the rat uterus during the estrous cycle. Eosinophils were seen to emigrate into the uterine connective tissues from the blood stream. Just prior to, during estrus, and 1 day postestrus, eosinophilic leukocytes underwent lysis releasing their contents into the extracellular spaces and both whole eosinophils and individual granules from lysed cells were ingested by resident macrophages. No phagocytic activity by eosinophils was observed. The possible relationship of the turnover of eosinophils to the profound morphologic and chemical changes in the uterus during the estrous cycle was discussed.
Elderly woman with post-traumatic locked shoulder
Authors: S A Mann, J M Leith, J H White, B B Forster
Journal: British Journal of Sports Medicine (2009)

A 60-year-old woman presented to an orthopaedic surgeon with a painless but very stiff right shoulder after an injury sustained from a fall 4 months earlier while on vacation. She was right-hand dominant. She had presented to the emergency department 1 day after directly landing on her shoulder, …
Late-breaking abstract: Exhalation of specific volatile compounds under changing ventilation in mechanically ventilated patients
Authors: Beate Brock, Svend Kamysek, Josephine Silz, Phillip Trefz, Wolfram Miekisch, Jochen Schubert
Journal: European Respiratory Journal (2014)

Disturbances in ventilation and occurrence of atelectasis are frequent problems in mechanical ventilation. Global parameters of gas exchange detected by blood gas analysis cannot differentiate causes sufficiently.  This study was intended to identify ventilation dependent concentration changes of volatile compounds in the breath. In 10 mechanically ventilated patients having undergone cardiac surgery standard monitoring was extended by electrical impedance tomography (EIT) visualizing dynamic changes in ventilation distribution in defined areas of the lung. Exhaled breath was analyzed in real-time by means of proton-transfer-reaction-time-of flight-mass spectrometry (PTR-TOF-MS). All patients underwent a defined pulmonary recruitement maneuver. On the basis of EIT-data we divided patients into two groups – responders (> 50%) and nonresponders (  Specific endogenous and exogenous VOCs in the breath mirror changes of ventilation. The combination of ventilation imaging by means of EIT and real time breath analysis can be used to identify markers of ventilatory disorders. These markers could be employed for non-invasive control of therapeutic ventilation strategies.
Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET/PTC1-expressing cell line
Authors: Dario Caccia, Francesca Miccichè, Giuliana Cassinelli, Piera Mondellini, Patrizia Casalini, Italia Bongarzone
Journal: Molecular Cancer (2010)

Abstract Background TPC-1 is a papillary thyroid carcinoma (PTC)-derived cell line that spontaneously expresses the oncogene RET/PTC1 . TPC-1 treated with the RET/PTC1 inhibitor RPI-1 displayed a cytostatic and reversible inhibition of cell proliferation and a strong activation of focal adhesion kinase (FAK). As dasatinib inhibition of Src results in reduction of FAK activation, we evaluated the effects of TPC-1 treatment with dasatinib in combination with RPI-1. Results Dasatinib (100 nM) strongly reduced TPC-1 proliferation and induced marked changes in TPC-1 morphology. Cells appeared smaller and more contracted, with decreased cell spreading, due to the inhibition of phosphorylation of important cytoskeletal proteins (p130 CAS , Crk, and paxillin) by dasatinib. The combination of RPI-1 with dasatinib demonstrated enhanced effects on cell proliferation (more than 80% reduction) and on the phosphotyrosine protein profile. In particular, RPI-1 reduced the phosphorylation of RET, MET, DCDB2, CTND1, and PLCγ, while dasatinib acted on the phosphorylation of EGFR, EPHA2, and DOK1. Moreover, dasatinib completely abrogated the phosphorylation of FAK at all tyrosine sites (Y576, Y577, Y861, Y925) with the exception of the autoactivation site (Y397). Notably, the pharmacological treatments induced an overexpression of integrin β1 (ITB1) that was correlated with a mild enhancement in phosphorylation of ERK1/2 and STAT3, known for their roles in prevention of apoptosis and in increase of proliferation and survival. A reduction in Akt, p38 and JNK1/2 activation was observed. Conclusions All data demonstrate that the combination of the two drugs effectively reduced cell proliferation (by more than 80%), significantly decreased Tyr phosphorylation of almost all phosphorylable proteins, and altered the morphology of the cells, supporting high cytostatic effects. Following the combined treatment, cell survival pathways appeared to be mediated by STAT3 and ERK activities resulting from integrin clustering and FAK autophosphorylation. EphA2 may also contribute, at least in part, to integrin and FAK activation. In conclusion, these data implicate ITB1 and EphA2 as promising therapeutic targets in PTC.
Effect of Lowering the Glycemic Load With Canola Oil on Glycemic Control and Cardiovascular Risk Factors: A Randomized Controlled Trial
Authors: David J.A. Jenkins, Cyril W.C. Kendall, Vladimir Vuksan, Dorothea Faulkner, Livia S.A. Augustin, Sandra Mitchell, Christopher Ireland, Korbua Srichaikul, Arash Mirrahimi, Laura Chiavaroli, Sonia Blanco Mejia, Stephanie Nishi, Sandhya Sahye-Pudaruth, Darshna Patel, Balachandran Bashyam, Edward Vidgen, Russell J. de Souza, John L. Sievenpiper, Judy Coveney, Robert G. Josse, Lawrence A. Leiter
Journal: Diabetes Care (2014)

OBJECTIVE Despite their independent cardiovascular disease (CVD) advantages, effects of α-linolenic acid (ALA), monounsaturated fatty acid (MUFA), and low-glycemic-load (GL) diets have not been assessed in combination. We therefore determined the combined effect of ALA, MUFA, and low GL on glycemic control and CVD risk factors in type 2 diabetes. RESEARCH DESIGN AND METHODS The study was a parallel design, randomized trial wherein each 3-month treatment was conducted in a Canadian academic center between March 2011 and September 2012 and involved 141 participants with type 2 diabetes (HbA1c 6.5%–8.5% [48–69 mmol/mol]) treated with oral antihyperglycemic agents. Participants were provided with dietary advice on either a low-GL diet with ALA and MUFA given as a canola oil–enriched bread supplement (31 g canola oil per 2,000 kcal) (test) or a whole-grain diet with a whole-wheat bread supplement (control). The primary outcome was HbA1c change. Secondary outcomes included calculated Framingham CVD risk score and reactive hyperemia index (RHI) ratio. RESULTS Seventy-nine percent of the test group and 90% of the control group completed the trial. The test diet reduction in HbA1c units of −0.47% (−5.15 mmol/mol) (95% CI −0.54% to −0.40% [−5.92 to −4.38 mmol/mol]) was greater than that for the control diet (−0.31% [−3.44 mmol/mol] [95% CI −0.38% to −0.25% (−4.17 to −2.71 mmol/mol)], P = 0.002), with the greatest benefit observed in those with higher systolic blood pressure (SBP). Greater reductions were seen in CVD risk score for the test diet, whereas the RHI ratio increased for the control diet. CONCLUSIONS A canola oil–enriched low-GL diet improved glycemic control in type 2 diabetes, particularly in participants with raised SBP, whereas whole grains improved vascular reactivity.
Effect of hyaluronidase and methylprednisolone on myocardial function, glucose metabolism, and coronary flow in the isolated ischemic rat heart.
Authors: M J Rovetto
Journal: Circulation Research (1977)

Ischemia in the isolated perfused rat heart resulted in an increase in coronary vascular resistance. Studies were undertaken to determine the effect of hyaluronidase and methylprednisolone on this increase in resistance as well as on glycolytic rate and mechanical function of ischemic hearts. Neither hyaluronidase nor methylprednisolone affected the rate of glucose utilization in working perfused control or ischemic rat hearts. However, both agents prevented a reduction in coronary flow during a 2-hour ischemic period. Associated with the higher coronary flows were higher tissue concentrations of creatine phosphate and lower concentrations of lactate. These agents also prevented accumulation of tissue water in the ischemic hearts. Such changes would appear to be beneficial to the ischemic heart, although mechanical function of post-ischemic hearts was not enhanced by the presence of either hyaluronidase or methylprednisolone. The results, however, suggest that the reduction in myocardial infarct size noted with hyaluronidase and methylprednisolone may be due to their prevention of further reduction of coronary flow in marginally eschemic tissue.
EWS-FLI-1-Targeted Cytotoxic T-cell Killing of Multiple Tumor Types Belonging to the Ewing Sarcoma Family of Tumors
Authors: Christopher H. Evans, Fangjun Liu, Ryan M. Porter, Regina P. O'Sullivan, Taha Merghoub, Elaine P. Lunsford, Kyle Robichaud, Frans Van Valen, Stephen L. Lessnick, Mark C. Gebhardt, James W. Wells
Journal: Clinical Cancer Research (2012)

The Ewing sarcoma family of tumors (ESFT) comprises a group of aggressive, malignant bone, and soft tissue tumors that predominantly affect children and young adults. These tumors frequently share expression of the EWS-FLI-1 translocation, which is central to tumor survival but not present in healthy cells. In this study, we examined EWS-FLI-1 antigens for their capacity to induce immunity against a range of ESFT types.Computer prediction analysis of peptide binding, HLA-A2.1 stabilization assays, and induction of cytotoxic T-lymphocytes (CTL) in immunized HLA-A2.1 transgenic mice were used to assess the immunogenicity of native and modified peptides derived from the fusion region of EWS-FLI-1 type 1. CTL-killing of multiple ESFT family members in vitro, and control of established xenografts in vivo, was assessed. We also examined whether these peptides could induce human CTLs in vitro.EWS-FLI-1 type 1 peptides were unable to stabilize cell surface HLA-A2.1 and induced weak CTL activity against Ewing sarcoma cells. In contrast, peptides with modified anchor residues induced potent CTL killing of Ewing sarcoma cells presenting endogenous (native) peptides. The adoptive transfer of CTL specific for the modified peptide YLNPSVDSV resulted in enhanced survival of mice with established Ewing sarcoma xenografts. YLNPSVDSV-specific CTL displayed potent killing of multiple ESFT types in vitro: Ewing sarcoma, pPNET, Askin's Tumor, and Biphenotypic sarcoma. Stimulation of human peripheral blood mononuclear cells with YLNPSVDSV peptide resulted in potent CTL-killing.These data show that YLNPSVDSV peptide is a promising antigen for ESFT immunotherapy and warrants further clinical development.