tbuckley/cabot-search huggingface dataset:
Bosentan Enhances Viral Load via Endothelin-1 Receptor Type-A–Mediated p38 Mitogen-Activated Protein Kinase Activation While Improving Cardiac Function During Coxsackievirus-Induced Myocarditis
Authors: David Marchant, Ying Dou, Honglin Luo, Farshid S. Garmaroudi, John E. McDonough, Xiaoning Si, Elizabeth Walker, Zongshu Luo, Anders Arner, Richard G. Hegele, Ismail Laher, Bruce M. McManus
Journal: Circulation Research (2009)

Reduced cardiac output is one of the consequences of myocarditis. Bosentan, an endothelin-1 receptor (ET1R) antagonist, could be useful to reduce cardiac afterload, preserving cardiac output. In this study, we investigated the potential therapeutic use of bosentan in an animal model of viral myocarditis. Using a mouse model of coxsackievirus B3 (CVB3)-induced myocarditis, we demonstrated preserved ejection fraction (EF) and fractional shortening (FS) by treatment with bosentan (68±5.8% EF and 40±3.7% FS for treated versus 48±2.2% EF and 25±2.6% FS for controls; P =0.028). However, bosentan enhanced cardiac viral load (10.4±6.7% in the bosentan group versus 5.0±5.5% in control group; P =0.02), likely through enhancement of p38 mitogen-activated protein kinase (MAPK) phosphorylation (0.77±0.40% ATF2 activation in the bosentan group versus 0.03±0.02% in controls; P =0.0002), mediated by endothelin receptor type-A. We further demonstrate that a water soluble inhibitor of p38 MAPK, SB203580 HCl, is a potent inhibitor of virus replication in the heart (0.28% antisense viral genome stained area for 3 mg/kg dose versus 2.9% stained area for controls; P =0.01), attenuates CVB3-induced myocardial damage (blinded cardiac histopathologic scores of 1.8±1.6 and 2.05±1.2 for the 3 mg/kg and 10 mg/kg doses, respectively, versus 3.25±1.2 for the controls), and preserves cardiac function (69±3.5% EF for 3 mg/kg dose and 71±6.7% EF for 10 mg/kg dose versus 60±1.5% EF control; P =0.038 and P =0.045, as compared to control, respectively). Bosentan, a prescribed vasodilator, improves cardiac function but enhances viral load and myocarditis severity through ETRA mediated p38 MAPK activation; p38 MAPK is a desirable antiviral target. Caution must be exercised during treatment of suspected infectious myocarditis with supportive vasoactive remedies.
Myocardial protection with verapamil during ischaemia and reperfusion: dissociation between myocardial salvage and the degree of ATP depletion during ischaemia
Authors: C. L Wolfe, T. J Donnelly, R. Sievers, W. W Parmley
Journal: Cardiovascular Research (1991)

Study objective – The aim was to evaluate the protective effect of verapamil during myocardial ischaemia and reperfusion. Design – In vivo phosphorus-31 (31P) magnetic resonance spectroscopy was performed on rats pretreated with verapamil (mg·kg−1 intraperitoneal) and controls during a 45 min left coronary artery occlusion and 60 min reperfusion. In separate groups of animals, haemodynamic measurements were taken at baseline, during ischaemia, and during reperfusion. Infarct size was determined by staining with triphenyltetrazolium chloride. Experimental material – Female Sprague-Dawley rats were used (control group n = 25, experimental group n = 24). Measurements and main results – Infarct size was significantly reduced in the verapamil group compared to controls: 9.9(SEM 2.3)%, n = 19 v 28.5(2.7)%, n = 19, p<0.001 (infarct % of left ventricular mass). Myocardial phosphocreatine and ATP levels were reduced to similar levels in both verapamil and control animals after 45 min ischaemia: 56.8(3.4)%, n = 10, v 61.4(1.8)%, n = 11, NS; 67.7(2.7)%, n = 10 v 69.7(2.9)%, n = 11, NS (% of baseline value). After 60 min reflow, there was significant recovery of phosphocreatine [91.1(4.2)% of baseline, p<0.05] and ATP [86.8(2.7)% of baseline, p<0.05] in the verapamil group, but no recovery of high energy phosphates in controls [66.3(2.8), NS; 69.6(2.7), NS]. The left ventricular systolic pressure, heart rate, rate-pressure product, and maximum rate of left ventricular pressure development were similar prior to ischaemia, and during ischaemia in both groups. There was an inverse correlation between infarct size and the degree of phosphocreatine recovery after 60 min of reperfusion (PCr recovery (%) = -0.99 × infarct size (%) + 101; r = 0.91; p<0.01; n = 14). Furthermore, in a separate group of animals (n = 9), there was a significant correlation between the size of the ischaemic area at risk and the degree of phosphocreatine decline after 15 min of coronary occlusion (PCr reduction (%) = 0.91 × risk area (%) + 5.6; r = 0.97; p<0.01). Conclusions – Pretreatment with verapamil extends the ischaemic time after which reperfusion results in myocardial salvage in this model of ischaemia and reperfusion. This protective effect is independent of the haemodynamic determinants of myocardial oxygen demand and the degree of ATP and phosphocreatine depletion during the ischaemic period. In this model of reversible ischaemia, 31P magnetic resonance spectroscopy is useful for quantitating both the size of the ischaemic region during coronary artery occlusion and infarct size after reperfusion.
Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe β thalassemia
Authors: George R. Honig, Carlos R. Suarez, Loyda N. Vida, Shi-Jiang Lu, Edison T. Liu
Journal: American Journal of Hematology (1998)

A 3-year-old Filipino-American child with recurrent fever, splenomegaly, anemia, and thrombocytopenia, was found to have a hemoglobin F level of 76.9%. His reticulocyte count was elevated (4.3%), and erythroblasts were present in his peripheral blood. The child's erythrocytes were microcytic (MCV 66.9 fl) but his serum ferritin level was normal. His bone marrow at initial presentation demonstrated normal cellularity without an increase in blast cells. The disease progressed with worsening anemia, leukocytosis, and thrombocytopenia, with increased blasts in his marrow and the appearance of a mediastinal mass. His liver, spleen, and lymph nodes were found to be infiltrated with myeloblasts, supporting a diagnosis of juvenile myelomonocytic leukemia (JMML). Analysis of the child's Hb F showed a Gγ/Aγ ratio of 2.2, which was within the characteristic range for JMML. A globin synthesis study using blood reticulocytes showed an α/non-α globin synthesis ratio of 2.24, typical of severe homozygous β thalassemia. Southern blot analysis of blood-leukocyte DNA from the patient and his parents demonstrated no apparent abnormality in the β-globin gene promoter or coding regions. The elevated level of Hb F in this child with JMML appeared to be part of an acquired Cooley's anemia-like hematologic phenotype. Am. J. Hematol. 58:67–71, 1998. © 1998 Wiley-Liss, Inc.
New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y
Authors: Suzanne Chanteau, Sylvie Dartevelle, Ali Elhadj Mahamane, Saacou Djibo, Pascal Boisier, Farida Nato
Journal: PLoS Medicine (2006)

Background Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African "meningitis belt," which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups. Methods and Findings Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C. Conclusions These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
Guest Authorship, Mortality Reporting, and Integrity in Rofecoxib Studies
Authors: Kent R. Johnson, Marissa N. D. Lassere
Journal: JAMA (2008)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Nasal CpG oligodeoxynucleotide administration induces a local inflammatory response in nonallergic individuals
Authors: A. Månsson, O. Bachar, M. Adner, L.‐O. Cardell
Journal: Allergy (2009)

Background: We have previously demonstrated the presence of toll‐like receptor 9 in the nasal mucosa of both healthy and allergic individuals. CpG motifs, found in bacterial and viral DNA, elicit strong immunostimulatory effects via this receptor. CpG is known to skew the immune system towards a T helper 1 (Th1) profile, thereby suppressing Th2‐driven allergic responses. This study was designed to examine the effects of CpG administration in the human nose. Methods: Twenty subjects, of whom 10 suffered from seasonal allergic rhinitis (AR), were challenged intranasally with CpG outside pollen season. Symptom scores, nasal airway resistance (NAR), and nasal and pulmonary nitric oxide (NO) levels were assayed prior to challenge and 30 min, 6, 24 and 48 h post challenge. The presence of leukocytes and various cytokines were analyzed in nasal lavage (NAL) fluids before and after CpG exposure. Results: Increased NAR, nasal NO production and secretion of interleukin (IL)‐1β, IL‐6, and IL‐8 were seen after CpG exposure. Further analysis revealed that this inflammatory response was more marked in healthy subjects than among patients with AR, although a higher basal inflammatory response was recorded in the allergic group. In vitro experiments suggest that the effects induced by CpG are mediated by epithelial cells and neutrophils. Conclusion: Nasal administration of CpG induces a local airway inflammation, more distinct among healthy than allergic individuals. The reduced responsiveness to CpG in allergic patients might be related to the ongoing minimal persistent inflammation. Results from cytokine analyses reflect the ability of CpG to induce a pro‐inflammatory Th1‐like immune response.
A STUDY OF NEOCINCHOPHEN IN THE TREATMENT OF RHEUMATIC FEVER
Authors: RALPH H. BOOTS
Journal: JAMA (1924)

In recent years, several favorable reports have appeared on the use of cinchophen (phenylcinchoninic acid) and its derivatives in the treatment of arthritis. Originally recommended as uric acid eliminants in gout, these drugs were found to be effectual in the relief of the polyarthritis and pyrexia of rheumatic fever. One of the derivatives, the ethyl ester of<i>para</i>-methylphenylcinchoninic acid,<sup>1</sup>besides having antirheumatic properties equivalent to those of phenylcinchoninic acid, has the additional advantage of being tasteless and nonirritating to the stomach. In a study of rheumatic fever, carried on for several years, we had already made detailed records of the effect of salicyl derivatives on certain symptoms of this disease, and therefore were in a position to compare the newer drug with the older. This communication is a report of these studies made during the last three years. <h3>REVIEW OF LITERATURE</h3> Heller,<sup>2</sup>Bendix,<sup>3</sup>Klemperer<sup>4</sup>and
Larrey's flying hospital
Authors: T. Delamothe
Journal: BMJ (2008)

“Why do people always expect me to talk about what’s wrong in the Middle East?” asked Daniel Barenboim. “This is what’s right with the Middle East,” he answered, indicating the orchestra he’d just been conducting through a programme of Haydn, Schoenberg, and Brahms. The orchestra was the West-Eastern Divan Orchestra, founded by Barenboim and Palestinian academic Edward Said in 1999 and made up of young musicians from Israel, Palestine, and various Arab countries. Their goal was to enable a dialogue between the various cultures of the Middle East. Visiting the BBC Proms this August, the orchestra received tumultuous applause—for the quality of its playing, certainly, but also for its aspirations.

What’s this got to do with …
The Proteasome Is a Molecular Target of Environmental Toxic Organotins
Authors: Guoqing Shi, Di Chen, Guangshu Zhai, Marina S. Chen, Qiuzhi Cindy Cui, Qunfang Zhou, Bin He, Q. Ping Dou, Guibin Jiang
Journal: Environmental Health Perspectives (2008)

Because of the vital importance of the proteasome pathway, chemicals affecting proteasome activity could disrupt essential cellular processes. Although the toxicity of organotins to both invertebrates and vertebrates is well known, the essential cellular target of organotins has not been well identified. We hypothesize that the proteasome is a molecular target of environmental toxic organotins.Our goal was to test the above hypothesis by investigating whether organotins could inhibit the activity of purified and cellular proteasomes and, if so, the involved molecular mechanisms and downstream events.We found that some toxic organotins [e.g., triphenyltin (TPT)] can potently and preferentially inhibit the chymotrypsin-like activity of purified 20S proteasomes and human breast cancer cellular 26S proteasomes. Direct binding of tin atoms to cellular proteasomes is responsible for the observed irreversible inhibition. Inhibition of cellular proteasomes by TPT in several human cell lines results in the accumulation of ubiquitinated proteins and natural proteasome target proteins, accompanied by induction of cell death.The proteasome is one of the molecular targets of environmental toxic organotins in human cells, and proteasome inhibition by organotins contributes to their cellular toxicity.
Excessive T-Tube Drainage Following Cholecystectomy
Authors: Robert J. Freeark
Journal: JAMA (1969)

To the Editor:—  I would like to comment on the question and answer to the letter regarding excessive t-tube drainage following cholecystectomy ( 208: 541, 1969).  The most common cause of t-tube drainage in excess of 1,000 cc/24 hr is reflux of pancreatic or duodenal secretions into the common duct. I have seen this commonly in patients with a short arm t-tube that does not enter the duodenum. Obviously, one may have a tight sphincter of Oddi with a common channel of  and pancreatic juice or patulous sphincter with duodenal contents refluxing up the common duct.  The diagnosis is easily confirmed by testing the bile for the presence of amylase.
MK-2461, a Novel Multitargeted Kinase Inhibitor, Preferentially Inhibits the Activated c-Met Receptor
Authors: Bo-Sheng Pan, Grace K.Y. Chan, Melissa Chenard, An Chi, Lenora J. Davis, Sujal V. Deshmukh, Jackson B. Gibbs, Susana Gil, Gaozhen Hang, Harold Hatch, James P. Jewell, Ilona Kariv, Jason D. Katz, Kaiko Kunii, Wei Lu, Bart A. Lutterbach, Cloud P. Paweletz, Xianlu Qu, John F. Reilly, Alexander A. Szewczak, Qinwen Zeng, Nancy E. Kohl, Christopher J. Dinsmore
Journal: Cancer Research (2010)

The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. Here, we describe MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC(50) values of 0.4 to 2.5 nmol/L. In contrast, MK-2461 was several hundredfold less potent as an inhibitor of c-Met autophosphorylation at the kinase activation loop. In tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinase-AKT and Ras-extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. BIAcore studies indicated 6-fold tighter binding to c-Met when it was phosphorylated, suggesting that MK-2461 binds preferentially to activated c-Met. MK-2461 displayed significant inhibitory activities against fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor, and other receptor tyrosine kinases. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met-dependent mitogenesis, migration, cell scatter, and tubulogenesis. Seven of 10 MK-2461-sensitive tumor cell lines identified from a large panel harbored genomic amplification of MET or FGFR2. In a murine xenograft model of c-Met-dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. Similarly, MK-2461 inhibited the growth of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants. Taken together, our findings support further preclinical development of MK-2461 for cancer therapy.
Abstract A36: ImmunoSPECT and ImmunoPET imaging of IGF-1R expression in a model for triple negative breast cancer
Authors: Sandra Heskamp, Otto C. Boerman, Wim J.G. Oyen, Janneke D.M. Molkenboer-Kuenen, Winette T.A. van der Graaf, Hanneke W.M. van Laarhoven
Journal: Clinical Cancer Research (2010)

Abstract Introduction: Triple negative breast cancer has a poor prognosis and chemotherapy is currently the mainstay of treatment. A potential new target for the treatment of triple negative breast cancer is the insulin-like growth factor 1 receptor (IGF-1R). Patients with triple negative breast cancer lesions that express the IGF-1R (30 to 40%) may be most suited to be treated with IGF-1R antibodies. Therefore, the aim of the present study was to develop a noninvasive, in vivo imaging method, using radiolabeled R1507, to visualize IGF-1R expression. Material and methods: R1507, a monoclonal antibody directed against an epitope on the extracellular domain of the IGF-1R, was radiolabeled with 111Indium (111In), 125Iodine (125I) and 89Zirconium (89Zr). In vitro, the affinity and internalization kinetics of 111In-R1507 were determined using the IGF-1R expressing breast cancer cell line SUM149 (ER, PR and HER2 negative). In vivo studies were performed in BALB/c nude mice with subcutaneous SUM149 xenografts. To determine the pharmacodynamics of R1507, mice received an intravenous injection of 111In-R1507 and 125I-R1507. One, three and seven days post injection, mice were killed and ex vivo tumor uptake was measured. Non-specific uptake was determined by coinjection of an excess unlabeled R1507. A dose escalation study was performed with 111In-R1507 to determine the optimal protein dose of R1507 for in vivo imaging (dose range 1 – 1000 μg). Finally, SPECT and PET images were acquired of mice with subcutaneous SUM149 tumors one, three and seven days post injection of 111In-R1507 and 89Zr-R1507, respectively. Results: 111In-R1507 (IC50 = 0.1 nM) was slowly internalized by SUM149 cells. 111In-R1507 specifically and efficiently accumulated in the SUM149 xenografts: the specific tumor uptake was 20% ID/g, 33% ID/g and 31% ID/g at one, three and seven days post injection, respectively. The dose escalation study showed that the optimal dose for imaging experiments was ≤ 3 μg (tumor uptake: 35% ID/g). MicroSPECT and microPET imaging of mice clearly visualized the subcutaneous SUM149 xenograft with increasing contrast at later time points. Conclusion: 111In-R1507 SPECT and 89Zr-R1507 PET are excellent methods to visualize IGF-1R expression in vivo in triple negative breast cancer xenografts. In the future, these techniques may enable selection of patients with triple negative breast cancer for IGF-1R targeted therapy. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A36
Spleen Scan in Histiocytic Lymphoma: Response to Therapy
Authors: VIDYA V. SAGAR, VINCENT DelDUCA, ROBERT L. MECKELNBURG
Journal: Clinical Nuclear Medicine (1979)

Spleen scan demonstration of space-occupying lesions in patients with histiocytic lymphoma is a sensitive but not a specific finding. However, response to therapy could be evaluated if pretreatment scans show welldefined space-occupying lesions and posttreatment scans showed resolution of those changes.
This column will make you slim
Authors: T. Dalrymple
Journal: BMJ (2011)

When I was a boy my mother had a book with the title Eat and Grow Beautiful . As my mother was already beautiful I could not see the point of her having the book but supposed that it was because of the author’s splendid name: Gayelord Hauser. For myself, I was disappointed that however much I ate I did not grow beautiful. Perhaps it was because I ate all the wrong things, such as chocolate biscuits. If I hadn’t eaten so many I should have been a film star by now.

All flesh is grass, of course, but few of us are a well tended lawn. Just how many of us are dissatisfied with ourselves, …