tbuckley/cabot-search huggingface dataset:
NOD1, a new player in cardiac function and calcium handling
Authors: Carmen Delgado, Gema Ruiz-Hurtado, Nieves Gómez-Hurtado, Silvia González-Ramos, Angelica Rueda, Gemma Benito, Patricia Prieto, Carlos Zaragoza, Esmerilda G. Delicado, Raquel Pérez-Sen, Maria Teresa Miras-Portugal, Gabriel Núñez, Lisardo Boscá, Maria Fernández-Velasco
Journal: Cardiovascular Research (2015)

Inflammation is a significant contributor to cardiovascular disease and its complications; however, whether the myocardial inflammatory response is harmonized after cardiac injury remains to be determined. Some receptors of the innate immune system, including the nucleotide-binding oligomerization domain-like receptors (NLRs), play key roles in the host response after cardiac damage. Nucleotide-binding oligomerization domain containing 1 (NOD1), a member of the NLR family, is expressed in the heart, but its functional role has not been elucidated. We determine whether selective NOD1 activation modulates cardiac function and Ca(2+) signalling.Mice were treated for 3 days with the selective NOD1 agonist C12-iE-DAP (iE-DAP), and cardiac function and Ca(2+) cycling were assessed. We found that iE-DAP treatment resulted in cardiac dysfunction, measured as a decrease in ejection fraction and fractional shortening. Cardiomyocytes isolated from iE-DAP-treated mice displayed a decrease in the L-type Ca(2+) current, [Ca(2+)]i transients and Ca(2+) load, and decreased expression of phospho-phospholamban, sarcoplasmic reticulum-ATPase, and Na(+)-Ca(2+) exchanger. Furthermore, iE-DAP prompted 'diastolic Ca(2+) leak' in cardiomyocytes, resulting from increased Ca(2+) spark frequency and RyR2 over-phosphorylation. Importantly, these iE-DAP-induced changes in Ca(2+) cycling were lost in NOD1(-/-) mice, indicating that iE-DAP exerts its actions through NOD1. Co-treatment of mice with iE-DAP and a selective inhibitor of NF-κB (BAY11-7082) prevented cardiac dysfunction and Ca(2+) handling impairment induced by iE-DAP.Our data provide the first evidence that NOD1 activation induces cardiac dysfunction associated with excitation-contraction coupling impairment through NF-κB activation and uncover a new pro-inflammatory player in the regulation of cardiovascular function.
Successful Therapy of Previously Intractable Gout.
Authors: Elmer C. Bartels
Journal: Annals of Internal Medicine (1966)

s1 May 1966Successful Therapy of Previously Intractable Gout.Elmer C. Bartels, M.D., F.A.C.P.Elmer C. Bartels, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-64-5-1173_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThree phases of gout management have now been well delineated—the preuricosuric, the uricosuric, and the anti-uric acid. During the first phase satisfactory control was not possible so therapy was chiefly symptomatic. With the advent of the uricosuric drugs, control of gout in almost all patients was feasible; reversible changes (decrease in size of tophi and bone recalcification) were observed in those with advanced tophaceous gout. In patients with associated gouty nephritis or complicating renal disease (nephrosclerosis, glomerulonephritis, pyelonephritis) gout commonly remained uncontrolled since usually a satisfactory uricosuric response could not be accomplished. There were some patients who could not tolerate... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Massachusetts PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByPyrazoles I. Synthesis of 4-Hydroxpyrazolo[3,4-d]-v-triazine A New Analog of Hypoxanthine 1 May 1966Volume 64, Issue 5Page: 1173-1173KeywordsBoneDrug regulationGlomerulonephritisGoutNephritisPyelonephritisRenal diseases Issue Published: 1 May 1966 PDF DownloadLoading ...
THE OPEN HOSPITAL
Authors: Henry S. Stark
Journal: JAMA (1925)

<h3>To the Editor:</h3> —I read with keen interest Dr. Goldwater's article inThe Journal, March 28, on the question of the open door in our hospitals. In this message he succinctly defines his attitude on the matter in his closing sentence when he announces that "their duty is plain—they must open wide the door of opportunity, so that the entire medical profession may enter in." That the stand taken by Dr. Goldwater is no innovation in hospital management is made clear by the perusal of an article in the same issue by Homer F. Sanger of Chicago, who epitomizes his survey of the question with a citation that "the 100 general hospitals that were opened in 1924 show seven open to one closed. The tendency, therefore, is rapidly toward the establishing of more hospitals with open staffs." These two articles bear eloquent testimony to the dissatisfaction of the profession with
Abstract 3045: Defining an elusive multiple myeloma stem cell population in mice
Authors: Joshua Kellner, Yunpeng Hua, Bei Liu, Zihai Li
Journal: Cancer Research (2014)

Abstract Multiple Myeloma (MM) is a debilitating disease of proliferating and malignant plasma cells that is currently incurable. The ability of monoclonal recurrence of disease suggests it might arise from a stem cell-like population capable of self-renewal. The difficulty to isolate the cancer stem-like cell in MM in both mice and men has introduced confusion toward this hypothesis. XBP1s is a key positive regulator for unfolded protein response and a master transcription factor for plasma cell development. It was previously reported that transgenic overexpression of XBP1s in the B cell lineage of mice (XBP1s-Tg), induces a multiple myeloma phenotype resembling human MM. We have now defined a post-germinal center, pre-plasma B cell population that was significantly increased in XBP1s-Tg mice as the hallmarks of MM was demonstrated. This non-memory B cell population resembled a stem/progenitor cell population, with increased expression of aldehyde dehydrogenase (ALDH), Notch1 and c-kit. Importantly, utilizing an in vitro culture for differentiating plasma cells, the increased population began to differentiate into plasma cells, increasing in size and gaining CD138 expression, the hallmark marker for plasma cells. In conclusion, we have defined a transitional pre-plasma cell population that could potentially be a stem/progenitor population of multiple myeloma. These results provide a novel insight into stem cell biology with regard to multiple myeloma and the use of murine models of myeloma to study the disease. Citation Format: Joshua Kellner, Yunpeng Hua, Bei Liu, Zihai Li. Defining an elusive multiple myeloma stem cell population in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3045. doi:10.1158/1538-7445.AM2014-3045
Fetal Malformations Following Anti-Cancer Therapy During Pregnancy-Reply
Authors: Charles L. Murray
Journal: JAMA (1985)

<h3>In Reply.—</h3> Another analysis by Schapira and Chudley<sup>1</sup>found nine (12.7%) of 71 patients receiving combination chemotherapy during the first trimester had children born with fetal malformations. I agree with Dr Savlov that this risk is not small, but it is "small" when compared with the incidence of malformations observed in animal studies, which at times exceeds 50%. Ideally, no patient should receive cancer chemotherapy drugs during the first trimester of pregnancy. When it has occurred, or when it is essential that such therapy is given, termination of pregnancy is offered. Our data were presented to give guidance in the management of patients who are reluctant to consider, or who refuse, termination of pregnancy.
Abstract 2243: Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach.
Authors: Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Daniel Simard, Maria Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Hui Cao, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Francisco Adrian, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron J. Morris
Journal: Cancer Research (2013)

Abstract Activating KRAS mutations are oncogenic and prevalent in multiple tumor types, being found in as high as 90% of pancreatic carcinomas and 50% of colorectal carcinomas. In spite of its attractiveness for therapeutic intervention to date no KRAS-targeted drug therapies have been approved. Most of the reported mutant KRAS directed cellular screening efforts utilize 2-dimensional assays. Because mutant KRAS driven tumor cell lines are much more strongly dependent on activated K-Ras signaling for anchorage independent growth relative to growth when anchored to plastic, we report herein a screening strategy that leverages a 3-dimensional clonogenic growth assay in soft agar. We have performed a multi-cell line parallel phenotypic high throughput screen with our proprietary compound collection to identify pathways, targets and chemical matter with selective anti-tumor activity in mutant KRAS dependent cell lines - a Synthetic Lethal approach. Our strategy has led to the identification of several chemical classes that inhibit the growth of multiple mutant KRAS cell lines of pancreatic and colorectal carcinoma origin, while sparing multiple wild-type KRAS cancer cell lines. Studies to elucidate their molecular mechanisms of action are underway. Citation Format: Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Daniel Simard, Maria Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Hui Cao, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Francisco Adrian, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron J. Morris. Clonogenic 3D high throughput screening in mutant KRAS dependent cancer cells - a chemogenomic approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2243. doi:10.1158/1538-7445.AM2013-2243
The FIP1L1-PDGFRA fusion gene and the KIT D816V mutation are coexisting in a small subset of myeloid/lymphoid neoplasms with eosinophilia
Authors: Annette Hildegard Schmitt-Graeff, Philipp Erben, Juliane Schwaab, Beate Vollmer-Kary, Georgia Metzgeroth, Karl Sotlar, Hans-Peter Horny, Hans-H Kreipe, Paul Fisch, Andreas Reiter
Journal: Blood (2014)
Echocardiography: M-Mode and Two-Dimensional Methods
Authors: RICHARD L. POPP
Journal: Annals of Internal Medicine (1980)

We review the basic similarities and differences of currently used M-mode and two-dimensional (2D) echocardiography. Discrete categories of disease are used to show the relative strengths of M-mode and 2D methods. The format of 2D echocardiography is well suited to analyze congenital heart disease, consequences of coronary artery disease, and distortions of anatomy due to acquired heart disease. Rapid structure movement is preserved with M-mode recording, facilitating detailed analysis of motion. The vast clinical experience with M-mode echocardiography can now be augmented by 2D echocardiography, but combination of 2D and M-mode methods is optimal for understanding each type of ultrasound recording and for best serving the patient.
Making sense of risk information on the web
Authors: S. Woloshin
Journal: BMJ (2003)

Don't forget the basics 

Web based risk calculators are among the newest information resources available to people who want to understand the health risks they face. The advantage of these calculators is their ability to generate tailored risk information based on personal factors. But their usefulness depends on their accuracy and whether they are complete or balanced. To focus on the second issue, we present a hypothetical case history highlighting some elements of good (and not so good) risk communication.

The case: Mr Jones is a 55 year old white man worried about prostate cancer after reading about a politician who had recently been diagnosed with the disease. His first search effort–using the Google search engine to look for “prostate cancer and risk calculator” yields 8410 hits. The first hit (http://www.yourcancerrisk.harvard.edu/) seems perfect. This asks him questions about himself and, based on his age, ethnic group, family history, height, vasectomy history (he had one), and dietary habits (he eats ext-link ≤5 servings of food with animal fat a day and ≤5 servings of tomato based foods a week), tells him his risk is above average. He is now even more worried and calls his doctor.

Mr Jones's doctor explains that three things are missing in this risk assessment: clarity about the risk, context, and an acknowledgment of uncertainty.

Clarity means knowing what specific risk is under consideration (is this about getting or dying …
Salmeterol Xinafoate as Maintenance Therapy Compared With Albuterol in Patients With Asthma
Authors: Gilbert E. D'Alonzo
Journal: JAMA (1994)

<h3>Objective.</h3> —To compare the efficacy and safety of inhaled salmeterol xinafoate, a long-acting β<sub>2</sub>-adrenoceptor agonist, with that of albuterol, a short-acting inhaled β<sub>2</sub>-agonist, in the treatment of asthma. <h3>Design.</h3> —Randomized, double-blind, placebo-controlled, parallel-group study. <h3>Setting.</h3> —Eleven outpatient clinical centers. <h3>Subjects.</h3> —A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy. <h3>Intervention.</h3> —Patients were treated with salmeterol xinafoate (42 μg inhaled twice daily), albuterol (180 μg inhaled four times daily), or placebo (four times a day) for 12 weeks; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms. <h3>Main Outcome Measures.</h3> —Serial 12-hour forced expiratory flow in 1 second (FEV<sub>1</sub>), peak expiratory flow (PEF), asthma symptoms, nocturnal awakenings due to asthma, episodes of asthma exacerbations, and electrocardiography. <h3>Results.</h3> —The mean area under the curve for FEV<sub>1</sub>throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart (<i>P</i>&lt;.001), with the difference ranging from 3.1 to 4.3 L·h. Salmeterol produced an average increase in morning and evening PEF of 26 and 29 L/min, respectively, over pretreatment values compared with decreases of —13 and —3 L/min, respectively, in the albuterol group and —2 L/min both in the morning and evening in the placebo group (<i>P</i>&lt;.001). Patients in the salmeterol group had significantly fewer days and nights with symptoms than did either the albuterol or placebo group (<i>P</i>&lt;.001). Responses to salmeterol were similar at day 1 and at week 12. Adverse events in all treatment groups were equally infrequent, and no clinically significant change in cardiac rhythm was observed with salmeterol treatment. <h3>Conclusion.</h3> —Salmeterol inhaled twice daily is more effective than albuterol inhaled four times a day (or as needed) in patients with asthma requiring maintenance therapy. No deterioration of asthma control was observed with the use of salmeterol over a 3-month period. (<i>JAMA</i>. 1994;271:1412-1416)
Nutlin-3a Is a Potential Therapeutic for Ewing Sarcoma
Authors: Kathleen I. Pishas, Fares Al-Ejeh, Irene Zinonos, Raman Kumar, Andreas Evdokiou, Michael P. Brown, David F. Callen, Paul M. Neilsen
Journal: Clinical Cancer Research (2010)

Although mutations in the TP53 gene occur in half of all cancers, approximately 90% of Ewing sarcomas retain a functional wild-type p53. The low frequency of TP53 alterations in Ewing sarcoma makes this tumor type an ideal candidate for p53-targeted therapies. In this study, we have examined the molecular and cellular responses of cultured Ewing sarcoma cell lines following exposure to Nutlin-3a, a recently developed MDM2 antagonist.The ability of Nutlin-3a to impart apoptosis or cell cycle arrest in a p53-dependent manner was determined in a comprehensive panel of Ewing sarcoma cell lines. The capacity of Nutlin-3a to augment the antitumor activity of MDM4 antagonists and cytotoxic agents currently used in the clinical treatment of Ewing sarcoma was also investigated.Apoptosis was the primary response of wild-type p53 expressing Ewing sarcoma cell lines. The cytotoxicity of Nultin-3a was also synergistic with the chemotherapeutic agents, vincristine, actinomycin D, doxorubicin, and etoposide in a concentration-dependent manner. Significant MDM4 protein overexpression was observed in Ewing sarcoma cell lines of wild-type p53 status, providing a mechanism through which Ewing sarcomas can develop in the absence of TP53 alterations. This study provides the first evidence of synergism between targeted inhibition of MDM2 and MDM4.Our findings suggest that p53-dependent apoptosis is the primary cellular response of Ewing sarcoma cell lines following exposure to Nutlin-3a. Furthermore, Nutlin-3a can synergize with the current Ewing sarcoma chemotherapy protocols, suggesting p53 activation as a novel systemic therapeutic approach for this disease.
Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection
Authors: Eric Lawitz, Greg Sullivan, Maribel Rodriguez-Torres, Michael Bennett, Fred Poordad, Mudra Kapoor, Prajakta Badri, Andrew Campbell, Lino Rodrigues, Yiran Hu, Tami Pilot-Matias, Regis A. Vilchez
Journal: Journal of Infection (2014)

To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naïve, non-cirrhotic adults with chronic HCV genotype 1-3 infection.Patients in this open-label, exploratory, phase 2, multicenter study received ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA < lower limit of quantitation (LLOQ) from week 4 through 12. Sustained virologic response 12 weeks post-treatment (SVR12) was a secondary endpoint.Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was<LLOQ from week 4 through 12 in 10 (100%; 95% CI 69-100), 9 (90%; 56-100), and 7 (70%; 35-93) receiving the RBV-containing regimen and 9 (90%; 56-100), 8 (80%; 44-97), and 2 (18%; 2-52) receiving the RBV-free regimen. Among genotype 1-, 2-, and 3-infected patients, respectively, SVR12 was achieved by 10 (100%), 8 (80%), and 5 (50%) receiving the RBV-containing regimen, and 6 (60%), 6 (60%), and 1 (9%) receiving the RBV-free regimen. The most common adverse events were fatigue, nausea, and headache. One patient discontinued due to an adverse event.In this study, ombitasvir and ABT-450/r ± RBV regimens were generally well-tolerated. Sustained virologic response was achieved in most patients with HCV genotype 1 or 2 infection, but low SVR rates were observed in HCV genotype 3-infected patients.
Abscess of the Cerebellum: Trephining: Death
Authors: R. J. Bryden
Journal: BMJ (1890)

DUIRING three years' clinical work at the German Hospital I had the opportunity of diagnosing and observing two cases of actino- mycosis hominis.The first case was of a comparatively simple nature.C. H., aged 45, a German teacher of music, suffered from a periosteal abscess on the left side of the lower jaw. 1 opened the abscess.The incision soon closed, but swelling and hard infiltra- tion remained and simulated malignant tumour.A fortnight afterwards I again let out some pus, and in it discovered the characteristic yellowish grains of actinomyces, which, under the microscope, showed both mycelium and clubs.A drainage tube was inserted into the wound, which, after two months, completely healed.I saw the man again one year afterwards.He was then in perfect health, no recurrence of the disease had taken place, and a hardly visible scar was all that was left of the former affection.The second case, which more especially forms the subject of this communication, was of a more complicated and serious character, and is, as far as I am aware, the first and only case up to this date in which actinomycosis of the brain was recognised as such during life, and also the first case in which trephining was resorted to for such an affection.E. H., a married woman, aged 40, suffered from pleurisy in the autumn of 1885.At the conmencement of the following year an
Impaired transforming growth factor signalling in Barrett's carcinogenesis due to frequent SMAD4 inactivation
Authors: Benjamin A Onwuegbusi, Alan Aitchison, Suet-Feung Chin, Tanja Kranjac, Ian Mills, Yinghui Huang, Pierre Lao-Sirieix, Carlos Caldas, Rebecca C Fitzgerald
Journal: Gut (2005)

<b>Background and aims:</b> Transforming growth factor β (TGF-β) is frequently involved in gastrointestinal carcinogenesis although its contribution to oesophageal adenocarcinoma (AC) and its precursor Barrett's oesophageal epithelium (BE) metaplasia are unclear. <b>Methods:</b> Expression of TGF-β signalling components was assessed by reverse transcription-polymerase chain reaction (PCR), western blot, and immunohistochemistry in oesophageal endoscopic biopsies and cell lines. Genomic alterations in <i>SMAD4</i> were characterised by fluorescence in situ hybridisation, methylation specific PCR, and sequencing. Functional integrity of TGF-β signalling was assessed by characterisation of p21 and proliferation status. Smad4 negative BIC-1 cells were transiently transfected with <i>smad4</i> and TGF-β responsiveness evaluated. <b>Results:</b><i>smad4</i> mRNA expression was progressively reduced in the metaplasia-dysplasia-adenocarcinoma sequence (p&lt;0.01). A quarter of AC samples displayed an abnormal Smad4 protein isoform, with no corresponding changes in gene sequence or organisation. Methylation of <i>smad4</i> has not been described previously but we found promoter methylation in 70% of primary AC samples. In 6/8 oesophageal cell lines, chromosomal rearrangements affected the <i>smad4</i> locus. Lack of <i>smad4</i> expression in BIC-1 cells occurred secondary to loss of one copy and extensive deletion of the second allele's promoter region. TGF-β dependent induction of p21 and downregulation of minichromosome maintenance protein 2 was lost in &gt;80% of BE and AC. TGF-β failed to inhibit proliferation in 5/8 oesophageal cell lines. In BIC-1, the antiproliferative response was restored following transient transfection of <i>smad4</i> cDNA. <b>Conclusions:</b> In BE carcinogenesis, downregulation of Smad4 occurs due to several different mechanisms, including methylation, deletion, and protein modification. Frequent alterations in TGF-β signalling lead to a functionally significant impairment of TGF-β mediated growth suppression.