tbuckley/cabot-search huggingface dataset:
Evaluation of Bromocriptine in the Treatment of Acute Severe Peripartum Cardiomyopathy
Authors: Karen Sliwa, Lori Blauwet, Kemi Tibazarwa, Elena Libhaber, Jan-Peter Smedema, Anthony Becker, John McMurray, Hatice Yamac, Saida Labidi, Ingrid Struman, Denise Hilfiker-Kleiner
Journal: Circulation (2010)

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that occurs in previously healthy women. We identified prolactin, mainly its 16-kDa angiostatic and proapoptotic form, as a key factor in PPCM pathophysiology. Previous reports suggest that bromocriptine may have beneficial effects in women with acute onset of PPCM.A prospective, single-center, randomized, open-label, proof-of-concept pilot study of women with newly diagnosed PPCM receiving standard care (PPCM-Std; n=10) versus standard care plus bromocriptine for 8 weeks (PPCM-Br, n=10) was conducted. Because mothers receiving bromocriptine could not breast-feed, the 6-month outcome of their children (n=21) was studied as a secondary end point. Blinded clinical, hemodynamic, and echocardiographic assessments were performed at baseline and 6 months after diagnosis. Cardiac magnetic resonance imaging was performed 4 to 6 weeks after diagnosis in PPCM-Br patients. There were no significant differences in baseline characteristics, including serum 16-kDa prolactin levels and cathepsin D activity, between the 2 study groups. PPCM-Br patients displayed greater recovery of left ventricular ejection fraction (27% to 58%; P=0.012) compared with PPCM-Std patients (27% to 36%) at 6 months. One patient in the PPCM-Br group died compared with 4 patients in the PPCM-Std group. Significantly fewer PPCM-Br patients (n=1, 10%) experienced the composite end point of poor outcome defined as death, New York Heart Association functional class III/IV, or left ventricular ejection fraction <35% at 6 months compared with the PPCM-Std patients (n=8, 80%; P=0.006). Cardiac magnetic resonance imaging revealed no intracavitary thrombi. Infants of mothers in both groups showed normal growth and survival.In this trial, the addition of bromocriptine to standard heart failure therapy appeared to improve left ventricular ejection fraction and a composite clinical outcome in women with acute severe PPCM, although the number of patients studied was small and the results cannot be considered definitive. Larger-scale multicenter and blinded studies are in progress to test this strategy more robustly.
The Country Doctor
Authors: J. O'Sullivan
Journal: BMJ (2010)

Doctors are now expected to see their role in a broader context than just their interaction with individual patients. They are encouraged to take an interest in the health consequences of global problems and to perform opportunistic testing on their patients to try to reduce the future burden of disease in the population. There is a point of view that society would benefit if the ministry of health were the most important department of state; and Balzac portrays this situation, in miniature, in The Country Doctor .

Benassis has been a successful Paris doctor but has decided to set up practice in a remote Alpine village near Grenoble. The village has a …
A cavitating pulmonary lesion with eosinophilia
Authors: Alastair Charles McGregor, Nyree Griffin, Ronan A Breen, William Newsholme
Journal: Thorax (2012)

A middle-aged individual of Ethiopian origin attended the emergency department with haemoptysis. The patient had no other significant medical problems and had not travelled for several years. The patient drank moderately and did not smoke but later admitted to chewing khat (a narcotic leaf) frequently over the past 6 months.

There were no significant findings on physical examination. Renal and liver function tests and C reactive protein were within normal limits, but a peripheral blood eosinophilia was noted (2.1×109/l). Serological tests for HIV, hepatitis B and C were negative. A poorly defined opacity was seen in the right lung on …
Prognosis of patients with chronic coronary artery disease and severe left ventricular dysfunction. The importance of myocardial viability
Authors: Jaroslav Meluzín, Jan Černý, Lenka Špinarová, Jiří Toman, Ladislav Groch, František Štětka, Milan Frélich, Petr Hude, Jan Krejčí, Lada Rambousková, Roman Panovský
Journal: European Journal of Heart Failure (2003)
Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-κB activation in rat hepatocytes
Authors: Masaki Kaibori, Kazushige Sakitani, Michio Oda, Yasuo Kamiyama, Yasuo Masu, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura
Journal: Journal of Hepatology (1999)
Two Single-Nucleotide Polymorphisms with Linkage Disequilibrium in the Human <i>Programmed Cell Death 5</i> Gene 5′ Regulatory Region Affect Promoter Activity and the Susceptibility of Chronic Myelogenous Leukemia in Chinese Population
Authors: Xi Ma, Guorui Ruan, Ying Wang, Qiyan Li, Ping Zhu, Ya-Zhen Qin, Jin-Lan Li, Yan-Rong Liu, Dalong Ma, Hongshan Zhao
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Chronic myelogenous leukemia (CML) is a disease characterized cytogenetically by the presence of the Philadelphia chromosome. Recent studies suggested that altered PDCD5 expression may have significant implications in CML progression. The aim of this study was to identify single-nucleotide polymorphisms (SNP) within the programmed cell death 5 (PDCD5) promoter region and show their functional relevance to PDCD5 expression as well as their genetic susceptibility to CML. Experimental Design: One hundred twenty-nine CML subjects and 211 healthy controls were recruited for identification of SNPs and subsequent genetic analysis. Luciferase reporter assays were carried out to show the functional significance of the SNPs located in the promoter region to PDCD5 expression. Real-time quantitative PCR and Western blot analysis were done to determine the expression differences of PDCD5 in CML patients with different genotypes. Results: Two SNPs were identified within the PDCD5 promoter. They are −27A&amp;gt;G and −11G&amp;gt;A (transcription start site as position 1), respectively. The complete linkage disequilibrium was found between these two polymorphisms. The frequencies of −27G+/−11A+ genotype and −27G/−11A allele were significantly higher in CML patients than in healthy controls (genotype: 26.36% versus 11.85%, χ2=11.75, P &amp;lt; 0.01; allele: 13.57% versus 6.40%, χ2 = 9.48, P &amp;lt; 0.01). Luciferase reporter assays revealed that the promoter with −27G/−11A had significantly lower transcriptional activity and could not be up-regulated after apoptotic stimulations compared with the promoter with −27A/−11G. PDCD5 expression analysis in mononuclear cells derived from CML patients and cell lines with different −27/−11 genotypes showed consistent results with the reporter assays. Conclusions: These data suggest that −27G/−11A is associated with reduced PDCD5 promoter activity and increased susceptibility to CML.
Discovery of novel src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma
Authors: Wei-Tien Tai, Chung-Wai Shiau, Pei-Jer Chen, Pei-Yi Chu, Hsiang-Po Huang, Chun-Yu Liu, Jui-Wen Huang, Kuen-Feng Chen
Journal: Hepatology (2013)

Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) is a major target of sorafenib and generates a series of sorafenib derivatives to search for potent SHP-1 agonists that may act as better anti-HCC agents than sorafenib. Sorafenib increases SHP-1 activity by direct interaction and impairs the association between the N-SH2 domain and the catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of sorafenib on SHP-1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and apoptosis, suggesting that sorafenib may affect SHP-1 by triggering a conformational switch relieving its autoinhibition. Molecular docking of SHP-1/sorafenib complex confirmed our findings in HCC cells. Furthermore, novel sorafenib derivatives SC-43 and SC-40 displayed more potent anti-HCC activity than sorafenib, as measured by enhanced SHP-1 activity, inhibition of p-STAT3, and induction of apoptosis. SC-43 induced substantial apoptosis in sorafenib-resistant cells and showed better survival benefits than sorafenib in orthotopic HCC tumors.In this study, we identified SHP-1 as a major target of sorafenib. SC-43 and SC-40, potent SHP-1 agonists, showed better anti-HCC effects than sorafenib in vitro and in vivo. Further clinical investigation is warranted.
Preoperative and perioperative chemotherapy with 5-fluorouracil as continuous infusion in operable breast cancer expressing a high proliferation fraction: cytotoxic treatment during the surgical phase
Authors: M. Colleoni, G. Curigliano, I. Minchella, G. Peruzzotti, F. Nolè, G. Mazzarol, G. Renne, L. Orlando, A. Rocca, P. Veronesi, M. Intra, G. Viale, M.T. Sandri, G. Severi, A. Goldhirsch
Journal: Annals of Oncology (2003)
THE ORIGIN AND STRUCTURE OF A FIBROUS TISSUE WHICH APPEARS IN LIVING CULTURES OF ADULT FROG TISSUES
Authors: George A. Baitsell
Journal: The Journal of Experimental Medicine (1915)

In living cultures of various kinds of adult frog tissues, which have been made according to the hanging drop method, there occurs, in many cases, a transformation of the plasma clot by which it becomes entirely changed from a typical fibrin net both in appearance and structure. The changes in the fibrin net generally begin when the culture is from two to three days old. During these changes it appears that the elements of the fibrin net fuse or consolidate, and as a result a great number of fine wavy fibrils are formed which unite to form wavy bundles of fibers, and these freely intertwine and anastomose as they ramify through the area of the plasma clot. The transformation of the fibrin net occurs first in the region of the clot which lies next to the imbedded tissue, gradually extends to the distal regions of the clot, and in time-as a rule in about two weeks-the entire plasma clot becomes changed from the fibrin net into a structure which to all appearances is identical with regular connective tissue. Photographs of both living and preserved cultures have been made to show the course of the transformation of the plasma clot and the development of the fibers. Experiments have been made which show that the fibers which are formed are not outgrowths of the imbedded tissue. Also they are not formed by an intracellular action, but arise directly by a transformation of the fibrin elements of the plasma clot. Experiments have been made which indicate that the transformation of the fibrin net will not occur unless it has come under the influence of living tissues or of living isolated cells. However, mechanical means, such as exerting tension on the clot with needles, may hasten the formation of the fibers. Also, in some cultures, movements of living isolated cells appear to aid in the formation of the fibers. The living tissues alone, however, are able to cause the fibers to form without the aid of any apparent mechanical factor. This is shown by cultures of various tissues in which no cell movement occurs and in which the plasma clot is undisturbed and yet a prolific formation of fibers may take place. Experiments have been made in order to determine the true nature of the transformed plasma clot and to see if the new fibrous tissue were still fibrin in character. The results that have so far been obtained from these tests have not been entirely conclusive and leave the question unsettled. The transformation of the fibrin net results in a shrinkage of the clot. It also becomes very tough and resistant to injury and, therefore, entirely different from the fragile and easily destroyed fibrin net when in its original condition. It is believed that such a reaction must play an important part in wound healing. A study of the relation between connective tissue fibers formed in wound healing and in embryonic development to the fibers formed in the plasma clot is being made, and the results will appear in a later paper.
A Way Forward on the Medically Appropriate Use of White Cell Growth Factors
Authors: Thomas J. Smith, Bruce E. Hillner
Journal: Journal of Clinical Oncology (2012)

Are Hematopoietic Colony-Stimulating Factors Overor Underused? Since their introduction, there has been debate about the benefits, risks, and costs of hematopoietic colony-stimulating factors (CSFs). We suggest that the use of CSFs to allow dose maintenance of chemotherapy for common metastatic solid tumors is unsupported by evidence, and we should reconsider using a $3,500-per-cycle injection for a supportive care drug without major benefit. Recent studies have documented concerns about appropriate CSF use. Potosky et al prospectively identified 1,849 patients with lung or colorectal cancer who received palliative chemotherapy from 2003 to 2005. Only 17% of high-risk patients received appropriate primary prophylaxis. CSFs were used to maintain dose-intensity in 257 patients, of whom 18% were at intermediate risk (10% to 20% risk) and 10% were at low risk ( 10% risk) of febrile neutropenia (FN). Compared with American Society of Clinical Oncology (ASCO) guidelines (Table 1), 96% of CSF use can be judged not appropriate. Two reports from Ramsey et al are relevant. The first found that in 2,728 patients with cancer at low risk of FN, 10% of those with breast, 7% of those with colorectal, and 21% of those with non–smallcell lung cancers received CSFs. Most use did not conform to product labeling or practice guidelines. The second linked Puget Sound Cancer Registry data with insurance claims from four payers representing 75% of those insured from 2002 to 2005 and found no evidence that CSF as primary prophylaxis was associated with a reduction in antibiotic use or inpatient or outpatient visits in breast, colorectal, or non– small-cell lung cancer. Kuderer et al rebutted that CSFs were perhaps underused. They argue that “initiation of the CSFs early in the first cycle of chemotherapy and continuation through all cycles of a chemotherapy regimen (primary prophylaxis) has been shown to substantially reduce the risk of FNaswellas infection-relatedandearlyall-causemortality,whiledecreasing the need for chemotherapy dose reductions and delays,” without referring to any specific cancer types.
Tumor Suppressor NF2/Merlin Is a Microtubule Stabilizer
Authors: Zlatko Smole, Claudio R. Thoma, Kathryn T. Applegate, Maria Duda, Katrin L. Gutbrodt, Gaudenz Danuser, Wilhelm Krek
Journal: Cancer Research (2013)

Abstract Cancer-associated mutations in oncogene products and tumor suppressors contributing to tumor progression manifest themselves, at least in part, by deregulating microtubule-dependent cellular processes that play important roles in many cell biological pathways, including intracellular transport, cell architecture, and primary cilium and mitotic spindle organization. An essential characteristic of microtubules in the performance of these varied cell processes is their ability to continuously remodel, a phenomenon known as dynamic instability. It is therefore conceivable that part of the normal function of certain cancer-causing genes is to regulate microtubule dynamic instability. Here, we report the results of a high-resolution live-cell image-based RNA interference screen targeting a collection of 70 human tumor suppressor genes to uncover cancer genes affecting microtubule dynamic instability. Extraction and computational analysis of microtubule dynamics from EB3-GFP time-lapse image sequences identified the products of the tumor suppressor genes NF1 and NF2 as potent microtubule-stabilizing proteins. Further in-depth characterization of NF2 revealed that it binds to and stabilizes microtubules through attenuation of tubulin turnover by lowering both rates of microtubule polymerization and depolymerization as well as by reducing the frequency of microtubule catastrophes. The latter function appears to be mediated, in part, by inhibition of hydrolysis of tubulin-bound GTP on the growing microtubule plus end. Cancer Res; 74(1); 353–62. ©2013 AACR.
EXPERIMENTAL ZOSTERIFORM HERPES SIMPLEX VIRUS INFECTION IN MOUSE SKIN
Authors: T. W. E. ROBINSON, J. R. DOVER
Journal: British Journal of Dermatology (1972)

SUMMARY.— A highly reproducible model in which linear zosteriform lesions are produced in the skin of Webster Schneider mice, using an oral strain of herpes simplex virus, (HSV) is described. The incidence of infection is high, and a large proportion of infected animals develop a highly characteristic ascending paralysis which is invariably fatal.
Superior Mesenteric Artery Syndrome in Type 1 Diabetes Masquerading as Gastroparesis
Authors: Luigi F. Meneghini, Anthony R. Hogan, Gennaro Selvaggi
Journal: Diabetes Care (2008)

To describe and discuss a case of superior mesenteric artery syndrome (SMAS) presenting with gastrointestinal signs and symptoms mistakenly attributed to, and treated as, diabetic gastroparesis.A case report was compiled describing the clinical presentation, including history and physical examination, evaluation, diagnosis, and treatment of a patient with type 1 diabetes presenting with gastrointestinal complications.Clinical suspicion combined with the appropriate radiological evaluation led to a diagnosis of SMAS, with classic findings of reduced aortomesenteric angle and distance. Surgical intervention resulted in resolution of symptoms and recovery of glycemic control.The possibility of SMAS should be considered in patients with type 1 diabetes presenting with gastrointestinal symptomatology, especially when associated with weight loss.
Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus
Authors: Federica Facciotti, Gundimeda S Ramanjaneyulu, Marco Lepore, Sebastiano Sansano, Marco Cavallari, Magdalena Kistowska, Sonja Forss-Petter, Guanghui Ni, Alessia Colone, Amit Singhal, Johannes Berger, Chengfeng Xia, Lucia Mori, Gennaro De Libero
Journal: Nature Immunology (2012)
A Cluster Randomized Trial of Decision Support Strategies for Reducing Antibiotic Use in Acute Bronchitis
Authors: Ralph Gonzales, Tammy Anderer, Charles E. McCulloch, Judith H. Maselli, Frederick J. Bloom, Thomas R. Graf, Melissa Stahl, Michelle Yefko, Julie Molecavage, Joshua P. Metlay
Journal: JAMA Internal Medicine (2013)

<h3>Background</h3>National quality indicators show little change in the overuse of antibiotics for uncomplicated acute bronchitis. We compared the effect of 2 decision support strategies on antibiotic treatment of uncomplicated acute bronchitis.<h3>Methods</h3>We conducted a 3-arm cluster randomized trial among 33 primary care practices belonging to an integrated health care system in central Pennsylvania. The printed decision support intervention sites (11 practices) received decision support for acute cough illness through a print-based strategy, the computer-assisted decision support intervention sites (11 practices) received decision support through an electronic medical record–based strategy, and the control sites (11 practices) served as a control arm. Both intervention sites also received clinician education and feedback on prescribing practices, as well as patient education brochures at check-in. Antibiotic prescription rates for uncomplicated acute bronchitis in the winter period (October 1, 2009, through March 31, 2010) following introduction of the intervention were compared with the previous 3 winter periods in an intent-to-treat analysis.<h3>Results</h3>Compared with the baseline period, the percentage of adolescents and adults prescribed antibiotics during the intervention period decreased at the printed decision support intervention sites (from 80.0% to 68.3%) and at the computer-assisted decision support intervention sites (from 74.0% to 60.7%) but increased slightly at the control sites (from 72.5% to 74.3%). After controlling for patient and clinician characteristics, as well as clustering of observations by clinician and practice site, the differences for the intervention sites were statistically significant from the control sites (P = .003 for control sites vs printed decision support intervention sites and P = .01 for control sites vs computer-assisted decision support intervention sites) but not between themselves (P = .67 for printed decision support intervention sites vs computer-assisted decision support intervention sites). Changes in total visits, 30-day return visit rates, and proportion diagnosed as having uncomplicated acute bronchitis were similar among the study sites.<h3>Conclusions</h3>Implementation of a decision support strategy for acute bronchitis can help reduce the overuse of antibiotics in primary care settings. The effect of printed vs computer-assisted decision support strategies for providing decision support was equivalent.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00981994
Inter-relationship between tumour necrosis factor-alpha (TNF-alpha ) and TNF soluble receptors in pulmonary sarcoidosis
Authors: L. Armstrong, N. M Foley, A. B Millar
Journal: Thorax (1999)

<h3>BACKGROUND</h3> The importance of tumour necrosis factor-alpha (TNF-α) in the pathogenesis of pulmonary sarcoidosis has remained uncertain because of the paucity of clinical features associated with excessive levels of this cytokine. Increased levels of soluble TNF receptors (TNF-R), which are known to inhibit TNF-α activity, were recently described in the lungs of subjects with sarcoidosis. We hypothesised that TNF-α bioactivity may be inhibited in sarcoidosis by the presence of TNF-R. A study was therefore undertaken to investigate for the first time the relationship between soluble receptors and TNF-α bioactivity in the lungs of subjects with sarcoidosis. <h3>METHODS</h3> Alveolar macrophages (AMs) from 16 subjects with histologically proven sarcoidosis and 13 healthy controls were cultured in the presence and absence of lipopolysaccharide (LPS). The subjects with sarcoidosis were grouped by radiological assessment into stage I (n = 6) and stage II/III (n = 10). The cell culture supernatants and bronchoalveolar lavage (BAL) fluid were assayed for TNF bioactivity using the WEHI 164 clone 13 assay. Immunoreactive (bound and free) TNF-α and free TNF-Rs (p55 and p75) were determined by ELISA. <h3>RESULTS</h3> Bioactive TNF-α was undetectable in the BAL fluid of all the subjects with sarcoidosis and most of the healthy controls. However, there was significantly more immunoreactive TNF-α in the BAL fluid from subjects with sarcoidosis than from the controls (median values 0.304 ng/ml and 0.004 ng/ml, respectively, 95% CI 0.076 to 0.455, p&lt;0.001). The levels of both p55 and p75 in the BAL fluid were higher in both sarcoidosis groups than in the controls (p&lt;0.0005 and p&lt;0.001, respectively). In LPS stimulated AM supernatants reduced TNF-α bioactivity was seen in subjects with stage I sarcoidosis compared with those with stage II/III disease and healthy controls (median 0.333 ng/ml vs 1.362 ng/ml and 2.385 ng/ml, respectively, p&lt;0.01). This contrasted with increased p55 levels in the AM supernatants derived from subjects with stage I sarcoidosis compared with those with stage II/III disease and healthy controls (median 0.449 ng/ml vs 0.058 ng/ml and 0.078 ng/ml, respectively, p&lt;0.01). The levels of p75 were increased in unstimulated AM cultures in subjects with stage II/III disease compared with those with stage I disease and healthy controls (median 0.326 ng/ml vs 0.064 ng/ml and 0.102 ng/ml, p&lt;0.05). <h3>CONCLUSIONS</h3> These results indicate that TNF-α bioactivity may be inhibited by increased soluble TNF-R in the lungs of subjects with sarcoidosis, and this inhibition may be greater in patients with stage I sarcoidosis than in those with stage II/III disease. This may represent a homeostatic mechanism which protects the lung from excessive TNF production characteristic of chronic inflammation.