tbuckley/cabot-search huggingface dataset:
Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone
Authors: Jens Hoffmann, Ilio Vitale, Bernd Buchmann, Lorenzo Galluzzi, Wolfgang Schwede, Laura Senovilla, Werner Skuballa, Sonia Vivet, Rosemarie B. Lichtner, José M. Vicencio, Theocharis Panaretakis, Gerhard Siemeister, Hermann Lage, Lisa Nanty, Stefanie Hammer, Kevin Mittelstaedt, Sebastian Winsel, Julia Eschenbrenner, Maria Castedo, Carine Demarche, Ulrich Klar, Guido Kroemer
Journal: Cancer Research (2008)

Abstract Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-XL, or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program. [Cancer Res 2008;68(13):5301–8]
A CASE OF BRONCHO-BILIARY FISTULA
Authors: A. G. Yates
Journal: BMJ (1922)

In mentioning these causes of failure I may-perhaps add *tthat a little practice and familiarity with the operation goes far to eliminate them, and I see far less of them now than formerly.With these few exceptions I have found the opera- tion entirely satisfactory.The children have nice supple active feet, permanently corrected, and they are from the beginning freed from the burden of instruments.PNEUMOCOCCAL INFLUENZA.
Sickle Cell Anemia, Stroke, and Transcranial Doppler Studies
Authors: J.P. Mohr
Journal: New England Journal of Medicine (1992)

In the 40 years after the first description of sickle cell disease in 1910, roughly a paper per decade described neurologic complications, including stroke, and attributed them to the likes of anemia, fever, meningitis, hemorrhage, and even cerebral fat embolism. Improvements in the diagnosis of sickle cell anemia allowed larger cohorts to be studied, and new techniques of brain imaging, first CT scans1 and then magnetic resonance imaging,2 , 3 have amply confirmed that stroke is a major problem in sickle cell disease, with a prevalence ranging from 5.5 percent1 to 17 percent.4 Infarction occurs mainly in younger patients, and hemorrhage in . . .
Ultrasonic identification of sources of gaseous microemboli during open heart surgery
Authors: E. G. Gallagher, D. T. Pearson
Journal: Thorax (1973)

An ultrasonic transducer was used to detect gaseous microemboli during open heart surgery. When placed over the carotid artery of patients during surgery it was recognized that gaseous emboli were released into the systemic circulation following recognizable surgical procedures and from the oxygenator during bypass. Fixation of the transducer on the arterial return from the oxygenator demonstrated that the two types of disposable bubble oxygenators and disc oxygenators tested delivered microbubbles in the arterial blood. Some factors affecting the number of bubbles released were recognized and are discussed. Case reports of two patients who received large volumes of gaseous microemboli from different sources are presented.
Primary amyloidosis associated with a novel heavy‐chain fragment (AH amyloidosis)
Authors: Alan Solomon, Deborah T. Weiss, Charles Murphy
Journal: American Journal of Hematology (1994)

Abstract Primary or AL amyloidosis occurs in patients with monoclonal plasma cell‐related disorders and is typically associated with the systemic deposition as amyloid fibrils of the light‐chain portion of the immunoglobulin molecule. Recently, the discovery that heavy chains could be involved in amyloid formation led to the designation of this type of disease process as AH amyloidosis. We have now identified a second example of heavy chain‐associated amyloidosis in a patient (MAD) who had a serum IgG monoclonal gammopathy and Bence Jones proteinuria. In this case, the renal and splenic amylold deposits consisted solely of the V H ‐D ‐encoded portion of the heavy polypeptide chain, in contrast to the first case, where the amyloid contained an immunoglobulin component composed of the entire heavy‐chain variable and third constant domains. In this respect, the chemical composition of the amyloid protein MAD differed not only from that of the first reported case of AH amyloidosis but from all other structurally abnormal components found in patients with heavy chain‐associated disease. The discovery that certain forms of heavy chains, as well as light chains, can form amyloid provides further information on the chemical basis of amyloidogenicity and the diverse nature of this disease. © 1994 Wiley‐Liss, Inc.
Treatment of periodontal disease in pregnancy
Authors: G. Macones
Journal: BMJ (2010)

Does not improve pregnancy outcomes, but should still be part of routine preventive care

Epidemiological studies have shown that clinical and subclinical periodontal infections during pregnancy are associated with preterm birth. Infection is thought to result in the release of proinflammatory cytokines, which have downstream effects on other biological pathways and tissues. The association was first noted for bacterial vaginosis in the 1980s and 1990s, and randomised controlled trials were then performed to assess whether screening and treating the infection during pregnancy would improve pregnancy outcomes. Most of these trials found no benefit, and such screening is not currently recommended.1 More recently, observational data have suggested that periodontal disease may also be linked to preterm birth and other adverse pregnancy outcomes.2 Several large clinical trials have since been performed to assess whether pregnancy outcomes can be improved with treatment⇓.



BSIP, LA/SPL

In the linked systematic review (doi:10.1136/bmj.c7017), Polyzos and …
The development of clinical knowledge. With a few words about targeted vs basic research
Authors: P. B. Beeson
Journal: JAMA (1977)

IN THIS symposium I have decided to concentrate on the development of new information about human disease, with special emphasis on the contribution that can be made by clinicians. My own career in academic medicine happens to have coincided with an era of extraordinary activity in biomedical research, in which change has been so rapid and continuous that even those of us who participated find difficulty in appreciating its extent. Here are just a few of the things I have witnessed: effective means for control of heart failure and hypertension, use of steroid hormones, renal dialysis and transplantation, ability to measure and correct fluid and electrolyte disturbances, development of techniques to make the diagnosis of fetal chromosomal abnormality, elimination of erythroblastosis, recognition of the role of lymphoid cells in immune phenomena, discovery of the functions of RNA and DNA (in fact, the whole field of molecular biology), curative treatments for
Favorable long-term outcomes of endoscopic submucosal dissection for locally recurrent early gastric cancer after endoscopic resection
Authors: Masau Sekiguchi, Haruhisa Suzuki, Ichiro Oda, Seiichiro Abe, Satoru Nonaka, Shigetaka Yoshinaga, Hirokazu Taniguchi, Shigeki Sekine, Ryoji Kushima, Yutaka Saito
Journal: Endoscopy (2013)

Close observation after noncurative endoscopic resection for early gastric cancer (EGC) is an acceptable option if a positive horizontal margin or piecemeal resection of differentiated-type adenocarcinoma is the only noncurative factor. When locally recurrent EGC is subsequently detected, endoscopic submucosal dissection (ESD) may be performed, although only limited research has been reported regarding the outcomes. We aimed to evaluate the effectiveness, safety, and long-term clinical outcomes of ESD performed for locally recurrent EGC.Endoscopic resection was performed in 3704 patients with a total of 4216 EGC lesions between January 1997 and December 2011 at our institution. During this period, 95 patients with 95 locally recurrent EGCs following their endoscopic resection underwent ESD performed by experts, which we retrospectively reviewed. The prior endoscopic resection procedures were endoscopic mucosal resection in 75 cases and ESD in 20.Of the 95 cases, en bloc resection was achieved in 90.5 %, R0 resection in 84.2 %, and curative resection in 81.1 %. Median procedure time was 70 minutes; no bleeding requiring blood transfusion was seen. There were six perforations (6.3 %), with one necessitating emergency surgery. Within a median follow-up period of 76.4 months (range, 10.5 - 170.0 months), second local recurrences occurred in three patients. Five-year overall and disease-specific survival rates were 92.8 % and 100 %, respectively.ESD was safe and effective with favorable long-term clinical outcomes for locally recurrent EGC following endoscopic resection.
CARDIAC TROPONINS AND NATRIURETIC PEPTIDES IN RUNNERS: USEFUL FOR CARDIAC RISK SCREENING?
Authors: C Le Goff, JF Kaux, M Fillet, P Mélon, E Cavalier
Journal: British Journal of Sports Medicine (2014)

Background Cardiac troponins (cTn) are considered as the best biomarkers for detection of myocardial cell injury and NT-proBNP as the best for the cardiac insufficiency. Objective Our aim was to compare cTnT and NT-proBNP levels before and after the stress tests, in sportive subjects. Design Prospective, cohort study. Setting Amateur marathon runners and ultrarunners. Patients 28 subjects (26 men, 42.5±11 yrs) were enrolled. Interventions Subjects ran the Maasmarathon (42.195 kilometers) and 33 subjects (33 men, 45.7±9.3 yrs) ran the Ultratour of Liège (Belgium; 67 km). All subjects gave their informed consent. We took blood sample before (T0), just after (T1) and 3 hours after the race (T3). Main outcome measurements cTnT concentrations were measured by high sensitive methods (hsTnT, Roche Diagnostics) on heparin plasma. The NT-proBNP was also determined with the kit Roche on heparin plasma. All statistical analyses were performed using Medcalc version 8.1 for Windows. P-value &lt;.01 was regarded as statistically significant. Results A significant difference between hsTnT concentrations at T0 and T1 (P&lt;.001), and between T0 and T3 (P&lt;.001) for NT-proBNP have been observed, but not between T1 and T3. This observation appeared only after a strenuous exercise. However, up to now this type of exercise is not reproducible easily in a laboratory. Moreover, nobody knows if these observations would have cardiac consequences at long terms. Conclusion Measurement of cardiac troponins by high sensitive methods allows detecting significant release of biomarkers from the heart during exercise. The value of NT-proBNP are also significant but less than TnThs. We think that the TnThs could be an interesting tool in the future to help sport medicine to detect risk of developing a cardiac problem in the future or a sudden death.
Unifying Concept of Pathology
Authors: W. G. Spector
Journal: BMJ (1969)

Reviewscanoe of the pulmonary vascular resistance in conditions with a left-to-right shunt.Thi.. is a situation where the society might be able to establish a uniform body of knowledge and practice.The deliberate exclusion of surgeons frwy the participants is a pity.Surgical tech- nique and postoperative care are often th- prime determinants of success or failure it a cardiac operation, and it would have beer good to learn about these aspects from thl surgeon himself.
Superiority of Frailty Over Age in Predicting Outcomes Among Geriatric Trauma Patients
Authors: Bellal Joseph, Viraj Pandit, Bardiya Zangbar, Narong Kulvatunyou, Ammar Hashmi, Donald J. Green, Terence O’Keeffe, Andrew Tang, Gary Vercruysse, Mindy J. Fain, Randall S. Friese, Peter Rhee
Journal: JAMA Surgery (2014)

The Frailty Index (FI) is a known predictor of adverse outcomes in geriatric patients. The usefulness of the FI as an outcome measure in geriatric trauma patients is unknown.To assess the usefulness of the FI as an effective assessment tool in predicting adverse outcomes in geriatric trauma patients.A 2-year (June 2011 to February 2013) prospective cohort study at a level I trauma center at the University of Arizona. We prospectively measured frailty in all geriatric trauma patients. Geriatric patients were defined as those 65 years or older. The FI was calculated using 50 preadmission frailty variables. Frailty in patients was defined by an FI of 0.25 or higher.The primary outcome measure was in-hospital complications. The secondary outcome measure was adverse discharge disposition. In-hospital complications were defined as cardiac, pulmonary, infectious, hematologic, renal, and reoperation. Adverse discharge disposition was defined as discharge to a skilled nursing facility or in-hospital mortality. Multivariate logistic regression was used to assess the relationship between the FI and outcomes.In total, 250 patients were enrolled, with a mean (SD) age of 77.9 (8.1) years, median Injury Severity Score of 15 (range, 9-18), median Glasgow Coma Scale score of 15 (range, 12-15), and mean (SD) FI of 0.21 (0.10). Forty-four percent (n = 110) of patients had frailty. Patients with frailty were more likely to have in-hospital complications (odds ratio, 2.5; 95% CI, 1.5-6.0; P = .001) and adverse discharge disposition (odds ratio, 1.6; 95% CI, 1.1-2.4; P = .001). The mortality rate was 2.0% (n = 5), and all patients who died had frailty.The FI is an independent predictor of in-hospital complications and adverse discharge disposition in geriatric trauma patients. This index should be used as a clinical tool for risk stratification in this patient group.
Multiple Cumulative Allergen Concentration Delivery for Nasal Allergen Challenge – a Refinement of the Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC) Protocol
Authors: Mena Soliman, Daniel Adams, Lisa Steacy, Louis-Philippe Boulet, Paul Keith, Harissios Vliagoftis, Susan Waserman, Helen Neighbour, Anne Ellis
Journal: Journal of Allergy and Clinical Immunology (2015)
Stiletto Heel Penetrating Fractures of the Skull
Authors: R. H. Ahmed
Journal: BMJ (1964)

Lupus Erythematosus-Gargouet al.MEDBIALJSHNALunusual manifestation of subacute lupus erythematosus without systemic evidence of the disease.It is not possible, on the basis of the evidence at hand, to decide whether the radicular syndrome results from a vascular lesion or is a manifestation of a primary reaction of nerve root or its myelin. SummaryThe case of a 32-year-old woman with a chronic polyneuropathy manifest as an anterior radicular syndrome is reported.Weakness evolved during a three-and-a-half-year period and was associated with high spinal-fluid protein, positive lupus erythematosus cells, and positive serum fluorescent antibody reaction.There was no evidence of systemic lupus.The possi- bility that lupus presents as an indolent disorder of nerve roots is suggested.
Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis.
Authors: M Shinohara, P J Thornalley, I Giardino, P Beisswenger, S R Thorpe, J Onorato, M Brownlee
Journal: Journal of Clinical Investigation (1998)

Methylglyoxal (MG), a dicarbonyl compound produced by the fragmentation of triose phosphates, forms advanced glycation endproducts (AGEs) in vitro. Glyoxalase-I catalyzes the conversion of MG to S-D-lactoylglutathione, which in turn is converted to D-lactate by glyoxalase-II. To evaluate directly the effect of glyoxalase-I activity on intracellular AGE formation, GM7373 endothelial cells that stably express human glyoxalase-I were generated. Glyoxalase-I activity in these cells was increased 28-fold compared to neo-transfected control cells (21.80+/-0.1 vs. 0. 76+/-0.02 micromol/min/mg protein, n = 3, P < 0.001). In neo-transfected cells, 30 mM glucose incubation increased MG and D-lactate concentration approximately twofold above 5 MM (35.5+/-5.8 vs. 19.6+/-1.6, P < 0.02, n = 3, and 21.0+/-1.3 vs. 10.0+/-1.2 pmol/ 10(6) cells, n = 3, P < 0.001, respectively). In contrast, in glyoxalase-I-transfected cells, 30 mM glucose incubation did not increase MG concentration at all, while increasing the enzymatic product D-lactate by > 10-fold (18.9+/-3.2 vs. 18.4+/- 5.8, n = 3, P = NS, and 107.1+/-9.0 vs. 9.4+/-0 pmol/10(6) cells, n = 3, P < 0.001, respectively). After exposure to 30 mM glucose, intracellular AGE formation in neo cells was increased 13.6-fold (2.58+/-0.15 vs. 0.19+/-0.03 total absorbance units, n = 3, P < 0.001). Concomitant with increased intracellular AGEs, macromolecular endocytosis by these cells was increased 2.2-fold. Overexpression of glyoxalase-I completely prevented both hyperglycemia-induced AGE formation and increased macromolecular endocytosis.
Predictive Factors of Restenosis After Coronary Implantation of Sirolimus- or Paclitaxel-Eluting Stents
Authors: Adnan Kastrati, Alban Dibra, Julinda Mehilli, Sandra Mayer, Susanne Pinieck, Jürgen Pache, Josef Dirschinger, Albert Schömig
Journal: Circulation (2006)

The efficacy of drug-eluting stents in reducing restenosis risk has not been uniform across patient subsets. Identifying predictive factors of restenosis may help improve outcomes after percutaneous coronary interventions.All patients who underwent successful implantation of sirolimus- or paclitaxel-eluting stents in native vessels for de novo lesions between August 2002 and December 2004 were eligible for this study. All data were prospectively collected. Angiographic restenosis was defined as diameter stenosis > or =50% at follow-up in the in-segment area. Target lesion revascularization was defined as any revascularization procedure involving the target lesion. Included in this study were 1845 patients with 2093 target lesions. Multivariable analysis showed that vessel size, final diameter stenosis, and drug-eluting stent type were the strongest predictors of restenosis. A 0.5-mm decrease in vessel size was associated with adjusted odds ratios (ORs) of 1.74 (95% CI, 1.31 to 2.32) for angiographic restenosis and 1.65 (95% CI, 1.22 to 2.23) for target lesion revascularization. A 5% increase in final diameter stenosis was associated with adjusted ORs of 1.30 (95% CI, 1.15 to 1.47) for angiographic restenosis and 1.18 (95% CI, 1.03 to 1.35) for target lesion revascularization. Compared with paclitaxel-eluting stent, sirolimus-eluting stent was associated with adjusted ORs of 0.60 (95% CI, 0.44 to 0.81) for angiographic restenosis and 0.67 (95% CI, 0.49 to 0.91) for target lesion revascularization.Vessel size and drug-eluting stent type are the most important predictors of angiographic and clinical restenosis, with drug-eluting stent type having a particular impact on restenosis of small coronary vessels.
Radiologic Estimation of Heart Volume-Reply
Authors: John S. Hanson
Journal: JAMA (1961)

<h3>To the Editor:—</h3> It is obviously true that any calculation involving linear mensuration can be no more accurate than the accuracy of the measurements themselves. However, Dr. Rawlings is "grossly" exaggerating the difficulties inherent in measuring the 3 diameters necessary for estimating radiological heart volume. In most adults and certainly in the vast majority of children, especially those with congenital heart disease, location of the pulmonary conus—left ventricular junction is usually obvious on a well-penetrated film. The problem of the pericardial fat pad is also a small one and can be obviated to a great extent with hard films. In criticizing the horizontal depth measurement, Dr. Rawlings cites the situation in which a decreased anteroposterior chest diameter gives a false sense of cardiac enlargement in the frontal view. It seems to me that one of the strongest arguments for utilizing 2-dimensional views and calculation of heart volume is precisely that
Bone Scintigraphy of Raynaudʼs Syndrome Secondary to Fibromuscular Dysplasia
Authors: Alexander Matthies, Susanne Meyka, Hans-Jürgen Biersack, Michael Reinhardt
Journal: Clinical Nuclear Medicine (2004)

The findings of bone scintigraphy in a 39-year-old woman with new-onset Raynaud's syndrome are presented. Shortly after being diagnosed with fibromuscular dysplasia, the patient developed bilateral Raynaud's syndrome of increasing severity accompanied by pain in all digits. In due course, 4-phase bone scintigraphy was performed to exclude possible arthritis. Imaging was done following intravenous injection of 740 MBq (20 mCi) Tc99m methylene diphosphonate (MDP).
Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback
Authors: Scott Thomson, Dingjiu Bao, Aihua Deng, Volker Vallon
Journal: Journal of Clinical Investigation (2000)

Nephron function is stabilized by tubuloglomerular feedback (TGF). TGF operates within the juxtaglomerular apparatus, sensing changes in tubular flow and eliciting compensatory changes in single nephron GFR (SNGFR). The mediator(s) of TGF remains unconfirmed. One theory is that ATP consumed in active transport by the macula densa leads to formation of adenosine, which causes glomerular vasoconstriction. We performed micropuncture in rats to test this hypothesis. Adenosine activity was manipulated by microperfusing nephrons with adenosine A1 receptor blocker, A1-agonist, or 5′-nucleotidase inhibitor. Effects on TGF were characterized by changes in TGF efficiency (the compensation for small perturbations in tubular flow) and by changes in the maximum range over which TGF can cause SNGFR to change. These data were further applied to generate TGF profiles [SNGFR versus late proximal flow (VLP)]. TGF efficiency was significantly reduced by blocking A1-receptors. TGF efficiency, TGF range, and the slope of the TGF profile (ΔSNGFR/ΔVLP) were all significantly reduced by blocking 5′-nucleotidase. When adenosine activity was clamped by combining 5′-nucleotidase inhibitor with A1-agonist to determine whether TGF requires adenosine to be present or to fluctuate, the TGF slope was reduced by 83%, indicating that adenosine activity must fluctuate for normal TGF to occur and that adenosine is a mediator of TGF.