tbuckley/cabot-search huggingface dataset:
Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C<sup>+</sup>macrophage infiltration in mice
Authors: Christer Baeck, Xiao Wei, Matthias Bartneck, Viktor Fech, Felix Heymann, Nikolaus Gassler, Kanishka Hittatiya, Dirk Eulberg, Tom Luedde, Christian Trautwein, Frank Tacke
Journal: Hepatology (2014)

Macrophages constitute a major proinflammatory component during chronic liver diseases and are considered a key factor in promoting hepatic fibrosis. However, there is increasing evidence that distinct monocyte and macrophage subsets exert critical functions in regression from organ fibrosis as well. Experimental mouse models of fibrosis regression have identified “restorative” macrophages as Ly-6C (Ly6C, Gr1) low-expressing, monocyte-derived cells. We investigated molecular pathways balancing proinflammatory and restorative macrophages during fibrosis regression as well as pharmacologically augmenting beneficial macrophage functionality in fibrosis resolution. Therefore, we employed a Spiegelmer-based inhibitor of the chemokine, C-C motif chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1), termed mNOX-E36, in the regression phase of two murine models of toxic (CCl4) and metabolic (methionine-choline–deficient diet) liver fibrosis. Although inflammation rapidly declined after cessation of injury, we observed a transient influx of Ly-6C+ infiltrating monocytes (iMΦ), which are characterized by typical macrophage morphology, up-regulated expression of CCR2, and the pro-inflammatory cytokine, tumor necrosis factor (TNF), in injured liver. By inhibiting the early influx of Ly-6C+ iMΦ by the CCL2 inhibitor, mNOX-E36, the intrahepatic macrophage equilibration shifted toward the “restorative” Ly-6C- subset of iMΦ. Consequently, fibrosis resolution was significantly accelerated upon mNOX-E36 administration in both models. Blocking transient recruitment of infiltrating Ly-6C+ monocytes, but not direct effects of the inhibitor on the remaining macrophages, resulted in reduced intrahepatic levels of proinflammatory cytokines. Conclusion: Transient CCL2-dependent recruitment of infiltrating Ly-6C+ monocytes during fibrosis regression counteracts scar resolution by perpetuating inflammatory reactions through release of proinflammatory cytokines such as TNF. Pharmacological inhibition of Ly-6C+ monocyte recruitment using the CCL2-inhibitor, mNOX-E36, accelerates regression from toxic and metabolic liver fibrosis in two independent experimental models. (Hepatology 2014;59:1060–1072)
Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage–induced apoptosis
Authors: Annemiek D. Tepper, Evert de Vries, Wim J. van Blitterswijk, Jannie Borst
Journal: Journal of Clinical Investigation (1999)

To evaluate the role of ceramide (Cer) in apoptosis signaling, we examined Cer formation induced by CD95, etoposide, or γ-radiation (IR) in relation to caspase activation and mitochondrial changes in Jurkat T cells. The Cer response to all three stimuli was mapped in between caspases sensitive to benzoyloxycarbonyl-VAD-fluoromethylketone (zVAD-fmk) and acetyl-DEVD-aldehyde (DEVD-CHO). Cer production was independent of nuclear fragmentation but associated with the occurrence of other aspects of the apoptotic morphology. Caspase-8 inhibition abrogated Cer formation and apoptosis induced by CD95 but did not affect the response to etoposide or IR, placing CD95-induced Cer formation downstream from caspase-8 and excluding a role for caspase-8 in the DNA damage pathways. CD95 signaling to the mitochondria required caspase-8, whereas cytochrome c release in response to DNA damage was caspase-independent. These results indicate that the caspases required for the Cer response to etoposide and IR reside at or downstream from the mitochondria. Bcl-2 overexpression abrogated the Cer response to etoposide and IR and reduced CD95-induced Cer accumulation. We conclude that the Cer response to DNA damage fully depends on mitochondrion-dependent caspases, whereas the response to CD95 partially relies on these caspases. Our data imply that Cer is not instrumental in the activation of inducer caspases or signaling to the mitochondria. Rather, Cer formation is associated with the execution phase of apoptosis.
Failure of Disodium Etidronate in Calcinosis Due to Dermatomyositis and Scleroderma
Authors: Allan L. Metzger, Frederick R. Singer, Rodney Bluestone, Carl M. Pearson
Journal: New England Journal of Medicine (1974)

DISODIUM etidronate has been reported to be effective in the management of calcification due to myositis ossificans progressiva1 , 2 and dermatomyositis.3 , 4 We have evaluated the efficacy of this agent in the treatment of ectopic calcification due to dermatomyositis and scleroderma in six patients for periods up to one year.Patients and ProtocolThree patients with ectopic calcification due to dermatomyositis and three with calcinosis secondary to scleroderma were studied. The respective diagnoses of these two disorders were based on well established criteria. The clinical details of the patients are summarized in Table 1. The extent of calcinosis was assessed by careful clinical . . .
Pitfalls of Regional Cerebral Blood Flow Analysis in Cerebrovascular Disease
Authors: HANS L. LAGREZE, ROSS L. LEVINE, JOHN S. SUNDERLAND, ROBERT J. NICKLES
Journal: Clinical Nuclear Medicine (1988)

In 20 patients with unilateral cerebrovascular disease, regional cerebral blood flow (rCBF) was measured by F-18-fluoromethane inhalation and positron emission tomography (PET). The purpose was to study various strategies of rCBF data analysis that are currently used in SPECT and PET. Methods of quantitative data analysis standardize rCBF values relative to an intraindividual reference, and thus create ratios as estimators of rCBF in the ischemic regions-of-interest (ROI). These ratios were compared as well as the absolute rCBF values in the ischemic ROI graphically and by Spearman's rank correlation coefficient (r). The results demonstrated that previously reported methods of data analysis failed to represent rCBF in the ischemic ROI; r values were 0.467, -0.406, -0.453, and 0.329, respectively (N.S.). This failure was due to a more widespread reduction of rCBF even in patients with minimal ischemic deficits. In conclusion, previously reported strategies of rCBF analysis based on intraindividual standardization should not be used in patients with cerebrovascular disease since they may produce misleading results.
Paroxysmal Atrial Fibrillation and Cerebral Embolism with Apparently Normal Heart
Authors: Gerald Weintraub, George Sprecace
Journal: New England Journal of Medicine (1958)

THE association of atrial fibrillation and arterial embolization is a well known clinical entity. However, this sequence in a patient with no clinical evidence of organic heart disease is exceedingly rare.Case ReportA 49-year-old woman was admitted to the hospital on January 15, 1958, because of a left-sided hemiparesis of sudden onset, unassociated with loss of consciousness. For 2 years before admission, she had experienced frequent attacks of palpitation, which had been increasing in frequency and which seemed to be related to exercise, amount of coffee consumed (10 to 15 cups a day) and excessive smoking. There was no . . .
Young adults with persistent, asymptomatic, isolated microscopic hematuria were at increased risk for ESRD
Authors: Donald A. Molony
Journal: Annals of Internal Medicine (2011)

Source Citation Vivante A, Afek A, Frenkel-Nir Y, et al. Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729-36. 21846854
ASSIGN, QRISK, and validation
Authors: H. Tunstall-Pedoe, M. Woodward, G. Watt
Journal: BMJ (2009)

We challenge the recent QRISK validation and editorial concluding that QRISK is the cardiovascular risk score for the United Kingdom.1 2

ASSIGN, QRISK’s precursor, was launched in Scotland before QRISK appeared.3 Predicting that scores omitting social deprivation (socioeconomic status) as a risk factor could exacerbate social gradients in disease, we developed ASSIGN to include it. ASSIGN was adopted without external validation …
Controlling genital chlamydial infection
Authors: A. M Johnson, L. Grun, A. Haines
Journal: BMJ (1996)

Controlling genital chiamydial infectionAdvances in diagnosis and treatment may make screening worthwhile Screening for asymptomatic Chlamydia trachomatis was first proposed in the early 1980s' and guidelines for selective screening in the United States were published by the Centers for Disease Control in 1993.2The condition fulfils many of the criteria for screening.3Most infections are initially asymptomatic but may subsequently cause considerable long term
If I Were a Rich Man Could I Buy a Pancreas? and Other Essays on the Ethics of Health Care
Authors: James M. Humber
Journal: JAMA (1993)

This text is an anthology composed of 19 articles, all written by Arthur L. Caplan. Seventeen of the articles reprint material published in other sources between 1982 and 1989. The two remaining essays are written especially for this volume; they are "Mapping Morality: Ethics and the Human Genome Project" (chapter 8), and "Can Autonomy Be Saved?" (chapter 16). All articles in Caplan's anthology are loosely grouped under six topic headings. Part I is entitled "The Nature of Applied Ethics" and contains two chapters. Part II includes four chapters under the title "Ethical Issues in Animal and Human Experimentation." The remaining four topic headings are as follows: Part III, "Advances in Reproduction and Genetics" (two chapters); Part IV, "Transplants and Other Unnatural Acts" (three chapters); Part V, "Aging, Chronic Illness, and Rehabilitation" (five chapters); and Part VI, "Money, Medicine, and Morality" (three chapters). Anyone familiar with Caplan's work knows that it
γ-Herpesvirus Kinase Actively Initiates a DNA Damage Response by Inducing Phosphorylation of H2AX to Foster Viral Replication
Authors: Vera L. Tarakanova, Van Leung-Pineda, Seungmin Hwang, Chiao-Wen Yang, Katie Matatall, Mickael Basson, Ren Sun, Helen Piwnica-Worms, Barry P. Sleckman, Herbert W. Virgin
Journal: Cell Host & Microbe (2007)
A BACTERIOLOGIC STUDY OF THE FACTORS AFFECTING THE EFFICACY OF STREPTOMYCIN THERAPY OF URINARY TRACT INFECTIONS 12
Authors: George T. Harrell, E. Garland Herndon, Charles M. Gillikin, Jerry K. Aikawa
Journal: Journal of Clinical Investigation (1947)

Streptomycin appears to be the most useful antibiotic available at present for the treatment of infections due to gram-negative bacilli. The absorption, distribution, and excretion of the drug following various modes of administration have been studied (1). The results of clinical trials of the drug in various types of infections have been reported (2). Treatment schedules and the influence of various factors in determining the optimum dosage of streptomycin have been investigated clinically, and the results are being reported elsewhere (3). The observation that the most common cause of therapeutic failure was the development of bacterial resistance or fastness 8 to streptomycin focused attention on the necessity for further bacteriologic studies in relation to concentrations of streptomycin. The cases of urinary tract infection afforded an opportunity for further investigation of the effect of streptomycin on bacteria.
Textbook of Biochemistry, With Clinical Correlations
Authors: Howard S. Tager
Journal: JAMA (1993)

As I noted 10 years ago in my review of the first edition of<i>Textbook of Biochemistry, With Clinical Correlations</i>, this is a big book. The third edition contains more than 1000 pages, contributions from 27 authors, and chapters on subjects as diverse as "Recombinant DNA and Biotechnology" and "Gas Transport and pH Regulation" (in addition, of course, to material on proteins, carbohydrates, lipids, amino acids, and nucleic acids/molecular biology). Balance is difficult to achieve in a work this large, especially in a text that does not seem to express a particular focus or approach. The exposition is as even as one could expect from a well-edited multiauthor volume, and most worthy subjects receive significant attention, if not at least passing mention.<i>Textbook of Biochemistry</i>tries to do a lot but, in the end, perhaps tries to do a little too much. An important aspect of<i>Textbook of Biochemistry</i>involves
Dominant nonresponsiveness in the induction of autoimmunity to liver-specific F antigen.
Authors: D M Silver, D P Lane
Journal: The Journal of Experimental Medicine (1975)

The liver-specific F antigen, although not an autoimmunogen, can induce the production of autoantibodies in responder strains. The ability to respond is under the control of two genes, one linked to the H-2 locus of mice, the other not. Responders possessing both genes produce high anti-F titers, while the H-2-linked gene alone permits a significant but low antibody response. (Responder X nonresponder) F1 hybrids derived from parents possessing identical F molecules are nonresponders, in contrast with the dominance of responsiveness in Ir gene systems. The presence of the H-2 locus from nonresponders appears involved in the inability to respond. This is discussed in terms of self-tolerance and suppression.
Meta-Analysis: Accuracy of Rapid Tests for Malaria in Travelers Returning from Endemic Areas
Authors: Arthur Marx, Daniel Pewsner, Matthias Egger, Reto Nüesch, Heiner C. Bucher, Blaise Genton, Christoph Hatz, Peter Jüni
Journal: Annals of Internal Medicine (2005)

Background: Microscopic diagnosis of malaria is unreliable outside specialized centers. Rapid tests have become available in recent years, but their accuracy has not been assessed systematically. Purpose: To determine the accuracy of rapid diagnostic tests for ruling out malaria in nonimmune travelers returning from malaria-endemic areas. Data Sources: The authors searched MEDLINE, EMBASE, CAB Health, and CINAHL (1988 to September 2004); hand-searched conference proceedings; checked reference lists; and contacted experts and manufacturers. Study Selection: Diagnostic accuracy studies in nonimmune individuals with suspected malaria were included if they compared rapid tests with expert microscopic examination or polymerase chain reaction tests. Data Extraction: Data on study and patient characteristics and results were extracted in duplicate. The main outcome was the likelihood ratio for a negative test result (negative likelihood ratio) for Plasmodium falciparum malaria. Likelihood ratios were combined by using random-effects meta-analysis, stratified by the antigen targeted (histidine-rich protein-2 [HRP-2] or parasite lactate dehydrogenase [LDH]) and by test generation. Nomograms of post-test probabilities were constructed. Data Synthesis: The authors included 21 studies and 5747 individuals. For P. falciparum, HRP-2–based tests were more accurate than parasite LDH–based tests: Negative likelihood ratios were 0.08 and 0.13, respectively (P = 0.019 for difference). Three-band HRP-2 tests had similar negative likelihood ratios but higher positive likelihood ratios compared with 2-band tests (34.7 vs. 98.5; P = 0.003). For P. vivax, negative likelihood ratios tended to be closer to 1.0 for HRP-2–based tests than for parasite LDH–based tests (0.24 vs. 0.13; P = 0.22), but analyses were based on a few heterogeneous studies. Negative likelihood ratios for the diagnosis of P. malariae or P. ovale were close to 1.0 for both types of tests. In febrile travelers returning from sub-Saharan Africa, the typical probability of P. falciparum malaria is estimated at 1.1% (95% CI, 0.6% to 1.9%) after a negative 3-band HRP-2 test result and 97% (CI, 92% to 99%) after a positive test result. Limitations: Few studies evaluated 3-band HRP-2 tests. The evidence is also limited for species other than P. falciparum because of the few available studies and their more heterogeneous results. Further studies are needed to determine whether the use of rapid diagnostic tests improves outcomes in returning travelers with suspected malaria. Conclusions: Rapid malaria tests may be a useful diagnostic adjunct to microscopy in centers without major expertise in tropical medicine. Initial decisions on treatment initiation and choice of antimalarial drugs can be based on travel history and post-test probabilities after rapid testing. Expert microscopy is still required for species identification and confirmation.
Tales of How Great Drugs Were Brought Down by a Flawed Rationale—Letter
Authors: Michel D. Wissing, Michael A. Carducci, Hans Gelderblom, Paul J. van Diest
Journal: Clinical Cancer Research (2013)

In a recent article, Komlodi-Pasztor and colleagues argued that cancer researchers used a flawed rationale to develop inhibitors of mitotic enzymes, such as polo-like kinase 1 (PLK1) and aurora kinases (1). Scientists had been misled by the success of microtubule-targeting agents (MTA) by assuming that MTAs act on cancer cells solely by mitotic inhibition, whereas their primary targets are microtubules in interphase. Inhibitors of enzymes solely expressed during mitosis would not have a significant antitumor effect on solid tumors in clinical studies, as most solid tumors have a mean mitotic index of less than 1%.However, despite the low mitotic index, mitotic enzymes are frequently overexpressed in cancer; for example, Weichert and colleagues reported that 52.6% of all human prostate carcinomas have strong expression of PLK1 (2). This suggests that mitotic enzymes also play a role beyond mitosis. Indeed, PLK1 has been found to regulate among others p53 and microtubule dynamics in interphase as well (3).The authors describe that cancer cells have mitotic slippage after 1 to 2 days of treatment with antimitotic agents (1). They fail to mention that such cells either become aneuploid or polyploid, or are arrested in interphase (4). Although cells may initially be viable, all these states eventually result in cell death.The authors explain the discrepancy between in vivo results and clinical efficacy of antimitotic agents further by the (twice) daily administration in mice, whereas in humans intravenous administration is done at a weekly or longer interval (1). With the discovery of orally bioavailable compounds, such as the aurora kinase-inhibitors alisertib (MLN-8237), ENMD-2076, PF-03814735, MK-5108, and AMG-900 and the PLK1-inhibitors HMN-214, TAK-960, and NMS-1286937, similar dosing frequencies can be achieved in humans as in mice.The major advantage of inhibitors of mitotic enzymes compared with MTAs is the lack of irreversible neuropathy after treatment; adverse events are fewer and rarely irreversible. Research is ongoing to increase the efficacy of aurora kinase- and PLK1-inhibitors, which could be accomplished by increased bioavailability to the tumor, that is, oral bioavailability, an improved pharmacokinetic profile, or activation by tumor-specific markers. Furthermore, addition of granulocyte colony-stimulating factor suppresses the adverse effect of mitotic inhibitors on the bone marrow, thereby allowing higher dosing. Aurora kinase- and PLK1-inhibitors could also have clinical potential in combination therapy, as combination therapy could result in equal/improved efficacy and decreased toxicity compared with current treatment protocols. We therefore think that these promising agents should be further developed and deserve thorough testing in clinical trials.See the Response, p. 1304M.A. Carducci is consultant/advisory board member of Amgen. No potential conflicts of interest were disclosed by the other authors.
Common Duodenitis—Of any Clinical Import?
Authors: Eddy D. Palmer
Journal: JAMA (1974)

NOW that the technical capabilities of gastroenterology have been developed to the point that about two thirds of the duodenum are routinely accessible for both endoscopy and biopsy, the clinician is finding it necessary—really for the first time—to decide what the discovery of "duodenitis" means for his patient. The older clinician no doubt remembers well his period of disillusionment over the importance of gastric mucosal inflammation generated during the World War II era by the gastroscopists and their wholly unrealistic interpretations of "gastritis." Perhaps he also remembers how clarification of the practical clinical aspects of the whole gastritis concept came only after peroral mucosal biopsy techniques had been developed. <h3>Definition of Duodenitis</h3> Will common duodenitis eventually prove more than a diagnostic excuse for the clinician? Is there danger of being drawn into another "gastritis" trap? A definition is in order and, lest an error be repeated, it must be a
Functionally mature virus-specific CD8+ T memory cells in congenitally infected newborns: proof of principle for neonatal vaccination?
Authors: P.G. Holt
Journal: Journal of Clinical Investigation (2003)

The presence in newborns of a mature and functional CD8+ T cell response to congenital cytomegalovirus infection suggests that the machinery necessary to prime such responses is present in utero and raises questions related to neonatal vaccination.
Randomised controlled trial of clinical decision support tools to improve learning of evidence based medicine in medical students
Authors: G. M Leung
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To assess the educational effectiveness on learning evidence based medicine of a handheld computer clinical decision support tool compared with a pocket card containing guidelines and a control. <b>Design</b> Randomised controlled trial. <b>Setting</b> University of Hong Kong, 2001. <b>Participants</b> 169 fourth year medical students. <b>Main outcome measures</b> Factor and individual item scores from a validated questionnaire on five key self reported measures: personal application and current use of evidence based medicine; future use of evidence based medicine; use of evidence during and after clerking patients; frequency of discussing the role of evidence during teaching rounds; and self perceived confidence in clinical decision making. <b>Results</b> The handheld computer improved participants9 educational experience with evidence based medicine the most, with significant improvements in all outcome scores. More modest improvements were found with the pocket card, whereas the control group showed no appreciable changes in any of the key outcomes. No significant deterioration was observed in the improvements even after withdrawal of the handheld computer during an eight week washout period, suggesting at least short term sustainability of effects. <b>Conclusions</b> Rapid and convenient access to valid and relevant evidence on a portable computing device can improve learning in evidence based medicine, increase current and future use of evidence, and boost students9 confidence in clinical decision making.
A chromosome study of patients with uveitis treated with chlorambucil.
Authors: B R Reeves, V L Pickup, S D Lawler, W J Dinning, E S Perkins
Journal: BMJ (1975)

A Chromosome study of patients with uveitis treated with chlorambucil A variety of nonmalignant conditions are being treated with immuno- suppressive drugs which may have carcinogenic, teratogenic, or mutagenic effects.One way of estimating possible hazards is
Allergen Concentration in Natural Rubber Latex
Authors: H.Y. Yeang, R.G. Hamilton, D.I. Bernstein, S.A.M. Arif, K.S. Chow, Y.H. Loke, M. Raulf-Heimsoth, S. Wagner, H. Breiteneder, R.E. Biagini
Journal: Journal of Allergy and Clinical Immunology (2006)