tbuckley/cabot-search huggingface dataset:
Myocardin regulates BMP10 expression and is required for heart development
Authors: Jianhe Huang, John Elicker, Nina Bowens, Xi Liu, Lan Cheng, Thomas P. Cappola, Xiaohong Zhu, Michael S. Parmacek
Journal: Journal of Clinical Investigation (2012)

Myocardin is a muscle lineage–restricted transcriptional coactivator that has been shown to transduce extracellular signals to the nucleus required for SMC differentiation. We now report the discovery of a myocardin/BMP10 (where BMP10 indicates bone morphogenetic protein 10) signaling pathway required for cardiac growth, chamber maturation, and embryonic survival. Myocardin-null (Myocd) embryos and embryos harboring a cardiomyocyte-restricted mutation in the Myocd gene exhibited myocardial hypoplasia, defective atrial and ventricular chamber maturation, heart failure, and embryonic lethality. Cardiac hypoplasia was caused by decreased cardiomyocyte proliferation accompanied by a dramatic increase in programmed cell death. Defective chamber maturation and the block in cardiomyocyte proliferation were caused in part by a block in BMP10 signaling. Myocardin transactivated the Bmp10 gene via binding of a serum response factor–myocardin protein complex to a nonconsensus CArG element in the Bmp10 promoter. Expression of p57kip2, a BMP10-regulated cyclin-dependent kinase inhibitor, was induced in Myocd–/– hearts, while BMP10-activated cardiogenic transcription factors, including NKX2.5 and MEF2c, were repressed. Remarkably, when embryonic Myocd–/– hearts were cultured ex vivo in BMP10-conditioned medium, the defects in cardiomyocyte proliferation and p57kip2 expression were rescued. Taken together, these data identify a heretofore undescribed myocardin/BMP10 signaling pathway that regulates cardiomyocyte proliferation and apoptosis in the embryonic heart.
Heparin induced thrombosis: an important complication of heparin prophylaxis for thromboembolic disease in surgery.
Authors: J B Hunter, R J Lonsdale, P W Wenham, S P Frostick
Journal: BMJ (1993)

Heparin induced thrombocytopenia with thrombosis, or the "white clot syndrome," is a rare but recognised complication of heparin therapy. The syndrome is idiosyncratic, immune mediated, and not dose dependent and therefore is equally likely to occur with prophylactic and therapeutic heparin dosage regimens. Despite published reports on the subject we were alarmed that many surgeons who regularly use heparin to prevent or treat thrombosis were unaware that heparin can induce thrombotic complications in susceptible patients. We present three typical case histories, a brief discussion of the condition, and some guidelines on its prevention and treatment.
The serious suicide attempt. Five-year follow-up study of 886 patients
Authors: D. H. Rosen
Journal: JAMA (1976)

A five-year follow-up study was undertaken of a previously reported 1968 cohort of 886 people who had attempted suicide. The working hypothesis that those who had seriously attempted suicide (21%) would have a higher suicide rate on long-term follow-up was confirmed. During the five-year follow-up period, a total of 34 suicides were found, which represented 3.84% of the total number at risk. Of those who had seriously attempted suicide, 12 (6.45%) of 186 succeeded later; of the other (nonserious or less serious) attempters, 22 (3.1%) of 700 succeeded. The serious-attempter suicide rate was 2.1 times that of the others, and this difference was statistically significant (<i>P</i>&lt;.05). In addition, patients who made attempts that were judged serious on medical but not on psychiatric grounds were found to have a suicide rate significantly higher (<i>P</i>&lt;.05) than patients who had made suicide attempts that were not a serious medical threat. (<i>JAMA</i>235:2105-2109, 1976)
Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion.
Authors: E J Claret, E P Alyea, E Orsini, C C Pickett, H Collins, Y Wang, D Neuberg, R J Soiffer, J Ritz
Journal: Journal of Clinical Investigation (1997)

The clinical efficacy of donor lymphocyte infusions (DLI) in patients with relapsed chronic myelocytic leukemia after allogeneic bone marrow transplantation has been demonstrated in several recent studies. Although it is presumed that allogeneic T cells mediate this graft-versus-leukemia (GVL) effect, the influence of DLI on the T cell compartment of recipients has not been determined. To characterize the immunologic effects of DLI and to identify T cell changes selectively associated with the GVL response, we analyzed the T cell receptor (TCR) repertoire in four patients with relapsed chronic myelocytic leukemia who achieved a complete remission after infusion of CD4+ lymphocytes from HLA-identical sibling donors. Only one of the four patients developed clinically significant graft-versus-host disease (GVHD) after infusion of donor lymphocytes. TCR repertoire was examined after PCR amplification of 24 Vbeta gene subfamilies in serial samples obtained over a 1-yr period before and after DLI. Results were compared to 10 normal donors. Before DLI, all four patients were found to have abnormal TCR Vbeta repertoire in peripheral T cells, associated with a large number of clonal and oligoclonal patterns. Abnormal TCR patterns persisted for at least 3 mo after DLI, but thereafter gradually began to normalize. By 1 yr after DLI, all patients demonstrated almost complete normalization of Vbeta repertoire with polyclonal representation within almost all Vbeta gene subfamilies. We also examined changes in the TCR Vbeta repertoire associated with the disappearance of Ph+ cells. In each patient, we were able to identify the expansion of at least 1 Vbeta gene subfamily that coincided with the time of the cytogenetic response. In one patient who was studied in greater detail, CDR3 size analysis of serial samples after DLI indicated that these changes were associated with the appearance of clonal T cells. This finding was confirmed through CDR3 sequence analysis and use of CDR3 clone-specific oligonucleotide probes. A putative GVL clone identified by this technique was not detectable in either donor or patient T cells before DLI, but persisted in peripheral T cells for approximately 1 yr. These experiments therefore provide evidence for the clonal expansion of allogeneic T cells that may be selective mediators of antileukemia activity without also mediating graft-versus-host disease.
The proportion of xanthine oxidase activity of total xanthine oxidoreductase activityin situ remains constant in rat liver under various (patho)physiological conditions
Authors: W M Frederiks, K S Bosch
Journal: Hepatology (1996)

Activity of xanthine oxidoreductase (total xanthine dehydrogenase plus xanthine oxidase) and xanthine oxidase was determined cytophotometrically in periportal and pericentral areas of livers of rats under various (patho)physiological conditions that are known to affect the content of reduced glutathione. For this purpose, rats were either normally fed or fasted for 24 hours, fasted for 24 hours, and treated with diethylmaleate that depleted glutathione or treated by in vivo ischemia for 2 hours in the livers. Xanthine oxidoreductase activity was shown histochemically with the use of a tetrazolium salt procedure, and xanthine oxidase activity was localized with a cerium-diaminobenzidine-cobalt-hydrogen peroxide technique in unfixed cryostat sections of the livers. Cytophotometric measurements showed that total xanthine oxidoreductase activity was decreased after fasting and ischemia, whereas only ischemia caused reduced xanthine oxidase activity. Moreover, the percentage of xanthine oxidase of total xanthine oxidoreductase activity was constant in both periportal and pericentral areas at the level of approximately 4% in normally fed and 24-hour fasted and diethylmaleate-treated rats. Ischemia reduced this percentage in both areas of the liver to 2%. It was concluded that the amount of endogenous reduced glutathione did not affect the percentage of xanthine oxidase. The low percentage of xanthine oxidase as determined in the present in situ histochemical study indicates that in vivo the percentage oxidase in rat liver is lower than is assumed on the basis of biochemical assays in liver homogenates even after strictly controlled homogenization procedures. Apparently, conversion of xanthine dehydrogenase into xanthine oxidase may occur in vitro to yield percentages of xanthine oxidase of 10%-20% as are reported in the literature. The latter increase in the percentage of xanthine oxidase may be caused by changes in the local environment of the enzymes, which is left completely intact in histochemical assays. The finding of this low percentage of xanthine oxidase further stresses that the main function of xanthine oxidoreductase in the liver is not the production of superoxide anion radicals and/or hydrogen peroxide but rather the metabolism of xanthine to uric acid, which can act as a potent antioxidant.
Head of Cancer Drugs Fund regrets its establishment, conference hears
Authors: N. Hawkes
Journal: BMJ (2015)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies. Here, we use targeted transcriptomics of FFPE tissue using the Nanostring GeoMX™ platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients. Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient-patient variation had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene <i>IFI27</i>, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.
Drug Therapy in the Elderly
Authors: JOSEPH G. OUSLANDER
Journal: Annals of Internal Medicine (1981)

Age-related biologic and physiologic changes in the elderly may lead to altered pharmacokinetics. Volume of distribution, half-life, systemic clearance, and receptor sensitivity have been shown to change with increasing age. Unique features of illness in the elderly may interfere with effective drug therapy more than changed pharmacokinetics in some patients. Physical, psychologic, and socioeconomic considerations often interfere with ability to obtain and comply with health care. Disease is often difficult to recognize in elderly patients. Multiple chronic conditions, many of which may be undetected, may be exacerbated by or alter drug therapy for other illnesses. Cognitive impairment and diminished vision and hearing may make patient education difficult, and compliance poor. The elderly are also more susceptible to adverse drug reactions. The recommendations for clinical practice and directions for future research that are presented should help make drug therapy in the elderly safer and more effective.
Angiotensin-Converting Enzyme DD Genotype and Cardiovascular Disease in Heterozygous Familial Hypercholesterolemia
Authors: Jean P. O’Malley, None BS, Cheryl L. Maslen, D. Roger Illingworth
Journal: Circulation (1998)

Background —Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries. Methods and Results —We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DI+II. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history. Conclusions —The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.
Quantitative structural study of pulmonary circulation in the newborn with pulmonary atresia.
Authors: S G Haworth, L Reid
Journal: Thorax (1977)

The lungs of eight newborn infants who had died from pulmonary atresia were studied by quantitative morphometric techniques. It was established for the first time that the abnormal pattern of blood flow through the heart and great vessels in a fetus with pulmonary atresia is associated with impaired lung development as shown by arteries that are too few, too small, and with an abnormally thin muscle coat, although the distribution of muscle along the arterial pathway is normal. Differences between the cases in the degree of impairment of lung development could be detected and related to the degree of reduction in pressure and flow before birth in the individual case. Although blood flow through the pulmonary circulation is small before birth lung development seems sensitive to any further reduction.
Systemic Use of Local Anesthetics
Authors: J. Eugene Ruben
Journal: JAMA (1966)

<h3>To the Editor:—</h3> Dr. John Adriani's otherwise excellent article (<b>196</b>:405, 1966) "Reactions to Local Anesthetics" contains one statement which I consider to be incorrect: The systemic effects of local anesthetics are of very little use clinically. Some physicians use them intravenously, but other drugs are more effective. Thus, there is little justification for using these drugs systemically. Since 1947 we have been using 0.5% or 1% procaine intravenously in combination with thiopental, nitrous oxide, ether, and cyclopropane in various combinations. We find intravenous administration of procaine of value because: It suppresses respiratory tract secretions so effectively that suction through the endotracheal catheter is almost never necessary. It suppresses sweat gland secretions so that the skin remains warm and dry and the loss of fluid and electrolytes during surgery is minimized. It decreases somatic and autonomic sensitivity, so that noxiousreflexes are minimized and the amount
POMPOUS WORDS IN MEDICAL LITERATURE.
Authors: EDMUND ANDREWS
Journal: JAMA (1894)

A good literary style is as important in medicine as in any other kind of writing. One feature of good style demanded by all standard critics, is that the sentences shall be expressed in simple, pure, crystalline English, and consist mainly of short Anglo-Saxon words, loaded as little as possible with pompous polysyllables of Latin and Greek derivation. James Russell Lowell laments our inferiority to English writers in this respect. He says: "It has long seemed to me that the great vice of American writing and speaking is a studied want of simplicity. "Whether it be for want of culture—for the highest outcome of culture is simplicity, or for whatever reason, it is certain that very few American writers or speakers wield their native language with the directness, force and precision that are common as the day in the mother country. While the schoolmaster has been busy 'starching' our language
PYP Maalox?? Localization in Liver and Spleen
Authors: BRIAN EISENBERG, DEBORAH OWENS, DANETTE L. STEWART, MICHAEL R. WILLIAMSON
Journal: Clinical Nuclear Medicine (1989)

RES uptake was seen on bone imaging in a patient who had been ingesting Maalox®. The altered uptake was probably associated with interaction of aluminum and Tc- 99m PYP.
Two Doses of Azithromycin to Eliminate Trachoma in a Tanzanian Community
Authors: Anthony W. Solomon, Emma Harding-Esch, Neal D.E. Alexander, Aura Aguirre, Martin J. Holland, Robin L. Bailey, Allen Foster, David C.W. Mabey, Patrick A. Massae, Paul Courtright, John F. Shao
Journal: New England Journal of Medicine (2008)

These authors found that one or two rounds of high-coverage mass treatment with azithromycin may be sufficient to eliminate ocular C. trachomatis in communities with moderate levels of infection. Had WHO recommendations on antibiotic use been followed, three or possibly five annual rounds of mass treatment would have been offered.
The Biliary HCO3 − Umbrella: A Unifying Hypothesis on Pathogenetic and Therapeutic Aspects of Fibrosing Cholangiopathies
Authors: Ulrich Beuers, Simon Hohenester, Lucas J. Maillette de Buy Wenniger, Andreas E. Kremer, Peter L. M. Jansen, Ronald P. J. Oude Elferink
Journal: Hepatology (2010)

This review focuses on the hypothesis that biliary HCO Symbol secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCO Symbol umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl−/ HCO Symbol exchange and HCO Symbol secretion, and alkaline phosphatase–mediated ATP breakdown may guarantee a stable biliary HCO Symbol umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO Symbol umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. (Hepatology 2010)
Biosynthesis of Thromboxane A2 in Renovascular Hypertension
Authors: G. A. Fitz-Gerald
Journal: JAMA (1984)

A variety of biologically active mediators are formed from arachidonic acid within the kidney. The most abundant metabolites are prostaglandins and thromboxane A<sub>2</sub>, formed via cyclic endoperoxide intermediates by the enzyme cyclooxygenase. These products are formed in response to phasic stimuli. They are not stored following synthesis, and their evanescent nature suggests that they are most likely to act locally as regulators of cellular homeostasis. Degradation products and metabolites of prostaglandins are generally biologically inactive. An exception is 6-keto-PGE<sub>1</sub>, a long-lived metabolite of prostacyclin formed by the enzyme 9α-hydroxy-prostaglandin-dehydrogenase. 6-Keto-PGE<sub>1</sub>, like prostacyclin, inhibits platelet aggregation, relaxes vascular smooth muscle, and is a potent renin secretagogue. However, although the kidney possesses the enzymatic machinery to generate 6-keto-PGE<sub>1</sub>, structural evidence that it is actually formed in vivo is still outstanding. In several species, the predominant cyclooxygenase product formed within the renal cortex is prostacyclin, virtually the exclusive metabolite
UK cancer death rates drop by more than a fifth over 20 years
Authors: J. Wise
Journal: BMJ (2013)

The age standardised death rate from cancer among women in the United Kingdom fell by 20% and that among men by 27% between 1990 and 2011, a new analysis shows.

Cancer Research UK said that the cancer death rate among women fell from 185 to 147 per 100 000 population and among men from 277 to 203 per 100 000. The charity said that better …
THE PERSON WHO MOST INFLUENCED ME
Authors: N S Baber
Journal: BMJ (1996)

Having chosen biology as my main sixth form subject, I looked forward with some trepidation to being taught by Miss Reynolds, the senior biology mistress, who had a reputation for expecting high standards and not tolerating any nonsense. But I knew that she was a good teacher; how good I was soon to find out.

I had little idea what career I wanted to follow. Indeed, I think most of us at that time looked forward only to continuing the educative process in some rather vague and comforting way. Whatever …
Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW
Authors: Devjit Tripathy, Stephen C. Clement, Dawn C. Schwenke, MaryAnn Banerji, George A. Bray, Thomas A. Buchanan, Amalia Gastaldelli, Robert R. Henry, Abbas E. Kitabchi, Sunder Mudaliar, Robert E. Ratner, Frankie B. Stentz, Nicolas Musi, Peter D. Reaven, Ralph A. DeFronzo
Journal: Diabetes Care (2014)

Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.