tbuckley/cabot-search huggingface dataset:
Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus
Authors: Tomasz J. Guzik, Shafi Mussa, Daniela Gastaldi, Jerzy Sadowski, Chandi Ratnatunga, Ravi Pillai, Keith M. Channon
Journal: Circulation (2002)

Increased superoxide production contributes to reduced vascular nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of diabetes. We characterized the sources and mechanisms underlying vascular superoxide production in human blood vessels from diabetic patients with coronary artery disease compared with nondiabetic patients.Vascular superoxide production was quantified in both saphenous veins and internal mammary arteries from 45 diabetic and 45 matched nondiabetic patients undergoing coronary artery bypass surgery. NAD(P)H-dependent oxidases were important sources of vascular superoxide in both diabetic and nondiabetic patients, but both the activity of this enzyme system and the levels of NAD(P)H oxidase protein subunits (p22phox, p67phox, and p47phox) were significantly increased in diabetic veins and arteries. In nondiabetic vessels, endothelial NO synthase produced NO that scavenged superoxide. However, in diabetic vessels, the endothelium was an additional net source of superoxide production because of dysfunctional endothelial NO synthase that was corrected by intracellular tetrahydrobiopterin supplementation. Furthermore, increased superoxide production in diabetes was abrogated by the protein kinase C inhibitor chelerythrine.These observations suggest important roles for NAD(P)H oxidases, endothelial NO synthase uncoupling, and protein kinase C signaling in mediating increased vascular superoxide production and endothelial dysfunction in human diabetes mellitus.
Aortic Insufficiency of Unusual Etiology
Authors: Fred T. Darvill
Journal: JAMA (1963)

Aortic insufficiency is usually caused by rheumatic or luetic involvement of the aortic valve. Unusual causes may include the following uncommon clinical conditions: (1) "functional" aortic insufficiency caused by dilatation of the aortic valve ring secondary to prolonged hypertension, (2) fenestrations of the aortic valve, (3) trauma to the aortic valve, (4) congenital abnormalities of the aortic valve, (5) dissecting aortic aneurysms, (6) bacterial endocarditis, (7) brucellosis, (8) Marfan's syndrome, (9) rheumatoid spondylitis, and (10) arteriosclerosis of the aortic valve per se, with or without calcific aortic stenosis. Three cases of aortic insufficiency which resulted from arteriosclerotic involvement of the valve are detailed. A fourth case, in which aortic insufficiency was caused by redundancy of the aortic valves, is perhaps the only case of its type recorded to date.
Tracking Down Salmonella typhi
Authors: Samuel Vaisrub
Journal: JAMA (1975)

Therapies based on a tentative diagnosis often hinder its confirmation at a later date. Liver or cyanocobalamin given to a patient with suspected pernicious anemia can vitiate subsequent microscopic diagnosis by altering the morphology of the blood and the bone marrow. Thyroid taken by a patient with suspected hyperthyroidism will so change the values of protein-bound iodine and thyroxine as to make their interpretations valueless for diagnostic corroboration. A particularly rich source of such therapeutically vitiated diagnoses is antibiotic therapy. An antibiotic taken for the treatment of an uninvestigated sore throat can render a throat swab useless should it become necessary to rule out a β-streptococcal infection. A bacteriologic diagnosis of bacterial endocarditis may become impossible after the patient has been treated with antibiotics for a fever as yet undiagnosed. Penicillin taken for the treatment of gonorrhea may suppress the clinical manifestations of a coexistent syphilitic infection. A recent addition
5‐Aminolevulinate synthase in sideroblastic anemias: mRNA and enzyme activity levels in bone marrow cells
Authors: Sylvia S. Bottomley, Mark A. Brandenburg, Helen M. Healy, Brian K. May
Journal: American Journal of Hematology (1992)

Abstract To examine the role of 5‐aminolevulinate synthase (ALAS) in the pathogenesis of sideroblastic anemias, levels of mRNAs for erythroid and housekeeping ALAS isozymes were examined, and total ALAS activity was assessed in bone marrow cells. In two patients with X‐linked sideroblastic anemia the levels of mRNA for erythroid ALAS as well as for α and β globin appear to be decreased while levels of mRNA for glycophorin A in both patients were the same as in normal individuals. However, amounts of housekeeping ALAS mRNA were increased two‐ to threefold in these patients. Total ALAS activity was also increased two‐ or threefold, perhaps reflecting increased transcription of the housekeeping gene in response to diminished cellular heme in erythroid cells and/or enhanced translation of the erythroid isoform in response to iron accumulation. In a third patient with X‐linked sideroblastic anemia ALAS activity was low but increased to twice the normal value after pyridoxine administration, suggesting a structural defect of the enzyme. In a fourth patient, with isolated congenital, pyridoxine‐responsive sideroblastic anemia, the erythroid ALAS mRNA was normal and a low enzyme activity was strikingly enhanced by pyridoxal‐phosphate albeit to subnormal levels. In idiopathic acquired sideroblastic anemia, ALAS mRNA for both isozymes was normal and enzyme activity was slightly elevated. These observations thus reflect heterogeneous aberrations of erythroid heme synthesis in the various types of sideroblastic anemia and suggest that defects involving erythroid ALAS underlie at least some of them. © 1992 Wiley‐Liss, Inc.
Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles
Authors: Christian Mueller, Qiushi Tang, Alisha Gruntman, Keith Blomenkamp, Jeffery Teckman, Lina Song, Phillip D Zamore, Terence R Flotte
Journal: Molecular Therapy (2012)

α-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently reduced by an average of 80%. Treated animals showed knockdown of Z-AAT in liver and serum with concomitant increased serum M-AAT as determined by allele-specific enzyme-linked immunosorbent assays (ELISAs). In addition, decreased globular accumulation of misfolded Z-AAT in hepatocytes and a reduction in inflammatory infiltrates in the liver was observed. Results from microarray studies demonstrate that endogenous miRNAs were minimally affected by this treatment. These data suggests that miRNA mediated knockdown does not saturate the miRNA pathway as has been seen with viral vector expression of short hairpin RNAs (shRNAs). This safe dual-therapy approach can be applied to other disorders such as amyotrophic lateral sclerosis, Huntington disease, cerebral ataxia, and optic atrophies.
Lamivudine prophylaxis for prevention of chemotherapy induced hepatitis B virus reactivation in hepatitis B virus carriers with hematological malignancies
Authors: R. Idilman, M. Arat, M. Toruner, I. Soykan, S. Karayalcin, E. Soydan, M. Ozcan, M. Beksac, O. Arslan, H. Akbulut, O. Ilhan, H. Akan, A. Ozden
Journal: Journal of Hepatology (2003)
Myocardial perfusion cold pressor test 99mTc MIBISPECT detects both microvascular and epicardial abnormal reactivity in patients with endothelial dysfunction and angiographically normal coronary arteries with intracoronary acetylcholine vasoconstriction
Authors: Néstor A. Perez Baliño, Osvaldo Masoli, Marcela Redruello, Sonia Traverso, Daniel Cragnolino, Alejandro Meretta, Carlos Rapallo, Jorge L. Szarfer, Ricardo Sarmiento, Miguel A. Riccitelli
Journal: Journal of the American College of Cardiology (2003)
ABC of Sports Medicine The overtraining syndrome
Authors: R Budgett
Journal: BMJ (1994)

Athletes may experience chronic fatigue for many reasons, but it often results from the stress of training and competition-when it is called the overtraining syndrome.The primary complaint is of reduced per- formance, which is objective and can be measured.Many athletes train at an elite level even to compete domestically, so fatigue due to the stress of training is not confined to Olympic athletes; 1 0% of college swimmers in the United States are described as "burning out" each year.Wingate test using rowing machine.(Steve Redgrave, triple Olympic winner.)---------------The cause of the overtraining syndrome is not known and there is no diagnostic or warning test.Intensive interval work (high intensity exer- cise with little rest) is most likely to precipitate the syndrome, so it is extremely rare in sprinters because they train with large amounts of rest.Sprinters may, however, suffer from postviral and other forms of chronic fatigue.l ~~~~~~Contro'l athletes j -jjOvertmined athletes Wingate test showing lower peak power in overtrained athletes.* Stress of competition and selection * Physical stresses -Glycogen depletion -Dehydration -Other illness or injury -Psychological stress of life events (for example, moving house, exams, relationship problems) Symptoms of overtraining * Underperformance * Depression (loss of purpose, competitive drive, and libido) * Loss of appetite, and weight * Increased anxiety and irritability * Fatigue * Sleep disturbance (in over 90% of cases)-difficulty getting to sleep, waking in the night, nightmares, and waking unre- freshed * Frequent minor infections, particularly of the upper respiratory tract * Raised resting pulse rate * Excessive sweating Signs of over-reaching (which is normal if athletes recover quickly) * High serum creatine kinase concentra- tion * Low ratio of serum testosterone to corti- sol concentrations * Falls in muscle glycogen concentration * Raised resting heart rate * Mood deterioration * Raised serum cortisol concentrations * Low serum glutamine concentrations * Low salivary IgA concentrations Early detection of overtraining syndrome is difficult Monitor: Performance Mood state Resting heart rate* Relaxation strategies and rest, with regular very light exercise * Communication with the coach * Strong reassurance that the prognosis is goodOvertrained athletes v patients with chronic fatigue * Their primary presenting complaint is of underperformance, which is an objective measure of their condition * They present earlier, are less severely affected, and recover more quickly * The main stresses in their lives are exercise and competition, which can be controlled * The main problem in rehabilitation is in holding them back, rather than having to encourage appropriate exercise
CONJUNCTIVAL IRRITATION EXCITED BY PROXIMITY TO A HORSE.
Authors: WILLIAM CAMPBELL POSEY
Journal: JAMA (1905)

A number of years ago I was consulted by a banker from one of the New England towns, on account of a high muscular error, which occasioned marked asthenopia. During the treatment of the case, it was elicited that in addition to the symptoms of eyestrain, the patient was the subject of a peculiar kind of inflammation of his eyes, which occasioned him great annoyance and distress, and from which he despaired of obtaining relief. This affection, as told in his own words, was as follows: <h3>Case 1.</h3> Since I was 30 years of age, whenever I drive behind a horse, I usually begin to sneeze somewhat during the first mile, but by the end of the second or third mile the sneezing gradually increases until I sneeze once every 100 feet. If the drive is a long one, the sneezing may relax somewhat for a time, only
Loss of Histone Deacetylase 4 Causes Segregation Defects during Mitosis of p53-Deficient Human Tumor Cells
Authors: Bruno Cadot, Mirko Brunetti, Sabina Coppari, Silvia Fedeli, Emanuele de Rinaldis, Claudio Dello Russo, Paola Gallinari, Raffaele De Francesco, Christian Steinkühler, Gessica Filocamo
Journal: Cancer Research (2009)

We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myelopoietic progenitors. HDAC4-/+ or HDAC4-/- murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53-wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors.
Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study
Authors: Marco Campos, Ashley Buchanan, Fuli Yu, Maja Barbalic, Yang Xiao, Lloyd E. Chambless, Kenneth K. Wu, Aaron R. Folsom, Eric Boerwinkle, Jing-fei Dong
Journal: Blood (2012)
Patients' experience and satisfaction in primary care: secondary analysis using multilevel modelling
Authors: C. Salisbury, M. Wallace, A. A. Montgomery
Journal: BMJ (2010)

<b>Objective </b>To explore whether responses to questions in surveys of patients that purport to assess the performance of general practices or doctors reflect differences between practices, doctors, or the patients themselves. <b>Design </b>Secondary analysis of data from a study of access to general practice, combining data from a survey of patients with information about practice organisation and doctors consulted, and using multilevel modelling at practice, doctor, and patient level. <b>Setting </b>Nine primary care trusts in England. <b>Participants </b>4573 patients who consulted 150 different doctors in 27 practices. <b>Main outcome measures</b> Overall satisfaction; experience of wait for an appointment; reported access to care; satisfaction with communication skills. <b>Results </b>The experience based measure of wait for an appointment was more discriminating between practices (practice level accounted for 20.2% (95% confidence interval 9.1% to 31.3%) of variance) than was the overall satisfaction measure (practice level accounted for 4.6% (1.6% to 7.6%) of variance). Only 6.3% (3.8% to 8.9%) of the variance in the doctors’ communication skills measure was due to differences between doctors; 92.4% (88.5% to 96.4%) of the variance occurred at the level of the patient (including differences between patients’ perceptions and random variation). At least 79% of the variance on all measures occurred at the level of the patient, and patients’ age, sex, ethnicity, and housing and employment status explained some of this variation. However, adjustment for patients’ characteristics made very little difference to practices’ scores or the ranking of individual practices. <b>Conclusions </b>Analyses of surveys of patients should take account of the hierarchical nature of the data by using multilevel models. Measures related to patients’ experience discriminate more effectively between practices than do measures of general satisfaction. Surveys of patients’ satisfaction fail to distinguish effectively between individual doctors because most of the variation in doctors’ reported performance is due to differences between patients and random error rather than differences between doctors. Although patients’ reports of satisfaction and experience are systematically related to patients’ characteristics such as age and sex, the effect of adjusting practices’ scores for the characteristics of their patients is small.
Measuring Coverage in MNCH: Determining and Interpreting Inequalities in Coverage of Maternal, Newborn, and Child Health Interventions
Authors: Aluísio J. D. Barros, Cesar G. Victora
Journal: PLoS Medicine (2013)

To monitor progress towards the Millennium Development Goals, it is essential to monitor the coverage of health interventions in subgroups of the population, because national averages can hide important inequalities. In this review, we provide a practical guide to measuring and interpreting inequalities based on surveys carried out in low- and middle-income countries, with a focus on the health of mothers and children. Relevant stratification variables include urban/rural residence, geographic region, and educational level, but breakdowns by wealth status are increasingly popular. For the latter, a classification based on an asset index is the most appropriate for national surveys. The measurement of intervention coverage can be made by single indicators, but the use of combined measures has important advantages, and we advocate two summary measures (the composite coverage index and the co-coverage indicator) for the study of time trends and for cross-country comparisons. We highlight the need for inequality measures that take the whole socioeconomic distribution into account, such as the relative concentration index and the slope index of inequality, although simpler measures such as the ratio and difference between the richest and poorest groups may also be presented for non-technical audiences. Finally, we present a framework for the analysis of time trends in inequalities, arguing that it is essential to study both absolute and relative indicators, and we provide guidance to the joint interpretation of these results.
Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse
Authors: M A Benjamin
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> Glucagon-like peptide-2 (GLP-2) is a recently identified potent intestinotrophic factor. We have evaluated the effect of GLP-2 treatment on intestinal epithelial barrier function in mice. <h3>METHODS</h3> CD-1 mice were injected subcutaneously with GLP-2 or a protease resistant analogue, h[Gly<sup>2</sup>]GLP-2, twice daily for up to 10 days. Saline injected mice served as controls. Jejunal segments were mounted in Ussing chambers. Tissue conductance was measured and unidirectional fluxes were determined for (i) Na<sup>+</sup> and the small inert probe Cr-EDTA (both transported via the paracellular pathway) and (ii) the macromolecule horseradish peroxidase (HRP, transported via the transcellular pathway). <h3>RESULTS</h3> Mice treated with GLP-2 or h[Gly<sup>2</sup>]GLP-2 for 10 days demonstrated significantly reduced intestinal conductance and fluxes of Na<sup>+</sup>, Cr-EDTA, and HRP. Electron microscopy confirmed that GLP-2 reduced endocytic uptake of HRP into enterocytes. Functional changes (evident by four hours) preceded morphological changes (evident by 48 hours). <h3>CONCLUSIONS</h3> GLP-2 enhances intestinal epithelial barrier function by affecting both paracellular and transcellular pathways and thus may be of therapeutic value in a number of gastrointestinal conditions.
Immunomonitoring Results of a Phase II/III Study of Malignant Ascites Patients Treated with the Trifunctional Antibody Catumaxomab (Anti-EpCAM × Anti-CD3)
Authors: Michael Jäger, Alexandra Schoberth, Peter Ruf, Juergen Hess, Michael Hennig, Barbara Schmalfeldt, Pauline Wimberger, Michael Ströhlein, Bettina Theissen, Markus M. Heiss, Horst Lindhofer
Journal: Cancer Research (2011)

Patients with malignant ascites secondary to primary carcinomas benefit from intraperitoneal therapy with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Here, we report the analysis of peritoneal fluid samples from 258 patients with malignant ascites randomized to catumaxomab or control groups to investigate the molecular effects of catumaxomab treatment. In the catumaxomab group, tumor cell numbers and peritoneal levels of VEGF decreased, whereas the activation status of CD4(+) and CD8(+) T-cell populations increased more than two-fold after treatment. Notably, CD133(+)/EpCAM(+) cancer stem cells vanished from the catumaxomab samples but not from the control samples. In vitro investigations indicated that catumaxomab eliminated tumor cells in a manner associated with release of proinflammatory Th1 cytokines. Together, our findings show that catumaxomab therapy activates peritoneal T cells and eliminates EpCAM(+) tumor cells, establishing a molecular and cellular basis to understand in vivo efficacy within the immunosuppressed malignant ascites tissue microenvironment.
Mechanism of short-term improvement in lung function after emphysema resection.
Authors: A F Gelb, N Zamel, R J McKenna, M Brenner
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

We prospectively investigated the mechanism of airflow limitation before and after targeted emphysematous resection in 12 consecutively studied adult patients 68 +/- 4 yr of age (mean +/- SD) with very severe COPD undergoing bilateral thoracoscopic stapling techniques. Lung function, static lung elastic recoil, and airway conductance was measured 2 wk before and 5 to 6 mo after surgery. After surgery, there was a significant (p < 0.01) reduction in TLC (9.3 +/- 0.3 [mean +/- SEM] to 7.7 +/- 0.4 L), functional residual capacity, and residual volume. Airway conductance, FVC, and FEV1 (0.7 +/- 0.1 to 1.2 +/- 0.2 L) all improved significantly (p < 0.01). Lung elastic recoil increased markedly at TLC (from 10.3 +/- 0.5 to 14.6 +/- 1.0 cm H20; p < 0.001) as did maximal expiratory airflow in every patient. Analysis of maximal expiratory flow-static elastic recoil pressure curve indicated that conductance of the S segment (Gs) increased from 0.20 +/- 0.03 (mean +/- SEM) to 0.27 +/- 0.03 L/s/cm H20 (p < 0.01), and the critical transmural pressure (Ptm') decreased from 3.1 +/- 0.2 to 2.4 +/- 0.2 cm H20 (p < 0.02). Mean airway conductance increased from 0.14 to 0.22 L/s/cm H20 (p < 0.01). The improvement in maximal expiratory airflow can be primarily attributed to increased lung elastic recoil and its secondary effect on enlarging airway diameter causing increased airway conductance, increased Gs, and decreased Ptm'.