tbuckley/cabot-search huggingface dataset:
Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts
Authors: P Di Napoli
Journal: Cardiovascular Research (2001)

We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia-reperfusion, and investigated potential mechanisms.Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of simvastatin (10-100 microM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D.Simvastatin (25 microM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 microM and reverted to increased damage at 100 microM. At 25 microM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N(pi)-nitro-L-arginine methylester (L-NAME, 30 microM) to 25 microM simvastatin-treated hearts significantly reduced cardioprotection against ischemia-reperfusion.In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterol-independent, NO-dependent mechanisms.
The Process and Development of Image-Guided Procedures
Authors: Robert L. Galloway
Journal: Annual Review of Biomedical Engineering (2001)

▪ Abstract Medical imaging has been used primarily for diagnosis. In the past 15 years there has been an emergence of the use of images for the guidance of therapy. This process requires three-dimensional localization devices, the ability to register medical images to physical space, and the ability to display position and trajectory on those images. This paper examines the development and state of the art in those processes.
Experiences with Sulphanilamide Derivatives in Some Tropical Conditions
Authors: K. V. Earle
Journal: BMJ (1941)

BRITISHthrown into sharp relief by the mobilization of oLur man- power for war.It would occasion little surprise if the qtickening tempo of modern life were fouLnd to have a direct bearing on the problem presented by the increasing occuLrrence of the dyspepsias.No entirely convincing clUe to this enigma has yet been offered, but it will be interesting to learn whether or not life in our Forces is adding significantly to the already high frequency of such dis- orders.Final judgment on this point must, of coulrse, await the conclusion of the present conflict.We are in entire agreement with the leading article in the British Medical Journial of December 14, 1940, which stated that "the Army still marches on its stomach even though it travels in mechanized vehicles," and the dyspeptic passenger mustbe carefully scruitinized before taking part in the journey.Summary and Conclusions In Army medicine digestive disorders are presenting a lar-ge and increasing problem.Of 790 medical in-patients 246
Randomised controlled trial of an interactive multimedia decision aid on hormone replacement therapy in primary
Authors: E. Murray, H. Davis, S. S. Tai, A. Coulter, A. Gray, A. Haines
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To determine whether a decision aid on hormone replacement therapy influences decision making and health outcomes. <b>Design:</b> Randomised controlled trial. <b>Setting:</b> 26 general practices in the United Kingdom. <b>Participants:</b> 205 women considering hormone replacement therapy. <b>Intervention:</b> Patients9 decision aid consisting of an interactive multimedia programme with booklet and printed summary. <b>Outcome measures:</b> Patients9 and general practitioners9 perceptions of who made the decision, decisional conflict, treatment choice, menopausal symptoms, costs, anxiety, and general health status. <b>Results:</b> Both patients and general practitioners found the decision aid acceptable. At three months, mean scores for decisional conflict were significantly lower in the intervention group than in the control group (2.5 <i>v</i> 2.8; mean difference −0.3, 95% confidence interval −0.5 to −0.2); this difference was maintained during follow up. A higher proportion of general practitioners perceived that treatment decisions had been made “mainly or only” by the patient in the intervention group than in the control group (55% <i>v</i> 31%; 24%, 8% to 40%). At three months a lower proportion of women in the intervention group than in the control group were undecided about treatment (14% <i>v</i> 26%; −12%, −23% to −0.4%), and a higher proportion had decided against hormone replacement therapy (46% <i>v</i> 32%; 14%, 1% to 28%); these differences were no longer apparent by nine months. No differences were found between the groups for anxiety, use of health service resources, general health status, or utility. The higher costs of the intervention were largely due to the video disc technology used. <b>Conclusions:</b> An interactive multimedia decision aid in the NHS would be popular with patients, reduce decisional conflict, and let patients play a more active part in decision making without increasing anxiety. The use of web based technology would reduce the cost of the intervention. <h3>What is already known on this topic</h3> Patients want more information about their conditions and treatment options, and many want to play an active part in decision making Decision aids improve patients9 knowledge of their conditions and treatment options <h3>What this study adds</h3> The decision aid was acceptable to both the patients and their general practitioners Decisional conflict was reduced in the intervention group Patients who viewed the programme played a more active part in the decision making process and were no more anxious than control patients Such aids could be introduced throughout the NHS at relatively low cost by using the internet
Arthritis of the large joints--in particular, the knee--at first presentation is predictive for a high level of radiological destruction of the small joints in rheumatoid arthritis
Authors: S P Linn-Rasker, A H M van der Helm-van Mil, F C Breedveld, T W J Huizinga
Journal: Annals of the Rheumatic Diseases (2006)

To investigate the predictive value of the distribution of inflamed joints at first presentation for the severity of the disease course in rheumatoid arthritis (RA).Of the 1009 consecutive patients included in the Leiden Early Arthritis Clinic (Leiden, The Netherlands), 285 patients fulfilled the American College of Rheumatology criteria for RA within 1 year of follow-up. Of these, 28 patients achieved remission. Radiographs of hands and feet were scored according to the Sharp-van der Heijde method, and the 28 patients with the most destructive disease were selected. The distribution of inflamed joints of the patients with the extreme disease courses was compared. The association between the distribution of inflamed joints and the level of destruction of the joints of hands and feet in the whole group of patients with RA was assessed using regression analysis.Comparison of patients with extreme disease courses using univariate and logistic regression analyses showed that arthritis of the large joints - in particular, the knee - was associated with severe RA. In the whole group of patients with RA, the total number of swollen joints and the presence of knee arthritis were associated independently with the level of destruction of the small joints. Patients with RA with knee arthritis had higher C reactive protein (CRP) levels than patients without knee arthritis, and investigating the distribution of inflamed joints together with other variables yielded the number of swollen joints, CRP, presence of anti-cyclic citrullinated peptide antibodies and symptom duration as predictors for severity of RA.Arthritis of large joints - in particular, the knee - at first presentation is associated with a destructive course of RA.
National Heart, Lung, and Blood Institute and the Translation of Cardiovascular Discoveries Into Therapeutic Approaches
Authors: Zorina S. Galis, Jodi B. Black, Sonia I. Skarlatos
Journal: Circulation Research (2013)

The molecular causes of ≈4000 medical conditions have been described, yet only 5% have associated therapies. For decades, the average time for drug development through approval has taken 10 to 20 years. In recent years, the serious challenges that confront the private sector have made it difficult to capitalize on new opportunities presented by advances in genomics and cellular therapies. Current trends are disturbing. Pharmaceutical companies are reducing their investments in research, and biotechnology companies are struggling to obtain venture funds. To support early-stage translation of the discoveries in basic science, the National Institutes of Health and the National Heart, Lung, and Blood Institute have developed new approaches to facilitating the translation of basic discoveries into clinical applications and will continue to develop a variety of programs that create teams of academic investigators and industry partners. The goal of these programs is to maximize the public benefit of investment of taxpayer dollars in biomedical research and to lessen the risk required for industry partners to make substantial investments. This article highlights several examples of National Heart, Lung, and Blood Institute-initiated translational programs and National Institutes of Health translational resources designed to catalyze and enable the earliest stages of the biomedical product development process. The translation of latest discoveries into therapeutic approaches depends on continued federal funding to enhance the early stages of the product development process and to stimulate and catalyze partnerships between academia, industry, and other sources of capital.
Psychological and Behavioral Approaches to Cancer Pain Management
Authors: Karen L. Syrjala, Mark P. Jensen, M. Elena Mendoza, Jean C. Yi, Hannah M. Fisher, Francis J. Keefe
Journal: Journal of Clinical Oncology (2014)

This review examines evidence for psychological factors that affect pain across the cancer continuum from diagnosis through treatment and long-term survivorship or end of life. Evidence is convincing that emotional distress, depression, anxiety, uncertainty, and hopelessness interact with pain. Unrelieved pain can increase a desire for hastened death. Patients with cancer use many strategies to manage pain, with catastrophizing associated with increased pain and self-efficacy associated with lower pain reports. A variety of psychological and cognitive behavioral treatments can reduce pain severity and interference with function, as indicated in multiple meta-analyses and high-quality randomized controlled trials. Effective methods include education (with coping skills training), hypnosis, cognitive behavioral approaches, and relaxation with imagery. Exercise has been tested extensively in patients with cancer and long-term survivors, but few exercise studies have evaluated pain outcomes. In survivors post-treatment, yoga and hypnosis as well as exercise show promise for controlling pain. Although some of these treatments effectively reduce pain for patients with advanced disease, few have been tested in patients at the end of life. Given the clear indicators that psychological factors affect cancer pain and that psychological and behavioral treatments are effective in reducing varying types of pain for patients with active disease, these methods need further testing in cancer survivors post-treatment and in patients with end-stage disease. Multidisciplinary teams are essential in oncology settings to integrate analgesic care and expertise in psychological and behavioral interventions in standard care for symptom management, including pain.
Targeting Hypoxic Cells through the DNA Damage Response
Authors: Monica Olcina, Philip S. Lecane, Ester M. Hammond
Journal: Clinical Cancer Research (2010)

Exposure to hypoxia-induced replication arrest initiates a DNA damage response that includes both ATR- and ATM-mediated signaling. DNA fiber analysis was used to show that these conditions lead to a replication arrest during both the initiation and elongation phases, and that this correlated with decreased levels of nucleotides. The DNA damage response induced by hypoxia is distinct from the classical pathways induced by damaging agents, primarily due to the lack of detectable DNA damage, but also due to the coincident repression of DNA repair in hypoxic conditions. The principle aims of the hypoxia-induced DNA damage response seem to be the induction of p53-dependent apoptosis or the preservation of replication fork integrity. The latter is of particular importance should reoxygenation occur. Tumor reoxygenation occurs as a result of spontaneous changes in blood flow and also therapy. Cells experiencing hypoxia and/or reoxygenation are, therefore, sensitive to loss or inhibition of components of the DNA damage response, including Chk1, ATM, ATR, and poly(ADP-ribose) polymerase (PARP). In addition, restoration of hypoxia-induced p53-mediated signaling may well be effective in the targeting of hypoxic cells. The DNA damage response is also induced in endothelial cells at moderate levels of hypoxia, which do not induce replication arrest. In this situation, phosphorylation of H2AX has been shown to be required for proliferation and angiogenesis and is, therefore, an attractive potential therapeutic target.
Attenuated Frontal Activation During a Verbal Fluency Task in Patients With Schizophrenia
Authors: Vivienne A. Curtis, Edward T. Bullmore, Michael J. Brammer, Ian C. Wright, Steve C.R. Williams, Robin G. Morris, Tonmoy S. Sharma, Robin M. Murray, Philip K. McGuire
Journal: American Journal of Psychiatry (1998)

Functional magnetic resonance imaging was used to study changes in cerebral blood oxygenation in schizophrenic patients during a verbal fluency task.Five right-handed male schizophrenic patients and five volunteers matched on demographic variables and verbal fluency performance participated in the study. Echoplanar images were acquired over 5 minutes at 1.5 T while the subjects performed two tasks. The first involved paced silent generation of words beginning with an aurally presented cue letter. This task alternated with paced silent repetition of the aurally presented word "rest." Generic brain activation maps were constructed from individual images by sinusoidal regression and non-parametric hypothesis testing. Between-group differences in the mean power of experimental response were identified on a voxelwise basis by an analysis of covariance that controlled for between-group differences in stimulus-correlated motion.The comparison group showed significant responses in the left prefrontal cortex, the insula bilaterally, the midline supplementary motor area, and the medial parietal cortex. Compared to those subjects, the schizophrenic subjects showed significantly reduced power of response in the left dorsal prefrontal cortex, the inferior frontal gyrus, and the insula but significantly increased power of response in the medial parietal cortex. In both groups frontal and parietal responses were negatively correlated.Schizophrenic patients displayed attenuated power of response in several frontal regions during word generation but greater power of response in the medial parietal cortex during word repetition.
Static and Dynamic Cognitive Deficits in Childhood Preceding Adult Schizophrenia: A 30-Year Study
Authors: Abraham Reichenberg, Avshalom Caspi, HonaLee Harrington, Renate Houts, Richard S.E. Keefe, Robin M. Murray, Richie Poulton, Terrie E. Moffitt
Journal: American Journal of Psychiatry (2010)

Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders?
Cell line-dependent differentiation of induced pluripotent stem cells into cardiomyocytes in mice
Authors: Shinji Kaichi, Koji Hasegawa, Tomohide Takaya, Noritaka Yokoo, Takahiro Mima, Teruhisa Kawamura, Tatsuya Morimoto, Koh Ono, Shiro Baba, Hiraku Doi, Shinya Yamanaka, Tatsutoshi Nakahata, Toshio Heike
Journal: Cardiovascular Research (2010)

Mouse and human fibroblasts can be directly reprogrammed to pluripotency by the ectopic expression of four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) to yield induced pluripotent stem (iPS) cells. iPS cells can be generated even without the expression of c-Myc. The present study examined patterns of differentiation of mouse iPS cells into cardiomyocytes in three different cell lines reprogrammed by three or four factors. During the induction of differentiation on feeder-free gelatinized dishes, genes involved in cardiogenesis were expressed as in embryonic stem cells and myogenic contraction occurred in two iPS cell lines. However, in one iPS cell line (20D17) generated by four factors, the expression of cardiac-specific genes and the beating activity were extremely low. Treating iPS cells with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased Nkx2.5 expression in all iPS cell lines. While the basal Nkx2.5 expression was very low in 20D17, the TSA-induced increase was the greatest. TSA also induced the expression of contractile proteins in 20D17. Furthermore, we demonstrated the increased mRNA level of Oct3/4 and nuclear protein level of HDAC4 in 20D17 compared with the other two iPS cell lines. DNA microarray analysis identified genes whose expression is up- or down-regulated in 20D17. Mouse iPS cells differentiate into cardiomyocytes in a cell line-dependent manner. TSA induces myocardial differentiation in mouse iPS cells and might be useful to overcome cell line variation in the differentiation efficiency.
Analysis of rpsL and rrs mutations in Beijing and non-Beijing streptomycin-resistant Mycobacterium tuberculosis isolates from Singapore
Authors: Y.-J. Sun, J.-T. Luo, S.-Y. Wong, A.S.G. Lee
Journal: Clinical Microbiology and Infection (2009)

The Beijing genotype of Mycobacterium tuberculosis has frequently been found to be associated with drug resistance. Mutation analysis of the genes encoding 16S rRNA (rrs) and ribosomal protein S12 (rpsL) revealed a high frequency (97/102; 95.1%) of alterations in streptomycin-resistant M. tuberculosis isolates from Singapore, with rpsL K43R being the most common rpsL mutation (82/92; 89%), which was significantly associated with Beijing strains compared to non-Beijing strains (odds ratio = 10.88, 95% confidence interval = 3.48-34.1). This is the first study to report the association of Beijing strains with the rpsL K43R mutation in STR-resistant M. tuberculosis isolates with de novo resistance, as determined by clustering analysis.
Polymerase pinch hitters
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

On page 1191, Delbos and colleagues provide the first proof that the error-prone polymerase η (polη) is responsible for mutations at A-T base pairs during somatic hypermutation (SHM) of immunoglobulin (Ig) genes in mice. But when polη is removed from mice, another sloppy enzyme, not previously thought to contribute to SHM, can fill in as a pinch hitter.

SHM generates high affinity antibodies in response to antigenic challenge; it does so by introducing point mutations into the antigen-binding regions of B cell antibody genes. Mutations at C-G base pairs during SHM are the work of the enzyme AID (activation-induced cytidine deaminase), which turns cytosine into uracil. A-T mutations have been harder to explain. Error-prone polymerases are thought be the culprits behind A-T mutation, but specific roles for these enzymes have been difficult to assign, as mice lacking individual polymerases have thus far shown no defects in SHM.

Polη has been the primary suspect charged with mutating A-T base pairs, as the pattern of errors made by polη in vitro is reminiscent of that seen in mutated Ig loci. In addition, humans lacking polη have fewer A-T mutations in their Ig genes than normal. Delbos et al. now solidify the evidence by showing that elimination of polη in mice decreases Ig gene mutations at A-T base pairs.

The few A-T mutations that occurred in the absence of polη—to the authors' surprise—bore the signature of another polymerase, polκ, which does not normally meddle in SHM. The authors suggest that the mismatch repair protein complex MSH2–MSH6, recently shown to recruit polη to AID-induced U-G mismatches, may in polη's absence instead bind polκ. The polκ would then cause mutations at nearby A-T sites.
Changes in Vigorous Physical Activity and Incident Diabetes in Male Runners
Authors: Paul T. Williams
Journal: Diabetes Care (2007)

OBJECTIVE—We examined the relationship between changes in reported vigorous exercise and self-reported physician-diagnosed diabetes in 25,988 active men. RESEARCH DESIGN AND METHODS—The dose-response relationship between changes in reported vigorous exercise (running distance, change in kilometers per week) and self-reported physician-diagnosed diabetes was followed prospectively for 7.8 ± 1.8 years (means ± SD). RESULTS—Logistic regression analyses showed that the log odds for diabetes declined significantly in relation to men's change in running distance (coefficient ± SE: −0.012 ± 0.004, P &amp;lt; 0.01), which remained significant when adjusted for BMI (−0.018 ± 0.003, P &amp;lt; 0.0001). The decline in the log odds for diabetes was related to the distance run at the end of follow-up when adjusted for baseline distance, with (−0.024 ± 0.005, P &amp;lt; 0.0001) or without (−0.027 ± 0.005, P &amp;lt; 0.0001) adjustment for BMI. Baseline distance was unrelated to diabetes incidence when adjusted for the distance at the end of follow-up. Compared with men who ran &amp;lt;8 km/week at the end of follow-up, incidence rates in those who ran ≥8 km/week were 95% lower between 35 and 44 years of age (P &amp;lt; 0.0001), 92% lower between 45 and 54 (P &amp;lt; 0.0001), 87% lower between 55 and 64 (P &amp;lt; 0.0001), and 46% lower between 65 and 75 (P = 0.30). For the subset of 6,208 men who maintained the same running distance during follow-up (±5 km/week), the log odds for diabetes declined with weekly distance run (−0.024 ± 0.010, P = 0.02) but not when adjusted for BMI (−0.005 ± 0.010, P = 0.65). CONCLUSIONS—Vigorous exercise significantly reduces diabetes incidence, due in part to the prevention of age-related weight gain and in part to other exercise effects.