tbuckley/cabot-search huggingface dataset:
Cerebral Vascular Dysfunction in Methionine Synthase–Deficient Mice
Authors: Sanjana Dayal, Angela M. Devlin, Ryan B. McCaw, Mei-Lan Liu, Erland Arning, Teodoro Bottiglieri, Barry Shane, Frank M. Faraci, Steven R. Lentz
Journal: Circulation (2005)

Background— Methionine synthase (MS) catalyzes the folate-dependent remethylation of homocysteine to methionine. We tested the hypothesis that deficiency of MS impairs endothelial function in mice heterozygous for disruption of the Mtr gene, which encodes MS. Methods and Results— Plasma total homocysteine was similar in wild-type ( Mtr +/+ ) and heterozygous ( Mtr +/− ) mice fed a control diet (4.5±0.3 and 5.3±0.4 μmol/L, respectively) and mildly elevated in Mtr +/+ and Mtr +/− mice fed a low-folate (LF) diet (7.5±0.7 and 9.6±1.2 μmol/L, respectively; P &lt;0.001 versus control diet). Dilatation of cerebral arterioles to the endothelium-dependent dilator, acetylcholine (10 μmol/L) was blunted in Mtr +/− mice compared with Mtr +/+ mice fed the control diet (21±4 versus 32±4%; P &lt;0.05). Both Mtr +/+ and Mtr +/− mice exhibited impaired dilatation of cerebral arterioles to acetylcholine when they were fed the LF diet (12±2 and 14±2%, respectively; P &lt;0.01 versus Mtr +/+ mice fed the control diet). Elevated levels of superoxide and hydrogen peroxide were detected by confocal microscopy in cerebral arterioles of Mtr +/− mice fed the control diet and in both Mtr +/+ and Mtr +/− mice fed the LF diet. Conclusions— These findings demonstrate that defective homocysteine remethylation caused by deficiency of either MS or folate produces oxidative stress and endothelial dysfunction in the cerebral microcirculation of mice.
P92 Improving Diagnosis And Management Of Patients With Copd In The Acute Medical Admission Unit: A "right Care" Approach
Authors: Z. Rutter-Locher, V. Patel, K. Taylor, P. Kelly, I. Patel
Journal: Thorax (2014)

<h3>Introduction</h3> COPD is the second most common cause of emergency admission and 5th cause of readmission to hospital. Appropriate identification and treatment is crucial to make every bed day count and reduce the burden of COPD. Characterising COPD exacerbations (ECOPD) and excluding differential diagnoses in acutely unwell co-morbid patients can be challenging. This study aimed to evaluate the accuracy of diagnoses/management of patients on the acute medical unit (AMU) in an inner London teaching hospital with 300 ECOPD admissions/yr, and to develop an improvement plan. <h3>Methods</h3> Admission records for COPD patients admitted acutely with increased shortness of breath, cough and/or wheeze over 6 weeks (Jan/Feb 2014) were reviewed. Diagnostic criteria and treatment were compared to national standards. 21 AMU junior staff completed a COPD knowledge questionnaire. An ECOPD pathway was developed, highlighting diagnostic and treatment differences between infective (IECOPD), non-infective COPD exacerbations (NIECOPD) and community acquired pneumonia (CAP), supported by electronic prescribing order sets. An online learning module was developed to support junior doctors. <h3>Results</h3> 44 COPD patients (26M, 18F) were admitted to AMU. 20% had an incorrect diagnosis. Of NIECOPD patients (20%): 66% received antibiotics; 11% did not receive prednisolone. Of IECOPD patients (47%): 65% received iv or incorrect oral antibiotics; 14% did not receive prednisolone. Of CAP patients (32%): in CURB &lt;3 89% received iv antibiotics. 5 CAP patients were documented as IECOPD; 2 were undertreated. 2 IECOPD patients were diagnosed with CAP and over treated. Only 13/21 (62%) of AMU junior doctors understood the difference between NIECOPD, IECOPD and CAP. After the improvement plan, incorrect diagnosis fell from 20% to 7%. Of NIECOPD patients (28%): only 18% received antibiotic therapy; 100% received prednisolone. Of IECOPD patients (48%): 74% received correct antibiotics; 100% received prednisolone. Of CAP patients (23%): in CURB &lt;3 iv antibiotic use reduced to 50%. <h3>Conclusion</h3> COPD patients commonly present acutely with ECOPD, NIECOPD or CAP. This can cause diagnostic uncertainty in an AMU setting. A right care approach focusing on accurate diagnosis first time and guideline based therapy, supported by joint working, education and electronic prescribing can improve staff knowledge and patient management.
Designing Nonviral Vectors for Efficient Gene Transfer and Long-Term Gene Expression
Authors: Dean A. Jackson, Stefan Juranek, Hans J. Lipps
Journal: Molecular Therapy (2006)

Although the genetic therapy of human diseases has been conceptually possible for many years we still lack a vector system that allows safe and reproducible genetic modification of eukaryotic cells and ensures faithful long-term expression of transgenes. There is increasing agreement that vectors that are based exclusively on chromosomal elements, which replicate autonomously in human cells, could fulfill these criteria. The rational construction of such vectors is still hindered by our limited knowledge of the factors that regulate chromatin function in eukaryotic cells. This review sets out to summarize how our current knowledge of nuclear organization can be applied to the design of extrachromosomal gene expression vectors that can be used for human gene therapy. Within the past years a number of episomal nonviral constructs have been designed and their replication strategies, expression of transgenes, mitotic stability, and delivery strategies and the mechanisms required for their stable establishment will be discussed. To date, these nonviral vectors have not been used in clinical trials. Even so, many compelling arguments can be developed to support the view that nonviral vector systems will play a major role in future gene therapy protocols.
Assessment of group B streptococcal opsonins in human and rabbit serum by neutrophil chemiluminescence.
Authors: V G Hemming, R T Hall, P G Rhodes, A O Shigeoka, H R Hill
Journal: Journal of Clinical Investigation (1976)

The factors important in host defense against group B streptococci are not well understood. The role of antibody and complement in the prevention of serious infection by these organisms is not known because, to date, a reliable measure of functional opsonic activity has not been developed. Recently, it has been shown that neutrophils produce a chemiluminescence after ingestion of particulate matter, and that this event can be detected and quantitated in a liquid scintillation system. We have adapted the chemiluminescence procedure to examine rabbit hyperimmune and human serum for the presence of group B streptococcal opsonins. Group B streptococci of types Ia, II, and III that were opsonized in homologous but not heterologous type serum produced a peak in chemiluminescence when added to normal human neutrophils. Such activity was correlated, in each instance, with ingestion of bacteria by neutrophils and deposition of immunoglobulin and C3 on the bacterial surface as detected by indirect immunofluorescence. With this assay, we have examined sera from colonized and diseased patients for the presence of opsonins to types Ia, II, and III group B streptococci. Maternal sera often contained type-specific opsonins which resided in the IgG fraction and which crossed the placenta to appear in paired cord specimens. 63% of patients colonized with group B streptococci had serum opsonins to their colonizing type of organism. In contrast, none of the 15 patients with sepsis or meningitis had opsonins directed against their infecting strain. These data suggest that the lack of type-specific opsonins to group B streptococci may be one of the important factors in determining host susceptibility to systemic infection with strains of this group.
Implantable defibrillator therapy for ventricular tachyarrhythmia in left ventricular assist device patients
Authors: Hanno Oswald, Claudia Schultz‐Wildelau, Ajmal Gardiwal, Ulrich Lüsebrink, Thorben König, Anna Meyer, David Duncker, Maximilian A. Pichlmaier, Gunnar Klein, Martin Strüber
Journal: European Journal of Heart Failure (2010)
Right ventricular dysfunction is associated with chronic kidney disease and predicts survival in patients with chronic systolic heart failure
Authors: Frank L. Dini, Ryan T. Demmer, Anca Simioniuc, Doralisa Morrone, Francesca Donati, Giacinta Guarini, Enrico Orsini, Paolo Caravelli, Mario Marzilli, Paolo C. Colombo
Journal: European Journal of Heart Failure (2012)
MEK inhibitors as a chemotherapeutic intervention in multiple myeloma
Authors: C Chang-Yew Leow, S Gerondakis, A Spencer
Journal: Blood Cancer Journal (2013)

The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration. Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies. In this review, we explore our current understanding of the Ras/MAPK pathway and its role in MM. Additionally, we summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use.
Endogenous nitric oxide attenuates ethanol-induced perturbation of hepatic circulation in the isolated perfused rat liver
Authors: Masahide Oshita, Yoshiyuki Takei, Sunao Kawano, Taizo Hijioka, Eiji Masuda, Moritaka Goto, Yoshiya Nishimura, Hirotaka Nagai, Sadaharu Iio, Shingo Tsuji, Hideyuki Fusamoto, Takenobu Kamada
Journal: Hepatology (1994)

The purpose of this study was to clarify the role of endogenous nitric oxide in ethanol-induced perturbation of microcirculation and hepatic injury in perfused rat liver. Infusion of ethanol into the portal vein at 25 and 100 mmol/L increased portal pressure, which is an indicator of hepatic vasoconstriction, in a concentration-dependent fashion. Portal pressure started to rise immediately after ethanol load, then decreased gradually and remained at higher than basal levels throughout the period of ethanol infusion. Release of lactate dehydrogenase into the effluent perfusate began to increase after 30 min of ethanol infusion and continued to increase during the 60-min period of ethanol infusion. The lactate dehydrogenase level in the effluent perfusate at 60 min was dependent on the ethanol concentration (0 mmol/L, 8 +/- 3 IU/L; 25 mmol/L, 16 +/- 2 IU/L; 100 mmol/L, 52 +/- 6 IU/L). Simultaneous infusion of NG-monomethyl-L-arginine, a nitric oxide synthesis inhibitor, enhanced significantly the ethanol-induced increase in portal pressure by 100% to 400% and increased lactate dehydrogenase release by 40% to 80%. The effect of NG-monomethyl-L-arginine on the ethanol-induced increase in portal pressure was completely reversed by the co-infusion of an excess dose of L-arginine. Change in portal pressure averaged over 60 min of ethanol infusion correlated with levels of lactate dehydrogenase release 60 min after the initiation of ethanol infusion (r = 0.77, p < 0.01). In conclusion, inhibition of the action of endogenous nitric oxide was associated with an increase in hepatic vasoconstriction and hepatocellular damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study
Authors: P. Henriksson, E. Westerlund, H. Wallen, L. Brandt, O. Hovatta, A. Ekbom
Journal: BMJ (2013)

To estimate the risk of pulmonary embolism and venous thromboembolism in pregnant women after in vitro fertilisation.Cross sectional study.Sweden.23,498 women who had given birth after in vitro fertilisation between 1990 and 2008 and 116,960 individually matched women with natural pregnancies.Risk of pulmonary embolism and venous thromboembolism (identified by linkage to the Swedish national patient register) during the whole pregnancy and by trimester.Venous thromboembolism occurred in 4.2/1000 women (n=99) after in vitro fertilisation compared with 2.5/1000 (n=291) in women with natural pregnancies (hazard ratio 1.77, 95% confidence interval 1.41 to 2.23). The risk of venous thromboembolism was increased during the whole pregnancy (P<0.001) and differed between the trimesters (P=0.002). The risk was particularly increased during the first trimester, at 1.5/1000 after in vitro fertilisation versus 0.3/1000 (hazard ratio 4.22, 2.46 to 7.26). The proportion of women experiencing pulmonary embolism during the first trimester was 3.0/10,000 after in vitro fertilisation versus 0.4/10,000 (hazard ratio 6.97, 2.21 to 21.96).In vitro fertilisation is associated with an increased risk of pulmonary embolism and venous thromboembolism during the first trimester. The risk of pulmonary embolism is low in absolute terms but because the condition is a leading cause of maternal mortality and clinical suspicion is critical for diagnosis, an awareness of this risk is important.ClinicalTrials.gov NCT01524393.
Revision of the Code of Ethics.
Authors: Fair Play
Journal: JAMA (1893)

<h3>To the Editor of the Journal of the American Medical Association:</h3><h3>Dear Sir:</h3> —We are glad to hear a nineteenth century voice from California. I, for one, can honestly concur in what he has written, living as I do near a medical center of some importance. What can we lesser lights do when the president of one of the best (if not the best) colleges in the State can trephine a case for a homœopath? Another who is a professor in the same school, and has had the honor of being chairman of one of the Sections of the American Medical Association, sending a nice little note to the dean of the homœopathic department of the University of Michigan, "who is a good friend of his," concurring in his opinion and advising him to follow the plan he recommended. Another professor holding an important position on last year's committee of
Update in Sleep Medicine 2011
Authors: Thomas B. Rice, Patrick J. Strollo, Mary J. Morrell
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Although it is unclear why all respiratory events in obstructive sleep apnea (OSA) are not terminated with a recognizable cortical arousal, it has been hypothesized that events terminated without arousal may lead to more stable breathing. Jordan and colleagues attempted to define the physiologic parameters immediately related to stable breathing, including airflow, genioglossus and tensor palatini muscle activity, and airway resistance, after respiratory events terminated with or without cortical arousal (1). They hypothesized that respiratory events terminated without cortical arousal would produce less hyperventilation and less secondary events due to higher pharyngeal dilator activity compared with events with arousal. Sixteen patients with mild to severeOSA already treated with continuous positive airway pressure (CPAP) were studied. Using a sudden drop in CPAP pressure to subtherapeutic levels, they found that respiratory events terminated without arousal led to less hyperventilation and less secondary events (primarily hypopneas) compared with events terminated with arousal. This reduction in inspiredminute ventilation and subsequent events was not accounted for by differences in residual pharyngeal dilator activity. Specifically, secondary events were marked by less flow limitation and greater pharyngeal dilator activity relative to the initial event whether cortical arousal was present or not. These findings question the notion of arousal predisposing patients to further obstructive events.
Epsilon germ‐line and IL‐4 transcripts are expressed in human intestinal mucosa and enhanced in patients with food allergy
Authors: M. Coëffier, A. Lorentz, M. P. Manns, S. C. Bischoff
Journal: Allergy (2005)

Background: The mechanisms of gastrointestinal (GI) food allergy (FA) are poorly understood. Immunoglobulin E (IgE) is increased in stools from patients with FA, as well as the number of cells carrying IgE in intestinal mucosa, but the origin of IgE production remains unknown. To investigate a local production of IgE in intestine, we analysed the levels of transcripts for epsilon germ‐line ( ε GT), and potential regulators of IgE production, IL‐4, IL‐13, IFN‐ γ , IL‐4R α , STAT6 and Fc ε RI α in intestinal mucosa of adult patients with FA. Methods: Endoscopic biopsies were obtained from the caecum of 25 patients with FA and 14 control patients. The levels of ε GT, IL‐4, IL‐13, IFN‐ γ , IL‐4R α , STAT6 and Fc ε RI α mRNA were analysed by real‐time RT‐PCR and compared with unpaired nonparametric Mann–Whitney test. Results: The mean ε GT transcript level in caecum was increased in FA patients compared with control patients ( P &lt; 0.05). IL‐4 mRNA expression was also increased in FA patients ( P &lt; 0.05), whereas mRNA expression for IL‐13, IFN‐ γ , IL‐4R α , STAT6 and Fc ε RI α mRNA expression was not altered. However, the ratio of IL‐4 mRNA/IFN‐ γ mRNA was significantly increased in FA patients ( P &lt; 0.05). No correlation was observed between ε GT transcripts expression in intestinal mucosa and total IgE levels in serum. Conclusions: This study shows that (i) ε GT transcripts are expressed in human intestinal mucosa; (ii) ε GT and IL‐4 transcripts are increased in caecal mucosa from patients with FA. These results suggest local production of IgE in intestine that might be of importance for inflammatory reactions in the GI tract.
Bleeding and mortality outcomes in ITP clinical trials: A review of thrombopoietin mimetics data
Authors: Ivy Altomare, Jeffrey Wasser, Vinod Pullarkat
Journal: American Journal of Hematology (2012)

Patients with ITP may have severe thrombocytopenia, putting them at risk for serious bleeding. ITP trials of new treatments must allow use of standard-of-care therapies to prevent serious bleeding. Thrombopoietin mimetic trials used platelet counts and rescue/concomitant medication use as endpoints. These trials were of insufficient size and duration to measure mortality or serious bleeding, which are infrequent with appropriate treatment. A recent Cochrane review criticized the thrombopoietin mimetic registrational trials for inadequately assessing bleeding and survival. We discuss how these endpoints are difficult to measure in clinical trials designed to improve platelet counts and minimize bleeding, in accordance with ethical trial design.
The Causes of Blindness in Childhood: A Study of 776 Children With Severe Visual Handicaps
Authors: Albert M. Potts
Journal: JAMA (1968)

This volume reports study done in England and Wales in the special schools for the blind. The study was performed on a sample of 724 blind children of a total population of 3,160. In addition, 52 children of a total of 2,202 partially sighted children were reviewed. For all categories except the preschool 0 to 5 age group, the sample averaged 25% of the total number of children and may be expected to be accurately representative of the group. Although we are not given a census figure on the total population under age 20 in England and Wales, the total number of blind children is evidently very small. Reasonably evident is the ephemeral nature of data such as these and the value of recording them. The value lies not in their immutability but their importance in documenting a stage in medical history. At this particular period, blindness due to infectious
Surgical Treatment of High Pressure Patent Ductus Arteriosus
Authors: HAROLD TSUJI, MORSE SHAPIRO, OSCAR MAGIDSON, EDWARD DUNNE, PETER DYKSTRA, JEROME HAROLD KAY
Journal: Circulation (1963)

Thirteen patients with high pressure patent ductus arteriosus were operated upon. There was no operative mortality in this group. Twelve patients have shown remarkable clinical improvement, and there was a decrease in the pulmonary arterial pressure at the time of recatheterization in 11 of these patients restudied. One patient developed severe pulmonary hypertension and died six and one-half years after operation. The pulmonary arterial systolic pressure dropped minimally in two patients, despite marked clinical improvement. Both patients had associated lesions: a large ventricular septal defect in one and severe congenital aortic stenosis in the other. Both patients are to be operated upon. All patients with a predominant left-to-right shunt and a patent ductus arteriosus should have division of the patent ductus arteriosus. If a concomitant lesion requiring open-heart operation, such as a ventricular septal defect or aortic stenosis, is present, it should be corrected at a later date.
War and the Health of Nations
Authors: Amesh A. Adalja
Journal: JAMA (2010)

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ABC of Sports Medicine: Temperature and Performance I: Cold
Authors: E L Lloyd
Journal: BMJ (1994)

Environmental temperature may cause problems through being either too cold or too hot; and the effects may be general, local, or secondary.These effects range from impairment of performance through injury or illness to possible death, either directly or indirectly.The effects of extreme cold in sport are more prevalent than are the results of extreme heat.For instance, for most sports in the world one of the numerically greatest hazards of cold is torn muscles or tendons.Hypothermia is also more common in Britain than is heatstroke.At milder degrees, cold can result in illness, injury, and death, whereas heat generally merely affects performance.
Slit1a Inhibits Retinal Ganglion Cell Arborization and Synaptogenesis via Robo2-Dependent and -Independent Pathways
Authors: Douglas S. Campbell, Sydney A. Stringham, Adam Timm, Tong Xiao, Mei-Yee Law, Herwig Baier, Michael L. Nonet, Chi-Bin Chien
Journal: Neuron (2007)