tbuckley/cabot-search huggingface dataset:
Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial
Authors: Hugh S Markus, Elizabeth Hayter, Christopher Levi, Adina Feldman, Graham Venables, John Norris
Journal: The Lancet Neurology (2015)

Extracranial carotid and vertebral artery dissection is an important cause of stroke, especially in young people. In some observational studies it has been associated with a high risk of recurrent stroke. Both antiplatelet drugs and anticoagulant drugs are used to reduce risk of stroke but whether one treatment strategy is more effective than the other is unknown. We compared their efficacy in the Cervical Artery Dissection in Stroke Study (CADISS), with the additional aim of establishing the true risk of recurrent stroke.We did this randomised trial at hospitals with specialised stroke or neurology services (39 in the UK and seven in Australia). We included patients with extracranial carotid and vertebral dissection with onset of symptoms within the past 7 days. Patients were randomly assigned (1:1) by an automated telephone randomisation service to receive antiplatelet drugs or anticoagulant drugs (specific treatment decided by the local clinician) for 3 months. Patients and clinicians were not masked to allocation, but investigators assessing endpoints were. The primary endpoint was ipsilateral stroke or death in the intention-to-treat population. The trial was registered with EUDract (2006-002827-18) and ISRN (CTN44555237).We enrolled 250 participants (118 carotid, 132 vertebral). Mean time to randomisation was 3·65 days (SD 1·91). The major presenting symptoms were stroke or transient ischaemic attack (n=224) and local symptoms (headache, neck pain, or Horner's syndrome; n=26). 126 participants were assigned to antiplatelet treatment versus 124 to anticoagulant treatment. Overall, four (2%) of 250 patients had stroke recurrence (all ipsilateral). Stroke or death occurred in three (2%) of 126 patients versus one (1%) of 124 (odds ratio [OR] 0·335, 95% CI 0·006-4·233; p=0·63). There were no deaths, but one major bleeding (subarachnoid haemorrhage) in the anticoagulant group. Central review of imaging failed to confirm dissection in 52 patients. Preplanned per-protocol analysis excluding these patients showed stroke or death in three (3%) of 101 patients in the antiplatelet group versus one (1%) of 96 patients in the anticoagulant group (OR 0·346, 95% CI 0·006-4·390; p=0·66).We found no difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection but stroke was rare in both groups, and much rarer than reported in some observational studies. Diagnosis of dissection was not confirmed after review in many cases, suggesting that radiographic criteria are not always correctly applied in routine clinical practice.Stroke Association.
Relationship between ventilatory constraint and muscle fatigue during exercise in COPD
Authors: S. J. Butcher, O. Lagerquist, D. D. Marciniuk, S. R. Petersen, D. F. Collins, R. L. Jones
Journal: European Respiratory Journal (2008)

Dynamic hyperinflation and leg muscle fatigue are independently associated with exercise limitation in patients with chronic obstructive pulmonary disease (COPD). The aims of the present study were to examine 1) the relationship between these limitations and 2) the effect of delaying ventilatory limitation on exercise tolerance and leg muscle fatigue. In total, 11 patients with COPD (with a forced expiratory volume in one second of 52% predicted) completed two cycling bouts breathing either room air or heliox, and one bout breathing heliox but stopping at room air isotime. End-expiratory lung volume (EELV), leg muscle fatigue and exercise time were measured. On room air, end-exercise EELV was negatively correlated with leg fatigue. Heliox increased exercise time (from 346 to 530 s) and leg fatigue (by 15%). At isotime, there was no change in leg fatigue, despite a reduction in EELV compared with end-exercise, in both room air and heliox. The change in exercise time with heliox was best correlated with room air leg fatigue and end-inspiratory lung volume. Patients with chronic obstructive pulmonary disease who had greater levels of dynamic hyperinflation on room air had less muscle fatigue. These patients were more likely to increase exercise tolerance with heliox, which resulted in greater leg muscle fatigue.
Childhood Conditions Influence Adult Progesterone Levels
Authors: Alejandra Núñez-de la Mora, Robert T Chatterton, Osul A Choudhury, Dora A Napolitano, Gillian R Bentley
Journal: PLoS Medicine (2007)

Background Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among populations. The causes of such chronic differences are not well understood, but it has been hypothesised that they may result from varying tempos of growth and maturation and, by implication, from diverse environmental conditions encountered during childhood and adolescence. Methods and Findings To test this hypothesis, we conducted a migrant study among first- and second-generation Bangladeshi women aged 19–39 who migrated to London, UK at different points in the life-course, women still resident in Bangladesh, and women of European descent living in neighbourhoods similar to those of the migrants in London (total n = 227). Data collected included saliva samples for radioimmunoassay of progesterone, anthropometrics, and information from questionnaires on diet, lifestyle, and health. Results from multiple linear regression, controlled for anthropometric and reproductive variables, show that women who spend their childhood in conditions of low energy expenditure, stable energy intake, good sanitation, low immune challenges, and good health care in the UK have up to 103% higher levels of salivary progesterone and an earlier maturation than women who develop in less optimal conditions in Sylhet, Bangladesh (F9,178 = 5.05, p < 0.001, standard error of the mean = 0.32; adjusted R2 = 0.16). Our results point to the period prior to puberty as a sensitive phase when changes in environmental conditions positively impact developmental tempos such as menarcheal age (F2,81 = 3.21, p = 0.03) and patterns of ovarian function as measured using salivary progesterone (F2,81 = 3.14, p = 0.04). Conclusions This research demonstrates that human females use an extended period of the life cycle prior to reproductive maturation to monitor their environment and to modulate reproductive steroid levels in accordance with projected conditions they might encounter as adults. Given the prolonged investment of human pregnancy and lactation, such plasticity (extending beyond any intrauterine programming) enables a more flexible and finely tuned adjustment to the potential constraints or opportunities of the later adult environment. This research is the first, to our knowledge, to demonstrate a postuterine developmental component to variation in reproductive steroid levels in women.
Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria.
Authors: L S Sidossis, C A Stuart, G I Shulman, G D Lopaschuk, R R Wolfe
Journal: Journal of Clinical Investigation (1996)

We tested the hypothesis that glucose plus insulin determine the rate of fat oxidation in humans by controlling the rate of fatty acid entrance into the mitochondria. We gave constant infusions of [1-13C]oleate, a long-chain fatty acid, and [1-14C]octanoate, a medium-chain fatty acid, for 3 h in seven volunteers (basal). Immediately after the basal period, a hyperinsulinemic (insulin infusion = 120 mU x m(-2) min(-1)), hyperglycemic (plasma glucose = 140 mg/dl) clamp was started and continued for 5 h. During the last 3 h of the clamp, the infusions of [1-13C]oleate and [1-14C]octanoate were repeated. Intracellular acylcarnitine concentrations were measured in muscle biopsies obtained before and after the clamp. Plasma oleate enrichment and FFA concentration were kept constant by means of variable infusions of lipids and heparin. Oleate, but not octanoate, requires carnitine binding to gain access to the mitochondrial matrix; hence, if glucose and/or insulin limit long-chain fatty acid entrance into the mitochondria, then, during the clamp, long-chain acylcarnitine formation should be decreased, causing a decrease in oleate, but not octanoate, oxidation. Oleate oxidation decreased from the basal value of 0.7+/-0.1 to 0.4+/-0.1 micromol x kg(-1) x min(-1) (P < 0.05). In contrast, octanoate oxidation remained unchanged. Long-chain acylcarnitine concentration decreased from 855+/-271 in the basal state to 376+/-83 nmol/gram dry weight during the clamp (P < 0.05). We conclude that glucose and/or insulin determine fatty acid oxidation by controlling the rate of long-chain fatty acid entrance into the mitochondria.
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature
Authors: J. Kluk, M. Rustin, P.A. Brogan, E. Omoyinmi, D.M. Rowczenio, L.C. Willcocks, L. Melly, H.J. Lachmann
Journal: British Journal of Dermatology (2013)

Dear Editor, Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a new autoinflammatory syndrome caused by mutations in the gene for proteasome subunit, beta type, 8 (PSMB8). We report a young adult with a novel homozygous PSMB8 mutation and marked skin disease.
Prorenin and Angiotensin-Dependent Renal Vasoconstriction in Type 1 and Type 2 Diabetes
Authors: Ana R Stankovic, Naomi D L Fisher, Norman K Hollenberg
Journal: Journal of the American Society of Nephrology (2006)

Prorenin is a powerful marker for risk of nephropathy and retinopathy in diabetes, but the responsible mechanism remains unclear. Studied were 35 patients with diabetes (18 with type 1 and 17 with type 2) and 69 age-matched healthy subjects with para-aminohippurate and inulin clearances and their response to captopril. All patients with diabetes had normal renal function and no microalbuminuria. Prorenin was calculated as the difference between total renin and active renin. Active renin level in patients with diabetes (11.6 +/- 0.9 microU/ml) was significantly lower than in normal subjects (14.5 +/- 1.3 microU/ml; P < 0.05); despite this, the renal vascular response to captopril was much larger (82.9 +/- 11.5 versus 13.6 +/- 5.8 ml/min per 1.73 m(2); P < 0.01). Prorenin in both patients with type 1 and type 2 diabetes (175.7 +/- 15.1 microU/ml) also was significantly higher than in normal subjects (128 +/- 5.8 microU/ml; P < 0.01). Active renin correlated with prorenin in normal subjects (r = 0.44, P = 0.0002), and this correlation was much more striking in patients with diabetes (r = 0.72, P = 0.0001). The active renin and prorenin correlation was identical in type 1 and type 2 diabetes. There was a clear correlation between plasma prorenin and the renovascular response to captopril in patients with diabetes (P < 0.01) but not in normal subjects (P > 0.13). The strong correlation between plasma prorenin concentration and the renovascular response to captopril in diabetes supports the hypothesis of a direct effect of prorenin, but the unanticipated high degree of correlation between plasma prorenin and active renin limits the conclusions that can be drawn.
Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays
Authors: Kelli L VanDussen, Jeffrey M Marinshaw, Nurmohammad Shaikh, Hiroyuki Miyoshi, Clara Moon, Phillip I Tarr, Matthew A Ciorba, Thaddeus S Stappenbeck
Journal: Gut (2014)

<h3>Objective</h3> The technology for the growth of human intestinal epithelial cells is rapidly progressing. An exciting possibility is that this system could serve as a platform for individualised medicine and research. However, to achieve this goal, human epithelial culture must be enhanced so that biopsies from individuals can be used to reproducibly generate cell lines in a short time frame so that multiple, functional assays can be performed (ie, barrier function and host–microbial interactions). <h3>Design</h3> We created a large panel of human gastrointestinal epithelial cell lines (n=65) from patient biopsies taken during routine upper and lower endoscopy procedures. Proliferative stem/progenitor cells were rapidly expanded using a high concentration of conditioned media containing the factors critical for growth (Wnt3a, R-spondin and Noggin). A combination of lower conditioned media concentration and Notch inhibition was used to differentiate these cells for additional assays. <h3>Results</h3> We obtained epithelial lines from all accessible tissue sites within 2 weeks of culture. The intestinal cell lines were enriched for stem cell markers and rapidly grew as spheroids that required passage at 1:3–1:4 every 3 days. Under differentiation conditions, intestinal epithelial spheroids showed region-specific development of mature epithelial lineages. These cells formed functional, polarised monolayers covered by a secreted mucus layer when grown on Transwell membranes. Using two-dimensional culture, these cells also demonstrated novel adherence phenotypes with various strains of pathogenic <i>Escherichia coli</i>. <h3>Conclusions</h3> This culture system will facilitate the study of interindividual, functional studies of human intestinal epithelial cells, including host–microbial interactions.
Is cardiac troponin T serum level an accurate surrogate for acute doxorubicin-related myocardial injury?
Authors: G. Ferretti, M. Mandalà, E. Bria, P. Papaldo, P. Carlini, A. Fabi, M. Milella, E.M. Ruggeri, C. Nisticò, F. Cognetti
Journal: Annals of Oncology (2005)
Feedback suppression of the immune response in vitro. I. Activity of antigen-stimulated B cells.
Authors: R H Zubler, H Cantor, B Benacerraf, R N Germain
Journal: The Journal of Experimental Medicine (1980)

Feedback regulation of the primary humoral immune response to sheep erythrocytes (SRBC) was studied in vitro. Whole spleen cells or spleen cell subpopulations were incubated with antigen for 4 d under Mishell-Dutton conditions (education) and the surviving cells tested for regulatory activity in fresh anti-SRBC spleen cell cultures assayed by measuring plaque-forming cells on day 4. The data indicate that (a) whole spleen cells educated with SRBC exert potent antigen-specific suppression in the assay culture, (b) surface Ig- (sIg-) cells (T cells) prepared by either nylon-wool separation or fractionation on rabbit anti-mouse-Ig-coated polystyrene Petri dishes failed to generate suppressive activity when educated alone, in 2-mercaptoethanol, or in the presence of additional macrophages, (c) surface Ig (sIg+) (B) cells educated alone also failed to generate suppressor cells, and (d) mixing sIg- (T) and sIg+, Lyt 123- (B) cells reconstituted the ability to induce suppressor cells under these conditions. The antigen-primed cell actually required to transfer suppression was also characterized by separating cells using anti-Ig coated dishes, by fluorescence-activated cell sorting and by anti-Lyt treatment. All these methods clearly identified sIg+ (B) and not sIg+ (T) cells as the important educated cells. It is concluded that under our conditions, T cell-dependent B cells triggered by antigen during primary in vitro cultures cause potent specific feedback suppression of humoral responses. Possible mechanisms for this suppression, including antigen blockade or anti-idiotypic responses, are discussed.
Inferring Demography from Runs of Homozygosity in Whole-Genome Sequence, with Correction for Sequence Errors
Authors: Iona M. MacLeod, Denis M. Larkin, Harris A. Lewin, Ben J. Hayes, Mike E. Goddard
Journal: Molecular Biology and Evolution (2013)

Whole-genome sequence is potentially the richest source of genetic data for inferring ancestral demography. However, full sequence also presents significant challenges to fully utilize such large data sets and to ensure that sequencing errors do not introduce bias into the inferred demography. Using whole-genome sequence data from two Holstein cattle, we demonstrate a new method to correct for bias caused by hidden errors and then infer stepwise changes in ancestral demography up to present. There was a strong upward bias in estimates of recent effective population size (Ne) if the correction method was not applied to the data, both for our method and the Li and Durbin (Inference of human population history from individual whole-genome sequences. Nature 475:493-496) pairwise sequentially Markovian coalescent method. To infer demography, we use an analytical predictor of multiloci linkage disequilibrium (LD) based on a simple coalescent model that allows for changes in Ne. The LD statistic summarizes the distribution of runs of homozygosity for any given demography. We infer a best fit demography as one that predicts a match with the observed distribution of runs of homozygosity in the corrected sequence data. We use multiloci LD because it potentially holds more information about ancestral demography than pairwise LD. The inferred demography indicates a strong reduction in the Ne around 170,000 years ago, possibly related to the divergence of African and European Bos taurus cattle. This is followed by a further reduction coinciding with the period of cattle domestication, with Ne of between 3,500 and 6,000. The most recent reduction of Ne to approximately 100 in the Holstein breed agrees well with estimates from pedigrees. Our approach can be applied to whole-genome sequence from any diploid species and can be scaled up to use sequence from multiple individuals.
Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial
Authors: Axel Grothey, Eric Van Cutsem, Alberto Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouché, Laurent Mineur, Carlo Barone, Antoine Adenis, Josep Tabernero, Takayuki Yoshino, Heinz-Josef Lenz, Richard M Goldberg, Daniel J Sargent, Frank Cihon, Lisa Cupit, Andrea Wagner, Dirk Laurent
Journal: The Lancet (2012)
Modern Management of Mitral Stenosis
Authors: Blase A. Carabello
Journal: Circulation (2005)

A lthough once rheumatic fever and its consequences were the major cause of valvular heart disease in the developed world, this disease has become exceedingly rare today.As a consequence, mitral stenosis (MS), which is usually caused by rheumatic fever, has also become rare.In fact, MS is most commonly found in the United States in patients who have emigrated here from areas where rheumatic fever is still endemic.Nonetheless, Ϸ1500 balloon mitral valvotomies (BMVs) were performed in the United States last year, which provides a rough index of severe disease prevalence.The following is a review of the current understanding and management of this disease. EtiologyAlthough the attack rate for rheumatic fever is roughly equal among genders, MS is 2 to 3 times more common in women.2][3] What factors cause susceptibility to the illness remain unclear.Likewise, factors responsible for the decline in MS incidence in developed countries are also obscure.Although the decline may be due in part to the introduction of antibiotics, a fall in the attack rate of rheumatic fever began well before antibiotics were widely available. 4nce begun, the rheumatic process leads to inflammation in all 3 layers of the heart: endocardium, myocardium, and pericardium.However, the disease primarily affects the endocardium, leading to inflammation and scarring of the cardiac valves.Although the process is punctuated by acute episodes of rheumatic fever, chronic inflammation and scarring continue well after the last attack, leading to severe valve damage years later.The mechanism of this chronic process is debatable and is thought to be due either to a continuing low-grade rheumatic process or to hemodynamic stresses on the now-injured valve.Elevated C-reactive protein levels, indicative of ongoing generalized inflammation, are found in many patients before BMV, which supports an inflammatory origin for MS. 5 Although all of the cardiac valves may be involved by the rheumatic process, the mitral valve is involved most prominently and in virtually all cases.Stenosis of this valve occurs from leaflet thickening, commissural fusion, and chordal shortening and fusion.Occasionally, mitral annular calcification rather than disease of the valve leaflets and chordae tendineae is the cause of mitral stenosis.Annular calcification appears to be closely related to aortic and aortic valve calcification, which have recently been associated with atherosclerosis rather than with rheumatic fever. 6Other exceedingly rare causes of MS include use of anorectic drugs and carcinoid syndrome.
Bone morphogenetic protein expression in human atherosclerotic lesions.
Authors: K Boström, K E Watson, S Horn, C Wortham, I M Herman, L L Demer
Journal: Journal of Clinical Investigation (1993)

Artery wall calcification associated with atherosclerosis frequently contains fully formed bone tissue including marrow. The cellular origin is not known. In this study, bone morphogenetic protein-2a, a potent factor for osteoblastic differentiation, was found to be expressed in calcified human atherosclerotic plaque. In addition, cells cultured from the aortic wall formed calcified nodules similar to those found in bone cell cultures and expressed bone morphogenetic protein-2a with prolonged culture. The predominant cells in these nodules had immunocytochemical features characteristic of microvascular pericytes that are capable of osteoblastic differentiation. Pericyte-like cells were also found by immunohistochemistry in the intima of bovine and human aorta. These findings suggest that arterial calcification is a regulated process similar to bone formation, possibly mediated by pericyte-like cells.
Subendomyocardial exhaustion of blood flow reserve and increased fibrosis in conscious dogs with heart failure.
Authors: L Hittinger, R P Shannon, S P Bishop, R J Gelpi, S F Vatner
Journal: Circulation Research (1989)

The effects of near-maximal coronary vasodilation were examined in conscious dogs with left ventricular (LV) failure after pressure overload hypertrophy induced by either aortic banding alone or aortic banding plus a peripheral arteriovenous shunt. The findings were compared with results in littermates with compensated LV hypertrophy and with a third group of normal dogs. At rest, there was a marked difference in the intramyocardial distribution of coronary flow, measured with radiolabeled microspheres. The endocardial/epicardial (endo/epi) flow ratio in the LV failure dogs was 0.96 +/- 0.08 as compared with control dogs (1.28 +/- 0.06, p less than 0.05) or dogs with compensated LV hypertrophy (1.23 +/- 0.08, p less than 0.05). During near-maximal coronary vasodilation with adenosine, all groups showed similar increases in subepimyocardial (epi) flow. While significant increases in subendomyocardial (endo) flow during adenosine infusion were seen in the control group (0.88 +/- 0.10 to 3.53 +/- 0.24 ml/min/g) and in dogs with compensated LV hypertrophy (1.12 +/- 0.14 to 3.60 +/- 0.16 ml/min/g), there was no change in endo flow in the LV failure dogs (1.55 +/- 0.20 to 1.71 +/- 0.47 ml/min/g) and a further significant reduction in the endo/epi flow ratio was observed (0.30 +/- 0.06, p less than 0.01). These hemodynamic changes were associated with chronic multifocal interstitial or discrete areas of fibrosis observed preferentially in endo layers. Thus, endo flow reserve is nearly exhausted in dogs with decompensated pressure overload LV hypertrophy, which may induced periodic episodes of endo ischemia resulting in myocyte necrosis and fibrosis, which in turn results in exacerbation of LV failure.