tbuckley/cabot-search huggingface dataset:
Individual use of antiasthmatic drugs in the European Community Respiratory Health Survey
Authors: C Janson, S Chinn, D Jarvis, P Burney
Journal: European Respiratory Journal (1998)

A previous analysis of drug utilization in the European Community Respiratory Health Survey found that only between 8 and 29% of subjects with asthma-related symptoms were using antiasthmatic medication in the different areas studied. The aim of this analysis was to investigate which variables were related to individual use of antiasthmatic medication in different geographical areas. Thirty-three centres in 14 countries were analysed, in which a total of 16,854 people (52.1% females, mean age 33.8 yrs, range 20-48) underwent a structured interview, measurement of specific immunoglobin E, spirometry and methacholine challenge test. The use of antiasthmatic drugs in individuals was, in most countries, independently related to asthma-related respiratory symptoms, bronchial hyperresponsiveness (BHR) and atopy. In all countries smokers with respiratory symptoms were less likely to be using antiasthmatic drugs than nonsmokers and exsmokers. In four of 14 countries females were significantly more likely to use antiasthmatic medication than males, while age and socioeconomic status were unrelated to medication. The use of inhaled anti-inflammatory drugs was positively related to symptoms, BHR and atopy and negatively related to current smoking. In conclusion, in many countries smokers were less likely to be using antiasthmatic drugs than were nonsmokers with comparable levels of symptoms and bronchial hyperresponsiveness. Age and socioeconomic status were unrelated to medication, while in some countries females were more likely than males to use antiasthmatic medication.
Transgenic Overexpression of Locally Acting Insulin-Like Growth Factor-1 Inhibits Ubiquitin-Mediated Muscle Atrophy in Chronic Left-Ventricular Dysfunction
Authors: P. Christian Schulze, Jennifer Fang, Kimberly A. Kassik, Joe Gannon, Mihaela Cupesi, Cathy MacGillivray, Richard T. Lee, Nadia Rosenthal
Journal: Circulation Research (2005)

Metabolic abnormalities develop in various chronic diseases and lead to progressive catabolism with decrements in the skeletal musculature that result in muscle atrophy. We investigated pathways of skeletal muscle proteolysis using an experimental model of chronic left-ventricular dysfunction. Skeletal muscle atrophy developed in wild-type mice 12 weeks following myocardial infarction accompanied by an increase in total protein ubiquitination and enhanced proteasome activity, activation of Foxo transcription factors, and robust induction of the ubiquitin-protein ligase atrogin-1/MAFbx . Further studies identified skeletal muscle myosin as a specific target of ubiquitin-mediated degradation in muscle atrophy. In contrast, transgenic overexpression of a local isoform of insulin-like growth factor-1 prevented muscle atrophy and increased proteasome activity, inhibited skeletal muscle activation primarily of Foxo4, and blocked the expression of atrogin-1/MAFbx . These results suggest that skeletal muscle atrophy occurs through increased activity of the ubiquitin–proteasome pathway. The inhibition of muscle atrophy by local insulin-like growth factor-1 provides a promising therapeutic avenue for the prevention of skeletal muscle wasting in chronic heart failure and potentially other chronic diseases associated with skeletal muscle atrophy.
Evolution of isopenicillin N synthase genes may have involved horizontal gene transfer.
Authors: G Landan, G Cohen, Y Aharonowitz, Y Shuali, D Graur, D Shiffman
Journal: Molecular Biology and Evolution (1990)

The isopenicillin N synthase genes from three fungal species, three Gram-positive species, and one Gram-negative bacterial species share an unusually high sequence similarity. A phylogenetic analysis was carried out to determine which type of evolutionary scenario best accounts for this similarity. The most plausible scenario is one in which a horizontal gene-transfer event, from the prokaryotes to the eukaryotes, occurred at a time close to the divergence between the Gram-positive and the Gram-negative bacteria.
Effect of Hormones and of Parity on the Occurrence of Hyperplastic Alveolar Nodules and Tumors in the Mammary Glands of Female A/Crgl Mice
Authors: Phyllis B. Blair, Sidney M. Blair, W. R. Lyons, Howard A. Bern, C. H. Li
Journal: Cancer Research (1960)

Within the A/Crgl strain of mice, virgin females almost never developed mammary tumors, whereas breeding females had a high incidence of tumor development. Tumor incidence was proportional to the number of litters borne. Appreciable tumor incidence could be induced in intact virgin females by administration of estradiol or a combination of estrone and progesterone. Induction of prelactational lobuloalveolar development by exogenous hormones resulted in 24 per cent tumor incidence. This incidence was not altered appreciably by one to four hormonal inductions of milk secretion. Exogenous hormone administration which led to tumor development also increased nodule incidence.
P176 Evaluating the role of triamcinolone in a difficult asthma service
Authors: R. Carter, A. Murphy, B. Hargadon, J. Agbetile, I. D. Pavord, A. J. Wardlaw, R. H. Green, P. Bradding
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> 10% of patients with asthma have disease that is refractory to conventional therapy. Two important factors in this group of patients are non-adherence to prescribed treatment and steroid insensitive airway inflammation. We report on our experience using intramuscular (IM) triamcinolone to evaluate such patients. <h3>Methods</h3> We identified 28 patients who were on BTS step 5 treatment for asthma and at risk of fatal or near fatal events, who were given IM triamcinolone in the Glenfield difficult asthma clinic. The primary reason for administration of IM triamcinolone was to evaluate whether these patients had evidence of steroid insensitivity or were potentially non adherent. Adherence was assessed objectively prior to commencing triamcinolone. Juniper asthma control questionnaire (JACQ), fraction of exhaled nitric oxide (FeNO), blood eosinophils, sputum eosinophils, FEV<sub>1</sub> (pre bronchodilator) were measured at baseline and whilst on triamcinolone. <h3>Results</h3> Triamcinolone was administered monthly at a dose of 40–80 mg for a median (range) course of 4 (1–19) months. Patient demographics were: 75% (21) female, mean age 40 y, mean BMI 29.1, median dose of ICS (BDP equivalent) 2000 mcg, median dose of maintenance prednisolone 20 mg, 29% (8) had previously been ventilated. Adherence was objectively assessed in 93% (26) with non-adherence demonstrated in 77% (20), either by prescription refill check or drug assays. Significant improvements were seen whilst on triamcinolone in the mean JACQ score from 3.66 to 2.52 (p=0.0003), geometric mean FeNO from 52.3 ppb to 17.8 ppb (p=0.0034), mean blood eosinophils from 0.59×10<sup>9</sup>/l to 0.22×10<sup>9</sup>/l (p=0.0032), geometric mean sputum eosinophil count from 12.93% to 1.24% (p&lt;0.0001) and in pre bronchodilator FEV<sub>1</sub> from 54% to 67% predicted (p=0.0003). Of 28 patients receiving IM triamcinolone, 68% (19) showed significant improvement in 2 or more disease markers, 7% (2) showed improvement in 1 disease marker, 18% (5) had an equivocal response and 7% (2) demonstrated no response to parenteral steroid. No significant adverse events were reported. <h3>Conclusions</h3> This study shows that IM triamcinolone is a useful tool that may identify non-adherence in difficult-to-control asthmatic patients prescribed maintenance oral corticosteroids. Absolute steroid resistance is uncommon in this group.
<i>S</i> -Nitrosylation in Cardiovascular Signaling
Authors: Brian Lima, Michael T. Forrester, Douglas T. Hess, Jonathan S. Stamler
Journal: Circulation Research (2010)

Well over 2 decades have passed since the endothelium-derived relaxation factor was reported to be the gaseous molecule nitric oxide (NO). Although soluble guanylyl cyclase (which generates cyclic guanosine monophosphate, cGMP) was the first identified receptor for NO, it has become increasingly clear that NO exerts a ubiquitous influence in a cGMP-independent manner. In particular, many, if not most, effects of NO are mediated by S-nitrosylation, the covalent modification of a protein cysteine thiol by an NO group to generate an S-nitrosothiol (SNO). Moreover, within the current framework of NO biology, endothelium-derived relaxation factor activity (ie, G protein-coupled receptor-mediated, or shear-induced endothelium-derived NO bioactivity) is understood to involve a central role for SNOs, acting both as second messengers and signal effectors. Furthermore, essential roles for S-nitrosylation have been implicated in virtually all major functions of NO in the cardiovascular system. Here, we review the basic biochemistry of S-nitrosylation (and denitrosylation), discuss the role of S-nitrosylation in the vascular and cardiac functions of NO, and identify current and potential clinical applications.
Somatosensory processes subserving perception and action
Authors: H. Chris Dijkerman, Edward H. F. de Haan
Journal: Behavioral and Brain Sciences (2007)

Abstract The functions of the somatosensory system are multiple. We use tactile input to localize and experience the various qualities of touch, and proprioceptive information to determine the position of different parts of the body with respect to each other, which provides fundamental information for action. Further, tactile exploration of the characteristics of external objects can result in conscious perceptual experience and stimulus or object recognition. Neuroanatomical studies suggest parallel processing as well as serial processing within the cerebral somatosensory system that reflect these separate functions, with one processing stream terminating in the posterior parietal cortex (PPC), and the other terminating in the insula. We suggest that, analogously to the organisation of the visual system, somatosensory processing for the guidance of action can be dissociated from the processing that leads to perception and memory. In addition, we find a second division between tactile information processing about external targets in service of object recognition and tactile information processing related to the body itself. We suggest the posterior parietal cortex subserves both perception and action, whereas the insula principally subserves perceptual recognition and learning.
Multiple immunoreactive forms of osteocalcin in uremic serum.
Authors: C M Gundberg, R S Weinstein
Journal: Journal of Clinical Investigation (1986)

Circulating osteocalcin, which normally reflects the rate of bone formation, is elevated in uremia. In 18 patients receiving maintenance hemodialysis, serum osteocalcin levels were directly related to the bone formation rate (r = 0.88, P less than 0.001), osteoblastic osteoid surface density (r = 0.65, P less than 0.01), and osteoclastic resorptive surface density (r = 0.75, P less than 0.001). Multiple regression analysis showed that osteocalcin levels remained positively correlated with osteoclastic resorption when the bone formation rate was held constant (P less than 0.01). The intimation that the coupling of bone formation and resorption could not explain the relationship between osteocalcin and resorption led us to determine whether fragments of this abundant matrix protein are released by bone resorption and retained in uremia. Sera from dialysis patients with renal osteodystrophy were fractionated by sequential gel filtration and HPLC, and assayed for immunoreactive osteocalcin. When normal serum was analyzed, a single sharp peak was found. In pooled sera from patients with high osteoclastic resorptive surfaces identified by histomorphometry, we found five additional immunoreactive peaks, while three additional peaks were detected in sera from patients with lower osteoclastic surfaces. Bio-Gel P-10 chromatography showed that these multiple peaks were of lower molecular weight than intact osteocalcin. We suggest that the liberation of bone matrix by osteoclasts contributes to the circulating osteocalcin immunoreactivity in uremia.
A new beginning for care for elderly people?
Authors: J. G. Evans
Journal: BMJ (2001)

The National Service Framework for Older People,1 discussed in last week's news,2 displays a personality split between its ERG and its IG. An external reference group (ERG) of selected experts offered advice,3 but the framework was written by an “in group” (IG) of civil servants. The IG subserves a political agenda, and that agenda, unchanged over 50 years, is to keep old people out of hospital.

IGians believe that care in proper hospitals is too expensive for old people. This partly reflects a preoccupation with cost per institutional day (money that might be saved by closing something down) rather than with cost per satisfied patient (money properly invested). But savings from putting old people in cheap, ill resourced accommodation are rapidly lost in unnecessarily prolonged lengths of stay, not to mention human misery. IGian fantasies are fed by studies of “inappropriate” use of hospital beds by older people. The definition of inappropriate is contentious, and the term is too readily attached to the patient rather than the treatment. Certainly some older people stay in hospital longer than they want because of the complexities and underfunding of social service care. There are probably many more old people, invisible to IGian research, who would benefit from acute hospital admissions that they are denied. The clearest expression of …
Individualizing Quality-of-Life Outcomes Reporting: How Localized Prostate Cancer Treatments Affect Patients With Different Levels of Baseline Urinary, Bowel, and Sexual Function
Authors: Ronald C. Chen, Jack A. Clark, James A. Talcott
Journal: Journal of Clinical Oncology (2009)

Although it is the most powerful predictor of early prostate cancer treatment-related complications and quality-of-life (QOL) outcomes, most studies do not stratify results by baseline function. Further, reporting functional outcomes as averaged numerical results may obscure informatively disparate courses. Using levels of treatment-related dysfunction, we address these problems and present the final QOL outcomes of our prospective cohort study of patients with early prostate cancer.We created categories for sexual, bowel, and urinary function, measured using numerical scores of the validated Prostate Cancer Symptom Indices and stratified into "normal," "intermediate" and "poor" levels of function by incorporating patient-reported symptom and distress information. We present QOL outcomes for 409 patients 36 months after radical prostatectomy, external-beam radiation therapy, and brachytherapy.Different levels of baseline sexual, bowel, and urinary function produced distinctive treatment-related changes from baseline to 36 months. In general, the average scale increases in dysfunction were greatest among patients with normal baseline function, although patients with normal and intermediate baseline function had similar increases in sexual dysfunction. For patients whose baseline urinary obstruction/irritation was poor, both average scale scores and most patients' level of function improved after treatment, particularly after surgery.The use of functional levels to stratify treatment-related outcomes by pretreatment functional status and to display the proportions of patients with improved, stable, or worsened function after treatment provides information that more specifically conveys the expected impact of treatment to patients choosing among localized prostate cancer treatments.
Phosphate Control and 25-Hydroxycholecalciferol Administration in Preventing Experimental Renal Osteodystrophy in the Dog
Authors: W. E. Rutherford, P. Bordier, P. Marie, K. Hruska, H. Harter, A. Greenwalt, J. Blondin, J. Haddad, N. Bricker, E. Slatopolsky
Journal: Journal of Clinical Investigation (1977)

Previous studies from this laboratory demonstrated that secondary hyperparathyroidism in dogs with chronic renal disease may occur, at least in part, as a consequence of the need for progressive adaptation in renal phosphorus (P) excretion that occurs as glomerular filtration rate falls. However, the studies were of relatively short duration. Moreover, no information emerged regarding a potential role of calcium malabsorption in the pathogenesis of secondary hyperparathyroidism. The short duration of the protocol did not lend itself to the study of the effect of P control or the administration of vitamin D in the pathogenesis of renal osteodystrophy. In the present studies, 14 dogs with experimental chronic renal disease were studied serially for a period of 2 yr. Each animal was studied first with two normal kidneys on an intake of P of 1,200 mg/day. Then, renal insufficiency was produced by 5/6 nephrectomy. The dogs then were divided into three groups. In group I, 1,200 mg/day P intake was administered for the full 2 yr. In group II, P intake was reduced from the initial 1,200 mg/day, in proportion to the measured fall in glomerular filtration rate, in an effort to obviate the renal adaptation in P excretion. In group III, "proportional reduction" of P intake also was employed; but in addition, 20 μg of 25(OH)D3 were administered orally three times a week.
A simple computer program for guiding management of cardiovascular risk factors and prescribing
Authors: A. D Hingorani, P. Vallance
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To describe, and to test against trial data, a simple and flexible computer program for calculating cardiovascular risk in individual patients as an aid to managing risk factors and prescribing drugs to lower cholesterol concentration and blood pressure. <b>Design:</b> Descriptive comparison of actual cardiovascular risk in randomised controlled trials of cholesterol reduction with risk predicted by a computer program based on the Framingham risk equation. Comparison of the program9s performance with that of tables and guidelines by means of hypothetical case examples. <b>Main outcome measures:</b> Average risk of coronary heart disease and myocardial infarction. <b>Results:</b> The computer program accurately predicted baseline absolute risk in a UK population as well as the relative and absolute reduction in risk from cholesterol lowering for primary prevention of coronary heart disease. The program also allowed a more refined estimate of absolute risk of coronary heart disease than some existing tables and enabled the impact of prescribing decisions to be quantified and costed. <b>Conclusions:</b> This simple computer program to estimate individuals9 cardiovascular disease risk and display the benefits of intervention should help clinicians and patients decide on the most effective packages of risk reduction and identify those most likely to benefit from modulation of risk factors.
The T cell receptor repertoire in synovial tissue of patients with early rheumatoid arthritis (RA) is dominated by highly expanded clones, which is not the case in established RA
Authors: P. L. Klarenbeek, M. E. Doorenspleet, M. J. de Hair, M. M. Herenius, B. D. C. van Schaik, C. A. Wijbrandts, M. G. van de Sande, R. E. Esveldt, A. H. C. van Kampen, F. Baas, P. P. Tak, N. de Vries
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Several lines of evidence support a role for the T cell receptor (TCR) in the pathogenesis of RA. Previously we demonstrated that many T cell clones are specifically present in the synovial tissue (ST) of patients with established RA (ESRA) suggesting TCR-driven involvement of T cells. To further unravel TCR-involvement in the development of RA we investigated the earliest stages of synovial inflammation, as defined clinically. We hypothesised that the synovial inflammation in RA leads to epitope spreading, reflected by accumulation of new clonal T cell expansions. Therefore, ST in early RA (ERA) should yield less, but more expanded T cell clones. <h3>Objective</h3> To compare the presence of T cell clones in ST and peripheral blood (PB) between patients with ERA and ESRA, using a new high-throughput sequencing protocol. <h3>Material and methods</h3> Three DMARD-naïve ERA patients (disease duration &lt; 1 year) and three ESRA patients (disease duration &gt;2 years) were included. All fulfilled the American College of Rheumatology1987 criteria for RA. mRNA was isolated from paired ST and PB samples. A linear amplification with primers for all V(ariable)-genes of the T cell receptor β-chain was performed. The amplified products contain the CDR3s of all T cells. Samples were processed using a Genome Sequencer (454) analysing up to 15 000 receptors per sample, The frequency of each clone was determined by its CDR3 frequency (% of all CDR3s analysed). Clones with a CDR3 frequency of &gt;1% were arbitrarily considered as highly expanded clones (HECs). <h3>Results</h3> T cell clones were found with a frequency of up to 10–20% in the ST of ERA patients while this was only 1–3% in ESRA patients (samples had equal numbers of T cells). Only a minority of the HECs could also be identified in PB, and always in low frequencies. Surprisingly, we identified twice as many HECs in ERA-ST compared to ESRA-ST (39.5 clones (± 5.8) (SEM) vs 18.8 (± 3.6)). However, the impact of the HECs in ERA was far higher in ERA-ST. In ESRA only 17.3% (± 5.0) of the T cells analysed belonged to the HECs, whereas this was 77% (± 8.0) for the ERA samples. <h3>Conclusion</h3> The TCR-repertoire in ST of ERA patients appears to be dominated by a few HECs (oligoclonal), in contrast to observations in ESRA (polyclonal). This is consistent with the notion of epitope spreading. Further research should therefore focus on the earliest phases of RA to unravel the role of T cells in the initiation of RA.
Automated Reconstruction of Whole-Genome Phylogenies from Short-Sequence Reads
Authors: Frederic Bertels, Olin K. Silander, Mikhail Pachkov, Paul B. Rainey, Erik van Nimwegen
Journal: Molecular Biology and Evolution (2014)

Studies of microbial evolutionary dynamics are being transformed by the availability of affordable high-throughput sequencing technologies, which allow whole-genome sequencing of hundreds of related taxa in a single study. Reconstructing a phylogenetic tree of these taxa is generally a crucial step in any evolutionary analysis. Instead of constructing genome assemblies for all taxa, annotating these assemblies, and aligning orthologous genes, many recent studies 1) directly map raw sequencing reads to a single reference sequence, 2) extract single nucleotide polymorphisms (SNPs), and 3) infer the phylogenetic tree using maximum likelihood methods from the aligned SNP positions. However, here we show that, when using such methods to reconstruct phylogenies from sets of simulated sequences, both the exclusion of nonpolymorphic positions and the alignment to a single reference genome, introduce systematic biases and errors in phylogeny reconstruction. To address these problems, we developed a new method that combines alignments from mappings to multiple reference sequences and show that this successfully removes biases from the reconstructed phylogenies. We implemented this method as a web server named REALPHY (Reference sequence Alignment-based Phylogeny builder), which fully automates phylogenetic reconstruction from raw sequencing reads.