tbuckley/cabot-search huggingface dataset:
Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes
Authors: Ralph A. DeFronzo, Marcus Hompesch, Sreeneeranj Kasichayanula, Xiaoni Liu, Ying Hong, Marc Pfister, Linda A. Morrow, Bruce R. Leslie, David W. Boulton, Agatha Ching, Frank P. LaCreta, Steven C. Griffen
Journal: Diabetes Care (2013)

To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique.Subjects with type 2 diabetes (n=12) and matched healthy subjects (n=12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves.At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects.The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.
A Time line of the Environmental Genetics of the Haptophytes
Authors: Hui Liu, Stéphane Aris-Brosou, Ian Probert, Colomban de Vargas
Journal: Molecular Biology and Evolution (2009)

The use of genomic data and the rise of phylogenomics have radically changed our view of the eukaryotic tree of life at a high taxonomic level by identifying 4-6 "supergroups." Yet, our understanding of the evolution of key innovations within each of these supergroups is limited because of poor species sampling relative to the massive diversity encompassed by each supergroup. Here we apply a multigene approach that incorporates a wide taxonomic diversity to infer the time line of the emergence of strategic evolutionary transitions in the haptophytes, a group of ecologically and biogeochemically significant marine protists that belong to the Chromalveolata supergroup. Four genes (SSU, LSU, tufA, and rbcL) were extensively analyzed under several Bayesian models to assess the robustness of the phylogeny, particularly with respect to 1) data partitioning; 2) the origin of the genes (host vs. endosymbiont); 3) across-site rate variation; and 4) across-lineage rate variation. We show with a relaxed clock analysis that the origin of haptophytes dates back to 824 million years ago (Ma) (95% highest probability density 1,031-637 Ma). Our dating results show that the ability to calcify evolved earlier than previously thought, between 329 and 291 Ma, in the Carboniferous period and that the transition from mixotrophy to autotrophy occurred during the same time period. Although these two transitions precede a habitat change of major diversities from coastal/neritic waters to the pelagic realm (291-243 Ma, around the Permian/Triassic boundary event), the emergence of calcification, full autotrophy, and oceanic lifestyle seem mutually independent.
The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML
Authors: Florian H. Heidel, Lars Bullinger, Patricia Arreba-Tutusaus, Zhu Wang, Julia Gaebel, Carsten Hirt, Dietger Niederwieser, Steven W. Lane, Konstanze Döhner, Valera Vasioukhin, Thomas Fischer, Scott A. Armstrong
Journal: The Journal of Experimental Medicine (2012)

A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.
Central lymph node changes and progressive massive fibrosis in coalworkers.
Authors: R M Seal, A Cockcroft, I Kung, J C Wagner
Journal: Thorax (1986)

Lungs from 123 coalworkers coming to necropsy were examined to determine the association between dust related changes in the central lymph nodes and progressive massive fibrosis and secondary foci in the lung parenchyma. Increasingly extensive changes of the central nodes were scored macroscopically, the highest scores indicating erosion through the walls of adjacent bronchi or branches of the pulmonary artery or both. In 88 cases (mainly with extensive changes) microscopic assessment was also made. Increasingly extensive changes of central nodes were associated with the presence of progressive massive fibrosis in the lungs (p less than 0.001) and the presence of secondary foci in lungs without progressive massive fibrosis (p less than 0.03). Microscopic assessments agreed fairly well with macroscopic assessments, but tended to be assigned lower scores. A hypothesis for the pathogenesis of progressive massive fibrosis is proposed whereby dust, accumulating in central lymph nodes, leads eventually to spread through the capsule and rupture into bronchi or pulmonary vessels, thereby sending dust laden activated cells back into the lungs to produce progressive massive fibrosis. These preliminary results are consistent with the hypothesis but more detailed studies are required.
Individualised unsupervised exercise training in adults with cystic fibrosis: a 1 year randomised controlled trial
Authors: A J Moorcroft
Journal: Thorax (2004)

Short term studies of exercise training have shown benefits in cystic fibrosis. Transferring exercise programmes to the community and sustaining them long term is a challenge for the patient. The effectiveness of an individualised unsupervised home based exercise programme was examined in adults with cystic fibrosis over a 1 year period.Subjects were randomised to undertake three sessions per week of upper and lower body exercise based on individualised preferences (n = 30) or to a control group (n = 18). They were evaluated at baseline and at 12 months. The primary outcome measure was improved fitness as assessed by change in blood lactate concentration at the end of an identical constant work rate for both arm and leg ergometric testing. Secondary outcome measurements were heart rate and pulmonary function.For leg exercise, significant differences were seen at 12 months between the active and control groups in the mean (SE) change in blood lactate levels (-0.38 (0.23) mmol/l v 0.45 (0.25) mmol/l, p<0.05) and heart rate (-4.8 (2.5) bpm v 3.4 (2.5) bpm, p<0.05), confirming a training effect. For arm ergometry there was no change in lactate levels at 12 months but there was a significant difference in forced vital capacity (46 (72) ml v -167 (68) ml, p<0.05).A training effect, as measured by a reduction in lactate levels and heart rate, can be achieved with unsupervised individualised home exercise in adults with cystic fibrosis. A benefit to pulmonary function was observed and together these findings suggest that exercise programmes should be encouraged as an important component of care in cystic fibrosis.
A new approach for evaluating risk factors in coronary artery disease: a study of lipid concentrations and severity of disease in 1847 males.
Authors: D W Scott, G A Gorry, R G Hoffman, J J Barboriak, A M Gotto
Journal: Circulation (1980)

Using recently developed statistical techniques, we estimated joint probability density functions for plasma cholesterol and plasma triglyceride concentrations in 12 subgroups of 1847 males with angiographically demonstrated coronary artery disease. The subjects were grouped by patterns of age, history of hypertension, history of smoking and severity of disease. From the estimated joint probability density functions, we determined the way in which the risk of severe vs moderate coronary artery disease varied with the joint variation of plasma lipids for given combinations of the other risk factors. The patterns of risk that we found are evidence of the complicated way in which the relationship between plasma lipids and the severity of coronary artery disease is affected by other risk factors.
Influence of long-term intermittent exposures to hypoxia on decompression-induced pulmonary haemorrhage.
Authors: H S Fang, C F Chen
Journal: Thorax (1976)

Healthy male rats were acclimatized by being placed in a decompression chamber at a simulated altitude of 18 000 feet (5486 m) for three hours daily for 84 days. The altitude acclimatized rats paired with unacclimatized rats were rapidly decompressed together. The range of decompression was performed from on atmospheric pressure to an ambient pressure of 30 mmHg in 0-2 seconds. It was found that in control rats, 14 of 20 lung (70%) exhibited pulmonary haemorrhage following rapid decompression. In altitude acclimatized rats, however, only 6 of 20 (30%) revealed decompression-induced haemorrhage. The difference was statistically significant. The present findings indicate that long-term intermittent exposures to hypoxia might increase the resistance of pulmonary tissue to rapid decompression, resulting in a decrease in frequency and severity of pulmonary haemorrhage. The possible mechanism of such a phenomenon is discussed.
Psychosexual Functioning Among Adult Female Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Jennifer S. Ford, Toana Kawashima, John Whitton, Wendy Leisenring, Caroline Laverdière, Marilyn Stovall, Lonnie Zeltzer, Leslie L. Robison, Charles A. Sklar
Journal: Journal of Clinical Oncology (2014)

Childhood cancer survivors may be at risk for impaired psychosexual functioning as a direct result of their cancer or its treatments, psychosocial difficulties, and/or diminished quality of life.
Belgium signs agreement to treat NHS patients
Authors: R. Watson
Journal: BMJ (2003)

A pioneering agreement was signed this week that opens the door for NHS patients in England to be treated in Belgium.

Although last year some 200 British citizens being treated on the NHS travelled to France and Germany for operations, this latest initiative is the first bilateral governmental accord the United Kingdom has reached in this area and is further evidence of the increasing trend for patients to move across borders for treatment.

Before signing the agreement with the Belgian minister for social affairs …
From genotype to EEG endophenotype: a route for post-genomic understanding of complex psychiatric disease?
Authors: Eco JC de Geus
Journal: Genome Medicine (2010)

Twin and family studies have shown the importance of biological variation in psychiatric disorders. Heritability estimates vary from 50% to 80% for cognitive disorders, such as schizophrenia, attention deficit hyperactivity disorder and autism, and from 40% to 65% for affective disorders, such as major depression, anxiety disorders and substance abuse. Pinpointing the actual genetic variants responsible for this heritability has proven difficult, even in the recent wave of genome-wide association studies. Brain endophenotypes derived from electroencephalography (EEG) have been proposed as a way to support gene-finding efforts. A variety of EEG and event-related-potential endophenotypes are linked to psychiatric disorders, and twin studies have shown a striking genetic contribution to these endophenotypes. However, the clear need for very large sample sizes strongly limits the usefulness of EEG endophenotypes in gene-finding studies. They require extended laboratory recordings with sophisticated and expensive equipment that are not amenable to epidemiology-scaled samples. Instead, EEG endophenotypes are far more promising as tools to make sense of candidate genetic variants that derive from association studies; existing clinical data from patients or questionnaire-based assessment of psychiatric symptoms in the population at large are better suited for the association studies themselves. EEG endophenotypes can help us understand where in the brain, in which stage and during what type of information processing these genetic variants have a role. Such testing can be done in the more modest samples that are feasible for EEG research. With increased understanding of how genes affect the brain, combinations of genetic risk scores and brain endophenotypes may become part of the future classification of psychiatric disorders.
Parents convicted of killing to have their cases reviewed
Authors: C. Dyer
Journal: BMJ (2004)

Major changes in England and Wales relating to the handling of cases in which mothers are suspected of killing their babies were announced this week by the Court of Appeal and the attorney general.

Hundreds of parents convicted of killing their babies are to have their cases urgently reviewed, said the attorney general after the appeal court called for an end to the prosecution of parents when experts' opinions on the cause of death differ.

In addition, thousands of parents whose children were taken away from them are to have their cases reopened as part …
Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions.
Authors: S Nikol, J M Isner, J G Pickering, M Kearney, G Leclerc, L Weir
Journal: Journal of Clinical Investigation (1992)

Human atheromata obtained in vivo were used to test the hypothesis that transforming growth factor-beta 1 plays a role in the development of vascular restenosis. We analyzed 28 specimens from patients with primary atherosclerotic or restenotic lesions; 26 of these were obtained by directional atherectomy and 2 at the time of coronary bypass surgery. Seven control tissues included operatively excised segments of human internal mammary artery, myocardium, and unused portions of vein graft obtained intraoperatively. From these 35 specimens, 210 sections were examined using in situ hybridization. Measurement of silver grains/nucleus disclosed that expression of transforming growth factor-beta 1 mRNA was highest in restenotic tissues (P < 0.001 vs. primary atherosclerotic tissues) and lowest in nonatherosclerotic (control) tissues. In cultures of human vascular smooth muscle cells grown from explants of internal mammary artery, expression of mRNA for transforming growth factor-beta 1 was significantly greater in subconfluent than in confluent smooth muscle cells (P = 0.05). Transforming growth factor type-beta III receptor was expressed in cell cultures and undetectable in the tissue specimens. Sections taken adjacent to those studied by in situ hybridization were examined by immunohistochemistry using antibodies against transforming growth factor-beta 1 and alpha-actin (as a marker for smooth muscle cells) and disclosed transforming growth factor-beta 1 in smooth muscle cells present in these sections. These findings are consistent with the concept that transforming growth factor-beta 1 plays an important role in modulating repair of vascular injury, including restenosis, after balloon angioplasty.
How Meaningful Are Bayesian Support Values?
Authors: Mark P. Simmons, Kurt M. Pickett, Masaki Miya
Journal: Molecular Biology and Evolution (2004)

In this study, we used an empirical example based on 100 mitochondrial genomes from higher teleost fishes to compare the accuracy of parsimony-based jackknife values with Bayesian support values. Phylogenetic analyses of 366 partitions, using differential taxon and character sampling from the entire data matrix of 100 taxa and 7,990 characters, were performed for both phylogenetic methods. The tree topology and branch-support values from each partition were compared with the tree inferred from all taxa and characters. Using this approach, we quantified the accuracy of the branch-support values assigned by the jackknife and Bayesian methods, with respect to each of 15 basal clades. In comparing the jackknife and Bayesian methods, we found that (1) both measures of support differ significantly from an ideal support index; (2) the jackknife underestimated support values; (3) the Bayesian method consistently overestimated support; (4) the magnitude by which Bayesian values overestimate support exceeds the magnitude by which the jackknife underestimates support; and (5) both methods performed poorly when taxon sampling was increased and character sampling was not increases. These results indicate that (1) the higher Bayesian support values are inappropriate (in magnitude), and (2) Bayesian support values should not be interpreted as probabilities that clades are correctly resolved. We advocate the continued use of the relatively conservative bootstrap and jackknife approaches to estimating branch support rather than the more extreme overestimates provided by the Markov Chain Monte Carlo–based Bayesian methods.
Clinimetric evaluation of shoulder disability questionnaires: a systematic review of the literature
Authors: S D M Bot
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To identify all available shoulder disability questionnaires designed to measure physical functioning and to evaluate evidence for the clinimetric quality of these instruments. <b>Methods:</b> Systematic literature searches were performed to identify self administered shoulder disability questionnaires. A checklist was developed to evaluate and compare the clinimetric quality of the instruments. <b>Results:</b> Two reviewers identified and evaluated 16 questionnaires by our checklist. Most studies were found for the Disability of the Arm, Shoulder, and Hand scale (DASH), the Shoulder Pain and Disability Index (SPADI), and the American Shoulder and Elbow Surgeons Standardised Shoulder Assessment Form (ASES). None of the questionnaires demonstrated satisfactory results for all properties. Most questionnaires claim to measure several domains (for example, pain, physical, emotional, and social functioning), yet dimensionality was studied in only three instruments. The internal consistency was calculated for seven questionnaires and only one received an adequate rating. Twelve questionnaires received positive ratings for construct validity, although depending on the population studied, four of these questionnaires received poor ratings too. Seven questionnaires were shown to have adequate test-retest reliability (ICC &gt;0.70), but five questionnaires were tested inadequately. In most clinimetric studies only small sample sizes (n&lt;43) were used. Nearly all publications lacked information on the interpretation of scores. <b>Conclusion:</b> The DASH, SPADI, and ASES have been studied most extensively, and yet even published validation studies of these instruments have limitations in study design, sample sizes, or evidence for dimensionality. Overall, the DASH received the best ratings for its clinimetric properties.
Surgical Stress Resistance Induced by Single Amino Acid Deprivation Requires <i>Gcn2</i> in Mice
Authors: Wei Peng, Lauren Robertson, Jordan Gallinetti, Pedro Mejia, Sarah Vose, Allison Charlip, Timothy Chu, James R. Mitchell
Journal: Science Translational Medicine (2012)

Dietary restriction, or reduced food intake without malnutrition, increases life span, health span, and acute stress resistance in model organisms from yeast to nonhuman primates. Although dietary restriction is beneficial for human health, this treatment is not widely used in the clinic. Here, we show that short-term, ad libitum feeding of diets lacking essential nutrients increased resistance to surgical stress in a mouse model of ischemia reperfusion injury. Dietary preconditioning by 6 to 14 days of total protein deprivation, or removal of the single essential amino acid tryptophan, protected against renal and hepatic ischemic injury, resulting in reduced inflammation and preserved organ function. Pharmacological treatment with halofuginone, which activated the amino acid starvation response within 3 days by mimicking proline deprivation, was also beneficial. Both dietary and pharmacological interventions required the amino acid sensor and eIF2α (eukaryotic translation initiation factor 2α) kinase Gcn2 (general control nonderepressible 2), implicating the amino acid starvation response and translational control in stress protection. Thus, short-term dietary or pharmacological interventions that modulate amino acid sensing can confer stress resistance in models of surgical ischemia reperfusion injury.
A Surrogate System for Informed Consent
Authors: Norman C. Fost
Journal: JAMA (1975)

Since "informed consent" is frequently obtained in a clinical setting where the patient is anxious and overwhelmed with feelings, toward the physician, of awe, trust, and dependency, it is often of dubious value in protecting human subjects. We devised, as a possible alternative mechanism for uncovering patient views toward a specific research protocol, a surrogate system of consent. The surrogates' responses seemed more candid and diverse than the responses one usually hears in the "real" clinical setting. Potential applications of such a system lie in further study of the consent process, and as a means for individual investigators to better gauge consumer attitudes toward specific projects.
Limited proteolysis by macrophage elastase inactivates human alpha 1-proteinase inhibitor.
Authors: M J Banda, E J Clark, Z Werb
Journal: The Journal of Experimental Medicine (1980)

Inflammatory mouse peritoneal macrophages secrete a metalloproteinase that is not inhibited by alpha 1-proteinase inhibitor. This proteinase, macrophage elastase, recognizes alpha 1-proteinase inhibitor with macrophage elastase does not involve a stable proteinase-inhibitor complex and results in the proteolytic removal of a peptide of apparent molecular weight 4,000-5,000 from the inhibitor. After degradation by macrophage elastase, alpha 1-proteinase inhibitor is no longer able to inhibit human granulocyte elastase, a serine proteinase implicated in the pathogenesis of emphysema. Macrophage elastase apparently does not degrade human granulocyte elastase-alpha 1-proteinase inhibitor complexes or release active granulocyte elastase from these complexes. The ability of macrophage elastase to degrade alpha 1-proteinase inhibitor is inhibited by EDTA and alpha 2-macroglobulin.