tbuckley/cabot-search huggingface dataset:
Molecular Recognition of Lipid Antigens by T Cell Receptors
Authors: Ethan P. Grant, Massimo Degano, Jean-Pierre Rosat, Steffen Stenger, Robert L. Modlin, Ian A. Wilson, Steven A. Porcelli, Michael B. Brenner
Journal: The Journal of Experimental Medicine (1999)

The T cell antigen receptor (TCR) mediates recognition of peptide antigens bound in the groove of major histocompatibility complex (MHC) molecules. This dual recognition is mediated by the complementarity-determining residue (CDR) loops of the α and β chains of a single TCR which contact exposed residues of the peptide antigen and amino acids along the MHC α helices. The recent description of T cells that recognize hydrophobic microbial lipid antigens has challenged immunologists to explain, in molecular terms, the nature of this interaction. Structural studies on the murine CD1d1 molecule revealed an electrostatically neutral putative antigen-binding groove beneath the CD1 α helices. Here, we demonstrate that α/β TCRs, when transferred into TCR-deficient recipient cells, confer specificity for both the foreign lipid antigen and CD1 isoform. Sequence analysis of a panel of CD1-restricted, lipid-specific TCRs reveals the incorporation of template-independent N nucleotides that encode diverse sequences and frequent charged basic residues at the V(D)J junctions. These sequences permit a model for recognition in which the TCR CDR3 loops containing charged residues project between the CD1 α helices, contacting the lipid antigen hydrophilic head moieties as well as adjacent CD1 residues in a manner that explains antigen specificity and CD1 restriction.
Drug treatment in heart failure
Authors: R. P Steeds, K. S Channer
Journal: BMJ (1998)

Heart failure is a clinical syndrome in which the heart fails to maintain an adequate output to vital organs. The responses to the resultant low blood pressure and underperfusion of organs include activation of the renin-angiotensin system with retention of salt and water, structural change of the heart and blood vessels with altered arterial compliance, and increased sympathetic drive. These result in an increase in heart rate, peripheral resistance, and myocardial contractility. Although these compensatory mechanisms are effective in the short term, they eventually become harmful. The adverse compensatory activation of the renin-angiotensin system can be modified by inhibitors, which improve symptoms and reduce mortality. Is the long term sympathetic overdrive that occurs as a consequence of heart failure also harmful?

The effect of adrenergic stimulation on the myocyte is to increase contractility and improve cardiac function. This should be a beneficial effect, yet all clinical trials of positively inotropic drugs have either failed to improve symptoms or have increased mortality in heart failure. The long list of drugs includes the phosphodiesterase inhibitors,1 dopaminergic inodilators …
Proportion of moderately exercising individuals responding to low-level, multi-hour ozone exposure.
Authors: W F McDonnell, P W Stewart, S Andreoni, M V Smith
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The purpose of this study was to describe the proportion of moderately exercising individuals experiencing significant respiratory responses to low-level, multi-hour ozone exposure as a function of ozone concentration and exposure duration. Sixty-eight healthy, nonsmoking adults, ages 18 to 34 yr, underwent two or more 6.6-h exposures to 0.0, 0.08, 0.10, or 0.12 ppm ozone. Five hours of exercise was performed during exposure, and lung function was measured before exposure and following each hour of exposure. For each combination of concentration and duration, each individual was determined to either have or not have experienced a 10% or greater decrement in FEV1. A logistic function was used to model the proportion of individuals experiencing such a decrement as a function of concentration and exposure duration. Bootstrap 90% confidence intervals (CIs) were calculated around the predictions. The model was found to give predictions that were in good agreement with observed data. The lowest level of exposure (C x T) for which the 90% CI excluded zero was approximately 0.2 ppm-h. For exposure to 0.12 ppm ozone for 6.6 h, 47% (90% CI = 30 to 65%) of exposed individuals were predicted to experience a 10% decrement in FEV1. A greater proportion of younger adults than of older adults were found to experience a given effect for a given exposure.
Abstract 3863: Transgenic model for early prostate metastasis to the lymph nodes.
Authors: Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W. Goodrich, Barbara A. Foster, Irwin H. Gelman
Journal: Cancer Research (2013)

Abstract Background: The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The SSeCKS/Gravin/AKAP12 (“SSeCKS”) gene, previously shown to suppress prostate cancer metastasis upon re-expression (1,2), as well as the tumor suppressor gene, Rb, are either transcriptionally downregulated or deleted in human prostate cancers (3,4). Mouse models deficient in either SSeCKS or Rb exhibit prostatic hyperplasia (5,6). Moreover, SSeCKS-null fibroblasts as well as SSeCKS-null prostates display Rb-dependent premature senescence markers (7). Methods: In order to determine whether the combined loss of AKAP12 and Rb in the prostate synergizes to induce oncogenic progression, Akap12-/- mice were crossed with Pb4-Cre;RbloxP/loxP mice to generate Akap12-/-;RbPE-/− progeny, with the Probasin-Cre passed only through males. Results: The combined loss of SSeCKS and Rb results in prostatic intraepithelial neoplasia (PIN) starting at 6 months of age that fails to progress to malignancy (adenocarcinoma) after 18 months. The PIN lesions were marked by increased Ki-67 proliferation of cytokeratin 8 (CK8), p63-negative luminal cells as well as p63-positive basal cells. Interestingly, these lesions also had increased numbers of androgen-receptor (AR)-positive, p63-positive, CK5-negative cells. There was evidence of reactive stroma including mural hyperplasia and inflammatory cell infiltration. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes (LN), marked by well-differentiated tumors cells expressing markers of basal (p63, CK14) and luminal (CK8 and AR) epithelial cells, although none expressed the basal marker, CK5. PCR-based tests for the deleted floxed Rb allele from laser capture microdissected LN lesions confirmed the prostatic origin of these metastatic cells. The LN lesions showed very limited inflammation, based on very few cells staining with the histiocyte marker, CD68. Conclusions: Taken together, these data suggest that in the context of Rb loss, SSeCKS suppresses the oncogenic proliferation and early metastatic spread of transitional, basal-luminal prostate tumor cells. Citation Format: Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W. Goodrich, Barbara A. Foster, Irwin H. Gelman. Transgenic model for early prostate metastasis to the lymph nodes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3863. doi:10.1158/1538-7445.AM2013-3863
Suicide in Teenagers
Authors: Alan J. Zametkin, Marisa R. Alter, Tamar Yemini
Journal: JAMA (2001)

Adolescents who kill themselves invariably have an underlying psychiatric disorder. Biological markers are not yet clinically useful for identifying adolescents at risk, and there is a paucity of research data on the effectiveness of behavioral intervention for suicidal teenagers. A case of a 16-year-old scholar and athlete is presented to illustrate how multiple risk factors and a family diathesis often go undetected, resulting in tragic consequences. Psychiatric, familial, genetic, and social risk factors of adolescent suicide are reviewed, and the efficacy of lithium and antidepressant pharmacotherapy in reducing suicide rates is discussed. The importance of screening adolescent patients for depression is emphasized. Although teenage suicide is rare and hard to predict, identifying and treating adolescents at risk is essential to further reduce teenage suicide.
Distribution of Coronary Artery Calcium by Race, Gender, and Age
Authors: Robyn L. McClelland, Hyoju Chung, Robert Detrano, Wendy Post, Richard A. Kronmal
Journal: Circulation (2005)

Coronary artery calcium (CAC) has been demonstrated to be associated with the risk of coronary heart disease. The Multi-Ethnic Study of Atherosclerosis (MESA) provides a unique opportunity to examine the distribution of CAC on the basis of age, gender, and race/ethnicity in a cohort free of clinical cardiovascular disease and treated diabetes.MESA is a prospective cohort study designed to investigate subclinical cardiovascular disease in a multiethnic cohort free of clinical cardiovascular disease. The percentiles of the CAC distribution were estimated with nonparametric techniques. Treated diabetics were excluded from analysis. There were 6110 included in the analysis, with 53% female and an average age of 62 years. Men had greater calcium levels than women, and calcium amount and prevalence were steadily higher with increasing age. There were significant differences in calcium by race, and these associations differed across age and gender. For women, whites had the highest percentiles and Hispanics generally had the lowest; in the oldest age group, however, Chinese women had the lowest values. Overall, Chinese and black women were intermediate, with their order dependent on age. For men, whites consistently had the highest percentiles, and Hispanics had the second highest. Blacks were lowest at the younger ages, and Chinese were lowest at the older ages. At the MESA public website (http://www.mesa-nhlbi.org), an interactive form allows one to enter an age, gender, race/ethnicity, and CAC score to obtain a corresponding estimated percentile.The information provided here can be used to examine whether a patient has a high CAC score relative to others with the same age, gender, and race/ethnicity who do not have clinical cardiovascular disease or treated diabetes.
Evidence of beta cell dysfunction which does not lead on to diabetes: a study of identical twins of insulin dependent diabetics.
Authors: D A Heaton, B A Millward, P Gray, Y Tun, C N Hales, D A Pyke, R D Leslie
Journal: BMJ (1987)

Ten non-diabetic identical twins of insulin dependent diabetics were studied to see whether they showed changes in insulin secretion. The twins were selected because more than 11 years had elapsed since the diagnosis of the diabetic twin and they were therefore unlikely to develop diabetes, and they had had islet cell antibodies. Despite similar glucose concentrations to the controls the twins had greater total immunoreactive insulin responses to both oral (mean 3280 (SD 699) versus 2338 (1110) pmol/dl at 180 minutes; p less than 0.05) and intravenous (1346 (690) versus 699 (294) pmol/dl at 30 minutes; p less than 0.05) glucose challenge. The C peptide responses to intravenous glucose were also increased consistent with increased insulin secretion. In addition, basal serum proinsulin concentrations in the twins were increased (2.1 (1.2) versus 1.0 (0.3) pmol/dl; p less than 0.01) and remained so throughout both tests. These twins, who were unlikely to develop insulin dependent diabetes, showed evidence of beta cell dysfunction which does not progress to diabetes.
TCT-366 Impact of gender on adverse cardiac events in patients with large anterior myocardial infarction: Results from the INFUSE-AMI trial
Authors: Nilusha Gukathasan, Roxana Mehran, Sorin Brener, Akiko Maehara, Ziad Sergie, D. Christopher Metzger, Keith Oldroyd, Helen Parise, Martin Fahy, C. Michael Gibson, Gregg Stone
Journal: Journal of the American College of Cardiology (2012)
Effect of topical tazarotene in the treatment of congenital ichthyoses
Authors: None Hofmann, None Stege, None Ruzicka, None Lehmann
Journal: British Journal of Dermatology (1999)

The clinical efficacy and tolerability of the topical receptor-selective retinoid tazarotene in the treatment of congenital ichthyoses was investigated. Twelve consecutive patients with different forms of congenital ichthyosis were enrolled in an open, non-randomized, intraindividually controlled, half-side pilot study. Diagnoses were X-linked recessive ichthyosis, non-erythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris and ichthyosis bullosa of Siemens (IBS). Tazarotene 0.05% gel was applied unilaterally daily on a defined body area measuring 10% of the body surface area. The contralateral side was treated with an ointment containing 10% urea. After 14 days, application frequency was reduced to three times a week, and stopped after another 2 weeks. The follow-up period was 3 months. Reduction in scaling and roughness was used to assess the clinical response in the tazarotene-treated area compared with the control area. Clinical and laboratory assessments were performed every 14 days during the trial. Unilateral improvement in favour of the tazarotene-treated side was observed in nine of 12 patients (75%). Four patients (33%) achieved an excellent response and four (33%) achieved a good response. No therapeutic effect was seen in patients with IBS. The remission persisted during the reduction phase and after discontinuation for up to 2 months. Local irritation in three patients was the only side-effect detectable. Short-term topical application of tazarotene 0.05% gel is a very effective and well-tolerated treatment modality in different forms of congenital ichthyoses and may be an alternative to systemic retinoid therapy.
New Haven survey of joint diseases. XVII. Relationship between some systemic characteristics and osteoarthrosis in a general population.
Authors: R.M Acheson, A.B Collart
Journal: Annals of the Rheumatic Diseases (1975)

In a survey of the general population the presence or absence of osteoarthrosis of the hand was determined radiologically in 685 adults (300 males and 385 females). Of these, 261 (124 males and 137 females), chosen randomly, were given a complete clinical examination of the musculoskeletal system which included x-ray of joints elsewhere in the body. Osteoarthrosis (OA) scores for the hand and for all body sites were computed for each subject by summing the number of affected joints. For all subjects soical class, height, weight, total serum protein, serum uric acid, haemoglobin, antistreptolysin O, (ASO), C-reactive protein (CRP), and rheumatoid factor were also measured. Analyses were carried out by simple comparison of means and by calculating multiple regressions and correlations.
Insulin Gene in Diabetes Analysis Through RFLP
Authors: M Alan Permutt, Steven C Elbein
Journal: Diabetes Care (1990)

Insulin deficiency is a prominent feature of non-insulindependent (NIDDM) and insulin-dependent (IDDM) diabetes mellitus that could result from defects in the insulin gene. Cloning of this gene has permitted molecular-genetic studies including the definition of multiple-DNA-sequence polymorphisms detected with restriction endonucleases, or restriction-fragment-length polymorphisms (RFLPs), and the mapping of the insulin gene to the short arm of chromosome 11 adjacent to the insulinlike growth factor II (ICF-II) and tyrosine hydroxylase genes. The combined RFLPs for the insulin, IGF-II, and tyrosine hydroxylase genes make this a highly informative locus for genetic studies of the insulin gene in diabetes. Early studies of an RFLP consisting of variable-number tandem repeats (VNTR) of DNA near the insulin gene suggested an association of certain alleles with ∼170 copies of the repeat unit with NIDDM. Although subsequent studies in NIDDM did not confirm this association, an association of different alleles defined by ∼40 copies of the repeat unit in this VNTR region with IDDM has been demonstrated in multiple studies. This VNTR region and the multiple other RFLPs for this region have been used in linkage analysis to study the segregation of insulin genes in families. These studies have failed to demonstrate a major significant role for insulin-gene defects in NIDDM, maturity-onset diabetes of the young, or IDDM in American Blacks and Whites and under various models of inheritance. Several pedigrees with diabetes and defects of the insulin gene have been described, however, and a minor role for this gene in NIDDM cannot be eliminated from available studies. Similarly, the association studies of the insulin gene and IDDM suggest a minor modifying role undetectable in pedigree studies. The role of defects in or near the insulin gene in a small subset of NIDDM or in IDDM must await direct investigation of the insulin gene in diabetic individuals with the most recent methods for gene amplification and sequence analysis.
Hospitals, Market Share, and Consolidation
Authors: David M. Cutler, Fiona Scott Morton
Journal: JAMA (2013)

A large reduction in use of inpatient care combined with the incentives in the Affordable Care Act is leading to significant consolidation in the hospital industry. What was once a set of independent hospitals having arms-length relationships with physicians and clinicians who provide ambulatory care is becoming a small number of locally integrated health systems, generally built around large, prestigious academic medical centers. The typical region in the United States has 3 to 5 consolidated health systems, spanning a wide range of care settings, and a smaller fringe of health care centers outside those systems. Consolidated health systems have advantages and drawbacks. The advantages include the ability to coordinate care across different practitioners and sites of care. Offsetting this is the potential for higher prices resulting from greater market power. Market power increases because it is difficult for insurers to bargain successfully with one of only a few health systems. Antitrust authorities are examining these consolidated systems as they form, but broad conclusions are difficult to draw because typically the creation of a system will generate both benefit and harm and each set of facts will be different. Moreover, the remedies traditionally used (eg, blocking the transaction or requiring that the parties divest assets) by antitrust authorities in cases of net harm are limited. For this reason, local governments may want to introduce new policies that help ensure consumers gain protection in the event of consolidation, such as insurance products that charge consumers more for high-priced clinicians and health care centers, bundling payments to clinicians and health care organizations to eliminate the incentives of big institutions to simply provide more care, and establishing area-specific price or spending targets.
Diarylheptanoid Phytoestrogens Isolated from the Medicinal Plant <i>Curcuma comosa</i> : Biologic Actions <i>in Vitro</i> and <i>in Vivo</i> Indicate Estrogen Receptor–Dependent Mechanisms
Authors: Wipawee Winuthayanon, Pawinee Piyachaturawat, Apichart Suksamrarn, Mathurose Ponglikitmongkol, Yukitomo Arao, Sylvia C. Hewitt, Kenneth S. Korach
Journal: Environmental Health Perspectives (2009)

Diarylheptanoids isolated from Curcuma comosa Roxb. have been recently identified as phyto estrogens. However, the mechanism underlying their actions has not yet been identified.We characterized the estrogenic activity of three active naturally occurring diarylheptanoids both in vitro and in vivo.We characterized mechanisms of estrogenic action of the diarylheptanoids (3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (D1), 1,7-diphenyl-(6E)-6-hepten-3-one (D2), and (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (D3) by using a real-time polymerase chain reaction assay, a mammalian transfection model, and a uterotrophic assay in mice.All diarylheptanoids up-regulated estrogen-responsive genes in estrogen-responsive breast cancer cells (MCF-7). In HepG2 cells transfected with estrogen receptor (ER) beta or different ERalpha functional receptor mutants and the Vit-ERE-TATA-Luc reporter gene, all diarylheptanoids induced transcription through a ligand-dependent human ERalpha-ERE-driven pathway, which was abolished with ICI 182,780 (ER antagonist), whereas only D2 was active with ERbeta. An ERalpha mutant lacking the functional AF2 (activation function 2) region was not responsive to 17beta-estradiol (E(2)) or to any of the diarylheptanoids, whereas ERalpha lacking the AF1 domain exhibited wild-type-like activity. D3 markedly increased uterine weight and proliferation of the uterine epithelium in ovariectomized mice, whereas D1 and D2 were inactive. D3, like E(2), up-regulated lactoferrin (Ltf) gene expression. The responses to D3 in the uterus were inhibited by ICI 182,780. In addition, D3 stimulated both classical (Aqp5) and nonclassical (Cdkn1a) ER-mediated gene regulation.The results suggest that the D3 diarylheptanoid is an agonist for ER both in vitro and in vivo, and its biological action is ERalpha selective, specifically requiring AF2 function, and involves direct binding via ER as well as ERE-independent gene regulation.
Releasing Resources to Achieve Health Gain
Authors: C. Paton
Journal: BMJ (1995)

Ed Christopher Riley, Morton Warner, Amanda Pullen, Carolyn Semple Piggot Radcliffe, £35, pp 254 ISBN 1 85775 018 7

Several assumptions underlie conventional wisdom on the need to do more with existing resources in the NHS. The first assumption is that fiscal retrenchment is here to stay and is a matter of neutral economics rather than of political choice. The second is that, paradoxically, although the NHS is a “good buy” by international standards, there is huge scope for making more savings. The third is that important budgetary savings can be made by transferring services from hospitals to what is loosely called primary care. A fourth assumption, sometimes accompanying this, is that prevention and promotion can reduce the need for acute medical care.

A book with the title Releasing Resources to Achieve Health Gain might be expected to justify its agenda empirically. That agenda is to improve …
Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy
Authors: Hagop M. Kantarjian, Francis J. Giles, Peter L. Greenberg, Ron L. Paquette, Eunice S. Wang, Janice L. Gabrilove, Guillermo Garcia-Manero, Kuolung Hu, Janet L. Franklin, Dietmar P. Berger
Journal: Blood (2010)