tbuckley/cabot-search huggingface dataset:
A7.9 Does Telomere Shortening in Women with Rheumatoid Arthritis Predict X Chromosome Inactivation Bias?
Authors: Sami Barna Kanaan, Onur Emre Onat, Nathalie Balandraud, Doua F Azzouz, Jean Roudier, Tayfun Ozcelik, Nathalie C Lambert
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid Arthritis (RA), like most auto-immune diseases, is a female predominant disease. As a possible explanation for gender bias, we have previously shown that women with RA have non-random X chromosome inactivation (XCI) that could trigger autoimmunity (article in preparation). Intriguingly, this bias in XCI correlates with presence of the shared epitope (SE) and with disease duration. Also associated with presence of the SE, premature immunosenescence, characterised by shorter telomere length, has been described in peripheral blood cells from patients with RA [1]. Moreover, telomeric non coding RNAs have been reported to be enriched near the inactive X chromosome in mammals [2] indicating a potential link between telomere length and XCI. <h3>Objectives</h3> In this context, we propose to test whether women with RA have shortened telomere length and whether that could influence the epigenetic mechanism of XCI. <h3>Methods</h3> A total of 73 women with RA and 48 healthy women with no history of autoimmune diseases, who had previously been tested for XCI and HLA-genotyped, were evaluated for telomere length. The relative telomere length was estimated by real-time PCR as originally described by Cawthon [3] with the 2<sup>-</sup><sup>∆∆</sup><sup>Ct</sup> method. <h3>Results</h3> Preliminary results show that women with RA have smaller telomere length than healthy women, although the difference is modest (p = 0.07) and has to be adjusted for age on a larger cohort. Contrary to expectations, shorter telomere length is not correlated with skewed XCI status, disease duration or the presence of shared epitope in our small cohort. <h3>Conclusions</h3> This preliminary study seems to confirm that women with RA have shorter telomeres than healthy women. Further telomere length measurements have to be done on a larger group of patients with RA and healthy controls, as well as HLA-genotyping them and evaluating their XCI status. This will be a step forward in understanding the relationship between immune senescence, female predisposition and genetic risk (SE) in RA. <h3>References</h3> SO Schonland<i> et al</i>, <i>Proc Natl Acad Sci U S A</i><b>100</b>, 13471 (Nov 11, 2003). S Schoeftner, M A Blasco, <i>Nat Cell Biol</i><b>10</b>, 228 (Feb, 2008). RM Cawthon, <i>Nucleic Acids Res</i><b>30</b>, e47 (May 15, 2002).
Newer antidepressants for the treatment of depression in adults
Authors: S. Hatcher, B. Arroll
Journal: BMJ (2012)

Antidepressants are prescribed mainly for people with depression, although some are also used for anxiety disorders and other conditions, including chronic pain and enuresis. They are one of the most commonly prescribed medications (more than 43 million prescriptions were written for them between April 2010 and March 2011 in England1).

Antidepressants were developed in the 1950s, and their mechanism of action is thought to be by increasing the levels of extracellular synaptic neurotransmitters such as serotonin, noradrenaline, and dopamine; they also have other effects, including increasing hippocampal neurogenesis. The original antidepressants were known as tricyclics because of their chemical structure. Since the 1980s a new generation of antidepressants has been developed and marketed based on their mode of action. The nomenclature for referring to these newer drugs is confusing as they can be classified by several criteria, including the target molecule and the number of neurotransmitter sites involved.2 Box 1 lists antidepressants grouped according to the current nomenclature used by the World Health Organization.

#### Box 1 World Health Organization’s current nomenclature for antidepressants, with examples of current drugs

##### Non-selective monoamine reuptake inhibitors

##### Selective serotonin reuptake inhibitors

##### Monoamine oxidase inhibitors (non-selective)

##### Monoamine oxidase A inhibitors

##### Other antidepressants

The focus of this article is on selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants (using the World Health Organization’s nomenclature (box 1)) and their use in adults presenting with depressive disorders. We have excluded non-reversible monoamine oxidase inhibitors such as phenelzine as recent guidelines recommend these should usually be prescribed only by specialist mental health professionals. …
Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model
Authors: M Courtemanche
Journal: Cardiovascular Research (1999)

Recent advances in molecular electrophysiology have made possible the development of more selective ion channel blockers for therapeutic use. However, more information is needed about the effects of blocking specific channels on repolarization in normal human atrium and in atrial cells of patients with atrial fibrillation (AF). AF-induced electrical remodeling is associated with reductions in transient outward current (Ito), ultrarapid delayed rectifier current (IKur), and L-type calcium current (ICa,L). Direct evaluation of the results of ion channel depression is limited by the nonspecificity of the available pharmacological probes. Objectives: Using a mathematical model of the human atrial action potential (AP), we aimed to: (1) evaluate the role of ionic abnormalities in producing AP changes characteristic of AF in humans and (2) explore the effects of specific channel blockade on the normal and AF-modified AP (AFAP). Methods: We used our previously developed mathematical model of the normal human atrial AP (NAP) based on directly measured currents. We constructed a model of the AFAP by incorporating experimentally-measured reductions in Ito (50%), IKur (50%), and ICa,L (70%) current densities observed in AF. Results: The AFAP exhibits the reductions in AP duration (APD) and rate-adaption typical of AF. The reduction in ICa,L alone can account for most of the morphological features of the AFAP. Inhibition of Ito by 90% leads to a reduction in APD measured at −60 mV in both the NAP and AFAP. Inhibition of the rapid component of the delayed rectifier (IKr) by 90% slows terminal repolarization of the NAP and AFAP and increases APD by 38% and 34%, respectively. Inhibition of IKur by 90% slows early repolarization and increases plateau height, activating additional IK and causing no net change in APD at 1 Hz in the NAP. In the presence of AF-induced ionic modifications, IKur inhibition increases APD by 12%. Combining IKur and IKr inhibition under both normal and AF conditions synergistically increases APD. In the NAP, altering the model parameters to reproduce other typical measured AP morphologies can significantly alter the response to K+-channel inhibition. Conclusions: (1) The described abnormalities in Ito, IKur and ICa,L in AF patients can account for the effects of AF on human AP properties; (2) AP prolongation by IKur block is limited by increases in plateau height that activate more IK; (3) Blockers of IKur may be more effective in prolonging APD in patients with AF; 4) Inhibition of both IKur and IKr produces supra-additive effects on APD. These observations illustrate the importance of secondary current alterations in the response of the AP to single channel blockade, and have potentially important implications for the development of improved antiarrhythmic drug therapy for AF.
Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5' gene with an imperfect polyadenylation signal sequence.
Authors: B Zieger, Y Hashimoto, J Ware
Journal: Journal of Clinical Investigation (1997)

Glycoprotein (GP) Ib is a major component of the platelet membrane receptor for von Willebrand factor, designated the GP Ib-IX-V complex. GP Ib is composed of two subunits (GP Ib(alpha) and GP Ib(beta)) each synthesized from separate genes. The 206 amino acid precursor of GP Ib(beta) is synthesized from a 1.0-kb mRNA expressed by megakaryocytes and was originally characterized from cDNA clones of human erythroleukemic (HEL) cell mRNA, a cell line exhibiting megakaryocytic-like properties. The cell line CHRF-288-11 also exhibits megakaryocytic-like properties, but synthesizes two related GP Ib(beta) mRNA species of 3.5 and 1.0 kb. We performed cDNA cloning experiments to identify the origin of the 3.5-kb transcript and determine its relationship to the 1.0-kb GP Ib(beta) mRNA found in megakaryocytes, platelets, and HEL cells. Our cloning experiments demonstrate that the longer transcript results from a nonconsensus polyadenylation recognition sequence, 5'AACAAT3', within a separate gene located upstream to the platelet GP Ib(beta) gene. In the absence of normal polyadenylation the more 5' gene uses the polyadenylation site within its 3' neighbor, the platelet GP Ib(beta) gene. This newly identified 5' gene contains an open reading frame encoding 369 amino acids with a high degree of sequence similarity to an expanding family of GTP-binding proteins.
New pathophysiological function of protein phosphatase 2A?
Authors: J. Neumann
Journal: Cardiovascular Research (2008)

In this issue of the Journal, there is an interesting study by Larsen et al. ,1 which provides evidence that in pulmonary hypoxia a new mechanism might be operational that explains the deterioration of heart function in primary pulmonary hypertension. The authors chronically exposed mice to 10% oxygen to mimic hypoxia in patients. The authors had noted in previous studies that this degree of pulmonary hypoxia leads to slower cardiac relaxation, putatively due to reduced phosphorylation of phospholamban on amino acid serine 16. In the present report, they provide evidence that the activity of phosphatase 2A but not phosphatase 1 is enhanced in sarcoplasmic reticulum-enriched membranes from these hearts. This led to reduced phosphorylation of phospholamban, which could explain reduced cardiac contractility. Surprisingly, a similar increase in phosphatase activity was noted in left ventricular as well as in right ventricular preparations. On the basis of … 

*Corresponding author. Tel: + 49 345 557 1686; fax: + 49 345 557 18 35. E-mail address: joachim.neumann{at}medizin.uni-halle.de
The effects of calcitriol treatment in glucocorticoid-resistant asthma
Authors: Alexandra M. Nanzer, Emma S. Chambers, Kimuli Ryanna, Anna T. Freeman, Grainne Colligan, David F. Richards, Peter M. Timms, Adrian R. Martineau, Christopher J. Griffiths, Christopher J. Corrigan, Catherine M. Hawrylowicz
Journal: Journal of Allergy and Clinical Immunology (2014)
Maternal Infanticide Associated With Mental Illness: Prevention and the Promise of Saved Lives
Authors: Margaret G. Spinelli
Journal: American Journal of Psychiatry (2004)

Although maternal infanticide is a rare event, a high proportion of cases occurs in the context of postpartum mental illness. The author reviews historical, legislative, and contemporary psychiatric perspectives on infanticide and discusses ways in which the psychiatric community can improve prevention of infanticide and promote appropriate treatment of mentally ill women who commit infanticide.The case of Texas v. Andrea Yates, involving a mother with mental illness who drowned her five children, is used to illustrate society's complicated reactions to infanticide in the context of postpartum mental illness.In the United States, the complexity of the response to infanticide is demonstrated by the judicial system's reaction to such cases. Whereas England's Infanticide Law provides probation and mandates psychiatric treatment for mothers with mental illness who commit infanticide, "killer mothers" may face the death penalty in the United States. Contemporary neuroscientific findings support the position that a woman with postpartum psychosis who commits infanticide needs treatment rather than punishment and that appropriate treatment will deter her from killing again. Psychiatrists have a vital role in recognizing the signs and symptoms of peripartum psychiatric disorders, particularly postpartum psychosis, and in early identification of and intervention with at-risk mothers.The absence of formal DSM-IV diagnostic criteria for postpartum psychiatric disorders promotes disparate treatment under the law. The psychiatric community should develop guidelines for the treatment of postpartum disorders, foster sharing of knowledge between psychiatry and the law, and do more to enlighten society about the effects of mental illness on thought and behavior so that decisions about the treatment and punishment of mentally ill persons will not be left exclusively in the hands of the judicial system.
Detection of Bladder Cancer Using a Point-of-Care Proteomic Assay
Authors: H. Barton Grossman
Journal: JAMA (2005)

A combination of methods is used for diagnosis of bladder cancer because no single procedure detects all malignancies. Urine tests are frequently part of an evaluation, but have either been nonspecific for cancer or required specialized analysis at a laboratory.To investigate whether a point-of-care proteomic test that measures the nuclear matrix protein NMP22 in voided urine could enhance detection of malignancy in patients with risk factors or symptoms of bladder cancer.Twenty-three academic, private practice, and veterans' facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy.The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner.Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ.The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cystoscopy, with test results available during the patient visit.
White House Aide Studying AIDS Commission Recommendations; Reports to President Soon
Authors: Charles Marwick
Journal: JAMA (1988)

PRESIDENT RONALD REAGAN says the final report of his Commission on the Human Immunodeficiency Virus (HIV) Epidemic is an impressive effort that "significantly increases our level of understanding to deal with acquired immunodeficiency syndrome." He is directing Donald Ian Macdonald, MD, the White House's special assistant for drug policy, to review the more than 600 recommendations (<i>JAMA</i>1988;260:16-17,<i>JAMA</i>1988;259:169-170, and<i>JAMA</i>1988;259:2195, 2199) and chart a future course of action to deal with the epidemic. This is an acknowledgment of a major message of the report, that control of the spread of the virus is related to drug abuse. Macdonald, previously administrator, Alcohol, Drug Abuse, and Mental Health Administration (<i>JAMA</i>1988;260:459), is to report back to the President in the next few days. <h3>Against Discrimination</h3> Another major, and more contentious, recommendation by the commission involves broadening and extending (to the private sector) the antidiscrimination provisions of the 1973 Rehabilitation
Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia.
Authors: J H Rowland, O J Glidewell, R F Sibley, J C Holland, R Tull, A Berman, M L Brecher, M Harris, A S Glicksman, E Forman
Journal: Journal of Clinical Oncology (1984)

A comparison of the late effects on intellectual and neuropsychologic function of three different CNS "prophylaxis" regimens was conducted in 104 patients treated for childhood acute lymphocytic leukemia. Of the children studied, 33 were randomized to treatment with intrathecal (IT) methotrexate alone, 36 to IT methotrexate plus 2,400 rad cranial irradiation, and 35 to IT methotrexate plus intravenous intermediate dose methotrexate. All patients were in their first (complete) continuous remission, were a minimum of one year post-CNS prophylaxis and had no evidence of CNS disease at the time of evaluation. In contrast to the other two treatment groups, children whose CNS prophylaxis included cranial irradiation attained significantly lower mean Full Scale IQs (P less than .001), performed more poorly on the Wide Range Achievement Test, a measure of school abilities, and exhibited a greater number of difficulties on a variety of other neuropsychologic measures. The poorer performance of the irradiated group was independent of sex of the patient, time since treatment and age at diagnosis. These data suggest that the addition of 2,400 rad cranial irradiation to CNS prophylaxis in ALL puts these children at greater risk for mild global loss in intellectual and neuropsychologic ability.
Sports Medicine and Ethics
Authors: Daniela Testoni, Christoph P. Hornik, P. Brian Smith, Daniel K. Benjamin, Ross E. McKinney
Journal: The American Journal of Bioethics (2013)

Physicians working in the world of competitive sports face unique ethical challenges, many of which center around conflicts of interest. Team-employed physicians have obligations to act in the club's best interest while caring for the individual athlete. As such, they must balance issues like protecting versus sharing health information, as well as issues regarding autonomous informed consent versus paternalistic decision making in determining whether an athlete may compete safely. Moreover, the physician has to deal with an athlete's decisions about performance enhancement and return to play, pursuit of which may not be in the athlete's long-term best interests but may benefit the athlete and team in the short term. These difficult tasks are complicated by the lack of evidence-based standards in a field influenced by the lure of financial gains for multiple parties involved. In this article, we review ethical issues in sports medicine with specific attention paid to American professional football.
Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells
Authors: Masanao Tabuse, Shigeki Ohta, Yohei Ohashi, Raita Fukaya, Aya Misawa, Kazunari Yoshida, Takeshi Kawase, Hideyuki Saya, Cécile Thirant, Hérve Chneiweiss, Yumi Matsuzaki, Hideyuki Okano, Yutaka Kawakami, Masahiro Toda
Journal: Molecular Cancer (2011)

HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies.In this study, we found high expression of the HOXD9 gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of HOXD9 in gliomas, we silenced its expression in the glioma cell line U87 using HOXD9-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that HOXD9 contributes to both cell proliferation and/or cell survival. The HOXD9 gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. HOXD9 siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of HOXD9 in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs).Our results suggest that HOXD9 may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target.
Direct non-genomic effects of follicular steroids on maturing human oocytes: oestrogen versus androgen antagonism
Authors: J Tesarik
Journal: Human Reproduction Update (1997)

Previously published data have suggested that oestradiol exerts direct beneficial effects on human oocytes during in-vitro maturation and that these effects are at least partly due to a non-genomic action of the steroid at the oocyte surface. Here we provide evidence showing that a non-genomic effect of oestradiol is counteracted by androstenedione. In contrast to these results from in-vitro experiments, in which changes in steroid concentrations are abrupt and the non-genomic responses are rapid, the progressively changing follicular steroid concentrations which occur during in-vivo development may rather have permissive or restrictive effects on the events of spontaneous oocyte cytoplasmic maturation. The oocyte is particularly sensitive at the germinal vesicle stage of development to non-genomic steroid actions. Ovarian stimulation protocols should thus be adjusted so as to avoid androgen predominance at the mid-follicular phase. In patients in whom this condition cannot be met, in-vitro maturation of oocytes may be a solution.
Causal theory and the etiology of periodontal diseases
Authors: Brenda Heaton, Thomas Dietrich
Journal: Periodontology 2000 (2011)

Abstract Causal theory and causal models have proven to be helpful in understanding the multi‐factorial causation of many diseases, including periodontitis. The design and application of causal models is essential to the appropriate design, conduct and analysis of studies on periodontal disease causation. This review discusses the principles of causation and causal theory, both in general and as they pertain to studies of the etiology of periodontitis. Specifically, we present an overview of models of causation, including the potential outcomes model, the sufficient component cause model, and directed acyclic graphical models. More thorough explanations and accompanying illustrations are provided for the sufficient component cause model and the directed acyclic graphical model. Topics related to the study of periodontitis, as illustrated by such models, include the principles of confounding and effect measure modification (interaction). Existing models of periodontitis etiology are critically reviewed in this context.