tbuckley/cabot-search huggingface dataset:
Tuberculosis in children and adults
Authors: Alexandre Alcaïs, Claire Fieschi, Laurent Abel, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2005)

Disseminated disease in children and pulmonary disease in adults constitute two major epidemiological and clinical forms of tuberculosis. Paradoxically, only a small fraction of infected individuals develop clinical tuberculosis, typically one form of the disease or the other. Mendelian and complex genetic predispositions to tuberculosis were reported recently in children and adults, respectively. Here, we argue that tuberculosis and its clinical expression largely reflect the underlying human genetic background.
A severe ‘stasis eczema’, associated with low plasma zinc, treated successfully with oral zinc
Authors: C.W.I. OWENS, A.A. AL-KHADER, M.J. JACKSON, B.N.C. PRICHARD
Journal: British Journal of Dermatology (1981)

SUMMARY We describe a case of non-ulcerating severe stasis eczema in an elderly female associated with a low plasma zinc and which responded to treatment with oral supplements. The dermatological changes were not accompanied by oedema and were most marked over the lower legs and ankles, with patchy erythematous lesions extending to the inner thighs, over the dorsal surface of both hands and the forearms. There was some excoriation and a degree of lichenification. These lesions were intensely pruritic and resolved almost completely following treatment with oral zinc sulphate (220 mg daily) on two separate occasions. Histological appearances of biopsy material included those of stasis eczema but there was also a marked degree of parakeratosis. The cause of the low plasma zinc was not identified.
Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure
Authors: Kirsten Leineweber, Michael Böhm, Gerd Heusch
Journal: Circulation (2006)

yclic adenosine monophosphate (cAMP) is a tightly regulated second messenger that is critically involved in many intracellular processes.In cardiomyocytes, the activation of a number of membrane receptors, notably ␤-receptors and muscarinic receptors, acts through stimulatory or inhibitory G-proteins (G␣s/G␣i) on adenylyl cyclase (AC), which synthesizes cAMP from ATP. cAMP is degraded by phosphodiesterases (PDE).Thereafter, cAMP activates protein kinase A (PKA), which, in turn, through phosphorylation of L-type calcium channels, ryanodine receptors, phospholamban, and troponin I, improves excitationcontraction coupling and increases heart rate, as well as contraction amplitude and relaxation.PKA also phosphorylates nuclear cAMP-response element binding proteins to activate transcription. 1 There are at least 9 isoforms of AC; the mammalian myocardium expresses mainly AC V and VI.AC V is the predominant isoform in adult cardiac tissue, whereas AC VI expression decreases with age.Both isoforms are phosphorylated by PKA and thereby inhibited, thus providing a feedback regulation and potential desensitization pathway. 2,3Transgenic mice with cardiac-directed overexpression of AC VI have normal cAMP and cardiac function at rest but increased responses in both cAMP and function to ␤-adrenergic stimulation, 4 as confirmed in the present study by Takahasi et al.
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial
Authors: Robert S. Bresalier, Robert S. Sandler, Hui Quan, James A. Bolognese, Bettina Oxenius, Kevin Horgan, Christopher Lines, Robert Riddell, Dion Morton, Angel Lanas, Marvin A. Konstam, John A. Baron
Journal: New England Journal of Medicine (2005)

Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas.
Informed Consent in Psychotherapy
Authors: J O Beahrs, T G Gutheil
Journal: American Journal of Psychiatry (2001)

The authors sought a rational approach to implementing informed consent within the practice of psychotherapy.The history of informed consent in psychotherapy was reviewed to define a common synthesis that maximizes the potential benefits and minimizes the potential hazards.The benefits of informed consent in psychotherapy include fostering a positive treatment outcome through enhancing patient autonomy, responsibility, and self-therapeutic activity; lessening the risks of regressive effects and therapist liability; and helping the practice of psychotherapy extend beyond particular parochialisms by providing checks and balances on therapist judgments. The hazards include the unpredictability of interactional outcomes and the possibilities of replacing positive expectancy with negative suggestion, replacing a therapeutic alliance with a legalistic stance, and misimplying that patients are passive recipients.Practical implementation of informed consent in psychotherapy must balance such tensions in service of optimal treatment. As a guiding principle, the authors recommend that psychotherapists convey to a prospective patient information that is material to the particular patient's decision. The level of detail needed in informed consent discussions varies directly with the cost and risks of the proposed treatment, the presence of viable alternatives and their relative grounding in scientific data and professional acceptance, and the presence of significant controversy. Unresolved is the question of how to address problematic or controversial psychotherapeutic trends that temporarily enjoy wide professional support.
Zoledronic Acid Inhibits Both the Osteolytic and Osteoblastic Components of Osteosarcoma Lesions in a Mouse Model
Authors: Agatha Labrinidis, Shelley Hay, Vasilios Liapis, Vladimir Ponomarev, David M. Findlay, Andreas Evdokiou
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To evaluate the efficacy of zoledronic acid (ZOL) against osteosarcoma (OS) growth, progression, and metastatic spread using an animal model of human OS that closely resembles the human disease. Experimental Design: Human K-HOS or KRIB OS cells, tagged or untagged with a luciferase reporter construct, were transplanted directly into the tibial cavity of nude mice. ZOL was given as weekly, or a single dose of 100 μg/kg body weight, equivalent to the 4 mg i.v. dose used clinically. Tumor growth at the primary site and as pulmonary metastases was monitored by bioluminescence imaging and histology, and OS-induced bone destruction was measured using high-resolution micro–computed tomography. Results: Mice transplanted with OS cells exhibited aberrant bone remodeling in the area of cancer cell transplantation, with areas of osteolysis mixed with extensive new bone formation extending from the cortex. ZOL administration prevented osteolysis and significantly reduced the amount of OS-induced bone formation. However, ZOL had no effect on tumor burden at the primary site. Importantly, ZOL failed to reduce lung metastasis and in some cases was associated with larger and more numerous metastatic lesions. Conclusions: Our data show that clinically relevant doses of ZOL, while protecting the bone from OS-induced bone destruction, do not inhibit primary tumor growth. Moreover, lung metastases were not reduced and may even have been promoted by this treatment, indicating that caution is required when the clinical application of the bisphosphonate class of antiresorptives is considered in OS.
An essential role for c-FLIP in the efficient development of mature T lymphocytes
Authors: Nu Zhang, You-Wen He
Journal: The Journal of Experimental Medicine (2005)

Apoptosis-related genes play important roles in thymocyte maturation. We show that cellular FLICE-like inhibitory protein (c-FLIP), a procaspase-8-like apoptotic regulator, plays an essential role in the efficient development of mature T lymphocytes. Mice conditionally lacking c-FLIP in T lymphocytes display severe defects in the development of mature T cells, as indicated by a dramatically reduced number of CD4+ and CD8+ T cells in the spleen and lymph nodes of mutant mice. The impaired T lymphocyte maturation in c-FLIP conditional knockout mice occurs at the single-positive thymocyte stage and may be caused by enhanced apoptosis in vivo. Moreover, although c-FLIP has been implicated in T cell receptor signaling through nuclear factor (NF)-kappaB and Erk pathways, activation of NF-kappaB and Erk in c-FLIP-deficient thymocytes appears largely intact. Collectively, our data suggest that the primary role of c-FLIP in thymocyte maturation is to protect cells from apoptosis.
Immunohistochemical Detection of <i>EGFR</i> Mutation Using Mutation-Specific Antibodies in Lung Cancer
Authors: Atsuko Kitamura, Waki Hosoda, Eiichi Sasaki, Tetsuya Mitsudomi, Yasushi Yatabe
Journal: Clinical Cancer Research (2010)

Patients with mutations of epidermal growth factor receptor (EGFR) receive more benefit from EGFR-tyrosine kinase inhibitor treatment. However, usually such treatment is used to treat advanced lung cancer and only small biopsy samples are available for mutational analysis. We used immunohistochemistry to examine recently developed antibodies specific to major hotspot mutations of L858R and DEL E746-A750.We used five series of lung cancers: 47 non-small cell lung cancers (NSCLC) to evaluate various types of EGFR mutations, a consecutive series of 238 NSCLCs to study the sensitivity and specificity, 11 NSCLCs with both EGFR mutation and amplification to examine the spatial distribution, 32 patients treated with gefitinib to compare clinical responses, and 15 NSCLCs to explore changes associated with acquired T790M mutation.Each antibody specifically recognized the corresponding mutation but also recognized other types of mutations. Overall specificity and sensitivity were 96% and 47%, respectively. The positive reaction showed heterogeneous distribution that agreed with the expression of the total EGFR molecule, part of which was associated with gene amplification. A clinical response to gefitinib treatment correlated with the reaction, although one of the two patients with a positive reaction responded well despite having the wild-type EGFR. Acquired T790M mutation did not change the reaction to the antibodies.On some characteristics, the positive reaction to mutation-specific antibodies differs from the molecular EGFR mutation. Therefore, this study revealed that not all patients with EGFR mutations can be selected using these mutation-specific antibodies.
O167 ADDITION OF SIMVASTATIN TO STANDARD TREATMENT IMPROVES SURVIVAL AFTER VARICEAL BLEEDING IN PATIENTS WITH CIRRHOSIS. A DOUBLE-BLIND RANDOMIZED TRIAL (NCT01095185)
Authors: J.G. Abraldes, C. Villanueva, C. Aracil, J. Turnes, M. Hernandez-Guerra, J. Genesca, C.A. Navascues, J. Castellote, J.L. Calleja, A. Albillos, J. Bosch
Journal: Journal of Hepatology (2014)
Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations
Authors: Suk-Kyun Yang, Myunghee Hong, Wanting Zhao, Yusun Jung, Jiwon Baek, Naeimeh Tayebi, Kyung Mo Kim, Byong Duk Ye, Kyung-Jo Kim, Sang Hyoung Park, Inchul Lee, Eun-Ju Lee, Won Ho Kim, Jae Hee Cheon, Young-Ho Kim, Byung Ik Jang, Hyun-Soo Kim, Jai Hyun Choi, Ja Seol Koo, Ji Hyun Lee, Sung-Ae Jung, Yeoun Joo Lee, Joo Young Jang, Hyoung Doo Shin, Daehee Kang, Hee-Shang Youn, Jianjun Liu, Kyuyoung Song
Journal: Gut (2013)

<h3>Objective</h3> Crohn9s disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations. <h3>Methods</h3> We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls. <h3>Results</h3> We confirmed four previously reported loci: <i>TNFSF15</i>, <i>IL23R</i>, the major histocompatibility complex region, and the <i>RNASET2-FGFR1OP-CCR6</i> region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10<sup>−14</sup>), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10<sup>−10</sup>) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10<sup>−9</sup>), implicating <i>ATG16L2</i> and/or <i>FCHSD2</i> as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of <i>ATG16L2</i> with stronger association (OR=1.61, combined p=2.44×10<sup>−12</sup>) than rs11235667, suggesting <i>ATG16L2</i> as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10<sup>−5</sup>)) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans. <h3>Conclusions</h3> Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.
Human choriogonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights
Authors: S.F. de Medeiros, R.J. Norman
Journal: Human Reproduction Update (2008)

Human chorionic gonadotrophin (hCG) is measured in serum and urine for the early detection of ectopic pregnancy, patients with higher risk of miscarriage, embryos or fetuses with chromosome abnormalities, prediction of pre-eclampsia or fetal growth restriction and identification or follow-up of trophoblast neoplasia. This review examines basic knowledge on the heterogeneity of hCG protein core and sugar branches and its relevance to assays used in a clinical setting. The databases Scielo and Medline/Pubmed were consulted for identification of the most relevant published papers. Search terms were gonadotrophin, glycoprotein structure, hCG structure and molecular forms of hCG. The synthesis of alpha (hCGα) and beta (hCGβ) peptide chains and their further glycosylation involve the complex action of different enzymes. After assembly, hCG reaches the cell surface and is secreted as a bioactive heterodimer. The complex cascade of enzymes acting in hCG secretion results in heterogeneous molecular forms. The hCG molecules are differently metabolized by the liver, ovary and kidney, but the majority of hCG forms are excreted in the urine. Intact hCG, hCGα, hCGβ, hyperglycosylated (hCGh), nicked (hCGn) and core fragment of hCGβ (hCGβcf) forms have relevant clinical use. The immunogenicity of each hCG variant, their epitopes distribution and the available antibodies are important for the development of specific assays. Depending on the prevalent form or proportion in relation to the intact hCG, the choice of assay for measurement of a specific molecule in a particular clinical setting is paramount. Measurement of hCG and/or its related molecules is useful in clinical practice, but greater awareness is needed worldwide regarding the use of new sensitive and specific assays tailored for different clinical applications.
Evolutionary Histories of Transposable Elements in the Genome of the Largest Living Marsupial Carnivore, the Tasmanian Devil
Authors: Susanne Gallus, Björn M Hallström, Vikas Kumar, William G Dodt, Axel Janke, Gerald G Schumann, Maria A Nilsson
Journal: Molecular Biology and Evolution (2015)

The largest living carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii), is the sole survivor of a lineage originating about 12 Ma. We set out to investigate the spectrum of transposable elements found in the Tasmanian devil genome, the first high-coverage genome of an Australian marsupial. Marsupial genomes have been shown to have the highest amount of transposable elements among vertebrates. We analyzed the horizontally transmitted DNA transposons OC1 and hAT-1_MEu in the Tasmanian devil genome. OC1 is present in all carnivorous marsupials, while having a very limited distribution among the remaining Australian marsupial orders. In contrast, hAT-1_MEu is present in all Australian marsupial orders, and has so far only been identified in a few placental mammals. We screened 158 introns for phylogenetically informative retrotransposons in the order Dasyuromorphia, and found that the youngest SINE (Short INterspersed Element), WSINE1, is no longer active in the subfamily Dasyuridae. The lack of detectable WSINE1 activity in this group may be due to a retrotransposon inactivation event approximately 30 Ma. We found that the Tasmanian devil genome contains a relatively low number of continuous full-length LINE-1 (Long INterspersed Element 1, L1) retrotransposons compared with the opossum genome. Furthermore, all L1 elements in the Tasmanian devil appeared to be nonfunctional. Hidden Markov Model approaches suggested that other potential sources of functional reverse transcriptase are absent from the genome. We discuss the issues associated with assembling long, highly similar L1 copies from short read Illumina data and describe how assembly artifacts can potentially lead to erroneous conclusions.
Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology
Authors: Danshi Li, Peter Melnyk, Jianlin Feng, Zhiguo Wang, Kevin Petrecca, Alvin Shrier, Stanley Nattel
Journal: Circulation (2000)

Background —Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology. Methods and Results —We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (mean±SEM capacitance, 89±2 pF versus 71±2 pF in control, n=160 cells per group, P &lt;0.001). CHF significantly reduced the density of L-type Ca 2+ current ( I Ca ) by ≈30%, of transient outward K + current ( I to ) by ≈50%, and of slow delayed rectifier current ( I Ks ) by ≈30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca 2+ currents were not altered by CHF. CHF increased transient inward Na + /Ca 2+ exchanger (NCX) current by ≈45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster rates, paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging mean AF duration from 8±4 to 535±82 seconds ( P &lt;0.01). Conclusions —Experimental CHF selectively decreases atrial I to , I Ca , and I Ks , increases NCX current, and leaves other currents unchanged. The cellular electrophysiological remodeling caused by CHF is quite distinct from that caused by atrial tachycardia, highlighting important differences in the cellular milieu characterizing different clinically relevant AF substrates.
Enolase from Trypanosoma brucei, from the Amitochondriate Protist Mastigamoeba balamuthi, and from the Chloroplast and Cytosol of Euglena gracilis: Pieces in the Evolutionary Puzzle of the Eukaryotic Glycolytic Pathway
Authors: V Hannaert, H Brinkmann, U Nowitzki, J A Lee, M A Albert, C W Sensen, T Gaasterland, M Müller, P Michels, W Martin
Journal: Molecular Biology and Evolution (2000)

Genomic or cDNA clones for the glycolytic enzyme enolase were isolated from the amitochondriate pelobiont Mastigamoeba balamuthi, from the kinetoplastid Trypanosoma brucei, and from the euglenid Euglena gracilis. Clones for the cytosolic enzyme were found in all three organisms, whereas Euglena was found to also express mRNA for a second isoenzyme that possesses a putative N-terminal plastid-targeting peptide and is probably targeted to the chloroplast. Database searching revealed that Arabidopsis also possesses a second enolase gene that encodes an N-terminal extension and is likely targeted to the chloroplast. A phylogeny of enolase amino acid sequences from 6 archaebacteria, 24 eubacteria, and 32 eukaryotes showed that the Mastigamoeba enolase tended to branch with its homologs from Trypanosoma and from the amitochondriate protist Entamoeba histolytica. The compartment-specific isoenzymes in Euglena arose through a gene duplication independent of that which gave rise to the compartment-specific isoenzymes in Arabidopsis, as evidenced by the finding that the Euglena enolases are more similar to the homolog from the eubacterium Treponema pallidum than they are to homologs from any other organism sampled. In marked contrast to all other glycolytic enzymes studied to date, enolases from all eukaryotes surveyed here (except Euglena) are not markedly more similar to eubacterial than to archaebacterial homologs. An intriguing indel shared by enolase from eukaryotes, from the archaebacterium Methanococcus jannaschii, and from the eubacterium Campylobacter jejuni maps to the surface of the three-dimensional structure of the enzyme and appears to have occurred at the same position in parallel in independent lineages.
Tuberculosis Toxin Blocking Phagosome Maturation Inhibits a Novel Ca2+/Calmodulin-PI3K hVPS34 Cascade
Authors: Isabelle Vergne, Jennifer Chua, Vojo Deretic
Journal: The Journal of Experimental Medicine (2003)

The capacity of Mycobacterium tuberculosis to infect latently over one billion people and cause two million fatalities annually rests with its ability to block phagosomal maturation into the phagolysosome in infected macrophages. Here we describe how M. tuberculosis toxin lipoarabinomannan (LAM) causes phagosome maturation arrest, interfering with a new pathway connecting intracellular signaling and membrane trafficking. LAM from virulent M. tuberculosis, but not from avirulent mycobacteria, blocked cytosolic Ca2+ increase. Ca2+ and calmodulin were required for a newly uncovered Ca2+/calmodulin phosphatidylinositol (PI)3 kinase hVPS34 cascade, essential for production of PI 3 phosphate (PI3P) on liposomes in vitro and on phagosomes in vivo. The interference of the trafficking toxin LAM with the calmodulin-dependent production of PI3P described here ensures long-term M. tuberculosis residence in vacuoles sequestered away from the bactericidal and antigen-processing organelles in infected macrophages.