tbuckley/cabot-search huggingface dataset:
An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2
Authors: Jae-Ho Cho, Onur Boyman, Hee-Ok Kim, Bumsuk Hahm, Mark P. Rubinstein, Chris Ramsey, David M. Kim, Charles D. Surh, Jonathan Sprent
Journal: The Journal of Experimental Medicine (2007)

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen–self–major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced “homeostatic” proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8+ T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.
Effectiveness of appropriately trained nurses in preoperative assessment: randomised controlled equivalence/non-inferiority trial
Authors: H. Kinley
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To determine whether preoperative assessments carried out by appropriately trained nurses are inferior in quality to those carried out by preregistration house officers. <b>Design</b>: Randomised controlled equivalence/non-inferiority trial. <b>Setting</b>: Four NHS hospitals in three trusts. Three of the four were teaching hospitals. <b>Participants</b>: All patients attending for assessment before general anaesthesia for general, vascular, urological, or breast surgery between April 1998 and March 1999. <b>Intervention</b>: Assessment by one of three appropriately trained nurses or by one of several preregistration house officers. <b>Main outcome measures</b>: History taken, physical examination, and investigations ordered. Measures evaluated by a specialist registrar in anaesthetics and placed in four categories: correct, overassessment, underassessment not affecting management, and underassessment possibly affecting management (primary outcome). <b>Results</b>: 1907 patients were randomised, and 1874 completed the study; 926 were assessed by house officers and 948 by nurses. Overall 121/948 (13%) assessments carried out by nurses were judged to have possibly affected management compared with 138/926 (15%) of those performed by house officers. Nurses were judged to be non-inferior to house officers in assessment, although there was variation among them in terms of the quality of history taking. The house officers ordered considerably more unnecessary tests than the nurses (218/926 (24%) <i>v</i> 129/948 (14%). <b>Conclusions</b>: There is no reason to inhibit the development of nurse led preoperative assessment provided that the nurses involved receive adequate training. However, house officers will continue to require experience in preoperative assessment.
Joint Disease. All the Arthropathies
Authors: A. B. Myles
Journal: Annals of the Rheumatic Diseases (1973)

In the words of the authors, this is a reference book which is not intended for reading, but for consultation when information is required.It is written in note form and covers the arthropathies under about 150 titles.Each is then subdivided under definition, incidence, joints affected, symptoms, signs, course, associations, radiological and laboratory tests, treatment, and variants; a few phrases being written on each.The term arthropathy is not defined, but seems to include the majority ofconditions which are associated with deformity or pain in or near a joint.It is, therefore, surprising that tennis elbow, the carpal tunnel syndrome, and neuralgic amyotrophy are all classified as arthropathies, whereas cervical and lumbar spondylosis are only briefly mentioned under osteoarthrosis, although hypophosphataemic spondy- lopathy and ankylosing vertebral hyperostosis are given separate sections.The space allotted to each disease varies from a few lines for uncommon conditions to three pages for rheumatoid arthritis.At least one reference is given to each condition, but it is a pity that titles of articles are not given.This is a surprising omission, because each condition is described on a separate page and there are many blank half pages which could have have been used not only for the titles but for further references, which would have greatly increased the value of this book.The authors have compiled useful information about arthropathies occurring in association with a wide range of conditions, including virus and tropical diseases, and the sections on incidence, complications, and associations are particularly helpful.The brevity of the style becomes misleading, however, in some of the sections on treatment.It is doubtful whether a rheumatologist would refer to this book for guidance on treatment, and other clinicians with little knowledge of the subject would have difficulty in managing an individual case from the available informa- tion, particularly where treatment is complicated, as in rheumatoid arthritis.For instance, no mention is made of systemic steroid treatment, unless it is concealed in the cryptic term 'immuno-suppressive' drugs, sandwiched in between penicillamine and chloroquine, and the phrase 'synovectomy, if all else fails' is capable of misinterpretation.The authors may have strong views about the use of steroids in rheumatoid arthritis, but since these substances are so widely used, they should not be ignored.It is stated that temporal arteritis and polymyalgia rheumatica are probably different manifestations of the same pathological process, and that 50 per cent of patients with polymyalgia rheumatica have giant cell arteritis.For the treatment of polymyalgia rheumatica 7-5 to 15 mg.prednisolone daily is recommended, but 40 mg.daily is suggested for temporal arteritis.This appears to be illogical and the authors are doubtless aware of this inconsistency.The statement that 'steroids have no effect on the arterial
Targeting Pathogenic Postischemic Self-Recognition by Natural IgM to Protect Against Posttransplantation Cardiac Reperfusion Injury
Authors: Carl Atkinson, Fei Qiao, Xiaofeng Yang, Peng Zhu, Nicholas Reaves, Liudmila Kulik, Martin Goddard, V. Michael Holers, Stephen Tomlinson
Journal: Circulation (2015)

Background— Natural IgM antibodies represent a class of innate pattern recognition receptors that recognize danger-associated molecular patterns expressed on stressed or dying cells. They play important roles in tissue homeostasis by disposing of prenecrotic cells and suppressing inflammation. However, ischemic insult leads to a pathogenic level of IgM binding and complement activation, resulting in inflammation and injury. We investigate the role of self-reactive IgM in the unique setting of transplantation where the donor organ undergoes both cold and warm ischemia and global ischemic insult. Methods and Results— By transplanting hearts from wild-type donor mice into antibody-deficient mice reconstituted with specific self-reactive IgM monoclonal antibodies, we identified neoepitopes expressed after transplantation and demonstrated a key role for IgM recognition of these epitopes in graft injury. With this information, we developed and characterized a therapeutic strategy that exploited the postischemia recognition system of natural antibodies. On the basis of neoepitope identification, we constructed an anti–annexin IV single-chain antibody (scFv) and an scFv linked to Crry, an inhibitor of C3 activation (scFv-Crry). In an allograft transplantation model in which recipients contain a full natural antibody repertoire, both constructs blocked graft IgM binding and complement activation and significantly reduced graft inflammation and injury. Furthermore, scFv-Crry specifically targeted to the transplanted heart and, unlike complement deficiency, did not affect immunity to infection, an important consideration for immunosuppressed transplant recipients. Conclusions— We identified pathophysiologically important epitopes expressed within the heart after transplantation and described a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches.
Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition
Authors: Hamdy Shaban, Yann Humeau, Cyril Herry, Guillaume Cassasus, Ryuichi Shigemoto, Stephane Ciocchi, Samuel Barbieri, Herman van der Putten, Klemens Kaupmann, Bernhard Bettler, Andreas Lüthi
Journal: Nature Neuroscience (2006)
ETIOLOGY OF OROYA FEVER
Authors: Hideyo Noguchi
Journal: The Journal of Experimental Medicine (1926)

The inoculation of a chimpanzee with cultures and a passage strain of Bartonella bacilliformis induced local reactions which, while definite and characteristic, progressed less rapidly and were much less striking than those in the control rhesus monkey. Bartonella bacilliformis was demonstrated in the blood corpuscles with difficulty, and the fever was slight compared with the high and persistent fever of the rhesus monkey. In both the swelling of the lymph glands was an early symptom and constantly present. Definite anemia developed in the chimpanzee only after accidental infection with Rocky Mountain spotted fever and may have been due to either one or both infections, though it disappeared when the blood had become negative by culture for Bartonella bacilliformis and the local lesions had disappeared. Incidentally, the chimpanzee was found in this one instance to be less susceptible to the spotted fever than Macacus rhesus and guinea pigs. In the ourang-utan, also, Bartonella bacilliformis induced a mild systemic and local infection. A rise of temperature occurred 10 days after inoculation) and fever continued for a week, though it was decidedly less severe than that in the control rhesus. The lesions induced by scarification were less definite than those which arose at the sites of intradermal inoculation. Bartonella bacilliformis was recovered from the blood on the 9th and on the 16th days after inoculation and from nodules excised on the 33rd and 53rd days. A few erythrocytes containing the organism were demonstrated in stained smears, but prolonged search was required to find them. The symptoms and lesions observed in the chimpanzee and ourangutan as a result of infection with Bartonella bacilliformis are far milder than those of rhesus monkeys and show less resemblance to human Oroya fever or verruga.
Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I
Authors: Trisha R. Sippel, Jason White, Kamalika Nag, Vadim Tsvankin, Marci Klaassen, B.K. Kleinschmidt-DeMasters, Allen Waziri
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell–derived peripheral immunosuppression in patients with GBM. Experimental Design: Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell–mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. Results: We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b+ cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. Conclusions: These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients. Clin Cancer Res; 17(22); 6992–7002. ©2011 AACR.
Sun damage in ultraviolet photographs correlates with phenotypic melanoma risk factors in 12-year-old children
Authors: Ryan G. Gamble, Nancy L. Asdigian, Jenny Aalborg, Victoria Gonzalez, Neil F. Box, Laura S. Huff, Anna E. Barón, Joseph G. Morelli, Stefan T. Mokrohisky, Lori A. Crane, Robert P. Dellavalle
Journal: Journal of the American Academy of Dermatology (2012)
Molecular Mechanism of Gonadotropin Releasing Hormone Action. II. The Effector System*
Authors: WILLIAM R. HUCKLE, P. MICHAEL CONN
Journal: Endocrine Reviews (1988)

GONADOTROPIN-releasing hormone (GnRH)1 is a decapeptide which is synthesized and stored in neurosecretory cells of the medial basal hypothalamus. The releasing hormone is released in a pulsatile manner into the hypophysial portal circulation and is transported to the anterior pituitary; here it regulates the secretion of the gonadotropins, LH and FSH, into the systemic circulation. Thus, GnRH is a humoral link between the neural and endocrine components of reproductive function (1). The preceding article dealt with the initial interaction of GnRH with the plasma membrane receptor for the releasing hormone. In this article the means by which occupancy of the receptor by an agonist is transduced into cellular responses is reviewed. GnRH is one of a family of hormones and neurotransmitters which require Ca2+ for their biological actions. The observation that omission or chelation of Ca2+ in the extracellular medium blocks depolarization- or hypothalamic extract-stimulated LH release from pituitary tissue (2) provided an early indication of the importance of Ca2+, and subsequently the role of Ca2+ in this aspect of GnRH action has been evaluated systematically (3, 4). Agents which increase intracellular Ca2+ concentrations, such as ionophores, KC1 (by depolarization), or calcium-loaded liposomes, release LH with efficacies similar to that of GnRH; other physiological cations (Na2, Mg2+) cannot substitute for calcium in this activity (5).
Passive smoking and risk of coronary heart disease and stroke: prospective study with cotinine measurement
Authors: Peter H Whincup, Julie A Gilg, Jonathan R Emberson, Martin J Jarvis, Colin Feyerabend, Andrew Bryant, Mary Walker, Derek G Cook
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To examine the associations between a biomarker of overall passive exposure to tobacco smoke (serum cotinine concentration) and risk of coronary heart disease and stroke. <b>Design</b> Prospective population based study in general practice (the British regional heart study). <b>Participants</b> 4729 men in 18 towns who provided baseline blood samples (for cotinine assay) and a detailed smoking history in 1978-80. <b>Main outcome measure</b> Major coronary heart disease and stroke events (fatal and non-fatal) during 20 years of follow up. <b>Results</b> 2105 men who said they did not smoke and who had cotinine concentrations &lt; 14.1 ng/ml were divided into four equal sized groups on the basis of cotinine concentrations. Relative hazards (95% confidence intervals) for coronary heart disease in the second (0.8-1.4 ng/ml), third (1.5-2.7 ng/ml), and fourth (2.8-14.0 ng/ml) quarters of cotinine concentration compared with the first (≥ 0.7 ng/ml) were 1.45 (1.01 to 2.08), 1.49 (1.03 to 2.14), and 1.57 (1.08 to 2.28), respectively, after adjustment for established risk factors for coronary heart disease. Hazard ratios (for cotinine 0.8-14.0 ν ≥ 0.7 ng/ml) were particularly increased during the first (3.73, 1.32 to 10.58) and second five year follow up periods (1.95, 1.09 to 3.48) compared with later periods. There was no consistent association between cotinine concentration and risk of stroke. <b>Conclusion</b> Studies based on reports of smoking in a partner alone seem to underestimate the risks of exposure to passive smoking. Further prospective studies relating biomarkers of passive smoking to risk of coronary heart disease are needed.
CpG-depleted adeno-associated virus vectors evade immune detection
Authors: Susan M. Faust, Peter Bell, Benjamin J. Cutler, Scott N. Ashley, Yanqing Zhu, Joseph E. Rabinowitz, James M. Wilson
Journal: Journal of Clinical Investigation (2013)

Due to their efficient transduction potential, adeno-associated virus (AAV) vectors are leading candidates for gene therapy in skeletal muscle diseases. However, immune responses toward the vector or transgene product have been observed in preclinical and clinical studies. TLR9 has been implicated in promoting AAV-directed immune responses, but vectors have not been developed to circumvent this barrier. To assess the requirement of TLR9 in promoting immunity toward AAV-associated antigens following skeletal muscle gene transfer in mice, we compared immunological responses in WT and Tlr9-deficient mice that received an AAV vector with an immunogenic capsid, AAVrh32.33. In Tlr9-deficient mice, IFN-γ T cell responses toward capsid and transgene antigen were suppressed, resulting in minimal cellular infiltrate and stable transgene expression in target muscles. These findings suggest that AAV-directed immune responses may be circumvented by depleting the ligand for TLR9 (CpG sequences) from the vector genome. Indeed, we found that CpG-depleted AAVrh32.33 vectors could establish persistent transgene expression, evade immunity, and minimize infiltration of effector cells. Thus, CpG-depleted AAV vectors could improve outcome of clinical trials of gene therapy for skeletal muscle disease.
The renal dopamine receptors.
Authors: P A Jose, J R Raymond, M D Bates, A Aperia, R A Felder, R M Carey
Journal: Journal of the American Society of Nephrology (1992)

Dopamine is an endogenous catecholamine that modulates many functions including behavior, movement, nerve conduction, hormone synthesis and release, blood pressure, and ion fluxes. Dopamine receptors in the brain have been classically divided into D1 and D2 subtypes, based on pharmacological data. However, molecular biology techniques have identified many more dopamine receptor subtypes. Several of the receptors cloned from the brain correspond to the classically described D1 and D2 receptors. Several D1 receptor subtypes have been cloned (D1A, D1B, and D5) and are each coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms, a shorter form, composed of 415 amino acids, is termed the D2short receptor. The long form, called the D2long receptor, is composed of 444 amino acids; both are coupled to the inhibition of adenylyl cyclase. The D3 and D4 receptors are closely related to, but clearly distinct from, the D2 receptor. They have not yet been linked to adenylyl cyclase activity. Outside of the central nervous system, the peripheral dopamine receptors have been classified into the DA1 and DA2 subtypes, on the basis of synaptic localization. The pharmacological properties of DA1 receptors roughly approximate those of D1 and D5 receptors, whereas those of DA2 receptors approximate those of D2 receptors. A renal dopamine receptor with some pharmacological features of the D2 receptor but not linked to adenylyl cyclase has been described in the renal cortex and inner medulla. In the inner medulla, this D2-like receptor, termed DA2k, is linked to stimulation of prostaglandin E2 production, apparently due to stimulation of phospholipase A2. Of the cloned dopamine receptors, only the mRNA of the D3 receptor has been reported in the kidney. The DA1 receptor in the kidney is associated with renal vasodilation and an increase in electrolyte excretion. The DA1-related vasodilation and inhibition of electrolyte transport is mediated by cAMP. The role of renal DA2 receptors remains to be clarified. Although DA1 and DA2 receptors may act in concert to decrease transport in the renal proximal convoluted tubule, the overall function of DA2 receptors may be actually the opposite of those noted for DA1 receptors. Dopamine has been postulated to act as an intrarenal natriuretic hormone. Moreover, an aberrant renal dopaminergic system may play a role in the pathogenesis of some forms of hypertension. A decreased renal production of dopamine and/or a defective transduction of the dopamine signal is/are present in some animal models of experimental hypertension as well as in some forms of human essential hypertension.
Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening
Authors: Eric T. Sawey, Maia Chanrion, Chunlin Cai, Guanming Wu, Jianping Zhang, Lars Zender, Alice Zhao, Ronald W. Busuttil, Herman Yee, Lincoln Stein, Dorothy M. French, Richard S. Finn, Scott W. Lowe, Scott Powers
Journal: Cancer Cell (2011)
Dehydroepiandrosterone suppresses interleukin 10 synthesis in women with systemic lupus erythematosus
Authors: D M Chang
Journal: Annals of the Rheumatic Diseases (2004)

To study the effects of dehydroepiandrosterone (prasterone, DHEA) 200 mg/day on cytokine profiles in adult women with active systemic lupus erythematosus (SLE).In a double blind, randomised, placebo controlled study conducted as part of a larger multicentre study, 30 adult women with active SLE received oral DHEA 200 mg/day or placebo for 24 weeks. Baseline prednisone (<10 mg/day) and other concomitant SLE medications were to remain constant. The levels of cytokines including interleukin (IL) 1, IL2, interferon gamma, IL4, and IL10 were determined by ELISA. The mean change from baseline to 24 weeks of therapy was analysed.The two groups (DHEA n = 15; placebo n = 15) were well balanced for baseline characteristics. Only IL1beta and IL10 could be detected in the serum of lupus patients; however, there was no significant mean (SD) difference in serum IL1beta before and after treatment (9.94 (8.92) v 9.20 (6.49) pg/ml). IL10 demonstrated a greater and significant reduction from baseline (9.21 (9.66) to 1.89 (1.47) pg/ml in the DHEA treatment group).In a 24 week study of adult Chinese women with mild to moderate SLE, treatment with DHEA 200 mg once daily resulted in significant reduction of serum levels of IL10. This finding may suggest why DHEA could significantly reduce lupus flares.