tbuckley/cabot-search huggingface dataset:
Impaired catecholaminergic signalling of B lymphocytes in patients with chronic rheumatic diseases
Authors: M Wahle
Journal: Annals of the Rheumatic Diseases (2001)

To investigate further the influence of the autonomic nervous system on chronic rheumatic diseases.The density and affinity of beta2 adrenergic receptors (beta2R) on CD19+ lymphocytes in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), as well as intracellular cAMP levels in patients with RA and SLE, were determined. Human peripheral blood mononuclear cells were separated from venous blood of patients and healthy controls by Ficoll-Hypaque density centrifugation. CD19+ lymphocytes were purified by magnetic cell sorting, and beta2R were determined by a radioligand binding assay with [125I]iodocyanopindolol. Intracellular cAMP levels and beta2R agonist induced cell death were measured by a radioimmunoassay and flow cytometry using annexin-V binding, respectively. Systemic disease activity of the patients was evaluated using multifactorial scoring systems.The density of beta2R on peripheral CD19+ lymphocytes was significantly decreased in patients with RA, SLE, and SSc compared with healthy controls. In patients with RA and SSc beta2R density was negatively correlated with systemic disease activity. Furthermore, although basal intracellular cAMP levels were raised in patients with RA and SLE, the increase of cAMP upon stimulation of beta2R was significantly reduced in these patients compared with control subjects. Preliminary data suggest that beta2R agonist induced cell death is diminished in patients with RA exhibiting decreased beta2R densities.The results of this study show a reduction of beta2R densities on B lymphocytes mirrored by an impaired intracellular cAMP generation in patients with chronic rheumatic diseases, indicating a decreased influence of the autonomic nervous system on B cells in these conditions.
Heterozygous<i>HPS1</i>mutations in a case of Hermansky-Pudlak syndrome with giant melanosomes
Authors: T. Horikawa, K. Araki, K. Fukai, M. Ueda, T. Ueda, S. Ito, M. Ichihashi
Journal: British Journal of Dermatology (2000)

We report a Japanese man with Hermansky-Pudlak syndrome, having oculocutaneous albinism with a bleeding diathesis. Gene analysis of the patient's peripheral blood cells revealed that he was a compound heterozygote for HPS1 gene mutations. One of the mutations was a novel frameshift mutation at codon 321 (a G insertion) in exon 11 ( approximately 962-963insG), and the other was a 5' splice-junction mutation of IVS5 (IVS5 + 5G-->A). The content of eumelanin in the patient's hairs was significantly reduced. Histological analysis using light and electron microscopy revealed that melanocytes in the patient's epidermis contained an appreciable number of giant melanosomes. Cultured melanocytes from the patient's skin also contained giant melanosomes. Our finding of mutations in the HPS1 gene in relation to abnormalities in melanosome morphology and melanin production shed light on the role and function of the HPS1 gene product in the synthesis of melanosomes and melanin pigment.
FURTHER STUDIES ON THE TITRATION AND NEUTRALIZATION OF THE WESTERN STRAIN OF EQUINE ENCEPHALOMYELITIS VIRUS IN TISSUE CULTURE
Authors: C. H. Huang
Journal: The Journal of Experimental Medicine (1943)

1. Titration and neutralization of the Western strain of equine encephalomyelitis virus can be carried out in vitro by means of tissue culture. 2. The in vitro titration test as presented is a more sensitive method than animal inoculation. 3. Tissue culture may be better than animal inoculation for the detection of small amounts of virus. 4. The neutralization obtained in tissue culture is 100 to 1,000 times greater than that observed in the intracerebral test in mice and is comparable to the potency obtained by the intraperitoneal route of inoculation. 5. The possibility of applying this method to the study of other viruses, known and unknown, is discussed. 6. Further applications of the method described above to evaluation and standardization of bacterial toxins and antitoxins and to the testing of the toxicity of biological and chemical products are suggested. 7. Evidence for the reactivation in vitro as well as in vivo of virus in neutral mixtures by dilution is presented.
Identification of Metastasis-Related Proteins and Their Clinical Relevance to Triple-Negative Human Breast Cancer
Authors: Baocun Sun, Shiwu Zhang, Danfang Zhang, Yan Li, Xiulan Zhao, Ye Luo, Yuhong Guo
Journal: Clinical Cancer Research (2008)

Currently, there are no definite biomarkers of triple-negative breast cancer. The study aims to identify the metastasis-associated proteins of triple-negative breast tumors.A murine metastatic breast cancer model has been established by using TA2 mice. Parallel proteomic analyses were done on a murine metastatic breast cancer model and its primary breast cancer using two-dimensional gel electrophoresis. The differentially expressed proteins were detected in TA2 mice developing spontaneous breast cancer and lung metastasis. Furthermore, their expression were detected in human breast cancer with or without metastasis, and their prediction values were assessed in a second set of samples.Nineteen of 36 differentially expressed proteins were identified by peptide mass fingerprinting using matrix-assisted laser-desorption ionization-time of flight-mass spectrometry. These proteins were also validated in mouse tumor tissues by immunohistochemical staining. Actin, 14-3-3, vimentin, HSP70, CK18, and moesin were up-regulated in the metastatic tumors, whereas HSP90 and tubulin were absent or down-regulated. Furthermore, 61 patients with triple-negative breast cancer and 39 patients with estrogen receptor-positive/progesterone receptor-positive breast cancer were selected for exploring the clinical relevance of these identified proteins to human breast cancer metastasis. Expression of 14-3-3 and HSP70 was significantly correlated with metastasis of human triple-negative breast cancer. Moreover, the validation study in the second set confirmed that 14-3-3, HSP70, and their combination had high sensitivities and specificities in predicting metastatic potential of triple-negative breast cancer.These tumor metastasis-associated proteins validated may be useful as biomarkers and targets for diagnosis and treatment of human triple-negative breast cancer.
Cryoelectron tomography reveals periodic material at the inner side of subpellicular microtubules in apicomplexan parasites
Authors: Marek Cyrklaff, Mikhail Kudryashev, Andrew Leis, Kevin Leonard, Wolfgang Baumeister, Robert Menard, Markus Meissner, Friedrich Frischknecht
Journal: The Journal of Experimental Medicine (2007)

Microtubules are dynamic cytoskeletal structures important for cell division, polarity, and motility and are therefore major targets for anticancer and antiparasite drugs. In the invasive forms of apicomplexan parasites, which are highly polarized and often motile cells, exceptionally stable subpellicular microtubules determine the shape of the parasite, and serve as tracks for vesicle transport. We used cryoelectron tomography to image cytoplasmic structures in three dimensions within intact, rapidly frozen Plasmodium sporozoites. This approach revealed microtubule walls that are extended at the luminal side by an additional 3 nm compared to microtubules of mammalian cells. Fourier analysis revealed an 8-nm longitudinal periodicity of the luminal constituent, suggesting the presence of a molecule interacting with tubulin dimers. In silico generation and analysis of microtubule models confirmed this unexpected topology. Microtubules from extracted sporozoites and Toxoplasma gondii tachyzoites showed a similar density distribution, suggesting that the putative protein is conserved among Apicomplexa and serves to stabilize microtubules.
Ancient DNA Chronology within Sediment Deposits: Are Paleobiological Reconstructions Possible and Is DNA Leaching a Factor?
Authors: James Haile, Richard Holdaway, Karen Oliver, Michael Bunce, M. Thomas P. Gilbert, Rasmus Nielsen, Kasper Munch, Simon Y. W. Ho, Beth Shapiro, Eske Willerslev
Journal: Molecular Biology and Evolution (2007)

In recent years, several studies have reported the successful extraction of ancient DNA (aDNA) from both frozen and nonfrozen sediments (even in the absence of macrofossils) in order to obtain genetic "profiles" from past environments. One of the hazards associated with this approach, particularly in nonfrozen environments, is the potential for vertical migration of aDNA across strata. To assess the extent of this problem, we extracted aDNA from sediments up to 3300 years old at 2 cave sites in the North Island of New Zealand. These sites are ideal for this purpose as the presence or absence of DNA from nonindigenous fauna (such as sheep) in sediments deposited prior to European settlement can serve as an indicator of DNA movement. Additionally, these strata are well defined and dated. DNA from sheep was found in strata that also contained moa DNA, indicating that genetic material had migrated downwards. Quantitative polymerase chain reaction analyses demonstrated that the amount of sheep DNA decreased as the age of sediments increased. Our results suggest that sedimentary aDNA is unlikely to be deposited from wind-borne DNA and that physical remains of organisms or their ejecta need to have been incorporated in the sediments for their DNA to be detected. Our study indicates that DNA from sediments can still offer a rich source of information on past environments, provided that the risk from vertical migration can be controlled for.
Unusual applications of noninvasive ventilation
Authors: N. Ambrosino, F. Guarracino
Journal: European Respiratory Journal (2011)

The use of noninvasive ventilation (NIV) in acute hypercapnic respiratory failure, cardiogenic pulmonary oedema, acute lung injury/acute respiratory distress syndrome (ARDS), community-acquired pneumonia and weaning/post-extubation failure is considered common in clinical practice. Herein, we review the use of NIV in unusual conditions. Evidence supports the use of NIV during fibreoptic bronchoscopy, especially with high risks of endotracheal intubation (ETI), such as in immunocompromised patients. During transoesophageal echocardiography as well as in interventional cardiology and pulmonology, NIV can reduce the need for deep sedation or general anaesthesia and prevent respiratory depression induced by deep sedation. NIV may be useful after surgery, including cardiac surgery, and, with a lower level of evidence, in patients with pulmonary contusion. NIV should not be considered as an alternative to ETI in severe communicable airborne infections likely to progress to ARDS. NIV is being used increasingly as an alternative to ETI in end-stage symptomatic patients, especially to relieve dyspnoea. The role of assisted ventilation during exercise training in chronic obstructive pulmonary disease patients is still controversial. NIV should be applied under close monitoring and ETI should be promptly available in the case of failure. A trained team, careful patient selection and optimal choice of devices, can optimise outcome of NIV.
Identification of a Novel Prostaglandin F2α Synthase in <i>Trypanosoma brucei</i>
Authors: Bruno Kilunga Kubata, Michael Duszenko, Zakayi Kabututu, Marc Rawer, Alexander Szallies, Ko Fujimori, Takashi Inui, Tomoyoshi Nozaki, Kouwa Yamashita, Toshihiro Horii, Yoshihiro Urade, Osamu Hayaishi
Journal: The Journal of Experimental Medicine (2000)

Members of the genus Trypanosoma cause African trypanosomiasis in humans and animals in Africa. Infection of mammals by African trypanosomes is characterized by an upregulation of prostaglandin (PG) production in the plasma and cerebrospinal fluid. These metabolites of arachidonic acid (AA) may, in part, be responsible for symptoms such as fever, headache, immunosuppression, deep muscle hyperaesthesia, miscarriage, ovarian dysfunction, sleepiness, and other symptoms observed in patients with chronic African trypanosomiasis. Here, we show that the protozoan parasite T. brucei is involved in PG production and that it produces PGs enzymatically from AA and its metabolite, PGH2. Among all PGs synthesized, PGF2α was the major prostanoid produced by trypanosome lysates. We have purified a novel T. brucei PGF2α synthase (TbPGFS) and cloned its cDNA. Phylogenetic analysis and molecular properties revealed that TbPGFS is completely distinct from mammalian PGF synthases. We also found that TbPGFS mRNA expression and TbPGFS activity were high in the early logarithmic growth phase and low during the stationary phase. The characterization of TbPGFS and its gene in T. brucei provides a basis for the molecular analysis of the role of parasite-derived PGF2α in the physiology of the parasite and the pathogenesis of African trypanosomiasis.
Phase I Study of a Novel Oral Janus Kinase 2 Inhibitor, SB1518, in Patients With Relapsed Lymphoma: Evidence of Clinical and Biologic Activity in Multiple Lymphoma Subtypes
Authors: Anas Younes, Jorge Romaguera, Michelle Fanale, Peter McLaughlin, Frederick Hagemeister, Amanda Copeland, Sattva Neelapu, Larry Kwak, Jatin Shah, Silvana de Castro Faria, Stefan Hart, Jeanette Wood, Ramesh Jayaraman, Kantharaj Ethirajulu, Joy Zhu
Journal: Journal of Clinical Oncology (2012)

The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma.Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks.Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%.SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.
Oxygen-Derived Free Radicals Contribute to Baroreceptor Dysfunction in Atherosclerotic Rabbits
Authors: Zhi Li, Hui Z. Mao, Francois M. Abboud, Mark W. Chapleau
Journal: Circulation Research (1996)

The goal of the present study was to determine whether oxygen-derived free radicals contribute to baroreceptor dysfunction in atherosclerosis. Baroreceptor activity was measured from the carotid sinus nerve during pressure ramps in isolated carotid sinuses of anesthetized rabbits. Rabbits fed a 0.5% to 1.0% cholesterol diet for 7.9±0.4 months (mean±SE; range, 5.5 to 10) developed atherosclerotic lesions in the carotid sinuses. Maximum baroreceptor activity measured at 140 mm Hg and the slope of the pressure-activity curve were reduced in atherosclerotic (n=15) compared with normal (n=13) rabbits (425±34 versus 721±30 spikes per second and 6.2±0.6 versus 10.8±0.8 spikes per second per mm Hg, respectively, P &lt;.05). The level of activity was inversely related to plasma cholesterol concentration ( r =.86, P &lt;.001) and total cholesterol load (plasma concentration×duration of diet, r =.92). Mean arterial pressure was normal in both groups. Exposure of the carotid sinus to the free-radical scavengers superoxide dismutase (SOD) and catalase significantly increased maximum baroreceptor activity by 25±4% in atherosclerotic rabbits (n=6) but caused only small and irreversible changes in activity in normal rabbits (n=8). Catalase alone but not SOD also increased baroreceptor activity in atherosclerotic rabbits (n=7). Exposure of the carotid sinus of normal rabbits to exogenous free radicals generated from the reaction between xanthine and xanthine oxidase inhibited baroreceptor activity in a dose-dependent and reversible manner (n=8, P &lt;.05). The inhibition of activity was attenuated by SOD and catalase but was not attenuated by the inhibitor of hydroxyl radical formation, deferoxamine. Neither restoration of baroreceptor activity in atherosclerotic rabbits by catalase nor inhibition of activity by xanthine/xanthine oxidase could be explained by changes in the carotid pressure-diameter relation or prostacyclin formation. These results indicate that oxidant stress inhibits baroreceptor activity and that endogenous oxyradicals produced in atherosclerotic carotid sinuses contribute to baroreceptor dysfunction.
NOTES ON THE CONSTRUCTION OF COTTAGE HOSPITALS
Authors: H. P. Adams
Journal: BMJ (1908)

JuI o,ugo. of the doctors in attendance, under the supbrvisidn of the medical superintendent.Calculated on the basis of the present cost of hcspital beds, it vould be easy to ehow how, even with such a liberal, allowance for maintenance as £150 a bed, a hospital of, say, 100 beds, let at weekly rates varying
Immunity to Helminths: Resistance, Regulation, and Susceptibility to Gastrointestinal Nematodes
Authors: Richard K. Grencis
Journal: Annual Review of Immunology (2014)

Helminth parasites are a highly successful group of pathogens that challenge the immune system in a manner distinct from rapidly replicating infectious agents. Of this group, roundworms (nematodes) that dwell in the intestines of humans and other animals are prevalent worldwide. Currently, more than one billion people are infected by at least one species, often for extended periods of time. Thus, host-protective immunity is rarely complete. The reasons for this are complex, but laboratory investigation of tractable model systems in which protective immunity is effective has provided a mechanistic understanding of resistance that is characterized almost universally by a type 2/T helper 2 response. Greater understanding of the mechanisms of susceptibility has also provided the basis for defining host immunoregulation and parasite-evasion strategies, helping place in context the changing patterns of immunological disease observed worldwide.
The suppressor of cytokine signaling–1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury
Authors: Hideo Yasukawa, Toshitaka Yajima, Hervé Duplain, Mitsuo Iwatate, Masakuni Kido, Masahiko Hoshijima, Matthew D. Weitzman, Tomoyuki Nakamura, Sarah Woodard, Dingding Xiong, Akihiko Yoshimura, Kenneth R. Chien, Kirk U. Knowlton
Journal: Journal of Clinical Investigation (2003)

Enteroviral infections of the heart are among the most commonly identified causes of acute myocarditis in children and adults and have been implicated in dilated cardiomyopathy. Although there is considerable information regarding the cellular immune response in myocarditis, little is known about innate signaling mechanisms within the infected cardiac myocyte that contribute to the host defense against viral infection. Here we show the essential role of Janus kinase (JAK) signaling in cardiac myocyte antiviral defense and a negative role of an intrinsic JAK inhibitor, the suppressor of cytokine signaling (SOCS), in the early disease process. Cardiac myocyte–specific transgenic expression of SOCS1 inhibited enterovirus-induced signaling of JAK and the signal transducers and activators of transcription (STAT), with accompanying increases in viral replication, cardiomyopathy, and mortality in coxsackievirus-infected mice. Furthermore, the inhibition of SOCS in the cardiac myocyte through adeno-associated virus–mediated (AAV-mediated) expression of a dominant-negative SOCS1 increased the myocyte resistance to the acute cardiac injury caused by enteroviral infection. These results indicate that strategies directed at inhibition of SOCS in the heart and perhaps other organs can augment the host-cell antiviral system, thus preventing viral-mediated end-organ damage during the early stages of infection.
Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study
Authors: Peter J Campbell, Linda M Scott, Georgina Buck, Keith Wheatley, Clare L East, Joanne T Marsden, Audrey Duffy, Elaine M Boyd, Anthony J Bench, Mike A Scott, George S Vassiliou, Donald W Milligan, Steve R Smith, Wendy N Erber, David Bareford, Bridget S Wilkins, John T Reilly, Claire N Harrison, Anthony R Green
Journal: The Lancet (2005)
Novel RNA-based Strategies for Therapeutic Gene Silencing
Authors: Christopher R Sibley, Yiqi Seow, Matthew JA Wood
Journal: Molecular Therapy (2010)

The past decade has seen intense scientific interest in non-coding RNAs. In particular, the discovery and subsequent exploitation of gene silencing via RNA interference (RNAi) has revolutionized the way in which gene expression is now studied and understood. It is now well established that post-transcriptional gene silencing (PTGS) by the microRNA (miRNA) and other RNAi-associated pathways represents an essential layer of complexity to gene regulation. Gene silencing using RNAi additionally demonstrates huge potential as a therapeutic strategy for eliminating pathogenic gene expression. Yet despite the early promise and excitement of gene-specific silencing, several critical hurdles remain to be overcome before widespread clinical adoption. These include off-target effects, toxicity due to saturation of the endogenous RNAi functions, limited duration of silencing, and effective targeted delivery. In recent years, a range of novel strategies for producing RNA-mediated silencing have been developed that can circumvent many of these hurdles, including small internally segmented interfering RNAs, tandem hairpin RNAs, and pri-miRNA cluster mimics. This review discusses RNA-mediated silencing in light of this recent research, and highlights the benefits and limitations conferred by these novel gene-silencing strategies.
Coronary Vascular Development in Response to Increased Right Ventricular Pressure Loads
Authors: H. R. Overy, John H. K. Vogel, Robert F. Grover, S. Gilbert Blount
Journal: Circulation Research (1966)

Pressure loads were applied to the right ventricles of newborn lambs and adult sheep by surgical narrowing of the lumen of the main pulmonary artery. Significant increases in right ventricular weight and in the diameter of the right coronary artery occurred in both age groups of animals, compared with corresponding control animals. The evidence suggests that the degree of increase in the arterial diameters, relative to the increase in ventricular muscle mass, is similar in both newborn and adult animals. However, the results suggest also that the capacity to respond to pressure loads, in terms of increased muscle mass, is relatively greater in the newborn animals than in the adults.