tbuckley/cabot-search huggingface dataset:
Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data
Authors: Caroline F Wright, Tomas W Fitzgerald, Wendy D Jones, Stephen Clayton, Jeremy F McRae, Margriet van Kogelenberg, Daniel A King, Kirsty Ambridge, Daniel M Barrett, Tanya Bayzetinova, A Paul Bevan, Eugene Bragin, Eleni A Chatzimichali, Susan Gribble, Philip Jones, Netravathi Krishnappa, Laura E Mason, Ray Miller, Katherine I Morley, Vijaya Parthiban, Elena Prigmore, Diana Rajan, Alejandro Sifrim, G Jawahar Swaminathan, Adrian R Tivey, Anna Middleton, Michael Parker, Nigel P Carter, Jeffrey C Barrett, Matthew E Hurles, David R FitzPatrick, Helen V Firth
Journal: The Lancet (2014)

Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount.
Patient mortality of active pulmonary tuberculosis requiring mechanical ventilation
Authors: P.L. Lee, J.S. Jerng, Y.L. Chang, C.F. Chen, P.R. Hsueh, C.J. Yu, P.C. Yang, K.T. Luh
Journal: European Respiratory Journal (2003)

Mortality remains high among patients with pulmonary tuberculosis requiring mechanical ventilation (TBMV). This study was carried out to establish the mortality rates of TBMV and to identify factors that contribute to in-hospital mortality. From January 1996–April 2001, there were 825 patients with active pulmonary tuberculosis at the National Taiwan University Hospital, Taipei, Taiwan. Of these, 41 suffered acute respiratory failure and required mechanical ventilation in the intensive care unit (ICU). Of these 41 patients, 38 were followed up for 180 days. In-hospital deaths were documented in the medical records and all possible parameters contributing to mortality were collected. Of the 41 patients, 27 died in the hospital and 14 were discharged alive (in-hospital mortality rate 65.9%), with (mean±sd) 40.7±35.4 admission days before death. Of the 27 that died, 25 died during ICU admission and two died after being transferred to the ward. The mortality rate for the 180-day monitoring period was 79%. Factors contributing to in-hospital mortality included consolidations on chest radiographs and multiple organ failure. The mortality rate in the patients with pulmonary tuberculosis requiring mechanical ventilation is very high, with two factors affecting in-hospital mortality. These factors were multiple organ failure and consolidation on chest radiographs.
PATHOGENESIS OF NONIMMUNE GLOMERULOPATHIES
Authors: Christopher Kwoh, M. Brendan Shannon, Jeffrey H. Miner, Andrey Shaw
Journal: Annual Review of Pathology Mechanisms of Disease (2006)

Nonimmune glomerulopathies are an area of significant research. This review discusses the development of focal segmental glomerulosclerosis, with particular attention to the role of the podocyte in the initiation of glomerulosclerosis and the contribution to glomerulosclerosis from capillary hypertension and soluble factors such as transforming growth factor beta, platelet-derived growth factor, vascular endothelial growth factor, and angiotensin. The effects of these factors on endothelial and mesangial cells are also discussed. In addition, we review our current understanding of the slit diaphragm (a specialized cell junction found in the kidney), slit diaphragm–associated proteins (including nephrin, podocin, α-actinin-4, CD2-associated protein, and transient receptor potential channel 6), and the role of these proteins in glomerular disease. We also discuss the most recent research on the pathogenesis of collapsing glomerulosclerosis, human immunodeficiency virus associated nephropathy, Denys-Drash, diabetic nephropathy, Alport syndrome, and other diseases related to the interaction between the podocyte and the glomerular basement membrane.
Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome.
Authors: J Dantal, Y Godfrin, R Koll, S Perretto, J Naulet, J F Bouhours, J P Soulillou
Journal: Journal of the American Society of Nephrology (1998)

Approximately 20 to 30% of patients with idiopathic nephrotic syndrome and focal glomerulosclerosis experience a relapse of their nephrotic syndrome after transplantation. Previously, it has been shown that ex vivo immunoadsorption on protein A strongly (although transiently) reduces proteinuria in relapsing patients. To investigate whether the factor(s) that give rise to albuminuria are bound directly to protein A in the immunoadsorption procedure or are part of a complex with Ig, four patients with relapse of focal glomerulosclerosis presenting as nephrotic syndrome after transplantation were treated, sequentially, using a (non-protein A) anti-Ig affinity column and a protein A column. This study reports that the effect on proteinuria of immunoadsorption using an anti-Ig immunoaffinity column is comparable in its magnitude and kinetics to that of immunoadsorption on protein A. The two procedures were also equally effective in depleting the relapsing patients' plasma of a factor capable of altering the albumin permselectivity of isolated glomeruli in vitro. This study demonstrates for the first time that immunoglobulins have a role in the nephrotic syndrome. In addition, the fact that the two different immunoadsorption procedures both resulted in the removal of the same putative albuminuric factor in these patients and that no autoreactivity of eluted immunoglobulins was observed on human tissues strongly suggests that the factor or factors that may be responsible for immediate nephrotic syndrome after transplantation are bound to an immunoglobulin. However, no firm evidence can be yet provided against a direct role of immunoglobulins.
Intra-arterial Targeted Islet-specific Expression of Sirt1 Protects β Cells From Streptozotocin-induced Apoptosis in Mice
Authors: Mi-mi Tang, Qin-e Zhu, Wen-zhu Fan, Shui-li Zhang, Di-zheng Li, Li-zhong Liu, Miao Chen, Mei Zhang, Jing Zhou, Chi-ju Wei
Journal: Molecular Therapy (2010)

Gene therapy provides a promising approach to curing diabetes. However, an effective route for islet-specific targeting has yet to be established. Toward this end, the pancreatic blood circulation system in Balb/c mice was determined by the injection of rhodamine-containing beads. The efficiency of islet targeting was then measured by the injection of adenoviral vectors carrying a green fluorescence gene via the celiac trunk (C.T.). The results showed that >95% of islets and about 60% of β cells within the pancreatic body and tail could be labeled 3 days after surgery. α-Cell labeling was not as efficient, whereas labeling of nonendocrine tissues was barely detectable. For proof of principle, adenoviral vectors carrying a Sirtuin transgene were injected similarly to test the islet protection effect in the streptozotocin (STZ)-induced type 1 diabetic model. The results demonstrated that overexpression of Sirtuin in STZ-treated mice reduced the level of β-cell death and extent of glucose intolerance. This study reports on efficient islet-specific targeting by using adenoviral injection. This procedure could be invaluable to the treatment of diabetes and the study of islet biology. Gene therapy provides a promising approach to curing diabetes. However, an effective route for islet-specific targeting has yet to be established. Toward this end, the pancreatic blood circulation system in Balb/c mice was determined by the injection of rhodamine-containing beads. The efficiency of islet targeting was then measured by the injection of adenoviral vectors carrying a green fluorescence gene via the celiac trunk (C.T.). The results showed that >95% of islets and about 60% of β cells within the pancreatic body and tail could be labeled 3 days after surgery. α-Cell labeling was not as efficient, whereas labeling of nonendocrine tissues was barely detectable. For proof of principle, adenoviral vectors carrying a Sirtuin transgene were injected similarly to test the islet protection effect in the streptozotocin (STZ)-induced type 1 diabetic model. The results demonstrated that overexpression of Sirtuin in STZ-treated mice reduced the level of β-cell death and extent of glucose intolerance. This study reports on efficient islet-specific targeting by using adenoviral injection. This procedure could be invaluable to the treatment of diabetes and the study of islet biology.
Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial
Authors: Johannes FE Mann, Roland E Schmieder, Matthew McQueen, Leanne Dyal, Helmut Schumacher, Janice Pogue, Xingyu Wang, Aldo Maggioni, Andrzej Budaj, Suphachai Chaithiraphan, Kenneth Dickstein, Matyas Keltai, Kaj Metsärinne, Ali Oto, Alexander Parkhomenko, Leopoldo S Piegas, Tage L Svendsen, Koon K Teo, Salim Yusuf
Journal: The Lancet (2008)
NHS trusts have more than £1bn surplus to spend in current year
Authors: Adrian O'Dowd
Journal: BMJ (2007)

NHS trusts in England should be thinking about how to spend a predicted surplus in funding of more than £1bn (€1.4bn; $2.1bn)—and possibly as much as £1.8bn—the head of the NHS has told MPs.

And NHS chief executive David Nicholson said that as most of this surplus for the current financial year lay with primary care trusts it was for them to decide how it should be spent.

That money was not being held centrally by the government, Mr Nicholson said, giving evidence as part of the parliamentary health select committee's inquiry into public expenditure last week.

The surplus was “relatively small” …
RELEASE OF AN ENDOGENOUS PYROGEN IN VITRO FROM RABBIT MONONUCLEAR CELLS
Authors: Elisha Atkins, Phyllis Bodel, Lorraine Francis
Journal: The Journal of Experimental Medicine (1967)

The capacity of rabbit mononuclear cells to release an endogenous pyrogen (EP) in vitro has been studied. After incubation with tuberculin, preparations of predominantly monocytic cells, derived from the respiratory passages of the lungs of rabbits sensitized with BCG, were activated to release EP. Pyrogen production occurred more slowly with lung monocytes than with blood leukocytes of similarly sensitized rabbits and 9 to 10 hr incubation in a fully supportive medium was required to produce clear-cut results. As previously reported with blood leukocytes, mononuclear cells from the lungs of normal animals were also activated by tuberculin but to a lesser degree than were those from specifically sensitized rabbits. Under a variety of conditions, mononuclear cells from either spleen or lymph nodes of the same sensitized rabbits failed to release detectable amounts of pyrogen when incubated with tuberculin in vitro but were activated in a majority of instances when phagocytosis of heat-killed staphylococci was used as the stimulus. Release of pyrogen from lung monocytes appears to be an active process that is both temperature-dependent and requires protein synthesis. Neither serum antibody nor complement appears to play a role in this process. Evidence is presented that the granulocyte is the main source of pyrogen evolved by blood leukocytes incubated in vitro with OT or heat-killed staphylococci, whereas the lung macrophage and/or monocyte is responsible for most of the pyrogen released from the lung cell preparations. From these studies, it is concluded that mononuclear cells can be activated in vitro by several microbial stimuli and must be considered an additional cellular source of EP. The clinical implications of these findings for the pathogenesis of fever in granulomatous diseases where the monocyte is the predominant cell are discussed.
House dust mite allergens accumulate more rapidly in synthetic and kapok mattresses than in coconut and sponge mattresses
Authors: Varakorn Chirdjirapong, V Poothong, S Ruangruk, C Komoltri, W Mahakittikun, Nualanong Visitsunthorn, Pakit Vichyanond
Journal: Journal of Allergy and Clinical Immunology (2002)
The relationship between longitudinal serum leptin measures and measures of magnetic resonance imaging-assessed knee joint damage in a population of mid-life women
Authors: Carrie A Karvonen-Gutierrez, Siobán D Harlow, Jon Jacobson, Peter Mancuso, Yebin Jiang
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and objective</h3> Serum leptin measures are associated with radiographic knee osteoarthritis, but no studies have examined leptin levels with respect to different measures of knee joint damage from MRI. <h3>Methods</h3> Participants in the Michigan Study of Women9s Health Across the Nation underwent bilateral knee MRIs at follow-up visit 11 for assessment of cartilage defects, bone marrow lesions, osteophytes, meniscal tears, synovitis and joint effusion. Serum leptin measures were available from baseline, follow-up visits 1 and 3–7. <h3>Results</h3> Baseline serum leptin levels were associated with greater odds of having more severe knee joint damage at follow-up visit 11 after adjustment for age, smoking status, menopause status and body mass index residuals. The greatest effect was observed for osteophytes; a 5 ng/ml increase in baseline leptin was associated with 24% higher odds of having larger osteophytes (95% CI 1.17 to 1.32). Correlations with baseline serum leptin were greatest for MRI-assessed osteophytes (r=0.41), followed by effusion (r=0.32), synovitis (r=0.30), cartilage defects (r=0.28), bone marrow lesions (r=0.24) and meniscal abnormalities (r=0.21). <h3>Conclusions</h3> Leptin levels 10 years prior to MRI assessment were associated with the presence of cartilage defects, bone marrow lesions, osteophytes, meniscal tears, synovitis and effusion among a population of middle-aged women. Understanding the role that leptin plays in the joint degradation process is critical for development of more targeted interventions for osteoarthritis.
Cross-regulation between the renin?angiotensin system and inflammatory mediators in cardiac hypertrophy and failure
Authors: K SEKIGUCHI
Journal: Cardiovascular Research (2004)

One of the major conceptual advances in our understanding of the pathogenesis of heart failure has been the insight that heart failure may progress as the result of the sustained overexpression of biologically active "neurohormones", such as norepinephrine and angiotensin II, which by virtue of their deleterious effects are sufficient to contribute to disease progression by provoking worsening left ventricular (LV) remodeling and progressive LV dysfunction. Recently, a second class of biologically active molecules, termed cytokines, has also been identified in the setting of heart failure. Analogous to the situation with neurohormones, the overexpression of cytokines is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between proinflammatory cytokines and the adrenergic system have been recognized in the heart for over a decade, the nature of the important interactions between proinflammatory cytokines and the renin–angiotensin system has become apparent only recently. Accordingly, in the present review, we will discuss the evidence which suggests that there is a functionally significant cross-talk between neurohormonal and inflammatory cytokine signaling in cardiac hypertrophy and failure.
Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation
Authors: Christopher Bredeson, Jennifer LeRademacher, Kazunobu Kato, John F. DiPersio, Edward Agura, Steven M. Devine, Frederick R. Appelbaum, Marcie R. Tomblyn, Ginna G. Laport, Xiaochun Zhu, Philip L. McCarthy, Vincent T. Ho, Kenneth R. Cooke, Elizabeth Armstrong, Angela Smith, J. Douglas Rizzo, Jeanne M. Burkart, Marcelo C. Pasquini
Journal: Blood (2013)
Definition of a possible genetic basis for susceptibility to acute myelogenous leukemia associated with the presence of a polymorphic Ia epitope.
Authors: S Seremetis, J Cuttner, R Winchester
Journal: Journal of Clinical Investigation (1985)

The polymorphic Ia epitope recognized by monoclonal antibody 109d6 is detectable on the leukemic cells of a significantly increased number of individuals with acute myelogenous leukemia, compared with its frequency in normal healthy control individuals. In control individuals, the presence of the 109d6 epitope is closely correlated with but not identical to the DRw53 allo-specificity. However, the frequency of particular conventional Ia allodeterminants, including DRw53, is not significantly elevated in the leukemia group. Considerable evidence supports the conclusion that the high frequency of the 109d6 epitope reflects an inherited basis for susceptibility to the development of acute myelogenous leukemia and not a differentiation event occurring in the leukemic lineage. The 109d6 determinant is expressed by leukemic myeloblasts as well as by homologous normal B cells and monocytes obtained from the same individuals during remission of the leukemia. Furthermore, in healthy family members the 109d6 epitope is encoded by Ia haplotypes that are shared with the patient. Of special interest, certain of these haplotypes have combinations of the 109d6 epitope and Ia specificities not commonly seen in normal individuals; here, also, healthy family members share these haplotypes.
Delivery of B Cell Receptor–internalized Antigen to Endosomes and Class II Vesicles
Authors: James R. Drake, Paul Webster, John C. Cambier, Ira Mellman
Journal: The Journal of Experimental Medicine (1997)

B cell receptor (BCR)-mediated antigen processing is a mechanism that allows class II–restricted presentation of specific antigen by B cells at relatively low antigen concentrations. Although BCR-mediated antigen processing and class II peptide loading may occur within one or more endocytic compartments, the functions of these compartments and their relationships to endosomes and lysosomes remain uncertain. In murine B cells, at least one population of class II– containing endocytic vesicles (i.e., CIIV) has been identified and demonstrated to be distinct both physically and functionally from endosomes and lysosomes. We now demonstrate the delivery of BCR-internalized antigen to CIIV within the time frame during which BCR-mediated antigen processing and formation of peptide–class II complexes occurs. Only a fraction of the BCR-internalized antigen was delivered to CIIV, with the majority of internalized antigen being delivered to lysosomes that are largely class II negative. The extensive colocalization of BCR-internalized antigen and newly synthesized class II molecules in CIIV suggests that CIIV may represent a specialized subcellular compartment for BCR-mediated antigen processing. Additionally, we have identified a putative CIIV-marker protein, immunologically related to the Igα subunit of the BCR, which further illustrates the unique nature of these endocytic vesicles.
Proteins and phospholipids in BAL from patients with hydrostatic pulmonary edema.
Authors: G Nakos, J Pneumatikos, I Tsangaris, C Tellis, M Lekka
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The purpose of the present study is twofold: to evaluate alterations in total phospholipid content and individual phospholipid classes of the surfactant, and to detect markers of inflammatory reaction in bronchoalveolar lavage (BAL) from patients with hydrostatic pulmonary edema (HPE). Mechanically ventilated patients with HPE (Group 1) were compared with mechanically ventilated patients without cardiopulmonary disease (Group 2), considered as the control group. Group 3, including patients with high-permeability pulmonary edema, was used for further comparison. BAL was obtained and immediately cooled at 4 degrees C. Total proteins, albumin, and platelet-activating factor--acetylhydrolase (PAF-AcH) were measured. Total lipids were extracted and analyzed after thin-layer chromatographic separation. PAF was determined with bioassay. Total BAL proteins and albumin were found significantly higher in patients with HPE compared with control, but were lower compared with adult respiratory distress syndrome (ARDS). PAF was elevated in patients with HPE and ARDS, whereas in the control group it was actually in nondetectable levels. PAF was significantly higher in ARDS than in HPE patients. BAL neutrophils concentration was higher in HPE compared with control, but lower compared with ARDS. There was an inverse correlation between PAF-AcH and PAF. Quantitative reduction of total BAL phospholipids (PL) and qualititative deficiency was observed in both patients with HPE and ARDS. The findings of this study suggest that there is evidence of inflammation in the airspaces of patients with HPE.
T Cell Activation
Authors: Jennifer E. Smith-Garvin, Gary A. Koretzky, Martha S. Jordan
Journal: Annual Review of Immunology (2009)

This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.Acronyms and DefinitionsAdapter protein: cellular protein that functions to bridge molecular interactions via characteristic domains able to mediate protein/protein or protein/lipid interactions Costimulation: signals delivered to T cells by cell surface receptors other than the TCR itself that potentiate T cell activation cSMAC: central supramolecular activation cluster Immunoreceptor tyrosine-based activation motif (ITAM): a short peptide sequence in the cytoplasmic tails of key surface receptors on hematopoietic cells that is characterized by tyrosine residues that are phosphorylated by Src family PTKs, enabling the ITAM to recruit activated Syk family kinases Inside-out signaling: signals initiated by engagement of immunoreceptors that lead to conformational changes and clustering of integrins, thereby increasing the affinity and avidity of the integrins for their ligands NFAT: nuclear factor of activated T cells PI3K: phosphoinositide 3-kinase PKC: protein kinase C PLC: phospholipase C pMHC: peptide major histocompatibility complex (MHC) complex pSMAC: peripheral supramolecular activation cluster PTK: protein tyrosine kinase Signal transduction: biochemical events linking surface receptor engagement to cellular responses TCR: T cell antigen receptor