tbuckley/cabot-search huggingface dataset:
Development of the airway intraepithelial dendritic cell network in the rat from class II major histocompatibility (Ia)-negative precursors: differential regulation of Ia expression at different levels of the respiratory tract.
Authors: D J Nelson, C McMenamin, A S McWilliam, M Brenan, P G Holt
Journal: The Journal of Experimental Medicine (1994)

The relative inefficiency of respiratory mucosal immune function during infancy is generally attributed to the immaturity of the neonatal T cell system. However, immune competence in the adult lung has recently been shown to be closely linked to the functional capacity of local networks of intraepithelial dendritic cells (DC). This study examines the density and distribution of these DC throughout the neonatal respiratory tract in rats, focusing particularly on microenvironmental regulation of their class II major histocompatibility complex (MHC) (Ia) expression. In animals housed under dust-controlled conditions, airway epithelial and alveolar Ia+ DC detectable by immunostaining with the monoclonal antibody (mAb) Ox6 are usually not seen until day 2-3 after birth, and adult-equivalent staining patterns are not observed until after weaning. In contrast, the mAb Ox62 detects large numbers of DC in fetal, infant, and adult rat airway epithelium. Costaining of these Ox62+ DC with Ox6 is rare in the neonate and increases progressively throughout infancy, and by weaning Ia+ DC comprised, on average, 65% of the overall intraepithelial DC population. In infant rats, Ia+ DC are observed first at the base of the nasal turbinates, sites of maximum exposure to inhaled particulates, suggesting that their maturation is driven in part by inflammatory stimuli. Consistent with this suggestion, densitometric analysis of Ia staining intensity of individual DC demonstrates that by 2-3 d after birth, Ia expression by nasal epithelial DC was comparable with that of Iahigh epidermal Langerhans cells in adjacent facial skin, at a time when expression by tracheal epithelial DC was 7-10-fold lower. Additionally, the rate of postnatal appearance of Iahigh DC in the airway epithelium was increased by administration of interferon gamma, and decreased by exposure of infant rats to aerosolized steroid. These findings collectively suggest that Ia expression by neonatal respiratory tract DC is locally controlled and can be upregulated by mediators that are produced within the lung and airway epithelium in response to inhalation of proinflammatory stimuli. It was also noted that Ialow neonatal airway DC expressed adult equivalent levels of class I MHC, which suggests differences in capacity to prime for CD8(+)-dependent versus CD4(+)-dependent immunity to inhaled pathogens, during the early postnatal period.
Management of Graves’ Ophthalmopathy: Reality and Perspectives*
Authors: Luigi Bartalena, Aldo Pinchera, Claudio Marcocci
Journal: Endocrine Reviews (2000)

Abstract Graves’ ophthalmopathy is an debilitating disease impairing the quality of life of affected individuals. Despite recent progress in the understanding of its pathogenesis, treatment is often not satisfactory. In mild cases, local therapeutic measures (artificial tears and ointments, sunglasses, nocturnal taping of the eyes, prisms) can control symptoms and signs. In severe forms of the disease (3–5%), aggressive measures are required. If the disease is active, high-dose glucocorticoids and/or orbital radiotherapy, or orbital decompression represent the mainstay of treatment. If the disease is severe but inactive, orbital decompression is preferred. Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation. Rehabilitative (extraocular muscle or eyelid) surgery is often needed after treatment and inactivation of eye disease. Correction of both hyper- and hypothyroidism is crucial for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may cause the progression of preexisting ophthalmopathy, especially in smokers. The exacerbation, however, is prevented by glucocorticoids. In addition, thyroid ablation may prove beneficial for the ophthalmopathy in view of the pathogenetic model relating eye disease to autoimmune reactions directed against antigens shared by the thyroid and the orbit.
Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis
Authors: F Baert, K Wouters, G D’Haens, P Hoang, S Naegels, F D’Heygere, J Holvoet, E Louis, M Devos, K Geboes
Journal: Gut (1999)

BACKGROUND AND AIMS It is not known whether lymphocytic colitis and collagenous colitis represent different clinical entities or constitute part of a spectrum of disease. METHODS Detailed clinical features and histological findings were compared in a large series of patients with confirmed lymphocytic and collagenous colitis. RESULTS Histological diagnosis was confirmed in 96 patients with collagenous colitis and 80 with lymphocytic colitis. Twenty eight per cent of patients with collagenous colitis and 26% of patients with lymphocytic colitis had overlapping but less pronounced histological features. Both groups were equal in terms of age, use of aspirin and non-steroidal anti-inflammatory drugs, associated autoimmune conditions, arthritis, diarrhoea, and abdominal pain. The male:female ratio was 27:73 for collagenous colitis and 45:55 for lymphocytic colitis (p=0.013). Twenty five per cent of patients with collagenous colitis compared with 14% of patients with lymphocytic colitis were active smokers; only 8.3% of patients with collagenous colitis had stopped smoking compared with 23% of patients with lymphocytic colitis (p=0.013). Drug induced disease was suspected for ticlopidine (two collagenous colitis, four lymphocytic colitis) and flutamide (four lymphocytic colitis). Mean duration of symptoms before diagnosis was two months for lymphocytic colitis and four months for collagenous colitis. Overall prognosis was generally mild; 84% of patients with lymphocytic colitis and 74% of patients with collagenous colitis reported resolution or significant improvement (p=0.033). CONCLUSIONS Collagenous and lymphocytic colitis are similar but not identical. Patients with lymphocytic colitis present somewhat earlier and are less likely to be active smokers. Symptoms are milder and more likely to disappear in lymphocytic colitis. Ticlopidine and flutamide should be added to the list of drugs inducing colitis.
Observations of Amino Acid Gain and Loss during Protein Evolution Are Explained by Statistical Bias
Authors: R. A. Goldstein
Journal: Molecular Biology and Evolution (2006)

The authors of a recent manuscript in “Nature” claim to have discovered “universal trends” of amino acid gain and loss in protein evolution. Here, we show that this universal trend can be simply explained by a bias that is unavoidable with the 3-taxon trees used in the original analysis. We demonstrate that a rigorously reversible equilibrium model, when analyzed with the same methods as the “Nature” manuscript, yields identical (and in this case, clearly erroneous) conclusions. A main source of the bias is the division of the sequence data into “informative” and “noninformative” sites, which favors the observation of certain transitions.
BRAF Inactivation Drives Aneuploidy by Deregulating CRAF
Authors: Tamihiro Kamata, Jahan Hussain, Susan Giblett, Robert Hayward, Richard Marais, Catrin Pritchard
Journal: Cancer Research (2010)

Aspartate-594 is the third most common BRAF residue mutated in human cancer. Mutants of this residue are kinase inactive, and the mechanism(s) by which they contribute to cancer has remained perplexing. Using a conditional knock-in mouse model, we show that the (D594A)Braf mutant does not drive tumor development per se but is able to induce aneuploidy in murine splenocytes and mouse embryonic fibroblasts and contributes to immortalization through the propagation of aneuploid cells. (D594A)Braf lacks kinase activity but induces the related gene product Craf as well as the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway. Here, we show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells. These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf.
A Study of the Impact of Adding HPV Types to Cervical Cancer Screening and Triage Tests
Authors: M. Schiffman, M. J. Khan, D. Solomon, R. Herrero, S. Wacholder, A. Hildesheim, A. C. Rodriguez, M. C. Bratti, C. M. Wheeler, R. D. Burk
Journal: JNCI Journal of the National Cancer Institute (2005)

Use of human papillomavirus (HPV) testing in cervical cancer prevention is increasing rapidly. A DNA test for 13 HPV types that can cause cervical cancer is approved in the United States for co-screening with cytology of women ≥30 years old and for triage of women of all ages with equivocal cytology. However, most infections with HPV are benign. We evaluated trade-offs between specificity and sensitivity for approximately 40 HPV types in predicting cervical intraepithelial neoplasia 3 and cancer in two prospective studies: a population-based screening study that followed 6196 women aged 30–94 years from Costa Rica for 7 years and a triage study that followed 3363 women aged 18–90 years with equivocal cytology in four U.S. centers for 2 years. For both screening and triage, testing for more than about 10 HPV types decreased specificity more than it increased sensitivity. The minimal increases in sensitivity and in negative predictive value achieved by adding HPV types to DNA tests must be weighed against the projected burden to thousands of women falsely labeled as being at high risk of cervical cancer.
Characterization of spatial patterns of flow within the reperfused myocardium by myocardial contrast echocardiography. Implications in determining extent of myocardial salvage.
Authors: F S Villanueva, W P Glasheen, J Sklenar, S Kaul
Journal: Circulation (1993)

BACKGROUND Since myocardial blood flow changes dynamically after reperfusion and since both hyperemia and impairment in microvascular function exist within the acutely reperfused bed, we sought to investigate the role of myocardial contrast echocardiography (MCE) in (1) defining the temporal variability in perfusion patterns after reflow and relating these to microsphere-derived blood flow; (2) differentiating viable from infarcted tissue during different periods of reflow; and (3) defining spatial perfusion patterns within the infarct bed in response to exogenously induced maximal vasodilation and relating these to infarct size and extent of myocardial salvage. METHODS AND RESULTS Twenty-one dogs with 3 hours of left anterior descending coronary artery occlusion and 2 to 3 hours of reflow were studied. MCE was performed at 15 and 45 minutes and 2 and 3 hours after reflow. It was also performed at either 2 or 3 hours after reflow in the presence of 0.56 mg/kg of dipyridamole. Radiolabeled microsphere-derived blood flow was measured at 15 minutes and 2 and 3 hours after reflow and during dipyridamole effect. Infarct size was measured at the end of the experiment by use of triphenyl tetrazolium chloride. MCE data were processed with color-coding schemes that highlighted differences in myocardial videointensities in proportion to the concentration of microbubbles within the microvasculature. There was significant variability in MCE-defined perfusion patterns after reflow, with contrast defects noted mainly within the endocardium. There were fair and significant (P &lt; .05) correlation (r = -.73 to r = -.55) between MCE defect size and normalized endocardial blood flow. Except at 15 minutes after reflow, there was poor correlation (r = .31 to r = .51) between MCE defect and infarct sizes. Even at 15 minutes after reflow, MCE defect size underestimated infarct size by 50%. In comparison, in the presence of dipyridamole, MCE defect size correlated strongly (r = .87, P &lt; .001) with infarct size and reasonably well with normalized transmural blood flow (r = -.62, P = .04). Moreover, the topography of the MCE perfusion defect reflected the topography of the infarct. CONCLUSIONS MCE revealed striking temporal heterogeneity in the spatial distribution of myocardial perfusion during postischemia reflow and either significantly underestimated or did not correlate with infarct size during reperfusion. Because of abnormalities in coronary vascular reserve specific to infarcted tissue, MCE in conjunction with intravenous dipyridamole depicted, in vivo, the actual topography of the infarct with remarkable accuracy.
Stable Conjugates Between A Novel Toll-Like Receptor 7 Ligand and Protein Allergens As Modulators Of Th2 Responses In Vitro and In Vivo
Authors: Lucia Filì, Alessandra Vultaggio, Elisa Cardilicchia, Cinzia Manuelli, Andrea Casini, Francesca Nencini, Laura Maggi, Sara Pratesi, Giulia Petroni, Francesca Boscaro, Ernesto Giovanni Occhiato, Sergio Romagnani, Enrico Maggi, Paola Parronchi
Journal: Journal of Allergy and Clinical Immunology (2014)
Toward Electronic Medical Record Alerts That Consume Less Physician Time
Authors: Clement J. McDonald
Journal: JAMA Internal Medicine (2013)

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Sharpen Available Tools for Tuberculosis Control, but New Tools Needed for Elimination
Authors: Bess Miller
Journal: JAMA (1996)

The article by Brewer et al<sup>1</sup>in this issue ofTHE JOURNALprovides an excellent opportunity to assess our nation's progress toward the elimination of tuberculosis (TB). In 1989, the secretary of the US Department of Health and Human Services approved the Strategic Plan for the Elimination of Tuberculosis in the United States.<sup>2</sup>In that plan, the elimination of TB is defined as a reduction in the incidence of TB to 1 case per million population by the year 2010. An expert advisory committee deemed TB elimination feasible on the basis of 3 factors: the retreat of TB into geographically and demographically definable foci; the existence of biotechnology to generate improved tools for TB diagnosis, treatment, and prevention; and the availability of computer, telecommunications, and other technologies to enhance the rapid transfer of new technology. See also p 1898. Between 1985 and 1992, coincident with the development and
Pseudo‐Chédiak‐Higashi inclusions together with Auer rods in acute myeloid leukemia
Authors: Abbas Hashim Abdulsalam, Nafila Sabeeh, Barbara J. Bain
Journal: American Journal of Hematology (2011)

An 8-year-old Iraqi male presented with fever and pallor of 2-months duration. There was no lymphadenopathy, splenomegaly or hepatomegaly. A full blood count showed: hemoglobin concentration 6.9 g/dl, white blood cell count 1.5 × 109/l and platelet count 217 × 109/l. Examination of a bone marrow aspirate showed acute myeloid leukemia (AML) with little maturation; blast cells were 85% of nucleated cells, and the case was classified as FAB (French–American–British) M1 AML. An unusual feature was the presence not only of Auer rods (left) but also of pseudo-Chédiak-Higashi inclusions, which on a Romanowsky stain varied from pink to deep purple (right). In addition to typical thin Auer rods there were also thick rod-shaped inclusions (left and right). Pseudo-Chédiak-Higashi inclusions are observed occasionally in AML1 (including acute promyelocytic leukemia) and also, rarely, in refractory anaemia with excess of blasts.2 The inclusions are formed by fusion of azurophilic (primary) granules and show myeloperoxidase activity and Sudan black B staining. On ultrastructural examination they are heterogeneous and, in contrast to the inclusions seen in the inherited anomaly, contain rod-shaped structures showing periodicity.1 The diagnostic significance of these inclusions is likely to be similar to that of Auer rods, indicating either AML or a high grade myelodysplastic syndrome.
Phase II trial of 5-fluorouracil, leucovorin and cisplatin for treatment of advanced pancreatic adenocarcinoma
Authors: T. André, J.P. Lotz, C. Bouleuc, K. Azzouzi, S. Houry, L. Hannoun, J. See, A. Esteso, D. Avenin, V. Izrael
Journal: Annals of Oncology (1996)
Guidelines for Field Surveys of the Quality of Medicines: A Proposal
Authors: Paul N Newton, Sue J Lee, Catherine Goodman, Facundo M Fernández, Shunmay Yeung, Souly Phanouvong, Harparkash Kaur, Abdinasir A Amin, Christopher J. M Whitty, Gilbert O Kokwaro, Niklas Lindegårdh, Patrick Lukulay, Lisa J White, Nicholas P. J Day, Michael D Green, Nicholas J White
Journal: PLoS Medicine (2009)

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines.
Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3)
Authors: J. S. Fitzgerald, T. G. Poehlmann, E. Schleussner, U. R. Markert
Journal: Human Reproduction Update (2008)

Trophoblast cells display a very unique capability: they physiologically invade into the surrounding tissue. This capability is widely associated with tumours, and, indeed, the invasive behaviour of both is rather similar. The imposing difference is that trophoblast cell invasion is temporally and locally controlled in contrast to unlimited tumour invasion. It initiates immediately after embryo implantation into the endometrium. Parallel to tumours, trophoblasts secrete proteases, such as matrix metalloproteinases, which dissolve the extracellular matrix and the surrounding tissue. Thereby, these proteases prepare and allow true invasion of trophoblasts. The invasive capacities of trophoblasts are positively and negatively regulated by numerous cytokines including leukaemia inhibitory factor (LIF), interleukin-6, hepatocyte growth factor, granulocyte macrophage-colony stimulating factor and others. They interact via specific receptors with the trophoblast cells, in which they activate intracellular signalling cascades. These will then induce expression of invasion relevant genes. One of these signalling pathways is the Janus kinase/signal transducers and activators of transcription (STAT) pathway. Especially phosphorylated STAT3 enhances invasiveness of tumours and trophoblast cells, where it is mainly activated by LIF. One of its most efficient physiological antagonists is suppressor of cytokine signalling 3. The balance of these two intracellular molecules seems to be a key regulator of tumour and trophoblast invasion.
Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia
Authors: Steven P. Treon, Christina K. Tripsas, Kirsten Meid, Diane Warren, Gaurav Varma, Rebecca Green, Kimon V. Argyropoulos, Guang Yang, Yang Cao, Lian Xu, Christopher J. Patterson, Scott Rodig, James L. Zehnder, Jon C. Aster, Nancy Lee Harris, Sandra Kanan, Irene Ghobrial, Jorge J. Castillo, Jacob P. Laubach, Zachary R. Hunter, Zeena Salman, Jianling Li, Mei Cheng, Fong Clow, Thorsten Graef, M. Lia Palomba, Ranjana H. Advani
Journal: New England Journal of Medicine (2015)

MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects.After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).
Remarks on the Functions of the Liver in Jaundice
Authors: J. W. Legg
Journal: BMJ (1876)

IT is well known that, in the old system of physiology preserved to us ir by Galen, the liver, besides being the source of the movement of the tl blood, was likewise the centre of animal heat and of san,uification.g' Shortly after the discovery of the circulation by Harvey, the liver was 1 robbed of all its functions save that of bile-making.Strange to say, o in our time, the liver has been restored to all the functions, nay, more tl than all, that it possessed in the belief of Galen, and physiologists are P now well assured that the liver is the centre of sanguification, of animal c heat, of bile-making, as well as of certain other functions not dreamt t of by the ancients.