tbuckley/cabot-search huggingface dataset:
High Fidelity Between Saliva Proteomics and the Biologic State of Salivary Glands Defines Biomarker Signatures for Primary Sjögren's Syndrome
Authors: Nicolas Delaleu, Piotr Mydel, Ivo Kwee, Johan G. Brun, Malin V. Jonsson, Roland Jonsson
Journal: Arthritis & Rheumatology (2014)

Objective Dependence on invasive procedures for classification of patients with Sjögren's syndrome (SS) hampers timely diagnosis and suitable patient followup. The aim of this study was to recapitulate the diagnosis of SS through noninvasive means and to define the biologic state of SS patients' salivary glands. Methods Using a 187‐plex capture antibody–based assay, salivary proteomic biomarker profiles were generated from patients with primary SS, patients with rheumatoid arthritis, and asymptomatic controls. Discriminant function analyses and Gene Ontology–based network analyses allowed data analyses with a reductionist approach and with a focus on systems biology. Results Characterized by significant changes in 61 and 55 proteins, respectively, the salivary proteome of SS patients appeared profoundly altered compared to that of individuals without SS. On this basis, 4‐plex and 6‐plex biomarker signatures, both including interleukin‐4 (IL‐4), IL‐5, and clusterin, achieved accurate prediction of an individual's group membership for at least 94% of cases. Of note, all misclassified SS patients presented with ectopic germinal center–like structures. Systematic inference of biologic meaning identified SS‐related protein patterns delineating B cell–dominated immune responses, macrophage differentiation, and signs of T cell chemotaxis. In addition, proteomic Multi‐Analyte Profiles provided insight about proteins related to collagen, cytokine, and growth factor synthesis as well as lipid transport. Conclusion The SS‐related molecular landscape conveyed by saliva showed great congruence with histopathologic features found in SS and advances understanding of this disease at a molecular level. Such salivary biomarker signatures harbor great potential for improving timeliness of SS diagnosis and enabling suitable patient followup.
Unbearable headache of temporal arteritis.
Authors: R V Jones
Journal: BMJ (1977)

toxaemia" were higher in every one of the six years.Deaths from these two causes in 1969 amounted to 6-8 per 1000 and in 1975 to 8-8 per 1000 births, an increase almost exactly equal to the reduction in the rate for the "mature, cause unknown" category.In- creases in both premature birth rates and maternal toxaemia have been reported in asso- ciation with high induction rates, so these changes may be more than coincidental.If this is the case it may explain the failure of high induction rates to reduce overall perinatal mortality rates, even if some unexplained deaths of mature infants are thereby pre- vented.
Congenital B cell lymphocytosis explained by novel germline <i>CARD11</i> mutations
Authors: Andrew L. Snow, Wenming Xiao, Jeffrey R. Stinson, Wei Lu, Benjamin Chaigne-Delalande, Lixin Zheng, Stefania Pittaluga, Helen F. Matthews, Roland Schmitz, Sameer Jhavar, Stefan Kuchen, Lela Kardava, Wei Wang, Ian T. Lamborn, Huie Jing, Mark Raffeld, Susan Moir, Thomas A. Fleisher, Louis M. Staudt, Helen C. Su, Michael J. Lenardo
Journal: The Journal of Experimental Medicine (2012)

Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)–induced NF-κB activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-κB activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.
Myths of exercise induced right ventricular injury: the bright side of the moon
Authors: Roman Leischik
Journal: British Journal of Sports Medicine (2014)

In their meta-analysis, the authors of the article1 describe an injury of the right ventricle (RV) and cite in this context the increase in biomarkers as an indication for such an injury. This statement is not tenable.2 The increase in biomarkers can hardly be used as an argument for a right ventricular injury and often has a different meaning.3 ,4

On the other hand, …
T-Tubule Function in Mammalian Cardiac Myocytes
Authors: Fabien Brette, Clive Orchard
Journal: Circulation Research (2003)

The transverse tubules (t-tubules) of mammalian cardiac ventricular myocytes are invaginations of the surface membrane. Recent studies have suggested that the structure and function of the t-tubules are more complex than previously believed; in particular, many of the proteins involved in cellular Ca2+ cycling appear to be concentrated at the t-tubule. Thus, the t-tubules are an important determinant of cardiac cell function, especially as the main site of excitation-contraction coupling, ensuring spatially and temporally synchronous Ca2+ release throughout the cell. Changes in t-tubule structure and protein expression occur during development and in heart failure, so that changes in the t-tubules may contribute to the functional changes observed in these conditions. The purpose of this review is to provide an overview of recent studies of t-tubule structure and function in cardiac myocytes.
Mesothelioma risk after 40 years since first exposure to asbestos: a pooled analysis
Authors: A Reid, N H de Klerk, C Magnani, D Ferrante, G Berry, A W Musk, E Merler
Journal: Thorax (2014)

<h3>Background</h3> The risk of malignant mesothelioma (MM) increases proportionally to the cumulative exposure, and to the 3rd or 4th power of time since first exposed, to asbestos. However, little is known about the risk of MM after more than 40 years since first exposure because most epidemiological studies do not have follow-up for sufficient periods of time. <h3>Methods</h3> The data from six cohort studies of exposed workers and two cohorts with residential exposure have been pooled. A nested case control design matched cases and controls on calendar period and age. Conditional logistic regression modelled the relationship between time since first exposure and risk of MM. <h3>Results</h3> The combined data consisted of 22 048 people with asbestos exposure (5769 women), 707 cases of pleural MM (165 in women) and 155 cases of peritoneal MM (32 in women). Median time since first exposure for pleural MM cases was 38.4 years (IQR 31.3–45.3). Median duration of exposure for pleural MM cases was 3.75 years (IQR 0.7–18.2). The rate and risk of pleural MM increased until 45 years following first exposure and then appeared to increase at a slower power of time since first exposure. The rate of increase in peritoneal MM over the 10–50 years since first exposure continued to increase. <h3>Conclusions</h3> Exposure to asbestos confers a long-term risk of developing pleural and peritoneal mesothelioma which increases following cessation of exposure. While the rate of increase appears to start to level out after 40–50 years no one survives long enough for the excess risk to disappear.
Gut instinct: Rifaximin for the prevention of hepatic encephalopathy
Authors: Asma Siddique, Kris Kowdley
Journal: Hepatology (2010)

Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P = 0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy.
The Paneth cell.
Authors: M J Sandow, R Whitehead
Journal: Gut (1979)

Progress reportThe Paneth cell It was Schwalbel in 1872 who first described the morphological appearances of the pyramidal cells at the bases of the small intestinal crypts of Lieberkiihn.Some 16 years later, Paneth2 reinvestigated the cells by light microscopy and left with them his name.The alternative name for the Paneth cell is 'enterocytus cum granulis acidophilis' which in part describes their location, morphology, and histochemistry.Human Paneth cells are usually found at the bases of crypts of Lieberkiihn in the duodenum, jejunum, and ileum.In normal adults they occur only sparsely in the proximal colon and appendix, but Bloch3 has shown that Paneth cells are common in the large intestine of neonates.Paneth cells are also found in mammals and birds, with the notable exception of cats and dogs and their distribution is typically human.They are also present in many amphibians and reptiles where they occur throughout the intestinal tract4'5.The Figure shows a schematic diagram of a Paneth cell depicting its truncated pyramidal shape and a short brush border (microvilli) at the apical part projecting into the crypt lumen6'7.There is a basal irregularly shaped nucleus with a well-developed nucleolus.The characteristic features of the cells are the apically located large cytoplasmic secretory granules8'9.An elaborate, highly developed, dilated, rough endoplasmic reticulum that is intimately involved in the elaboration of the secretory material virtually fills the cytoplasm not occupied by the organelles.This endoplasmic reticulum is most extensive in the paranuclear basal portion of the cell, with extensive Golgi apparatus of small membrane bound vesicles in the supranuclear cytoplasm'0.As early as 1888 Paneth2 had recognised the likely secretory function of these cells.Their ultrastructural organisation is very similar to that of other cell types such as pancreatic acinar cells which elaborate abundant protein- rich secretions".The secretions are granular and described as varying from 1-3 ,um, and being either homogeneous or double-structured with a dense core and clear halo'2,13,"4,15There is some evidence that granule morphology may be determined in part by fixation technique16'17.The granules take up numerous dyes and consist of a carbohydrate-protein core and an acid-mucopolysaccharide capsule'8"19.There may be species dif- ferences, for Sheahan and Jervis20 could demonstrate acid mucosubstances only in rodent Paneth cells.They also contain lysosomal enzymes2 122 23 and some heavy metals, especially zinC6'24 as well as mercury, lead, and coblat25.Lewin 26 has detailed their staining reactions, methylene blue, Lendrum's phloxine-tartarazine, and Masson's trichrome being the most effective.Like the zymogen rich cells of the pancreas, however, they quickly degranulate during autolysis and are destroyed by acetic acid fixation.
A Transgenic Rat Model of Charcot-Marie-Tooth Disease
Authors: Michael Sereda, Ian Griffiths, Anja Pühlhofer, Helen Stewart, Moritz J Rossner, Frank Zimmermann, Josef P Magyar, Armin Schneider, Ernst Hund, Hans-Michael Meinck, Ueli Suter, Klaus-Armin Nave
Journal: Neuron (1996)
Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation
Authors: Armin Finkenstedt, Elisabeth Wolf, Elmar Höfner, Bethina Isasi Gasser, Sylvia Bösch, Rania Bakry, Marc Creus, Christian Kremser, Michael Schocke, Milan Theurl, Patrizia Moser, Melanie Schranz, Guenther Bonn, Werner Poewe, Wolfgang Vogel, Andreas R. Janecke, Heinz Zoller
Journal: Journal of Hepatology (2010)

Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders, retinal degeneration, and diabetes mellitus. Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin.A novel homozygous ceruloplasmin gene mutation, c.2554+1G>T, was identified as the cause of aceruloplasminemia in three affected siblings. Two siblings presented with movement disorders and diabetes. Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809-852 while preserving the open reading frame. Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver. Aceruloplasminemia was associated with severe brain and liver iron overload, where hepatic mRNA expression of the iron hormone hepcidin was increased, corresponding to the degree of iron overload. Hepatic iron concentration normalized after 3 and 5months of iron chelation therapy with deferasirox, which was also associated with reduced insulin demands. During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload.Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain. Iron accumulation in aceruloplasminemia is a result of defective cellular iron export, where hepcidin regulation is appropriate for the degree of iron overload. Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron.
Electrophysiological delineation of the specialized A-V conduction system in patients with corrected transposition of the great vessels and ventricular septal defect.
Authors: A L Waldo, A D Pacifico, L M Bargeron, T N James, J W Kirklin
Journal: Circulation (1975)

The specialized atrioventricular (A-V) conduction system was electrophysiologically delineated during open-heart surgery in four patients with congenitally corrected transposition of the great vessels and associated ventricular septal defect and one patient with single ventricle. Two consistent observations were made: 1) In no case was the specialized A-V conduction system found in the right atrium, whether or not there was a coronary sinus ostium present. 2) Specialized A-V conduction system electrograms were never delineated posterior to the ventricular septal defect, in contradistinction to this usual location in hearts having ventricular septal defects associated with other congenital lesions. In three of five patients, the initial course of the A-V conduction system of the ventricles was delineated between the anterior aspect of the ventricular septal defect and the pulmonary artery. In one patient the proximal portion of the A-V conduction system was delineated on the anterior aspect of the pulmonary conus. The course and extent of the A-V conduction system delineated in the morphological left ventricle suggests it is a left bundle branch. The surgical implications of the ectopic location of the A-V conduction system anterior to the ventricular septal defect, and the variability of the more proximal portion of the A-V conduction system are discussed.
Oleate upregulates lectin galactoside-binding soluble 2 (LGALS2) in in vitro model of cellular steatosis
Authors: K. A. Lockman, N. Plevris, A. Pryde, P. Lee, P. Cowan, P. C. Hayes, C. Filippi, J. N. Plevris
Journal: Gut (2011)

<h3>Introduction</h3> Galectin-2 (LGALS2) has been shown to co-localise with and bind to lymphotoxin-α (LTA); a cytokine that have been associated with insulin resistance. Thus, LGALS2 has been implicated in metabolic syndrome traits. The association between a common polymorphism of LGALS2 with myocardial infarction has further supported this notion. However, a recent study also demonstrates a contrasting finding of lower fasting insulin and glucose levels with LGALS2. The association between LGALS and the hepatic manifestation of insulin resistance, non-alcoholic fatty liver disease (NAFLD), has not been examined. Here, the authors investigated in vitro whether hepatic steatosis influenced the expression of LGALS2. <h3>Methods</h3> Human hepatoblastoma HepG2/C3A cells were pretreated for 3 days with oleate (0.25 mM) or octanoate (2 mM) to induce triglyceride accumulation. The authors have previously demonstrated that the addition of gluconeogenic substrates; lactate (L), pyruvate (P) and ammonia (N) to octanoate resulted in increased cellular steatosis that manifests many of the key features associated with steatohepatitis such as impaired mitochondrial structure/function, enhanced oxidative stress, decreased PTEN expression and altered cell cycle. LGALS2 mRNA expression was measured using quantitative real time PCR. Insulin resistance was determined by measuring concentration of glucose after a 4 h incubation of rinsed pretreated cells in the presence of insulin (0–10 nM). <h3>Results</h3> As previously demonstrated, all pretreatment induced significant intracellular triglyceride accumulation. The authors found that oleate upregulated LGALS2 expression. In contrast, the expression of LGALS2 was unchanged with LPON. Despite a higher triglyceride accumulation with octanoate, LGALS2 mRNA expression was also unaltered (oleate 1.24±0.06, octanoate 1.19±0.04, LPON 1.09±0.06, untreated 0.95±0.02 fold change from β-actin, p=0.0006). Glucose concentration in oleate showed a stepwise reduction with increasing insulin concentration (insulin 0 nM: 1.23±0.21 μg/gTP/h; 10 nM: 0.92±0.15 μg/gTP/h, where TP, total protein) contrasting to the unchanged glucose with LPON (Insulin 0 nM: 1.94±0.28 μg/gTP/h; 10 nM: 2.05±0.25 μg/gTP/h). <h3>Conclusion</h3> This data demonstrate that different FFA induces different LGALS2 expression. The presence of cellular steatosis per se or triglyceride concentration does not influence LGALS2 expression. Similar to the recent study, the upregulation of LGALS2 with oleate is associated with lower glucose concentration with preserved insulin sensitivity.
Vascular Endothelial Growth Factor-C Induces Lymphangitic Carcinomatosis, an Extremely Aggressive Form of Lung Metastases
Authors: Suvendu Das, Daniel S. Ladell, Simona Podgrabinska, Vladimir Ponomarev, Chandandeep Nagi, John T. Fallon, Mihaela Skobe
Journal: Cancer Research (2010)

Abstract The lymphatic system is an important pathway for tumor dissemination to the lymph nodes, but to which extent it contributes to the formation of distant metastases remains unknown. We report that induction of lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) at the secondary site, in the lung, facilitates expansion of already disseminated cancer cells throughout the lung tissue. By using orthotopic spontaneous metastasis models in nude mice, we show that VEGF-C expression by tumor cells altered the pattern of pulmonary metastases from nodular to diffuse and facilitated disease progression. Metastases expressing VEGF-C were tightly associated with the airways, in contrast to the control cells that were scattered in the lung parenchyma, throughout the alveolar region. VEGF-C induced lung lymphangiogenesis and promoted intralymphatic spread of metastases in the lung and formation of tumor emboli in the pulmonary arteries. This pattern of metastasis corresponds to lymphangitic carcinomatosis metastatic phenotype in human cancer patients, an extremely aggressive pattern of pulmonary metastases. In accordance, pulmonary breast cancer metastases from patients which were classified as lymphangitic carcinomatosis showed high levels of VEGF-C expression in cancer cells. These data show that VEGF-C promotes late steps of the metastatic process and identify the VEGF-C/VEGF receptor-3 pathway as the target not only for prevention of metastases, but also for treatment of established metastatic disease. Cancer Res; 70(5); 1814–24
Self-management of asthma in general practice, asthma control and quality of life: a randomised controlled trial
Authors: B P A Thoonen
Journal: Thorax (2003)

<b>Background:</b> A study was undertaken to determine the effectiveness of asthma self-management in general practice. <b>Methods:</b> Nineteen general practices were randomly allocated to usual care (UC) or self-management (SM). Asthma patients were included after confirmation of the GP diagnosis. Follow up was 2 years. Patients kept diary cards and visited the lung function laboratory every 6 months. Outcomes were number of successfully treated weeks, limited activity days, asthma specific quality of life, forced expiratory volume in 1 second (FEV<sub>1</sub>), FEV<sub>1</sub> reversibility, concentration of histamine provoking a fall in FEV<sub>1</sub> of 20% or more (PC<sub>20</sub> histamine), and amount of inhaled steroids. <b>Results:</b> A total of 214 patients were included in the study (104 UC/110 SM; one third of the total asthma population in general practice); 62% were female. The mean percentage of successfully treated weeks per patient in the UC group was 72% (74/103 weeks) compared with 78% (81/105 weeks) in the SM group (p=0.003). The mean number of limited activity days was 1.2 (95% CI 0.5 to 1.9) in the SM group and 3.9 (95% CI 2.5 to 5.4) in the UC group. The estimated increase in asthma quality of life score was 0.10 points per visit in the UC group and 0.21 points per visit in the SM group (p=0.055). FEV<sub>1</sub>, FEV<sub>1</sub> reversibility, and PC<sub>20</sub> histamine did not change. There was a saving of 217 puffs of inhaled steroid per patient in favour of the SM group (p&lt;0.05). <b>Conclusion:</b> Self-management lowers the burden of illness as perceived by patients with asthma and is at least as effective as the treatment usually provided in Dutch primary care. Self-management is a safe basis for intermittent treatment with inhaled corticosteroids.