tbuckley/cabot-search huggingface dataset:
Pulmonary Cystic Disorder Related to Light Chain Deposition Disease
Authors: Magali Colombat, Marc Stern, Odile Groussard, Dominique Droz, Michel Brauner, Dominique Valeyre, Hervé Mal, Camille Taillé, Isabelle Monnet, Michel Fournier, Serge Herson, Claire Danel
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Light chain deposition disease (LCDD) is a rare disorder that very uncommonly affects the lung. We report three cases of severe cystic pulmonary LCDD leading to lung transplantation. Such a presentation has never been previously reported. The three patients present with a progressive obstructive pulmonary pattern associated with numerous cysts diffusely distributed in both lungs. The disease was histologically characterized by non-amyloid amorphous deposits in the alveolar walls, the small airways and the vessels. It was associated with emphysematous-like changes and small airway dilation. Monotypic kappa light chain fixation was demonstrated on the abnormal deposits and along the basement membranes. Electron microscopy revealed coarsely granular electron-dense deposits in the same localizations. Mild extrapulmonary deposits were found in salivary glands in one patient. No immunoproliferative disorder was identified. We conclude that LCDD may primarily affect the lung, present as a pulmonary cystic disorder, and lead to severe respiratory insufficiency.
Modulation of ozone-induced airway hyperresponsiveness and inflammation by interleukin-13
Authors: A. S. Williams, P. Nath, S-Y. Leung, N. Khorasani, A. N. J. McKenzie, I. M. Adcock, K. F. Chung
Journal: European Respiratory Journal (2008)

The present study aimed to determine whether the T-helper cell type 2-derived cytokines, interleukin (IL)-4 and -13, can modulate the lung response to ozone exposure. IL-13 -/- , IL-4/13 -/- and IL-13-overexpressing transgenic (Tg) mice were exposed to ozone (3 ppm; 3 h) or air. Wild-type (Wt) Balb/c mice and transgenic-negative littermates (IL-13Wt) were used as controls for gene-deficient and IL-13Tg mice, respectively. IL-4/13 -/- and IL-13 -/- mice developed a lesser degree of ozone-induced airway hyperresponsiveness (AHR) while IL-13Tg mice developed a greater degree of AHR compared with ozone-exposed wild-type or IL-13Wt mice, respectively. Ozone caused a time-dependent increase of bronchoalveolar lavage (BAL) neutrophils and macrophages in wild-type mice, maximal at 20–24 h, which was attenuated in the IL-13 -/- and IL-4/13 -/- mice. In IL-13Tg mice, there was a greater increase in BAL neutrophils after ozone exposure compared with IL-13Wt mice. Using quantitative real-time PCR, ozone-induced mRNA expression for IL-6 and keratinocyte chemokine was further enhanced in IL-13 -/- and IL-4/13 -/- mice, and was inhibited in IL-13Tg mice. Macrophage inflammatory protein (MIP)-3α/CCL20 expression was enhanced after ozone exposure in wild-type mice, inhibited in IL-13 -/- and IL-4/13 -/- mice, while in IL-13Tg mice it was enhanced. A similar pattern of expression was observed with lipopolysaccharide-induced cytokine (LIX/CXCL5/ENA-78) expression. In conclusion, interleukin-13 augments ozone-induced airway hyperresponsiveness and neutrophilic inflammation, possibly through modulation of certain cytokines induced by ozone exposure.
Clinical and Methodological Factors Related to Reliability of the Best-Estimate Diagnostic Procedure
Authors: M A Roy, G Lanctôt, C Mérette, D Cliche, J P Fournier, P Boutin, C Rodrigue, L Charron, M Turgeon, M Hamel, N Montgrain, L Nicole, A Pirès, H Wallot, A M Ponton, Y Garneau, C Dion, J C Lavallée, A Potvin, P Szatmari, M Maziade
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: The reliability and accuracy of the best-estimate diagnostic procedure were examined, and factors associated with reliability were determined. METHOD: The subjects were 134 members of large multigenerational pedigrees densely affected by bipolar disorders or schizophrenia. Three best-estimate diagnoses were derived: first, by a research psychiatrist and research assistant unblind to the relatives' diagnoses; second, by two blind independent psychiatrists; third, by a panel of four blind psychiatrists. The subjects were characterized on several clinical and methodological variables, which were used to compare the agreements of two types of best-estimate diagnoses with the disagreements. RESULTS: There was satisfactory agreement between the unblind and blind consensus best-estimate diagnoses and between the two blind independent psychiatrists. Latent class analyses revealed that limited sensitivity was the main source of imperfect reliability. Confusability analyses revealed that the most problematic diagnostic distinctions involved schizoaffective disorder, which was confused with schizophrenia, bipolar I disorder, and schizophreniform disorder. Blindness significantly affected diagnostic outcome in latent class analyses. Moreover, for diagnostic disagreements, unblind diagnoses had greater continuity with the most predominant diagnosis in the pedigree than did blind diagnoses. Diagnostic disagreements were associated with the presence of mixed affective and psychotic symptoms, less diagnostic certainty, and shorter duration of illness. CONCLUSIONS: These results suggest that it is possible to identify cases that are more likely to lead to diagnostic disagreements in family and epidemiological studies and that blind diagnoses may help to prevent false positive diagnoses, which may be particularly detrimental to genetic linkage analyses. (Am J Psychiatry 1997; 154:1726–1733)
Abstract 491: The roles of homologous recombination repair and cell cycle checkpoints in radiosensitization by the Chk1/2 inhibitor, AZD7762
Authors: Meredith Ann Morgan, Leslie Parsels, Lili Zhao, Joshua Parsels, Mary Davis, Sankari Arumugarajah, Christine Canman, Sonya Zabludoff, Jonathan Maybaum, Theodore Lawrence
Journal: Cancer Research (2010)

Abstract The combination of gemcitabine and radiation is superior to gemcitabine alone for locally advanced pancreatic cancer however the median survival is only approximately one year. We have previously demonstrated that inhibition of Chk1 (checkpoint kinase 1) sensitizes pancreatic cancer cell lines, as well as patient-derived tumor xenografts, to both radiation and gemcitabine-radiation. The exact mechanism(s) for this sensitization, however, remains unclear. Based on the abilities of Chk1 to induce cell cycle arrest and promote HRR (homologous recombination repair) in response to DNA damage, we set out to determine the relevance of these mechanisms to radiosensitization by AZD7762, an AstraZenca Chk1/2 inhibitor currently in Phase I clinical trials. We tested the effects of AZD7762 on survival, cell cycle checkpoints, Rad51 focus formation and HRR activity in response to radiation and gemcitabine-radiation in two pancreatic cancer cell lines, Panc-1 and MiaPaCa-2. We began this study with the observation that AZD7762 sensitized MiaPaCa-2 cells to radiation and gemcitabine-radiation with enhancement ratios of 1.5 ± 0.08 (AZD7762), 1.2 ± 0.07 (50 nM gemcitabine), and 1.9 ± 0.16 (AZD7762 + 50 nM gemcitabine) but did not sensitize Panc-1 cells where enhancement ratios were 1.0 ± 0.03 (AZD7762), 1.5 ± 0.11 (100 nM gemcitabine), and 1.4 ± 0.05 (AZD7762 + 100 nM gemcitabine). AZD7762 inhibited Chk1 in both cell lines as evidenced by accumulation of Cdc25A and abrogation of the radiation-induced G2 arrest. To begin to determine the contribution of HRR to radiosensitization by AZD7762, we utilized a DR-GFP reporter assay which measures homology directed repair of an I-SceI endonuclease-induced DNA double strand break in an integrated GFP reporter gene in MiaPaCa-2 and Panc-1 cells. Treatment of cells expressing the DR-GFP reporter with 100 nM AZD7762 produced a 2- to 3-fold (P&amp;lt;0.05) inhibition of HRR activity in MiaPaCa-2 cells but minimal to no inhibition in Panc-1 cells. Inhibition of HRR by AZD7762 was accompanied by a reduction in the number of MiaPaCa-2 cells which stained positive for Rad51 foci in response to radiation (32 ± 3% versus 9 ± 3%; P&amp;lt;0.05). Taken together these results suggest that inhibition of HRR may play a role in the mechanism(s) of radiosensitization by Chk1 inhibition. It will be important in future studies to further decipher the contributions of cell cycle checkpoint abrogation and HRR inhibition to the mechanisms of radiosensitization by Chk1 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 491.
Serological diagnosis of tuberculosis: a report of 12 months' clinical experience.
Authors: A C Nicholls, K Horsfield
Journal: Thorax (1976)

This study reports the use of an agglutination test as a routine diagnostic aid for tuberculosis. We have found this to be both useful and reliable in clinical practice. The overall reliability was greater than 90%, 13 false results being obtained in the 222 patients tested. False negatives (4) were less common than false positives (9). The major advantage of the test is its speed, serological diagnosis being available overnight as compared with an average of one month for diagnosis by culture.
Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer
Authors: Martin J. Edelman, Ruth Smith, Petr Hausner, L. Austin Doyle, Kavita Kalra, Joyce Kendall, Michelle Bedor, Sonia Bisaccia
Journal: Journal of Clinical Oncology (2005)

Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, a plateau in efficacy with currently available agents has been reached. Previous studies of the retinoid, bexarotene, a retinoid X receptor-specific ligand, have indicated that it may improve outcome in advanced NSCLC.Patients with previously untreated stage IIIB or stage IV disease, a performance status of 0 to 2, and adequate organ status were entered. Treatment consisted of up to six cycles of carboplatin (area under the curve = 5.0 on day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) administered every 21 days. Bexarotene 400 mg/m2 orally was to be administered continuously beginning on day 1 and until progression of disease. All patients received atorvastatin 10 mg orally beginning before bexarotene. The objective was to demonstrate a 1-year survival rate of more than 50%.Forty-eight patients were entered; all were assessable for survival, and 47 were assessable for toxicity and response. The therapeutic regimen was well tolerated except for hypertriglyceridemia. The median time to progression was 6.7 months, and overall median survival was 12.7 months. There was a 25% response rate and a 1-year survival rate of 53%. These results were compared with the outcome of 33 patients treated at our institution with two-drug, platinum-based chemotherapy on controlled trials with similar entry criteria in the previous 5 years.Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia. The median time to progression and overall survival are promising and warrant further evaluation of bexarotene in advanced NSCLC.
Dynamic stiffness of barium-contractured cardiac muscles with different speeds of contraction.
Authors: T Shibata, W C Hunter, K Sagawa
Journal: Circulation Research (1987)

The dynamic stiffness of excised cardiac muscles that would be likely to have different intrinsic speeds of contraction, as judged by previous biochemical reports of their myosin ATPase rates, was compared. This study included muscles from thyrotoxic rabbits and newborn rabbits, rabbit atria, and normal papillary muscles at different temperatures. The usual excitation-contraction coupling process was bypassed by replacing bathing Ca2+ with Ba2+. The ensuring actively maintained contracture allowed us to focus more specifically on the contractile properties of the myofilaments. Dynamic stiffness was determined by sinusoidally oscillating muscle length at many different frequencies over the range 0.05-50 Hz while holding average muscle length at 95% of the systolic length, thus giving maximal developed force. The form of the stiffness modulus spectrum was similar for all muscles studied: stiffness was fairly constant at low frequencies, decreased to a minimum at an intermediate frequency, and then increased steeply, followed by a milder rate of increase over high frequencies. Differences in contraction speed were evident by shifts in the frequencies at which corresponding portions of the stiffness spectrum appeared. The clearest landmark was the frequency where stiffness became minimum (fmin). This varied strongly with temperature (Q10 = 2.9). Compared to normal adult papillary muscles (fmin = 1.2 Hz), fmin was 2.2 times faster in thyrotoxic myocardium, 1.9 times faster in 1-week-old rabbits, and 3.7 times faster in atrial trabeculae. These ratios of functional speed are similar to the corresponding ratios of myosin Ca2+-ATPase activities reported in the literature.
Hepatocyte–Stellate Cell Cross-Talk in the Liver Engenders a Permissive Inflammatory Microenvironment That Drives Progression in Hepatocellular Carcinoma
Authors: Cédric Coulouarn, Anne Corlu, Denise Glaise, Isabelle Guénon, Snorri S. Thorgeirsson, Bruno Clément
Journal: Cancer Research (2012)

Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features that are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the cross-talk between hepatocytes (human hepatoma cells) and activated human HSCs. Unsupervised genome-wide expression profiling showed that hepatocyte-HSC cross-talk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of proinflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte-HSC cross-talk also generated a permissive proangiogenic microenvironment, particularly by inducing VEGFA and matrix metalloproteinase (MMP)9 expression in HSCs. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte-HSC cross-talk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCCs. Interestingly, the effects of cross-talk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings, therefore, indicate that the cross-talk between hepatoma cells and activated HSCs is an important feature of HCC progression, which may be targeted by epigenetic modulation.
Beta 2 microglobulin measurements in saliva of patients with primary Sjogren's syndrome: influence of flow.
Authors: S A van der Geest, H M Markusse, A J Swaak
Journal: Annals of the Rheumatic Diseases (1993)

OBJECTIVES--To determine the diagnostic value of beta 2 microglobulin in parotid saliva, its concentration in relation to salivary flow was determined in 29 patients with primary Sjögren9s syndrome and in 30 normal controls. The specific secretion rate of beta 2 microglobulin was calculated. METHODS--Parotid saliva samples were collected within a 20 minute period directly from Stensen9s duct with Lashley cups: sample 1 without gustatory stimulation during the first 10 minutes and samples 2 and 3 during the next five to 10 minutes, when saliva production was stimulated by a 500 mg vitamin C tablet. The sample volumes were measured and the beta 2 microglobulin concentration was determined by radioimmunoassay. RESULTS--During gustatory stimulation the mean beta 2 microglobulin secretion rate in patients with primary Sjögren9s syndrome was 0.31 microgram/min; in normal controls it was 0.14 microgram/min. The sensitivity and specificity of this test were 56 and 87% respectively. The mean salivary flow without stimulation in patients with primary Sjögren9s syndrome was lower than that in normal controls, but no difference was found during stimulation. CONCLUSIONS--Our results support the hypothesis of local beta 2 microglobulin production in the parotid gland of patients with primary Sjögren9s syndrome. The test cannot be used as a screening test owing to low sensitivity, but it may be used as a supplementary diagnostic test as it has the advantage of being non-invasive.
Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia
Authors: G B T von Boyen
Journal: Gut (2004)

Enteric glia protect the integrity of the gut, as loss of enteric glial fibrillary acidic protein (GFAP) positive (+) glia leads to a haemorrhagic jejunoileitis. Crohn's disease (CD) and necrotising enterocolitis (NEC) show pathological changes in enteric glia. Therefore, factors controlling GFAP+ enteric glia are of great interest. The aim of the present study was to characterise enteric glia and determine the effect of interleukin 1beta (IL-1beta), interleukin 4 (IL-4), tumour necrosis factor alpha (TNF-alpha), and lipopolysaccharides (LPS) on cultured enteric glia.Dissected rat colon and cultured enteric glia cells were double labelled with anti-GFAP and anti-S-100 antibodies. For regulatory studies, enteric glia cells were treated with cytokines and LPS. Proliferation was assayed using bromodeoxyuridine (BrdU) and mitosis of enteric glia was blocked by demecolcine.We were able to distinguish GFAP negative (-) from GFAP+ glia subtypes in situ and in primary cultures. Incubation of cells with IL-1beta, TNF-alpha, and LPS led to a significant increase in GFAP+ enteric glia while IL-4 had no effect on GFAP expression. After incubation with IL-1beta, total intracellular GFAP of enteric glia cells was increased. Upregulation of GFAP+ enteric glia could also be observed after stimulation with IL-1beta on blocking mitosis. BrdU uptake in stimulated enteric glia showed no increased proliferation rate.Two different types of enteric glia based on GFAP expression exist in the gut. Proinflammatory cytokines and LPS cause a dramatic increase in GFAP+ enteric glia. This suggests that cytokines play an important role in controlling GFAP+ enteric glia which might in turn be involved in modulating the integrity of the bowel during inflammation.
Higher Levels of Basal Serial CSF Cortisol in Combat Veterans With Posttraumatic Stress Disorder
Authors: Dewleen G Baker, Nosa N Ekhator, John W Kasckow, Boris Dashevsky, Paul S Horn, Ludmila Bednarik, Thomas D Geracioti
Journal: American Journal of Psychiatry (2005)

Results of basal peripheral cortisol measures in posttraumatic stress disorder (PTSD) have been variable. The authors' goal was to measure CSF cortisol concentrations, which more accurately reflect brain glucocorticoid exposure, in subjects with or without PTSD.CSF was withdrawn from a subarachnoid catheter and plasma from a venous catheter, both indwelling, over a 6-hour interval to determine hourly plasma ACTH and cortisol concentrations and hourly CSF cortisol levels in eight well-characterized combat veterans with PTSD and eight matched healthy volunteers.Mean CSF cortisol concentrations were significantly higher in the subjects with PTSD (3.18 ng/ml, SD=0.33) than in the normal volunteers (2.33 ng/ml, SD=0.50), largely due to higher CSF cortisol concentration nadirs. No group differences were observed in either plasma ACTH or peripheral (plasma or urinary free) cortisol. CSF corticotropin-releasing hormone and CSF cortisol concentrations were positively and significantly correlated.Despite normal peripheral cortisol indexes in the veterans with PTSD, their CNS exposure to cortisol was greater than that of normal comparison subjects.
Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties
Authors: Jing Wang, Fei Lu, Qi Ren, Hong Sun, Zhengshuang Xu, Rongfeng Lan, Yuqing Liu, David Ward, Junmin Quan, Tao Ye, Hui Zhang
Journal: Cancer Research (2011)

Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties.
Primovist, Eovist: What to expect?
Authors: Bernard E. Van Beers, Catherine M. Pastor, Hero K. Hussain
Journal: Journal of Hepatology (2012)

Gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA, Primovist® in Europe and Eovist® in the USA) is a liver-specific magnetic resonance imaging contrast agent that has up to 50% hepatobiliary excretion in the normal liver. After intravenous injection, Gd-EOB-DTPA distributes into the vascular and extravascular spaces during the arterial, portal venous and late dynamic phases, and progressively into the hepatocytes and bile ducts during the hepatobiliary phase. The hepatocyte uptake of Gd-EOB-DTPA mainly occurs via the organic anion transporter polypeptides OATP1B1 and B3 located at the sinusoidal membrane and biliary excretion via the multidrug resistance-associated proteins MRP2 at the canalicular membrane. Because of these characteristics, Gd-EOB-DTPA behaves similarly to non-specific gadolinium chelates during the dynamic phases, and adds substantial information during the hepatobiliary phase, improving the detection and characterization of focal liver lesions and diffuse liver disease. This information is particularly relevant for the detection of metastases, and for the detection and characterization of nodular lesions in liver cirrhosis, including early hepatocellular carcinomas. Finally, GD-EOB-DTPA-enhanced magnetic resonance imaging may provide quantitative assessment regarding liver perfusion and hepatocyte function in diffuse liver diseases. The full potential of GD-EOB-DTPA-enhanced magnetic resonance imaging has to be established further. It is already clear that GD-EOB-DTPA-enhanced magnetic resonance imaging provides anatomic and functional information in the setting of focal and diffuse liver disease that is unattainable with magnetic resonance imaging enhanced with non-specific contrast agents.