tbuckley/cabot-search huggingface dataset:
New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival Outcomes
Authors: Giovanni Palladini, Angela Dispenzieri, Morie A. Gertz, Shaji Kumar, Ashutosh Wechalekar, Philip N. Hawkins, Stefan Schönland, Ute Hegenbart, Raymond Comenzo, Efstathios Kastritis, Meletios A. Dimopoulos, Arnaud Jaccard, Catherine Klersy, Giampaolo Merlini
Journal: Journal of Clinical Oncology (2012)

To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population.We gathered for analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed.There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation.This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.
Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition
Authors: E. Dony, Y-J. Lai, R. Dumitrascu, S. S. Pullamsetti, R. Savai, H. A. Ghofrani, N. Weissmann, C. Schudt, D. Flockerzi, W. Seeger, F. Grimminger, R. T. Schermuly
Journal: European Respiratory Journal (2007)

Phosphodiesterase (PDE) inhibitors are currently under investigation for the therapy of pulmonary hypertension. The present study was designed to investigate chronic effects of oral pumafentrine, a mixed selective PDE-3/4 inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension in rats. Treatment with pumafentrine (10 mg·kg<sup>−1</sup> daily) from week 4 to 6 after a single injection of MCT (60 mg·kg<sup>−1</sup>) partially reversed pulmonary hypertension and right heart hypertrophy in rats. In addition, small pulmonary arterial muscularisation, media hypertrophy and decrease in lumen area were largely reversed. Inhibition of smooth muscle proliferation under pumafentrine was demonstrated <i>in vivo</i> as was a pro-apoptotic effect of pumafentrine on vascular cells. Moreover, pumafentrine dose-dependently increased cyclic adenosine monophosphate levels and inhibited proliferation of cultured pulmonary arterial smooth muscle cells. In conclusion, oral pumafentrine partially reverses monocrotaline-induced pulmonary hypertension, lung vascular remodelling and right heart hypertrophy in rats.
Exhaled single-breath nitric oxide measurements are reproducible, repeatable and reflect levels of nitric oxide found in the lower airways
Authors: E Gabbay, AJ Fisher, T Small, AJ Leonard, PA Corris
Journal: European Respiratory Journal (1998)

Measurement of exhaled nitric oxide (NO) may allow noninvasive assessment of inflammatory disease in the lung. We determined immediate and day-to-day reproducibility of single-breath NO measurements at different points on the exhaled test, and whether levels recorded reflect levels of NO in the lower airways. Using a rapid chemiluminescence analyser, 55 healthy control subjects performed three sequential tests on each of two days. NO levels were compared at the level corresponding with: 1) the time the mouth pressure fell below 4 cmH2O (MP); 2) the plateau of end-exhaled CO2 (CO2); and 3) the NO plateau (NOp). NO levels were measured directly from the lower airways of 15 lung transplant recipients and compared with NO levels from a single-breath test performed in the same cohort. For measurements performed at MP, CO2 and NOp, the mean +/- SD differences between the two closest levels performed on the same day were 0.11+/-0.18, 0.095+/-0.16 and 0.094+/-0.13 parts per billion (ppb), respectively, and between days were 0.18+/-0.76, 0.19+/-0.78 and 0.17+/-0.8 ppb, respectively. End-expiratory levels recorded at the mouth from a single-breath test and in the lower airways were highly correlated (mouth versus trachea r2=0.95, p&lt;0.0001, mouth versus bronchus r2=0.92, p&lt;0.0001). Single-breath exhaled nitric oxide levels are a simple, reproducible and valid measure of nitric oxide production from the lower respiratory tract.
Long-lasting CD8 T cell memory in the absence of CD4 T cells or B cells.
Authors: F Di Rosa, P Matzinger
Journal: The Journal of Experimental Medicine (1996)

The cellular basis of immunological memory has been a debated issue. It is not clear whether CD8 T cell memory is maintained by long-lived cells or by specific or nonspecific restimulation. Here, we have approached the question from a different angle, asking whether the cellular interactions that are required to maintain memory are the same as those necessary to activate cytotoxic T lymphocytes. We studied the CD8 memory response to the male antigen H-Y in mice deficient in CD4 cells, or B cells and found that memory in these mice was virtually unimpaired. These results suggest that CD8 memory is CD4 independent and that there is no requirement for long term retention of immune complexes on follicular dendritic cells, nor for B cells as antigen-presenting cells.
Clinical experience with the oxygen concentrator.
Authors: T W Evans, J Waterhouse, P Howard
Journal: BMJ (1983)

The oxygen concentrator is an accepted means of delivery of long term domiciliary oxygen treatment. Conditions of use, however, need to be carefully defined. Fourteen concentrators were used for one year by patients with hypoxaemic chronic obstructive airways disease, and mechanical reliability, patient compliance with a regimen of 15 hours9 use a day, smoking habits, and variation in arterial gas tensions studied. Though many patients failed to achieve either the desired daily use or the recommended arterial oxygen tension, problems were generally minor and could probably be overcome by careful supervision and planning. Overall the concentrator appeared to be the most economical means of providing oxygen treatment at home and was much preferred by patients who had previously used oxygen cylinders.
Detection of Iron Deficiency Anemia
Authors: J. D. Bessman, S. McClure
Journal: JAMA (1991)

<h3>To the Editor.</h3> — Iron deficiency is a common disorder in ambulatory subjects.<sup>1,2</sup>While most such subjects are neither anemic nor symptomatic, even early iron deficiency reflects abnormal blood loss (usually due to bleeding) that requires medical attention. To screen such subjects for early iron deficiency rapidly, inexpensively, and accurately, serum transferrin saturation or ferritin values are too expensive. Since an isolated high red cell distribution width (RDW) has been shown to precede other blood count abnormalities during development of iron deficiency,<sup>3</sup>we studied the value of the automated blood cell count as a screening instrument in 783 unselected asymptomatic outpatient adult volunteers (57% women, 81% white, 19% black). Simultaneous serum ferritin, folate, and vitamin B<sub>12</sub>levels were determined. The blood cell count was determined on a Coulter Counter S-Plus Sr (Coulter Electronics, Hialeah, Fla).<sup>4</sup>Iron deficiency was defined as a serum ferritin level of less
Glomerular Cell Cross-Talk Influences Composition and Assembly of Extracellular Matrix
Authors: Adam Byron, Michael J. Randles, Jonathan D. Humphries, Aleksandr Mironov, Hellyeh Hamidi, Shelley Harris, Peter W. Mathieson, Moin A. Saleem, Simon C. Satchell, Roy Zent, Martin J. Humphries, Rachel Lennon
Journal: Journal of the American Society of Nephrology (2014)

The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus that contains tissue-restricted isoforms of collagen IV and laminin. It is integral to the capillary wall and therefore, functionally linked to glomerular filtration. Although the composition of the GBM has been investigated with global and candidate-based approaches, the relative contributions of glomerular cell types to the production of ECM are not well understood. To characterize specific cellular contributions to the GBM, we used mass spectrometry–based proteomics to analyze ECM isolated from podocytes and glomerular endothelial cells in vitro. These analyses identified cell type–specific differences in ECM composition, indicating distinct contributions to glomerular ECM assembly. Coculture of podocytes and endothelial cells resulted in an altered composition and organization of ECM compared with monoculture ECMs, and electron microscopy revealed basement membrane–like ECM deposition between cocultured cells, suggesting the involvement of cell–cell cross-talk in the production of glomerular ECM. Notably, compared with monoculture ECM proteomes, the coculture ECM proteome better resembled a tissue-derived glomerular ECM dataset, indicating its relevance to GBM in vivo. Protein network analyses revealed a common core of 35 highly connected structural ECM proteins that may be important for glomerular ECM assembly. Overall, these findings show the complexity of the glomerular ECM and suggest that both ECM composition and organization are context-dependent.
Research pointers: Peak expiratory flow sequence in acute exacerbations of asthma
Authors: S. S Birring
Journal: BMJ (2001)

Peak expiratory flow sequence in acute exacerbations of asthmaThe effect of deep inspiration on airway calibre in asthma may be a marker of the pathophysiology of airflow obstruction.Dilator responses occur with predominant airway smooth muscle spasm, 1 and constrictor responses with more severe inflammatory bronchoconstriction. 2 We investigated whether the effect of deep inspiration, as reflected by the change in peak expiratory flow from the first to last of a sequence of three blows, in acute exacerbations of asthma is a marker of more chronic bronchoconstriction and longer length of stay in hospital.
AN OUTER MEMBRANE PROTEIN OF <i>NEISSERIA MENINGITIDIS</i> GROUP B RESPONSIBLE FOR SEROTYPE SPECIFICITY
Authors: Carl E. Frasch, Emil C. Gotschlich
Journal: The Journal of Experimental Medicine (1974)

Meningococcal groups B and C have been subdivided into a series of serotypes based upon the antigenic specificity of protein serotype antigens (STA). The purpose of these studies was to obtain the STA by gentle methods and determine its anatomic location in the meningococcal cell. The STA was extracted from group B meningococcal strains by either 0.2 M LiCl or 0.2 M CaCl(2) and isolated from the extracts by gel filtration on Sepharose 6B or by pelleting the STA by centrifugation at 100,000 g. The isolated STA was a lipoprotein-lipopolysaccharide complex with a mol wt of approximately 4 x 10(6) daltons. Antisera prepared against the type 2 STA were bactericidal only for homologous serotype strains. The STA proved to be a constituent of the outer membrane of the cell envelope. This was shown by SDS-polyacrylamide gel electrophoresis (PAGE) of the isolated outer membrane and of the purified STA. The type 2 STA complex contains three principal proteins, one of which is predominant with a mol wt of 41,000 daltons. The type 2 STA was dissociated by Triton X-100 and separated by sucrose gradient isodensity centrifugation into two peaks. The denser peak (rho = 1.26 g/cm(3)) contained the majority of the 41,000 dalton major outer membrane protein as shown by SDS-PAGE. This peak also contained the type 2 antigenic determinant. Thus the major outer membrane protein, extracted as part of a lipoprotein-lipopolysaccharide complex, contains the type 2 STA determinant.
Changes in Invasive Breast Cancer and Ductal Carcinoma In Situ Rates in Relation to the Decline in Hormone Therapy Use
Authors: Ghada N. Farhat, Rod Walker, Diana S.M. Buist, Tracy Onega, Karla Kerlikowske
Journal: Journal of Clinical Oncology (2010)

To assess trends in invasive breast cancer and ductal carcinoma in situ (DCIS) incidence in association with changes in hormone therapy (HT) use in regular mammography screeners.We included 2,071,814 screening mammography examinations performed between January 1997 and December 2006 on 696,385 women age 40 to 79 years; 9,586 breast cancers were diagnosed within 12 months of a screening examination. We calculated adjusted annual rates (mammogram level) for prevalent HT use, incident invasive breast cancer (overall and by tumor histology and estrogen receptor [ER] status), and incident DCIS.After a precipitous decrease in HT use in 2002, the incidence of invasive breast cancer decreased significantly in 2002 to 2006 among women age 50 to 69 years (P(trend(2002-2006)) = .005) and 70 to 79 years (P(trend(2002-2006)) = .003) but not in women age 40 to 49 years (P(trend(2002-2006)) = .45). DCIS rates significantly decreased in women age 50 to 69 years after 2002 (P(trend(2002-2006)) = .02). Invasive ductal tumors significantly declined in women age 50 to 69 years and 70 to 79 years in 2002 to 2006. In women age 50 to 69 years, invasive lobular and ER-positive cancer rates declined steadily in 2002 to 2005 (P(trend(2002-2005)) = .02 and .03, respectively), but an elevated rate in 2006 rendered the overall trend nonsignificant (P(trend(2002-2006)) = .89 and .91, respectively).In parallel to the sharp decline in HT use in women undergoing regular mammography screening, invasive breast cancer rates decreased in women age 50 to 69 and 70 to 79 years after 2002, and DCIS rates decreased in women age 50 to 69 years, consistent with evidence that HT cessation reduces breast cancer risk. However, the decrease in incidence may have started to level off in 2006; this finding has not been uniformly reported in other populations, warranting further investigation.
Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage
Authors: Hiroki Mizukami, Yide Mi, Ryuichi Wada, Mari Kono, Tadashi Yamashita, Yujing Liu, Norbert Werth, Roger Sandhoff, Konrad Sandhoff, Richard L. Proia
Journal: Journal of Clinical Investigation (2002)

Gaucher disease, the most common lysosomal storage disease, is caused by a deficiency of glucocerebrosidase resulting in the impairment of glucosylceramide degradation. The hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause many of the clinical manifestations of the disease. We have developed adult mice carrying the Gaucher disease L444P point mutation in the glucocerebrosidase (Gba) gene and exhibiting a partial enzyme deficiency. The mutant mice demonstrate multisystem inflammation, including evidence of B cell hyperproliferation, an aspect of the disease found in some patients. However, the mutant mice do not accumulate large amounts of glucosylceramide or exhibit classic Gaucher cells in tissues.
Age, Serum Cholesterol and Coronary Artery Disease
Authors: MENARD M. GERTLER, STANLEY MARION GARN, E. F. BLAND
Journal: Circulation (1950)

The question of an age-associated rise in serum cholesterol has been undecided. This communication presents evidence in favor of a rise in serum cholesterol with increasing age between the third and the fifth decades. In a control group of 146 individuals and a coronary disease group of 97 individuals, there was a positive correlation between age and serum cholesterol. In the coronary disease group, there was a rise in serum cholesterol superimposed upon an initially higher level of serum cholesterol. The concept of "cholesterol age" is presented on the basis that a patient with coronary heart disease at 25 has a serum cholesterol similar to a "normal" male at the age of 45. The role of serum phospholipids is considered in the age-associated rise in serum cholesterol.
VEGF regulates the proliferation of acid-exposed alveolar lining epithelial cells
Authors: A Ohwada
Journal: Thorax (2003)

<b>Background:</b> Acid induced pneumonitis resulting in acute respiratory distress syndrome (ARDS) is characterised by increased alveolar permeability and accumulation of neutrophils. It is hypothesised that vascular endothelial growth factor (VEGF) is involved in the development of lung oedema. Furthermore, lower levels of VEGF are detected in bronchoalveolar lavage fluid from patients with ARDS than from non-ARDS patients. We hypothesised that VEGF acts cytoprotectively and have investigated this possibility in vitro with A549 cells. <b>Methods:</b> A549 cells were incubated in 24 well culture dishes 24 hours before exposure to acid, then incubated with serum free medium containing various concentrations of HCl for 30 minutes at 37°C in 5% CO<sub>2</sub>. The acidified medium was changed to normal complete medium; at specified incubation periods the supernatants were collected and the VEGF concentration measured and the number of adherent cells counted. <b>Results:</b> Proliferation of A549 cells and VEGF production were suppressed for at least 48 hours in HCl at a concentration of 50 mM. Restoration of cellular proliferation occurred following exogenous administration of VEGF (concentration of 1–250 ng/ml) and was inhibited by co-incubation with neutralising anti-VEGF antibody, indicating an interaction between VEGF molecules and A549 cells. Control cells were not influenced by administration of exogenous VEGF or anti-VEGF antibody. Treatment with neutralising anti-VEGF receptor (VEGFR) antibodies against VEGFR-1 and VEGFR-2 suppressed proliferation of acid exposed A549 cells but had no effect on control cells. <b>Conclusions:</b> Exogenous VEGF interacts with VEGFR-1 and VEGFR-2 on the surface and regulates the proliferation of injured alveolar lining epithelial cells in an autocrine or paracrine fashion.
Enhanced Antitumor Immunity in Mice Deficient in CD69
Authors: Enric Esplugues, David Sancho, Javier Vega-Ramos, Carlos Martínez-A, Uta Syrbe, Alf Hamann, Pablo Engel, Francisco Sánchez-Madrid, Pilar Lauzurica
Journal: The Journal of Experimental Medicine (2003)

We investigated the in vivo role of CD69 by analyzing the susceptibility of CD69−/− mice to tumors. CD69−/− mice challenged with MHC class I− tumors (RMA-S and RM-1) showed greatly reduced tumor growth and prolonged survival compared with wild-type (WT) mice. The enhanced anti–tumor response was NK cell and T lymphocyte–mediated, and was due, at least in part, to an increase in local lymphocytes. Resistance of CD69−/− mice to MHC class I− tumor growth was also associated with increased production of the chemokine MCP-1, diminished TGF-β production, and decreased lymphocyte apoptosis. Moreover, the in vivo blockade of TGF-β in WT mice resulted in enhanced anti–tumor response. In addition, CD69 engagement induced NK and T cell production of TGF-β, directly linking CD69 signaling to TGF-β regulation. Furthermore, anti-CD69 antibody treatment in WT mice induced a specific down-regulation in CD69 expression that resulted in augmented anti–tumor response. These data unmask a novel role for CD69 as a negative regulator of anti–tumor responses and show the possibility of a novel approach for the therapy of tumors.
Endoscopic ultrasonography-guided interstitial implantation of iodine 125-seeds combined with chemotherapy in the treatment of unresectable pancreatic carcinoma: a prospective pilot study
Authors: Z. Jin, Y. Du, Z. Li, Y. Jiang, J. Chen, Y. Liu
Journal: Endoscopy (2008)

Intraoperative and transdermal ultrasonography-mediated brachytherapy has been proved to be effective in postponing the development of abdominal carcinomas. The main purpose of this study was to evaluate the clinical efficacy and safety of endoscopic ultrasonography (EUS)-guided interstitial implantation of radioactive iodine 125 seeds in advanced pancreatic cancer.In total, 22 patients with advanced pancreatic cancer and positive fine-needle aspiration results underwent EUS-guided interstitial implantation of iodine seeds. All enrolled patients received routine gemcitabine-based 5-fluorouracil chemotherapy 1 week after brachytherapy.All 22 patients were successfully implanted with 125I seeds via EUS, with a median of 10 seeds and a maximum of 30 seeds per procedure. The median follow-up time of patients was 9.3 months, and the estimated median survival time was 9.0 months (95 % confidence interval 6.7 - 11.3 months). Partial remission was achieved in three cases (13.6 %) during the 4-week period, and disease in 10 patients (45.5 %) remained stable. Cancer finally progressed in 20 patients, all of whom died during 2 years of follow-up. Visual analog scale pain score dropped from 5.07 +/- 2.63 to 1.73 +/- 1.91 ( P< 0.01) 1 week after brachytherapy but increased again to 3.53 +/- 1.51 1 month later ( P< 0.05 vs. baseline). There were no obvious complications following therapy.EUS-guided interstitial implantation of 125I seeds may represent a safe alternative treatment option for locally advanced pancreatic cancer. Our preliminary data suggest improvement in pain, but no long-term survival benefit.
Simplification of the IDSA/ATS criteria for severe CAP using meta-analysis and observational data
Authors: Waleed Salih, Stuart Schembri, James D. Chalmers
Journal: European Respiratory Journal (2013)

The 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines proposed "minor" criteria to predict intensive care unit (ICU) admission in patients with community-acquired pneumonia. These criteria were based on expert opinion. Consequently, the authors of the guidelines asked investigators to determine whether the score could be simplified by excluding noncontributory variables. Each IDSA/ATS minor criterion was validated using a random effects meta-analysis of seven studies. Variables present in <5% of cases or that were nonsignificantly associated with mortality/ICU admission were excluded. A simplified score excluding these variables was tested for prediction of mortality and ICU admission in an established database. Prediction was assessed using the area under the receiver operator characteristic curve (AUC). Leukopenia (<4000 cells·mm(-3)), thrombocytopenia (<100,000 cells·mm(-3)) and hypothermia <36°C occurred in <5% of cases. A simplified score excluding these variables was performed similarly for prediction of mortality, AUC 0.77 (95% CI 0.73-0.81) versus 0.78 (95% CI 0.74-0.82) (p=0.9) and intensive care unit admission, AUC 0.85 (95% CI 0.82-0.87) versus 0.85 (95% CI 0.82-0.88) (p=0.9). Additional predictors suggested by the IDSA/ATS were associated with mortality and ICU admission, but only incorporating acidosis (pH <7.35) altered the AUC (0.82 (95% CI 0.78-0.86) (p=0.6) for mortality and 0.86 (95% CI 0.82-0.88) (p=0.8) for ICU admission). No improvements were statistically significant. The IDSA/ATS criteria can be simplified by removing three infrequent variables.