tbuckley/cabot-search huggingface dataset:
Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema
Authors: Khalil J. Diab, Jeremy J. Adamowicz, Krzysztof Kamocki, Natalia I. Rush, Jana Garrison, Yuan Gu, Kelly S. Schweitzer, Anastasia Skobeleva, Gangaraju Rajashekhar, Walter C. Hubbard, Evgeny V. Berdyshev, Irina Petrache
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism.Objectives: The aims of our work were to investigate the sphingosine–S1P–S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of S1P signaling is sufficient to functionally antagonize alveolar space enlargement.Methods: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1) agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography–tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase–mediated dUTP nick end labeling assays, and airspace morphometry.Measurements and Main Results: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-S1P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor–induced lung apoptosis.Conclusions: Strategies aimed at augmenting the S1P–S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.
Cardiovascular Complications and Mortality After Diabetes Diagnosis for South Asian and Chinese Patients
Authors: Baiju R. Shah, J. Charles Victor, Maria Chiu, Jack V. Tu, Sonia S. Anand, Peter C. Austin, Douglas G. Manuel, Janet E. Hux
Journal: Diabetes Care (2013)

OBJECTIVE Many non-European ethnic groups have an increased risk for diabetes; however, the published literature demonstrates considerable uncertainty about the rates of diabetes complications among minority populations. The objective of this study was to determine the risks of cardiovascular complications and of mortality after diabetes diagnosis for South Asian and Chinese patients, compared with European patients. RESEARCH DESIGN AND METHODS A population-based cohort study identified all 491,243 adults with newly diagnosed diabetes in Ontario, Canada, between April 2002 and March 2009. Subjects were followed until March 2011 for the first occurrence of any cardiovascular complication of diabetes (coronary artery disease, stroke, or lower-extremity amputation) and for all-cause mortality. Median follow-up was 4.7 years. RESULTS The crude incidence of cardiovascular complications after diabetes diagnosis was 17.9 per 1,000 patient-years among European patients, 12.0 among South Asian patients, and 7.7 among Chinese patients. After adjusting for baseline characteristics, the cause-specific hazard ratios (HRs) for cardiovascular complications relative to European patients were 0.95 (95% CI 0.90–1.00; P = 0.056) and 0.50 (0.46–0.53; P &amp;lt; 0.001) for South Asian and Chinese patients, respectively. Mortality was lower for both minority groups (adjusted HR for South Asian patients 0.56 [95% CI 0.52–0.60]; P &amp;lt; 0.001; for Chinese patients 0.58 [0.55–0.62]; P &amp;lt; 0.001). CONCLUSIONS Chinese patients were at substantially lower risk than European patients for cardiovascular complications after diabetes diagnosis, whereas South Asian patients were at comparable risk. Mortality after diabetes diagnosis was markedly lower for both minority populations.
Role of converting enzyme in the responses of rabbit atria, aortas, and adrenal zona glomerulosa to [des-Asp1]angiotensin I.
Authors: J A Ackerly, B S Tsai, M J Peach
Journal: Circulation Research (1977)

Conversion of angiotensin I (A I) and [des-Asp' |angiotensin I (des'-A I) to angiotensin II (A II) and angiotensin III (A III), respectively, was studied in aortic strips, left atria, adrenal zone glomerulosa cell suspensions from rabbits, and with purified rabbit lung converting enzyme.Conversion of A I and [des'-A I] was estimated in the presence and absence of Bothrops jararaca nonapeptide, converting enzyme inhibitor (CEI), by measuring the changes in peptide-induced tension development in aortas and atria and on steroidogenesis in cell suspensions.The liberation of histidyl-leucine from A I and des'-A I by the enzyme preparation was studied.Angiotensin I and des'-A I possessed 23% and 1% contractile activity (aorta), and 34% and 4% positive inotropic activity (atria), respectively, when compared to A II. Inhibition of aortic and atrial converting enzymes attenuated responses to A I and des'-A I without significantly altering responses to AH and A HI.The steroidogenic activity of A I and des'-A I in adrenal cells was dependent on conversion since treatment with CEI specifically abolished aldosterone biosynthesis induced by A I and des'-A I without changing the activities of A II or A III.The Km values for AI and des'-A I determined with lung enzyme were 80 /IM and 30 /IM, respectively.The hydrolysis of A I and des'-A I was competitively inhibited by CEI, A II, and A HI. Angiotensin III was the most potent CEI among several metabolites of A I. These results indicate that des'-A I was a better substrate than A I for isolated pulmonary converting enzyme.The present investigation clearly indicates that des'-A I is rapidly converted by purified and tissue converting enzymes.The data are consistent with the postulated alternative pathway for formation of A HI from des'-A I subsequent to N-terminal degradation of A I.
Macromolecular transport within heart valves.
Authors: R G Tompkins, J J Schnitzer, M L Yarmush
Journal: Circulation Research (1989)

The present study documents the permeability characteristics of heart valvular endothelium to low-density lipoprotein (LDL), albumin, and horseradish peroxidase (HRP). Using quantitative autoradiography, LDL and albumin concentrations were measured within aortic valves of squirrel monkeys and rabbits after 30 minutes of in vivo circulation. The valvular concentration profiles were analyzed using theoretical mathematical models based on fundamental transport principles. In vivo transvalvular concentration profiles of LDL and albumin displayed the highest tissue concentrations immediately beneath the endothelium and displayed the lowest concentrations near the midline of the valve. Tissue concentrations of LDL and albumin displayed large differences in magnitudes between different regions of individual valve leaflets suggesting marked spatial variation in the permeability properties of the valvular endothelium to LDL and albumin; this was also seen visually with HRP. The results of the theoretical analysis showed that 1) the aortic valvular endothelium limits the uptake of LDL and albumin into the valvular tissue, 2) the permeability of the valvular endothelium differs widely from one region of a valve to another and even from one side of the valve to the other within a single valvular region, and 3) intramural diffusion is the predominant mode of transport for LDL and albumin within the aortic valve, even in valvular regions exposed to large pressure differences across the valve.
MICROBIC VIRULENCE AND HOST SUSCEPTIBILITY IN PARATYPHOID-ENTERITIDIS INFECTION OF WHITE MICE
Authors: Ida W. Pritchett
Journal: The Journal of Experimental Medicine (1926)

Epidemics of mouse typhoid set up among the Rockefeller Institute strain of mice were studied over a period of 6 months. During this time the relationship of cage number of mouse typhoid bacilli to mortality, total population, and survival time was determined. A single virulence titration of the epidemic strain was made, and at the end of the experiment all survivors were examined for evidence of infection. The following conclusions may be drawn for the data here presented. 1. The available dosage of mouse typhoid bacilli varied directly with the mortality (plus a time constant of 6 to 8 days) and inversely with the survival time. 2. The virulence of the epidemic strain appeared to be practically the same as that of the original stock culture. 3. About 53.5 per cent of the survivors of one epidemic and 68 per cent of those in the other showed, at the end of the experiment, no signs of infection; the others had either specific blood agglutinins, or living bacteria in their heart's blood, spleen, feces, or gall bladder. 4. During the course of the epidemic, the original infecting strain (mouse typhoid Type II—Bacillus pestis caviæ) was almost entirely replaced by an antigenically dissimilar strain (mouse typhoid Type I—Bacillus enteritidis), probably introduced through the inadvertent inclusion of fecal carriers among the normal mice added as contacts.
Mapping of ventricular tachycardia induced by programmed stimulation in canine preparations of myocardial infarction.
Authors: R Cardinal, P Savard, D L Carson, J B Perry, P Pagé
Journal: Circulation (1984)

To investigate the mechanism of uniform ventricular tachycardia induced by programmed stimulation, we recorded His bundle electrograms and unipolar electrograms from 64 subepicardial, subendocardial, and intramural sites in dogs. Isochronal maps were generated off-line by computer. Two groups of dogs were studied 3 days after occlusion of their left anterior descending coronary arteries; one group underwent reperfusion after 2 to 2.5 hr of occlusion and the other methylprednisolone treatment before permanent occlusion. In the former, subepicardial sequences presented either a pattern suggesting circus movement or a radial pattern in which excitation at intramural sites could precede earliest subepicardial excitation. In the latter preparations, subepicardial excitation patterns consistently suggested circus movement in the subepicardial muscle layer surviving over necrotic tissue. Assuming complete circus movement, the "missed" time interval, measured as the interval left unaccounted for by actual recording of local excitation between ventricular tachycardia cycles, ranged from 3% to 64% of the cycle length of ventricular tachycardia. While surviving subepicardial and intramural layers appeared to be involved in the mechanism of ventricular tachycardia, a late second breakthrough on the right ventricle, in conjunction with fixed-coupled H deflections on the His bundle electrograms, suggested the involvement of the conducting system in propagation of the impulse.
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Authors: Laura R. Pacione, Michael J. Szego, Sakae Ikeda, Patsy M. Nishina, Roderick R. McInnes
Journal: Annual Review of Neuroscience (2003)

▪ Abstract More than 80 genes associated with human photoreceptor degenerations have been identified. Attention must now turn toward defining the mechanisms that lead to photoreceptor death, which occurs years to decades after the birth of the cells. Consequently, this review focuses on topics that offer insights into such mechanisms, including the one-hit or constant risk model of photoreceptor death; topological patterns of photoreceptor degeneration; mutations in ubiquitously expressed splicing factor genes associated only with photoreceptor degeneration; disorders of the retinal pigment epithelium; modifier genes; and global gene expression analysis of the retina, which will greatly increase our understanding of the downstream events that occur in response to a mutation.
Electrochemical Control of the Enzymatic Polymerization of PEG Hydrogels: Formation of Spatially Controlled Biological Microenvironments
Authors: Vincent Milleret, Benjamin R. Simona, Philipp S. Lienemann, János Vörös, Martin Ehrbar
Journal: Advanced Healthcare Materials (2013)

Control of pH gradient profile at the electrode–electrolyte interfaces allows the control of the enzymatic PEG-hydrogel polymerization. By tuning the solution pH, buffer capacity, and the applied current, the extent of the local inhibition and confinement of the Factor XIII-mediated polymerization of PEG are controlled. This technology opens new perspectives for the production of 3D-structured biological microenvironments. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin
Authors: J. Douglas Bremner, Negar Fani, Ali Ashraf, John R. Votaw, Marijn E. Brummer, Thomas Cummins, Viola Vaccarino, Mark M. Goodman, Lai Reed, Sajid Siddiq, Charles B. Nemeroff
Journal: American Journal of Psychiatry (2005)

Although there have been case reports suggesting a relationship between treatment with the acne medication isotretinoin and the development of depression and suicide, this topic remains controversial. In order for isotretinoin to cause depression, it must have an effect on the brain; however, the effects of isotretinoin on brain functioning in acne patients have not been established. The purpose of this study was to assess the effects of isotretinoin on brain functioning in acne patients.Brain functioning in adults was measured with [(18)F]fluorodeoxyglucose positron emission tomography before and after 4 months of treatment with isotretinoin (N=13) or an antibiotic (N=15).Isotretinoin but not antibiotic treatment was associated with decreased brain metabolism in the orbitofrontal cortex (-21% change versus 2% change for antibiotic), a brain area known to mediate symptoms of depression. There were no differences in the severity of depressive symptoms between the isotretinoin and antibiotic treatment groups before or after treatment.This study suggests that isotretinoin treatment is associated with changes in brain functioning.
Evaluating the utility of mesothelin in diagnosing mesothelioma
Authors: Patrick Bradley, Jurgen Herre, Stefan Marciniak, James Wason, Pasupathy Sivasothy
Journal: European Respiratory Journal (2013)

Background   Malignant pleural mesothelioma (MPM) is difficult to diagnose at an early stage, when management options can be more beneficial. The biomarker, which is found both in serum and pleural fluid, has been proposed to improve early diagnosis in selected cases.   Aims   We set out to evaluate in consecutive cases referred to a pleural investigation service the diagnostic utility of serum and pleural fluid mesothelin levels alone and in conjunction with history of asbestos exposure, radiological and cytological findings. We wished to assess whether mesothelin offers added diagnostic value to standard investigations, which may have the potential to reduce the number of invasive investigations.   Methods   Serum and pleural fluid mesothelin concentrations were measured in samples from 18 patients with suspected malignant effusions. These patients were followed up until a definitive diagnosis was made. Sensitivities and specificities were calculated, alone or in relation to asbestos exposure, radiological findings and cytology.   Results   Six of the patients were eventually confirmed to have MPM. Pleural mesothelin had greater sensitivity and positive predictive value (PPV) than serum mesothelin (0.83 and 0.63 vs 0.67 and 0.50). Neither added diagnostic value to the current initial investigations.   Conclusions   Mesothelin measurements did not add diagnostic value to standard investigations in suspected cases of malignant effusion in this study. This type of interim analysis, incorporating current-practice investigations, may warrant further data collection in a larger study for adequately powered statistical analysis.
Premorbid knee osteoarthritis is not characterised by diffuse thinness: the Framingham Osteoarthritis Study
Authors: D J Hunter, J B Niu, Y Zhang, M LaValley, C E McLennan, M Hudelmaier, F Eckstein, D T Felson
Journal: Annals of the Rheumatic Diseases (2008)

It is hypothesised that, like low bone density and fracture, thin cartilage predisposes to osteoarthritis (OA). Inferences about the effects of cartilage thickness on the development of OA can be made by evaluating the status of an unaffected non-diseased contralateral knee, in persons with unilateral OA, which we shall label the "premorbid knee". The primary objective of this analysis was to compare cartilage thickness in premorbid knees with non-OA knees drawn from persons without any knee OA to determine if cartilage in the premorbid knee was thinner than in the knee drawn from someone without OA in either knee.From 2002 to 2005, The Framingham Osteoarthritis Study recruited subjects without respect to OA from the community. We obtained posteroanterior, semiflexed and lateral films of both knees and knee magnetic resonance imaging to quantify cartilage volume in one knee. The cartilage plates of the patella, medial and lateral femur, medial and lateral tibia were quantified, using a 3D FLASH-water excitation sequence (in plane resolution 0.3x0.3 mm, 512 matrix, slice thickness 1.5 mm) and digital post-processing, involving three-dimensional reconstruction. Radiographs were used to define the OA status of knees with disease defined as Kellgren and Lawrence grade > or = 2 and or patellofemoral OA on the lateral film. Of 1020 participants included in this analysis, 720 had no OA in either knee (no-knee OA sample), and 55 subjects had no OA in the knee that was examined using magnetic resonance imaging and OA in the contralateral knee (premorbid knee OA sample). We compared cartilage thickness and percentage of cartilage coverage (total bone interface covered with cartilage) between these groups. After initial plate-specific univariate comparisons we performed a multiple regression to assess the association between OA status (premorbid versus no OA knee) and cartilage thickness adjusting for age, sex and body mass index. We used the Generalised Estimating Equation to account for correlation between plates. To further determine if the cartilage was diffusely thinned or had only increased areas of denuded cartilage, we removed plates with denuded areas (less than 95% cartilage coverage) from the analysis.55% of subjects were women. There was no difference in cartilage thickness between the premorbid knees and the no-knee OA sample. After adjusting for age, sex and body mass index and removing plates with less than 95% coverage from the analysis, we found the same or even thicker cartilage in premorbid knees compared with the knee OA sample.Premorbid knees do not have diffuse cartilage thinness. Rather the cartilage is normal or thicker with denuded areas suggesting that this may be the initial pathology rather than diffuse thinning.
Fas/FasL interaction: A novel immune therapy approach with immobilized biologicals
Authors: Martin Scholz, Jindrich Cinatl
Journal: Medicinal Research Reviews (2004)

Systemically applied agents to modulate the Fas/FasL system, e.g., by stimulation of Fas on activated leukocytes or tumor cells failed as strategies in immune therapy due to severe toxic effects in the host. Recently, a novel strategy has been developed by using immobilized immune active biologicals in a medical device that may allow immune management without expensive systemic therapy. This review reports on the potential role of Fas/FasL in immune therapy and summarizes current experimental and clinical data with the leukocyte inhibition module (LIM), an immobilized anti-Fas antibody containing device yet used in extracorporeal blood circulation. This proof of principal may stimulate the development of other devices based on the regulation of Fas/FasL or other targets relevant for immune disorders.
Expression of Cholesterol Sulfotransferase (SULT2B1b) in Human Platelets
Authors: Hidekatsu Yanai, Norman B. Javitt, Yuko Higashi, Hirotoshi Fuda, Charles A. Strott
Journal: Circulation (2003)

Cholesterol sulfate, the most important sterol sulfate in the human circulation, has emerged as a multifaceted molecule. Among its many demonstrated regulatory actions is its ability to influence blood clotting and fibrinolysis. Additionally, cholesterol sulfate is a constituent of human platelets, where it has been shown to support platelet aggregation.We have documented the presence of the enzyme (SULT2B1b) that sulfonates cholesterol in human platelets and examined the influence of plasma lipoproteins on the expression and activity of this enzyme. SULT2B1b mRNA was detected by reverse transcription-polymerase chain reaction and found to be the only steroid/sterol sulfotransferase expressed in these discoid anucleate particles. Using real-time polymerase chain reaction for quantification, we found that the level of SULT2B1b mRNA in platelets was maintained at 4 degrees C but substantially diminished over a period of 4 hours at 37 degrees C. The loss of SULT2B1b mRNA, however, was markedly reduced in the presence of HDL but not LDL. The stabilizing influence of HDL was attributable specifically to its apolipoprotein (apo) A-I component, whereas apoA-II and apoE were without effect. Importantly, there was a direct correlation between platelet SULT2B1b mRNA and protein levels in the presence or absence of lipoprotein that was reflected in enzymatic activity and cholesterol sulfate production.Human platelets selectively express SULT2B1b, the physiological cholesterol sulfotransferase. Furthermore, the stability of SULT2B1b mRNA and protein in platelets maintained at 37 degrees C is subject to regulation by the apoA-I component of HDL.