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More frequent in either summer or winter in half the cases. Eleven percent of patients noted more frequent symptoms in the morning. Comorbidity was present in 32 53% ; of patients and is detailed in Table 1. Eight subjects had a history of hypertension, six ischaemic heart disease, six cerebrovascular disease, six asthma, three chronic obstructive airways disease and one mild valvular heart disease mild mitral and tricuspid regurgitation ; . Childhood or teenage fainting was present in 7 27% ; cases. Three patients had migraine and three had tinnitus. One suffered from epilepsy and one had atrial fibrillation. A family history of vasovagal syncope was present in 18 29% ; cases.
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The extracellular domain of the GHR coimmunoprecipitated with B2036. In the cell lysates cells ; , both antibodies detected the 110-kDa precursor p ; and the 130-kDa mature m ; forms of the receptor. Together, these results show that the release of TCA-precipitated B2036 into the medium is due to proteolysis of the GHR, which results in shedding of GHBP. Internalization and shedding represent two potential mechanisms for regulating receptor availability at the cell surface, and B2036 is the ideal tool to monitor both of these processes. Other methods, like surface biotinylation, often induce artifacts due to changes in binding characteristics of ligands and receptors, and to stress conditions from rapid warming and or cooling of the cells 42 ; . As seen in Fig. 4A, after 30 min of chase, 13% of the 125I-B2036 was bound to GHBP in the medium pellet, whereas at the same time, 40% was detected intracellular in Fig. 2 ; . This result indicates that the internalization pathway is approximately three times more efficient in removing GHR from the cell surface than extracellular proteolysis. The cytosolic tail sequence does not play a role in GHBP release because truncated GH receptor isoforms with intracellular domains of only seven amino acids, lacking both boxes 1 and 2, produce large amounts of GHBP 44, 45 ; . Therefore, it is unlikely that mutations in the UbE motif of the receptor tail affect GHBP shedding. To define the role of the UbE motif in both mechanisms, we compared the shedding process in the wild-type GHR and mutant GHR F327A ; . Cells were incubated with 125I-GH or 125 I-B2036, chased for 90 min in the absence of ligand, and TCA-precipitated radioactivity was measured in the medium Fig. 4D ; . The endocytosis-deficient GHR F327A ; mutant showed an increased amount of precipitated 125I-B2036 22% ; , compared with 13% in the wild-type GHR-expressing cells, while release of intact 125I-GH was low 6% and 4%, respectively ; . This result shows that the prolonged half-life of GHR F327A ; as measured in Fig. 1 is not due to an inhibition of receptor proteolysis. Instead GHBP release increased, a change that was most likely due to an inhibition of endocytosis. For truncated receptor isoforms, it is suggested that the lack of internalization of these receptors can cause increased amounts of GHBP, as more receptor is available for shedding 44 ; . Inhibition of endocytosis with the proteasome inhibitor MG-132 also resulted in an increase in the release of 125I-B2036 Fig. 4D ; . As the process of GHR shedding is probably not affected by the presence of B2036, as it is by conclude that conditions of complete inhibition of GHR endocytosis identify the process of shedding as an important factor for the half-life of the GHR at the cell surface. However, under standard conditions with no GH present, we conclude that internalization and subsequent lysosomal degradation is the main process in GHR turnover. Inhibition of endocytosis, although it increases GHR proteolysis, results in a 200% increase in receptors at the cell surface. Thus, for the greater part, the availability of the GHR at the cell surface of Chinese hamster lung cells is regulated by the rate of ubiquitin-proteasome pathwayincubated for 90 min at 30 C the absence of ligand. The medium was analyzed as in A and the precipitated radioactivity is plotted as a percentage of total radioactivity in cells and medium. The values represent the mean SD of two experiments.
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Additional mechanism other than NO ; contributing to the insulin-induced vasodilation that could only be seen in the absence of ROS. Also, SOD-induced vasodilation may be the result of increased generation of hydrogen peroxide, a known vasodilator 48 ; . Alternatively, ROS were shown to reduce insulin sensitivity by inhibiting various critical steps involved in insulin's signal transduction pathways 4, 46 ; and were implicated in the pathogenesis of insulin resistance. Thus it is possible that scavenging of ROS may have restored the insulin sensitivity and vasodilation in ZO arteries. However, SOD was able to prevent insulin-induced vasoconstriction in ZL and ZO arteries, strongly suggesting that, apart from contributing to IR in rats, superoxide mediates insulin-induced vasoconstriction in both groups of rats. Our vascular studies suggested enhanced production of ROS in ZO coronary arteries in response to insulin. Our subsequent measurement of ROS using the lucigenin-enhanced chemiluminescence method also found significantly greater production of ROS at baseline and also in the presence of insulin 330 ng ml ; in than in ZL arteries. Furthermore, this insulininduced ROS generation was significantly inhibited by cotreatment with apocynin, a specific inhibitor of NADPH oxidase. This provided further evidence that insulin-induced vasoconstriction was potentially mediated by ROS in ZL and ZO arteries and that increased vasoconstriction in ZO arteries may likely be the result of increased generation of ROS in response to high insulin levels. A higher concentration of insulin than in vascular experiments ; was required in the lucigenin assay to consistently show enhanced production of ROS. It may be explained by a more potent effect of insulin on the pressurized than on the nonpressurized arteries. The source of increased insulin-induced ROS generation appears primarily to be the vascular NADPH oxidase, inasmuch as apocynin was able to restore insulin-induced vasodilation. The measurement of ROS generation by insulin-treated coronary arteries in the presence and absence of apocynin provided further evidence to implicate NADPH oxidase in ZO arteries. The present study, however, did not evaluate the exact location of ROS generation endothelium vs. smooth muscle ; or the specific identity of ROS. Further studies are needed to identify the potential other sources of ROS, including xanthine oxidase, lipoxygenases, mitochondrial oxidases, cytochrome P-450 enzymes, and eNOS, in low tetrahydrobiopterin states 45 ; . However, consistent with the previous reports, it appears that the NADPH oxidase system is the primary source of ROS in ZO and ZL coronary arteries 17, 19, 31 ; . Also, the exact mechanisms underlying the insulin activation of excess ROS production were not determined in this model, so further studies are required to evaluate whether insulin activates ROSgenerating enzymes directly or indirectly through production of endothelin-1, a known activator of ROS production 8 ; . Increased oxidative stress has been implicated in several disease models, including diabetes, heart failure, cardiomyopathy, and atherosclerosis. It was shown to lead to initial depletion of antioxidant defenses and subsequent overexpression of antioxidant enzymes such as SODs, catalase, and glutathione peroxidase. Our immunoblot studies of coronary arteries showed that expression of Mn SOD and Cu, Zn SOD in ZO arteries was comparable to that in ZL arteries. Apparently, the increase in oxidative stress in ZO arteries has not yet.
MS77 RheoPlast: Open-Source Modular Parallel Finite Difference Phase Field Software RheoPlast is a multi-physics finite difference simulation code which includes modules for: binary and ternary Cahn-Hilliard and vector-valued Allen-Cahn phase field, transport-limited electrochemistry, velocity-vorticity and velocity-pressure flow, elastic shear strain for fluidstructure interactions, and heat conduction; these can be combined arbitrarily at runtime. Based on the PETSc suite of parallel solvers and data objects, RheoPlast runs in two or three dimensions, features flexible time stepping, and can use periodic, symmetry, and module-specific programmed boundary conditions. Adam C. Powell Veryst Engineering LLC apowell veryst MS77 Computational Informatics for Materials Design In this presentation we discuss how statistical learning techniques can be used to augment more classical approaches to computational based design of materials. The role of data mining to identify dominant parameters influencing phase stability calculations is demonstrated. The use of such informatics based techniques to accelerate the computational approaches for first principle calculations is discussed. Examples are provided for a variety of multicomponent alloy design platforms. Krishna Rajan Department of Materials Science and Engineering Iowa State University krajan iastate MS77 On-Line Microstructure Repository for Predictive Analyses Many materials properties can be understood by analyzing the temporal and spatial evolution of microstructures under different conditions. Performing such analysis requires compact representation to store and manipulate a large set of microstructures and techniques to determine relationships between properties, structure and processing parameters from such large data sets. We discuss how these challenges can be addressed through computational and software techniques implemented in our web-portal applications for designing Aluminum-rich alloys. Zi-Kui Liu Department of Materials Science and Engineering Penn State University zikui matse.psu Keita Teranishi Department of Computer Science and Engineering The Pennsylvania State University teranish cse.psu Padma Raghavan The Pennsylvania State Univ. Dept of Computer Science Engr. raghavan cse.psu Long-Qing Chen and sulfinpyrazone.
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The deiodinase activities were measured as previously described e.g. Ref. 18 ; . The tissue samples were homogenized individually on ice in 5 6 vol 0.25 m sucrose, 10 mm HEPES pH 7.0 ; containing 10 mm DTT, immediately frozen in a dry ice acetone bath, and stored at 80 C until assay. The measurement of D1, D2, and D3 was based on the release of radioiodide from the 125I labeled substrates. D1 and D2 assay. The activity of D1 was determined by measuring the release of radioiodide from 100, 000 cpm 2.5 kBq ; 5 -125I ; rT3 at 5 nm rT3, 20 mm DTT, in the presence for D2 ; and absence D1 D2 ; of PTU. D2 activity was determined using 5 -125I ; T4 as substrate in the presence of 6 nm T4, 30 mm DTT, 1 mm PTU, and 1 m T3, to inhibit the inner ring deiodination of T4 in the tissues containing significant D3 activity. The measurement was conducted after 4590 min usually 60 min ; incubation at 37 C with 50 100 g of protein from the crude homogenate in 100 l 0.1 m potassium phosphate buffer pH 7.0 ; , 1 mm EDTA. The reaction was started by the addition of the tissue homogenate and stopped by adding 50 l ice-cold 5% BSA and 10 mm PTU, followed by 400 l 10% ice-cold trichloroacetic acid. After centrifugation at 4, 000 g for 30 min, the supernatant containing the 125I was further purified by cation exchange chromatography. The iodide was then eluted with two 1-ml aliquots of 10% acetic acid and the radioactivity was counted in a -counter. D3 assay. For determination of D3 inner-ring deiodinase ; 20 70 g protein were incubated in a final volume of 100 l 0.1 m potassium phosphate buffer pH 7.4 ; , 1 mm EDTA with approximately 1.2 kBq 50, 000 cpm ; inner-ring labeled [5-125I]T3, at 50 nm T3, 20 nm DTT, and 1 mm PTU for 60 min at 37 C. Radioiodide release was measured as described above and sulindac.
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In the past, much population-based field research has been focused on measuring easily quantifiable outcomes, e.g. infection prevalence and intensity, along with liver size, splenomegaly, haematuria, ultrasound abnormalities, etc. For the latter outcomes, there was the implicit assumption that these `objective' abnormalities implied disability. Some measures, such as hepatosplenomegaly and haematuria, were seen to be more common with heavy infection, and infection intensity was then taken as a proxy for morbidity risk in formulating diseasecontrol strategies.21, 22 Yet we, and others, have come to observe that infection proxies do not necessarily map one-to-one with morbidity states see e.g.23 ; , and these do not necessarily map one-to-one with disability outcomes.24 and surmontil.
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Fig 5. Absolute number of cells per microliter in blood with the phenotypes A ; CD4'. B ; CD8'. C ; CD4' HLA + , D ; CD8 + HLA + , E ; CD3- CD16' or CD56' ie, NK cells ; , F ; CD20 + , G ; CDZO'ICD5'. H ; CD20' CD23 + , according to days from start of CdA treatment. Thick solid lines indicate median values, thin solid lines quartiles, and dotted lines extreme values. Normal ranges are indicated by horizontal hatched lines and symlin.
YMPHOBLASTIC lymphoma LBL ; is a high-grade non-Hodgkin's lymphoma first described as a distinctive pathologic entity in 1975.' * Patients are most commonly children or young adults who typically present with an anterior mediastinal mass. The malignant progenitor cells in LBL usually display a T-cell immunophenotype, although B-cell and biphenotypic variants have been r e p Since the original description of LBL, considerable clinical heterogeneity has been reported. Patients with LBL whose malignant cells manifest a T-cell immunophenotype have a variable degree of bone marrow involvement. The distinction between LBL and T-cell acute lymphoblastic leukemia ALL ; is arbitrarily based on the percentage of bone marrow blasts. LBL with a B-cell immunophenotype, in contrast, tends to present without a mediastinal mass, and bone marrow involvement is more common. Eosinophilia has occasionally been described in association with LBL, 6, 7although eosinophilia is more commonly associated with ALL.'"' Finally, acute myelogenous leukemia AML ; has rarely been described in conjunction with LBL.7.".'2 Abruzzo et a17 first reported three cases of a syndrome consisting of LBL associated with eosinophilia and myeloid hyperplasia. Two of these patients subsequently developed AML, while the third developed granulocytic sarcoma and a myeloproliferative disorder. Cytogenetic analysis of the bone marrow from one of these patients showed t 8; 13 ; p23; q14 ; at initial presentation. Three subsequent case reports have described similar clinical presentations in patients with 8; 13 ; trans location .' " We report two additional patients with LBL, eosinophilia, and myeloid hyperplasidmalignancy associated with t 8; 13 ; pll; qll ; chromosome translocation. The present report, together with the previously reported cases, suggest the existence of a distinctive cytogenetic-clinicopathologic syndrome that manifests as a biphenotypic hematologic malignancy and sudafed.
Marco Cipolli, MD Chair Gastroenterologist Cystic Fibrosis Center Verona, Italy Blanche Alter, MD, MPH National Cancer Institute Bethesda, MD F. Jean Perrault, MD Montreal Children's Hospital Montreal, Canada Peter Durie, MD The Hospital for Sick Children Toronto, Canada Van S. Hubbard, MD, Ph.D. Director, NIH Division of Nutrition Research Coordination Bethesda, MD Lynda Ellis, RN GI Nutrition Dept. Hospital for Sick Children, Toronto, Canada Michael Glogauer, DDS, PhD University of Toronto Canada Thierry Leblanc, MD Hospital Saint Louis Paris, France and symmetrel.
Intradialytic hypotension IDH ; remains a significant cause of morbidity in the haemodialysis HD ; population, occurring in 2030% of treatments [1]. It is also recognized that a fall in blood pressure during dialysis predicts mortality [2]. One of the simplest manoeuvres to combat IDH is to reduce the dialysate temperature, first described by Maggiore et al. in the 1980s [3]. This approach takes account of the fact that body temperature rises during standard dialysis [4]. The reasons for this are not entirely clear, but may include heat transfer to the patient from warm dialysate especially as many dialysis patients have low baseline core temperatures ; , reduced heat loss from the skin due to vasoconstriction or increased thermogenesis from an inflammatory response to a blood-membrane reaction. However, cooling the dialysate remains a relatively under-utilized technique. In part, this may be due to the fears of causing unacceptable symptoms of cold and shivering, as empirical reduction of dialysate temperature may in some patients lead to excessive cooling. In addition, there has also been concern that cooling the dialysate will lead to a reduction in dialysis adequacy.
Correspondence and offprint requests to: hideki hirakata md, the second department of internal medicine, faculty of medicine, kyushu university, maidashi 31-1, higashi-ku, fukuoka, 812 8582, japan and synagis.
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