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meta_pmid int64	meta_language string	meta_mesh_ids list	meta_mesh_terms list	meta_pubdate_year string	meta_pubdate_month string	text string
9,633,918	eng	[ "D000255", "Q000378", "D000818", "D002118", "Q000378", "D006332", "Q000378", "D003600", "Q000378", "D003971", "Q000502", "D004195", "D004558", "D004594", "D005456", "D006973", "Q000378", "D066298", "D007211", "D008297", "D008928", "Q000378", "D009206", "Q000378", "D009210", "Q000378", "D009243", "Q000378", "D010085", "D051381", "D017207", "D013599", "Q000502" ]	[ "Adenosine Triphosphate", "Animals", "Calcium", "Cardiomegaly", "Cytosol", "Diastole", "Disease Models, Animal", "Electric Stimulation", "Electrophysiology", "Fluorescent Dyes", "Hypertension", "In Vitro Techniques", "Indoles", "Male", "Mitochondria", "Myocardium", "Myofibrils", "NAD", "Oxidative Phosphorylation", "Rats", "Rats, Sprague-Dawley", "Systole" ]	1998	Jun	Regulation of mitochondrial [NADH] by cytosolic [Ca2+] and work in trabeculae from hypertrophic and normal rat hearts. Pressure overload hypertrophy has previously been shown to reduce contractility but paradoxically to increase O2 consumption rates at a given force. Because O2 consumption rates are related to mitochondrial [NADH] ([NADH]m), we tested the hypothesis that with hypertrophy, control of [NADH]m may be altered. Left ventricular trabeculae were isolated from banded and control rat hearts, and fluorescence spectroscopy was used to monitor [NADH]m and cytosolic [Ca2+] ([Ca2+]c). The hearts from banded rats developed hypertrophy (heart-to-body weight ratio increased from 4.1+/-0.1 to 4.9+/-0.1 mg/g) and hypertension (systolic arterial pressure increased from 117+/-4 to 175+/-5 mm Hg). Muscle workload was increased by stepwise increases in pacing frequency (up to 2 Hz). After increased work, [NADH]m fell and then slowly recovered toward control levels. When work was decreased, [NADH]m overshot control values and then slowly returned. The Ca2+-independent initial fall was larger for trabeculae from rats with hypertrophied hearts than from control rats (eg, 17+/-2% versus 11+/-1% when work was increased by increasing the frequency from 0.25 to 1 Hz). At 1 Hz, average [Ca2+]c was approximately 280 nmol/L, and the Ca2+-dependent [NADH]m recovery was larger for trabeculae from rats with hypertrophied hearts (17+/-4% versus 10+/-2%) despite similar average [Ca2+]c. At steady state after Ca2+-dependent recovery, there was no difference in [NADH]m (fall of 1+/-2% versus 1+/-1%). Furthermore, the Ca2+-dependent overshoot was larger for trabeculae from hypertrophied than from control hearts (increase of 14+/-2% versus 9+/-2% when frequency was decreased from 1 to 0.25 Hz). We conclude that (1) there is initially a larger imbalance in NADH production versus consumption rate in hypertrophy (because NADH fell more) and (2) the Ca2+-dependent recovery mechanism is enhanced in hypertrophy (because NADH recovered and overshot more), thus compensating for the larger imbalance.
9,633,920	eng	[ "D000200", "Q000502", "D001145", "Q000209", "Q000503", "D002118", "Q000378", "D015220", "Q000502", "D002478", "D003198", "D006329", "Q000166", "Q000503", "D006333", "Q000150", "Q000503", "D006352", "Q000737", "Q000166", "Q000378", "D006801", "D008955", "D018485", "Q000737", "Q000378", "D009206", "Q000737", "Q000166", "Q000378", "D018408", "D015221", "Q000502", "D024661", "D019831", "Q000502", "D000254", "Q000502", "D018487", "Q000503" ]	[ "Action Potentials", "Arrhythmias, Cardiac", "Calcium", "Calcium Channels", "Cells, Cultured", "Computer Simulation", "Heart Conduction System", "Heart Failure", "Heart Ventricles", "Humans", "Models, Cardiovascular", "Muscle Fibers, Skeletal", "Myocardium", "Patch-Clamp Techniques", "Potassium Channels", "Potassium Channels, Inwardly Rectifying", "Sodium-Calcium Exchanger", "Sodium-Potassium-Exchanging ATPase", "Ventricular Dysfunction, Left" ]	1998	Jun	Simulation study of cellular electric properties in heart failure. Patients with severe heart failure are at high risk of sudden cardiac death. In the majority of these patients, sudden cardiac death is thought to be due to ventricular tachyarrhythmias. Alterations of the electric properties of single myocytes in heart failure may favor the occurrence of ventricular arrhythmias in these patients by inducing early or delayed afterdepolarizations. Mathematical models of the cellular action potential and its underlying ionic currents could help to elucidate possible arrhythmogenic mechanisms on a cellular level. In the present study, selected ionic currents based on human data are incorporated into a model of the ventricular action potential for the purpose of studying the cellular electrophysiological consequences of heart failure. Ionic currents that are not yet sufficiently characterized in human ventricular myocytes are adopted from the action potential model developed by Luo and Rudy (LR model). The main results obtained from this model are as follows: The action potential in ventricular myocytes from failing hearts is longer than in nonfailing control hearts. The major underlying mechanisms for this prolongation are the enhanced activity of the Na+-Ca2+ exchanger, the slowed diastolic decay of the [Ca2+]i transient, and the reduction of the inwardly rectifying K+ current and the Na+-K+ pump current in myocytes of failing hearts. Furthermore, the fast and slow components of the delayed rectifier K+ current (I(Kr) and I(Ks), respectively) are of utmost importance in determining repolarization of the human ventricular action potential. In contrast, the influence of the transient outward K+ current on APD is only small in both cell groups. Inhibition of I(Kr) promotes the development of early afterdepolarizations in failing, but not nonfailing, myocytes. Furthermore, spontaneous Ca2+ release from the sarcoplasmic reticulum triggers a premature action potential only in failing myocytes. This model of the ventricular action potential and its alterations in heart failure is intended to serve as a tool for investigating the effects of therapeutic interventions on the electric excitability of the human ventricular myocardium.
9,633,919	eng	[ "D000818", "D003243", "D003326", "Q000502", "D003327", "Q000473", "Q000503", "D004699", "Q000473", "D006439", "Q000502", "D009200", "Q000502", "D017682", "Q000473", "Q000503", "D009206", "Q000473", "D009336", "D010496", "Q000473", "D013552" ]	[ "Animals", "Consciousness", "Coronary Circulation", "Coronary Disease", "Endocardium", "Hemodynamics", "Myocardial Contraction", "Myocardial Stunning", "Myocardium", "Necrosis", "Pericardium", "Swine" ]	1998	Jun	Ineffective perfusion-contraction matching in conscious, chronically instrumented pigs with an extended period of coronary stenosis. Several models purported to represent hibernating myocardium involve a coronary stenosis (CS) to reduce blood flow (BF) and function without eliciting necrosis in anesthetized pigs. The goal of the present study was to determine whether sustained moderate reduction in coronary BF in conscious pigs induced hibernating myocardium, ie, perfusion-contraction matching with no necrosis. These experiments were conducted in conscious pigs chronically instrumented with a coronary artery BF probe and hydraulic occluder, left ventricular (LV) pressure gauge, and wall thickening (WT) crystals in the potentially ischemic and nonischemic zones. The hydraulic occluder was inflated to induce a stable 41+/-4% reduction in BF for 24 hours. Ischemic zone systolic WT fell initially with CS and then continued to decline during the period of CS even though blood flow did not change further, suggesting the induction of myocardial stunning. At 2 days after release of CS, WT was still depressed by 48+/-15%. Assessment of necrosis by histology or triphenyltetrazolium chloride showed 40+/-5% multifocal patchy necrosis interspersed with normal tissue involving the inner one third to one half of the ventricular wall. Regional myocardial BF (radioactive microsphere technique) was assessed by dividing the entire LV into an average of 488+/-59 pieces and examining the spatial distribution of BF within the area at risk (AAR). BF in the samples in the area of patchy necrosis was reduced (-66+/-4% from a baseline of 1.55+/-0.27 mL x min(-1) x g(-1)), whereas BF was maintained in samples in the AAR without necrosis (-2+/-7% from a baseline of 1.25+/-0.22 mL x min(-1) x g(-1)). These findings indicate that when hypoperfusion induced by CS in conscious pigs is sustained, the result is necrosis rather than hibernating myocardium. The remainder of the AAR, which lacked necrosis, might have been mistaken for hibernating myocardium had only histology been evaluated and BF not been measured and found to be at normal levels.
9,633,921	eng	[ "D000818", "D001921", "Q000378", "D003176", "Q000235", "D003186", "Q000235", "D017931", "D005786", "D008099", "Q000378", "D008297", "D009203", "Q000378", "D017202", "Q000378", "D015428", "Q000378", "D019696", "Q000235", "D012333", "Q000378", "D011817", "D013154", "Q000378" ]	[ "Animals", "Brain", "Complement C3", "Complement C9", "DNA Primers", "Gene Expression Regulation", "Liver", "Male", "Myocardial Infarction", "Myocardial Ischemia", "Myocardial Reperfusion Injury", "Peptidylprolyl Isomerase", "RNA, Messenger", "Rabbits", "Spleen" ]	1998	Jun	Complement gene expression by rabbit heart: upregulation by ischemia and reperfusion. Activation of the complement system has been implicated in the pathogenesis of myocardial ischemia/reperfusion injury. It has always been assumed that liver is the primary source of complement components. In the present study, we used the reverse-transcriptase polymerase chain reaction technique to establish that the mRNAs for complement proteins C3 and C9 are expressed in rabbit heart. Rabbit liver, brain, spleen, and kidney were also shown to express C3 and C9 mRNAs. We used Western blotting to establish that these mRNAs in heart are translated into the corresponding proteins. We further established that dramatic upregulation of the mRNAs occurred in Langendorff-perfused isolated hearts subjected to ischemia and reperfusion. C3 mRNA was always expressed at higher levels than was C9 mRNA, but C9 mRNA showed greater upregulation under stress. Compared with levels in control hearts subjected to 5 minutes of normoxic perfusion, hearts subjected to 0.5 hours of ischemia followed by 1 hour of reperfusion had a 4.72-fold increase in C3 mRNA and a 19.5-fold increase in C9 mRNA. By contrast, C3 mRNA in hearts subjected to 3.5 hours of normoxic perfusion showed no change, and those subjected to 3.5 hours of ischemia showed only a 1.72-fold increase, whereas C9 mRNA levels increased by 5.17-fold after 3.5 hours of normoxic perfusion and 12.5-fold after 3.5 hours of ischemia. The results of this study demonstrate for the first time that heart tissue is capable of expressing genes and proteins of the complement system, although it is not yet known which cell types are responsible. They further demonstrate that ischemia and reperfusion of the heart promotes a rapid upregulation of the mRNAs encoding the complement proteins C3 and C9 and that these abnormal levels considerably exceed those of normal liver. These observations are consistent with the hypothesis that local production of complement proteins may contribute significantly to the degree of ischemic injury to the myocardium and that complement expression is augmented by reperfusion.
9,633,923	eng	[ "D000818", "D006801", "D007554", "D050356", "D008432", "D008954" ]	[ "Animals", "Humans", "Isotopes", "Lipid Metabolism", "Mathematical Computing", "Models, Biological" ]	1998	Jun	Development of compartmental models in stable-isotope experiments: application to lipid metabolism. Kinetic experiments are of great importance in lipid research because they further the understanding of lipid metabolism in vivo and help to explain the physiopathology of lipid disorders in humans. At present, due to species specificity, no valid animal model can efficiently replace a study in humans to explore lipid metabolism, and the use of radioactive tracers is restricted in humans. Thus, stable-isotope tracer kinetic studies have become an important component of research programs to achieve in humans a quantitative understanding of the dynamics of metabolic processes in vivo. The aim of this review is to describe the practical aspects of compartmental model development in stable-isotope experiments. The recent development of computer hardware and modeling software has dramatically facilitated the task of the modeler in his or her calculations. In the current review, we show that the model may be considered an integral component of the experimental design and that model development must obey strict rules to provide a rigorous solution. The main difficulties of model development in tracer experiments, such as experiment design, model identifiability, data expression, comparison of models, or tracer recycling, are presented with extensive references. We have paid particular attention to kinetic modeling in stable-isotope experiments because they have shown the greatest development in recent years.
9,633,924	eng	[ "D000328", "D015703", "Q000096", "D001792", "Q000187", "Q000378", "D002118", "Q000378", "D002462", "Q000378", "D003029", "Q000494", "D000242", "Q000378", "D017868", "Q000378", "D004075", "Q000378", "D005340", "Q000378", "D006801", "D015544", "Q000378", "D007424", "D008075", "Q000378", "D008875", "D010712", "Q000378", "D019269", "Q000378", "D010766", "D015539", "D010974", "D011493", "Q000378", "D015290", "D013379", "D013917", "Q000494", "D013997" ]	[ "Adult", "Antigens, CD", "Blood Platelets", "Calcium", "Cell Membrane", "Coagulants", "Cyclic AMP", "Cyclic AMP-Dependent Protein Kinases", "Diglycerides", "Fibrinogen", "Humans", "Inositol 1,4,5-Trisphosphate", "Intracellular Fluid", "Lipoproteins, HDL", "Middle Aged", "Phosphatidic Acids", "Phosphatidylinositol 4,5-Diphosphate", "Phosphorylation", "Platelet Activation", "Platelet Aggregation", "Protein Kinase C", "Second Messenger Systems", "Substrate Specificity", "Thrombin", "Time Factors" ]	1998	Jun	HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. We demonstrate that physiological concentrations of HDL3 inhibit the thrombin-induced platelet fibrinogen binding and aggregation in a time- and concentration-dependent fashion. The underlying mechanism includes HDL3-mediated inhibition of phosphatidylinositol 4,5-bis-phosphate turnover, 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate formation, and intracellular calcium mobilization. The inhibitory effects of HDL3 on inositol 1,4,5-tris-phosphate formation and intracellular calcium mobilization were abolished after covalent modification of HDL3 with dimethylsuberimidate. Furthermore, they could be blocked by calphostin C and bis-indolylmaleimide, 2 highly selective and structurally unrelated protein kinase C inhibitors. However, the inhibitory effects of HDL3 were not blocked by H89, a protein kinase A inhibitor. In addition, HDL3 failed to induce cAMP formation but stimulated the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. We observed a close temporal relationship between the HDL3-mediated inhibition of thrombin-induced inositol 1,4,5-tris-phosphate formation, intracellular calcium mobilization, and fibrinogen binding and the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. Taken together, these findings indicate that the HDL3-mediated inhibition of thrombin-induced fibrinogen binding and aggregation occurs via inhibition of phosphatidylinositol 4,5-bis-phosphate turnover and formation of 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Protein kinase C may be involved in this process.
9,633,926	eng	[ "D000208", "D000328", "D000368", "D000369", "D001161", "Q000378", "D003327", "Q000378", "D005260", "D006801", "D015227", "D008077", "Q000378", "D008297", "D008875", "D009203", "Q000378", "D019158", "Q000378" ]	[ "Acute Disease", "Adult", "Aged", "Aged, 80 and over", "Arteriosclerosis", "Coronary Disease", "Female", "Humans", "Lipid Peroxidation", "Lipoproteins, LDL", "Male", "Middle Aged", "Myocardial Infarction", "N-Acetylneuraminic Acid" ]	1998	Jun	Sialic acid content of LDL in coronary artery disease: no evidence of desialylation in subjects with coronary stenosis and increased levels in subjects with extensive atherosclerosis and acute myocardial infarction: relation between desialylation and in vitro peroxidation. We recently showed that sialic acid content of LDL was not a marker of early cardiovascular disease (Arterioscler Thromb Vasc Biol. 1995;15:334-339). Here, we investigated this parameter in patients with advanced coronary artery disease (CAD). We first examined 100 patients having undergone coronary angiography. The distribution of LDL sialic acid values was very similar in subjects with no coronary stenosis (31.3+/-3.7 nmol/mg LDL protein, mean+/-SD) and those with > or = 75% stenosis in at least one main coronary artery or > or = 50% stenosis in at least two main coronary arteries (32.1+/-5.5 nmol/mg LDL protein). In contrast, LDL sialic acid content was significantly increased in patients with both coronary stenosis and peripheral arterial atherosclerotic lesions compared with those with either no lesion or only one or the other type of lesion. We then examined LDL sialic acid content in 20 patients with acute myocardial infarction. LDL sialic acid content was significantly higher (35.9+/-3.2 nmol/mg LDL protein) than that in the CAD(-) control group. These data suggest that LDL sialic acid content increases with the extension of atherosclerosis and its progression to acute complications. To explain the discordance with Orekhov and coworkers (Atherosclerosis. 1991;86:153-161), who showed that LDL sialic acid content in patients with advanced CAD was lower than that in healthy subjects, we studied the time courses of sialic acid, TBARS, and vitamin E levels in LDL dialyzed in different experimental conditions. A continuous decrease in both sialic acid and vitamin E levels and an increase in TBARS levels were observed in LDL samples containing less than 1 mmol/L EDTA, the intensity and rapidity of which varied with the EDTA concentration in the buffer. Our data support the idea that desialylation may result from in vitro peroxidation of LDL.
9,633,925	eng	[ "D001809", "D003327", "Q000097", "Q000503", "D006801", "D016015", "D008297", "D008875", "D009203", "Q000097" ]	[ "Blood Viscosity", "Coronary Disease", "Humans", "Logistic Models", "Male", "Middle Aged", "Myocardial Infarction" ]	1998	Jun	Relationship between plasma viscosity and the severity of coronary heart disease. Several studies have indicated that plasma viscosity contributes to cardiovascular risk in men. So far, a significant relationship between plasma viscosity and the severity of coronary heart disease has not been found. Thus, the present study is the first to report on the relationship of plasma viscosity and the severity of coronary heart disease. In a collective of 1142 male myocardial infarction patients, plasma viscosity and additional laboratory parameters were determined. Atherosclerotic changes were quantified by coronary angiography. Patients were divided into groups without any, and with one to three stenosed vessels. We found a positive relationship between plasma viscosity and the severity of coronary heart disease, even after adjusting groups for age, fibrinogen, and use of diuretics. Mean plasma viscosity ranged from 1.141+/-0.035 mPa s in patients without stenosed vessels to 1.162+/-0.044 mPa s in patients who had three coronary vessels with stenoses >50%. Differences between the groups were significant (P<0.001 to 0.05), with two exceptions: differences between patients without any and with one stenosed vessel, as well as between patients with one and two stenosed vessels, did not reach the significance level. On the whole, we can give further support to the hypothesis that cardiovascular risk factors and coronary heart disease may be linked by plasma viscosity.
9,633,927	eng	[ "D000328", "D000818", "D001158", "Q000378", "Q000473", "Q000648", "D002448", "D004195", "D004730", "Q000378", "Q000648", "D006801", "D018799", "Q000096", "Q000235", "D008077", "Q000378", "D008297", "D009000", "Q000378", "D016328", "Q000378", "D010084", "D051381", "D017207" ]	[ "Adult", "Animals", "Arteries", "Cell Adhesion", "Disease Models, Animal", "Endothelium, Vascular", "Humans", "Intercellular Adhesion Molecule-1", "Lipoproteins, LDL", "Male", "Monocytes", "NF-kappa B", "Oxidation-Reduction", "Rats", "Rats, Sprague-Dawley" ]	1998	Jun	An animal model to study local oxidation of LDL and its biological effects in the arterial wall. Oxidized LDL (oxLDL) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis. Mainly on the basis of cell culture studies, oxLDL has been shown to produce many biological effects that influence the atherosclerotic process. To study LDL oxidation in vivo, we have established a model in which Sprague-Dawley rats are given a single injection of unmodified human LDL (> or = 4 mg/kg body weight). Within 6 hours, an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media. The presence of oxLDL is associated with activation of the transcription factor nuclear factor-kappaB in the endothelium as well as endothelial expression of intercellular adhesion molecule-1. Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B, but the expression of oxLDL-specific epitopes was reduced at 24 hours. Thus, this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo.
9,633,929	eng	[ "D000818", "D001011", "D001161", "Q000097", "Q000139", "Q000517", "D002784", "Q000097", "D002791", "Q000008", "D004357", "D004958", "Q000494", "D005260", "D008074", "Q000097", "D009640", "Q000031", "Q000494", "D000077563", "D010052", "D011817" ]	[ "Animals", "Aorta", "Arteriosclerosis", "Cholesterol", "Cholesterol, Dietary", "Drug Synergism", "Estradiol", "Female", "Lipoproteins", "Norethindrone", "Norethindrone Acetate", "Ovariectomy", "Rabbits" ]	1998	Jun	Norethindrone acetate enhances the antiatherogenic effect of 17beta-estradiol: a secondary prevention study of aortic atherosclerosis in ovariectomized cholesterol-fed rabbits. The influence of progestogens in combination with 17beta-estradiol (E2) on cardiovascular disease remains controversial. This study investigated the effect of norethindrone acetate (NETA) combined with E2 on aortic atherosclerosis. Eighty mature female rabbits were ovariectomized, then fed a cholesterol-rich diet (240 mg/d) for 14 weeks to induce aortic atherosclerosis. They were randomized to four equally large groups for the following 38-week intervention period. One group received placebo, another group oral E2 4 mg daily (E2), and the last two groups oral E2 4 mg daily combined with either NETA 1 mg (E2NETA1) or NETA 3 mg (E2NETA3). The cholesterol intake was reduced to a "maintenance" level of 80 mg/d during the intervention period. Total serum cholesterol and ultracentrifuged lipoproteins were analyzed enzymatically throughout the study. The cholesterol content in the aortic wall was 2.76+/-0.44 micromol/cm2 (mean+/-SEM) in the E2NETA1 group, 1.77+/-0.37 micromol/cm2 in the E2NETA3 group, 5.46+/-0.77 micromol/cm2 in the E2 group, and 7.20+/-0.94 micromol/cm2 in the placebo group (ANOVA P<0.0001). The difference (in the aortic cholesterol accumulation) between the E2 and each of the combined E2/NETA groups was statistically significant (P<0.01) but could only partly be explained by the differences in serum lipids and lipoproteins. In conclusion, NETA enhances the antiatherogenic effect of E2 in cholesterol-fed rabbits. This effect is only partially mediated through changes in serum lipids and lipoproteins.
9,633,930	eng	[ "D000818", "D000925", "Q000627", "D003328", "Q000097", "Q000503", "Q000517", "D003331", "D004195", "D004285", "D004305", "D017984", "Q000627", "D015951", "Q000378", "D005260", "D006439", "D006493", "Q000627", "D008297", "D010314", "D011516", "Q000378", "D011517", "D012008" ]	[ "Animals", "Anticoagulants", "Coronary Thrombosis", "Coronary Vessels", "Disease Models, Animal", "Dogs", "Dose-Response Relationship, Drug", "Enoxaparin", "Factor Xa", "Female", "Hemodynamics", "Heparin", "Male", "Partial Thromboplastin Time", "Prothrombin", "Prothrombin Time", "Recurrence" ]	1998	Jun	Inhibition of repetitive thrombus formation in the stenosed canine coronary artery by enoxaparin, but not by unfractionated heparin. Experiments were designed to compare the antithrombotic efficacy of enoxaparin and unfractionated heparin (UH) in a model of platelet-dependent cyclic flow reductions (CFRs) in the stenosed canine circumflex coronary artery. Low-molecular-weight heparins (LMWHs) are safe and effective in the prevention and treatment of venous thromboembolism. The present experiments were designed to evaluate the potential use of LMWHs in arterial thrombotic indications by comparing the antithrombotic effect of an LMWH with that of UH in an animal model of unstable angina. After establishment of consistent CFRs by experimentally induced vascular stenosis and damage, vehicle (saline), enoxaparin, or UH was administered intravenously as a loading dose plus a continuous infusion for 1 hour. The inhibition of CFRs was taken as an indicator of antithrombotic efficacy. Enoxaparin inhibited repetitive platelet thrombus formation in a dose-dependent manner, with significant inhibition of CFRs achieved at 0.5 mg/kg + 5 microg/kg per minute. This dose of enoxaparin resulted in anti-Xa levels of 0.9 to 1.0 IU/mL, anti-IIa levels of 0.2 to 0.3 IU/mL, activated partial thromboplastin time (APTT) of 1.3-fold over baseline, and a 1.4-fold increase (NS) in template bleeding time. Near-complete abolishment of CFRs was achieved with enoxaparin at 1.0 mg/kg + 10 microg/kg per minute. This dose of enoxaparin produced anti-Xa levels of 2 to 2.2 IU/mL, anti-IIa levels of 0.5 to 0.6 IU/mL, an increase in APTT of 1.4- to 1.5-fold over baseline, and a 1.9-fold increase (P<0.05) in template bleeding time. In contrast, UH had no significant effect on CFRs at a dose (100 U/kg + 10 U/kg per minute) that resulted in anti-Xa levels of 1.2 to 1.6 IU/mL, anti-IIa levels of 1.8 to 2.4 IU/mL, an increase in APTT greater than 10-fold over baseline, and a 2.5-fold increase (P<0.05) in template bleeding time. Compared with the vehicle group, circulating platelet count and hematocrit were not changed significantly by any dose of enoxaparin or UH tested. Enoxaparin, unlike UH, prevented repetitive platelet-dependent thrombus formation in the dog, thereby supporting the potential use of enoxaparin as a replacement for heparin in the treatment of arterial thrombotic disorders such as unstable angina.
9,633,931	eng	[ "D000818", "D018821", "Q000378", "D002339", "Q000473", "D016893", "Q000209", "Q000473", "D004487", "Q000209", "D005434", "D016179", "Q000008", "D007958", "D008297", "D009504", "Q000502", "D011817", "D012867", "Q000503" ]	[ "Animals", "CD18 Antigens", "Carotid Arteries", "Carotid Stenosis", "Edema", "Flow Cytometry", "Granulocyte Colony-Stimulating Factor", "Leukocyte Count", "Male", "Neutrophils", "Rabbits", "Skin" ]	1998	Jun	Role of polymorphonuclear leukocytes in collar-induced intimal thickening in the rabbit carotid artery. In this study, the involvement of polymorphonuclear leukocytes (PMNs) in the development of intimal thickening was investigated. A fibromuscular intima was induced by placing a silicone collar around the rabbit carotid artery for 3 days or 2 weeks; the contralateral artery was sham operated. Rabbits received placebo treatments (groups 1 and 3), granulocyte-colony stimulating factor (group 2; G-CSF, 20 microg x kg(-1) x d(-1), delivered by subcutaneous osmotic pumps), or an anti-CD18 monoclonal antibody (group 4; 1.5 mg/kg i.v.). The G-CSF treatment raised the peripheral PMN count 5- to 12-fold but had no effect on intimal thickening on day 3, 12, or 14. A single injection of anti-CD18 prevented PMN extravasation 6 hours after collar implantation without influencing intimal hyperplasia on day 14. Repeated daily administration of anti-CD18 strongly bound to CD18 on peripheral PMNs and inhibited both PMN-dependent plasma extravasation in the skin and accumulation of CD14-immunoreactive leukocytes in the intima and media. However, anti-CD18 did not suppress early intimal thickening or accumulation of alpha-smooth muscle actin-immunoreactive cells by day 3. It thus appears that the PMN influx in the intima and media evoked by the perivascular collar is of little functional relevance to the subsequent smooth muscle cell migration and intimal thickening in this model.
9,633,928	eng	[ "D002478", "D018932", "Q000235", "D016207", "Q000378", "D004730", "Q000378", "D006801", "D016209", "Q000235", "D007473", "Q000378", "D010812", "D011493", "Q000502", "D011505", "Q000502", "D012333", "Q000378", "D010738", "Q000502", "D015854" ]	[ "Cells, Cultured", "Chemokine CCL2", "Cytokines", "Endothelium, Vascular", "Humans", "Interleukin-8", "Ion Channels", "Physical Stimulation", "Protein Kinase C", "Protein-Tyrosine Kinases", "RNA, Messenger", "Type C Phospholipases", "Up-Regulation" ]	1998	Jun	Cyclic stretch upregulates production of interleukin-8 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in human endothelial cells. In vivo, vascular walls are exposed to mechanical stretch, which may promote atherogenesis. This study was designed to investigate the effect of mechanical stretch on the production and gene expression of cytokines in endothelial cells (ECs) of human umbilical veins. ECs were cultured on flexible silicone membranes and exposed to cyclic mechanical stretch. Although the secretion levels of interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, granulocyte (G) -colony stimulating factor (CSF), G and macrophage (M) -CSF, and M-CSF were not affected by cyclic stretch over 24 hours, the levels of IL-8 and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein-1 (MCP-1) were significantly increased by cyclic stretch. Northern blot analysis indicated that the mRNA levels of IL-8 and MCAF/MCP-1 were upregulated by cyclic stretch as a function of its intensity. Cytochalasin D, which disrupts the actin cytoskeleton, abolished the stretch-induced gene expression of IL-8 and MCAF/MCP-1. In contrast, neither inhibition of stretch-activated ion channels nor disruption of microtubules affected the induction of these chemokines by cyclic stretch. Northern blot analysis using enzyme inhibitors showed that phospholipase C, protein kinase C, and tyrosine kinase were involved in the stretch-induced gene expression of IL-8 and MCAF/MCP-1, whereas cAMP- or cGMP-dependent protein kinase was not. In conclusion, cyclic stretch enhanced the secretion and gene expression of IL-8 and MCAF/MCP-1 in a stretch-dependent fashion, and the integrity of the actin cytoskeleton and activities of phospholipase C, protein kinase C, and tyrosine kinase may be essential in the process of stretch-induced gene induction of IL-8 and MCAF/MCP-1.
9,633,932	eng	[ "D000818", "D001011", "Q000378", "D001696", "D002135", "Q000096", "D002148", "Q000096", "D003285", "Q000096", "D004730", "Q000378", "D064448", "D008297", "D008840", "Q000096", "D009131", "Q000378", "D009218", "Q000096", "D009924", "D011312", "D011817", "D000096985" ]	[ "Animals", "Aorta", "Biomechanical Phenomena", "Calcium-Binding Proteins", "Calmodulin-Binding Proteins", "Contractile Proteins", "Endothelium, Vascular", "Filamins", "Male", "Microfilament Proteins", "Muscle, Smooth, Vascular", "Myosins", "Organ Culture Techniques", "Pressure", "Rabbits", "Calponins" ]	1998	Jun	Intraluminal pressure is essential for the maintenance of smooth muscle caldesmon and filamin content in aortic organ culture. Different forms of mechanical stimulation are among the physiological factors constantly acting on the vessel wall. We previously demonstrated that subjecting vascular smooth muscle cells (VSMCs) in culture to cyclic stretch increased the expression of high-molecular-weight caldesmon, a marker protein of a differentiated, contractile, VSMC phenotype. In the present work the effects of mechanical factors, in the form of circumferential stress and shear stress, on the characteristics of SM contractile phenotype were studied in an organ culture of rabbit aorta. Application of an intralumininal pressure of 80 mm Hg to aortic segments cultured in Dulbecco's modified Eagle's medium containing 20% fetal calf serum for 3 days prevented the decrease in high-molecular-weight caldesmon content (70+/-4% of initial level in nonpressurized vessel, 116+/-17% at 80 mm Hg) and filamin content (80+/-5% in nonpressurized vessel, 100+/-2% at 80 mm Hg). SM myosin and low-molecular-weight caldesmon contents showed no dependence on vessel pressurization. Neither endothelial denudation nor alteration of intraluminal flow rates affected marker protein content in 3-day vessel culture, thus excluding the possibility of any shear or endothelial effects. Maintenance of high high-molecular-weight caldesmon and filamin levels in the organ cultures of pressurized and stretched vessels demonstrates the positive role of mechanical factors in the control of the VSMC differentiated phenotype.
9,633,933	eng	[ "D001794", "D015992", "D002318", "Q000453", "Q000209", "Q000378", "D005951", "D006801", "D007328", "Q000097", "D020738", "D008297", "D008875", "D015999", "D011506", "Q000378", "D012307", "D013577" ]	[ "Blood Pressure", "Body Mass Index", "Cardiovascular Diseases", "Glucose Tolerance Test", "Humans", "Insulin", "Leptin", "Male", "Middle Aged", "Multivariate Analysis", "Proteins", "Risk Factors", "Syndrome" ]	1998	Jun	Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. In humans, production of the adipocyte-derived peptide leptin has been linked to adiposity, insulin, and insulin sensitivity. We therefore considered that alterations in plasma leptin concentrations could constitute an additional component of a metabolic syndrome of cardiovascular risk. To explore this hypothesis, we employed factor analysis, a multivariate statistical technique that allows reduction of large numbers of highly intercorrelated variables to composite, biologically meaningful factors. Seventy-four men [age, 48.4+/-1.3 years (mean+/-SEM); body mass index (BMI), 25.6+/-0.3 kg/m2] who were free of coronary heart disease and diabetes underwent anthropometric measurements (subscapular-to-triceps [S:T] and subscapular-to-biceps [S:B] skinfold thickness ratios, measurement of fasting plasma leptin, and an intravenous glucose tolerance test (IVGTT) for assessment of insulin sensitivity. Plasma leptin concentrations were correlated with BMI (r=0.57, P<0.001), S:T (r=0.34, P=0.003), S:B (r=0.37, P<0.001), systolic and diastolic blood pressures (both r=0.24, P=0.044), fasting triglycerides (r=0.31, P=0.007), serum uric acid (r=0.35, P=0.003), fasting glucose (r=0.32, P=0.003) and insulin (r=0.33, P=0.004), and IVGTT insulin (r=0.63, P<0.001). A negative correlation was observed between leptin and insulin sensitivity (r=-0.32, P=0.006). No significant correlations emerged between plasma leptin concentrations and age, high density lipoprotein cholesterol, or IVGTT glucose. In multivariate regression analyses, BMI (standardized coefficient [SC]=0.40, P=0.001), fasting insulin (SC=0.23, P=0.036), and IVGTT insulin (SC=0.51, P<0.001) emerged as independent predictors of plasma leptin concentrations (R2=0.56, P<0.001). After adjustment for BMI, only IVGTT insulin emerged as a significant predictor of plasma leptin concentrations (SC=0.56, P<0.001, R2=0.45, P<0.001). Factor analysis of plasma leptin concentrations and the variables that are considered relevant to the insulin resistance syndrome revealed a clustering of plasma leptin concentrations with a factor dominated by insulin resistance and high IVGTT insulin, separate from a high IVGTT glucose/central obesity factor and a high triglyceride/low high density lipoprotein cholesterol factor. Together, these factors accounted for 55.9% of the total variance in the dataset. In conclusion, interindividual variations in plasma leptin concentrations are strongly related to the principal components of the insulin resistance syndrome. Further studies are needed to determine whether the insulin-leptin axis plays a coordinating role in this syndrome and whether plasma leptin concentrations could provide an additional measure of cardiovascular risk.
9,633,934	eng	[ "D002478", "D018932", "Q000235", "D003546", "Q000378", "D015853", "Q000494", "D004730", "Q000378", "D005786", "D006801", "D007375", "Q000502", "D007976", "Q000494", "D009097", "Q000378", "D016328", "Q000378", "D046988", "D015842", "Q000494", "D014108", "Q000494" ]	[ "Cells, Cultured", "Chemokine CCL2", "Cysteine Endopeptidases", "Cysteine Proteinase Inhibitors", "Endothelium, Vascular", "Gene Expression Regulation", "Humans", "Interleukin-1", "Leupeptins", "Multienzyme Complexes", "NF-kappa B", "Proteasome Endopeptidase Complex", "Serine Proteinase Inhibitors", "Tosylphenylalanyl Chloromethyl Ketone" ]	1998	Jun	IL-1beta-induced monocyte chemoattractant protein-1 gene expression in endothelial cells is blocked by proteasome inhibitors. Human monocyte chemoattractant protein-1 (MCP-1) is expressed by a variety of cell types in response to various stimuli. MCP-1 expressed by the endothelium plays an important role in cell migration and activation. MCP-1 is a major chemoattractant for monocytes, T lymphocytes, and basophils. In the present study, we present evidence that the proteasome complex is involved in mediating the interleukin (IL)-1beta induction of MCP-1 in endothelial cells. We present evidence that a proteasome inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal (norLeu), and the protease inhibitor tosyl-Phe-chloromethylketone (TPCK) block IL-1beta induction of MCP-1 protein expression. norLeu and TPCK also blocked IL-1beta-induced MCP-1 promoter-driven reporter gene expression as well as nuclear factor (NF)-kappaB-mediated reporter gene expression. The effects of norLeu were due to its inhibition of the proteasome rather than calpain, because other calpain inhibitors had no effect on MCP-1 expression. In contrast to TPCK, which blocked NF-kappaB translocation to the nucleus, norLeu had no effect on NF-kappaB nuclear translocation or IL-1beta-induced phosphorylation of p65. This study demonstrates that the proteasome pathway is involved in IL-1beta-induced MCP-1 gene expression in human endothelial cells.
9,633,935	eng	[ "D001120", "D001794", "D015992", "D008078", "Q000097", "D015331", "D003924", "D004562", "D005260", "D005787", "D005838", "D006801", "D007564", "D008297", "D008875", "D009765", "Q000097", "Q000235", "D017354", "D011943", "Q000235", "D022702", "D014280", "Q000097", "D014364" ]	[ "Arginine", "Blood Pressure", "Body Mass Index", "Cholesterol, LDL", "Cohort Studies", "Diabetes Mellitus, Type 2", "Electrocardiography", "Female", "Gene Frequency", "Genotype", "Humans", "Japan", "Male", "Middle Aged", "Obesity", "Point Mutation", "Receptors, Adrenergic, beta", "Receptors, Adrenergic, beta-3", "Triglycerides", "Tryptophan" ]	1998	Jun	Clinical features associated with the homozygous Trp64Arg mutation of the beta3-adrenergic receptor: no evidence for its association with obesity in Japanese. To characterize the clinical features associated with the Trp64Arg mutation of the beta3-adrenergic receptor (beta3-AR), the effects of this mutation, in particular the homozygous state (Arg/Arg), on obesity, blood pressure, and plasma lipoproteins were investigated in 2 populations: subjects residing on a small isolated island (group 1; n=746) and patients residing in Tokyo who attend a clinic for metabolic diseases (group 2; n=371). The allelic frequency of the Trp64Arg mutation was 23.4% in group 1 and 18.3% in group 2. No significant difference in the body mass index was observed between subjects with 3 different genotypes in each group. There was a trend that the Arg/Arg had higher systolic blood pressure than the Trp/Trp in both groups, but the differences were not statistically significant. The plasma LDL cholesterol levels were significantly lower in Arg/Arg than in Trp/Trp in men from the group 1 cohort (2.82+/-0.84 versus 3.19+/-0.7 mmol/L, P<0.05). These results suggest that the homozygous Trp64Arg mutation is not a major contributing factor for obesity, but potentially contributed to higher systolic blood pressure and low plasma levels of LDL cholesterol in Japanese men.
9,633,936	eng	[ "D000818", "D001013", "Q000378", "D001786", "Q000032", "D001794", "D002448", "D003921", "Q000378", "Q000503", "D004730", "Q000503", "D006973", "Q000378", "Q000503", "D007328", "Q000097", "D008297", "D051379", "D009000", "Q000378", "D051381", "D011918", "D011921", "D014280", "Q000097" ]	[ "Animals", "Aorta, Thoracic", "Blood Glucose", "Blood Pressure", "Cell Adhesion", "Diabetes Mellitus, Experimental", "Endothelium, Vascular", "Hypertension", "Insulin", "Male", "Mice", "Monocytes", "Rats", "Rats, Inbred SHR", "Rats, Inbred WKY", "Triglycerides" ]	1998	Jun	Interaction of diabetes and hypertension on determinants of endothelial adhesiveness. Epidemiological studies have established that diabetes mellitus and hypertension are independent risk factors for atherosclerosis. One of the earliest abnormalities seen in atherogenesis is enhanced monocyte adherence to the endothelium. The mechanisms by which diabetes mellitus or hypertension enhances monocyte-endothelial cell interactions are incompletely characterized. It is not known whether there are additive interactions between these risk factors on endothelial adhesiveness for monocytes. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were fed a normal or fructose-enriched diet. In some cases, animals were injected with streptozotocin (35 mg/kg body weight) to induce diabetes. After 2 weeks, plasma was drawn for biochemical measurements, and thoracic aortas were harvested, opened longitudinally, and exposed to fluorescently labeled mouse monocytoid cells (WEHI 78/24, 2 x 10(6)/mL) for 30 minutes on a rocking platform. Adherent cells were counted by epifluorescence microscopy. WEHI 78/24 binding to aortic segments from SHR animals was elevated compared with segments from WKYs. Fructose feeding alone had no effect on endothelial adhesiveness. When WKYs were made hyperglycemic by STZ injection, monocyte binding was 160% of the control value. Elevated monocyte binding was also observed in aortas derived from SHR animals injected with STZ, indicating an additive effect of hypertension and hyperglycemia. To determine whether alterations in oxidative state played a role in the endothelial adhesiveness, aortic segments were exposed to lucigenin (250 micromol/L) for measurement of superoxide anion. Aortic segments from SHR elaborated 120% more superoxide anion than did controls. Elevated free-radical production was also observed in aortas from diabetic WKYs. Furthermore, thoracic aortas derived from diabetic SHR animals elaborated more superoxide anion than did any of the other groups (374%, P<0.05). Immunohistochemical staining for monocyte chemotactic protein-1 demonstrated increased expression in aortas isolated from diabetic WKY and SHR compared with control vessels. These studies demonstrate that both diabetes and hypertension lead to increased monocyte adherence to the endothelium. This abnormality is associated with increased vascular superoxide production and monocyte chemotactic protein-1 expression. Furthermore, there appears to be an additive interaction between hyperglycemia and hypertension in their effects on endothelial adhesiveness and its determinants.
9,633,937	eng	[ "D000818", "D001555", "Q000737", "Q000494", "D002118", "Q000097", "D002341", "Q000097", "Q000473", "Q000517", "D002951", "D004195", "D004285", "D005260", "D006493", "D008297", "D015394", "D010975", "Q000494", "D019038", "D010980", "D011956", "Q000037" ]	[ "Animals", "Benzene Derivatives", "Calcium", "Carotid Artery Thrombosis", "Citrates", "Disease Models, Animal", "Dogs", "Female", "Heparin", "Male", "Molecular Structure", "Platelet Aggregation Inhibitors", "Platelet Glycoprotein GPIb-IX Complex", "Platelet Membrane Glycoproteins", "Receptors, Cell Surface" ]	1998	Jun	In vivo efficacy of SM-20302, a GP IIb/IIIa receptor antagonist, correlates with ex vivo platelet inhibition in heparinized blood but not in citrated blood. We tested the hypothesis that the in vivo antithrombotic efficacy of SM-20302, a GP IIb/IIIa receptor antagonist, correlates with the ex vivo platelet inhibition in heparinized platelet rich plasma (hPRP) but not in citrated PRP (cPRP). The studies were performed in a canine model of carotid artery thrombosis in which thrombus formation was induced by electrolytic injury. Thrombosis of the right carotid artery was induced immediately after the administration of saline (n=12). Thirty minutes after persistent occlusive thrombosis was obtained, the vessel segment was ligated, and the time to occlusion and thrombus weight were noted. Subsequently, thrombosis of the left carotid artery was initiated in the presence of SM-20302 (100, 300, 600, or 1000 microg/kg i.v.; n=4 to 6). All the doses of SM-20302 inhibited (by > or = 90%) the ex vivo platelet aggregation induced by ADP and arachidonic acid (AA) in cPRP. In hPRP, a dose-dependent inhibition of ex vivo platelet aggregation was observed. The maximal inhibition produced by 100 to 1000 microg/kg SM-20302 ranged from 18% to 80% for ADP and 44% to 88% for AA. Maximal prolongation of the template bleeding time induced by the 100-, 300-, 600-, and 1000-microg/kg doses were 2.5-, 9.5-, 10-, and > 10-fold, respectively. All the injured carotid arteries (n=12) in the saline-treated group occluded. SM-20302 pretreatment produced a dose-dependent maintenance of the carotid artery patency, and the incidence of occlusion at 4 hours was 5/6, 3/6, 0/6, and 0/6 for the 100-, 300-, 600-, and 1000-microg/kg doses, respectively. The results indicate that SM-20302 prevents carotid artery thrombosis in response to electrolytic arterial wall injury and that its in vivo antithrombotic efficacy can be correlated accurately with the ex vivo platelet inhibition in PRP prepared from heparinized blood but not from citrated blood.
9,633,938	eng	[ "D000328", "D001792", "Q000187", "Q000378", "D002118", "Q000378", "D000242", "Q000378", "D006152", "Q000378", "D004958", "Q000378", "Q000494", "D005260", "D006801", "D008297", "D009569", "Q000096", "D010974", "Q000187", "D010975", "Q000378", "Q000494" ]	[ "Adult", "Blood Platelets", "Calcium", "Cyclic AMP", "Cyclic GMP", "Estradiol", "Female", "Humans", "Male", "Nitric Oxide", "Platelet Aggregation", "Platelet Aggregation Inhibitors" ]	1998	Jun	Effect of 17beta-estradiol on inhibition of platelet aggregation in vitro is mediated by an increase in NO synthesis. The low prevalence of coronary heart disease in premenopausal women and its increase after menopause are well established. Although estrogen is thought to play a role in protecting the vasculature, the mechanism has not been fully clarified. The contribution of platelets to atherosclerotic cardiovascular diseases is well recognized. The present study focused on the still-controversial effect of estrogen on platelet function. We investigated the in vitro effects of estrogen on human platelets, including their aggregation, Ca2+ metabolism, the synthesis of cyclic nucleotides, and NO (nitrite/nitrate) synthesis after stimulation with thrombin or ADP. Pretreatment of platelets with 17beta-estradiol reduced the platelet aggregation induced by thrombin or ADP, whereas 17alpha-estradiol had no effect. 17Beta-estradiol accelerated the recovery of [Ca2+]i after the agonist-induced peak and reduced the area under the curve of accumulated platelet [Ca2+]i but did not alter the baseline [Ca2+]i, Ca2+ influx induced by thrombin or ADP, the release of Ca2+ from internal stores, or the size of internal Ca2+ stores. Pretreatment of platelets with 17beta-estradiol had no effect on the intracellular concentration of cAMP but increased that of cGMP in agonist-stimulated platelets. Additionally, 17beta-estradiol increased the platelet concentration of nitrite/nitrate in a dose-dependent manner. These effects of 17beta-estradiol on platelet aggregation, Ca2+ metabolism, and NO synthesis were abolished by exposure to N(G)-monomethyl-L-arginine, an NO synthesis inhibitor. These results suggest that 17beta-estradiol plays an important role in inhibiting platelet aggregation by promoting Ca2+ extrusion or reuptake activity that is dependent on the production of cGMP by increasing NO synthesis.
9,633,939	eng	[ "D000906", "Q000378", "D053299", "D053283", "D001055", "Q000378", "D002914", "Q000378", "D005347", "Q000378", "D006493", "Q000378", "Q000494", "D006801", "D007781", "Q000378", "Q000494", "D008071", "Q000378", "D008079", "Q000378", "D008264", "Q000378", "D009000", "Q000378", "D011973", "Q000378", "D018110", "Q000378", "D014280", "Q000378", "D014407" ]	[ "Antibodies", "Apolipoprotein B-100", "Apolipoprotein B-48", "Apolipoproteins B", "Chylomicrons", "Fibroblasts", "Heparin", "Humans", "Lactoferrin", "Lipoprotein Lipase", "Lipoproteins, VLDL", "Macrophages", "Monocytes", "Receptors, LDL", "Receptors, Lipoprotein", "Triglycerides", "Tumor Cells, Cultured" ]	1998	Jun	Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor. Studies in animals and humans have demonstrated uptake of plasma chylomicrons (triglyceride-rich lipoprotein [TGRLP] of Sf>400) by accessible macrophages in vivo. One potential mechanism is via a unique receptor pathway we previously identified in human blood and THP-1 monocytes and macrophages for the lipoprotein lipase (LpL)- and apolipoprotein (apo) E-independent, high-affinity, specific binding of plasma chylomicrons and hypertriglyceridemic VLDL (HTG-VLDL) to cell-surface membrane-binding proteins (MBP 200, 235; apparent Mr 200, 235 kD on SDS-PAGE) that leads to lipid accumulation in vitro. Competitive binding studies reported here demonstrate that anti-apoB antibodies specifically block the high-affinity binding of TGRLP to this receptor on THP-1 cells and on ligand blots. LpL, which binds to an N-terminal domain of apoB, also inhibits TGRLP binding both to this site on THP-1s and to MBP 200, 235 by binding to apoB. Chylomicrons of Sf>1100 that contain apoB-48, but not apoB-100, bind specifically to MBP 200, 235, and this binding is blocked by anti-apoB IgG. In contrast, lactoferrin and heparin do not inhibit TGRLP binding. We conclude that the receptor-binding domain is within apoB-48 (or an equivalent in apoB-100) near the LpL-binding domain, but not a heparin-binding domain. Uptake of TGRLP by this mechanism could provide essential nutrients or, in HTG, cause excess lipid accumulation and foam cell formation.
9,633,940	eng	[ "D000818", "D001011", "Q000473", "D001161", "Q000209", "Q000473", "D002784", "Q000378", "D002791", "Q000378", "D008078", "Q000097", "D015243", "Q000378", "D008297", "D010084", "D011817" ]	[ "Animals", "Aorta", "Arteriosclerosis", "Cholesterol", "Cholesterol, Dietary", "Cholesterol, LDL", "Cholesterol, VLDL", "Male", "Oxidation-Reduction", "Rabbits" ]	1998	Jun	Oxidized cholesterol in the diet accelerates the development of aortic atherosclerosis in cholesterol-fed rabbits. Oxidized lipoproteins may play a role in atherosclerosis. Recently, we have demonstrated that the levels of oxidized fatty acids in the circulation correlate directly with the quantity of oxidized fatty acids in the diet and that dietary oxidized fatty acids accelerate atherosclerosis in rabbits. The present study tests the hypothesis that oxidized cholesterol in the diet accelerates the development of atherosclerosis. Rabbits were fed a diet containing 0.33% nonoxidized cholesterol (control diet) or the same diet containing 0.33% cholesterol of which 5% was oxidized (oxidized diet). Serum cholesterol levels increased to a similar extent in both groups, with the majority of cholesterol in the beta-VLDL fraction. Moreover, in the serum beta-VLDL fraction and liver, there was a significant increase in the oxidized cholesterol levels. Most importantly, feeding a diet enriched in oxidized cholesterol resulted in a 100% increase in fatty streak lesions in the aorta. Western diets contain high concentrations of oxidized cholesterol products, and our results suggest that these foods may be a risk factor for atherosclerosis.
9,633,941	eng	[ "D000818", "D001053", "Q000235", "D053241", "D002478", "D016207", "Q000494", "D005786", "Q000187", "D006801", "D015850", "Q000494", "D017270", "Q000235", "D008099", "Q000166", "D008252", "D008297", "D012333", "D016212", "Q000494", "D014409", "Q000494" ]	[ "Animals", "Apolipoproteins", "Apoprotein(a)", "Cells, Cultured", "Cytokines", "Gene Expression Regulation", "Humans", "Interleukin-6", "Lipoprotein(a)", "Liver", "Macaca fascicularis", "Male", "RNA, Messenger", "Transforming Growth Factor beta", "Tumor Necrosis Factor-alpha" ]	1998	Jun	Dominant negative effect of TGF-beta1 and TNF-alpha on basal and IL-6-induced lipoprotein(a) and apolipoprotein(a) mRNA expression in primary monkey hepatocyte cultures. Lipoprotein(a) [Lp(a)] consists of apolipoprotein(a) [apo(a)] disulfide linked to apolipoprotein B-100 of LDL. Elevated plasma Lp(a) is an independent risk factor for a variety of vascular diseases. Lp(a) has been reported to be an acute-phase reactant, suggesting that cytokines may regulate its levels. To determine whether Lp(a) expression was subject to modulation by cytokines, primary monkey hepatocytes that endogenously express Lp(a) were used. Hepatocytes were treated with interleukin (IL)-6, the major mediator of the acute-phase response, and several other cytokines. IL-6 treatment (0.3 to 10 ng/mL) resulted in a marked, dose-dependent, 2- to 4-fold enhancement of Lp(a) accumulation in the hepatocyte culture media that was highly correlated with changes in apo(a) mRNA levels (r>0.9). Several other cytokines, such as IL-2, IL-8, and hepatocyte growth factor, had no significant effect on Lp(a) levels; however, transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) were very active in inhibiting Lp(a) accumulation in the culture media, with IC50s of approximately 0.3 and 1 ng/mL, respectively. Both TGF-beta1 and TNF-alpha also decreased the apo(a) transcript. Mixing experiments, in which hepatocytes were treated with 10 ng/mL of IL-6 and 0.3 to 10 ng/mL of TGF-beta1 or TNF-alpha, demonstrated that the IL-6-mediated induction of Lp(a) and apo(a) mRNA was ablated with very low levels of either inhibitory cytokine, suggesting a dominant negative effect of TGF-beta1 and TNF-alpha. These results show that Lp(a) and apo(a) mRNA expression in primary monkey hepatocytes is subject to both positive (IL-6) and negative (TGF-beta1 and TNF-alpha) regulation by physiological levels of cytokines. Thus, in vivo Lp(a) levels may be dependent on the balance between stimulatory and inhibitory cytokines.
9,633,942	eng	[ "D000818", "D000906", "Q000378", "Q000494", "D003994", "Q000494", "D002460", "D002478", "D002788", "Q000378", "D005260", "D005487", "Q000166", "D015870", "D006868", "D008264", "Q000378", "D017737", "Q000378", "D051379", "D008810", "D051381", "D002787", "Q000235", "Q000378", "D014162" ]	[ "Animals", "Antibodies", "Bucladesine", "Cell Line", "Cells, Cultured", "Cholesterol Esters", "Female", "Foam Cells", "Gene Expression", "Hydrolysis", "Macrophages", "Macrophages, Peritoneal", "Mice", "Mice, Inbred C57BL", "Rats", "Sterol Esterase", "Transfection" ]	1998	Jun	Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells. Atherosclerosis is a complex physiopathologic process initiated by the formation of cholesterol-rich lesions in the arterial wall. Macrophages play a crucial role in this process because they accumulate large amounts of cholesterol esters (CEs) to form the foam cells that initiate the formation of the lesion and participate actively in the development of the lesion. Therefore, prevention or reversal of CE accumulation in macrophage foam cells could result in protection from multiple pathological effects. In this report, we show that the CE hydrolysis catalyzed by neutral cholesterol ester hydrolase (nCEH) can be modulated by overexpression of hormone-sensitive lipase (HSL) in macrophage foam cells. For these studies, RAW 264.7 cells, a murine macrophage cell line, were found to be a suitable model of foam cell formation. HSL expression and nCEH activity in these cells and in peritoneal macrophages were comparable. In addition, antibody titration showed that essentially all nCEH activity in murine macrophages was accounted for by HSL. To examine the effect of HSL overexpression on foam cell formation, RAW 264.7 cells were stably transfected with a rat HSL cDNA. The resulting HSL overexpression increased hydrolysis of cellular CEs 2- to 3-fold in lipid-laden cells in the presence of an acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor. Furthermore, addition of cAMP produced a 5-fold higher rate of CE hydrolysis in cholesterol-laden, HSL-overexpressing cells than in control cells and resulted in nearly complete hydrolysis of cellular CEs in only 9 hours, compared with <50% hydrolysis in control cells. Thus, HSL overexpression stimulated the net hydrolysis of CEs, leading to faster hydrolysis of lipid deposits in model foam cells. These data suggest that HSL overexpression in macrophages, alone or in combination with ACAT inhibitors, may constitute a useful therapeutic approach for impeding CE accumulation in macrophages in vivo.
9,633,943	eng	[ "D016632", "Q000096", "Q000235", "D016633", "Q000096", "Q000235", "D002352", "Q000378", "D004958", "Q000494", "D006801", "D008075", "D011257", "D012333", "D019998", "D014158", "Q000187", "D014407" ]	[ "Apolipoprotein A-I", "Apolipoprotein A-II", "Carrier Proteins", "Estradiol", "Humans", "Lipoproteins, HDL", "Pregnancy Proteins", "RNA, Messenger", "Racemases and Epimerases", "Transcription, Genetic", "Tumor Cells, Cultured" ]	1998	Jun	Estradiol stimulates apolipoprotein A-I- but not A-II-containing particle synthesis and secretion by stimulating mRNA transcription rate in Hep G2 cells. Estrogen therapy increases plasma HDL levels, which may reduce cardiovascular risk in postmenopausal women. The mechanism of action of estrogen in influencing various steps in hepatic HDL and apolipoprotein (apo) A-I synthesis and secretion are not fully understood. In this study, we have used the human hepatoblastoma cell line (Hep G2) as an in vitro model system to delineate the effect of estradiol on multiple regulatory steps involved in hepatic HDL metabolism. Incubation of Hep G2 cells with estradiol resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake/removal of radiolabeled HDL-protein; (2) accelerated incorporation of [3H]leucine into apoA-I; (3) selective increase in [3H]leucine incorporation into lipoprotein (LP) A-I but not LP A-I+A-II HDL particles (HDL particles without and with apoA-II, respectively); (4) increased ability of apoA-I-containing particles to efflux cholesterol from fibroblasts; (5) stimulated steady state apoA-I but not apoA-II mRNA expression; and (6) increased newly transcribed apoA-I mRNA message without effect on apoA-I mRNA half-life. The data indicate that estradiol stimulates newly transcribed hepatic apoA-I mRNA, resulting in a selective increase in LP A-I, a subfraction of HDL that is associated with decreased atherosclerotic cardiovascular disease, especially in premenopausal women.
9,633,944	eng	[ "D000293", "D000924", "Q000494", "D001055", "Q000097", "D002170", "D002648", "D008078", "Q000097", "D004311", "D005260", "D006579", "D006801", "D019161", "Q000494", "D006938", "Q000097", "Q000188", "Q000235", "D008074", "Q000097", "D008297", "D017354", "D011973", "Q000235", "D019821", "Q000494" ]	[ "Adolescent", "Anticholesteremic Agents", "Apolipoproteins B", "Canada", "Child", "Cholesterol, LDL", "Double-Blind Method", "Female", "Heterozygote", "Humans", "Hydroxymethylglutaryl-CoA Reductase Inhibitors", "Hyperlipoproteinemia Type II", "Lipoproteins", "Male", "Point Mutation", "Receptors, LDL", "Simvastatin" ]	1998	Jun	Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia. In familial hypercholesterolemia (FH), the efficacy of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase shows considerable interindividual variation, and several genetic and environmental factors can contribute to explaining this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG-CoA reductase inhibitor, was conducted in 63 children and adolescents with heterozygous FH. The patients were grouped according to known LDL receptor genotype. After 6 weeks of treatment with 20 mg/d simvastatin, the mean reduction in plasma LDL cholesterol in patients with the W66G mutation (n=14) was 31%, whereas in the deletion>15 kb (n=23) and the C646Y mutation groups (n=10), it was 38% and 42%, respectively (P<0.05). After treatment with simvastatin, HDL cholesterol levels were increased in all groups, and triglyceride concentrations were significantly reduced. Multiple regression analyses suggested that 42% of the variation of the LDL cholesterol response to simvastatin can be attributed to variation in the mutant LDL receptor locus, apolipoprotein E genotype, and body mass index, while 35% of the variation in HDL cholesterol response was explained by sex and baseline HDL cholesterol. These results show that simvastatin was an effective and well-tolerated therapy for FH in the pediatric population for all LDL receptor gene mutations. Moreover, the nature of LDL receptor gene mutations and other genetic and constitutional factors play a significant role in predicting the efficacy of simvastatin in the treatment of FH in children and adolescents.
9,633,945	eng	[ "D000071479", "D000818", "D053299", "D001055", "Q000235", "Q000378", "D015197", "D003564", "Q000096", "Q000235", "D006801", "D008077", "Q000378", "D008107", "Q000209", "D008113", "Q000209", "D051379", "D008810", "D008813", "D008822", "D017393", "D051381", "D019076" ]	[ "APOBEC-1 Deaminase", "Animals", "Apolipoprotein B-100", "Apolipoproteins B", "Carcinogenicity Tests", "Cytidine Deaminase", "Humans", "Lipoproteins, LDL", "Liver Diseases", "Liver Neoplasms", "Mice", "Mice, Inbred C57BL", "Mice, Inbred ICR", "Mice, Transgenic", "RNA Editing", "Rats", "Transgenes" ]	1998	Jun	Low expression of the apolipoprotein B mRNA-editing transgene in mice reduces LDL levels but does not cause liver dysplasia or tumors. Hepatic expression of apolipoprotein (apo) B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1) has been proposed as a gene therapy approach for lowering plasma low density lipoprotein (LDL) levels. However, high-level expression of APOBEC-1 in transgenic mouse and rabbit livers causes liver dysplasia and hepatocellular carcinoma. To determine the physiological and pathological effects of low-level hepatic expression of APOBEC-1, we used a 52-kb rat APOBEC-1 genomic clone (RE4) to generate transgenic mice expressing low levels of APOBEC-1 (2 to 5 times those in nontransgenic mice). Liver function, liver histology, editing of apoB mRNA at the normal editing site (C6666), and abnormal editing at multiple sites (hyperediting) in these mice were compared with those in transgenic mice expressing intermediate (I-20) or high (I-28) levels of APOBEC-1 in the liver. Hyperediting of mRNA coding for the novel APOBEC-1 target 1 (NAT1) was also examined. In the high-expressing I-28 line, 50% of the mice had palpable tumors at 15 weeks of age, whereas in the intermediate-expressing I-20 line, 50% of the mice had evidence of liver tumors after 1 year. In contrast, low-expressing RE4 mice had normal liver function and histology and did not develop liver tumors when examined at 3 to 17 months of age. Moreover, hyperediting of apoB and NAT1 mRNA in the liver was robust in the I-20 mice but barely detectable in the RE4 mice. The low-level expression resulted in sufficient APOBEC-1 to edit essentially all apoB mRNA at the normal editing site, virtually eliminating apoB-100 and LDL in the plasma of RE4 mice. When RE4 mice were crossed with human apoB transgenic mice, which possess high plasma LDL concentrations, plasma LDL levels in the offspring were reduced to very low levels. These results indicates that long-term hepatic expression of APOBEC-1 at low levels sufficient to eliminate LDL does not cause apparent liver damage or liver tumors in transgenic mice. RE4 APOBEC-1 transgenic mice should prove valuable for studying the roles of apoB-containing lipoproteins in lipid metabolism and atherosclerosis.
9,633,946	eng	[ "D002516", "D008670", "D008854", "Q000379", "D013048", "Q000379", "D013499" ]	[ "Ceramics", "Metals", "Microscopy, Electron", "Specimen Handling", "Surface Properties" ]	1998	May	Applications of the FIB lift-out technique for TEM specimen preparation. A site-specific technique for cross-section transmission electron microscopy specimen preparation of difficult materials is presented. A focused ion beam was used to slice an electron transparent membrane from a specific area of interest within a bulk sample. Micromanipulation lift-out procedures were then used to transport the electron-transparent specimen to a carbon-coated copper grid for subsequent TEM analysis. The FIB (focused ion beam) lift-out technique is a fast method for the preparation of site-specific TEM specimens. The versatility of this technique is demonstrated by presenting cross-sectioned TEM specimens from several types of materials systems, including a multi-layered integrated circuit on a Si substrate, a galvanized steel, a polycrystalline SiC ceramic fiber, and a ZnSe optical ceramic. These specimens have both complex surface geometry and interfaces with complex chemistry. FIB milling was performed sequentially through different layers of cross-sectioned materials so that preferential sputtering was not a factor in preparing TEM specimens. The FIB lift-out method for TEM analysis is a useful technique for the study of complex materials systems for TEM analysis.
9,633,947	eng	[ "D000447", "D005404", "D019276", "Q000648", "D006801", "D008239", "D008854", "D012430", "D013194", "D013210", "Q000648", "D013997" ]	[ "Aldehydes", "Fixatives", "Glycocalyx", "Humans", "Lysine", "Microscopy, Electron", "Ruthenium Red", "Staining and Labeling", "Staphylococcus", "Time Factors" ]	1998	May	Superior preservation of the staphylococcal glycocalyx with aldehyde-ruthenium red and select lysine salts using extended fixation times. The utility of lysine-based aldehyde-ruthenium red fixatives for the preservation and/or staining of the fibrous staphylococcal glycocalyx was improved by substitution of alternative forms of lysine for the free amino form. Paraformaldehyde-glutaraldehyde fixatives containing alternative lysines, with or without ruthenium red, were compared at short 20-minute prefixation times and at extended overnight fixation times. Although inclusion of paraformaldehyde made longer fixation times possible, the length of time for "safe" fixation varied per sample and could not be predicted. All alternative lysine forms permitted fixation of at least 24 hours without sample loss. The L-lysine monohydrochloride or L-lysine acetate forms permitted longer fixation times than the L-lysine free amino form, and they had comparable or better preservation of the staphylococcal glycocalyx. Thus, the usefulness of aldehyde-lysine-based fixatives with minor changes has been enhanced.
9,633,948	eng	[ "D000161", "D000818", "D001306", "Q000033", "Q000502", "D001933", "Q000033", "Q000502", "D002415", "D003847", "Q000378", "D005456" ]	[ "Acoustic Stimulation", "Animals", "Auditory Pathways", "Brain Stem", "Cats", "Deoxyglucose", "Fluorescent Dyes" ]	1998	May	Lack of topography in the ventral nucleus of the lateral lemniscus. In contrast to the ease of finding tonotopicity in other nuclei, both anatomical and electrophysiological methods have failed to demonstrate a clear and simple tonotopic map within the ventral nucleus of the lateral lemniscus (VLL). The present study was undertaken in cat with the hope that methods not used previously in studies of VLL might succeed in demonstrating an orderliness in its exiting fibers (i.e., efferents) or its incoming fibers (i.e., afferents). Since the same organization of ascending frequencies present in the cochlea is maintained in these fibers as well as in all main auditory nuclei, demonstration of a similar organization of frequencies in VLL would be evidence of the cochleo- or tono-topicity of this nucleus. Using triple injection of 3 different fluorescent dyes in inferior colliculus to study efferents, orderly and tonotopic cell-labeling is found in each of the brainstem auditory nuclei, with the notable exception of VLL. Instead, labeling of cell clusters, each cluster containing a small number of cells, is found randomly distributed throughout VLL in all 3 of its spatial dimensions. Using the 2-deoxyglucose (2-DG) method, during stimulation at 6 different frequencies, afferent orderliness, indeed, tonotopicity is found in all major brainstem auditory nuclei, again with the notable exception of VLL. Rather, each frequency evokes 2-DG label throughout VLL. In agreement with the results based on electrophysiological methods, therefore, the anatomical methods used here also yield no evidence of tonotopicity in VLL. Thus, if there is orderliness in VLL's efferents or afferents, it is based on an auditory dimension incommensurate with frequency.
9,633,949	eng	[ "D000135", "Q000032", "D000469", "Q000032", "D000818", "D001853", "Q000187", "Q000502", "Q000648", "D001862", "D016222", "Q000494", "D007150", "D017403", "D008297", "D008854", "D010006", "Q000201", "Q000648", "D010010", "Q000201", "Q000648", "D010012", "D015676", "Q000235", "D053495", "D051381", "D017208", "D012795", "Q000032", "D013997" ]	[ "Acid Phosphatase", "Alkaline Phosphatase", "Animals", "Bone Marrow", "Bone Resorption", "Fibroblast Growth Factor 2", "Immunohistochemistry", "In Situ Hybridization", "Male", "Microscopy, Electron", "Osteoblasts", "Osteoclasts", "Osteogenesis", "Osteonectin", "Osteopontin", "Rats", "Rats, Wistar", "Sialoglycoproteins", "Time Factors" ]	1998	May	Morphological examination of bone synthesis via direct administration of basic fibroblast growth factor into rat bone marrow. Woven bone induced by direct injection of basic fibroblast growth factor (bFGF) into rat bone marrow was examined. On the first day after injection, fibrous tissues formed in the treated region of the bone marrow. Tissue-nonspecific alkaline phosphatase (TNAPase)-immunopositive osteoblastic cells and osteopontin immunopositive-extracellular matrices were observed in the fibrous tissues, indicating bone induction. On the fifth day, the bFGF-induced bone was found broadly in the bone marrow. In the originally existing bone, osteopontin-immunoreactivity was observed at cement lines, but not in the fully calcified matrix, whereas the woven bone displayed immunoreactivity throughout the matrix. Numerous TRAPase-positive osteoclasts were present on the surfaces of the woven bone, but no obvious cement line was observed. Therefore, both bone formation and resorption appeared highly active, without normal cellular coupling equilibrated between bone formation and resorption performed by osteoblasts and osteoclasts. On the tenth day, the bFGF-induced bone was almost replaced by bone marrow. Thus, bone formation actively occurred in the first half of the experimental period, whereas bone resorption came to be predominant thereafter. This study demonstrated that bFGF stimulates bone formation, which, however, is subject to subsequent resorption, probably due in part to the absence of coordinated cellular coupling between osteoclasts and osteoblasts.
9,633,950	eng	[ "D015100", "D000818", "D002196", "Q000648", "D003051", "Q000098", "Q000648", "D015834", "Q000139", "Q000473", "D006168", "D008027", "D008855", "D010777", "D012395", "D013194", "Q000379", "D013927" ]	[ "3,3'-Diaminobenzidine", "Animals", "Capillaries", "Cochlea", "Cochlear Diseases", "Guinea Pigs", "Light", "Microscopy, Electron, Scanning", "Photochemistry", "Rose Bengal", "Staining and Labeling", "Thrombosis" ]	1998	May	Photochemically induced focal cochlear lesions in the guinea pig: I. DAB staining and SEM study. A photochemical reaction was used to produce focal microcirculation disorders in the guinea pig cochlea. Temporal bones were removed at various intervals between 5 minutes and 1 month after infusion of rose bengal (RB) and illumination. Infused but unilluminated contralateral cochleae served as controls. Dissected cochlear structures were stained by 3,3'-diaminobenzidine (DAB) peroxidase substrate medium. After observation by light microscopy (LM), the same specimens were processed and observed by scanning electron microscopy (SEM). Dilation of strial capillaries and destruction of strial epithelial cells became apparent at 1 hour after illumination. Tightly packed red blood cells were found filling the severed end of markedly dilated strial capillaries at 24 hours after the procedure. DAB staining of the osseous spiral lamina indicated vascular change with vessel dilation in the illuminated area. At 1 week after illumination, the lesion area of the stria vascularis and spiral prominence was replaced by a layer of larger, flat cells. At 1 month after illumination, all vascular supply to the cochlear lateral wall disappeared at the site of illumination. All lesions remained focal and showed no sign of expansion or reduction throughout the observation period. The cochlear duct of the guinea pig appears to be segmentally nourished by the capillary system. Observation of DAB stained tissue by LM and SEM proved to be informative in the study of microcirculation disorders of the inner ear.
9,633,951	eng	[ "D000818", "D002196", "Q000648", "D003051", "Q000098", "Q000648", "D015834", "Q000139", "Q000473", "D005260", "D006168", "D008027", "D008854", "D009925", "Q000648", "D010777", "D012395", "D013194", "Q000379", "D013316", "Q000648", "D013927", "D013997" ]	[ "Animals", "Capillaries", "Cochlea", "Cochlear Diseases", "Female", "Guinea Pigs", "Light", "Microscopy, Electron", "Organ of Corti", "Photochemistry", "Rose Bengal", "Staining and Labeling", "Stria Vascularis", "Thrombosis", "Time Factors" ]	1998	May	Photochemically induced focal cochlear lesions in the guinea pig: II. A transmission electron microscope study. Photochemically induced focal lesions in guinea pig cochleas were studied by light microscopy and transmission electron microscopy. The lesions were induced in the second cochlear turns of 35 adult guinea pigs by illumination for 10 minutes with a focused green light immediately after a rose bengal solution was injected into the jugular vein. The cochlear lateral wall and organ of Corti were examined 5, 10, 20, 30, and 90 minutes, 12 and 24 hours, and 3, 7, and 30 days after the procedure. Aggregations of platelets and red blood cells were found in strial capillaries at 5 minutes after illumination. After 30 minutes, marginal cell surfaces protruded into the endolymphatic space; surface membranes were ruptured and the cytoplasm was expelled into the space. In outer hair cells, disruption of the cellular membrane was found near the cuticular plate 12 hours after the procedure. All cellular elements of the lateral wall and organ of Corti were markedly degenerated in the 30-day specimens. Histological changes found in the stria vascularis were consistent with cell damage caused by active oxygen species. It is likely that the stria vascularis is more sensitive to the photochemical reaction than other parts of the cochlea. Cell damage in other parts of the cochlea seemed to have been caused by local microvascular ischemia in addition to the action of active oxygen species induced by the photochemical reaction.
9,633,952	eng	[ "D000818", "D001011", "Q000000981", "D005240", "D008297", "D012077", "Q000000981", "D012756", "D018615", "D018616", "D018084" ]	[ "Animals", "Aorta", "Feasibility Studies", "Male", "Renal Artery", "Sheep", "Ultrasonography, Doppler, Color", "Ultrasonography, Doppler, Duplex", "Ultrasonography, Interventional" ]	1998	May	Biplane color flow duplex intravenous intravascular ultrasound for arterial visualization. To describe a feasibility study in a sheep model using an intravascular ultrasound (IVUS) instrument in an intravenous position to produce color flow, B-mode images of arterial segments along with Doppler blood flow velocities. Four healthy adult male sheep were anesthetized for surgical exposure of the right external jugular vein. A 9.0F sheath was also introduced in the common femoral artery for arteriography and device insertion. A 7.5-MHz ultrasound probe with 1-cm graduation markers was passed into the jugular vein. B-mode and color flow pictures were captured at aortic branches in cross and longitudinal sections. Length measurements between aortic branches and Doppler spectral velocities were obtained. Guidewire, balloon, and stent maneuvers were monitored by the stationary intravenous IVUS probe. High-quality visualization of the entire abdominal aorta and its branches was achieved in all animals. With the probe stationary in the vena cava, a 1.5-cm linear segment of the aorta could be continuously observed in both B-mode and color flow ultrasound scans. Insertion and implantation of a Palmaz balloon-expandable stent was guided by intravenous IVUS alone. Selective catheterization of the right renal artery was followed visually by moving the intravenous IVUS probe sequentially. Intravenous IVUS appears feasible as a guidance and monitoring tool for endovascular interventions. While conventional IVUS provides only cross-sectional images in B-mode, intravenous IVUS captures color flow and Doppler velocity data as well. These added ultrasound modalities may offer potential advantages for guidance of endovascular procedures and endoleak detection.
9,633,953	eng	[ "D000328", "D000368", "D000369", "D000783", "Q000000981", "D019917", "D002445", "Q000000981", "D005260", "D005263", "Q000000981", "D006801", "D007083", "Q000000981", "D007432", "D008297", "D008875", "D015607", "D018084" ]	[ "Adult", "Aged", "Aged, 80 and over", "Aneurysm", "Blood Vessel Prosthesis Implantation", "Celiac Artery", "Female", "Femoral Artery", "Humans", "Iliac Artery", "Intraoperative Period", "Male", "Middle Aged", "Stents", "Ultrasonography, Interventional" ]	1998	May	Intravascular ultrasound in endovascular stent-grafts for peripheral aneurysm: a clinical study. To evaluate the potential diagnostic information of intraprocedural intravascular ultrasound (IVUS) in patients undergoing endovascular stent-grafting for peripheral aneurysm. IVUS was used in 17 patients preprocedurally to measure the diameter of the proximal and distal neck and the length of the aneurysm. Balloon and stent-graft sizes were selected based on these measurements. Following stent-graft deployment, angiography and IVUS were used to document stent apposition and the configuration and diameter of the stent-graft. Stent-graft insertion was considered successful in 8 patients based on angiography and IVUS images. In 9 others, both imaging modalities showed inadequate results, necessitating 12 additional procedures: balloon angioplasty for stent-graft stenosis (2) and inadequate stent-graft apposition (1); an additional stent-graft (4); an extra stent (1); thrombectomy (2); and conversion (2) for inadequate stent-graft position and a graft rupture. In these patients, intraprocedural IVUS was superiorto angiography in contributing vital information to aid in the selection of the additional interventions. During management of peripheral aneurysms with endovascular stent-grafts, IVUS monitoring was a useful adjunct when the initial procedure was unsatisfactory and/ or when intraprocedural angiographic studies were inconclusive.
9,633,954	eng	[ "D001014", "Q000628", "D002404", "Q000295", "D006801", "D011312" ]	[ "Aortic Aneurysm", "Catheterization", "Humans", "Pressure" ]	1998	May	Diameter of large balloons used in endoluminal graft deployment varies with inflation pressure. To evaluate the characteristics of large-diameter balloon catheters used during endoluminal repair of aortic aneurysms. Thirty-three large balloon dilatation catheters in the diameter range of 15 to 30 mm were measured at controlled pressures from 1 to 4 atm. The balloons were inflated with water using an inflation syringe connected to a pressure transducer. Diameters at stable pressure and pressure changes against time were recorded for each balloon. Dilation catheters in the range of 15 to 20 mm in diameter were significantly smaller (p < 0.005) than their nominal diameter at 1 and 2 atm; they reached nominal diameter only at the relatively high pressure of 4 atm. Most larger diameter balloons (25 and 30 mm) did not attain their nominal diameter even with pressures up to 4 atm. All sizes of balloon catheters tested became relatively compliant at pressures > 3 atm. The large balloon catheters tested in this study were designed for arterial angioplasty or valvuloplasty. They attained a significantly smaller size than their nominal diameter at pressures < 3 atm and became compliant at pressures exceeding 3 atm. Interventionists should be aware of these characteristics when using balloon catheters such as these during endoluminal graft deployment. Large balloons that reach predictable diameter at lower pressures should be designed specifically for use in endoluminal graft procedures.
9,633,955	eng	[ "D000328", "D017541", "Q000209", "Q000601", "D001013", "Q000293", "D017545", "Q000209", "Q000601", "D001807", "D019917", "Q000379", "D006801", "D008297", "D015607", "D014950", "Q000150" ]	[ "Adult", "Aneurysm, False", "Aorta, Thoracic", "Aortic Aneurysm, Thoracic", "Blood Vessel Prosthesis", "Blood Vessel Prosthesis Implantation", "Humans", "Male", "Stents", "Wounds, Penetrating" ]	1998	May	Treatment of traumatic false aneurysm of the thoracic aorta with endoluminal grafts. Traumatic false aneurysms of the thoracic aorta presenting at a time remote from the original injury are a rare but complex problem. The treatment of a traumatic false aneurysm by endovascular techniques may offer many advantages over conventional open surgery. Two male patients presented with traumatic false aneurysm of the thoracic aorta after being treated emergently for visceral injuries from a gunshot wound in one and an automobile accident in the other. In both cases, the aneurysm was situated so that only the T11 intercostal artery would be sacrificed by endoluminal exclusion. Commercially available endoluminal stent-grafts (Talent) were deployed successfully. Recovery in both patients was rapid and uneventful with no neurological sequelae. Spiral computed tomographic scans at 1 year indicated sustained aneurysm exclusion and satisfactory endograft position. A customized endoluminal stent-graft can be used with great accuracy to exclude thoracic false aneurysms, avoiding the potential complexity and morbidity of an open thoracic approach.
9,633,956	eng	[ "D000818", "D002404", "D004285", "D008433", "D015588", "D019047", "D014159", "D018084" ]	[ "Animals", "Catheterization", "Dogs", "Mathematics", "Observer Variation", "Phantoms, Imaging", "Transducers", "Ultrasonography, Interventional" ]	1998	May	The effect of angulation on intravascular ultrasound imaging observed in vascular phantoms. To quantify the error introduced by noncoaxial intravascular ultrasound (IVUS) imaging and to evaluate the use of a balloon-tipped catheter in compensating for intraluminal angulation and subsequent dimensional inaccuracy. The effect of noncoaxial IVUS imaging was investigated in both a polyvinyl chloride phantom and an in vitro canine aorta using a calibrated setup to measure angulation off axis. Imaging was performed at increasing angulation (creating an elliptical image) in both phantoms, with the transducer centered and off center. Diameters were compared to the original coaxial diameter, as well as calculated diameters based on specific angles off axis. The percentage change (error) was also calculated at these angles. The measurements were repeated using a balloon-tipped catheter to center the transducer. The measured diameters and percentage changes compared closely with their calculated counterpart. Up to 25 degrees off axis, the apparent increase in diameter measurement was nearly 10%. Angulation from 30 degrees to 70 degrees resulted in an increase of 15% to 192%. Use of the centering balloon reduced the amount of error by 70% to 85% but was limited to angles < or = 25 degrees due to the design of the test apparatus. The error introduced by noncoaxial IVUS imaging can be significant and may be partially corrected by the use of a centering balloon. Further studies in the clinical application of a centering device are warranted.
9,633,957	eng	[ "D000328", "D000792", "D017544", "Q000000981", "Q000601", "D001019", "Q000000981", "Q000601", "D019917", "D004630", "D004638", "D005260", "D006801", "D015607", "D013997" ]	[ "Adult", "Angiography", "Aortic Aneurysm, Abdominal", "Aortic Rupture", "Blood Vessel Prosthesis Implantation", "Emergencies", "Emergency Treatment", "Female", "Humans", "Stents", "Time Factors" ]	1998	May	Emergent endoluminal repair of delayed abdominal aortic rupture after blunt trauma. To report the emergency repair of a traumatic abdominal aortic rupture using endoluminal techniques. A 25-year-old female sustained multiple head, chest, and abdominal injuries in a motorcycle accident. Six days after emergency treatment (including splenectomy and repair of a superficial hepatic rupture and lacerations to the stomach, small bowel, and colon), she became hemodynamically unstable. A massive retroperitoneal hematoma had evolved from a distal aortic rupture. Owing to a hostile abdomen and possibility of bacterial contamination, a self-expanding stent-graft was inserted transfemorally to repair the aortic injury. The patient recovered uneventfully and continues in good health with a patent endograft repair 2 years after treatment. This experience would support the efficacy of endograft implantation for emergent repair of trauma aortic injuries; however, proper facilities, an experienced interventional team, and an assortment of endografts and stents must be available.
9,633,958	eng	[ "D000368", "D017541", "Q000209", "Q000601", "D001166", "D019917", "D006801", "D008297", "D011138", "Q000627", "D011183", "D006435", "D015607" ]	[ "Aged", "Aneurysm, False", "Arteriovenous Shunt, Surgical", "Blood Vessel Prosthesis Implantation", "Humans", "Male", "Polytetrafluoroethylene", "Postoperative Complications", "Renal Dialysis", "Stents" ]	1998	May	Transluminal stent-graft repair for pseudoaneurysm of PTFE hemodialysis grafts. To report the use of endovascular techniques to treat two cases of nonanastomotic pseudoaneurysm of a bridge graft fistula (BGF). Two men with fully functional polytetrafluoroethylene (PTFE) BGFs both presented with an enlarging mass adjacent to their arteriovenous shunt. The false aneurysm in both instances was located by ultrasound and confirmed by shunt angiography at the time of surgery. Both fistulas were repaired by transluminally introducing a stented graft composed of a balloon-expandable Palmaz stent covered with a PTFE graft. Completion arteriography confirmed normal flow through the graft with no communication between the lumen and the aneurysmal cavity. Both patients recovered without complications and were discharged on the day of the procedure. Follow-up data reveal that both fistulas remain fully functional up to 5 and 6 months, respectively. Endovascular repair using stent-grafts can be a safe and effective method of excluding pseudoaneurysms associated with PTFE BGFs.
9,633,959	eng	[ "D000368", "D000369", "D000783", "Q000150", "D001166", "D019917", "D004621", "D005268", "D006801", "D007083", "D007084", "D008297", "D019060", "D011312", "D015607", "D013924", "Q000209", "Q000601" ]	[ "Aged", "Aged, 80 and over", "Aneurysm", "Arteriovenous Shunt, Surgical", "Blood Vessel Prosthesis Implantation", "Embolization, Therapeutic", "Femoral Vein", "Humans", "Iliac Artery", "Iliac Vein", "Male", "Minimally Invasive Surgical Procedures", "Pressure", "Stents", "Thrombophlebitis" ]	1998	May	Iliofemoral venous thrombosis caused by compression of an internal iliac artery aneurysm: a minimally invasive treatment. To report the success of a minimally invasive treatment for phlegmasia cerulea dolens without gangrene caused by compression from an internal iliac artery aneurysm. An 81-year-old male with a 1-month history of paralysis owing to a hemorrhagic stroke presented with massive edema and skin mottling of the right lower extremity. Imaging confirmed right iliofemoral deep vein thrombosis caused by compression from a 4-cm internal iliac artery aneurysm. With thrombolysis ruled out, a minimally invasive treatment plan was undertaken, featuring percutaneous coil embolization of the aneurysm and surgical venous thrombectomy with proximal arteriovenous fistula creation and iliac vein stent placement. Failure of the coils to embolize the iliac aneurysm prompted the use of an endovascular graft to exclude the aneurysm. The patient's symptoms subsided, and he has a patent right iliofemoral venous system and internal iliac artery at his latest (16-month) follow-up. This case demonstrates that minimally invasive endovascular and open techniques can be combined to achieve an optimum outcome in patients at high risk for standard surgical approaches.
9,633,963	eng	[ "D000402", "Q000473", "D000818", "D002356", "Q000473", "D002675", "D004195", "D004933", "Q000473", "D006801", "D007223", "D007231", "D051381", "D014132", "Q000473", "D014133", "Q000473", "D014138", "Q000473" ]	[ "Airway Obstruction", "Animals", "Cartilage", "Child, Preschool", "Disease Models, Animal", "Esophageal Atresia", "Humans", "Infant", "Infant, Newborn", "Rats", "Trachea", "Tracheal Diseases", "Tracheoesophageal Fistula" ]	1998	Jun	Understanding tracheomalacia. Tracheomalacia is an abnormality of the trachea that probably is present to some degree in all infants and children with oesophageal atresia. It causes the trachea to collapse during breathing, leading to obstruction of the upper airway. Our knowledge of the structural abnormalities underlying tracheomalacia is limited, mainly because patients with oesophageal atresia usually survive. Recently, the Adriamycin-induced rat model of oesophageal atresia and tracheomalacia has clarified some aspects of its pathology and the factors which may influence its development. The rat model suggests that the same detrimental factors that cause oesophageal atresia might also affect the development of the trachea, and that anomalous great vessels may exacerbate the severity of tracheomalacia locally.
9,633,964	eng	[ "D000553", "D001315", "D002648", "D002669", "Q000639", "D003153", "Q000639", "D003479", "Q000639", "D004504", "Q000639", "D005544", "D006801", "D010372", "Q000193", "D018794" ]	[ "Ambulatory Care", "Australia", "Child", "Child Welfare", "Community Health Services", "Curriculum", "Education, Medical, Undergraduate", "Forecasting", "Humans", "Pediatrics", "Problem-Based Learning" ]	1998	Jun	Medical student education in paediatrics and child health: where are we going? In most undergraduate medical curricula, learning is becoming less content based and the emphasis is changing to problem based learning, continuing self directed learning, and the use of a wide range of learning resources. Particular needs in paediatrics and child health are an increasing emphasis on learning in ambulatory care and community based health facilities, and on assessment processes which are formative and reflect the learning objectives appropriately. A wide range of resources is needed for learning at a time when teaching hospital and health system facilities face significant financial restraints.
9,633,965	eng	[ "D001315", "D019317", "D006801", "D007223", "D017410", "D012307", "D013398", "Q000209", "Q000517" ]	[ "Australia", "Evidence-Based Medicine", "Humans", "Infant", "Practice Guidelines as Topic", "Risk Factors", "Sudden Infant Death" ]	1998	Jun	Reducing the risk of sudden infant death syndrome: a review of the scientific literature. In March 1997 a multidisciplinary forum was convened by the National SIDS Council of Australia to review recent evidence concerning risk factors of sudden infant death syndrome (SIDS) and to revise and refine the current guidelines for reducing the risk of SIDS. The forum provided an assessment of the evidence for recommendations to reduce the risk of SIDS using an evidence-based process. Strong evidence has now accumulated that the intervention campaigns to reduce prone sleeping during infancy have been followed by SIDS rate declines. Recent data indicate that the supine position is not associated with an increase in significant morbidity outcomes and provides greater protection for SIDS than the side position, which may be unstable. Covering of the baby's head by bedding is strongly related to SIDS. The infant's sleeping environment should be carefully set up to ensure that the baby's head, including the face, cannot be obstructed during sleep. Parental smoking is strongly associated with SIDS. Structural supportive interventions for parental smoking cessation are required. Bedsharing increases the risk of SIDS amongst smokers and the data are currently not sufficient to provide complete reassurance to nonsmoking parents that bedsharing is safe. Infants should be maintained in a comfortable temperature zone. The evidence for a protective effect of breast-feeding is conflicting, so breast-feeding cannot be promoted strongly as reducing the risk of SIDS. Immunisation has not been associated with SIDS. Parents and carers should be aware of the current guidelines. Health professionals should also be aware of the evidence on which the current recommendations are based. Effective health education programmes should lead to a further decline in SIDS mortality in Australia.
9,633,966	eng	[ "D002648", "D019988", "Q000193", "D004519", "D006801", "D008282", "D010348" ]	[ "Child", "Disabled Children", "Education, Special", "Humans", "Mainstreaming, Education", "Patient Care Team" ]	1998	Jun	Education for children with disabilities: the rationale for inclusion. To discuss issues in the education of children with disabilities, particularly with respect to inclusion in mainstream classes. Review of the literature on education for children with disabilities, focusing on the inclusion versus segregation debate. The literature provides no support for segregation and some support for the view that segregated children are disadvantaged. What seems to be important is the way the child is educated rather than where the education takes place. In addition, there are ethical, sociological, and legal arguments in favour of an inclusive educational system. There are good arguments to encourage inclusive education for children with disabilities. In advising parents, doctors should focus on how rather than where the child with a disability should be educated.
9,633,967	eng	[ "D000293", "Q000502", "D044466", "D002118", "Q000652", "D003404", "Q000652", "D003431", "D005260", "D006723", "D006801", "D008297", "D012016", "D044465" ]	[ "Adolescent", "Asian People", "Calcium", "Creatinine", "Cross-Cultural Comparison", "Female", "Hong Kong", "Humans", "Male", "Reference Values", "White People" ]	1998	Jun	Urinary calcium excretion in Chinese adolescents. To obtain normative reference values for urinary calcium excretion in Chinese adolescents. A random group of 425 healthy Chinese adolescents aged 12-19 years were recruited from secondary schools in Hong Kong. Each subject provided a sample of morning urine for the assessment of calcium and creatinine excretion. A subgroup of 80 subjects provided a 24-h urine sample for assessment of daily calcium excretion. The mean (+/-S.D.) and median urinary calcium/creatinine concentration ratios (UCa/Cr) expressed in mmolmmol creatinine were 0.18 (+/-0.16) and 0.12. Girls had a higher UCa/Cr than boys (P < 0.0001). The mean+/-S.D. 24-h urinary calcium excretion was 0.043+/-0.025 mmol kg day(-1) (1.71+/-1.01 mg kg day(-1)). The UCa/Cr ratio and 24-h urinary calcium excretion are low when compared with published values for Caucasian children. The apparent rarity of nephrolithiasis and microscopic haematuria associated with hypercalciuria may be related to the low urinary calcium excretion in this population.
9,633,969	eng	[ "D000015", "Q000453", "Q000235", "D000013", "Q000453", "Q000235", "D003430", "D005260", "D006801", "D015994", "D007223", "D007231", "D008297", "D011247", "D012307", "D014739", "Q000453" ]	[ "Abnormalities, Multiple", "Congenital Abnormalities", "Cross-Sectional Studies", "Female", "Humans", "Incidence", "Infant", "Infant, Newborn", "Male", "Pregnancy", "Risk Factors", "Victoria" ]	1998	Jun	Congenital malformations in Victoria, Australia, 1983-95: an overview of infant characteristics. To provide an overview of the characteristics of Victorian infants born between 1983 and 1995 who are affected by one or more of 27 sentinel birth defects. Using data on congenital malformations supplied to the Victorian Perinatal Data Collection Unit from multiple sources between 1983 and 1995, information was summarised for 25231 infants (born at 20 weeks or more) and 1566 terminations of pregnancy before 20 weeks' gestation. During the 13-year study period in Victoria, 3.2% of babies had at least one malformation. Congenital dislocation of the hip was the most common defect with a prevalence of 28.9 per 10000 pregnancies or 1/346. Increase in birth prevalence between 1983 and 1995 is greatest in obstructive defects of the renal pelvis, hypospadias and the trisomies 21,13 and 18. Nearly 50% of pregnancies affected by anencephaly were terminated before 20 weeks compared to 26% affected by spina bifida. The perinatal mortality of infants born at 20 weeks or more with congenital malformations is more than 10 times greater than that of infants without any malformations. Males are more at risk of being born with a malformation than females. Congenital malformations are more common in infants of multiple pregnancies and those of low birthweight. This large data collection is a valuable source of information for perinatal epidemiologists, for providers of prenatal diagnostic services and for the care of the disabled. In addition, the continued reporting and monitoring of birth defects will allow for targeted research that may lead to a better understanding of their aetiology.
9,633,968	eng	[ "D000818", "D000941", "Q000276", "D002417", "D002675", "D003968", "Q000276", "D005260", "D005500", "D006801", "D007223", "D007768", "Q000276", "D007782", "Q000276", "D008297", "D008892", "Q000276", "D016269", "Q000276", "D010047", "Q000276", "D012307", "D012400", "Q000276", "D012710", "Q000276" ]	[ "Animals", "Antigens", "Cattle", "Child, Preschool", "Diarrhea, Infantile", "Female", "Follow-Up Studies", "Humans", "Infant", "Lactalbumin", "Lactoglobulins", "Male", "Milk", "Milk Hypersensitivity", "Ovalbumin", "Risk Factors", "Rotavirus Infections", "Serum Albumin, Bovine" ]	1998	Jun	Humoral immune and clinical responses to food antigens following acute diarrhoea in children. To investigate the effect of acute watery diarrhoea in children upon humoral immune responses to food antigens and the subsequent development of food allergy. Serum antibodies to cows' milk, beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin and ovalbumin were measured in 30 children with acute diarrhoea in the acute phase and 1 month after recovery. The children were followed for 1 year to assess the development of food allergy. IgG antibeta-lactoglobulin titres for the study group increased 1 month after recovery compared to the titres during the acute phase (P = 0.02). Antibody concentration for the other antigens studied did not rise. Four children developed positive IgE antibodies to one or more of the allergens after the diarrhoeal episode, although the titres were very low. None showed evidence of allergy to cows' milk or egg during the year-long follow-up. Acute diarrhoea in children resulted in increased production of IgG antibody to beta-lactoglobulin and had a priming effect for development of positive IgE antibody to cows' milk. Clinical food allergy was not observed in any of the children during the year-long follow-up.
9,633,971	eng	[ "D001315", "D019090", "D002648", "D002653", "Q000175", "Q000534", "D002675", "D003479", "D002658", "Q000175", "Q000534", "D005260", "D006801", "D008297", "D010348", "D010372", "Q000193", "D012017" ]	[ "Australia", "Case Management", "Child", "Child Behavior Disorders", "Child, Preschool", "Curriculum", "Developmental Disabilities", "Female", "Humans", "Male", "Patient Care Team", "Pediatrics", "Referral and Consultation" ]	1998	Jun	Developmental-behavioural problems in general paediatrics. To determine the current role of private general paediatrics in the care of children with problems of development and behaviour. We surveyed all general paediatricians registered with the Australian College of Paediatrics to assess their current role in developmental-behavioural (DB) problems--their rate of referrals, their role in the continuing management, and opinions regarding duration of training in this area. Of 394 questionnaires sent, 284 replies were received (72%). From these 284 we analysed results for all 172 who spent more than 25% of their time in private general paediatric practice. On average, 32% of new referrals were for DB problems. With 10 DB clinical vignettes presented, paediatricians chose to continue to manage in conjunction with allied health services in 65% of cases. Other management choices included referral to a multidisciplinary team (16%), referral elsewhere (10%) and manage alone (7%). For training to be a general paediatrician, they indicated 3 months should be spent during basic training in each of the three areas of; DB paediatrics, developmental disabilities and child psychiatry (separately or concurrently); and 6 months of each during advanced training. Free comments highlighted lack of public allied health and psychosocial services. Private community-based general paediatricians are deeply involved in this area of work. The results raise questions about services for training and for clinical collaboration between public and private child health providers.
9,633,972	eng	[ "D018798", "Q000453", "Q000517", "D003430", "D005260", "D006801", "D015994", "D007223", "D019266", "Q000008", "D008297", "D009751", "D013021", "Q000453" ]	[ "Anemia, Iron-Deficiency", "Cross-Sectional Studies", "Female", "Humans", "Incidence", "Infant", "Iron, Dietary", "Male", "Nutritional Requirements", "South Australia" ]	1998	Jun	Iron status and dietary iron intake of 6-24-month-old children in Adelaide. Chronic iron deficiency in children is associated with anaemia and impaired mental and psychomotor development. The aim of this study was to assess the iron status and dietary intake of 6-24-month-old Caucasian and Asian children living in metropolitan Adelaide. A total of 234 healthy children (82% Caucasian and 18% Asian) aged 6-24 months were studied. Dietary iron intake of children was estimated from semiquantitative diet recall questionnaire administered to their parents. Blood samples for full blood count, serum ferritin (SF), serum iron (SI) and transferrin (TF) level estimations were obtained by venesection. Based on the laboratory test results, infants were classified as iron sufficient (IS) if the haemoglobin (Hb) concentration was > 110 g L(-1), SF > or = 15 microg L(-1), TF2 3.0 g L(-1), SI > or = 8 micromol L(-1) and iron saturation (ISAT) > or = 12%; or nonanaemic iron deficiency (NAID) if the Hb concentration was > 110 g L(-1) and SF < 15 microg L(-1) or SI < 8 micromol L(-1), TF > 3.0 g L(-1), and ISAT < 12%; or as iron deficiency anaemia (IDA) if the Hb concentration was < 110 g L(-1) in association with SF < 15 microg L(-1) or with SI < 8 micromol L(-1), TF > 3.0 g L(-1) and ISAT < 12%. Sixty-nine per cent of Caucasian children were classified IS, 25% as NAID and 6% were IDA; while 72% of Asian children were classified IS, 14% as NAID and 14% were IDA. Multivariate analysis demonstrated that factors associated with iron deficiency (SF </5 microg L(-1)) included age, duration of breast-feeding and cows' milk intake. Iron deficiency is common in our young population. Additional strategies to prevent IDA need be developed and evaluated in Australian infants.
9,633,970	eng	[ "D000773", "D001034", "D002585", "D005260", "D006301", "D006801", "D007231", "D008297", "D008485", "D010348", "D010372", "D011247", "D011446", "D012151", "D012307", "D013648" ]	[ "Anesthesia, Obstetrical", "Apgar Score", "Cesarean Section", "Female", "Health Services Needs and Demand", "Humans", "Infant, Newborn", "Male", "Medical Audit", "Patient Care Team", "Pediatrics", "Pregnancy", "Prospective Studies", "Resuscitation", "Risk Factors", "Tasmania" ]	1998	Jun	Is a paediatrician needed at all Caesarean sections? The need for a skilled neonatal resuscitator in the form of a paediatrician or paediatric registrar to attend a vaginal delivery or Caesarean section (CS) is not clearly defined. This study was undertaken in order to ascertain the level of resuscitation a neonate might require dependent on the delivery mode and type of anaesthesia used. We analysed the Tasmanian Obstetric Audit from 1980 to 1989 for the need for intubation and Apgar scores at 1 min of term singleton deliveries by the mode of delivery. The number of singleton term deliveries was 64739. When the data were analysed annually there was a trend for a reduction in the need for intubation in CS deliveries during the first 5 years, although this was not paralleled by an improvement in Apgar scores. Thus the intubation rate data are also presented for the last 5 years of the study. The intubation rate, Apgar score at 1 min of < 4, and Apgar score at 1 min of > or = 4 < 7 for repeat CS under epidural anaesthesia were 0.55% (0.26% for 1985-89) 0.83% and 3.58%, respectively, with relative risks when compared with spontaneous normal vaginal delivery of 1.8 (1.2 for 1985-89), 0.7 and 0.5, respectively. The relative risk of these outcomes was higher than for normal vaginal delivery for all other modes of delivery including repeat CS under general anaesthesia. It is concluded that a paediatrician or paediatric registrar is not required to routinely attend repeat CS under epidural anaesthesia, but should be present for repeat CS under general anaesthesia.
9,633,973	eng	[ "D000293", "D001315", "D002648", "D002675", "D003431", "D004739", "D005260", "D007722", "D006801", "D008297", "D009381", "Q000209", "Q000517", "D009520", "D012878", "Q000209", "Q000517", "D013471", "Q000209", "Q000517", "D013472", "Q000009", "D013473", "Q000008" ]	[ "Adolescent", "Australia", "Child", "Child, Preschool", "Cross-Cultural Comparison", "England", "Female", "Health Knowledge, Attitudes, Practice", "Humans", "Male", "Neoplasms, Radiation-Induced", "New Zealand", "Skin Neoplasms", "Sunburn", "Sunlight", "Sunscreening Agents" ]	1998	Jun	Children's understanding of sun protection behaviours: a comparative analysis. To investigate awareness of sun protection behaviours in a sample of primary school children in New Zealand. Information was collected from 824 primary school children in New Zealand using a drawing and writing technique. The data revealed a bias towards sunscreen as a method of sun protection compared with other methods such as clothing and the use of shade. Comparisons between results obtained from children resident in Australia and England indicated a greater awareness of sun protection methods amongst the children from Australia and New Zealand compared with those children living in England. Children as young as 5 and 6 can describe the consequences of overexposure to the sun, and can illustrate methods of sun protection. Sunscreen is seen as the main method of sun protection.
9,633,974	eng	[ "D000328", "D001521", "D019052", "Q000175", "Q000523", "Q000628", "D005260", "D005500", "D006801", "D007223", "D008297", "D010348", "D012892" ]	[ "Adult", "Behavior Therapy", "Depression, Postpartum", "Female", "Follow-Up Studies", "Humans", "Infant", "Male", "Patient Care Team", "Sleep Deprivation" ]	1998	Jun	Sleep deprivation or postnatal depression in later infancy: separating the chicken from the egg. To explore the association between maternal distress and depression in the first years of a newborn's life and the child's sleeping behaviour and problems associated with this behaviour. To asses the effectiveness of an outpatient-based individualised behaviour modification programme to modify children's sleep behaviour and to decrease levels of maternal distress and depression. Families were referred to an outpatient childhood sleep problems clinic. Intervention consisted of an individualised management programme including recognised modes of child sleep behaviour management ('controlled crying', 'cold turkey,' rewards) together with occasional use of short-term (less than 2 weeks) tapering dose sedating medication for the child. Two months after the initial contact with the clinic, families completed a second questionnaire collating similar data to that collected at time of enrolment. A total of 114 consecutive families referred to the clinic provided initial data. Follow-up questionnaires were returned by 70 (61%). Significant change was recorded in children's sleep parameters including reduction in mean number of night time awakenings (4.1-1.3, P < 0.001), proportion of children requiring longer than 30 min to settle at night (49% to 21%, P < 0.01) and in the proportion of children settling after 8 pm (51% to 33%, P < 0.01). Sleep problem rating on a 0-10 scale decreased from a mean of 8.1-3.1 (P < 0.001). On initial assessment, 40% of mothers had Edinburgh Postnatal Depression Scale (EPNDS) scores greater than 12 (screening cut-off point). At repeat assessment, 4.3% had scores greater than 12. The mean score on the EPNDS fell from 11.2 to 5.8 (P < 0.001). An outpatient-based individualised approach to modifying children's problematic sleep behaviour using recognised behaviour management techniques is effective. Modification of problematic childhood sleep behaviour is associated with significant improvement in maternal mood. Given the high incidence of childhood sleep problem and diagnosed postnatal depression, it is likely significant numbers of mothers being diagnosed as having postnatal depression are suffering the effects of chronic sleep deprivation. Management of postnatal mood disorder and childhood sleep behaviour must occur with due recognition to their close association.
9,633,976	eng	[ "D000293", "D001925", "Q000175", "Q000453", "Q000628", "D002648", "D002653", "Q000175", "Q000453", "Q000628", "D015897", "D002658", "Q000175", "Q000453", "Q000628", "D005260", "D006801", "D008297", "D019965", "Q000175", "Q000453", "Q000628", "D009483", "D010348", "D012114", "D014904" ]	[ "Adolescent", "Brain Damage, Chronic", "Child", "Child Behavior Disorders", "Comorbidity", "Developmental Disabilities", "Female", "Humans", "Male", "Neurocognitive Disorders", "Neuropsychological Tests", "Patient Care Team", "Residential Treatment", "Western Australia" ]	1998	Jun	Paediatric assessment in a residential child and adolescent psychiatry unit. To document the health status, comorbidity and functional impairments experienced by a group of psychiatrically disturbed children and adolescents. A detailed study of consecutive admissions to a residential unit over a two-year period was undertaken. All admissions had a comprehensive paediatric, speech pathology and psychiatric assessment. Compared to the general population, there was a significant history of developmental delay and low birthweight, but only a slightly greater prevalence of antenatal problems. Clumsiness (37%), severe speech and language disorder (32%), and hearing loss (15%) were prominent. Only 25% had no history of comorbid medical or neurological disorders. Children and adolescents presenting with moderate to severe mental health morbidity may have pre-existing comorbid medical problems, as well as unrecognised difficulties and impairments in other skills areas. Multidisciplinary assessment and intervention should be an integral part of the residential programme.
9,633,975	eng	[ "D000223", "D000293", "D000328", "D002648", "D002662", "D019052", "Q000175", "Q000523", "D005260", "D006801", "D007223", "D008297", "D009034", "D010343", "D011247", "D011248", "Q000175", "Q000523", "D012307", "D012892", "D012893", "Q000175", "Q000523" ]	[ "Adaptation, Psychological", "Adolescent", "Adult", "Child", "Child Health Services", "Depression, Postpartum", "Female", "Humans", "Infant", "Male", "Mother-Child Relations", "Patient Admission", "Pregnancy", "Pregnancy Complications", "Risk Factors", "Sleep Deprivation", "Sleep Wake Disorders" ]	1998	Jun	Childhood sleep problems: association with prenatal factors and maternal distress/depression. To determine whether problems with childhood sleep behaviour are associated with either maternal sleep patterns and emotional status during the pregnancy period, or levels of maternal distress and depression during the postnatal period. A case/control comparison study. Cases were families presenting for admissions to a mother/baby hospital in Brisbane with the major presenting problem being the child's sleep behaviour. The control group consisted of families presenting for well child health care to one of four child health centres in suburban Brisbane. Each participating mother provided information by way of a self-report questionnaire on social and demographic variables, children's sleep patterns, maternal emotional adjustment and maternal sleep pattern during the pregnancy, and current problem with child's sleep behaviour. Current level of maternal distress/depression, was measured using the Edinburgh Postnatal Depression Scale. Cases were compared with controls on all these variables. Significant differences were found between groups in childhood sleep parameters, degree of problem related to childhood sleep, maternal sleep variables during the entire pregnancy, and current levels of maternal distress/depression. The origins of problematic childhood sleep behaviour may lie in the pregnancy period. Levels of maternal distress and depression are associated with problematic childhood sleep behaviour. The issue of whether childhood sleep problem predisposes to maternal distress/depression needs exploration. Assessment of maternal mood disorder or childhood sleep problems should be comprehensive and involve both the maternal infant dyad and the family network.
9,633,977	eng	[ "D000328", "D000361", "Q000175", "Q000235", "Q000276", "D001402", "Q000276", "D002648", "D002675", "D005091", "D005260", "D006580", "D006801", "D007223", "D008297", "D016133", "D011944", "Q000235", "D016511", "Q000175", "Q000235", "Q000276", "D012729", "Q000235", "D013601", "Q000276", "D018911", "Q000235", "D014960" ]	[ "Adult", "Agammaglobulinemia", "B-Lymphocytes", "Child", "Child, Preschool", "Exons", "Female", "Genetic Carrier Screening", "Humans", "Infant", "Male", "Polymerase Chain Reaction", "Receptors, Androgen", "Severe Combined Immunodeficiency", "Sex Chromosome Aberrations", "T-Lymphocytes", "Trinucleotide Repeats", "X Chromosome" ]	1998	Jun	Carrier identification in X-linked immunodeficiency diseases. Carrier identification in X-linked immunodeficiency disorders can be based on the demonstration of non-random X inactivation (NRXI) in affected blood cell lineages when growth is impaired in cells expressing the abnormal gene. We examined the utility of seeking evidence of NRXI to test the carrier status of women in families affected by X-linked severe combined immunodeficiency (XSCID) and X-linked hypogammaglobulinaemia (XLH), to identify as carriers the mothers of boys with SCID or hypogammaglobulinaemia whose phenotype suggested X-linkage and to infer X-linkage in boys with SCID or hypogammaglobulinaemia whose disease was not clearly X-linked on the basis either of family history or clinical and immunological characteristics. A polymerase chain reaction-based method was used to amplify a polymorphic CAG repeat in the first exon of the androgen receptor gene after selective digestion of the active X chromosome with a methylation-sensitive enzyme, HpaII to distinguish between the paternal and maternal alleles and to identify their methylation status. Heterozygosity was found in 24 of 31 female subjects (77%). As anticipated, NRXI could be demonstrated in all lymphoid cells studied from obligate carriers of XSCID and an obligate carrier of XLH but not on a carrier of X-linked immunodeficiency with hyper-IgM. The finding of NRXI in the mother of a boy with a SCID variant showed her to be a carrier of XSCID and establishes that her son has XSCID, not otherwise evident from available data. This PCR assay provides a rapid method for carrier detection of X-linked immunodeficiencies, and has allowed us to expand the phenotype of XSCID
9,633,978	eng	[ "D001289", "Q000188", "D002606", "Q000008", "D002648", "D002653", "Q000188", "Q000453", "D002675", "D003000", "Q000506", "Q000627", "D003422", "D005260", "D005751", "D006801", "D007223", "D007902", "D008297", "D011041", "Q000453", "Q000517", "Q000628", "D011379", "D013565", "Q000506", "Q000627", "D013981", "Q000188" ]	[ "Attention Deficit Disorder with Hyperactivity", "Charcoal", "Child", "Child Behavior Disorders", "Child, Preschool", "Clonidine", "Critical Care", "Female", "Gastric Lavage", "Humans", "Infant", "Length of Stay", "Male", "Poisoning", "Prognosis", "Sympatholytics", "Tic Disorders" ]	1998	Jun	Clonidine poisoning--an emerging problem: epidemiology, clinical features, management and preventative strategies. To ascertain whether the incidence of clonidine poisoning in children has increased given the probable increase in clonidine use for treatment of childhood behavioural disorders. Cases of clonidine poisoning requiring hospital admission between 1985-95 inclusive were reviewed and demographic data pertinent to each admission were recorded. A literature review was also performed, with particular emphasis on incidence, clinical presentation and management of clonidine poisoning. There were 14 cases of clonidine poisoning during the specified period eight cases presenting in the last 2 years. These eight children or their siblings had been prescribed clonidine for behavioural disorders. The most common signs at presentation were alteration of conscious state (71%) and bradycardia (50%). Nine children were given activated charcoal while seven cases underwent gastric lavage or induced emesis. Although six children were admitted to intensive care, length of hospital stay was less than 24 h in all cases and all had a favourable outcome. We concluded that the incidence of clonidine poisoning had increased over the specified period and that, based on our results, this was likely to be due to an increase in clonidine use in childhood behavioural disorders. Based on our data and that from literature review it was evident that there are inconsistencies in the management of clonidine poisoning and that safety measures, namely packaging and education, are inadequate given the increasing profile of clonidine use.
9,633,980	eng	[ "D000293", "D001289", "Q000188", "Q000523", "D001294", "D000697", "Q000009", "Q000627", "D002648", "D002675", "D018592", "D003913", "Q000009", "Q000627", "D004305", "D004334", "D005260", "D006801", "D008297", "D008774", "Q000009", "Q000627", "D010290", "Q000523", "D017060", "D010552", "D016896" ]	[ "Adolescent", "Attention Deficit Disorder with Hyperactivity", "Attitude to Health", "Central Nervous System Stimulants", "Child", "Child, Preschool", "Cross-Over Studies", "Dextroamphetamine", "Dose-Response Relationship, Drug", "Drug Administration Schedule", "Female", "Humans", "Male", "Methylphenidate", "Parents", "Patient Satisfaction", "Personality Assessment", "Treatment Outcome" ]	1998	Jun	Child and parent perceptions of stimulant medication treatment in attention deficit hyperactivity disorder. To evaluate child and parent perceptions of treatment with stimulant medication in a sample of children with attention deficit hyperactivity disorder (ADHD). Child and parent perceptions questionnaires were completed for 102 subjects participating in a double-blind, crossover trial of methylphenidate (MPH) and dexamphetamine (DEX). Most children viewed medication effects favourably, although 12.7% and 18.8% of children reported feeling worse than usual when taking MPH and DEX, respectively. There was disagreement between the child's and parents' perceptions of response in over one quarter of cases. Most disagreements involved parents viewing the child's response favourably, but the child rating reporting an unfavourable outcome. Side-effects were the main determinant of children's perceptions of adverse response. A substantial proportion of children with ADHD experience treatment with stimulant medication adversely. Side-effects are the principal determinant of negative child perceptions. Parental report is usually in agreement with child report; however, parental report alone is not infallible in providing reliable information regarding effects as experienced by the child.
9,633,979	eng	[ "D001921", "Q000473", "D001932", "Q000175", "Q000235", "D002648", "D002675", "D003952", "D005260", "D006338", "Q000175", "Q000235", "D006801", "D007223", "D007231", "D008297", "D009206", "Q000473", "D009460", "D012640", "Q000209", "D014402", "Q000175", "Q000235" ]	[ "Brain", "Brain Neoplasms", "Child", "Child, Preschool", "Diagnostic Imaging", "Female", "Heart Neoplasms", "Humans", "Infant", "Infant, Newborn", "Male", "Myocardium", "Neurologic Examination", "Seizures", "Tuberous Sclerosis" ]	1998	Jun	Cardiac manifestations in tuberous sclerosis: a 10-year review. Tuberous sclerosis is a genetic disorder with multisystem involvement. The aim of this study was to focus primarily on the cardiac aspects of this condition. This review included 10 children with tuberous sclerosis presenting to our department during a 10-year period. From our data, 80% were found to have cardiac involvement. There was an equal prevalence of neurologic complications. Cardiac tumours and seizures were the most common problems encountered. Whereas most patients had no symptoms referable to the cardiovascular system and required no active intervention, many of those with neurologic involvement needed appropriate treatment.
9,633,982	eng	[ "D016470", "Q000000981", "D004292", "Q000502", "D004927", "Q000000981", "D005066", "D005260", "D005317", "Q000000981", "D006408", "Q000000981", "D006801", "D006849", "Q000000981", "D007231", "D007235", "Q000000981", "D019102", "D007710", "Q000000981", "D007711", "D018447", "D014057" ]	[ "Bacteremia", "Dominance, Cerebral", "Escherichia coli Infections", "Euthanasia, Passive", "Female", "Fetal Growth Retardation", "Hematoma, Subdural", "Humans", "Hydrocephalus", "Infant, Newborn", "Infant, Premature, Diseases", "Infant, Very Low Birth Weight", "Klebsiella Infections", "Klebsiella pneumoniae", "Medical Futility", "Tomography, X-Ray Computed" ]	1998	Jun	Massive subdural haematoma: an unusual complication of septicaemia in preterm very low birthweight infants. Non-traumatic massive subdural haematoma is a rare condition in newborn infants and is usually associated with hereditary coagulation disorders or congenital vascular malformation. Its occurrence in preterm very low birthweight infants secondary to systemic bacterial infection has not been reported. We describe two extremely preterm neonates who developed massive subdural haematoma as a result of gram-negative septicaemia and disseminated intravascular coagulation. Both infants suffered severe parenchymal cerebral injury and hydrocephalus. Clinicians should be aware of this unusual and catastrophic complication if a very low birthweight infant with severe sepsis and disseminated intravascular coagulation suddenly deteriorates despite successful treatment with antibiotics. Radiological imaging by cranial ultrasound or computed tomography scanning should be routinely considered in all such infants for the detection of intracranial bleeding.
9,633,981	eng	[ "D002648", "D003937", "D006801", "D006977", "Q000000981", "Q000601", "D008297", "D009392", "D014398", "Q000000981", "Q000601", "D014517", "Q000000981", "Q000601", "D014567" ]	[ "Child", "Diagnosis, Differential", "Humans", "Hypertension, Renal", "Male", "Nephrectomy", "Tuberculosis, Renal", "Ureteral Obstruction", "Urography" ]	1998	Jun	Renal tuberculosis in an Australian-born child. This report describes a case of renal tuberculosis, complicated by hypertension and ureteric obstruction, in a previously well Australian born child. Despite antituberculous chemotherapy and ureteric stenting, there was a progressive loss of renal function in the right kidney until surgical nephrectomy allowed full recovery. A high level of clinical suspicion is necessary for a diagnosis of genitourinary tuberculosis. Ureteric cicatrisation and obstruction occasionally may occur with healing, and therefore serial renal tract imaging during treatment is necessary to detect this complication.
9,633,983	eng	[ "D003937", "D004900", "D017707", "D005260", "D005500", "D006452", "D006801", "D007223", "D002546", "Q000097", "Q000175", "Q000628", "D009460" ]	[ "Diagnosis, Differential", "Erythroblasts", "Erythrocyte Transfusion", "Female", "Follow-Up Studies", "Hemoglobinometry", "Humans", "Infant", "Ischemic Attack, Transient", "Neurologic Examination" ]	1998	Jun	Transient erythroblastopenia of childhood associated with transient neurologic deficit: report of a case and review of the literature. Patients with transient erythroblastopenia of childhood (TEC) may also have a transient neurologic disorder. We present a case history and propose a mechanism for this syndrome. PATIENT AND METHODOLOGY: We describe a 20-month-old girl with TEC and transient hemiparesis. Records from the period January 1993 through December 1994 were reviewed to identify other patients with TEC and to determine whether neurologic deficits were noted in these cases. Of seven patients diagnosed with TEC over a 2-year period, only one had a neurologic deficit. This child's hemiparesis resolved within 24 h after the appearance of her symptoms. Her TEC resolved within 4 weeks, without long-term sequelae. Our experience and review of the literature suggest that focal neurologic deficits in TEC patients are uncommon, transient, lack long-term sequelae, and usually resolve prior to hematologic recovery. Previous reports suggested that the anaemia resulting from TEC might induce neurologic deficits. We suggest an alternative mechanism in which viral infection triggers a host immune response that independently leads to both TEC and neurologic abnormalities. Future studies should address the role of viral infection in TEC patients with focal neuropathies.
9,633,984	eng	[ "D000592", "Q000175", "Q000235", "Q000652", "D002547", "Q000175", "Q000201", "Q000235", "D002675", "D003937", "D004421", "Q000175", "Q000201", "Q000235", "D005260", "D005977", "Q000652", "D050770", "D006801", "D007223", "D008297", "D008928", "Q000201", "D009069", "Q000175", "Q000201", "Q000235", "D010088", "Q000172", "D044925", "D011296" ]	[ "Amino Acid Metabolism, Inborn Errors", "Cerebral Palsy", "Child, Preschool", "Diagnosis, Differential", "Dystonia", "Female", "Glutarates", "Glutaryl-CoA Dehydrogenase", "Humans", "Infant", "Male", "Mitochondria", "Movement Disorders", "Oxidoreductases", "Oxidoreductases Acting on CH-CH Group Donors", "Prenatal Diagnosis" ]	1998	Jun	Glutaric aciduria type 1: an underdiagnosed cause of encephalopathy and dystonia-dyskinesia syndrome in children. Two cases of glutaric aciduria type 1 (GA 1) are presented. GA 1 is probably underdiagnosed and misdiagnosed, and may explain a proportion of cases of extrapyramidal and 'postencephalitic' cerebral palsy. Most cases of GA 1 present with a severe dystonic-dyskinetic syndrome following an acute encephalopathy. Asymptomatic cases have also been described, complicating genetic counselling and prenatal diagnosis. We raise awareness of GA 1 and stress that if clinically suspected, immediate institution of therapy may reduce late morbidity. Moreover, if recognised in the presymptomatic stage, early institution of treatment may prevent the onset of neurological symptoms. GA 1 is an inborn error of lysine and tryptophan catabolism, caused by deficiency of the enzyme, glutaryl coenzyme-A dehydrogenase. Urine organic acid analyses may be negative. Blood acylcarnitine profile has recently been employed as a more sensitive test but was negative in both our patients. Enzyme assay remains the definitive diagnostic test.
9,633,989	eng	[ "D000900", "Q000737", "Q000494", "D001896", "Q000737", "Q000494", "D004351", "Q000235", "D006571", "Q000737", "Q000494", "D009154", "D013329" ]	[ "Anti-Bacterial Agents", "Boron Compounds", "Drug Resistance", "Heterocyclic Compounds", "Mutation", "Structure-Activity Relationship" ]	1998	May	Mechanism of action of diazaborines. The diazaborine family of compounds have antibacterial properties against a range of gram-negative bacteria. Initially, this was thought to be due to the prevention of lipopolysaccharide synthesis. More recently, the molecular target of diazaborines has been identified as the NAD(P)H-dependent enoyl acyl carrier protein reductase (ENR), which catalyses the last reductive step of fatty acid synthase. ENR from Mycobacterium tuberculosis is the target for the front-line antituberculosis drug isoniazid. The emergence of isoniazid resistance strains of M. tuberculosis, a chronic infectious disease that already kills more people than any other infection, is currently causing great concern over the prospects for its future treatment, and it has reawakened interest in the mechanism of diazaborine action. Diazaborines only inhibit ENR in the presence of the nucleotide cofactor, and this has been explained through the analysis of the x-ray crystallographic structures of a number of Escherichia coli ENR-NAD+-diazaborine complexes that showed the formation of a covalent bond between the boron atom in the diazaborines and the 2'-hydroxyl of the nicotinamide ribose moiety that generates a noncovalently bound bisubstrate analogue. The similarities in catalytic chemistry and in the conformation of the nucleotide cofactor across the wider family of NAD(P)-dependent oxidoreductases suggest that there are generic opportunities to mimic the interactions seen here in the rational design of bisubstrate analogue inhibitors for other NAD(P)H-dependent oxidoreductases.
9,633,990	eng	[ "D019380", "Q000008", "Q000494", "D002986", "D015224", "Q000494", "D004357", "D004359", "D004791", "Q000494", "D015497", "Q000187", "D006801", "D006918", "Q000008", "Q000494", "D012264", "Q000037", "D015215", "Q000008", "Q000494" ]	[ "Anti-HIV Agents", "Clinical Trials as Topic", "Dideoxynucleosides", "Drug Synergism", "Drug Therapy, Combination", "Enzyme Inhibitors", "HIV-1", "Humans", "Hydroxyurea", "Ribonucleotide Reductases", "Zidovudine" ]	1998	May	Selective depletion of DNA precursors: an evolving strategy for potentiation of dideoxynucleoside activity against human immunodeficiency virus. Human immunodeficiency virus type 1 (HIV-1) is wholly dependent on its host cell for a variety of essential metabolites. Among the latter are the deoxynucleoside-5'-triphosphates (dNTPs) required for reverse transcription of the single-stranded RNA viral genome into double-stranded viral DNA. Since viral DNA synthesis has an absolute requirement for all four dNTPs, restriction of a single one of these is sufficient to inhibit HIV-1 replication. To date, this therapeutic strategy has been most successful when depletion of the individual dNTP is coupled with exposure to its corresponding chain-terminating dideoxynucleoside (ddN). While several examples of such combined therapy have been defined and studied in vitro, that which has been investigated most extensively at both the laboratory and the clinical level is ddATP exposure combined with dATP depletion [with dATP restriction being induced by the ribonucleotide reductase inhibitor hydroxyurea (HU) and ddATP generated from its prodrug 2',3'-dideoxyinosine (ddI)]. Several long-term clinical trials of the hydroxyurea/2',3'-dideoxyinosine combination have been completed, with plasma viral RNA being reduced to undetectable levels in a substantial fraction (one-third to one-half) of the patients treated. The major advantages of this and analogous combinations discussed in this review are their low cost relative to other current multiple drug protocols and their potential for retention of activity against drug-resistant HIV mutants.
9,633,991	eng	[ "D000082", "Q000009", "Q000493", "D000818", "D001189", "D001711", "D019392", "Q000378", "D065691", "D051544", "D065607", "D003577", "Q000378", "D004357", "D004791", "Q000494", "D000431", "Q000009", "Q000494", "D008099", "Q000187", "D010089", "Q000037", "Q000378", "D013375" ]	[ "Acetaminophen", "Animals", "Aryl Hydrocarbon Hydroxylases", "Biotransformation", "Cytochrome P-450 CYP2E1", "Cytochrome P-450 CYP2E1 Inhibitors", "Cytochrome P-450 CYP3A", "Cytochrome P-450 Enzyme Inhibitors", "Cytochrome P-450 Enzyme System", "Drug Synergism", "Enzyme Inhibitors", "Ethanol", "Liver", "Oxidoreductases, N-Demethylating", "Substance Withdrawal Syndrome" ]	1998	May	Alcohol-mediated increases in acetaminophen hepatotoxicity: role of CYP2E and CYP3A. This commentary focuses on the roles of CYP3A and CYP2E in alcohol-mediated increases in acetaminophen hepatotoxicity. CYP2E has been considered to be the main form of P450 responsible for such toxicity in animals and humans. However, CYP3A, which is also induced by alcohol, has been shown to have a greater affinity for acetaminophen than CYP2E. Previous experiments implicating CYP2E in alcohol-mediated increases in acetaminophen hepatotoxicity have used inhibitors of this form of P450 that are now proving to be non-specific. Triacetyloleandomycin (TAO) is a potent inhibitor of CYP3A that maintains specificity in vitro over a large concentration range. In rats treated with ethanol or the combination of ethanol and isopentanol, the major higher chain alcohol in alcoholic beverages, TAO protects animals from increases in acetaminophen hepatotoxicity, suggesting a major role of CYP3A. CYP2E may not have a major role due to the rapid loss of induced levels in the absence of continued exposure to ethanol. Knockout mice, which are being used to define the role of particular proteins in biological responses, have been developed for CYP2E1 and CYP1A2 but not CYP3A. Cyp2e1(-/-) and Cyp1a2(-/-) mice are more resistant to acetaminophen hepatotoxicity than wild-type strains, even though the amounts of the other forms of P450s are unaltered in the liver. These findings suggest that the relative amounts of P450s and not just kinetic characteristics determine their role in acetaminophen hepatotoxicity. The clinical implications of the findings that CYP3A can have a major role in acetaminophen-mediated hepatotoxicity are discussed.
9,633,992	eng	[ "D000998", "Q000494", "D001483", "D017931", "D004259", "Q000235", "D004352", "Q000235", "D006515", "Q000187", "Q000201", "Q000235", "D006801", "D019259", "Q000494", "D016297", "D009154", "D014407" ]	[ "Antiviral Agents", "Base Sequence", "DNA Primers", "DNA-Directed DNA Polymerase", "Drug Resistance, Microbial", "Hepatitis B virus", "Humans", "Lamivudine", "Mutagenesis, Site-Directed", "Mutation", "Tumor Cells, Cultured" ]	1998	May	Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance. L(-)SddC (3TC) has been shown to be the most promising nucleoside analogue used for the treatment of hepatitis B virus (HBV) infection. Unfortunately, it has been reported that about 12% of HBV-infected patients experience a recurrence of HBV after a period of treatment with 3TC. Point mutations were detected in the HBV polymerase of those viruses from 3TC-resistant patients. A common mutation occurred at methionine in the YMDD motif. In this report, we present mutants that were generated from the HBV genome (adr subtype) by site-directed mutagenesis based on clinical reports from other investigators. With the transient transfection system, it was found that by changing methionine to valine or isoleucine at the YMDD motif, the viral DNA replication would be more than 100-fold less efficient than that of the wild-type virus. Some additional mutations outside the YMDD motif could enhance the replication of the virus containing a YMDD mutation. Various levels of resistance to 3TC were observed in HBV mutants containing point mutations both inside and outside the YMDD motif. These results suggest that the mutations outside the YMDD motif compensate the YMDD mutation to some extent for the viral replication and may also contribute to clinical viral resistance to 3TC.
9,633,993	eng	[ "D000818", "D000838", "D003545", "Q000031", "Q000378", "Q000494", "D004952", "D005260", "D005978", "Q000031", "Q000378", "Q000494", "D066298", "D008168", "Q000187", "Q000378", "D051381", "D017208", "D013438", "Q000378", "D014132", "Q000187", "Q000378" ]	[ "Animals", "Anions", "Cysteine", "Esters", "Female", "Glutathione", "In Vitro Techniques", "Lung", "Rats", "Rats, Wistar", "Sulfhydryl Compounds", "Trachea" ]	1998	May	Elevation of endogenous nucleophiles in rat lung by cysteine and glutathione esters in vitro. In this study, we have compared the uptake of L-cysteine (L-CySH), D-cysteine (D-CySH), L-cysteine isopropyl ester (L-CIPE) and D-cysteine isopropyl ester (D-CIPE) in rat lung slices and tracheal sections and determined the effectiveness of glutathione (GSH), GSH isopropyl monoester, GSH isopropyl diester, gamma-glutamylcysteine (gamma-glu-cys) isopropyl monoester and gamma-glu-cys isopropyl diester to elevate and prolong intracellular GSH concentrations in rat lung slices. Lung slices were incubated with 1.0 mM of thiol and the concentrations determined intracellularly and extracellularly with time. Slices incubated with GSH, GSH isopropyl diester and gamma-glu-cys isopropyl diester had cellular GSH concentrations increased by up to 60%, 95% and 58%, respectively, whereas GSH isopropyl monoester and gamma-glu-cys isopropyl monoester did not increase the intracellular GSH concentration. Extracellularly, the GSH concentration had decreased by 15%, GSH isopropyl diester by 27%, gamma-glu-cys isopropyl diester by 66% and both isopropyl monoesters by over 90% at 120 min. Lung slices and tracheal sections incubated with L- or D-CySH at 37 degrees had increased cellular concentrations of L- and D-CySH which ranged between 0.88-1.25 nmol mg(-1) and 1.35-2.25 nmol mg(-1) , respectively. Reducing the incubation temperature to 4 degrees had little effect on the accumulation of D-CySH; however, L-CySH concentrations increased progressively in the trachea and lung to reach 2.73 and 2.63 nmol mg(-1) at 90 min, respectively. Lung slices incubated with L- or D-CIPE had increased L- or D-CySH concentrations up to a max of 13.7 and 11.1 nmol mg(-1) and tracheal sections up to a max of 5.56 and 11.09 nmol mg(-1). In the lung slice medium, L- and D-CIPE levels had decreased by 75.2% and 74.0% at 90 min, respectively, and from the tracheal section medium, L- and D-CIPE concentrations had decreased by 66.7% and 32.7%, respectively. Preincubation of lung slices and tracheal sections with the carboxylesterase inhibitor, bis (p-nitrophenyl) phosphate (BNPP), almost completely prevented the disappearance of L- and D-CIPE extracellularly and greatly reduced the appearance of cellular L- and D-CySH. GSH, GSH isopropyl diester and gamma-glu-cys isopropyl diester elevated and prolonged GSH concentrations in rat lung slices, but GSH isopropyl monoester and gamma-glu-cys isopropyl monoester did not increase GSH levels. The uptake of L-CySH, but not D-CySH, is temperature sensitive in rat lung slices and tracheal sections and carboxylesterases appear to have a major influence on the uptake and metabolism of L- and D-CIPE by rat lung slices and tracheal sections.
9,633,994	eng	[ "D000818", "D003907", "Q000494", "D004851", "Q000037", "Q000235", "Q000378", "D005720", "D015971", "Q000187", "Q000528", "D005982", "Q000037", "Q000235", "Q000378", "D008099", "Q000201", "Q000473", "Q000528", "D008297", "D051379", "D008813", "D011719", "Q000494", "D011837", "Q000494", "D015996", "D013871", "D013876" ]	[ "Animals", "Dexamethasone", "Epoxide Hydrolases", "Gamma Rays", "Gene Expression Regulation, Enzymologic", "Glutathione Transferase", "Liver", "Male", "Mice", "Mice, Inbred ICR", "Pyrazines", "Radiation-Protective Agents", "Survival Rate", "Thiones", "Thiophenes" ]	1998	May	In vivo radioprotective effects of oltipraz in gamma-irradiated mice. Previous studies in this laboratory have shown that oltipraz (Olt), a chemopreventive agent, enhances radiation(Rad)-inducible glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) expression in the liver. The present study was designed to investigate the in vivo radioprotective effect of Olt in ICR mice exposed to a lethal dose of Rad. The 30-day survival rate of mice irradiated at the dose of 8 Gy was substantially increased to 91% by Olt pretreatment (100 mg/kg/day for 2 days), compared with 48% in animals irradiated alone. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray Rad resulted in hepatocyte degeneration in the surviving animals from Day 1 through Day 22 after irradiation with certain degrees of necrosis observed at early times, whereas Olt treatment provided protection of the liver against irradiation with no hepatic necrosis noted. Mice irradiated at the dose of 8 Gy exhibited time-related decreases in the white blood cell (WBC), red blood cell (RBC), and platelet counts with maximal reduction noted at Day 10. Animals irradiated with Olt treatment showed no difference in peripheral blood cell counts or in the ratio of myeloid to erythroid bone marrow cells, compared with those irradiated alone. Northern RNA blot analysis showed that treatment of mice with Olt at the dose of 100 mg/kg in combination with 8 Gy irradiation resulted in 12-fold increases in hepatic mEH and mGSTA3 mRNA levels at 24-hr post-treatment, whereas mGSTP1 mRNA levels were not altered. The mRNA levels for mEH and mGSTA3 were elevated after exposure of animals to both Olt and 8 Gy-gamma ray to a greater extent than after irradiation alone. The enhanced survival rate (91%) in 8 Gy-irradiated animals after treatment with Olt (100 mg/kg/day for 2 days) was completely reversed by concomitant pretreatment with dexamethasone (Dexa) (0.1 and 1 mg/kg/day for 2 days), a known inhibitor of mEH and GST expression, resulting in a 42% and 28% survival rate, respectively. Mice irradiated after dexamethasone treatment at a dose of 1 mg/kg showed a reduced mean survival time compared with those treated with 0.1 mg/kg of dexamethasone (9 vs 14 days). The current study demonstrates that Olt is effective in increasing the survival rate of mice against ionizing Rad and that protective effects of Olt associated with enhanced expression of mEH and GST genes may represent its radioprotective efficacy.
9,633,995	eng	[ "D000085", "Q000494", "D002784", "Q000097", "D003300", "Q000097", "D006801", "D008077", "Q000097", "D018716", "D007470", "Q000494", "D010084", "D013970", "Q000494", "D014280", "Q000097" ]	[ "Acetates", "Cholesterol", "Copper", "Humans", "Lipoproteins, LDL", "Molecular Mimicry", "Monoiodotyrosine", "Oxidation-Reduction", "Thyronines", "Triglycerides" ]	1998	May	Effects of iodotyrosines, thyronines, iodothyroacetic acids and thyromimetic analogues on in vitro copper-induced oxidation of low-density lipoproteins. We studied the effect of different thyroid compounds [(I2, monoiodo-L-tyrosine (MIT), diiodo-L-tyrosine (DIT), L-thyronine (T0), 3,5-diiodo-L-thyronine (T2), 3,5,3'-triiodo-L-thyronine (T3), 3,3',5'-triiodo-L-thyronine (rT3), 3,5,3',5'-tetraiodo-L-thyronine (T4), 3,5-diiodothyroacetic acid (TA2), 3,5,3'-triiodothyroacetic acid (TA3) and 3,5,3',5'-tetraiodothyroacetic acid (TA4)] or thyromimetics [(3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) and 3,5-diiodo-3'-isopropyl-thyroacetic acid (IpTA2)] on in vitro copper-induced oxidation of low-density lipoproteins (LDL). Human native LDL (0.05 g protein/L) oxidation was induced by 2.5 micromol/L of CuCl2. Conjugated dienes were measured spectrophotometrically for up to 10 hr. The length of the lag phase (Tlag), maximum velocity of the reaction (Vmax) and the maximum amount of generated dienes were obtained from kinetic data. T3 increased Tlag and decreased Vmax with a dependence upon concentration (0 to 3 micromol/L). There was no difference between the Dmax obtained with Cu2+ alone or in the presence of the various compounds (1 micromol/L). I2, MIT and DIT did not modify any parameter of the oxidation kinetic. T0 and T2 had the same antioxidant efficiency as T3, whereas T4 only decreased Vmax. rT3 increased Tlag less than did T3, whereas DIMIT was the thyronine that had the most important effect. TA2 and TA, were the most efficient antioxidant compounds. TA4 decreased Tlag less than TA3 did, whereas IpTA2 had an effect weaker than that of the physiological acetic derivatives. The data suggest that thyroid hormones and derivatives have LDL-antioxidant properties, their importance being related to their 4'-hydroxy diphenyl ether structure and depending upon the nature and the position of substituents in this structure.
9,633,996	eng	[ "D000818", "D000906", "Q000276", "D037263", "D002478", "D000431", "Q000008", "D007457", "D008099", "Q000187", "Q000378", "D008297", "D008985", "Q000494", "D011485", "D011499", "D051381", "D017208", "D011956", "Q000187", "Q000276", "Q000378" ]	[ "Animals", "Antibodies", "Asialoglycoprotein Receptor", "Cells, Cultured", "Ethanol", "Iodine Radioisotopes", "Liver", "Male", "Monensin", "Protein Binding", "Protein Processing, Post-Translational", "Rats", "Rats, Wistar", "Receptors, Cell Surface" ]	1998	May	Differential effects of monensin on asialoglycoprotein receptor function after short-term ethanol administration. Chronic ethanol consumption is associated with multiple impairments in receptor-mediated endocytosis (RME) by the hepatic asialoglycoprotein receptor (ASGP-R). Previous work on this receptor has shown that its activity can be perturbed by the carboxylic ionophore monensin. This agent has been shown to preferentially affect receptor-ligand dissociation and receptor redistribution of one subset (State 2) of ASGP-R, while receptor function in a second subset (State 1 receptors) is unaffected. In the present study, we examined the effect of monensin on ASGP-R activity and intracellular receptor-ligand dissociation after 7-10 days of ethanol feeding, a time when we have shown altered ASGP-R function in ethanol-fed animals. Hepatocytes from male Wistar rats (fed an ethanol-containing or control diet) were utilized. Ethanol administration decreased total ligand binding by 35-40% (P < 0.01) without a change in receptor protein content. After monensin treatment, surface receptors on cells from control animals were inactivated and redistributed to the cell interior. In cells from ethanol-fed animals, a similar pattern of monensin-induced inactivation was shown, but no redistribution occurred. Intracellular receptor-ligand dissociation was impaired in both cell types, although the monensin-induced effect on dissociation was significantly less dramatic (two-fold) in the hepatocytes from ethanol-fed animals as compared with controls. Thus, although receptors on both cell types were susceptible to monensin, cells from the ethanol-fed animals were less vulnerable to the added effects of this agent. Since monensin affects functioning of State 2, but not State 1 receptors, a very early effect of ethanol may be a preferential impairment in the State 2 receptor population.
9,633,997	eng	[ "D000998", "Q000037", "Q000097", "Q000493", "D001086", "Q000031", "Q000037", "Q000097", "Q000493", "D001692", "D004176", "Q000494", "D004912", "Q000378", "D005461", "D006801", "D009682" ]	[ "Antiviral Agents", "Arabinofuranosyluracil", "Biological Transport", "Dipyridamole", "Erythrocytes", "Fluorine", "Humans", "Magnetic Resonance Spectroscopy" ]	1998	May	19F NMR study of the uptake of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil in erythrocytes: evidence of transport by facilitated and nonfacilitated pathways. The 19F NMR resonances of intra- and extracellular 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) in suspensions of human erythrocytes are well resolved. This phenomenon allows its transport behavior to be monitored in a 19F NMR time-course experiment. The rate of L-FMAU uptake at 25 degrees in a suspension containing L-FMAU at an initial extracellular concentration of 4 mM was 7.6 +/- 1.0 x 10(-7) pmol cell(-1) sec(-1) (N = 5). Concentration-dependent uptake studies of L-FMAU indicate the existence of both saturable and nonsaturable transport mechanisms, with a Km for the saturable uptake of approximately 1 mM. Although the transport of L-FMAU at 25 degrees was inhibited significantly (54-65%) by nitrobenzylthioinosine (NBTI) and dipyridamole, consistent with the participation of the nucleoside transporter, these inhibitors did not achieve complete blockage of L-FMAU uptake. The participation of the nucleobase transporter in L-FMAU uptake was ruled out by the absence of competition with uracil uptake, and by the lack of inhibition by papaverine. In addition, the NBTI-insensitive uptake of L-FMAU was not affected by pretreatment of the cells with the sulfhydryl reagent, p-chloromercuriphenylsulfonic acid (pCMBS). However, the NBTI- and dipyridamole-insensitive transport of L-FMAU was found to increase upon treatment of the erythrocytes with butanol, an agent that affects membrane fluidity. The partition coefficient of L-FMAU in octanol/phosphate-buffered saline determined by absorption spectrophotometry was 0.31. These data indicate that under the conditions of the studies, L-FMAU uptake by erythrocytes proceeds by both the nucleoside transporter and nonfacilitated membrane diffusion.
9,633,998	eng	[ "D000818", "D002374", "Q000494", "D002478", "D004247", "Q000378", "D015971", "Q000187", "D007375", "Q000494", "D007700", "D009131", "Q000166", "Q000187", "Q000201", "D011451", "Q000235", "D012333", "Q000096", "Q000235", "D051381", "D014157", "Q000378" ]	[ "Animals", "Catalase", "Cells, Cultured", "DNA", "Gene Expression Regulation, Enzymologic", "Interleukin-1", "Kinetics", "Muscle, Smooth, Vascular", "Prostaglandin-Endoperoxide Synthases", "RNA, Messenger", "Rats", "Transcription Factors" ]	1998	May	Regulation of cyclo-oxygenase gene expression in rat smooth muscle cells by catalase. We have studied, in detail, the effect of catalase, one of the naturally occurring antioxidant enzymes, on the expression of cyclo-oxygenase (COX) mRNA and protein in rat aortic smooth muscle cells (RASMC). The activity of COX enzyme within the cells was also determined. Catalase either alone or in combination with interleukin-1beta (IL-1beta) enhanced mRNA and protein expression for cyclo-oxygenase 2 (COX-2) in a concentration-dependent manner. However, it did not affect the expression of mRNA or protein for cyclo-oxygenase 1 (COX-1). The expression of mRNA for COX-2 induced by catalase was blocked completely by actinomycin D (ACT) or cycloheximide (CHX). In comparison, expression of mRNA for COX-2 stimulated by IL-1beta was inhibited by actinomycin D, but not by cycloheximide. This suggests that induction of the synthesis of mRNA for COX-2 by catalase and IL-1beta involves different mechanisms. In particular, the induction of mRNA for COX-2 by catalase requires on-going protein and RNA synthesis, but the induction following exposure to IL-1beta does not. The increase in expression of mRNA for COX-2 induced by catalase may be related to the ability of catalase to stimulate cyclic AMP response element (CRE) and NF-IL6 transcription factors, but not nuclear factor kappa B (NF-kappaB), for electrophoretic mobility shift assays (EMSA) showed that catalase enhanced nuclear factor binding to cyclic AMP response element and NF-IL6 but not to NF-kappaB. Catalase exerted a biphasic effect on prostaglandin synthesis. At low concentrations it enhanced prostaglandin production, but at high concentrations it tended to inhibit it. These findings suggest that catalase has differential and multiple effects on COX expression and activity in rat aortic smooth muscle cells.
9,633,999	eng	[ "D000818", "D000911", "Q000494", "D001189", "D002460", "D065702", "D065607", "D003577", "Q000378", "D003975", "Q000378", "D006801", "D008099", "Q000201", "D051379", "D008807", "D010089", "Q000037", "Q000378", "D010616", "Q000378", "D011994", "Q000037", "D018411", "D013379" ]	[ "Animals", "Antibodies, Monoclonal", "Aryl Hydrocarbon Hydroxylases", "Cell Line", "Cytochrome P-450 CYP2B6", "Cytochrome P-450 Enzyme Inhibitors", "Cytochrome P-450 Enzyme System", "Diazepam", "Humans", "Liver", "Mice", "Mice, Inbred BALB C", "Oxidoreductases, N-Demethylating", "Phenanthrenes", "Recombinant Proteins", "Spodoptera", "Substrate Specificity" ]	1998	May	Inhibitory monoclonal antibody to human cytochrome P450 2B6. The human cytochrome P450 2B6 metabolizes, among numerous other substrates, diazepam, 7-ethoxycoumarin, testosterone, and phenanthrene. A recombinant baculovirus containing the human 2B6 cDNA was constructed and used to express 2B6 in Sf9 insect cells. The 2B6 was present at 1.8 +/- 0.4% of the total cellular protein and was purified to a specific content of 13.3 nmol/mg protein. Mice were immunized with the purified 2B6, and a total of 811 hybridomas were obtained from the fusion of NS-1 myeloma cells and spleen cells of the immunized mice. Monoclonal antibodies (MAbs) from 24 of the hybrids exhibited immunobinding to 2B6 as determined by ELISA. One of the MAbs, 49-10-20, showed a strong immunoblotting activity and was highly inhibitory to 2B6 enzyme activity. MAb 49-10-20 inhibited cDNA-expressed 2B6-catalyzed metabolism of diazepam, phenanthrene, 7-ethoxycoumarin, and testosterone by 90-91%. MAb 49-10-20 showed extremely high specificity for 2B6 and did not bind to 17 other human and rodent P450s or inhibit the metabolism of phenanthrene catalyzed by human 1A2, 2A6, 2C8, 2C9, 2D6, 2E1, 3A4, and 3A5. MAb 49-10-20 was used to determine the contribution of 2B6 to the metabolism of phenanthrene and diazepam in human liver. In ten liver samples, MAb 49-10-20 inhibited phenanthrene metabolism variably by a wide range of 8-42% and diazepam demethylation by 1-23%. The degree of inhibition by the 2B6 specific MAb 49-10-20 defines the contribution of 2B6 to phenanthrene and diazepam metabolism in each human liver. This technique using inhibitory MAb 49-10-20 determines the contribution of 2B6 to the metabolism of its substrates in a human tissue containing multiple P450s. This study is a prototype for the use of specific and highly inhibitory MAbs to determine individual P450 function.
9,634,000	eng	[ "D003470", "D006150", "Q000737", "Q000378", "D006801", "D015122", "Q000378", "D008727", "Q000494", "D008745", "D013866", "Q000737", "D014407" ]	[ "Culture Media", "Guanine Nucleotides", "Humans", "Mercaptopurine", "Methotrexate", "Methylation", "Thioguanine", "Tumor Cells, Cultured" ]	1998	May	Increased concentrations of methylated 6-mercaptopurine metabolites and 6-thioguanine nucleotides in human leukemic cells in vitro by methotrexate. The effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism was studied in four human leukemic cell lines in vitro. CCRF-CEM, WI-L2, TBJ, and HL-60 all expressed thiopurine methyltransferase (TPMT) activity. The cells were grown in horse serum-supplemented RPMI 1640 medium to which was added 4 microM of 6-MP or 4 microM of 6-MP and 20 nM of MTX. The presence of MTX resulted in a 2.1-, 1.7-, 2.4- and 8-fold increase in the concentrations of methylmercaptopurine ribonucleotides (MMPRP) in CEM, WI-L2, TBJ, and HL-60 cells, respectively (P < 0.0008). The concentrations of 6-thioguanine nucleotides (6 TGN) increased 1.9-, 1.4-, 2.4- and 1.9-fold in the same cell lines (P < 0.02). The four cell lines differed with respect to the effect of MTX on the consumption of 6-MP from the medium; CEM consumed more 6-MP and WI-L2 less 6-MP from media containing MTX than from media containing 6-MP only (P = 0.005 and 0.02, respectively). MTX did not affect the consumption of 6-MP by TBJ cells (P = 0.17). Media in which HL-60 cells had been grown did not contain detectable amounts of 6-MP at the end of the experiment. The simultaneous increase in methylated 6-MP metabolites and 6-TGN represents a possible explanation for the synergism of MTX and 6-MP; however, the clinical importance of increased MMPRP remains to be elucidated.
9,634,001	eng	[ "D000273", "Q000187", "Q000378", "D000818", "D001483", "D022762", "D004247", "Q000378", "D004268", "Q000037", "Q000096", "Q000235", "D018836", "Q000494", "D008099", "Q000187", "Q000378", "D008297", "D051379", "D008810", "D009687", "Q000037", "Q000096", "Q000235", "D000072317", "Q000494", "D011485", "D012333", "Q000235", "Q000378", "D018336", "Q000378", "D014407" ]	[ "Adipose Tissue", "Animals", "Base Sequence", "CCAAT-Enhancer-Binding Proteins", "DNA", "DNA-Binding Proteins", "Inflammation Mediators", "Liver", "Male", "Mice", "Mice, Inbred C57BL", "Nuclear Proteins", "Polychlorinated Dibenzodioxins", "Protein Binding", "RNA, Messenger", "Receptors, Aryl Hydrocarbon", "Tumor Cells, Cultured" ]	1998	May	Suppression of C/EBPalpha and induction of C/EBPbeta by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse adipose tissue and liver. We examined the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on two transcription factors, CAAT/enhancer binding protein-alpha (C/EBPalpha) and beta (C/EBPbeta), involved in the coordination of gene expression in adipose and liver. A single dose of TCDD (100 microg/kg) to male C57BL mice resulted in a time- and dose-dependent decrease in the level of C/EBPalpha mRNA in adipose tissue and liver, and a reciprocal increase in C/EBPbeta mRNA. Gel shift analysis using hepatic nuclear extracts from control and TCDD-treated mice and an oligonucleotide containing a C/EBP recognition element revealed a time-dependent change in DNA-protein complexes formed. Bands corresponding to C/EBPalpha, as determined by supershift analysis, diminished in TCDD-treated animals over a 7-day time period, whereas two new bands corresponding to C/EBPbeta, not present in control extracts, were increased significantly in treated samples. TCDD induced C/EBPbeta mRNA in wild-type mouse hepatoma cells, but not in aryl hydrocarbon receptor (AhR) nuclear translocator-deficient hepatoma cells. Induction in wild-type hepatoma cells was antagonized effectively by a molar excess of alpha-naphthoflavone. These results showed that TCDD caused rapid, reciprocal changes in C/EBPalpha and C/EBPbeta mRNAs and DNA binding in the adipose and liver of male C57BL mice and induced C/EBPbeta in hepatoma cells in an AhR-dependent manner. C/EBPs play vital roles in the coordination of energy homeostasis, and their alteration by TCDD may provide insight into the mechanism by which TCDD perturbs energy storage and utilization in vivo.
9,634,002	eng	[ "D002999", "D018076", "D003854", "Q000378", "D019008", "Q000235", "D006801", "D006918", "Q000494", "D012333", "Q000235", "D012264", "Q000235", "D014162", "D014407" ]	[ "Clone Cells", "DNA, Complementary", "Deoxyribonucleotides", "Drug Resistance, Neoplasm", "Humans", "Hydroxyurea", "RNA, Messenger", "Ribonucleotide Reductases", "Transfection", "Tumor Cells, Cultured" ]	1998	May	Determination of deoxyribonucleoside triphosphate pool sizes in ribonucleotide reductase cDNA transfected human KB cells. Ribonucleotide reductase (RR) is a rate-limiting enzyme in DNA synthesis, which is responsible for controlling deoxyribonucleoside triphosphate (dNTP) pool size. It has been shown that transfection of RR M2 cDNA in human KB cells (M2-D clone) results in overexpression for the M2 subunit and resistance to hydroxyurea (HU). In this study, dNTP pool assays were performed to measure the pool sizes in six cell lines: two controls, three transfectants, and drug-induced HU-resistant (HUR) cells. Total dNTP levels among the six cell lines rose in the following order: KB wild-type, KB vector-only transfectant, M1 cDNA transfectant, M2 cDNA transfectant, M1/M2 cDNA transfectant, and HU-induced resistant clone. The dCTP levels of the cells mimicked the total dNTP pools on a smaller scale. The significant increases in the dCTP pool sizes of the M2-D, X-D, and HUR clones were proportional to their respective increases in RR activity. Relative to all other transfectants, the M1-D clone demonstrated lower dCTP levels but increased dATP pools. The M1-D clone demonstrated a significant resistance to dNTP inhibition of RR activity compared with the control KB wild-type cells. In contrast, a profound inhibition of dCTP and a decreased sensitivity to dATP inhibition was observed in M2-D, X-D, and HUR clones. In summary, M2 cDNA transfectants and HUR clones had increased RR activity as well as expanded dNTP pools, particularly dCTP, when compared with wild-type KB cells. These data provide evidence for the intertwined relationship between RR activity and dNTP pools.
9,634,003	eng	[ "D000818", "D002851", "D006146", "Q000008", "Q000737", "D007668", "Q000737", "D008099", "Q000737", "D051379", "D011732", "Q000737", "D012545", "Q000737" ]	[ "Animals", "Chromatography, High Pressure Liquid", "Guanidines", "Kidney", "Liver", "Mice", "Pyridoxal Phosphate", "Schiff Bases" ]	1998	May	In vivo formation of a Schiff base of aminoguanidine with pyridoxal phosphate. Aminoguanidine (AG) is considered to be a promising compound for the treatment of diabetic complications. We examined the in vitro and in vivo formation of Schiff bases of AG with pyridoxal 5'-phosphate (PLP) and pyridoxal (PL). AG reacted in vitro far more rapidly with PLP to form a Schiff base (PLP-AG) than with PL to form another Schiff base (PL-AG). Administration of AG at 7 mM in drinking water for 18 weeks caused the formation of PLP-AG in the liver and kidney of mice (12.1 +/- 1.6 and 3.8 +/- 0.64 nmol/g of tissue, respectively, mean +/- SD, N = 6). The amount of PLP in the liver of mice AG administered was significantly lower than that of control mice (4.0 +/- 1.4 vs 17.4 +/- 1.3 nmol/g of wet tissue, mean +/- SD, N = 6). Simultaneous administration of pyridoxine (1 mM in drinking water) with AG (7 mM in drinking water) did not ameliorate the decrease in tissue PLP and caused the excess formation of PLP-AG. The results suggest that attention should be paid to the deficiency of tissue PLP in the clinical use of AG.
9,634,004	eng	[ "D016475", "D000225", "Q000031", "Q000378", "D000818", "D002455", "Q000187", "D002460", "D003513", "Q000494", "D004247", "Q000187", "Q000378", "D005472", "Q000494", "D006801", "D051379", "D019384", "Q000494", "D011500", "Q000494", "D011687", "Q000378", "D012313", "Q000187", "Q000378" ]	[ "3T3 Cells", "Adenine", "Animals", "Cell Division", "Cell Line", "Cycloheximide", "DNA", "Fluorouracil", "Humans", "Mice", "Nucleic Acid Synthesis Inhibitors", "Protein Synthesis Inhibitors", "Purines", "RNA" ]	1998	May	Metabolism and metabolic actions of 6-methylpurine and 2-fluoroadenine in human cells. Activation of purine nucleoside analogs by Escherichia coli purine nucleoside phosphorylase (PNP) is being evaluated as a suicide gene therapy strategy for the treatment of cancer. Because the mechanisms of action of two toxic purine bases, 6-methylpurine (MeP) and 2-fluoroadenine (F-Ade), that are generated by this approach are poorly understood, mechanistic studies were initiated to learn how these compounds differ from agents that are being used currently. The concentration of F-Ade, MeP, or 5-fluorouracil required to inhibit CEM cell growth by 50% after a 4-hr incubation was 0.15, 9, or 120 microM, respectively. F-Ade and MeP were also toxic to quiescent MRC-5, CEM, and Balb 3T3 cells. Treatment of CEM, MRC-5, or Balb 3T3 cells with either F-Ade or MeP resulted in the inhibition of protein, RNA, and DNA syntheses. CEM cells converted F-Ade and MeP to F-ATP and MeP-ribonucleoside triphosphate (MeP-R-TP), respectively. The half-life for disappearance of HeP-ribonucleoside triphosphate from CEM cells was approximately 48 hr, whereas the half-lives of F-ATP and ATP were approximately 5 hr. Both MeP and F-Ade were incorporated into the RNA and DNA of CEM cells. These studies indicated that the mechanisms of action of F-Ade and MeP were quite different from those of other anticancer agents, and suggested that the generation of these agents in tumor cells by E. coli PNP could result in significant advantages over those generated by either herpes simplex virus thymidine kinase or E. coli cytosine deaminase. These advantages include a novel mechanism of action resulting in toxicity to nonproliferating and proliferating tumor cells and the high potency of these agents during short-term treatment.
9,634,005	eng	[ "D000818", "D000964", "Q000493", "D001692", "D001943", "Q000378", "Q000473", "D002352", "Q000378", "D002455", "Q000187", "D005492", "Q000378", "D006801", "D008565", "D026901", "D008727", "Q000493", "D051379", "D058978", "D014407" ]	[ "Animals", "Antimetabolites, Antineoplastic", "Biological Transport", "Breast Neoplasms", "Carrier Proteins", "Cell Division", "Folic Acid", "Humans", "Membrane Proteins", "Membrane Transport Proteins", "Methotrexate", "Mice", "Reduced Folate Carrier Protein", "Tumor Cells, Cultured" ]	1998	May	Concentrating capacity of the human reduced folate carrier (hRFC1) in human ZR-75 breast cancer cell lines. Human RFC1 (hRFC1) transfected in transport-deficient methotrexate MTXR(R)ZR-75-1 human breast carcinoma cells (MTX(R)ZR-75/RFC) were used to investigate the impact of hRFC1 overexpression on influx and concentrative transport of methotrexate (MTX). Eight-fold overexpression of hRFC1, as determined by northern analysis, resulted in a 4-fold increase in MTX influx accompanied by a 2.4-fold increase in the steady-state level of free drug as compared with wild-type ZR-75-1 cells when the extracellular MTX level was 0.5 microM. When extracellular MTX was increased to 10 microM, the increase in influx equaled the increase in the transmembrane chemical gradient for MTX in the transfectant relative to wild-type cells. By 50 min, approximately 16-20 and 25% of the intracellular 3H represented MTX polyglutamates by HPLC analysis at [MTX]e = 0.5 and 10 microM in wild-type and transfected cells, respectively. Overexpression of hRFC1 enhanced sensitivity to MTX in MTX(R)ZR-75-1 cells by more than 250-fold. The data indicate that overexpression of hRFC1 in human cells results in comparable increases in influx and transmembrane gradients. This is different from what was reported when mouse RFC1 was transfected into murine leukemia cells, resulting in large, more symmetrical increases in the MTX bidirectional transport kinetics with a much smaller change in steady-state levels. The changes in the human cells transfected with hRFC1 however, were similar to what has been observed by other investigators when RFC1 expression is increased by low folate selective pressure.
9,634,006	eng	[ "D000081", "D000970", "Q000494", "D004790", "D004988", "Q000494", "D016195", "Q000187", "D006801", "D007527", "Q000378", "D008543", "Q000096", "D008545", "Q000235", "Q000378", "Q000473", "D008938", "Q000187", "D014442", "Q000096", "D010766", "D011493", "Q000378", "D051745", "D011714", "D013141", "D014158", "Q000187", "D014407" ]	[ "Acetamides", "Antineoplastic Agents", "Enzyme Induction", "Ethers, Cyclic", "G2 Phase", "Humans", "Isoenzymes", "Melanins", "Melanoma", "Mitosis", "Monophenol Monooxygenase", "Phosphorylation", "Protein Kinase C", "Protein Kinase C-delta", "Pyrans", "Spiro Compounds", "Transcription, Genetic", "Tumor Cells, Cultured" ]	1998	May	Stimulation of melanogenesis in a human melanoma cell line by bistratene A. The polyether toxin, bistratene A, induced morphological and functional differentiation of a human melanoma cell line (MM96E). The cells became blocked at the G2/M transition and elaborated a number of processes. Tyrosinase activity and melanin content were substantially increased. Northern blot analysis showed up-regulation of mRNA for several genes known to be involved in melanin biosynthesis (pmel17, pmel34, and tyrosinase related proteins, TRP-1 and TRP-2). Bistratene A induced the phosphorylation of several proteins as assessed by 2D gel electrophoresis and one of these was identified as stathmin (oncoprotein 18), a cell-cycle regulated phosphoprotein. Bistratene A specifically induced the translocation of protein kinase Cdelta (PKCdelta) from a soluble to a particulate fraction without affecting other isoforms. These results implicate a role for protein kinase Cdelta in the induction of differentiation of this human melanoma cell line.
9,634,007	eng	[ "D000818", "D002265", "Q000378", "D002478", "D004791", "Q000494", "D004952", "D006147", "Q000031", "Q000737", "Q000378", "Q000493", "D006801", "D006868", "D015394", "D019853", "Q000037", "D011355", "Q000378", "Q000493", "D013552", "D014407" ]	[ "Animals", "Carboxylic Ester Hydrolases", "Cells, Cultured", "Enzyme Inhibitors", "Esters", "Guanine", "Humans", "Hydrolysis", "Molecular Structure", "O(6)-Methylguanine-DNA Methyltransferase", "Prodrugs", "Swine", "Tumor Cells, Cultured" ]	1998	May	O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases. To modulate the bioavailability and perhaps improve the tumor cell selectivity of O6-alkylguanine-DNA alkyltransferase (AGT) inactivators, pivaloyloxymethyl ester derivatives of O6-benzylguanine (BG) were synthesized and tested as AGT inactivators and as substrates for cellular esterases. The potential prodrugs examined were the 7- and 9-pivaloyloxymethyl derivatives of O6-benzylguanine (7- and 9-esterBG), and of 8-aza-O6-benzylguanine (8-aza-7-esterBG and 8-aza-9-esterBG) and the 9-pivaloyloxymethyl derivative of 8-bromo-O6-benzylguanine (8-bromo-9-esterBG). The benzylated purines were all potent inactivators of the pure AGT and of the AGT activity in HT29 cells and cell extracts. Each ester was at least 75 times less potent than the corresponding benzylated purine against the pure human AGT. In contrast, the activities of esters and their respective benzylated purine were similar in crude cell extracts and in intact cells. The increase in potency of esters in cellular extracts could be explained by a conversion of the respective prodrug to the more potent benzylated purine in the presence of cellular esterases. The apparent catalytic activity (Vmax/Km) of liver microsomal esterase for 8-azaBG ester prodrugs was 70-130 times greater than for BG prodrugs and 10-20 times greater than for 8-bromo-9-esterBG. Tumor cell hydrolysis of the esters varied considerably as a function of cell type and prodrug structure. These data suggest that these or related prodrugs may be advantageous for selective AGT inactivation in certain tumor types.
9,634,008	eng	[ "D017209", "Q000187", "D001932", "Q000201", "Q000378", "Q000473", "D002467", "Q000378", "D053938", "D004791", "Q000494", "D005434", "D018816", "D005909", "Q000201", "Q000378", "Q000473", "D006801", "D007150", "D007211", "Q000494", "D018972", "Q000096", "D011493", "Q000037", "D014407", "D016159", "Q000378" ]	[ "Apoptosis", "Brain Neoplasms", "Cell Nucleus", "DNA Fragmentation", "Enzyme Inhibitors", "Flow Cytometry", "Genes, cdc", "Glioblastoma", "Humans", "Immunohistochemistry", "Indoles", "Insulin-Like Growth Factor Binding Protein 3", "Protein Kinase C", "Tumor Cells, Cultured", "Tumor Suppressor Protein p53" ]	1998	May	Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1-binding protein-3. Increased protein kinase C(alpha) (PKC(alpha)) expression in glioblastoma cells is associated with proliferation and resistance to drug-induced apoptosis by an undefined anti-apoptotic pathway. To clarify the role of PKC in apoptosis, we have investigated the effect of the selective PKC inhibitor Ro 31-8220 (3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H -pyrrole-2,5-dione methanesulfonate) in two glioblastoma cell lines whose proliferation is dependent on high levels of PKC(alpha). U-87 and A172 cells treated with an IC50 of Ro 31-8220 exhibited nucleosomal DNA fragmentation that coincided with an increase in the number of apoptotic cells. This effect was preceded by the rapid nuclear accumulation of wild-type p53 within 2 hr, and an increased level of the pro-apoptotic protein, insulin-like growth factor-1-binding protein-3, (IGFBP3) but not other p53-regulated proteins such as p21WAF1 or Bax. Accumulation of p53 was also associated with the hypophosphorylated and activated form of the retinoblastoma tumor suppressor protein (RB) at later times after treatment. These results suggest that PKC(alpha) suppresses apoptosis in glioblastoma cells primarily by restricting the accumulation of p53 and the expression of insulin-like growth factor-1-binding protein, as well as by maintaining RB in an inactive hyperphosphorylated state.
9,634,009	eng	[ "D018938", "D002463", "D005960", "Q000378", "D006801", "D007413", "Q000378", "D011794", "Q000378" ]	[ "Caco-2 Cells", "Cell Membrane Permeability", "Glucosides", "Humans", "Intestinal Mucosa", "Quercetin" ]	1998	May	Transport of quercetin and its glucosides across human intestinal epithelial Caco-2 cells. There is mounting evidence from human epidemiological, animal in vivo, and in vitro studies to suggest beneficial effects related to the consumption of quercetin and its glucosides. However, there is limited knowledge on the oral bioavailability of these natural products. This study examined the intestinal epithelial membrane transport of quercetin, quercetin 4'-glucoside, and quercetin 3,4'-diglucoside, using the Caco-2 human colonic cell line, a model of human intestinal absorption. The apparent permeability (Papp) of each agent was measured in both apical to basal and basal to apical directions. The apical to basolateral flux of quercetin, Papp 5.8 +/- 1.1 x 10(-6) cm x sec(-1) (mean +/- SEM), was more than 10-fold higher than for the paracellular transport marker mannitol, 0.48 +/- 0.09 x 10(-6) cm x sec(-1) (P < 0.01). Under identical conditions, the Papp for the transcellular marker propranolol was about 5-fold higher than for quercetin (P < 0.001). Interestingly, the reverse, basolateral to apical, flux of quercetin (Papp 11.1 +/- 1.2 x 10(-6) cm x sec(-1)) was almost 2-fold higher than the apical to basolateral flux (P < 0.001). In similar experiments, quercetin 4'-glucoside demonstrated no absorption, Papp < 0.02 x 10(-6) cm x sec(-1) in the apical to basal direction, but did demonstrate basal to apical flux, Papp 1.6 +/- 0.2 x 10(-6) cm x sec(-1). Quercetin 3,4'-diglucoside showed a low apical to basolateral transport (Papp 0.09 +/- 0.03 x 10(-6) cm x sec(-1)); its reverse, basolateral to apical, transport was, however, 4-fold higher (P < 0.05). In these cells, glucose was actively transported with an apical to basolateral Papp of 36.8 +/- 1.1 x 10(-6) cm x sec(-1). These observations suggest facile absorption of quercetin through the human intestinal epithelium, but contrary to a previous proposal, they do not support an active transport process for quercetin glucosides.
9,634,010	eng	[ "D000818", "D001692", "D002331", "Q000378", "D002352", "Q000378", "D004195", "D004622", "Q000166", "Q000378", "D005347", "Q000378", "D018628", "D006579", "D006720", "D006801", "D007700", "D008052", "Q000235", "Q000378", "D051379", "D008817" ]	[ "Animals", "Biological Transport", "Carnitine", "Carrier Proteins", "Disease Models, Animal", "Embryo, Mammalian", "Fibroblasts", "Gene Dosage", "Heterozygote", "Homozygote", "Humans", "Kinetics", "Lipid Metabolism, Inborn Errors", "Mice", "Mice, Mutant Strains" ]	1998	May	Gene-dose effect on carnitine transport activity in embryonic fibroblasts of JVS mice as a model of human carnitine transporter deficiency. Recently, the marked decline in renal carnitine reabsorption has been thought to account fotr the systemic carnitine deficiency in juvenile visceral steatosis (JVS) mice. We have conducted a kinetic analysis using embryonic fibroblasts derived from normal, heterozygous, and homozygous jvs mice and found that the high-affinity carnitine transporter (Km = 5.5 microM), which shows Na+ and temperature dependency and stereospecificity, is defective in homozygous jvs mice. Moreover, a gene dose-dependent decrease of carnitine transport activity, which was due to a decrease in the number of the transporter molecules, was found in heterozygous jvs mice. Similar phenomena have been observed in human primary carnitine deficiency. Therefore, JVS mice may be useful for understanding this extremely rare human hereditary disorder.
9,634,011	eng	[ "D000544", "Q000188", "Q000201", "D000581", "Q000037", "D000818", "D002800", "Q000494", "Q000627", "D002802", "Q000378", "D004593", "D006801" ]	[ "Alzheimer Disease", "Amidohydrolases", "Animals", "Cholinesterase Inhibitors", "Cholinesterases", "Electrophorus", "Humans" ]	1998	May	Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease. The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BuChE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BuChE-associated AAA activity. Serotonin and related amines were very weak on BuChE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BuChE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA.
9,634,014	eng	[ "D000280", "D000293", "D000328", "D002648", "D002675", "D003894", "Q000008", "Q000009", "D004305", "D004775", "Q000188", "D005260", "D006801", "D008134", "D008297", "D012008", "D012076", "Q000008", "Q000009", "D016896" ]	[ "Administration, Inhalation", "Adolescent", "Adult", "Child", "Child, Preschool", "Deamino Arginine Vasopressin", "Dose-Response Relationship, Drug", "Enuresis", "Female", "Humans", "Long-Term Care", "Male", "Recurrence", "Renal Agents", "Treatment Outcome" ]	1998	May	Long-term use and tapered dose reduction of intranasal desmopressin in the treatment of enuretic children. To determine the time taken to achieve complete dryness, the management of desmopressin dosage to reduce the relapse rate, the mean dosage in those responding and any side effects of long-term treatment. Enuretic children (155, 68% boys and 32% girls, mean age 8 years, range 5-19) were treated with desmopressin and assessed. Treatment (intranasal spray) was started with 20 microg desmopressin and titrated to 40 microg (maximum 50 microg) after 2 days if the child did not become dry within 48 h. The maximum dosage was maintained for at least 4-6 weeks. After 4 weeks of complete dryness, the dosage was reduced by 10 microg initially, and after each additional 4 dry weeks, by a further 10 microg; medication was stopped only after 4 dry weeks at 10 microg. Of the children, 85% responded to intranasal desmopressin therapy; 71% achieved complete dryness with no relapses, remaining dry with no further treatment, 7% achieved dryness after relapses during or after therapy, 7% improved (no more than two wet nights per week) and 15% did not respond to therapy or improved only slightly (> 2 wet nights per week). The mean duration of therapy was 28 weeks, the mean dose of desmopressin was 30 microg and the median follow-up 18 months. There were no significant side-effects. This study indicates that rapid titration until dryness within 1-3 days, a long maintenance therapy of at least 4-6 weeks and a slow stepwise reduction of dose decreases the frequency of relapse and improves the outcome.
9,634,013	eng	[ "D000284", "D000293", "D000328", "D002648", "D003894", "Q000627", "D004775", "Q000188", "D005260", "D005500", "D006801", "D008134", "D008297", "D012076", "Q000627", "D012890", "Q000502", "D011795", "D016896", "D001745", "Q000150" ]	[ "Administration, Oral", "Adolescent", "Adult", "Child", "Deamino Arginine Vasopressin", "Enuresis", "Female", "Follow-Up Studies", "Humans", "Long-Term Care", "Male", "Renal Agents", "Sleep", "Surveys and Questionnaires", "Treatment Outcome", "Urinary Bladder Diseases" ]	1998	May	Desmopressin in the treatment of severe nocturnal enuresis in adolescents--a 7-year follow-up study. To evaluate the role of long-term oral desmopressin (over a 7-year follow-up) in refractory enuretics, particularly in assessing the potential curative effect, and to analyse the results for specific types of patient to obtain clues about possible mechanisms of cure. The effect of oral desmopressin was investigated in 25 adolescents (aged 11-21 years) with severe monosymptomatic nocturnal enuresis. The long-term study consisted of two 12-week treatment periods, with the efficacy of the drug assessed as the reduction in the number of wet nights per week. Subsequently, the patients were followed-up for up to 7 years. Close contact was maintained with the families over this period ('good doctoring' approach). At 3-, 5- and 7-year intervals after completing the study, patients were assessed for dryness, frequency, treatment and sleeping habits, using postal questionnaires and telephone follow-up. At the end of the long-term study, 35% of the patients remained dry without therapy. Within 2 years of ending treatment, 15 patients were dry, compared with an expected estimate of six by spontaneous resolution, and after 7 years, 19 patients were cured. Nocturia occurred in 75% of the enuretic patients but in only 5% of the healthy controls. Active treatment of primary nocturnal enuresis with oral desmopressin has a clinically significant effect on the cure rate, which is maintained after ceasing therapy. The cure rate was higher than would be expected from spontaneous recovery alone during the first 2 years of the study and there was a significant further increase in the cure rate 7 years after ending therapy, again greater than the expected spontaneous cure rate. There also seemed to be a better response to treatment when it was prolonged. Furthermore, this therapy is safe when administered in the long-term.
9,634,015	eng	[ "D000293", "D000328", "D001285", "Q000008", "D002648", "D003894", "Q000008", "D003692", "D004305", "D004359", "D004775", "Q000188", "D005260", "D005500", "D006801", "D008297", "D018727", "Q000008", "D012076", "Q000008", "D012189", "D016896" ]	[ "Adolescent", "Adult", "Atropine", "Child", "Deamino Arginine Vasopressin", "Delayed-Action Preparations", "Dose-Response Relationship, Drug", "Drug Therapy, Combination", "Enuresis", "Female", "Follow-Up Studies", "Humans", "Male", "Muscarinic Antagonists", "Renal Agents", "Retrospective Studies", "Treatment Outcome" ]	1998	May	Combination therapy in the treatment of persistent nocturnal enuresis. To evaluate, in a retrospective study, the response rate of older children to combination therapy using a sustained-release anticholinergic agent, hyoscyamine, and a synthetic analogue of antidiuretic hormone, desmopressin acetate. Twenty-eight patients (20 males and eight females, aged 9-18 years) diagnosed with nocturnal enuresis were evaluated using a questionnaire, history and physical examination. None had success with single-agent pharmacological therapy. All were begun on 0.375 mg of hyoscyamine and 20 microg of desmopressin intranasally at bedtime. The response rate was monitored at 2 and 4 weeks, and then every 3 months by recording dry nights on a calendar. To improve efficacy, the dosage of medication was adjusted up to 0.750 mg of hyoscyamine and 60 microg of desmopressin. Upon achieving dryness and spontaneous awakening to void, medication doses were tapered. Within 6 months 16 (57%) patients were completely dry and six (21%) were dry at least 80% of nights. Nine patients relapsed during dose tapering and therapy was reinstituted. Presently, 17 (60%) patients are off medication (after a mean of 8 months of medication). Eight patients are still on medication and are dry at least 80% of nights. Combination therapy failed in three patients and they have transferred to a different regimen. None experienced untoward side-effects from the medications. Most older children with nocturnal enuresis responded to combination therapy. These children require long-term follow-up and may need medication for up to 6 months because the relapse rate is fairly high. Combination therapy appears safe and reliable in treating nocturnal enuresis in older children who have had no success with other treatment modalities.
9,634,016	eng	[ "D000281", "D000284", "D000293", "D001294", "D002648", "D003894", "Q000008", "D004775", "Q000188", "Q000523", "D005260", "D006801", "D008019", "D008297", "D010290", "Q000523", "D012076", "Q000008", "D012649", "D013315", "Q000209", "D016896" ]	[ "Administration, Intranasal", "Administration, Oral", "Adolescent", "Attitude to Health", "Child", "Deamino Arginine Vasopressin", "Enuresis", "Female", "Humans", "Life Style", "Male", "Parents", "Renal Agents", "Self Concept", "Stress, Psychological", "Treatment Outcome" ]	1998	May	The effectiveness of desmopressin in the treatment of childhood nocturnal enuresis: predicting response using pretreatment variables. To determine the factors that predict the effectiveness of desmopressin in the treatment of childhood nocturnal enuresis. Sixty-six children with monosymptomatic nocturnal enuresis were treated with intranasal or oral desmopressin for a 4-week period. starting with a standard dose of 20 microg (0.2 mg oral) and increasing after 2 weeks where no progress was apparent to 40 microg (0.4 mg oral). Before treatment a range of variables (demographic, situational, enuretic history, physiological, parental attitude and child) were recorded. Three parameters of success acted as dependent variables, with stepwise linear regression models used to determine pretreatment predictors of success with desmopressin. Each outcome variable produced a very similar model of predictors. Success, as assessed by the most dry nights over a 14-night period, was associated with less severe enuresis before treatment, a parental belief that the child's enuresis was unstable and higher birthweight. From the analysis, a model of arginine vasopressin release is proposed and the clinical implications of the findings addressed.
9,634,019	eng	[ "D000284", "D000293", "D001127", "Q000097", "D002648", "D003894", "Q000008", "D015232", "Q000652", "D004775", "Q000097", "Q000188", "Q000652", "D005260", "D006801", "D008297", "D009994", "D012008", "D012076", "Q000008", "D017211", "D014554", "Q000502", "D014556", "Q000502" ]	[ "Administration, Oral", "Adolescent", "Arginine Vasopressin", "Child", "Deamino Arginine Vasopressin", "Dinoprostone", "Enuresis", "Female", "Humans", "Male", "Osmolar Concentration", "Recurrence", "Renal Agents", "Treatment Failure", "Urination", "Urine" ]	1998	May	Monosymptomatic primary enuresis: differences between patients responding or not responding to oral desmopressin. To evaluate the 24-h diuresis, urinary osmolality, plasma arginine vasopressin (AVP) and urinary prostaglandin E2 (PGE2) before and during desmopressin treatment in patients with monosymptomatic primary enuresis (MPE), and to investigate the possible depressor effect of desmopressin on the detrusor in such patients with urodynamically confirmed bladder instability. Seven healthy children (control group) and 11 consecutive patients with MPE (mean age 10.4 years, range 7-15) were assessed using laboratory tests, renal and bladder ultrasonography, and video-urodynamic investigations. A 24-h inpatient assessment with a controlled water intake of 20 mL/kg per day included determinations of diuresis, urinary osmolality, AVP and PGE2 in both normal children and those with MPE. After 30 days of treatment at optimal doses of desmopressin, all children were hospitalized and re-evaluated during desmopressin treatment; all completed 3 months of treatment at optimal doses. At the end of this period, patients whose symptoms improved by > or = 80% were defined as 'responders' while those in whom they did not were defined as 'non-responders'. After treatment, six of the 11 patients with MPE were 'responders' and five 'non-responders'. Urodynamic evaluation showed bladder instability in seven of the 11 patients with MPE but in those with bladder dysfunction, urodynamic studies carried out during desmopressin treatment showed no changes in detrusor activity. There were significant differences in the morning values of AVP between normal children and responders (P < 0.03), and between responders and non-responders (P < 0.02); none of the non-responders had AVP levels of < 2.5 pg/mL, while none of the responders exceeded this value. At midnight, responders had the lowest mean AVP and non-responders the highest; this correlated with the highest PGE2 value in the nonresponders at 00.00-08.00 hours. Non-responders had an overnight mean PGE2 level greater than that in normal subjects or responders. Polyuria occurred in all patients with MPE, independently of the response to desmopressin. Responders had the lowest AVP values over the 24 h; the morning AVP levels differentiated normal subjects from enuretic patients and responders from non-responders. In patients with MPE, clinically undetected bladder instability was unrelated to the results of treatment and there were no urodynamic changes during desmopressin treatment. The differences between enuretic patients suggested a different aetiology of MPE, probably related to an increase in PGE2 concentration and an antagonistic mechanism of action of AVP or desmopressin.
9,634,021	eng	[ "D000293", "D002648", "D018680", "Q000627", "D003894", "Q000627", "D004359", "D004775", "Q000097", "Q000188", "D005260", "D006801", "D008134", "D008297", "D008333", "Q000627", "D012076", "Q000627", "D014667", "Q000097" ]	[ "Adolescent", "Child", "Cholinergic Antagonists", "Deamino Arginine Vasopressin", "Drug Therapy, Combination", "Enuresis", "Female", "Humans", "Long-Term Care", "Male", "Mandelic Acids", "Renal Agents", "Vasopressins" ]	1998	May	Evaluation of antidiuretic hormone before and after long-term treatment with desmopressin in a group of enuretic children. To determine the effect of long-term desmopressin therapy in enuretic patients on the levels of antidiuretic hormone (ADH) during and after the end of therapy. The study comprised 25 outpatients (18 boys and seven girls) aged 8-12 years at the start of therapy and 12-16 years at the end. The morning (08.00 hours) plasma ADH level was determined before treatment (T0) with desmopressin and 2 years after (T1) ending the therapy. Seven of the 25 patients evaluated had monosymptomatic (simple enuresis, SE) and 18 had other symptoms (complex enuresis, CE). In the patients with SE, the mean (SD) duration of therapy was 305 (183) days and they were reevaluated 2.5 (0.67) years later. Of 18 patients with CE, eight were treated only with desmopressin for 204 (117) days. In 10 with an incomplete response after 30 days with only desmopressin, oxybutynin (5 mg twice daily) was added; the duration of their therapy was 255 (152) days and they were re-evaluated 3.9 (0.6) years later. The mean (SD) ADH level in those with SE and CE was 2.14 (0.93) ng/L and 2.53 (1.16) ng/L), respectively, both significantly lower (P < 0.001) than in controls, at 5.1 (1.6) ng/L. On re-evaluation at T1, there was a significant (P < 0.001) increase in ADH levels over those at T0 in both groups, at 5.2 (0.8) and 5.3 (1.9) ng/L, respectively. These results seem to confirm the role played by ADH in the pathophysiology of enuresis.
9,634,020	eng	[ "D000293", "D017677", "D002648", "D002675", "D004775", "Q000503", "D005260", "D006801", "D008297", "D001745", "Q000503", "D014554", "Q000502", "D014563" ]	[ "Adolescent", "Age Distribution", "Child", "Child, Preschool", "Enuresis", "Female", "Humans", "Male", "Urinary Bladder Diseases", "Urination", "Urodynamics" ]	1998	May	Primary enuresis: a urodynamic evaluation. To assess urodynamic and clinical data in patients with primary enuresis for potential prognostic indicators of detrusor instability. The records of 33 patients (mean age 8.8 years, range 5-14) with monosymptomatic primary enuresis (MPE, bedwetting as the sole symptom) and 47 patients (mean age 7.1 years, range 5-12) with complicated primary enuresis (CPE, bedwetting associated with diurnal urinary loss, squatting and urge incontinence) were reviewed. The children underwent urodynamic studies to detect detrusor instability and the prevalence was compared with the type of enuresis. Of 33 patients with MPE, 17 (49%) showed either typical unstable detrusor contractions (16) or low-compliance bladders (one); in the remaining 16 patients, filling cystometry was normal and micturition was normal in all. Of the 47 patients with CPE, 35 (79%) showed detrusor instability and two decreased bladder compliance; the remaining 10 had stable bladders and micturition was also normal in all patients. The type of primary enuresis and the maximum cystometric bladder capacity were good indicators of bladder dysfunction.
9,634,023	eng	[ "D001143", "Q000502", "D001519", "D002648", "D004775", "Q000523", "D005260", "D006801", "D008297", "D011602", "Q000523", "D012890", "Q000502", "D011795" ]	[ "Arousal", "Behavior", "Child", "Enuresis", "Female", "Humans", "Male", "Psychophysiologic Disorders", "Sleep", "Surveys and Questionnaires" ]	1998	May	Sleep and night-time behaviour of enuretics and non-enuretics. To investigate connections between nocturnal enuresis and sleep factors such as the subjective depth of sleep and classical parasomnias. One hundred school children aged 6-10 years answered a questionnaire, with their parents, and the same questions were asked of a group of 29 children of the same age suffering from severe nocturnal enuresis. There were significant differences in arousability, with the enuretic group being 'deep sleepers', and in the prevalence of onset insomnia, nightmares, interrupted sleep and bedtime struggles, which were all less common among the enuretics. The prevalence of classical parasomnias did not differ between the groups. A high arousal threshold is one of the pathogenetic factors underlying nocturnal enuresis and we propose that this group of therapy-resistant enuretic children might not only sleep more deeply than their nonenuretic peers, but perhaps have 'better' sleep.
9,634,025	eng	[ "D000553", "D002648", "D002675", "D004775", "Q000503", "D006801", "D007223", "D007259", "D011312", "D013686", "D001745", "Q000503", "D014563" ]	[ "Ambulatory Care", "Child", "Child, Preschool", "Enuresis", "Humans", "Infant", "Infrared Rays", "Pressure", "Telemetry", "Urinary Bladder Diseases", "Urodynamics" ]	1998	May	Continuous real-time ambulatory urodynamic monitoring in infants and young children using infrared telemetry. To assess the feasibility of continuous real-time ambulatory bladder monitoring in infants and young children using a specially developed ambulatory urodynamic data logger with built-in infrared telemetric on-line facilities. Twenty-nine infants and young children (mean age 3.9 years, range 7 weeks to 9.5 years) with various types of bladder dysfunction underwent urodynamic studies performed using an ambulatory urodynamic recorder with a specially developed integral transmitter that converts digital pressure signals to modulated infrared waves (935 nm). A receiver mounted on the ceiling of the room receives the signals emitted from the recorder. During the investigation, the infant can conduct normal activities, be totally mobile and be accompanied by the mother undisturbed in a private cubicle. The urodynamicist in the next room can observe all the patient's activities through a one-way mirror while continuous real-time on-line pressure signal displays are recorded and monitored using a computer, with event markers placed as necessary. For security, the data recorded during ambulatory investigation are stored in the internal memory of the ambulatory recorder. All 29 infants and young children completed the urodynamic studies using the new system; the results were satisfactory and reliable, with no data lost during ambulatory recording. The results obtained using infrared telemetry were not significantly different from conventional natural-filling urodynamic studies performed with a cabled on-line urodynamic recorder. The infrared telemetry system provides a reliable and effective way of performing continuous real-time ambulatory urodynamic monitoring in infants and young children. With the development of more powerful telemetric data transmission technologies, such a method could be extended in the near future to a truly ambulatory urodynamic recording with real-time on-line facilities, either at home or in the clinic, both for adults and for children.
9,634,024	eng	[ "D000293", "D001143", "Q000502", "D002648", "D003700", "D004569", "D004775", "Q000209", "Q000503", "D005260", "D006801", "D008297", "D011602", "Q000503", "D012890", "Q000502" ]	[ "Adolescent", "Arousal", "Child", "Delta Rhythm", "Electroencephalography", "Enuresis", "Female", "Humans", "Male", "Psychophysiologic Disorders", "Sleep" ]	1998	May	Changes in the structure of sleep spindles and delta waves on electroencephalography in patients with nocturnal enuresis. To evaluate the mechanism of the dysfunction of arousal in patients with Type I and Type IIa enuresis. The numbers of sleep spindles and delta waves were analysed during electroencephalography in 19 patients with enuresis (17 male, two female, mean age 9.7 years, range 8-14). In four patients with Type I enuresis, who awoke spontaneously and remained dry as a result of urinary sensation, the numbers of sleep spindles and delta waves diminished gradually and finally disappeared just before the patients awoke completely. In the remaining nine patients with Type I enuresis, there was no decrease in the number of sleep spindles and delta waves, and enuresis occurred without the subjects awakening. In the six patients with Type IIa enuresis, there was no arousal reaction or generation of sleep spindles on urination while asleep. An immaturity in the function of the thalamus might be a cause of the arousal dysfunction in patients with Type I enuresis. In Type IIa enuresis, a possible abnormal or immature arousal mechanism in the pons or the lower tract may be responsible.
9,634,026	eng	[ "D000293", "D002648", "D002675", "D006801", "D009119", "D011312", "D014521", "Q000002", "D001745", "Q000503", "D014554", "Q000502", "D014563" ]	[ "Adolescent", "Child", "Child, Preschool", "Humans", "Muscle Contraction", "Pressure", "Urethra", "Urinary Bladder Diseases", "Urination", "Urodynamics" ]	1998	May	Detrusor hypocontractility in children with posterior urethral valves arises before puberty. To assess prepubertal boys with posterior urethral valves (PUV) using an analysis of pressure-flow studies to evaluate the voiding phase and thus determine if myogenic failure (hypocontractility) arises before puberty and if it can be detected early. Eleven boys (8-13 years old) with PUV underwent urodynamics and the results were analysed using pressure-flow mathematical analysis (PFA) of the following variables of detrusor activity: contraction velocity (Vdet), detrusor contractile power expressed as power factor (WF) and Schafer's diagram, which differentiates a 'strong', 'normal' and 'weak' detrusor. Vdet and WF were compared with normal values previously determined in boys of similar age and considered 'low' if more than 2 SDs below the mean. The results of PFA were compared with standard pressure-flow studies and the three classical urodynamic patterns in boys with PUV, as determined by voiding symptoms. The subsequent PFA of seven of the 11 boys were also assessed as they had undergone previous urodynamics when < 8 years old. As assessed by the three patterns of dysfunction, two boys had bladder instability, two had low compliance and three had hypocontractility, with four boys being normal. From the PFA, the Vdet and WF were lower than normal, respectively, in seven and nine of the 11 boys; Schafer's nomogram showed a 'weak' detrusor in seven boys. The PFA suggested a pathology in four of five boys with symptoms and in three of six with no symptoms (two of the six showing a 'low' WF). Moreover, in older (11-13 years) boys, all five had a 'weak' detrusor, a 'low' WF and four a 'low' Vdet. Of the seven patients who underwent repeat PFA, three had a stable WF 3 years later, one (normal) worsened slightly and two were clearly worse, while one, who underwent late (at 3 years old) valve ablation, had an increased WF. The PFA showed hypocontractility in two-thirds of prepubertal boys with PUV, including asymptomatic patients. These findings confirm the hypothesis that bladder dysfunction in boys with PUV eventually causes detrusor myogenic failure and finally a postpubertal overdistended bladder.
9,634,027	eng	[ "D000293", "D001294", "D002648", "D004775", "Q000453", "Q000523", "D005260", "D006801", "D007558", "Q000453", "D008297", "D010290", "Q000523", "D015995", "D012307" ]	[ "Adolescent", "Attitude to Health", "Child", "Enuresis", "Female", "Humans", "Italy", "Male", "Parents", "Prevalence", "Risk Factors" ]	1998	May	An Italian epidemiological multicentre study of nocturnal enuresis. To estimate the prevalence of enuresis in schoolchildren in Italy. The Italian Club of Nocturnal Enuresis promoted a prevalence study of nocturnal enuresis using a self-administered questionnaire in seven cities in Northern, Central and Southern Italy. The association between enuresis and potential risk factors, e.g. a family history of enuresis, stress, socio-economic status and abnormal diurnal voiding habits, was investigated. The perceived impact on the child and on the family was also evaluated. A random-cluster sampling scheme was used to obtain a sample of primary and secondary schoolchildren from each city. One primary school and one secondary school for each socio-economic level was sampled in each city, giving a total of 42 schools surveyed; 9086 children were covered by the survey. In a cluster sampling method, the variance of prevalence is divided into two components, binomial and extra-binomial variability. Both the DSM III and DSM IV definitions of enuresis were used because at present, there is no consensus on the diagnostic criteria. Completed questionnaires were received from 7012 children, an overall response rate of 77.2%. Those aged 6-14 years were analysed, restricting the sample to 6892 children. There were 250 enuretic children using the DSM III definition of enuresis and 112 using the DSM IV definition. The overall prevalence was 3.88% and showed a decreasing trend with increasing age. Bedwetting was more frequent in boys than in girls. The prevalence of enuresis was higher when the child was from a family of low socio-economic status despite the child's age group. The logistic analysis showed that familiality, stress, birthweight, age of attaining diurnal continence, soiling and, for girls, menstruation, were statistically significant variables and thus contributed to predicting the probability of bedwetting, confirming the findings of previous studies. There was a large difference in prevalence using the two DSM definitions; a high percentage of DSM III enuretic children had more than two wet nights per week. It is important that a consensus about the 'working definitions' of enuresis is reached to avoid bias in the recruitment step, to carry out comparable epidemiological studies and to obtain adequate therapeutic responses.
9,634,028	eng	[ "D000293", "D002648", "D015331", "D004327", "D004739", "Q000453", "D004775", "Q000453", "Q000209", "D006801", "D007845", "D008137", "D015995", "D011446", "D014549", "Q000453" ]	[ "Adolescent", "Child", "Cohort Studies", "Drinking Behavior", "England", "Enuresis", "Humans", "Laughter", "Longitudinal Studies", "Prevalence", "Prospective Studies", "Urinary Incontinence" ]	1998	May	The natural history of urinary symptoms during adolescence. To determine the prevalence and natural history of urinary symptoms and incontinence among healthy adolescent schoolchildren. A prospective longitudinal study using a confidential questionnaire administered to an original cohort of 1176 local schoolchildren at 11-12 years and again at 15-16 years old. There was a decrease in the prevalence of urinary symptoms with age. Daywetting was reported by 12.5% of children aged 11-12 years and 3.0% of children aged 15-16 years. Nocturnal enuresis was reported by 4.7% of children at 11-12 years and 1.1% at 15-16 years. Some of the children reporting daywetting and nocturnal enuresis at 15-16 years old had not reported these symptoms at 11-12 years old. Urinary symptoms become less prevalent with age, but are reported by a significant number of healthy schoolchildren.
9,634,029	eng	[ "D000293", "D017677", "D001519", "D002648", "D002908", "D004775", "Q000453", "Q000523", "Q000628", "D005260", "D005387", "Q000453", "D005500", "D006801", "D008297", "D001523", "Q000150", "Q000453", "D015995" ]	[ "Adolescent", "Age Distribution", "Behavior", "Child", "Chronic Disease", "Enuresis", "Female", "Finland", "Follow-Up Studies", "Humans", "Male", "Mental Disorders", "Prevalence" ]	1998	May	A follow-up of enuresis from childhood to adolescence. To determine the prevalence and treatment of enuresis in a national population-based follow-up study of children aged 8-14 years, to evaluate possible factors that enhance or hamper the attainment of continence and to examine the relationships between enuresis and psychiatric disturbance. An initial study was carried out in 1989 as part of the Finnish Child Psychiatric National Epidemiological Study. Three types of questionnaires were used; the Rutter Scale A for completion by parents, including a question about enuresis, the Rutter scale B for completion by teachers and the Children's Depression Inventory (CDI), completed by the children. Parents were also asked about demographic and family issues, teachers about school achievements and children about additional psychosomatic symptoms. In a follow-up in 1995, the target population comprised all previous enuretics and their controls, matched by age, gender, class and school, in the first phase of the study. Replies were received from 315 enuretic boys and 186 girls, with the corresponding values for controls being 310 and 183. The parents were asked about the adolescents' present enuresis and for permission for a treatment trial, if needed. The adolescents completed the CDI, and a questionnaire about enuresis, previous treatments and possible willingness for a treatment trial. They also reported basic somatic data, their life events and living habits. In the initial study, the enuretic children had higher total and subscores as reported by parents, teachers and themselves, except for emotional items reported by the teachers. Additionally, a significantly greater proportion of these children soiled, had sleeping difficulties and difficulties in falling asleep. Enuretic boys had more frequent nightly arousal and early morning waking, while the enuretic girls had more nightmares than non-enuretic girls. At 14 years old, the parents reported that 13 adolescents were enuretic; from the children's replies, nine boys and seven girls were enuretic. The prevalence of enuresis in those previously enuretic was surprisingly low, probably because of the efficient treatment methods, conditioning and medication. There were evident connections between childhood enuresis and mental well-being.