bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ontogeny of P-Glycoprotein in Mouse Intestine, Liver, and Kidney
Authors: Mahmood Burhan , Daood Monica J. , Hart Claudia , Hansen Thor W.R. , Watchko Jon F. 
Published: August 2007

BackgroundP-glycoprotein (Pgp) is an ATP-dependent, integral plasma-membrane efflux pump that is constitutively expressed on (i) adult apical brush-border epithelial cells of the intestine, (ii) the bile canalicular face of hepatocytes, and (iii) the brush border epithelium of renal proximal tubules. This Pgp tissue distribution and localization affects the absorption, distribution, metabolism, and excretion of Pgp substrates. Little is known regarding the ontogeny of Pgp expression in these tissues.MethodsPostnatal expression of Pgp on brush border membranes of small intestine, liver, and kidney as a function of maturity from birth through adulthood was determined using Western immunoblotting and immunohistochemical techniques. Tissue was isolated from FVB mice at four different ages: day of life 0 (D0), day of life 7 (D7), day of life 21 (D21), and adult (Ad). The relative expression of Pgp protein on Western immunoblots was assessed by scanning densitometry and indexed as a percentage (mean±SEM) of the adult levels.ResultsOn Western immunoblots, Pgp expression was limited at birth (19±6% of Ad) and increased significantly with maturation in intestine (ANOVA, P <0.005). In contrast, hepatic (113±12% of Ad) and renal (96±15% of Ad) Pgp expression were at adult levels at birth. The tissue-specific developmental pattern of Pgp expression was confirmed by immunohistochemistry.ConclusionsWe conclude that Pgp is expressed in a tissue-specific and developmentally regulated fashion and speculate that developmental modulation of intestine-Pgp expression may affect the oral bioavailability of Pgp substrates.
Gamma-Irradiation Markedly Inhibits the Hydrated Collagen Gel Contraction by Arterial Smooth Muscle Cells
Authors: Keller Pierre-Frederic , Verin Vitali , Ziegler Thierry , Mermillod Bernadette , Popowski Youri , Delafontaine Patrice 
Published: August 2007

Background Vessel wall responses to percutaneous transluminal coronary angioplasty include neointimal proliferation and arterial remodeling. The contraction of a collagen gel is a good in vitro model of wound repair and vascular remodeling. Because irradiation is an important new therapeutic modality capable of preventing restenosis, the purpose of this study was to evaluate the effect of irradiation on the contraction of a collagen gel by smooth muscle cells (SMCs), on SMCs viability, and on DNA synthesis. Methods We studied the effect of different doses of gamma-irradiation (0 [control], 6, 12, and 18 Gy) on the contraction of a collagen gel seeded with SMCs (calf carotid arteries) during a period of 15 days. Results Maximal gel diameter reduction (from 35 to 6.8 mm, ±0.5 mm in control) was markedly inhibited in the 6-, 12-, and 18-Gy groups (35 to 13.7 mm, ±0.8 mm; 35 to 15.5 mm, ±0.9 mm; and 35 to 16.1 mm, ±0.9 mm, respectively; P<0.0001). The irradiated gels showed a dose-dependent reduction in the SMC proliferation rate ( P<0.0001) and an increase in the number of nonviable SMCs ( P<0.002) 15 days after irradiation. Conclusions Gamma-irradiation produces a significant dose-dependent inhibition of the contraction of collagen gels seeded with arterial SMCs. This effect is related to a significant decrease in SMC viability and a decrease in SMC proliferation rate. These findings shed light on mechanisms whereby irradiation may positively affect arterial remodeling after percutaneous transluminal coronary angioplasties.
Synapsin I Identified as a Novel Brain-Specific Autoantigen
Authors: Gitlits Veronika M. , Sentry John W. , Matthew Mary L.S.M. , Smith Ian A. , Toh Ban Hock 
Published: August 2007

Background We report the identification and characterization of a novel 74-kd brain-specific autoantigen that is reactive with serum from a patient with discoid lupus erythematosus and chronic lymphocytic leukemia. Methods We determined the molecular weight, tissue distribution and subcellular distribution of the autoantigen and obtained limited amino acid sequence after purification by ion-exchange chromatography and trypsin digestion. Results We identified the 74-kd autoantigen as synapsin I on the basis of the following observations. First, the autoantigen has properties consistent with synapsin I: molecular weight of ≈74 kd, brain-specific distribution, presence in cytosol and on synaptosomes, and association with taxol-stabilized microtubules. Second, limited amino acid sequence determination after trypsin digestion of the autoantigen shows identity with synapsin I. Third, the autoimmune serum immunoblots fusion proteins that incorporate rat synapsin Ia. The autoantibodies reactive to synapsin Ia are of immunoglobulin (Ig) G and IgM class. Conclusions This is the first report of autoantibodies that are reactive to synapsin Ia. Autoantibodies that are reactive to synapsin Ia are not restricted to discoid lupus erythematosus patients, because we found identical reactivity in two of 18 sera from dsDNA-positive systemic lupus erythematosus patients and in two of 14 rheumatoid factor-positive sera. Whether autoantibodies to synapsin I are associated with neuropsychiatric manifestations is currently unknown.
Endstage Renal Disease Owing to Diabetic Nephropathy in Mississippi: An Examination of Factors Influencing Renal Survival in a Population Prone to Late Referral
Authors: Crook Errol D. , Harris Jonathan , Oliver Bonnie , Fleischman Erwin , Crenshaw Gregory , Taylor Robert 
Published: August 2007

Background Diabetic nephropathy (DN) is the leading cause of endstage renal disease (ESRD) in the United States. We reviewed our experience with DN as a cause of ESRD in a predominantly poor, African American (AA) population. Methods Charts of patients who entered the ESRD program through the University of Mississippi Medical Center with a primary diagnosis of DN from 1993 through 1998 were reviewed for factors that may affect renal survival. Time from initial clinic visit to entry into the ESRD program, or time to ESRD (TTE), was the primary end point. Results Five hundred sixty-two patients entered the ESRD program (85% AA), and 210 of them had DN as their primary ESRD diagnosis. DN accounted for 50.5% of ESRD cases among AA females, but for less than 20% among AA males. In contrast, hypertension was the ESRD diagnosis in 48% of AA males. Patients observed in our nephrology clinic were analyzed further (n=171). At presentation, patients had advanced disease (serum creatinine [Cr]=5.92 mg/dL), were hypertensive, obese, and not likely to be on an angiotensin-converting enzyme (ACE) inhibitor. Determinants of TTE in univariate analysis were race (AA did better), initial blood urea nitrogen and plasma serum Cr levels, starting an ACE inhibitor at the University of Mississippi Medical Center, and the level of mean arterial pressure (MAP) during the course of follow-up. On multivariate analysis only initial Cr and race remained significant. The 142 AA diabetics (111 female) were analyzed separately. The only significant sex difference was body mass index (female, 33.6 vs male, 28.4 kg/m2; P=0.0069), but females tended to have relatively shorter TTE and higher blood pressure (BP). Univariate and multivariate analyses revealed the same factors as above as determinants of TTE; however, among AAs, presenting on a calcium channel blocker was negatively correlated with TTE in univariate analysis. Among the entire cohort and the AAs, patients who had MAP between 100 and 110 mm Hg during the course of follow-up did better in terms of renal survival than those who fell outside of that range. Conclusions We conclude that AA females in Mississippi are significantly more predisposed to DN as a cause of ESRD than are AA males. Patients with DN in our population had poor BP control, presented to nephrologists with advanced disease, and often were not on an ACE inhibitor. The optimal level of BP control and which BP agents are best for this population need to be determined.
Use of Potassium Tellurite for Rapid-Drug Susceptibility Testing of Mycobacterium avium Complex
Authors: Afghani Behnoosh , Fujiyama Dave 
Published: August 2007

Background Mycobacterium avium complex (MAC) is a major cause of infection in immunocompromised patients. MAC possesses an enzyme that reduces potassium tellurite in less than 3 days and results in formation of a black precipitate. The objective of this study was to determine whether reduction of potassium tellurite by mycobacteria can be used as a means of testing the susceptibility of MAC to clarithromycin. Methods Minimum inhibitory concentrations (MICs) for 104 clinical isolates of MAC were determined by the tellurite method and compared with those tested by a recommended microdilution method. Microdilution breakpoints were used for interpretation of susceptibility. MIC of less than 8 μg/mL was considered as susceptible, and MIC of greater than or equal to 8 μg/mL was resistant. Results There was agreement within a 2-fold dilution between MICs for 89% of isolates. Of the 53 isolates that had discrepant MICs by the two methods, 70% had higher MICs by the tellurite method. When the MICs were classified into interpretive categories, there was 100% agreement by the two methods. The MIC tested by the tellurite method was available within 5 days. Conclusions These data suggest that use of potassium tellurite is a more rapid, reliable, and inexpensive method of testing the susceptibility of MAC to clarithromycin.
Silica and its Antagonistic Effects on Transforming Growth Factor-β in Lung Fibroblast Extracellular Matrix Production
Authors: Baroni Tiziano , Bodo Maria , D'Alessandro Alessandra , Conte Carmela , Calvitti Mario , Muzi Giacomo , Lumare Alessandro , Bellocchio Silvia , Abbritti Giuseppe 
Published: August 2007

Background Silicosis, a pneumoconiosis marked by interstitial pulmonary fibrosis, is caused by inhalation of free crystalline silica particles. When silica particles are injected into the lower lung, they are translocated across the epithelium into the interstitial space, where macrophage-derived growth factors affect lung fibroblast proliferation and collagen deposition. We hypothesized that silica may act directly on pulmonary fibroblasts modifying extracellular matrix (ECM) synthesis and that the effects of silica may be mediated by transforming growth factor-β (TGFβ) overproduction. Methods To test this hypothesis, we studied a human lung fibroblast cell line (WI-1003) exposed to silica in vitro. We investigated cell morphology by electron microscopic procedure, cell growth, collagen production, and glycosaminoglycans (GAG) composition by radiolabeled precursors. Cytokine and growth factor synthesis were evaluated by specific enzyme-linked immunoadsorbent assay kits and Northern blotting analysis. Results Pulmonary fibroblasts internalized silica particles without detectable cell damage. Silica directly stimulated collagen synthesis and decreased the amount of 3H-glucosamine-labeled GAG. Silica-treated fibroblasts secreted less TGFβ than untreated controls, antagonized the stimulatory effect of TGFβ on ECM synthesis, and reversed TGFβ-induced inhibition of cell proliferation. Northern blotting analysis showed increased interleukin-1α (IL-1α) mRNA after silica treatment. IL-1α had no influence on collagen synthesis but increased the number of WI-1003 fibroblasts. Conclusions These results support our hypothesis that lung fibroblasts are direct silica targets. However, contradicting our hypothesis, silica antagonized TGFβ activities through a TGFβ downregulation and an IL-1α upregulation. The complex pattern of TGFβ and IL-1α regulation in pulmonary fibroblasts is imbalanced by silica exposure and might play a key role in silica-mediated pulmonary fibrosis.
How Low can you Go? Chronic Hypoglycemia versus Normal Glucose Homeostasis
Authors: Sood Vidushi , Costello Brian A. , Burge Mark R. 
Published: August 2007

Background Set point errors in glucose homeostasis that result in chronic, mild hyperglycemia in the setting of maturity onset diabetes of the young have been described. Similar set point errors may exist that result in chronic, asymptomatic glucopenia. Case A healthy 39-year-old female was referred for evaluation of chronic, persistent, and asymptomatic glucopenia that persisted over the prior several years with a record of numerous random plasma glucose concentrations between 35 and 45 mg/dL. She denied ethanol intake and family history of hypoglycemia or diabetes. She was not taking any medications known to cause hypoglycemia, and a urine sulfonylurea screen was negative. Fasting insulin and C-peptide levels were not elevated, and pancreatic imaging studies were normal. We hypothesized that this patient possessed an error in glucose metabolism that resulted in chronic, asymptomatic glucopenia. Results In a series of clinical studies, we demonstrated a nadir plasma glucose concentration of 35 mg/dL in the absence of symptoms during a 60-hour fast. C-peptide secretion was appropriately suppressed during symptomatic hypoglycemia with exogenous insulin infusion, and counterregulatory hormone secretion was intact during insulin-induced symptomatic hypoglycemia. Finally, the patient demonstrated an incremental increase in insulin concentration in response to minimal increases in plasma glucose during a sequential, stepped infusion of 10% dextrose. Conclusions We conclude that this patient exhibits features of a set point error in glucose homeostasis that manifests as chronic, asymptomatic glucopenia. Although the mechanism for this condition remains to be elucidated, such set point errors do exist and should be considered in the differential diagnosis of chronic hypoglycemia.
Relationship of Lipoprotein(a) to Variables of Coagulation in Hypertensive Subjects
Authors: Sechi Leonardo A. , De Marchi Sergio 
Published: August 2007

Background Coagulation factors are independent predictors of cardiovascular damage in the general population. The purpose of this study was to investigate the relationships between general cardiovascular risk factors, lipoprotein(a) (Lp(a)), and some hemostatic variables, and to characterize the isoforms of apolipoprotein(a) (apo(a)) in hypertensive subjects. Methods Plasma lipids, apolipoproteins, Lp(a), apo(a) isoforms, fibrinogen, and parameters that directly reflect the coagulation activation were measured in 389 untreated essential hypertensive patients recruited at a hypertension clinic. Hypertensive patients were compared with 323 normotensive controls. Results In normotensive subjects, Lp(a) concentrations were significantly correlated with fibrinogen ( r=0.138; P<0.02) but not D-dimer ( r=0.074; not significant). In hypertensive subjects, log Lp(a) concentrations were significantly correlated with age ( r=0.127; P<0.02), apo-B ( r=0.128; P<0.02), plasma fibrinogen ( r=0.193; P<0.001), and fibrin D-dimer ( r=0.200; P<0.001) levels, but not with body mass index, blood pressure, cholesterol, triglycerides, apo-AI, prothrombin fragment 1+2, and antithrombin III. The relationship of Lp(a) with fibrinogen (male: r=0.198, P<0.002; female: r=0.177, P<0.01) and D-dimer (male: r=0.211, P<0.002; female: r=0.188, P<0.01) was significant in both sexes, whereas the relationship of Lp(a) with age and apo-B was found only in males. Multivariate analysis showed that both fibrinogen and D-dimer were independently related with Lp(a). Elevated fibrinogen, D-dimer, and Lp(a) levels were significantly and independently associated with clinical evidence of atherosclerotic disease. Apo(a) phenotypes were analyzed to investigate the genetic background of the relationships between Lp(a) and coagulation parameters. In both hypertensive and normotensive subjects, Lp(a) levels were inversely correlated with apo(a) isoform protein size, whereas fibrinogen and D-dimer concentrations were comparable in patients with apo(a) isoforms of different size. Conclusions The relationship between Lp(a) and clotting variables is significantly stronger in hypertensive than in normotensive subjects, providing a compelling argument for accelerated progression of atherothrombosis in these patients.
Superoxide Dismutase SOD1, Encoded on Chromosome 21, but Not SOD2 is Overexpressed in Brains of Patients with down Syndrome
Authors: Gulesserian Talin , Seidl Rainer , Hardmeier Rosmarie , Cairns Nigel , Lubec Gert 
Published: August 2007

Background The antioxidant enzyme Cu/Zn-superoxide dismutase-1 ( SOD1) gene is localized to chromosome 21q22.1 and catalyzes the dismutation of superoxide anions to hydrogen peroxide, which may lead to the increased production of active oxygen species in Down Syndrome (DS), trisomy 21. Although a number of studies have addressed this question, proposing the overexpression hypothesis, no specific protein-chemical data on SOD protein levels in the brains of patients with DS are available. Methods We therefore determined the protein SOD-1 and SOD-2 levels in the brains of controls (n=9) and adult patients with DS (n=9) and Alzheimer disease (AD; n=9). Two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization-mass spectroscopy detection and identification was used for the analyses. Results We found significantly increased SOD-1 levels in DS temporal, parietal, and occipital cortex, whereas SOD-1 was decreased in the AD temporal cortex and SOD-2 was comparable between all groups. Conclusions Increased SOD-1 levels in patients with DS may reflect the overexpression by the trisomic state, as a response to the oxidative stress, as has been proposed in DS by several authors. However, it well may be that glial proliferation, which is markedly increased in DS brain, may underlie the increased brain levels of this ubiquitous protein. The decrease of SOD1 in the temporal cortex of patients with AD may reflect an antiapoptotic mechanism or simply cell loss in the brain.
Primate Mammary Gland Insulin-Like Growth Factor System: Cellular Localization and Regulation by Sex Steroids
Authors: Zhou Jian , Anderson Kristin , Bievre Marsha , Ng Sui , Bondy Carolyn A. 
Published: August 2007

Background Insulin-like growth factor 1 (IGF1) plays a critical role in estrogen-induced uterine proliferation, but it is unclear whether this estromedin function occurs in other estrogen-sensitive tissues such as the mammary gland. To elucidate this possibility, we investigated the cellular localization and hormonal regulation of mRNAs for IGF1 and 2, their cognate receptors (IGF1R, IGF2R), and IGF binding proteins 2-5 (BPs 2-5) in the rhesus monkey mammary gland. Methods Ovariectomized monkeys were treated with placebo, estradiol (E2), and E2 plus progesterone (E2/P4) for 3 days, after which mammary tissue was harvested for in situ hybridization and immunohistochemical analyses. Results IGF1 and IGF2 mRNA levels were significantly increased and BP2 mRNA decreased by E2 and by E2/P4 treatment. IGF1R mRNA was increased by combined E2/P treatment but not by E2 alone. BP5 mRNA was decreased by E2/P4. No differences in IGF2R, BP3, and BP4 mRNA levels were detected in any treatment group. Mammary IGF1 and IGF2 mRNA levels were both positively correlated with local epithelial proliferation, assessed by immunodetection of the proliferation-specific antigen, Ki67. IGF1 and IGF1R expression were negatively correlated with local programmed cell death, as assessed by the in situ TUNEL method. In contrast, BP2 expression was negatively correlated with epithelial proliferation and positively correlated with programmed cell death. IGF2R, BP3, BP4, and BP5 levels were not significantly correlated with either proliferation or death. Conclusions Thus, E2-induced proliferation is associated with upregulation of both IGF1 and IGF2 expression and downregulation of BP2 expression. These data suggest that the local mammary IGF system is involved in sex steroid-induced mammary epithelial cell hyperplasia.
Cigarette Smoke and Asbestos Activate Poly-ADP-Ribose Polymerase in Alveolar Epithelial Cells
Authors: Kamp David W. , Srinivasan Malathi , Weitzman Sigmund A. 
Published: August 2007

Background Cigarette smoke augments asbestos-induced bronchogenic carcinoma in a synergistic manner by mechanisms that are not established. One important mechanism may involve alveolar epithelial cell (AEC) injury resulting from oxidant-induced DNA damage that subsequently activates poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA repair that can deplete cellular energy stores. We previously showed that whole aqueous cigarette smoke extracts (CSE) augment amosite asbestos-induced DNA damage and cytotoxicity to cultured AEC in part by generating iron-induced free radicals. We hypothesized that CSE increase asbestos-induced AEC injury by triggering PARP activation resulting from DNA damage caused by iron-induced free radicals. Methods Aqueous CSE were prepared fresh on the day of each experiment. PARP activity in WI-26 (a type I-like cell line) and A549 (a type II-like cell line) cells was assessed by the uptake of labeled NAD over 4 hours and confirmed on the basis of the reduction of PARP levels in the presence of a PARP inhibitor, 3-aminobenzamide (3-ABA). Cell survival was assessed by trypan blue dye exclusion. Results Hydrogen peroxide (H2O2; 1-250 μM), CSE (0.4-10 vol%), and amosite asbestos (5-250 μg/cm2) each caused PARP activation in WI-26 and A549 cells. The combination of asbestos (5 μg/cm2) and CSE (0.04-10%) induced WI-26 and A549 cell PARP activation without evidence of synergism. 3-ABA significantly attenuated WI-26 and A549 cell PARP activity and cell death after exposure to H2O2, CSE, and asbestos. Phytic acid, an iron chelator, catalase, and superoxide dismutase each decreased WI-26 cell PARP activation caused by asbestos and CSE. Conclusions CSE and asbestos induce PARP activation in cultured AEC in a nonsynergistic manner. These data provide further support that asbestos and cigarette smoke are genotoxic to relevant lung target cells and that iron-induced free radicals in part cause these effects.