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Biomedical subjects

M Nord

Publications and source records attributed to M Nord.

18 recordsLinked to original sources
PubMed2000

CYP2B1 is regulated by C/EBP alpha and C/EBP delta inlung epithelial cells.

Pulmonary expression of several cytochrome P450 (CYP) monooxygenases is detected late in gestation. Little is known of the factors involved in this differentiation-dependent expression. C/EBP factors are known regulators of differentiation and differentiation-dependent gene expression in several tissues. In this study we demonstrate the importance of C/EBP alpha and C/EBP delta in pulmonary epithelial CYP2B1 gene expression. A 1.3 kb CYP2B1 promoter fragment which recently has been shown to confer lung tissue- and cell-specific expression of CYP2B1 in transgenic mice was used in transient transfection studies. Both C/EBP alpha and C/EBP delta transactivated the CYP2B1 promoter in the lung epithelial cell lines A549 and NCI-H441. C/EBP alpha in nuclear extracts from isolated rat primary bronchiolar Clara cells was capable of interacting with a C/EBP-binding site in the proximal CYP2B1 promoter. Site-directed mutagenesis studies showed that this proximal C/EBP-binding site is necessary for transactivation of the CYP2B1 gene by C/EBP alpha and C/EBP delta. Thi study shows that C/EBP factors have a role in pulmonary CYP2B1 expression and suggests that these transcription factors may be important for the differentiation-dependent expression of CYP2B1 in the lung.

Animals↗
PubMed2000

Decreased pulmonary levels of the anti-inflammatory Clara cell 16 kDa protein after induction of airway inflammation in asthmatics.

The Clara cell 16 kDa protein (CC16) maps to an atopy-associated region of chromosome 11 and has been ascribed an anti-inflammatory function. Using reverse-phase HPLC and Western blot analysis, we have evaluated the polypeptide pattern in bronchoalveolar lavage (BAL) fluid retrieved from asthmatics, before and after induction of airway inflammation by low-dose allergen inhalation challenge. A prominent decrease of CC16 was seen after induction of inflammation, and a further CC16 decrease was observed in lavage fluid where surfactant had been removed. Reduced levels of pulmonary CC16 may cause loss of anti-inflammatory activity in the airways and contribute to the development of airway inflammation in asthma.

Albumins↗
PubMed2000

Regulation of the Clara cell secretory protein/uteroglobin promoter in lung.

Clara cell secretory protein/uteroglobin (CCSP/UG) is specifically expressed in the conducting airway epithelium of the lung in a differentiation-dependent manner. The proximal promoter region of the rodent CCSP/UG gene directs Clara cell specificity. Previously, it was shown that the forkhead transcription factors HNF-3 alpha and beta and the homeodomain factor TTF-1 are important transcription factors acting through this region, suggesting that they contribute to cell specificity of the CCSP/UG gene. Members of the C/EBP family of transcription factors can also interact with elements of the proximal rat and mouse CCSP/UG promoters. The onset of C/EBP alpha expression in Clara cells correlates with the strong increase of CCSP/UG expression. Thus, C/EBP alpha may play a crucial role for differentiation-dependent CCSP/UG expression. Transfection studies demonstrate that C/EBP alpha and TTF-1 can synergistically activate the murine CCSP/UG promoter. Altogether, these results suggest that C/EBP alpha, TTF-1, and HNF-3 determine the Clara cell-specific, differentiation-dependent expression of the CCSP/UG gene in murine lung. The relative importance of these three transcription factors, however, differs in rabbits and humans.

Animals↗
PubMed2000

C/EBPalpha and C/EBPdelta activate the clara cell secretory protein gene through interaction with two adjacent C/EBP-binding sites.

The Clara cell secretory protein (CCSP) gene is a cell-specific differentiation marker for the bronchiolar Clara cell. Previous studies suggest that CCAAT/enhancer binding protein (C/EBP)alpha is involved in controlling differentiation-dependent gene expression in the distal lung. In this study, immunofluorescence studies demonstrated high level expression of C/EBPdelta in the bronchiolar epithelium as well as lower levels of C/EBPalpha. Cotransfection studies in the lung epithelial cell line A549 showed that both C/EBPalpha and C/EBPdelta activate the murine CCSP gene and that a C/EBP-response element resides in the proximal CCSP promoter. C/EBPdelta exhibits an approximately 2-fold higher transactivation potential than does C/EBPalpha. DNase I footprint analyses revealed a footprint region located at -100 to -62 bp, corresponding to two C/EBP-binding sites. Mutation of either site resulted in abolished or strikingly reduced transactivation of the CCSP promoter by C/EBPalpha and C/EBPdelta, as well as impaired binding of both factors, indicating that the two C/EBP-binding sites form a compound response element. In electrophoretic mobility shift assays, it was shown that C/EBPalpha and C/EBPdelta can bind to both C/EBP sites, whereas in DNase I footprint analyses, the interaction of C/EBPalpha with the proximal site was weak. Furthermore, electrophoretic mobility shift assays demonstrated that C/EBPalpha and C/EBPdelta preferentially form heterodimers at both binding sites. Cotransfections with C/EBPalpha and C/EBPdelta together resulted in a superinduction of the CCSP promoter, indicating a regulatory role for the C/EBPalpha-C/EBPdelta heterodimers. Our findings demonstrate that C/EBPalpha and C/EBPdelta regulate the CCSP gene through a compound response element and suggest that these factors are important for the differentiation-dependent expression of CCSP.

Adenocarcinoma↗
PubMed2000

Clara cell secretory protein. Levels in BAL fluid after smoking cessation.

STUDY OBJECTIVES: The bronchiolar Clara cell is a major target for tobacco smoke exposure. To improve our understanding of the putative regenerative/repair mechanism(s) in the bronchiolar epithelium, we measured the levels of the Clara cell secretory protein (CCSP) in BAL fluid in healthy volunteers following smoking cessation. DESIGN: BAL was performed before smoking cessation, and at 1, 3, 6, 9, and 15 months following smoking cessation, in eight healthy volunteers with a previous mean cigarette consumption of 19 pack-years. The levels of CCSP in BAL fluid were assessed in immunoblotting experiments using an antibody against human CCSP. RESULTS: Significantly (p < 0.05) higher levels of CCSP in BAL fluid were observed at 3, 6, and 9 months after smoking cessation, while the levels of CCSP in BAL fluid at 15 months after smoking cessation were the same as those before smoking cessation. CONCLUSIONS: Despite the long history of smoking among patients in the present study group, signs of early regeneration in the bronchiolar epithelium were noted, in that the levels of CCSP in BAL fluid were elevated at the indicated time points following smoking cessation. Furthermore, we propose that the insult to the bronchiolar epithelium made by cigarette smoking caused the levels of CCSP in the BAL fluid at 15 months after smoking cessation to return to the levels noted before smoking cessation. The present study suggests a role for CCSP as a marker for nonciliated bronchiolar cell function.

Adult↗
PubMed1999

In vivo modulation of glucocorticoid receptor mRNA by inhaled fluticasone propionate in bronchial mucosa and blood lymphocytes in subjects with mild asthma.

BACKGROUND: In vivo regulation of the glucocorticoid receptor (GR) by glucocorticoids provides a means of modulating sensitivity of targeted cells. OBJECTIVE: We sought to determine the in vivo modulation of GR mRNA expression by fluticasone propionate (FP) in subjects with mild asthma. METHODS: Ten atopic asthmatic subjects were treated with FP 250 microg twice daily for 4 weeks. Before and after treatment, the patients underwent fiberoptic bronchoscopy with endobronchial biopsy and sampling of venous blood for measurements of GR mRNA levels. A solution hybridization assay was used for quantitative analysis of GR mRNA. In addition, a 24-hour urinary cortisol excretion and an adrenocorticotropic hormone test before and after treatment with FP were performed. RESULTS: A high interindividual variation in GR mRNA expression was seen. However, we detected a significant reduction of the GR mRNA levels in the endobronchial biopsy specimens after FP treatment (36.6 +/- 23.1 and 25.0 +/- 10.9 amol GR mRNA/microg RNA, respectively; P <.01). In the peripheral blood lymphocytes an even more striking downregulation of the GR by its cognate ligand was documented (30.3 +/- 26.5 and 8.8 +/- 5 amol GR mRNA/microg RNA, respectively; P <.001), possibly reflecting differences in glucocorticoid sensitivity between tissues. A small but significant reduction of the 24-hour urinary cortisol excretion was observed (233 +/- 109 and 157 +/- 66 nmol/L, respectively; P <.01), whereas the feedback regulation of glucocorticoid synthesis by means of the hypothalamic-pituitary-adrenal axis as assessed by the adrenocorticotropic hormone test remained normal after treatment with FP. CONCLUSION: The results in this study confirm the potency of the inhaled corticosteroid FP and provide evidence for a considerable tissue-specific interindividual variation in the expression of the GR.

Adrenocorticotropic Hormone↗
PubMed1998

Regulation of CCSP (PCB-BP/uteroglobin) expression in primary cultures of lung cells: involvement of C/EBP.

The Clara-cell secretory protein (CCSP) is a cell-specific differentiation marker for the bronchiolar Clara cell. Isolated rat Clara and alveolar type 2 cells kept in primary culture proliferate and dedifferentiate, providing the opportunity to study differentiation-dependent mechanisms. In freshly isolated Clara cells, high levels of CCSP and the corresponding mRNA were detected. During culture in vitro, these levels decreased. In the type 2 cell fraction, low levels of CCSP were detected, which decreased further during culture. A promoter fragment of the rat CCSP gene encompassing the sequence from -188 to +53 was able to drive high-level expression of reporter genes in transfected Clara cells. Reporter gene expression in transfected type 2 cells was markedly lower, and no expression could be detected in alveolar macrophages. Expression of transcription factors previously described to stimulate CCSP expression appeared not to parallel CCSP levels in the primary Clara cells. However, expression of the transcription factor C/EBP alpha correlated with the CCSP expression pattern. In electrophoretic mobility shift assays, we were able to demonstrate binding of C/EBP alpha from rat Clara cell nuclear extracts to an element located 85 bp upstream of the start site of transcription. Overexpression of C/EBP alpha increased expression from the CCSP -188 promoter fragment up to fivefold in NCI-H441-cells and 30-fold in A549-cells, establishing the functional importance of C/EBP alpha. Our results show that primary cultures of Clara cells constitute a useful model for investigating terminal airway differentiation and suggest a role for C/EBP-factor(s) in this process.

Animals↗
PubMed1998

Poor people on the move: county-to-county migration and the spatial concentration of poverty.

"Poverty rates in high-poverty and low-poverty rural [U.S.] counties, and, thus, the spatial concentration of poverty, are affected by poverty-specific differences in in-migration and out-migration patterns. These patterns are investigated using 1985-90 county-to-county migration data from the decennial census. Effects on poverty rates of four migration flows (in- and out-migration of poor, in- and out-migration of nonpoor) are quantified, and their impacts on spatial concentration of poverty are assessed. The effect of selected county characteristics on the migration of the poor and nonpoor in nonmetro counties [is] estimated."

Americas↗
PubMed1997

[A new concept in digestive surgery: the computer assisted surgical procedure, from virtual reality to telemanipulation].

Surgical simulation increasingly appears to be an essential aspect of tomorrow's surgery. The development of a hepatic surgery simulator is an advanced concept calling for a new writing system which will transform the medical world: virtual reality. Virtual reality extends the perception of our five senses by representing more than the real state of things by the means of computer sciences and robotics. It consists of three concepts: immersion, navigation and interaction. Three reasons have led us to develop this simulator: the first is to provide the surgeon with a comprehensive visualisation of the organ. The second reason is to allow for planning and surgical simulation that could be compared with the detailed flight-plan for a commercial jet pilot. The third lies in the fact that virtual reality is an integrated part of the concept of computer assisted surgical procedure. The project consists of a sophisticated simulator which has to include five requirements: visual fidelity, interactivity, physical properties, physiological properties, sensory input and output. In this report we will describe how to get a realistic 3D model of the liver from bi-dimensional 2D medical images for anatomical and surgical training. The introduction of a tumor and the consequent planning and virtual resection is also described, as are force feedback and real-time interaction.

Computer Simulation↗
PubMed1997

[Telesurgery: standards--consultations--continuing education].

The aim of the TESUS project is to bring together several European university hospitals in a federation as well as a certain number of clinical centers in a network, the purpose of which is the online and offline transmission of surgical procedure imaging and advice. The innovation is threefold: It provides the surgeon with online information, diagnostic and therapeutic tools and expert advice, the need for which might come up before and during surgical procedures, as well as the same services in the context of teaching and training through regular staff. The developed services will be a major contribution to EU-wide standardisation of health care procedures and therapeutic approaches.

Computer Communication Networks↗
PubMed1996

Structural basis for calcium binding by uteroglobins.

Uteroglobins, i.e. proteins with similar three-dimensional structure and ligand binding specificity to uteroglobin from rabbit uterus, have been found in rat, mouse and human lung. We have recently demonstrated the binding of calcium by human uteroglobin, and we have therefore tried to find potential binding sites for metals in the three-dimensional structure of uteroglobin by the use of two different computational procedures. A putative binding site for calcium in uteroglobin was identified by means of a hydrophobic contrast function. The spatial disposition of atoms that could ligand calcium in the putative calcium-binding site appears similar to that of the primary calcium-binding site of secretory phospholipase A2 enzymes, consisting of the carboxyl group of an aspartic acid residue and a loop providing three backbone carbonyl oxygens. From inspection of their primary sequences and three-dimensional structures, it became clear that this putative calcium-binding motif is conserved among uteroglobins from different species. The potential significance of the predicted site was investigated by site-directed point mutagenesis of human uteroglobin in which Asp46 was replaced by Asn or Lys. In both mutants, the ruthenium red and 45Ca2+ binding was significantly reduced. Sodium dodecyl sulphate/polyacrylamide gel electrophoresis under non-reducing conditions indicated that the mutant proteins had the expected molecular masses and that their ability to dimerize was not disturbed by these mutations. Valence calculations also identified the putative calcium-binding site, but only after optimization of its conformation by the use of molecular dynamics with a restrained calcium ion. Our results support the notion that Asp46 of uteroglobins acts as a "cap" residue in a calcium-binding site structurally similar to the primary calcium binding sites of phospholipases A2.

Amino Acid Sequence↗
PubMed1996

Clara cell secretory protein: a determinant of PCB bioaccumulation in mammals.

Clara cell secretory protein (CCSP) is a product of nonciliated cells of the conducting airway epithelium. The normal physiological function of CCSP is unknown. However, the ability of CCSP to bind small lipophilic molecules, such as steroid hormones and certain pollutants, has led to speculation that this protein may mediate the biological accumulation of potentially harmful polychlorinated biphenyl (PCB) metabolites within the lung. To investigate the contribution of CCSP in the in vivo accumulation of methylsulfonyl-PCB, a line of mice was established that were homozygous for a null allele of the CCSP gene. CCSP-deficient mice were healthy and fertile, with no gross physiological or pathological abnormalities Parenteral challenge with the PCB metabolite 4-methylsulfonyl-2,2',4',5,5'-pentachlorobiphenyl (MeSO2-PCB) demonstrated that CCSP-deficient mice no longer accumulate this class of pollutants within lung and kidney tissues. These data demonstrate that CCSP is the determinant for MeSO2-PCB accumulation within mice and support the notion that bioconcentration of MeSO2-PCB pollutants occurs at sites of CCSP localization, such as the respiratory and reproductive tracts of humans.

Animals↗
PubMed1995

Calcium-dependent binding of uteroglobin (PCB-BP/CCSP) to negatively charged phospholipid liposomes.

To investigate interactions between the polychlorinated biphenyl-binding protein uteroglobin and phospholipids, we used a liposome-pelletting assay. PCB-BP/uteroglobin bound to liposomes made from negatively charged phospholipids (PtdSer and PtdIns) in the presence of 5 mM calcium. No binding to liposomes made from phospholipids without net charge (PtdChol and PtdEtn) was observed, nor could we detect binding in the absence of calcium or when magnesium was substituted for calcium. This suggests that PCB-BP/uteroglobin can bind to phospholipids in vivo and may have a role in the phospholipid homeostasis of the airway and/or secretory pathway of the Clara cell.

Calcium↗
PubMed1992

Rat lung polycholorinated biphenyl-binding protein: effect of glucocorticoids on the expression of the Clara cell-specific protein during fetal development.

Certain metabolites of polychlorinated biphenyls (PCBs) are retained in the Clara cells and in the airway lumen of rodent lung due to their interaction with a secretory 13-kDa protein. The expression of this Clara cell-specific, PCB-binding protein (PCB-BP) during the fetal development of the rat lung was studied by means of ligand binding and a monospecific antiserum. The PCB-BP and specific 4,4'-bis([3H]methylsulfony)-2,2',5,5'-tetrachlorobiphenyl binding was first detected on gestational Day 19 and subsequently the levels of PCB-BP and specific ligand binding increased as a function of gestational age. The start site of transcription for the rat PCB-BP gene was determined by primer extension analysis and the information thus obtained was used to develop a quantitative assay for the corresponding mRNA based on solution hybridization and S1 nuclease mapping. The appearance of PCB-BP mRNA during fetal lung development preceded the detection of immunoreactive protein and ligand binding by 1 day. By Day 21, the level of PCB-BP mRNA was 15 ng/100 micrograms total lung RNA which is approximately 30-40% of adult levels. In utero exposure to the synthetic glucocorticoid betamethasone was shown to increase specific 4,4'-bis([3H]methylsulfonyl)2,2',5,5'- tetrachlorobiphenyl binding, PCB-BP protein, and PCB-BP mRNA if administered from gestational Day 18 and onward. By Days 21-22, glucocorticoid treatment resulted in a two- to threefold increase in the levels of specific ligand binding, immunoreactivity, and mRNA, i.e., to approximately adult levels.

Animals↗
PubMed1988

[Isolated tracheoesophageal fistulas. Apropos of 3 cases revealed in the newborn].

We report here on 3 cases of isolated tracheoesophageal fistula. This corresponds to approx. 2.7% of esophageal congenital abnormalities treated in our service. In all 3 cases, diagnosis could be evoked in the neonate in front of respiratory symptoms appearing with feeding. Esophageal contrast radiological studies confirmed in all cases the fistula and its level C7-T1. No other invasive investigation was necessary to the diagnosis. We did not observe associated malformations. Surgical approach was made by a right cervical incision to obtain in good conditions divisions of the fistula and suture of the esophageal and tracheal ends; in one case, a muscular flap was interposed. Followup and longterm results (up to 17 years) were excellent, with one case of regressive recurrent laryngeal nerve paresthesia.

Age Factors↗