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Biomedical subjects

A Munck

Publications and source records attributed to A Munck.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Use of GEE for modeling censored correlated data: application to the study of risk factors for withdrawal of totally implantable vascular access devices in cystic fibrosis].

BACKGROUND: The proportional hazards model proposed by Cox for modeling censored data is not suited for correlated delays, for instance when several events can be observed on each subject. METHODS: To analyze correlated delays, we propose to use a log-linear marginal model equivalent to Cox model. Correlations are taken into account through the use of Liang and Zeger's Generalized Estimating Equations (GEE) and of their robust variance estimator. An advantage of this method is that it can be implemented through the SAS GENMOD procedure. When ties are observed, we propose to use multiple imputations, creating M data sets without ties from the original one. RESULTS: This method is applied to a retrospective survey on the risk of withdrawing totally implantable vascular access devices (TIVAD) because of complication in cystic fibrosis patients: 265 TIVAD implanted in 200 patients were observed. Risk factors were characteristics of the device or of the patient. Results obtained with the robust variance estimator and ten imputations show that the use of the device for taking blood (vs exclusive perfusion of antibiotics), polyurethane catheter (vs. silicon), use of counterpressure for upkeeping and pulmonary colonization by Pseudomonas Aeruginosa are significantly associated to withdrawal. Under the Cox model which does not account for the correlations, some conclusions differ because the robust variance of the estimators is smaller than the variance obtained under the working assumption of independent delays. CONCLUSION: This approach allows the modeling of correlated survival data with SAS software. Our results illustrate the necessity of accounting for existing correlations.

Catheters, Indwelling↗
PubMed1998

Pharmacokinetics of intravenous methylprednisolone and oral prednisone in paediatric patients with inflammatory bowel disease during the acute phase and in remission.

OBJECTIVE: The present study was undertaken to evaluate the influence of inflammatory bowel disease on the pharmacokinetics of intravenous methylprednisolone and prednisolone (after oral administration of prednisone). PATIENTS: Twelve children with inflammatory bowel disease, aged 12.3 years were studied during the active phase and in remission. In 6 patients the disease responded to oral prednisone while 6 did not respond. METHODS: During the acute phase, intravenous methylprednisolone (2 mg x kg(-1)) and oral prednisone (2 mg x kg(-1)) were administered in a random order and blood was sampled over 48 h. Prednisone (2 mg x kg(-1)) was readministered after remission. The concentrations of methylprednisolone and prednisolone were measured by high-pressure liquid chromatography. RESULTS: During the acute phase, the systemic clearance of methylprednisolone was 0.98 (1 kg(-1) x h(-1)) and the elimination half-life was 1.67 h. The area under the plasma concentration-versus-time curve of prednisolone was 4.00 and 3.20 x mg x h x l(-1) respectively during the active disease and remission, while its elimination half-life was 3.51 h during the acute phase and 2.42 h in remission. There were no pharmacokinetic differences between the patients who responded or did not respond to oral treatment. CONCLUSION: In children with inflammatory bowel disease, the initial response to corticosteroid therapy was not influenced by the pharmacokinetics of prednisolone and methylprednisolone. In addition, the pharmacokinetics of prednisolone was not modified by the inflammatory syndrome.

Acute-Phase Reaction↗
PubMed1998

[Iterative intestinal intussusception and appendiceal mucocele in an infant with mucoviscidosis].

UNLABELLED: Cystic fibrosis is a common and potentially life-threatening hereditary disease which can affect numerous organs, particularly the digestive tract. CASE REPORT: A 4.5-year-old boy exhibited two little known clinical manifestations: an appendiceal mucocele and repeated intussusceptions. In spite of an appendectomy, intussusception relapsed and an ileocolic resection was necessary 2 years later. DISCUSSION: Appendiceal diseases in cystic fibrosis represent a large spectrum, ie, distention on the appendiceal lumen, engorged with sticky mucous matter, which becomes an appendiceal mucocele, peritonitis with an appendiceal perforation due to delayed diagnosis since acute appendicitis is difficult to diagnose in these patients. Intussusception is rarely observed in cystic fibrosis. CONCLUSION: Appendiceal mucocele could be a cause of intussusception. If an appendectomy is performed, resection of a part of the cecum, around the appendix, could be useful in preventing again mucocele formation.

Appendectomy↗
PubMed1998

Glucocorticoid receptor phosphorylation: overview, function and cell cycle-dependence.

All steroid hormone receptors are phosphorylated and undergo hormone-induced hyperphosphorylation. Most phosphorylated residues identified so far are serines in the N-terminal domain. Other residues and domains may also be phosphorylated, e.g. the estrogen receptor is phosphorylated on tyrosine in the hormone-binding domain. Many sites lie in consensus sequences for proline-directed, cell cycle-associated kinases. In some receptors hyperphosphorylation is induced by hormone antagonists as well as agonists, and leads to new phosphorylated sites. With glucocorticoid receptors, hyperphosphorylation is specific for glucocorticoid agonists, follows receptor activation and produces no new sites. Rate studies suggest that hyperphosphorylation is due to accelerated phosphorylation rather than delayed dephosphorylation. Evidence to date indicates that steroid hormone receptor phosphorylation serves not as an on-off switch but modulates function more subtly. Mutations of phosphorylated sites to alanine have been found to decrease activity by 0 to 90%, depending on mutated site, cell type, reporter gene and hormone concentration. With glucocorticoid receptors, some alanine mutants are up to 75% less active in hormone-induced transactivation of certain reporter genes. They are also inactive in hormone-induced repression of transcription of their own gene and down regulation of the receptor protein. Furthermore, they are much less sensitive to degradation. Both basal phosphorylation and hormone-dependent hyperphosphorylation of these receptors are cell cycle-dependent, basal phosphorylation being low in S phase and high in G2/M and hyperphosphorylation the reverse, suggesting a causal relation to the cell cycle-dependence of glucocorticoid activity reported with several cell lines. Hyperphosphorylation appears to be regulated by basal phosphorylation through negative charge in the N-terminal domain, which in S phase is relatively low and permits hyperphosphorylation, but in G2/M is relatively high and blocks hyperphosphorylation.

Cell Cycle↗
PubMed1998

Out-of-hours service in Denmark: the effect of a structural change.

BACKGROUND: In Denmark, the provision of out-of-hours care by general practitioners (GPs) was reformed at the start of 1992. Rota systems were replaced locally by county-based services. The new out-of-hours service resulted in a considerable reduction in the total number of GPs on call. AIM: To describe how the patients experienced the change from a satisfaction point of view, and how the pattern of patient contact and the fee for GPs changed with the new system. METHOD: The county of Funen was chosen as the geographical area where data were collected. A questionnaire measuring patient satisfaction was posted before the change, immediately after the change, and three years later to a random selection of patients who had been in contact with the out-of-hours service within two weeks before the mailing date. All primary care services for the Danish population are stored in a database (National Health Service Registry). From this continuously updated database, the contact pattern and the fee for GPs were extracted for 1991, 1992, and 1995. RESULTS: The total number of patient contacts was reduced by 16% in the first year, but by only 6% three years later. Three years after the change, there were more than twice as many telephone consultations as before the change, and there were only a third as many home visits. After three years, the GPs' fees were reduced by 20%. There was a significant decrease in patient satisfaction, although the overall level remained high. This decrease was lower three years after the change than immediately after the new system was introduced. CONCLUSION: The new service had a major cost-effectiveness benefit, but there was a price to pay in patient satisfaction.

Denmark↗
PubMed1997

Mouse glucocorticoid receptor phosphorylation status influences multiple functions of the receptor protein.

Although studies have shown that the mouse glucocorticoid receptor (mGR) contains eight phosphorylation sites (Bodwell, J. E., Ortí, E. , Coull, J. M., Pappin, D. J. C., Smith, L. I., and Swift, F. (1991) J. Biol. Chem. 266, 7549-7555), the effect of phosphorylation on receptor function is unclear. We have examined the consequences of single or multiple phosphorylation site mutations on several properties of mGR including receptor expression, ligand-dependent nuclear translocation, hormone-mediated transactivation, ligand-dependent down-regulation of mGR, and receptor protein half-life. Mutations had little effect on receptor expression, subcellular distribution, ligand-dependent nuclear translocation, or on the ability to activate hormone-mediated transcription from a complex (murine mammary tumor virus) promoter. In contrast, the phosphorylation status of the mGR had a profound effect on the ability to transactivate a minimal promoter containing simple glucocorticoid response elements after hormone administration. Similarly, ligand-dependent down-regulation by glucocorticoids of both receptor mRNA and protein was abrogated in mutants containing three or more phosphorylation site alterations. Finally, we show that the phosphorylation status of mGR has a profound effect on the stability of the glucocorticoid receptor protein. Receptors containing seven or eight mutated sites have a markedly extended half-life and do not show the ligand-dependent destabilization seen with wild type receptor. These data show that receptor phosphorylation may play a crucial role in regulating receptor levels and hence control receptor functions.

Animals↗
PubMed1997

Control by basal phosphorylation of cell cycle-dependent, hormone-induced glucocorticoid receptor hyperphosphorylation.

Mouse glucocorticoid receptors (GRs) are phosphorylated in the N-terminal domain at serine/ threonine residues, most lying in consensus sequences for cell cycle-associated kinases. Glucocorticoid agonists, but not antagonists, induce hyperphosphorylation. Phosphorylation of GRs overexpressed in Chinese hamster ovary (CHO) cells is cell cycle-dependent: basal phosphorylation in S phase is one third that in G2/M; glucocorticoids induce hyperphosphorylation in S but not G2/M, paralleling the reported sensitivity in S and resistance in G2/M of proliferating cells to transcriptional activation by glucocorticoids. This parallel led us to investigate what controls hyperphosphorylation. We tested three hypotheses: hyperphosphorylation is controlled by 1) negative charge due to basal GR phosphorylation, being permitted in S by low charge and blocked in G2/M by high charge; 2) presence in S and absence in G2/M of required kinases; 3) availability in S and lack in G2/M of unoccupied phosphorylatable sites. Our results are inconsistent with 2) and 3), but strongly support 1). GR mutants with alanines (A7GR) or glutamates (E7GR) replacing all but one phosphorylated site were overexpressed in CHO cells. Serine 122 remained intact to report GR phosphorylation. Consistent with hypothesis 1, with A7GRs hormone-induced hyperphosphorylation occurred in both S and G2/M (thus revealing kinase activity for hyperphosphorylation of at least serine 122 in both phases), whereas with E7GRs it occurred in neither phase. We conclude that basal GR phosphorylation controls hormone-induced GR hyperphosphorylation by modulating negative charge in the N-terminal domain and could potentially control other cell cycle-dependent GR properties.

Animals↗
PubMed1996

In situ management and molecular analysis of candidaemia related to a totally implantable vascular access in a cystic fibrosis patient.

We describe a case of candidaemia in a paediatric cystic fibrosis (CF) patient with a totally implantable vascular access (TIVA). Serial quantitative blood cultures during therapy with amphotericin B delivered via the catheter suggested that the patient was responding to therapy. The TIVA was finally removed because of persistent fever, but its culture remained sterile. Randomly amplified polymorphic DNA (RAPD) analysis of Candida albicans from various anatomical sites showed that the patient's sputum was the most likely source of TIVA contamination. Investigation of TIVA-related candidaemia by molecular analysis could guide rational antifungal chemoprophylaxis of TIVA-related candidaemia.

Amphotericin B↗
PubMed1996

[Contribution of endosonography to the diagnosis and follow-up of pediatric gastric neurofibroma revealing von Recklinghausen's disease].

BACKGROUND: Gastrointestinal involvement in von Recklinghausen's disease (RD) is rare during childhood; its symptoms are late and its prognosis is poor, related to local recurrence and risk of malignant transformation. CASE REPORT: A 13 year-old boy was admitted for hematemesis revealing gastric ulcer. A second episode of hematemesis led to identify a sessile gastric tumor in this patient having numerous skin café-au-lait spots. Recurrent bleeding required laparotomy that showed diffuse infiltration into the anterior gastric wall: histological examination of the excised piece showed characteristic features of neurofibromatosis. The patient was not compliant to the endosonographic survey so that a symptomatic relapse led to total gastrectomy: histological examination did not show malignant transformation. CONCLUSION: Endoscopy is a major tool for identifying gastrointestinal localization of RD but endosonography is necessary to precise the extent of the tumor.

Adolescent↗
PubMed1996

Is nasal polyposis in cystic fibrosis a direct manifestation of genetic mutation or a complication of chronic infection?

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians. It is characterized by abnormal transepithelial sodium and chloride transport. The clinical expressions of the disorder are highly variable including nasal polyposis. Some authors have found that CF children with nasal polyposis form a distinct subgroup of patients within the clinical heterogeneity of the disease with milder gastrointestinal and pulmonary symptoms. The aim of this prospective study was to verify whether the clinical manifestations in CF children with nasal polyposis are different from control CF patients, and to identify any correlation between a phenotype of nasal polyposis and a genotype. Sixty-six CF children, aged 1-25 years, consecutively underwent ENT examination including nasal endoscopy. Twenty-one had nasal polyposis. The remainder formed the control group. There was no statistical difference in the mode and age of presentation of the disease between the two groups. The clinical manifestations (Schwachman and Kulczycki score, colonization by Staphylococcus aureus and Pseudomonas aeruginosa) were comparable between the two groups. We found no statistical difference in the repartition of genotypes between the polyposis and the control groups. Nasal polyposis does not seem to be genetically dependent, but a larger sample of patients is needed to reach an accurate conclusion.

Adolescent↗
PubMed1995

[Nasal transepithelial difference of potential in mucoviscidosis. Clinical application of the measurement].

OBJECTIVES: To demonstrate the value of nasal transepithelial potential difference measurements in the diagnosis and assessment of therapeutic effect in cystic fibrosis. METHOD: Nasal transepithelial potential difference was measured in 50 patients with cystic fibrosis (mean age 10 years) and 21 controls (mean age 8 years). RESULTS: There was a very significant increase in nasal transepithelial potential in cystic fibrosis patients (-28 +/- 8 mv) compared with controls (-8 +/- 3 mv) (p < 0.0001). The sensitivity and specificity of this test for the diagnosis of cystic fibrosis were 92% and 95% respectively. Nasal transepithelial potential difference was positively correlated with age (r = 0.43; p < 0.002) in cystic fibrosis patients but no correlation was found in controls. There was no significant difference in potential differences as a function of sex or Delta F508 genotype (homozygous vs heterozygous; Delta F508 vs non-Delta F508). CONCLUSION: These findings demonstrated the value of transepithelial potential difference in the diagnosis of cystic fibrosis and emphasized its capacity to assess the effect of new therapeutic protocols aimed at modifying C1- and Na+ ion transport. It could be particularly helpful for the interpretation of doubtful sweat tests.

Adolescent↗
PubMed1995

[Perspective of use of rhDNase and new therapeutics for cystic fibrosis].

The prognosis of cystic fibrosis has dramatically improved during the last three decades. This improvement was due to optimization of symptomatic treatment: antibiotics to combat infection, nutritional support, emphasis on bronchial drainage by physiotherapy and aerosols. The discovery of the gene responsible for the disease and the encoded protein opens the way to a specific and curative approach based upon the knowledge of the intrinsic properties of the protein, and its role in ionic flux. Recently, owing to the development of bioengineering, a recombinant human DNase has become available for clinical use. When aerosolized in the patients, it leads to deep changes in rheological parameters of the secretions that facilitate bronchial drainage and clearing of the airways. Gene therapy, the ultimate expression of these advances, will soon enter the era of clinical applications. Unsolved methodological and ethical issues still preclude immediate use in the patients. The results of transplantation surgery have also dramatically improved since the beginning. Indications are more precisely defined and restricted to the more advanced forms of the disease, according to severe criteria of inclusion.

Administration, Inhalation↗
PubMed1995

Hormone-induced hyperphosphorylation of specific phosphorylated sites in the mouse glucocorticoid receptor.

The glucocorticoid receptor (GR) is phosphorylated in its basal state, and rapidly undergoes hormone-induced hyperphosphorylation after binding glucocorticoids. Previously, we have identified seven phosphorylated sites in the mouse GR. Most of the sites are located in the regions of the N-terminal domain that are necessary for maximum transcriptional activity and reduce nonspecific binding to DNA. Using WCL2 cells, which overexpress mouse GRs, we now quantitate hormone-induced hyperphosphorylation at each of these sites. Addition of triamcinolone acetonide to WCL2 cells results in significant hyperphosphorylation at the majority of the sites. The hyperphosphorylation ratio, i.e. the 32P incorporation into GRs from hormone-treated cells divided by 32P incorporation into GRs from untreated cells, was above 1.0 for all sites but serine 150 and threonine 159. Serine 220 displays marked hormone dependence, with a ratio of 3. For most sites the ratio was about 1.5. Hormone-induced hyperphosphorylation not only increases the charge at selected phosphorylated sites but also provides a substantial increase in the overall negative charge around the region of the N-terminal domain that is involved in transactivation.

Animals↗
PubMed1995

Latent pulmonary function abnormalities in children with Crohn's disease.

Recently, latent pulmonary involvement has been described in adult patients with inflammatory bowel disease. It is unknown, however, whether this also occurs in children, and whether the pulmonary abnormalities differ between the acute phase and remission. The incidence of pulmonary abnormalities has been investigated in 26 children with acute or quiescent Crohn's disease in terms of the following parameters: clinical pulmonary symptoms, chest roentgenograms and pulmonary function tests, including lung transfer factor for carbon monoxide (TLCO). One child had a severe digital clubbing. Chest radiographs were normal in all subjects. No significant differences were found between acute and quiescent phase for pulmonary volumes and expiratory flows, but TLCO (% predicted) was significantly decreased during the active phase of the disease as compared to remission (53 +/- 15 vs 81 +/- 19% predicted). These data suggest that latent pulmonary involvement is also present in a paediatric population with active Crohn's disease, despite a short disease history and absence of smoking. Although the nature of this abnormality remains unclear, this extradigestive epiphenomenon should be taken into account with respect to the aetiopathogenesis of Crohn's disease.

Adolescent↗