PubMed Health⌕ Search

Biomedical subjects

A Munck

Publications and source records attributed to A Munck.

At least 19 recordsLinked to original sources
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↗
PubMed1995

[Mucoviscidosis and nutrition].

Digestive disorders in patients with cystic fibrosis cause nutritional deficiencies which have a major effect on the clinical course and outcome. A better understanding of the mechanisms involved and a more adapted therapeutic attitude have helped improve the life expectancy in this disease.

Adult↗
PubMed1994

Glucocorticoids and stress: permissive and suppressive actions.

Protection against stress by glucocorticoids is discussed in relation to their permissive and suppressive actions. Evidence from the last decade is summarized regarding the physiological nature of the suppressive actions, and the hypothesis that they prevent stress-activated defense mechanisms from overshooting and damaging the organism. Support for this hypothesis has come from observations on how endogenous or administered glucocorticoids control inflammatory and immune responses, protect in endotoxic and hemorrhagic shock, regulate central nervous system responses to stimuli, and moderate many defense reactions through suppression of cytokines and other mediators. Studies showing that glucocorticoids permissively induce receptors for several mediators that they suppress have led to a model in which stimulated activity of a mediator system is increased permissively through induction of mediator receptors and decreased through suppression of mediator production.

Animals↗
PubMed1994

Glucocorticoid receptors in ATP-depleted cells. Dephosphorylation, loss of hormone binding, HSP90 dissociation, and ATP-dependent cycling.

Dependence of hormone binding to glucocorticoid receptors (GRs) on cellular ATP levels suggested that GRs traverse an ATP-dependent cycle, and without ATP accumulate in forms that cannot bind hormone. Such "null" receptors (NRs) were identified in ATP-depleted WEHI-7 cells, where they are tightly associated with the nuclear fraction and partly dephosphorylated. With WCL2 cells (Chinese hamster ovary cells with overexpressed GRs) depleted of ATP with azide, we have now identified dephosphorylated sites on NRs, studied possible roles of phosphorylation using GR mutants, and measured association with the 90-kDa heat shock protein (hsp90). Most NRs in WCL2 cells are dephosphorylated at serines 220 and 234, but GRs with those serines mutated to alanines do not resemble NRs since they bind hormone. They do not associate strongly with nuclei. On azide treatment, however, mutated GRs lose hormone binding capacity faster than normal GRs. Association of hsp90 (and presumably other heat shock proteins) with cytosolic GRs is drastically reduced by azide treatment, sufficient to account for decreased hormone binding. We conclude that: (a) dephosphorylation of GRs does not yield NRs, but may weaken association with hsp90. (b) The postulated ATP-dependent GR cycle can be accounted for by dissociation, and ATP-dependent reconstitution, of GR-hsp90 complexes. (c) ATP depletion blocks reconstitution of complexes. Uncomplexed GRs may accumulate as one form of NR; they are probably also the precursors for other forms of NR.

Adenosine Triphosphate↗
PubMed1994

Cell cycle-dependent glucocorticoid receptor phosphorylation and activity.

Proliferating cells display striking cell cycle dependence in sensitivity to gene activation by glucocorticoids; they are sensitive in late gap 1/synthesis (G1/S) (late G1 and S phases) but resistant in gap 2/mitotic (G2/M). Here we describe large cell cycle-dependent variations in glucocorticoid receptor (GR) phosphorylation that accompany, and may account for, the changes in sensitivity. GRs are basally phosphorylated and undergo hyperphosphorylation after hormone-induced activation. Identified phosphorylated sites are all in the N-terminal domain. Several lie in a region required for full transactivating activity and reduction of nonspecific binding to DNA. Most are in consensus sequences for cell cycle-associated kinases, suggesting that such kinases phosphorylate GRs. We now show with WCL2 cells (Chinese hamster ovary cells with overexpressed GRs) that: 1) glucocorticoid treatment fails to hyperphosphorylate GRs in G2/M but doubles phosphorylation in S, more than seen with unsynchronized cells; and 2) basal GR phosphorylation is almost three times higher in G2/M than S. These results, along with earlier observations, implicate GR phosphorylation with mechanisms of glucocorticoid resistance in G2/M. Such mechanisms might underlie some forms of glucocorticoid resistance in inflammatory and lymphoproliferative diseases. HPLC phosphopeptide maps of GRs from S and G2/M reveal no significant qualitative differences in phosphorylated sites, consistent with a general increase during G2/M in negative charge of the N-terminal domain. We also show that the previously described increase in GR hormone-binding capacity from G1 to S is accompanied by a parallel increase in GR protein.

Animals↗
PubMed1994

[Contribution of genetic typing for the diagnosis of familial adenomatous polyposis in pediatrics].

BACKGROUND: The gene responsible for familial adenomatous polyposis, (APC), has been recently cloned and genetic map with several polymorphic markers has been established. POPULATION AND METHODS: Blood samples (20 ml) were taken from 34 subjects belonging to four families at risk for familial adenomatous polyposis. Nineteen of these 34, less than 20 years old, had one parent having polyposis or dead because of it. Polyposis was diagnosed, in ten of these 19 by endoscopy. Genomic DNA was extracted from peripheral leukocytes and Southern blot analyses were performed in each family, using RFLPs on both sides of the APC locus. RESULTS: DNA analysis identified normal and mutant haplotypes at the APC locus in each family. It was thus possible to follow the segregation of mutant alleles. These results were compared with the anamnestic and endoscopic data. Bearing in mind the risk of recombination when using extragenic markers, RFLPs allowed early diagnosis of APC in pre and/or asymptomatic patients. CONCLUSIONS: Genetic analysis can be used to diagnose APC in affected families, provided the risk of recombination is taken into account. Intragenic microsatellites markers will soon be available. These will provide more information on the APC gene, and hence direct molecular diagnosis of APC.

Adenomatous Polyposis Coli↗
PubMed1993

Duodenal manometry in postobstructive enteropathy in infants with a transient enterostomy.

Intestinal motility was studied in 11 children with a transient enterostomy secondary to a neonatal organic small intestine obstruction (5 total colon Hirschsprung's disease, 2 necrotizing enterocolitis, 1 intussusception, 3 ileal atresia). Eight children presented with a postobstructive enteropathy (severe grade I [5], moderate grade II [3]) and three were considered as controls (grade III). They were assigned to one of the three groups on the basis of the duration of parenteral nutrition and constant rate enteral nutrition needed and the oral feeding tolerance. Barium small intestine transit showed no persistent partial obstruction or peritoneal adhesions. The abnormal inert marker transit times were statistically correlated with the clinical groups as well as duodenal manometric abnormalities. Manometric recordings were characterised by the absence (grade I) or abnormal phase III (grade II) of the migrating motor complex and decreased motility index (grades I and II). This study confirms that this enteropathy is due to a chronic alteration in motility induced by prenatal or postnatal obstructions.

Barium Sulfate↗
PubMed1993

Glucocorticoid receptors: ATP-dependent cycling and hormone-dependent hyperphosphorylation.

The dependence of hormone binding to glucocorticoid receptors (GRs) on cellular ATP levels led us to propose that GRs normally traverse an ATP-dependent cycle, possibly involving receptor phosphorylation, and that without ATP they accumulate in a form that cannot bind hormone. We identified such a form, the null receptor, in ATP-depleted cells. GRs are basally phosphorylated, and become hyperphosphorylated after treatment with hormone (but not RU486). In mouse receptors we have identified 7 phosphorylated sites, all in the N-terminal domain. Most are on serines and lie within a transactivation region. The time-course of hormone-induced hyperphosphorylation indicates that the primary substrates for hyperphosphorylation are the activated receptors; unliganded and hormone-liganded nonactivated receptors become hyperphosphorylated more slowly. After dissociation of substrates for hyperphosphorylation are the activated receptors; unliganded and hormone-liganded nonactivated receptors become hyperphosphorylated more slowly. After dissociation of hormone, most receptors appear to be recycled and reutilized in hyperphosphorylated form. From these and related observations, we have concluded that the postulated ATP-dependent cycle can be accounted for by hormone-induced or spontaneous dissociation of receptor-Hsp90 complexes, followed by reassociation of unliganded receptors with Hsp90 via an ATP-dependent reaction like that demonstrated in cell-free systems. Other steroid hormone receptors might traverse a similar cycle. Four of the 7 phosphorylated sites in the N-terminal domain are in consensus sequences for p34cdc2 kinases important in cell cycle regulation. This observation, along with the known cell cycle-dependence of sensitivity to glucocorticoids and other evidence, point to a role for receptor phosphorylation in controlling responses to glucocorticoids through the cell cycle.

Adenosine Triphosphate↗
PubMed1993

Liver cirrhosis in cystic fibrosis--therapeutic implications and long term follow up.

Experience gained from liver studies in 450 patients with cystic fibrosis, seen in a 38 year period from 1964 to 1992, is surveyed. Of these, 31 (7%) showed findings that indicated multilobular cirrhosis. There was a slight but not significant male predominance: 19 males against 12 females. Liver disease had its onset during childhood in most cases. The natural course of liver disease and of cirrhosis is protracted. All patients were routinely evaluated by way of: (i) clinical examination, (ii) biochemical studies and specifically estimation of transaminases and gamma glutamyltransferase, and (iii) liver imaging, ultrasonography, and computed tomography. The study aimed to detect early liver disease, that is multilobular cirrhosis and its complications, with a view to optimal introduction of treatment with ursodeoxycholic acid as this drug shows promise for preventing or stabilising the cirrhotic process. Effects of surgical treatment on portal hypertension are surveyed. These include portacaval shunting, partial splenectomy (considered the procedure of choice), liver transplant in the event of liver failure, or a triple transplant (liver, lungs, and heart) if necessary. One triple transplant was successfully performed in a boy of 10 years with a 2 year follow up.

Adolescent↗
PubMed1992

Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.

Abetalipoproteinemia is a human genetic disease that is characterized by a defect in the assembly or secretion of plasma very low density lipoproteins and chylomicrons. The microsomal triglyceride transfer protein (MTP), which is located in the lumen of microsomes isolated from the liver and intestine, has been proposed to function in lipoprotein assembly. MTP activity and the 88-kilodalton component of MTP were present in intestinal biopsy samples from eight control individuals but were absent in four abetalipoproteinemic subjects. This finding suggests that a defect in MTP is the basis for abetalipoproteinemia and that MTP is indeed required for lipoprotein assembly.

Abetalipoproteinemia↗