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Biomedical subjects

A Michel

Publications and source records attributed to A Michel.

At least 91 records · Page 5Linked to original sources
PubMed1997

Dissociation between phosphodiesterase inhibition and antiproliferative effects of phosphodiesterase inhibitors on the Dami cell line.

Phosphodiesterase (PDE) inhibitors were shown to inhibit proliferation of various cell types. The present investigation was designed to study the activity of selective PDE inhibitors (8-MeoMIX, milrinone, trequinsin, rolipram, RO-201724, zaprinast, and MY-5445) on the proliferation of the Dami cell line in relation to their effects on cAMP levels and PDE isoenzymes isolated from Dami cells. All compounds, except 8-MeoMIX, elicited antiproliferative effects. Trequinsin, RO-201724, and MY-5445 (100 microM) were found to inhibit cell growth up to 60%, 83%, and 85%, respectively; milrinone, rolipram and zaprinast elicited only weak effects (19-21% at 100 microM). Their growth-inhibitory effects could not be related to their effects on cAMP levels. In addition, although PDE type III and IV inhibitors potentiated cAMP formation due to adenylycyclase activation, no potentiation could be observed when considering their antiproliferative effect. Separation and characterization of PDE of Dami cells revealed the existence of types III, IV, and V isoenzymes. The PDE inhibition found for the PDE inhibitors could not explain their antiproliferative effects. The lack of correlation with cAMP concentrations or PDE inhibition and the high concentrations needed to elicit antiproliferative effects suggest the implication of other parameters, such as cytotoxicity or lipophilicity, or other targets in addition to PDE for the PDE inhibitors tested. Lipophilicity did not seem to be of importance in antiproliferative effects. In contrast, cytotoxic effects, in particular those of trequinsin and MY-5445, could partially explain their negative action on cell growth.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1997

Effect of extracellular AMP on cell proliferation and metabolism of breast cancer cell lines with high and low glycolytic rates.

In differentiated tissues, such as muscle and brain, increased adenosine monophosphate (AMP) levels stimulate glycolytic flux rates. In the breast cancer cell line MCF-7, which characteristically has a constantly high glycolytic flux rate, AMP induces a strong inhibition of glycolysis. The human breast cancer cell line MDA-MB-453, on the other hand, is characterized by a more differentiated metabolic phenotype. MDA-MB-453 cells have a lower glycolytic flux rate and higher pyruvate consumption than MCF-7 cells. In addition, they have an active glycerol 3-phosphate shuttle. AMP inhibits cell proliferation as well as NAD and NADH synthesis in both MCF-7 and MDA-MB-453 cells. However, in MDA-MB-453 cells glycolysis is slightly activated by AMP. This disparate response of glycolytic flux rate to AMP treatment is presumably caused by the fact that the reduced NAD and NADH levels in AMP-treated MDA-MB-453 cells reduce lactate dehydrogenase but not cytosolic glycerol-3-phosphate dehydrogenase reaction. Due to the different enzymatic complement in MCF-7 cells, proliferation is inhibited under glucose starvation, whereas MDA-MB-453 cells grow under these conditions. The inhibition of cell proliferation correlates with a reduction in glycolytic carbon flow to synthetic processes and a decrease in phosphotyrosine content of several proteins in both cell lines.

Adenosine Monophosphate↗
PubMed1997

Apoptotic effects of imidazo[1,2-a]pyrazine derivatives in the human Dami cell line.

cAMP-elevating agents like phosphodiesterase inhibitors and purines have been shown to induce apoptosis. In the present work we have studied the effects of imidazo[1,2-a]pyrazine derivatives with a purine-like structure: PAB13 (6-bromo-8-(methylamino)imidazo[1,2-a] pyrazine), PAB15 (6-bromo-8-(ethylamino)imidazo[1,2-a]pyrazine), PAB23 (3-bromo-8-(methylamino)imidazo[1,2-a]pyrazine) on the growth of the Dami cell line in comparison to that of adenosine. The growth effect of PAB13, PAB15 and PAB23 was investigated in relation to their phosphodiesterase-inhibitory action and their activity on purinoceptors. Inhibition in cell growth was up to 71.0%, 76.3% and 89.7% for PAB23, PAB13 and PAB15, respectively and 100% for adenosine. Cell viability was affected in a concentration-dependent manner by PAB13, PAB15 and adenosine, with a correlation between growth inhibition and cytotoxicity. These effects of imidazo[1,2-a]pyrazine derivatives were found to be unrelated to an action on purinoceptors, but rather appear quantitatively linked to their ability in inducing apoptosis through their cAMP-increasing and phosphodiesterase-inhibitory potency.

Adenosine↗
PubMed1997

The association between clinical findings on physical examination and self-reported severity in back pain. Results of a population-based study.

STUDY DESIGN: A cross-sectional population-based study of back pain. OBJECTIVE: To evaluate the association between clinical findings on physical examination and subjective severity in nonspecific back pain. SUMMARY OF BACKGROUND DATA: Assessment of severity of back pain always has been controversial. Most studies evaluating the role of clinical findings in back pain have been hospital- or clinic-based, often representing a highly select population. This selection is avoided in the population-based approach of the present study. METHODS: Approximately 4,000 German inhabitants of Lubeck, aged 25-74, were selected randomly from the local population registry and received a postal questionnaire. Those who reported "back pain today" (n = 1200) or "back pain within the past 12 months but no back pain before" (n = 75) were invited to come in for a clinical examination. Thirty-four physical measurements were taken. They were divided into four groups: static measurements, dynamic measurements, neurologic findings, and non-organic physical signs. Self-reported severity of back pain was measured by a pain questionnaire and a 12-item activities of daily living list to assess functional disability. RESULTS: Within each of the four groups of physical measurements, those that corresponded best with the subjective severity of back pain could be identified (e.g., rotation, lateral flexion, and fingertip-floor distance, scoliosis, the position of the side plumb line, and pain on percussion of the spine pseudo-Lasegue and hand muscle-strength). Those that corresponded best could be differentiated statistically from less correlative measurements such as kyphosis and lordosis; flexion of the lumbar, thoracic, or cervical spine, abdominal muscle strength, and axial loading. The agreement between the classification of back pain severity based on clinical findings and the classification based on self-reports was moderate (kappa = 0.47). CONCLUSIONS: Assessment of severity in back pain can only partly be based on the clinical findings of a physical examination. There is a relatively weak agreement between the results of physical examination and the subjective reporting of pain and disability.

Activities of Daily Living↗
PubMed1997

Risk for periodontal disease in patients with longstanding rheumatoid arthritis.

OBJECTIVE: To quantify periodontal disease in rheumatoid arthritis (RA) patients and controls, and to correlate the degree of destruction from periodontal disease and from RA. METHODS: Fifty RA patients were matched for age, sex, smoking status, and oral hygiene with 101 controls. Correlations between indices of chronic destruction in periodontal disease (gingival attachment loss) and in RA (Larsen radiographic score) were determined. RESULTS: Patients with longstanding active RA (mean +/- SD 13 +/- 8 years) who were receiving treatment with disease-modifying antirheumatic drugs (n = 46), corticosteroids (n = 38), or nonsteroidal antiinflammatory drugs (n = 43) had a higher rate of gingival bleeding (increased by 50%), greater probing depth (increased by 26%), greater attachment loss (increased by 173%), and higher number of missing teeth (increased by 29%) compared with controls. No correlation was found between the Larsen radiographic score and gingival attachment. CONCLUSION: Patients with longstanding active RA have a substantially increased frequency of periodontal disease, including loss of teeth, compared with controls. Antiinflammatory treatment interferes with periodontal disease and might have masked a possible correlation between the indices of chronic destruction in RA and periodontal disease.

Adult↗
PubMed1997

Identification of an amplified gene cluster in glioma including two novel amplified genes isolated by exon trapping.

Gene amplification, which occurs in more than 50% of malignant gliomas, is considered to play a pivotal role in tumorigenesis. There are, however, few studies aimed toward the isolation of novel genes from amplified sequences. Previously, we reported amplification of the protooncogene MET (hepatocyte growth factor receptor; 7q31) in more than 20% of glioblastomas. For an approximate size estimation of the amplification unit we analyzed three glioblastomas all of which carried an amplified MET gene, by Southern blot analysis and/or competitive polymerase chain reaction using eight DNA markers. Although the extent of the amplified domain varied, the close vicinity of the MET gene was the only region consistently amplified in these glioblastomas. A yeast artificial chromosome (YAC) contig of 900 kb was refined spanning the amplified region flanking the MET gene. The YAC inserts were subcloned into 59 cosmids, which were used for exon trapping. Eight sequences were identical to parts of the genes MET and CAPZA2 (human actin capping protein alpha-subunit). Two newly identified exons and the CAPZA2 exons were amplified in tumor TX3095, which retains an amplified MET gene. The new exons were localized close to MET and CAPZA2. Characterization of the clones, which were termed glioma-amplified sequence (GAS)7-1 and GAS7-2, showed an open reading frame and a different expression pattern in multiple human tissues. This study reports the identification of a cluster of amplified genes including two novel genes in a region amplified in more than 20% of glioblastomas.

Actin Capping Proteins↗
PubMed1997

Cloning of a novel transcription factor-like gene amplified in human glioma including astrocytoma grade I.

Gene amplification, which is generally considered to occur late in tumor development, is a common feature of high grade glioma. Up until now, there have been no reports on amplification in astrocytoma grade I. In this study, we report cloning and sequencing of a cDNA termed glioma-amplified sequence (GAS41) which was identified recently in a glioblastoma cell line by microdissection-mediated cDNA capture. This technique is tailored to isolate amplified genes from human tumors. An increased copy number of GAS41 was found in glioblastoma multiforme and astrocytoma III, and at a high frequency in astrocytoma grades I and II. Sequence comparison indicates a high homology between the GAS41 protein, the yeast and human AF-9 and the human ENL proteins. Both AF-9 and ENL belong to a new class of transcription factors, indicating that GAS41 might also represent a transcription factor. With GAS41 being the first gene found with increased copy number in low grade glioma, this study provides the first evidence that gene amplification can occur in early tumor development.

Amino Acid Sequence↗
PubMed1997

Modulation of the megakaryoblastic Dami cell line differentiation by phosphodiesterase inhibitors and imidazo[1,2-a]pyrazine derivatives.

Phosphodiesterase inhibitors have been shown to modulate cell differentiation. We have previously shown that a series of imidazo[1,2-a]pyrazine derivatives displayed inhibitory effects on phosphodiesterase isoenzymes types III. IV and V isolated from Dami cells and on Dami cell growth. In the present study we have investigated the effect of these derivatives on the expression of two differentiation markers, glycoproteins Ib and IIb/IIIa of the human megakaryoblastic leukaemic Dami cell line in comparison to those elicited by 3-isobutyl-1-methylxanthine and selective phosphodiesterase inhibitors of types 1 (8-methoxymetyl-1-methyl-3-(2-methylpropyl) xanthine), III (Milrinone), IV (RO-201724) and V (Zaprinast). Imidazo[1,2-a]pyrazine derivatives, 3-isobutyl-1-methylxanthine and selective phosphodiesterase inhibitors, except 8-methoxymethyl-1-methyl-3-(2-methylpropyl) xanthine, decreased glycoprotein Ib expression. SCA40, SCA41, SCA44 and 3-isobutyl-1-methylxanthine-but not the other compounds affected the expression of glycoprotein IIb/IIIa in a positive manner. The effects of imidazo[1,2-a]pyrazine derivatives on glycoprotein expression appeared to be related to their phosphodiesterase inhibitory potency.

Cell Differentiation↗
PubMed1997

Extracorporeal photochemotherapy: a treatment for organ graft rejection.

Extracorporeal photochemotherapy (ECPC) has been investigated experimentally and in clinical conditions in transplant rejection treatment and prevention. Repeated injections of photochemically modified syngeneic alloreactive T cells prior to transplant significantly delay rejection in a mouse skin graft model as well as in a heterotopic heart transplant model in rats. In the latter, we found this effect to be dependent on 3 main parameters, i.e., treatment intensity (number of injections), schedule (injections before and after transplant), and associated immunosuppression (because there is no detectable effect in animals without immunosuppression). In human beings, ECPC was first used for the treatment of acute rejection episode after heart transplantation. At least 2 studies provided evidence that ECPC is as effective as high dose corticosteroids in controlling moderate acute rejections, and several case reports showed that ECPC could be effective in recurrent and/or steroid resistant rejections. ECPC has also been investigated in an open trial to prevent rejection episodes after heart transplantation in patients at high risk of acute rejection because of human leukocyte antigen (HLA) immunization and/or a second or third transplant and found to be successful. In heart transplant recipients at standard risk of rejection episodes, a small scale randomized trial showed a reduction in both rejection episodes and infections in the ECPC treated vs. the standard group. Beyond these studies and other isolated case reports, several large scale randomized trials in heart, lung, and even kidney transplantations (some of them already ongoing), will enable us to define the role of ECPC in the management of transplant recipients.

Animals↗
PubMed1997

Early complications and value of initial clinical and paraclinical observations in victims of smoke inhalation without burns.

OBJECTIVE: To evaluate the incidence of early pulmonary complications and the value of initial clinical signs and paraclinical investigations in victims of smoke inhalation not suffering from burns following structural fires. DESIGN: Retrospective chart review. SETTING: Thirteen-bed ICU. PATIENTS: Sixty-four victims of smoke inhalation following household fires were admitted to the ICU between January 1987 and December 1992. Exclusion criteria from the study were patients with cutaneous burns or multiple trauma or blast injury, and patients found in cardiac arrest. METHODS: Clinical, biological, and radiologic parameters were collected over a 5-day period. RESULTS: The mortality rate in relation to progressive respiratory failure was 3.1%. Mean ICU stay was 5.8 days (range, 1 to 33 days), and was longer in the patients presenting with soot deposits in the oropharynx (p = 0.02), dysphonia (D) (p = 0.05), or ronchi (R) (p = 0.0004) at the first examination, and in those having a positive sputum bacteriologic analysis (p = 0.003) or requiring parenteral bronchodilator agents for more than 24 h (p = 0.04). Thirty-five patients underwent mechanical ventilation (MV) for a mean of 101.2 h (range, 8 to 648 h). Mean MV duration was higher in the patients presenting initially with R (p = 0.003), high carbon monoxide (but not cyanide) levels (p = 0.02), or a positive bacteriologic sample (p = 0.0001). Positive bacteriologic sampling correlated with the presence of D (p = 0.02) or R (p = 0.04) and with immediate intubation (p = 0.0003). No correlation was found with chest radiograph. CONCLUSIONS: In this selected series of fire victims without cutaneous burns, respiratory injury was frequent. The initial clinical signs may be helpful to predict pulmonary complications.

Adult↗
PubMed1997

A structural rationale for the design of water soluble peptide-derived neurokinin-1 antagonists.

Molecular models of a pharmacophore for NK1 neurokinin antagonists and of ligand-receptor complexes for the human NK1 G protein-coupled receptor are presented. The models develop a structural rationale for the discovery of the recently described highly potent peptidomimetic NK1 antagonists S18523 and S19752 which were designed to be water soluble. Water solubility was conferred on these compounds by introduction of an anionic butyl-tetrazole substituent on the scaffold of dipeptide-derived NK1 antagonist analogues. The models provide convincing evidence that the anionic butyl-tetrazole moieties of S18523 and S19752 protrude outside the membrane-spanning domain of the receptor and do not interfere significantly with the core of the antagonist binding site. It is emphasized that this result could only be obtained through the combination of the two modelling approaches. The result suggest a general way to modify the transport properties of the peptidomimetic antagonists without altering the receptor-binding interaction, and it outlines the potential of including the combination of pharmacophore models and crude models of receptor-ligand complexes early in the drug design process.

Animals↗
PubMed1997

From WING to MMSA: experiences with the implementation of a distributed HIS.

The following paper analyses the transition from a host centered to a client-server based Hospital Information System (HIS) which takes place at the University Hospital of Giessen, Germany, since 1995. It focuses on the overall concept and practical realisation of the cornerstone within this transition, the Macintosh Mosaic Software Architecture (MMSA) which delivers now more than 90% of the clinical data which is entered on the wards and within the operating rooms. Besides the technical problems of the project, the paper also describes some aspects of the organisational challenges which took place within a typical German University Hospital during the last 4 Years and which mainly affect the daily management of a large HIS.

Germany↗
PubMed1997

Does TISS pave a way towards the nurses care documentation?

New functions have been integrated in the Giessen Hospital Information System WING to support the classification of all intensive care patients into the Therapeutic Intervention Scoring System TISS. The use of those functions has been pushed by legal requirements which made it essential to assess the staffing of intensive care wards in comparison with the accumulated TISS scores. This paper describes the experiences made within two years of TISS scoring. We think that TISS gave a major impact to the construction and implementation of nursing documentation into our HIS.

Forms and Records Control↗
PubMed1996

High frequency of somatic mutations in the VH genes expressed in prolymphocytic leukemia.

Prolymphocytic leukemia (PLL) is a chronic lymphoproliferative disorder, characterized by prominent splenomegaly, prolymphocytes accounting for more than 55% of circulating lymphocytes, and short-term survival. To better characterize the nature of the cellular origin in this disease, we analyzed lg heavy chain variable region (VH) genes in eleven cases of de novo PLL Leukemic cells expressed a skewed repertoire characterized by predominant use of the V3 family members (73%), with preferential use of the V3-23 gene (50% of the VH3 genes). All sequences from expressed VH genes diverged from their putative germline counterpart, and in eight cases the divergence was greater than 5%. In seven cases, which expressed the V3-23 gene and VH4 family members, nucleotide substitutions could be confidently attributed to somatic mutations. The type and distribution of these mutations clearly indicated that in three cases the cells had been subjected to an antigen selection process. Taken together, these results suggest that B-PLL cells display a skewed repertoire of lg VH regions and probably represent, at least in some instances, expansion of postgerminal center cells that have undergone antigen driven selection.

Adult↗
PubMed1996

Ferritin mRNAs in Schistosoma mansoni do not have iron-responsive elements for post-transcriptional regulation.

Schistosoma mansoni possesses two isoforms of ferritin, soma and yolk ferritin. The soma ferritin occurs at a low level in most cells of both genders, whereas the yolk ferritin is a female-specific gene product that is expressed at high level in the vitellarium. In higher animals, ferritin mRNA is regulated by iron via the interaction of cytoplasmic binding proteins (IRPs) with a specific sequence element in the 5' untranslated region (UTR) referred to as the iron-responsive element (IRE). Sequence studies of the 5' UTRs, gel retardation assays, and hybridization experiments show that neither ferritin mRNAs of S. mansoni is regulated by an IRE/IRP mechanism. It is suggested that ferritins in schistosomes are controlled only at the transcriptional level.

Animals↗
PubMed1996

Amino acid conservation in animal glucokinases. Identification of residues implicated in the interaction with the regulatory protein.

To delineate the regions of liver glucokinase that are involved in the binding of its regulatory protein and have therefore been conserved throughout evolution, we have cloned the cDNA of the Xenopus laevis enzyme. It contains an open reading frame of 1374 nucleotides and encodes a protein of 458 amino acids, which displays 78 and 79% overall identity to rat and human liver glucokinases, respectively. The conserved regions are predicted to be present mainly in the small domain and the hinge region of glueokinase, and the nonconserved regions in the large domain of the enzyme. We constructed five mutants of Xenopus glucokinase by replacing sets of 2-5 glucokinase-specific residues with their counterparts in the C-terminal half of rat hexokinase I. The affinity for the regulatory protein was not markedly changed for mutants B, D, and E despite a decreased affinity for glucose in mutants B and D. Two other mutants (A and C) were 9- and 250-fold less sensitive to the rat regulator and 40- and 770-fold less sensitive to the Xenopus regulator, respectively, but presented a normal affinity for glucose. The double mutant (A-C) was completely insensitive to inhibition by the regulatory protein. A control mutant (F), obtained by replacing 3 residues that were not conserved in all glucokinases, had a normal affinity for glucose and for the regulatory protein. The property of glucokinase to be inhibited by palmitoyl-CoA was not affected by the mutations described. It is concluded that His-141 to Leu-144, which are located close to the tip of the small domain, as well as Glu-51 and Glu-52, which are present in the large domain of the enzyme close to the hinge region, or nearby residues participate in the binding of the regulatory protein.

Amino Acid Sequence↗