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Biomedical subjects

D Muller

Publications and source records attributed to D Muller.

At least 145 records · Page 8Linked to original sources
PubMed1993

Blockade of long-term potentiation and of NMDA receptors by the protein kinase C antagonist calphostin C.

We have studied the effects of calphostin C, an antagonist of the regulatory subunit of protein kinase C, on the induction and expression of long-term potentiation (LTP) and on responses mediated by activation of N-methyl-D-aspartate (NMDA) receptors in rat hippocampal slices. No effect of calphostin C was observed on pre-established LTP, even at concentrations of 2-3 mumol/l. In contrast, the drug was found to prevent LTP induction. This effect was concentration-dependent, although high concentrations were needed (1-2 mumol/l), and, at the lower concentrations, it could be partially antagonized by using coactivation of two pathways instead of single input activation. While calphostin C did not alter synaptic transmission mediated by activation of alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) receptors, it considerably interfered with the function of NMDA receptors. The drug blocked the NMDA receptor-mediated component of burst responses, significantly antagonized the NMDA receptor-mediated synaptic responses recorded in the presence of an AMPA receptor antagonist, and blocked the effect of iontophoretic application of NMDA on regular synaptic transmission. These results are consistent with the idea that calphostin C prevents the induction of long-term potentiation by interfering with the function of NMDA receptors.

Animals↗
PubMed1993

Lesion-induced neurite sprouting and synapse formation in hippocampal organotypic cultures.

By sectioning, using a razor blade, one- and three-week-old rat hippocampal organotypic cultures, we have tested the possibility that neurite outgrowth and reactive synaptogenesis would take place even after several weeks in culture in this in vitro model. At the light-microscopic level, recovery from the section and formation of a thin scar were observed within six days following the lesion. Immunostainings using neurofilament antibodies showed the presence of numerous degenerative and regenerative images one day after the cut and many fibres crossing the section six days after the lesion. Electrophysiological recordings of synaptic responses elicited across the section indicated the formation of new functional synaptic contacts and complete recovery of transmission within three to six days. Interestingly, functional recovery in three-week-old cultures was found to be significantly slower than in one-week-old tissue. These findings were confirmed at the electron-microscopic level. Evidence was obtained for an effective cleaning of the lesion site by macrophages and astroglial cells, the existence of many degenerative and regenerative images one day after the cut and the presence of new dendrites, axonal fibres and synapses in the area of the section six days after the lesion. All these changes were slower in three- than in one-week-old cultures. These results indicate that organotypic cultures can be used as an interesting model for studies of reactive synaptogenesis.

Animals↗
PubMed1993

Transfer of lymphocytic choriomeningitis disease in beta 2-microglobulin-deficient mice by CD4+ T cells.

In this study we have investigated the role of CD4+, MHC class II-restricted cytotoxic T lymphocytes (CTLs) in the disease caused by lymphocytic choriomeningitis virus (LCMV) in beta 2-microglobulin deficient (beta 2m-) mice. Intracranial (i.c.) infection with LCMV resulted in death of six out of 11 beta 2m- mice. Mice that survived showed a marked loss in body weight. Death and loss of body weight could be prevented by immunosuppressing the mice with irradiation or cyclosporine prior to i.c. injection of LCMV. This treatment also prevented induction of virus-specific, MHC class II-restricted CTL following peripheral inoculation with LCMV. In vivo depletion of CD4+ cells with antibody also prevented death following i.c. injection whereas in vivo depletion of CD8+ cells had no effect. Disease could be transferred to recipient beta 2m- mice by adoptive transfer of beta 2m- derived immune spleen cells. Transfer of non-immune spleen cells did not result in illness. In vitro treatment of immune spleen cells with anti-CD4 antibody and complement eliminated class II-restricted CTL activity and also prevented mortality of recipients after adoptive transfer. Treatment with anti-CD8 antibody had no effect. We were unable to transfer LCM disease to beta 2m- recipients by adoptive transfer of immune spleen cells from C57BL/6 mice. These results suggest that, unlike normal mice, the pathology of LCM disease in beta 2m- mice is dependent upon virus-specific, CD4+CD8-, MHC class II-restricted T cells.

Animals↗
PubMed1993

Plasma antioxidants and risk of cortical and nuclear cataract.

We evaluated nutritional risk factors for cataract in 660 subjects enrolled in the Baltimore Longitudinal Study on Aging. As a part of a regular cycle of visits, nuclear and cortical lens photographs were taken over a 2-year period. Measurements of plasma antioxidants (beta-carotene, ascorbic acid, and alpha-tocopherol) were obtained in this cohort as part of the study protocol up to 4 years before lens photographs were taken. We found that plasma beta-carotene and ascorbic acid levels were not associated with risk of nuclear or cortical lens opacities. Higher levels of plasma alpha-tocopherol, however, were associated with a reduced risk of nuclear opacity [odds ratio (OR) for highest quartile vs lowest quartile = 0.52, 95% confidence interval (CI) = 0.27-0.98; OR for middle two quartiles vs lowest quartile = 0.55, 95% CI = 0.30-0.98], after adjusting for age, sex, and history of diabetes. Middle levels of alpha-tocopherol were associated with a reduced risk of cortical opacity (OR = 0.57, 95% CI = 0.32-1.02), but no such association was observed for high levels of alpha-tocopherol. We constructed an index of overall antioxidant status, which indicated that higher levels of plasma antioxidants were not associated with risk of nuclear or cortical opacities.

Adult↗
PubMed1993

The age-related advancement of arterial disease measured by Doppler ultrasound diastolic flow analysis.

OBJECTIVE: To quantify by A-mode Doppler sonography the age-related progression of arterial disease so that age dependent normal values may be established for the screening Doppler peripheral arterial exam. Arterial distensibility was assessed by A-mode Doppler diastolic flow analysis as a measure of atherogenesis. These values will increase the sensitivity and decrease the incidence of false-positive results when the Doppler exam is utilized to differentially diagnosis vascular and sciatic neurogenic claudication. The relationship between age and results from the standard ankle/arm index ultrasound pneumatic cuff examination was also analyzed. DESIGN: A two by three analysis of variance with orthogonal Helmert contrast codes and simple linear regression analysis was utilized for this cross-sectionally designed investigation. The dependent measures of diastolic flow analysis and ankle/arm pressure index were obtained within three nested successively increasing age groups. SETTING: Chiropractic office. SUBJECTS: Studied were a total of 90 sedentary nonsmoking subjects, aged 23-79 yr, all of whom had normally accepted levels of serum glucose, cholesterol and blood pressure. Subjects were screened for evidence of aortic coarctation, myocardial infarction, tachyarrhythmia, aortic valve stenosis, mitral prolapse, hypertension, hypercholesterolemia, diabetes and peripheral occlusive arterial disease. Anthropometric measurements and percent body fat were obtained. A predictive oxygen consumption bike ergometer test was performed to obtain aerobic capacity. The commonly utilized standard ankle/arm index ultrasound pneumatic cuff examination and arterial diastolic flow analysis were performed with A-mode Doppler ultrasound on all subjects. RESULTS: These results demonstrate that a significant inverse linear relationship exists between aging and arterial compliance (p < .0001) in our population. Diastolic flow analysis had a greater sensitivity to arterial disease than the standard ankle/arm index ultrasound pneumatic cuff procedure. CONCLUSION: When utilizing A-mode Doppler ultrasound diastolic flow analysis as an indicator of early peripheral atherosclerotic arterial disease, increased sensitivity may be obtained when the age-related elevation in atherogenesis is taken into account.

Adult↗
PubMed1993

An automated analysis program for the evaluation of cardiac PET studies: initial results in the detection and localization of coronary artery disease using nitrogen-13-ammonia.

Positron emission tomography (PET), in combination with myocardial blood flow tracers, allows highly accurate diagnosis of coronary artery disease using visual data interpretation. To increase the objectivity of data analysis and to reduce interobserver variability, we developed an automated analysis method for the three-dimensional definition of myocardial activity, which includes true volumetric data extraction and mathematical constraints of activity sampling to the expected shape of the left ventricle. Data are displayed in a standardized polar map or three-dimensional format for comparison with a normal database. The first clinical evaluation of this method in 52 patients using receiver operating characteristics (ROC) curve analysis demonstrated high diagnostic accuracy for detection as well as localization of coronary artery stenosis in predefined vascular territories. The interobserver and intraobserver agreement for localization of disease was excellent, with correlation coefficients varying from 0.85 to 0.99 for individual vascular territories. Thus, this automated quantitative analysis program provides highly accurate and reproducible evaluation of cardiac PET flow studies. Definite determination of its diagnostic accuracy requires a prospective multicenter trial in a larger patient population employing the criteria for abnormality established in this initial clinical evaluation.

Adenosine↗
PubMed1992

LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice.

Intracranial infection of normal mice with lymphocytic choriomeningitis virus (LCMV) causes meningitis and death mediated by CD8+ major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs). beta 2-Microglobulin-deficient mice (beta 2M-/-) do not express functional MHC class I proteins and do not produce significant numbers of CD8+ T cells. When beta 2M-/- mice were infected with LCMV, many died from LCMV disease and produced a specific response to LCMV mediated by CD4+ CTLs that were class II-restricted. In these mice, CD4+ CTLs may compensate for the lack of CD8+ CTLs.

Animals↗
PubMed1992

Induction of stable long-term potentiation in the presence of the protein kinase C antagonist staurosporine.

We have studied the effects of staurosporine, an antagonist of the catalytic subunit of protein kinase C, on the mechanisms of long-term potentiation (LTP) in rat hippocampal slices maintained in vitro. Application of staurosporine did not affect pre-established LTP, but resulted in a decaying potentiation when high frequency stimulation was delivered in its presence. However, coactivation of two inputs to the same group of CA1 neurons during high frequency stimulation transformed the decaying potentiation into stable LTP. Staurosporine also reduced the NMDA receptor-mediated component of synaptic responses to burst stimulation. It is concluded that the PKC antagonist interferes with LTP induction, but not expression mechanisms.

2-Amino-5-phosphonovalerate↗
PubMed1992

Factors governing the potentiation of NMDA receptor-mediated responses in hippocampus.

A modified medium containing an AMPA receptor antagonist and low concentrations of magnesium was used to investigate the factors governing the potentiation of synaptic responses mediated by NMDA receptors. When long-term potentiation (LTP) was induced in standard medium and NMDA responses were analyzed by changing to the modified medium, no statistically significant differences were observed between potentiated and control pathways. Returning the slices to the standard medium showed that LTP was still present, indicating that the potentiation effect was not reversed by the modified medium. High-frequency stimulation applied in the modified medium produced an enhancement of synaptic responses, but this was not occluded by prior potentiation in standard medium. The degree of potentiation induced in the modified medium and expressed by NMDA responses was larger in the presence than in the absence of inhibition and, unlike LTP, was proportionately larger when recorded in the stratum pyramidale than in the stratum radiatum. These results indicate that the potentiation of NMDA receptor-mediated responses triggered by high-frequency stimulation applied in modified medium differs in several respects from the LTP induced in standard conditions. They confirm that LTP is expressed to a markedly different degree by NMDA and non-NMDA receptors and suggest that events that do not necessarily accompany LTP affect the potentiation of NMDA receptor-dependent synaptic responses.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 16 non-Japanese cases.

Kabuki make-up (Niikawa-Kuroki) syndrome has been described mainly in Japanese patients. In this paper we report sixteen new cases from Europe and North America, suggesting that Kabuki make-up syndrome may be more common outside of Japan than supposed. Their features are compared with those of the Japanese patients and most of our findings are similar to those previously reported. The facial phenotype is specific and easily recognizable, regardless of ethnic origin. Postnatal growth retardation and mild mental retardation are confirmed to be cardinal manifestations of the syndrome. Skeletal anomalies were present in all cases but most of the radiological changes were non-specific. The specificity of metacarpophalangeal pattern profile is not confirmed. Conversely, dermatoglyphic analysis is helpful in the diagnosis of this condition. Two differences have emerged between the Japanese patients and those in this study. Firstly, two-thirds of the patients in this series had significant neurological dysfunction other than mental retardation. Secondly, joint hypermobility appears more common in non-Japanese patients. Confirmation of these findings requires further studies.

Abnormalities, Multiple↗
PubMed1992

Doppler ultrasound diastolic flow analysis for the early identification of peripheral arterial disease.

OBJECTIVE: The viscoelastic mechanical compliance properties of the human arterial system were examined in 100 subjects with A-mode Doppler ultrasound diastolic flow analysis. This technique of diastolic flow analysis is utilized to identify early atherogenic peripheral arterial disease. The sensitivity of the commonly utilized standard traditional ultrasound pressure-grade pneumatic cuff examination will be increased when accompanied by the diastolic flow analysis technique. SETTING: Diastolic flow analysis will aid in the early identification of lower extremity vascular claudication when lumbar spinal canal stenosis and elevated cardiovascular risk factors are present. This examination may be performed in the office setting with standard A-mode Doppler ultrasound equipment along with the usual pneumatic cuff procedure. The standard ultrasound cuff examinations are based on pressure gradients to identify lower extremity arterial disease. The low level of sensitivity of this test requires arterial obstruction of at least 50% to be present before positive identification is possible. Pathological alterations of the arterial wall occur during the early stages of atherosclerotic disease, are reflected by reduced wall distensibility and may be quantified by Doppler ultrasound. SUBJECTS: Studied were a total of 100 subjects, 50 with arterial disease risk factors and 50 normal controls. All subjects were screened for aortic coarctation, myocardial infarction, tachyarrhythmia, aortic value stenosis and mitral prolapse. The risk group subjects were all smokers and had a mixed distribution of hypertension, hypercholesterolemia and hyperglycemia. The commonly utilized standard traditional ultrasound pneumatic cuff examination was negative in all subjects. Anthropometric measurements and percent body fat were also obtained. Arterial diastolic antegrade flow analysis was performed with Doppler ultrasound on each subject. RESULTS: This study demonstrated that the elevated vascular risk factor group had a mean arterial distensibility measurement of 4.4 +/- 5.0%, and the control group displayed a mean measurement of 20.0 +/- 6.0%. The 50 elevated risk factor subjects showed approximately 5 times greater arterial stiffness and were identified with significance at an F test level of (p less than .001). CONCLUSION: This arterial compliance evaluation procedure is shown to be a reliable sensitive indicator of early atherosclerotic disease prior to the development of obstructive arterial lesions.

Adipose Tissue↗
PubMed1991

A single amino acid substitution in an MHC class I molecule allows heteroclitic recognition by lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes.

Class I molecules of the MHC bind foreign and endogenous peptides allowing recognition by the TCR on CTL. The recognition and killing of cells infected with lymphocytic choriomeningitis virus (LCMV) depends on the recognition of LCMV peptides bound to class I MHC. Mutations in class I MHC molecules have enabled the delineation of regions in the class I molecule important for binding peptides and for interaction with the TCR. We have constructed a library of class I mutants using saturation mutagenesis and report a phenotypic change resulting from a single amino acid substitution that results in the heteroclitic (increased) killing of LCMV-infected cells. This amino acid change, asparagine to serine at position 30, is in a conserved region of the class I molecule contacting the alpha 3 domain. This mutation does not result in increased expression of the class I molecule on the cell surface, does not affect the binding of CD8, and does not affect allogeneic recognition. Cold target experiments show that this heteroclitic killing is due to increased recognition by CTL. These data point toward a critical function for this region of the class I molecule in the binding of peptides or their presentation to CTL.

Animals↗
PubMed1991

Affinity of trypsin for amidine derivatives immobilized on dextran-coated silica supports.

The pancreas contains two very analogous enzymes: trypsin and chymotrypsin. These two enzymes are very similar in their physicochemical characteristics and are therefore quite difficult to separate by classical purification procedures. They constitute a good model for affinity chromatography. It was previously demonstrated that amidine derivatives are able to interact strongly and specifically with these serine proteases and are often used as ligand in affinity chromatography. To understand the trypsin interaction mechanism, we synthesized different amidines and immobilised them with or without spacer arm on silica beads previously coated by dextran substituted with a calculated amount of positively charged diethylaminoethyl functions, in order to minimize the non-specific interactions of silanol groups of the silica material. First the affinity constant and the adsorption capacity of these supports for trypsin were determined in batch procedures, then they were used in affinity chromatography. The effects of ionic strength, pH and competitive inhibitors on proteins desorption were also studied. Last, to demonstrate the importance of passivation, the chromatographic performances of dextran-coated silica phases and a commercial support grafted with the same amidine were compared.

Adsorption↗
PubMed1991

Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours.

We address the question as to whether increased metalloproteinase production might be related to the high regional recurrence rate of some carcinomas, and particularly head and neck squamous-cell carcinomas (SCC). Northern blot of total RNA prepared from 26 lung carcinomas, 107 head and neck carcinoma samples and corresponding normal tissue samples demonstrates the frequent and sometimes concomitant over-expression of the 2 stromelysin genes, the type-I collagenase gene and the pump-I gene in the head and neck tumour tissue samples. In these SCC, over-expression of the 2 stromelysin genes and the type-I collagenase gene (but not the pump-I gene) is associated with a high degree of tumour differentiation. Moreover, a tumour with high levels of the stromelysin mRNAs is more likely to show high local invasiveness, suggesting that the stromelysins may be implicated in the clinical course of head and neck tumours. Evaluation of the corresponding mRNA levels may prove a useful indicator for predicting the clinical aggressiveness of these tumours.

Biomarkers, Tumor↗
PubMed1991

Immobilization of dermatan sulphate on a silica matrix and its possible use as an affinity chromatography support for heparin cofactor II purification.

Dermatan sulphate (DS) is a glycosaminoglycan which catalyses specifically thrombin inhibition by a plasmatic inhibitor, Heparin cofactor II (HCII). DS was insolubilized on a silica matrix to study its interaction with HCII. The immobilization of DS was performed with a good yield on a silica previously coated with polysaccharides in order to neutralize the negatively charged silanol groups. The value of the affinity constant of insolubilized DS for HCII, measured by the adsorption isotherm, is consistent with the value obtained for soluble DS. The DS bound to the silica matrix was also tested as a chromatographic support for the purification of HCII from human plasma; the optimum conditions for HCII adsorption and desorption were determined. The eluted HCII was obtained with a good yield (21%) and with no contamination by antithrombin III, the other main plasmatic inhibitor of thrombin.

Chromatography, Affinity↗
PubMed1991

Affinity chromatography of fibroblast growth factors on coated silica supports grafted with heparin.

Dextran-coated silica beads are excellent supports for affinity chromatography of proteins. They can be easily grafted using conventional coupling methods with different active ligands, such as heparin. Fibroblast growth factors develop specific interactions with heparin through well-defined amino acids sequences. The heparin-dextran coated silica phases exhibit an affinity for these growth factors. Under our experimental conditions, the basic form can be absorbed on the solid support at a moderate salt concentration (0.5 M sodium chloride) and can be selectively desorbed by increasing the ionic strength of the eluent. The purification performances of such phases are compared to those obtained on the heparin grafted soft gels. Because of their mechanical properties, the dextran-coated silica supports were also used in high-performance affinity chromatography to purify fibroblast growth factors from a bovine brain crude extract.

Animals↗