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J Metz

Publications and source records attributed to J Metz.

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

Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells.

Molecular mechanisms underlying the generation of distinct cell phenotypes is a key issue in developmental biology. A major paradigm of determination of neural cell fate concerns the development of sympathetic neurones and neuroendocrine chromaffin cells from a common sympathoadrenal (SA) progenitor cell. Two decades of in vitro experiments have suggested an essential role of glucocorticoid receptor (GR)-mediated signalling in generating chromaffin cells. Targeted mutation of the GR should consequently abolish chromaffin cells. The present analysis of mice lacking GR gene product demonstrates that animals have normal numbers of adrenal chromaffin cells. Moreover, there are no differences in terms of apoptosis and proliferation or in expression of several markers (e.g. GAP43, acetylcholinesterase, adhesion molecule L1) of chromaffin cells in GR-deficient and wild-type mice. However, GR mutant mice lack the adrenaline-synthesizing enzyme PNMT and secretogranin II. Chromaffin cells of GR-deficient mice exhibit the typical ultrastructural features of this cell phenotype, including the large chromaffin granules that distinguish them from sympathetic neurones. Peripherin, an intermediate filament of sympathetic neurones, is undetectable in chromaffin cells of GR mutants. Finally, when stimulated with nerve growth factor in vitro, identical proportions of chromaffin cells from GR-deficient and wild-type mice extend neuritic processes. We conclude that important phenotypic features of chromaffin cells that distinguish them from sympathetic neurones develop normally in the absence of GR-mediated signalling. Most importantly, chromaffin cells in GR-deficient mice do not convert to a neuronal phenotype. These data strongly suggest that the dogma of an essential role of glucocorticoid signalling for the development of chromaffin cells must be abandoned.

Adrenal Glands↗
PubMed1998

Occurrence of a terminal vascularisation after experimental myocardial infarction.

Physiological data indicate a residual vascularisation within ischemic myocardial regions where necrosis of most cells have been reported to occur after myocardial infarction. We therefore studied, by means of immunohistochemistry, computer-assisted morphometry, and electron microscopy, the terminal vascularisation in correlation to cardiomyocytes in ten canine hearts 1 and 3 weeks after occlusion of the left anterior descending (LAD) coronary artery. In comparison to non-infarcted myocardium we found the following alterations in infarcted myocardium: (1) the area density of cardiomyocytes decreased from 98% (control) to 7.9% (1 week after occlusion) and to 2.7% (3 weeks after occlusion); (2) the number of capillaries was diminished to 11.6% and to 2.6%; respectively; (3) smooth muscle alpha-actin was induced in endothelial (EC) cells of the microvessels; and (4) terminal resistance vessels increased 11-fold and 20-fold in number, respectively. Our findings confirm the necrosis of the vast majority of cardiomyocytes and capillaries within the first 3 weeks after myocardial infarction. Besides a small number of capillaries, many terminal resistance vessels, however, seem to persist in the scarring infarcted tissue. The occurrence of these microvessels is supposed to be important for the granulation tissue as well as for the control and regulation of a residual blood supply during scar formation.

Animals↗
PubMed1998

Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent.

Oxidized low density lipoprotein (oxLDL) induces apoptosis in human macrophages (Mphi), a significant feature in atherogenesis. We found that induction of apoptosis in Mphi by oxLDL, C2-ceramide, tumor necrosis factor alpha (TNF-alpha), and hydrogen peroxide (H2O2) was associated with enhanced expression of manganese superoxide dismutase (MnSOD) and p53. Treatment of cells with p53 or MnSOD antisense oligonucleotides prior to stimulation with oxLDL, C2-ceramide, TNF-alpha, or H2O2 caused an inhibition of the expression of the respective protein together with a marked reduction of apoptosis. Exposure to N-acetylcysteine before treatment with oxLDL, C2-ceramide, TNF-alpha, or H2O2 reversed a decrease in cellular glutathione concentrations as well as the enhanced production of p53 and MnSOD mRNA and protein. In apoptotic macrophages of human atherosclerotic plaques, colocalization of MnSOD and p53 immunoreactivity was found. These results indicate that in oxLDL-induced apoptosis, a concomitant induction of p53 and MnSOD is critical, and suggest that it is at least in part due to an enhancement of the sphingomyelin/ceramide pathway.

Apoptosis↗
PubMed1998

Complement C6 deficiency protects against diet-induced atherosclerosis in rabbits.

Low-density lipoprotein (LDL) can be transformed to an atherogenic moiety by nonoxidative, enzymatic degradation. Enzymatically degraded LDL induces macrophage foam cell formation, provokes release of cytokines, and also activates complement. To determine whether complement activation may contribute to atherogenesis, 6 pairs of homozygous C6-deficient rabbits and their non-C6-deficient heterozygous siblings were fed a cholesterol-rich diet for 14 weeks. Cholesterol levels and plasma lipoprotein profiles of the animals in the C6-competent and C6-deficient groups did not significantly differ, and the high density lipoprotein and LDL cholesterol ratios at the end of the experiment were 0.07+/-0.01 and 0.08+/-0.01 (SEM), respectively. However, differences in atherosclerotic plaque formation were discernible macroscopically, with extensive aortic lesions being visible in all C6-competent animals and absent in all C6-deficient animals. Aortas were sectioned from thorax to abdomen, and 10 sections were stained from each aorta. Quantification of atherosclerotic lesions and lumen stenosis with the use of computer-based morphometry documented a dramatic protective effect of C6 deficiency on the development of diet-induced atherosclerosis. We conclude that the terminal complement sequence is centrally involved in atherosclerotic lesion progression.

Animals↗
PubMed1998

Interclass drug effects and changes in regional brain glucose metabolism.

We have developed an innovative use of positron emission tomography that has broad applications in drug development. Based on the FDG method (Phelps et al. 1979) for assessing glucose metabolism, the method requires rigorous experimental control of subjects and standardized data acquisition and analyses. In localizing net metabolic drug effects, measured in quantifiable terms, we have derived a new conceptual basis for examining pharmacologically induced changes in brain function and a new model for predicting drug effectiveness. We applied this method to studies of drugs in three different classes and noted marked differences in distribution and magnitude of metabolic effects. This approach presents an opportunity to selectively examine measurements of the glucose metabolic changes induced by specific pharmacological probes on intermediary metabolic pathways, including regulation of gene expression and the metabolic consequences of neurotransmitter alteration in pharmacologically targeted neuronal systems. Development of these methods provides new approaches for studying neurobiological mechanisms, and can contribute significantly to the process of new drug development.

Brain↗
PubMed1997

Reduction of inappropriate use of blood products by prospective monitoring of transfusion request forms.

OBJECTIVE: To determine the effect of prospective monitoring on appropriateness of transfusions of red cells, platelets and fresh frozen plasma (FFP). DESIGN: Prospective interventional study. SETTING: Royal Melbourne Hospital (a tertiary teaching hospital), Melbourne, Victoria, March-May 1996. INTERVENTION: The blood product request form was modified to incorporate indications for transfusion and clinical and laboratory data. Requests were monitored by blood bank laboratory staff for conformation with hospital transfusion guidelines; non-conforming requests were discussed with the requesting medical practitioner by the Haematology Registrar before blood products were issued. In case of disagreement, blood products were always issued. SUBJECTS: 200 consecutive transfusion episodes for each product (red cells, platelets and FFP). OUTCOME MEASURES: Appropriateness of transfusion, assessed by a Consultant Haematologist according to hospital guidelines. Rates of inappropriate transfusion episodes after intervention were compared with rates in a previous study. RESULTS: After intervention, rates of inappropriate transfusion episodes fell significantly (red cells, 16% to 3% [P = 0.004]; platelets, 13% to 2.5% [P = 0.02]; and FFP, 31% to 15% [P = 0.02]). Almost all inappropriate FFP transfusion episodes post-intervention were due to failure to demonstrate prolongation of prothrombin or activated partial thromboplastin times more than 1.5 times the control value. CONCLUSION: Prospective monitoring of request forms can reduce rates of inappropriate transfusions. High rates of inappropriate FFP transfusions possibly reflect uncertainty about appropriate laboratory criteria for FFP transfusion. While results of large prospective randomised controlled clinical trials of FFP transfusions are awaited, currently laboratory criteria can be retained, but should be applied with flexibility.

Blood Component Transfusion↗
PubMed1997

Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin-ceramide pathway in human macrophages.

Exposure of human blood monocytes derived macrophages to modified (oxidized or acetylated) LDL induced a approximately 40% elevation (60 pmol/10(6) cells) of the endogenous level of the sphingolipid ceramide. A rise of both neutral and acidic SMase activity was found after treatment with oxidized LDL (250 and 80%), while addition of acLDL stimulated only the neutral enzyme (280%). Sphingo(phospho)lipids from LDL were transferred to the cell membrane and distributed into intracellular compartments as observed with acLDL containing BODIPY-FL-C5-SM. Quantitation of ceramide after the addition of [3H-N-acetyl]- or BODIPY-FL-C5-SM-labeled modified LDL (27 microg/ml) to the cell culture medium indicated that approximately 210 pmol CA/10(6) cells was generated from exogenous (ox/acLDL) SM. These results demonstrate a stimulation of the sphingomyelin-ceramide pathway by modified LDL utilizing primarily exogenous (LDL-derived) substrate and suggest that the effects of modified LDL are at least partially due to an increased level of the messenger ceramide.

Boron Compounds↗
PubMed1997

Effect of alterations of blood cholesterol levels on macrophages in the myocardium of New Zealand White rabbits.

We investigated the effect of alterations of blood cholesterol levels on macrophages (mphi) in the myocardium of New Zealand White (NZW) rabbits. Three groups of NZW rabbits were used: controls, rabbits fed a 0.5% cholesterol-enriched diet (CH-D) for 96 days, and rabbits fed a 0.5% CH-D for 96 days followed by normal chow for 4 months. Immunohistochemical analysis by mAbs directed against mphi (RAM-11) and Mn superoxide dismutase (MnSOD) were quantified by computer-assisted morphometry. Using cultured human and rabbit mphi, a cross-reaction of the human MnSOD mAbs was found as well as the predominant localization of MnSOD-immunoreactivity (IR) in mitochondria. In group 1, only a very few RAM-11-immunoreactive (ir) mphi occurred in the interstitial space of the myocardium. In group II blood cholesterol levels significantly increased in parallel with the numbers of mphi, which often contained lipid droplets (foam cells). Although blood cholesterol concentrations regressed about 10-fold in group III, mphi in the myocardium were found to be reduced only about 20%. Most mphi were also MnSOD-ir. In atherosclerotic coronary arteries RAM-11-IR was located in mphi and also extracellularly, whereas MnSOD-IR was found only in mphi. Drastically induced MnSOD in the mitochondria of mphi is suggested as an indicator of increased oxidative stress caused by in vitro conditions or by phagocytosis of low-density lipoprotein in vivo. Elevation of the cholesterol level leads to a long-term increase and its regression results in a delayed reduction of such mphi, which seem to play a key role in the atherogenesis of the coronary arteries as well.

Animals↗
PubMed1997

A novel form of hereditary sideroblastic anaemia with macrocytosis.

We describe a pedigree with maternally inherited sideroblastic anaemia in which the red cells are dimorphic with a raised MCV. To our knowledge, this form of hereditary sideroblastic anaemia (HSA) has not been reported previously. 16 members of the family were investigated, revealing eight affected members. Two further family members were not tested but were presumed affected on the histories available. The proband, born in 1967, presented during pregnancy with a macrocytic anaemia (Hb 7.0 g/dl, MCV 106 fl) and a dimorphic red cell picture. Post partum, a bone marrow biopsy showed hypercellularity, mild dyserythropoiesis and ring sideroblasts. Cytogenetics were normal. Other causes of macrocytosis were excluded. Six other family members (three female, three male) have similar findings. There is no evidence of paternal transmission. An additional female relative who presented in 1992 with refractory anaemia with excess blasts in transformation and a dimorphic blood film, died from progression to AML. Affected members show a raised metal-free red cell protoporphyrin level suggestive of a defect at the level of Fe2+ incorporation into protoporphyrin. We propose that this form of HSA is due to a mitochondrial mutation. A search for deletions or point mutations in the mitochondrial DNA is currently underway.

Adult↗
PubMed1997

Suitability of preadmission blood samples for pretransfusion testing in elective surgery.

BACKGROUND: North American transfusion guidelines do not stipulate a time limit between drawing the specimen for pretransfusion testing and giving the transfusion to patients who have not received a transfusion or been pregnant in the preceding 3 months. British guidelines suggest that separated plasma and serum can be stored at -30 degrees C for up to 6 months, but they draw attention to the paucity of evidence concerning the use of stored samples. In Australia, transfusion guidelines recommend a maximum of 10 days' validity for pretransfusion specimens, which requires the patient to present for pretransfusion testing within 10 days of admission or to undergo retesting after admission, which in turn necessitates additional time in the hospital before operation. The study was performed to document the safety of using for pretransfusion testing a blood sample collected more than 10 days before surgery. STUDY DESIGN AND METHODS: Samples from 500 patients scheduled for elective surgery who had not been pregnant or received a transfusion in the previous 3 months were separately tested in blood group and antibody screens at an interval from 11 to 335 days before admission and again on admission. RESULTS: No clinically significant change was detected in the red cell antibody status of the paired samples of any patient. CONCLUSION: For patients who have not been transfused or pregnant in the previous 3 months, it is safe to crossmatch blood for transfusion by using a sample collected well in advance of elective surgery and stored at -30 degrees C.

Blood Grouping and Crossmatching↗
PubMed1997

Four years of practice-based and exercise-supported behavioural medicine in one community of the German CINDI area. Countrywide Integrated Non-Communicable Diseases Intervention.

The main goal of the preventive intervention study in one community of the German CINDI (Countrywide Integrated Non-Communicable Diseases Intervention programme of the WHO) area was to improve cardiovascular health by reducing the risk factors smoking, hypertension, obesity, hypercholesterolaemia, and by changing sedentary lifestyle. The intervention was performed by using the special "Three-Level-Strategy", which is characterised by activities of primary care physicians in the usual consulting hour (1st level), with patient groups in their practices (2nd level), and at community level (3rd level) where a special work group and a co-ordinating general practice are co-operating. To evaluate the occurrence of the risk factors in practice and the local population, four cross-sectional random samples (N(total) = 4881) were carried out in seven practices from 1992 to 1995. On the community level, 23 special exercise-based health groups (N(total) = 600) were established and were investigated by means of a questionnaire, related to behaviour and health beliefs. A "Local Health Information System" facilitated the evaluation, the management of the data, and the organisation of the health programme. The results of the practice samples showed a significant reduction of smoking (-17.8%) and hypertension (-31.5%) (p < 0.01). The exercise-based groups were combined with nutritional counselling or relaxation and were accepted very well by the participants (83.8%). The participants considerably improved their health behaviour: 82% discussed health in their family, 37.3% stated an increase of healthy nutrition, 52% of relaxation; 86.2% intended to regularly increase physical activity in leisure time and 82 % could not imagine regular health training without exercise meetings. We conclude that the practice-based "Three-Level-Strategy" provides a strong support for successful long-term prevention of cardiovascular risk, particularly, when exercise-based health training sessions are performed in order to change sedentary lifestyle. When organised on community level, they might have a positive impact on the health behaviour of the whole community. Physical activity can be used as a "prodrug" for health promotion in a holistic way.

Adult↗
PubMed1997

Induction of mitochondrial manganese superoxide dismutase in macrophages by oxidized LDL: its relevance in atherosclerosis of humans and heritable hyperlipidemic rabbits.

The objective of the study was to analyze the intracellular antioxidative response of macrophages (Mphi) exposed to increased levels of low density lipoprotein (LDL). We studied manganese superoxide dismutase (MnSOD) and, in part, GSH in cultured human and rabbit Mphi, and in atheromatous arterial tissue of humans and heritable hyperlipidemic (HHL) rabbits. Incubation of human Mphi with oxidized-LDL (ox-LDL) resulted in an induction of MnSOD mRNA production as shown by RT-PCR. MnSOD immunoreactivity (IR) was found to be located in the mitochondria of Mphi. In HHL rabbits, MnSOD activity and GSH concentration were significantly increased in atherosclerotic intima compared to the media of the aorta, but significantly decreased (P<0.01) in larger plaques compared with smaller ones, resulting in a significant inverse correlation of MnSOD activity (r=-0.67, P<0.001) and GSH concentration (r=-0.57, P<0.01) with plaque size. Immunohistology of the atherosclerotic intima revealed MnSOD-IR in Mac-1 (CD 11b/CD 18)-immunoreactive (ir) Mphi of human arteries and, similarly, in RAM-11-ir Mphi of rabbit ones. The relation of MnSOD-ir Mphi decreased with plaque advancement, which is consistent with biochemical findings. Most MnSOD-ir Mphi in atherosclerotic plaques revealed TUNEL-positive nuclei, indicating DNA strand breaks, and p53-IR. We conclude that mitochondrial antioxidants such as MnSOD are induced in Mphi in vitro and in atherosclerotic arteries as a reply to increased mitochondrial oxidation. As normal consequences of an increased oxidative stress due to the exposure to ox-LDL nuclear DNA strand breaks occur, which are suggested to be a signal to increase p53 protein levels. Reactive oxygen species-mediated mitochondrial-dependent pathways are suggested as major contributing pathomechanisms to nuclear damage, which eventually may result in apoptosis. A common response to increased oxidative stress due to modified LDL is presumed in rabbit and human atherosclerotic plaques.

Animals↗
PubMed1997

Apoptosis after stent implantation compared with balloon angioplasty in rabbits. Role of macrophages.

Both cell proliferation and apoptosis (programmed cell death) are supposed to play a role in restenosis after angioplasty. We studied these processes in smooth muscle cells (SMCs) and macrophages 1, 4, and 12 weeks after balloon angioplasty or Palmaz-Schatz stent implantation in rabbit iliac arteries. Proliferating cells were visualized by immunostaining with antibodies directed against proliferating cell nuclear antigen. Apoptotic cells were detected using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling) technique, propidium iodide staining, and transmission electron microscopy. At all time points, the neointimal cross-sectional area of the arteries was twofold to fourfold greater after stent implantation than after balloon angioplasty. The total number of neointimal cells was similar 1 and 12 weeks after both interventions. The neointimal cell density, however, decreased by 58% between the 1st and the 12th week after stent implantation compared with a 20% decrease after balloon angioplasty (P < .01). Stent implantation induced more cell proliferation but also more apoptosis in the media than balloon angioplasty after 1 and 4 weeks. In addition, stent implantation caused more macrophage accumulation and apoptosis in the neointima, but cell proliferation rates did not differ significantly in comparison with balloon angioplasty. The higher rate of apoptosis in the neointima 1 week after stent implantation compared with balloon angioplasty is due to an increased rate of SMC and macrophage death. Macrophage accumulation and apoptosis in the early phase after stent implantation appear to play a role in extracellular matrix secretion, which increases neointima formation after 4 and 12 weeks compared with balloon angioplasty in this model.

Angioplasty, Balloon↗
PubMed1996

Improved quality of life in patients with generalized cardiovascular metabolic disease on a prepared diet.

Current dietary recommendation for cardiovascular disease risk reduction and recommended dietary allowances (RDAs) were used to develop a nutritionally complete prepackaged prepared meal plan specifically designed to reduce the risk of cardiovascular disease. In the current study we tested patient acceptance of the diet as defined by measures of quality of life. In a randomized, parallel-design, multicenter clinical trial, 77 persons with hypertension, diabetes mellitus, dyslipidemia, or a combination of two or more of these conditions were recruited and randomly assigned to either a prepared meal plan (n = 39) or a comparable self-selected diet (n = 38) for 10 wk. The prepared meal plan met both the RDAs for all essential micronutrients and the dietary recommendations of national health organizations for macronutrients, cholesterol, sodium, and fiber. The prescribed self-selected diet was matched for macronutrients. Quality of life, as measured by a battery of instruments, was the major endpoint. Individuals consuming the prepared meal plan had significant improvements in mental health (P < 0.01), general perceived health (P < 0.005), daily activities (P < 0.05), work performance (P < 0.005), affect (P < 0.01), and nutritional health perceptions (P < 0.001), and reductions in nutrition hassles based on a standardized questionnaire (P < 0.001). The self-selected-diet group had significant improvements in nutritional health perceptions (P < 0.001) and affect (P < 0.001). There were significant improvements in weight (P < 0.001), blood pressure (P < 0.001), cholesterol (P < 0.002), low-density lipoproteins (P < 0.001), glucose (P < 0.014), and glycated hemoglobin (Hb A(1c) (P < 0.004) that were comparable in both groups. In summary, this study shows that a nutritionally complete diet, whether prepackaged or self-selected, improves multiple risk factors for cardiovascular disease. The prepackaged prepared meal plan had the added benefit of a greater improvement in quality of life.

Blood Glucose↗
PubMed1996

The significance of subnormal serum vitamin B12 concentration in older people: a case control study.

OBJECTIVES: To determine the clinical significance of subnormal serum vitamin B12 concentration in older people by comparing the hematological, neurological, and biochemical findings in patients with subnormal serum B12 with a control group with normal B12 levels. DESIGN: Clinical and laboratory assessment of hospital patients selected to represent a wide range of serum B12 levels. SETTING: Patients in the medical wards of two hospitals, one a general hospital and the other a geriatric hospital. PARTICIPANTS: Ninety-four older patients, 43 with subnormal (< 150 pmol/L) and 51 with normal serum B12 concentrations. MEASUREMENTS: Mini-Mental State Examination, neurological score, full blood examination, mean neutrophil lobe count; serum B12, holotranscobalamin II, total homocysteine, folate, creatinine and gastrin red folate; parietal cell antibodies, intrinsic factor antibodies. RESULTS: Of all the measurements, only mean neutrophil lobe count and mean serum total homocysteine were significantly different in the low serum B12 compared with the control group. There was a significant correlation between serum B12 and homocysteine levels. Eighty-eight percent of patients in the test group compared with 76% in the control group showed at least one of the following; elevated serum total homocysteine, neutrophil hypersegmentation, or elevated MCV. This overlap was much reduced when patients with borderline values for serum B12 (150-250 pmol/L) were included in the low B12 group. Most of the older subjects had little or no B12 on transcobalamin II, irrespective of the serum B12 level. CONCLUSION: Almost 90% of older patients with serum B12 < 150 pmol/L show evidence of tissue vitamin B12 deficiency. Deficiency becomes manifest in older patients at relatively higher concentrations of serum B12 than in younger subjects, possibly because of lower levels of holotranscobalamin II in the older patients.

Age Factors↗