Heat shock protein expression in cerebral X-linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss.

AIMS: X-linked adrenoleukodystrophy (X-ALD) is a genetic white matter disorder in which demyelination occurs due to accumulation of very long-chain fatty acids. Inflammation in the brain white matter is a hallmark of the pathology of cerebral X-ALD, but the underlying pathogenic mechanisms are still largely unknown. In other inflammatory demyelinating disorders, such as multiple sclerosis, the expression of heat shock proteins (HSPs) in combination with interferon-γ (IFN-γ) has been suggested to play a prominent role in the initiation of demyelination and inflammation. We therefore investigated these pathways in X-ALD lesions. METHODS: By immunohistochemistry, we examined the expression of small HSPs (HSPB1, HSPB5, HSPB6, HSPB8) and higher molecular weight HSPs (HSPA, HSPD1), and the expression of elements of the IFN-γ pathway on autopsy material of five patients with X-ALD. RESULTS: The expression of the larger HSPs, HSPA and HSPD1, as well as small HSPs is increased in X-ALD lesions compared with normal-appearing white matter. Such upregulation can already be detected before demyelination and inflammation occur, and it is predominant in astrocytes. The IFN-γ pathway does not seem to play a leading role in the observed inflammation. CONCLUSIONS: The finding that astrocytes show signs of cellular stress before demyelination suggests that they play a major role early in the pathogenesis of cerebral X-ALD, and may therefore be involved in the initiation of inflammation and demyelination.

[Disease modelling in diabetes mellitus]. / Erkrankungsmodellierung bei Diabetes mellitus.

Disease modelling increasingly plays an important role in planning and implementing medical decision making in diabetes care. For a general practitioner it is difficult to find access to application, benefit, arithmetic background and quality criteria of modelling. This review provides a comprehensive overview about the current methods in disease modelling in order to access quality criteria for disease modelling and modelling studies in diabetes care. The following criteria are essential for good quality in disease modelling: adequate choice of data sources, assessment of medical and economic data according to criteria of evidence-based medicine, reasonable time horizons, realistic use of discounting and inflation rates, representative target populations and a realistic perspective of the cost-benefit analysis. Furthermore, validation of disease models and the adequate use of those instruments are of importance.

[Costs of type 2 diabetes in Germany. Results of the CODE-2 study]. / Kosten des Typ-2-Diabetes in Deutschland. Ergebnisse der CODE-2-Studie.

BACKGROUND AND OBJECTIVE: Diabetes is an increasing and widespread chronic disease causing considerable costs for the health care system. In the CODE-2 Study (Costs of Diabetes in Europe-Type 2) the total expenses for type 2 diabetics in Germany were evaluated and analyzed for the first time. PATIENTS AND METHODS: The CODE-2-study has been performed in eight European countries. In the German arm of the study, medical, demographic, and economic data of 809 patients were obtained retrospectively for a one year period, using face-to-face interviews with 135 physicians. These results were projected for the overall population of type 2 diabetes patients in Germany. RESULTS: The annual costs caused by type 2 diabetes patients in Germany in 1998 amount to 31.4 billion DM. The majority of these costs (61%) were covered by statuatory and private health insurance. The annual expenses of the statuatory Health Insurance (SHI) for these patients amounted to 18.5 billion DM. These costs divided in 50% spent for inpatient treatment, 13% for ambulatory care, and 27% for medication. Diabetes medication (insulin, oral antidiabetic drugs) accounted for only 7% of total SHI costs. Only 26% of all diabetic patients were adjusted to HbA1c values < 6.5% according to the therapeutic targets of the European Diabetes policy group. 50% of the type 2 diabetic patients exhibited severe macro- and/or microvascular complications. The costs per patient--compared to the average expenses for SHI insured patients--increased with complication state from the 1.3-fold (no complications) up to the 4.1-fold (macro- and microvascular complications). CONCLUSIONS: The overall costs for patients with type 2 diabetes are higher than expected from previous estimates. Diabetes related complications and concomitant diseases are the predominant reasons for these high costs. Control of blood glucose is inadequate for the majority of diabetic patients. To prevent long-term complications, an optimized treatment of type 2 diabetes is imperative not only from a medical but also from a health economics point of view.

Bending vibrations of the femur and the oscillatory behavior of a cemented femoral hip endoprosthesis.

The paper presents a novel method for recording amplitude and phase of 6D-vibrations of a spatial pendulum over a wide frequency range (10 Hz up to 20 kHz). The six degrees of freedom of the pendulum mass were monitored by three electrodynamic stereo pickups. At rest, the tips of the needles and the pendulum's center of mass defined the reference system with respect to which the oscillations of the mass were recorded in terms of their amplitudes and phases. Its small dimensions, constant transfer characteristics, linearity, high dynamics, and virtual lack of reaction onto the moving system over the entire frequency range provided the advantages of the measuring system. This method was used to analyze the spatial 6D-vibrations of the head of a cemented femoral hip endoprosthesis when the femur was stimulated to bending vibrations. The head of the prosthesis carried out axial rotational vibrations at every frequency used to stimulate the femur. The amplitudes of the axial rotations of the cortical bone were small in comparison to the ones of the prosthesis head, indicating that axial rotational vibrations following femur bending vibrations mainly stressed the spongiosa and the cement layer. This was observed over the entire frequency range, including at the low frequencies relevant for gait. Over the low-frequency range, as well as at some of the higher resonance frequencies, stationary instantaneous helical axes characterized the vibrations. The measurements suggest the mechanism that the interface "implant-bone" may already be stressed by axial torsional loads when the femur is loaded by bending impacts that are known to occur during walking.

[An optical method for determining deformation and form changes in polyethylene surfaces of explanted acetabular cups of hip endoprostheses]. / Ein optisches Verfahren zur Bestimmung des Abriebs und der Gestaltsänderung der Polyethylenoberfläche explantierter Pfannen von Hüftendoprothesen.

AIM: Most methods used for the determination of volumetric wear of polyethylene cups are based on the assumption that the head of the prosthesis penetrates the cup in "cylindrical" fashion. The new accurate optical method is independent of this disputable assumption. METHOD: The articulating surface of the cup is scanned with light and a data set of 60,000 pixels obtained in this way is stored in a computer. Data obtained from used cups were compared with those obtained from unused cups. The volumetric wear was calculated directly by threefold integration. To assess the changes in surface shape, the data are fitted by an ellipsoid whose long axis defines the mean direction of load. A total of 18 retrieved and 3 unused cups of different types were studied. RESULTS: The unused acetabular cups deviated only slightly from ideal hemispheres. The surfaces showed rotational symmetry, and an undulation having an amplitude of 0.1 mm between dome and equator. For all explanted cups, the assumption of cylindrical penetration of the head into the polyethylene was shown not to represent the true situation. The cup expands in all directions, and the volumetric wear is underestimated by 50% with the traditional methods. The data suggest that long-term survival may be jeopardized when the main direction of loading is centered on the dome of the cup. Ceramic heads were associated with smaller rates of volumetric wear. CONCLUSION: The new optical method is characterised by short measuring times, precision and simple application. Analysis of the wear patterns of polyethylene components using this technique may contribute to a further understanding of the complex mechanisms of aseptic loosening.

Cell cycle specific induction of HL-60 cell differentiation and apoptosis by mycophenolic acid.

HL-60 cells undergo terminal differentiation and apoptosis in response to different types of sub-toxic and toxic perturbations respectively. The mechanism by which cells sense different amounts of perturbation to activate pathways that lead to the engagement of a relevant biological response is not known. The response of HL-60 cells to treatment with the immunosuppressant mycophenolic acid (MPA), a specific inhibitor of dGTP/GTP-synthesis, allowed quantitation of a metabolic perturbation which triggered a cellular response. 1.5 microM MPA induced 38% terminal differentiation to CD14 positive, early monocyte-like cells and 22% cell death by apoptosis, whereas 3 microM MPA induced 70% apoptosis but no differentiation. Despite the difference in biological outcomes, 72 h exposure to both 1.5 microM and 3 microM MPA caused a similar ( approximately 75%) depletion of total GTP levels. Cells synchronized by centrifugal elutriation were treated with MPA. Elutriated cells were overall less sensitive to the effects of MPA but 3 microM MPA induced significantly less apoptosis and more differentiation in an elutriation-enriched G1-population than in a population normally distributed in the cell cycle, suggesting that the effects of MPA in S-phase may subsequently lead to cell death. However, analysis of apoptosis by using a terminal deoxynucleotidyltransferase assay and measurement of bromodeoxyuridine incorporation showed that apoptosis was engaged in G1. Analysis of the phosphorylation status of the retinoblastoma protein demonstrated that Rb was hypophosphorylated prior to apoptosis and that in apoptotic cells, separated by flow cytometry, Rb protein was absent, presumably due to proteolysis. The loss of Rb protein did not appear to permit transit to S-phase, and was not accompanied by an expression of c-Myc. Surprisingly, therefore, an antimetabolite inducing a loss of GTP brought about cell death by apoptosis in the G1 phase of the cell cycle.

A microcorrosion cast study for analyzing a new method of indirect myocardial revascularization.

In order to study the process of angiogenesis a free skeletal muscle flap was transplanted onto the myocardium of the dog. A microvascular anastomosis with the internal mammary artery (IMA) provided the blood flow to the free graft. In 6 dogs, a myocardial infarction of the anterior wall was induced in order to produce a tissue injury. Four weeks later the skeletal muscle flap was transplanted onto the area of infarction in two dogs with its pars anterior in contact with the heart. In two dogs, the muscle was grafted with its pars posterior, i.e. the muscle fascia between the heart and the graft. In two other dogs, the flap was transplanted with its pars anterior in contact with the heart onto a healthy myocardium. Two animals with infarction were left as controls. Eighteen weeks later a microcorrosion cast was prepared from the hearts with the muscle flap. This evidenced neoangiogenesis in the heart only after transplantation of the graft with its pars anterior onto the myocardium whether it was ischemic or not. The intact muscle fascia, though, inhibited sprouting of vessels. In the controls no angiogenic activity was noted. Results are discussed with regard to the probable origin of the neovessels.