The activation of the Akt/PKB signalling pathway in the brains of clozapine-exposed rats is linked to hyperinsulinemia and not a direct drug effect.

The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy.

The influence of tibial tray design on the wear of fixed-bearing total knee replacements.

Debris-induced osteolysis due to surface wear is a potential long-term problem in total knee replacements (TKRs). Wear between the tibial tray and ultra-high molecular weight polyethylene insert is thought to contribute to the wear. This study investigated the influence of tibial tray design on the wear of fixed-bearing TKRs. Specifically, this study investigated the influence of the material's surface finish and design characteristics of the locking mechanism of the tibial tray on the wear in fixed-bearing knees for both cruciate-retaining (CR) and posterior-stabilized designs. A new fixed-bearing tibial tray design using Co-Cr and with an improved locking mechanism significantly reduced polyethylene wear from 22.8 +/- 6.0 mm3 per 10(6) cycles to 15.9 +/- 2.9 mm3 per 10(6) cycles compared with a previous titanium alloy tray with a CR design. The wear rates were similar to those of a fixed-bearing insert clamped into a tibial tray, suggesting that the decrease in wear was due to a reduction in backside wear. There was no significant difference between the wear rates of a cruciate-retaining design and a posterior-stabilized design under the two kinematic conditions tested.

Isolation and characterization of UHMWPE wear particles down to ten nanometers in size from in vitro hip and knee joint simulators.

There is currently considerable interest in the wear debris and osteolytic potential of different types of bearings used in total joint replacements. The biological activity of the wear debris is dependent on the size and volume of the particles produced. Wear volume also plays an important role in the functional biological activity of a joint replacement. In vitro studies have shown that crosslinking of ultra high molecular weight polyethylene (UHMWPE) acetabular cups and tibial trays produces a reduction in wear volume, and crosslinking has now been introduced clinically for both types of prostheses. Previous studies have identified both micron and submicron-sized polyethylene wear particles. The aim of this study was to characterize the wear and wear particles generated from moderately crosslinked GUR 1,020 GVF UHMWPE acetabular cups and tibial trays in hip and knee joint wear simulators down to 10 nanometers in size. The wear rates of the two prosthesis types were very similar at 25.6 +/- 5.3 mm(3) per million cycles for the hip prostheses and 22.75 +/- 5.95 mm(3) per million cycles for the knee prostheses. Nanometer-sized wear particles were isolated and characterized from both hip and knee simulator lubricants for the first time. Significantly higher numbers (p < 0.05) of particles in the nanometer (<0.1 microm) size range were produced by the hip prostheses compared to the knee prostheses. The knee prostheses produced larger particles, with the mode of particle size in the 0.1-1.0 microm size range, compared to <0.1 microm size range for the hip prostheses. In addition, the knee prostheses produced a greater volumetric concentration of wear particles in the 1.0-10 microm size range, and consequently lower specific biological activity and functional biological activity indices. These results indicated that the knee prostheses had a lower osteolytic potential compared to the hip prostheses.

The influence of design, materials and kinematics on the in vitro wear of total knee replacements.

Debris-induced osteolysis due to surface wear of ultra high molecular weight polyethylene (UHMWPE) bearings is a potential long-term failure mechanism of total knee replacements (TKR). This study investigated the effect of prosthesis design, kinematics and bearing material on the wear of UHMWPE bearings using a physiological knee simulator. The use of a curved fixed bearing design with stabilised polyethylene bearings reduced wear in comparison to more flat-on-flat components which were sterilised by gamma irradiation in air. Medium levels of crosslinking further improved the wear resistance of fixed bearing TKR due to resistance to strain softening when subjected to multidirectional motion at the femoral-insert articulating interface. Backside motion was shown to be a contributing factor to the overall rate of UHMWPE wear in fixed bearing components. Wear of fixed bearing prostheses was reduced significantly when anterior-posterior displacement and internal-external rotation kinematics were reduced due to decreased cross shear on the articulating surface and a reduction in AP displacement. Rotating platform mobile bearing prostheses exhibited reduced wear rates in comparison to fixed bearing components in these simulator studies due to redistribution of knee motion to two articulating interfaces with more linear motions at each interface. This was observed in two rotating platform designs with different UHMWPE bearing materials. In knee simulator studies, wear of TKR bearings was dependent on kinematics at the articulating surfaces and the prosthesis design, as well as the type of material.

Influences of sterilising techniques on polyethylene wear.

Over the last 10 years there has been increasing concern over wear of polyethylene and osteolytic potential in the knee. During this period there have been considerable developments in both the design, materials and sterilisation techniques used for polyethylene in the knee. This paper reviews wear performance of polyethylene sterilised by different techniques, under a range of kinematics conditions in a single knee joint simulator system. Reducations in polyethylene wear were found with both stabilised polyethylene and cross-linked polyethylene, and with rotating platform mobile bearing designs.

Microscopic asperity contact and deformation of ultrahigh molecular weight polyethylene bearing surfaces.

The effect of the roughness and topography of ultrahigh molecular weight polyethylene (UHMWPE) bearing surfaces on the microscopic contact mechanics with a metallic counterface was investigated in the present study. Both simple sinusoidal roughness forms, with a wide range of amplitudes and wavelengths, and real surface topographies, measured before and after wear testing in a simple pin-on-plate machine, were considered in the theoretical analysis. The finite difference method was used to solve the microscopic contact between the rough UHMWPE bearing surface and a smooth hard counterface. The fast Fourier transform (FFT) was used to cope with the large number of mesh points required to represent the surface topography of the UHMWPE bearing surface. It was found that only isolated asperity contacts occurred under physiological loading, and the real contact area was only a small fraction of the nominal contact area. Consequently, the average contact pressure experienced at the articulating surfaces was significantly higher than the nominal contact pressure. Furthermore, it was shown that the majority of asperities on the worn UHMWPE pin were deformed in the elastic region, and consideration of the plastic deformation only resulted in a negligible increase in the predicted asperity contact area. Microscopic asperity contact and deformation mechanisms may play an important role in the understanding of the wear mechanisms of UHMWPE bearing surfaces.

Investigation of wear of knee prostheses in a new displacement/force-controlled simulator.

The performance of two knee simulators designed by ProSim (Manchester, UK) was evaluated by comparison of the wear seen in the press-fit condylar (PFC) Sigma (DePuy) knee prosthesis. Twelve specimens of the same design and manufacturing specification, were subjected to a wear test of 2 x 10(6) cycles duration using bovine serum as a lubricant. The anterior/posterior displacement and internal/external rotation inputs were based on the kinematics of the natural knee. International Standards Organization (ISO) standards were used for the flexion and axial load. The wear rates and wear scar areas were compared across all stations. The mean wear rates found were 17.6+/-5 mm3/10(6) cycles for stations 1 to 6 and 19.6+/-4 mm3/10(6) cycles for stations 7 to 12, resulting in an overall mean wear rate of 18.1+/-3 mm3/10(6) cycles. The differences between the two simulators were not significant. The average wear scar area seen on inserts from stations I to 6 was calculated at 32.4+/-1 per cent of the intended articulating surface. Similarly on stations 7 to 12 the average wear scar area was 30.7+/-3 per cent. The wear scars seen were a good physiological representation of those found from clinical explant data. This study has shown good repeatability from the simulator, both within and between the simulators.

A comparison of the wear and physical properties of silane cross-linked polyethylene and ultra-high molecular weight polyethylene.

Cross-linked polyethylenes are being introduced widely in acetabular cups in hip prostheses as a strategy to reduce the incidence of wear debris-induced osteolysis. It will be many years before substantial clinical data can be collected on the wear of these new materials. Silane cross-linked polyethylene (XLPE) was introduced into clinical practice in a limited series of acetabular cups in 1986 articulating against 22.225-mm alumina ceramic femoral heads and showed reduced wear rates compared with conventionally sterilized (gamma irradiation in air) ultra-high molecular weight polyethylene (UHMWPE). We compared the wear of XLPE manufactured in 1986 with the wear of UHMWPE manufactured in 1986 in nonirradiated and irradiated forms. In the nonirradiated forms, the wear of XLPE was 3 times less than UHWMPE when articulating against smooth counterfaces. The nonirradiated materials did not show signs of oxidation. In the irradiated forms, only UHMWPE showed high levels of oxidation, and this caused a substantial increase in wear. Antioxidants added to XLPE during processing gave resistance to oxidative degradation. When sliding against scratched counterfaces, the wear of UHMWPE increased by a factor of 2 to 3 times. Against the same scratched counterfaces, the wear of XLPE increased dramatically by 30 to 200 times. This difference may be attributed to the reduction in toughness of XLPE. Clinically, XLPE has been articulated against damage-resistant ceramic heads, and this probably has been an important factor in contributing to reduced wear. New cross-linked polyethylenes differ considerably from XLPE. This study indicates that it is prudent to examine the wear of new polyethylenes under a range of conditions that may occur in vivo.

Wear of fixed bearing and rotating platform mobile bearing knees subjected to high levels of internal and external tibial rotation.

In order to extend the lifetime of total knee replacements (TKR) in vivo, reduction of the volumetric wear rate of ultra high molecular weight polyethylene (UHMWPE) bearings remains an important goal. The volume of wear debris generated in fixed bearing total knee devices increases significantly when subjected to higher levels of internal-external rotation and anterior-posterior displacement. Six PFC Sigma fixed bearing TKR were compared with six LCS rotating platform mobile bearing knees using a physiological knee simulator with high rotation kinematic inputs. The rotating platform polyethylene inserts exhibited a mean wear rate which was one-third of that of the fixed bearing inserts despite having increased femoral contact areas and additional tibial wear surfaces. The rotating platform design decouples knee motions, by allowing unidirectional motion at the tray-insert articulation, which reduces rotation at the femoral-insert counterface. This translation of complex knee motions into more unidirectional motions results in molecular orientation of the UHMWPE and reduced volumetric wear.

Effect of preseasonal enzyme potentiated desensitisation (EPD) on plasma-IL-6 and IL-10 of grass pollen-sensitive asthmatic children.

EPD is a method of preventive immunotherapy which employs b-glucuronidase as a biological response modifier. Plasma IL-6 and IL-10 were measured before a single injection of EPD, 24 hours later and 15 days after in a group of 17 children suffering from grass pollen asthma. 17 normal untreated children were used as controls. Although the study was conducted before the grass pollen season when the allergic children were free of symptoms, their plasma IL-6 and IL-10 were significantly elevated before the injection of EPD. 24 hours after treatment the plasma IL-10 had increased significantly and there was also a slight rise in IL-6. 15 days after treatment IL-6 had fallen to normal but IL-10 was still elevated. These findings suggest antigen-specific and non-specific mechanisms by which EPD may produce clinical improvement.

Experience with a hospital-based weight reduction program.

A pilot project "Nutritional Service for Weight Reduction", utilizing allied health personnel, was organized by the Departments of Medicine and Dietetics at the Calgary General Hospital. Body measurements and biochemical tests were required at the beginning and end of the 12-week program. Meetings were held at which the subjects submitted their weekly food record, received counselling by nutritionists, and attended lectures on physiology, metabolism of food, nutrition and the importance of exercise. Thirty-one subjects completed the program. All lost weight, the total for the group being 197 kg. At the first follow-up meeting, 17 subjects showed further weight loss, three maintained their weight and 11 regained some weight.