The chemokine system in allogeneic stem-cell transplantation: a possible therapeutic target?

Further improvements in allogeneic stem-cell transplantation will probably depend on a better balance between immunosuppression to control graft-versus-host disease and immunological reconstitution sufficient to ensure engraftment, reduction of infection-related mortality and maintenance of post-transplant antileukemic immune reactivity. The chemokine network is an important part of the immune system, and, in addition, CXCL12/CXCR4 seem to be essential for granulocyte colony-stimulating factor-induced stem-cell mobilization. Partial ex vivo graft T-cell depletion based on the expression of specific chemokine receptors involved in T-cell recruitment to graft-versus-host disease target organs may also become a future therapeutic strategy; an alternative approach could be pharmacological inhibition (single-receptor inhibitors or dual-receptor inhibitors) in vivo of specific chemokine receptors involved in this T-cell recruitment. Future clinical studies should therefore be based on a better characterization of various immunocompetent cells, including their chemokine receptor profile, both in the allografts and during post-transplant reconstitution.     

Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism

PURPOSE: Long-term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats. METHODS: Female rats received PHT (50 mg/kg), VPA (300 mg/kg), or LEV (50 and 150 mg/kg) for 90 days. Dissected femurs were analyzed using dual energy x-ray absorptiometry (DXA), three-point cantilever bending, and histomorphological evaluation. Serum levels of biochemical bone turnover markers were monitored using immunoassay quantification. RESULTS: PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, whereas LEV did not. VPA induced increased bone turnover, whereas modest changes were observed for PHT. Interestingly, low-dose LEV was associated with reduced biomechanical strength of the femoral neck (mainly trabecular bone). In addition, low-dose LEV treatment resulted in significantly reduced levels of serum osteocalcin, a marker of bone formation. Histomorphological analyses indicated increased retention of cartilage remnants at the growth plate metaphysis of rats treated with low-dose LEV vs. controls. CONCLUSIONS: PHT, VPA, and LEV exert differential effects on bone mass and strength, suggesting different mechanisms of action. The weakening effect of low-dose LEV on the femoral neck, despite a constant BMD, suggests a primary effect on bone quality. These findings warrant further human studies of possible adverse effects of LEV on bone development and growth, particularly in children and adolescents.     

Simulation model for assessing quality of ultrasound strain estimation in abdominal aortic aneurysm

The purpose of this study was to develop a simulation model for evaluating methods for ultrasound strain estimation in abdominal aortic aneurysms. Wall geometry was obtained from a real ultrasound image and wall motion was simulated applying realistic blood pressures to a nonlinear viscoelastic wall model. The ultrasound simulation included speckle, absorption and angle dependent reflection. Gaussian white noise was added to simulate various noise levels. Despite not fully replicating real ultrasound images, the model simulated realistic circumferential variations in intensity and realistic speckle patterns and has potential for initial evaluation of strain estimation methods.     

No effect of increasing protein intake during military exercise with severe energy deficit on body composition and performance

In this study, we compare the effects of isocaloric high- (HIGH: 2 g kg⁻¹ d⁻¹, n = 19) and low-protein diet (LOW: 1 g kg⁻¹ d⁻¹, n = 19) on changes in body composition, muscle strength, and endocrine variables in response to a 10-day military field exercise with energy deficit, followed by 7 days of recovery. Body composition (DXA), one repetition maximum (1RM) bench and leg press, counter-movement jump height (CMJ) and blood variables were assessed before and after the exercise. Performance and blood variables were reassessed after 7 days of recovery. The 10-day exercise resulted in severe energy deficit in both LOW and HIGH (−4373 ± 1250, −4271 ± 1075 kcal d⁻¹) and led to decreased body mass (−6.1%, −5.2%), fat mass (−40.5%, −33.4%), 1RM bench press (−9.5%, −9.7%), 1RM leg press (−7.8%, −8.3%), and CMJ (−14.7%, −14.6%), with no differences between groups. No change was seen for fat-free mass. In both groups, the exercise led to a switch toward a catabolic physiological milieu, evident as reduced levels of anabolic hormones (testosterone, IGF-1) and increased levels of cortisol (more pronounced in HIGH, P < .05). Both groups also displayed substantial increases in creatine kinase. After 7 days of recovery, most variables had returned to close-to pre-exercise levels, except for CMJ, which remained at reduced levels. In conclusion, increased protein intake during 10-day military field exercise with severe energy deficiency did not mitigate loss of body mass or impairment of physical performance.     

Effects of ocean acidification on early life stages of shrimp (Pandalus borealis) and mussel (Mytilus edulis)

Ocean acidification (OA) resulting from anthropogenic emissions of carbon dioxide (CO(2)) has already lowered and is predicted to further lower surface ocean pH. There is a particular need to study effects of OA on organisms living in cold-water environments due to the higher solubility of CO(2) at lower temperatures. Mussel larvae (Mytilus edulis) and shrimp larvae (Pandalus borealis) were kept under an ocean acidification scenario predicted for the year 2100 (pH 7.6) and compared against identical batches of organisms held under the current oceanic pH of 8.1, which acted as a control. The temperature was held at a constant 10°C in the mussel experiment and at 5°C in the shrimp experiment. There was no marked effect on fertilization success, development time, or abnormality to the D-shell stage, or on feeding of mussel larvae in the low-pH (pH 7.6) treatment. Mytilus edulis larvae were still able to develop a shell in seawater undersaturated with respect to aragonite (a mineral form of CaCO(3)), but the size of low-pH larvae was significantly smaller than in the control. After 2 mo of exposure the mussels were 28% smaller in the pH 7.6 treatment than in the control. The experiment with Pandalus borealis larvae ran from 1 through 35 days post hatch. Survival of shrimp larvae was not reduced after 5 wk of exposure to pH 7.6, but a significant delay in zoeal progression (development time) was observed.     

Internalization and action of an immunotoxin containing mistletoe lectin A-chain

An immunotoxin consisting of the enzymatically active A-chain of mistletoe lectin I and a monoclonal antibody against a surface protein on mouse leukemia L1210V cells was found to inhibit protein synthesis in these cells as efficiently as the native mistletoe toxin. The immunotoxin was somewhat more slowly endocytosed than the native toxin, but in both cases the endocytic uptake continued under conditions in which uptake from clathrin-coated pits was inhibited by mild acidification of the cytosol. This indicates that the toxin and the immunotoxin were at least partially internalized by a non-clathrin-dependent uptake mechanism and that uptake by this pathway is responsible for most of the toxic effect on the cells. The results indicate that efficient immunotoxins can be made with antibodies against cell surface epitopes that are endocytosed by a mechanism not involving clathrin-coated pits.     

In vitro sensitivity of human melanoma xenografts to cytotoxic drugs. Correlation with in vivo chemosensitivity

Single-cell suspensions prepared from five human melanomas, grown serially as xenografts in athymic nude mice, were exposed in vitro to increasing concentrations of DTIC (Dacarbazine), CCNU (Lomustine), procarbazine, vinblastine, and the cancerostatic lectins abrin and ricin. The in vitro chemosensitivity of the cells, as measured by the drug concentrations required to inhibit colony formation in soft agar by 50%, was correlated with the growth delay of the xenografts in vivo, previously observed after treatment of the animals with maximum tolerable doses of the same drugs. It was found that for each drug the in vitro sensitivity of the different xenografts was strongly correlated with their response in vivo. The results provide evidence that the soft agar test, as carried out here, adequately reflects the relative sensitivity of the xenografts in vivo. The data indicate that human xenografts may be used to develop quantitative in vitro chemosensitivity tests.