Vascular protectants for the treatment of atherosclerosis

AGI-1067, the monosuccinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed vascular protectants. It has strong antioxidant properties, equipotent to those of probucol, and anti-inflammatory properties. It inhibits gene expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and has been effective at preventing atherosclerosis in all tested animal models. It also improved luminal dimensions of reference segments in the percutaneous coronary intervention (PCI) vessels in the CART-1 clinical trial, which suggests a direct anti-atherosclerosis effect. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis, and the Aggressive Reduction of Inflammation Stops Events trial, which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.     

Cell surface CD43 determination improves diagnostic precision in late B-cell diseases

Panels of immunological markers are useful in refining diagnosis in view of certain variability between B-cell leukaemias. A statistical multivariate approach was used on 100 B leukaemias (preliminary sample) to explore the potential value of the combination of CD43, and the classical markers CD5, CD23, CD79b, FMC7, CD22 and surface immunoglobulin to differentiate chronic lymphoid leukaemia (CLL) from lymphoma (non-CLL). CD43 was highly effective (P < 0.00001) and its inclusion in the panels improved the accuracy of discrimination in a 'control' sample of 74 B leukaemias to 98.6%. Inclusion of CD43 facilitates the diagnosis of B-lymphoproliferative disorders and improves their classification.     

Upregulation of galectins-1 and -3 in human colon cancer and their role in regulating cell migration

To probe the potential contribution of beta-galactoside-contributing epitopes and receptor proteins (gal-1 and gal-3) to colon malignancy, we first examined the expression of galectins and binding sites in clinical specimens by lectin and immunohistochemistry. Sixty-seven colonic surgical resections were studied, including 10 normal, 10 mild dysplasias, 10 severe dysplasias and 37 cancers. gal-1 and gal-3 were expressed in variable amounts in the epithelial cells and the connective tissue of normal colon. Their expression significantly increased with the degree of dysplasia, suggesting that gal-1 and gal-3 and their binding sites are related to malignant progression, while gal-8 has been associated with suppressor activity. To study the functional aspects, the influence of these galectins on the migration of 4 human colorectal cancer cell lines (HCT-15, LoVo, DLD-1, CoLo201) was studied. In agreement with histopathologic monitoring, these tumor cells were found to produce gal-3, while only CoLo201 was positive for gal-1. Except for DLD-1 and gal-1, the lines exhibited gal-1 binding sites on the surface, prompting study by computer-assisted videomicroscopy of the effect on cell migration of the presence of galectin on the culture substrate. The level of cell migration for HCT-15, LoVo and CoLo201 cells was significantly reduced by 0.15 microg/cm(2) gal-1, and the presence of a blocking antibody at least reduced this effect. gal-3 significantly reduced cell migration in all 4 of the in vitro cell lines.     

Plasma compartment filling after exercise or heat exposure

PURPOSE: The present study was assessed to study the restoration of the vascular compartment by rehydration after heat exposure or exercise. METHODS: Eight subjects completed four trials in a randomized order: 2.7% dehydration of body mass by passive controlled hyperthermia once with rehydration and once without rehydration during recovery, and 2.7% dehydration of body mass by treadmill exercise once with rehydration and once without rehydration during recovery. An isotonic glucose electrolyte beverage was provided twice during the recovery period for a total volume, which was equivalent to the target value of body mass loss during dehydration procedures. Plasma volume (PV) was measured using Evans Blue dilution technique, and PV changes (deltaPV) were determined using hematocrit and hemoglobin measurements. RESULTS: PV was better maintained during exercise than during heat exposure, and the difference in deltaPV between the two patterns of dehydration was maintained during the first 3 h of recovery. Plasma protein seemed to be accountable for the difference in deltaPV during heat exposure and exercise but not during the 270 min of recovery. Rehydration partly restored body fluid losses, but the plasma compartment was privileged, because 26-30% of the net fluid gain was found in the plasma compartment (about 300 mL). Rehydration restored plasma osmolality and diminished the drive for arginin-vasopressin response. CONCLUSION: The similar selective retention of water in the plasma compartment might essentially be explained by osmotic factors provided by the beverage. As PV was completely restored by rehydration after exercise and only partly restored after heat exposure, the volume of ingested beverage should be higher after heat exposure to completely restore the plasma compartment.     

TrkC overexpression enhances survival and migration of neural stem cell transplants in the rat spinal cord

Although CNS axons have the capacity to regenerate after spinal cord injury when provided with a permissive substrate, the lack of appropriate synaptic target sites for regenerating fibers may limit restoration of spinal circuitry. Studies in our laboratory are focused on utilizing neural stem cells to provide new synaptic target sites for regenerating spinal axons following injury. As an initial step, rat neural precursor cells genetically engineered to overexpress the tyrosine kinase C (trkC) neurotrophin receptor were transplanted into the intact rat spinal cord to evaluate their survival and differentiation. Cells were either pretreated in vitro prior to transplantation with trkC ligand neurotrophin-3 (NT-3) to initiate differentiation or exposed to NT-3 in vivo following transplantation via gelfoam or Oxycel. Both treatments enhanced survival of trkC-overexpressing stem cells to nearly 100%, in comparison with approximately 30-50% when either NT-3 or trkC was omitted. In addition, increased migration of trkC-overexpressing cells throughout the spinal gray matter was noted, particularly following in vivo NT-3 exposure. The combined trkC expression and NT-3 treatment appeared to reduce astrocytic differentiation of transplanted neural precursors. Decreased cavitation and increased beta-tubulin fibers were noted in the vicinity of transplanted cells, although the majority of transplanted cells appeared to remain in an undifferentiated state. These findings suggest that genetically engineered neural stem cells in combination with neurotrophin treatment may be a useful addition to strategies for repair of spinal neurocircuitry following injury.