James M. Fox

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

In a retrospective review of 3,261 arthroscopic procedures on the knee, 2,640 met the criteria for inclusion in this analysis. The patients' ages ranged from eight to eighty-three years. There were 1,541 male and 1,099 female patients. Eight hundred and ninety-five of the injuries were work-related. A tourniquet was used in 1,175 procedures and the average tourniquet time was thirty minutes. There were 216 complications over-all (8.2 per cent), 126 being designated as major and ninety-seven, as minor. The major complications that were evaluated were infections, hemarthrosis, adhesions, effusions, cardiovascular, neurological, reflex sympathetic dystrophy, and instrument breakage, and the minor complications were difficulties with wound-healing and ecchymosis. Chi-square analysis showed the following factors to be significant (p less than 0.05). Patients with an industrial injury had a higher rate of neurological complications and reflex sympathetic dystrophy. Diagnostic arthroscopy had the lowest over-all complication rate. Partial medical meniscectomy was associated with a higher over-all complication rate and the highest hemarthrosis rate, and partial lateral meniscectomy was associated with the highest rate of instrument breakage. Abrasion arthroplasty had the highest rate of complications of wound-healing, and subcutaneous lateral release was associated with the most adhesions. The sex of the patient and whether or not a tourniquet had been used had no effect on complications. The experience of the surgeon with arthroscopic procedures also had no correlation with the complication rate. Multiple regression analysis showed that two factors (age and, if a tourniquet was used, the tourniquet time) were dominant predictors of complications. From these data, a model was devised for predicting which patients were at risk for complications and their relative levels of risk. Certain complications may be preventable, and for others the risk factors can be reduced. The high-risk patients in our series were fifty years old or older and had a tourniquet time of sixty minutes or longer.

The use of adult stem cells to regenerate damaged tissue circumvents the moral and technical issues associated with the use of those from an embryonic source. Mesenchymal stem cells (MSC) can be isolated from a variety of tissues, most commonly from the bone marrow, and, although they represent a very small percentage of these cells, are easily expandable. Recently, the use of MSC has provided clinical benefit to patients with osteogenesis imperfecta, graft-versus-host disease and myocardial infarction. The cellular cues that enabled the MSC to be directed to the sites of tissue damage and the mechanisms by which MSC then exert their therapeutic effect are becoming clearer. This review discusses the relative therapeutic importance of the ability of MSC to differentiate into multiple cell lineages or stimulate resident or attracted cells via a paracrine mode of action. It also reviews recent findings that MSC home to damaged tissues in a similar, but somewhat distinct, manner to that of leucocytes via the utilisation of adhesion molecules, such as selectins and integrins, and chemokines and their receptors in a manner reminiscent of leucocytes trafficking from the blood stream to inflammatory sites.

The intracellular bacterium Francisella tularensis is the causative agent of tularemia and poses a serious threat as an agent of bioterrorism. We have developed a highly effective molecular subtyping system from 25 variable-number tandem repeat (VNTR) loci. In our study, multiple-locus VNTR analysis (MLVA) was used to analyze genetic relationships and potential population structure within a global collection of 192 F. tularensis isolates, including representatives from each of the four subspecies. The VNTR loci displayed between 2 and 31 alleles with Nei's diversity values between 0.05 and 0.95. Neighbor-joining cluster analysis of VNTR data revealed 120 genotypes among the 192 F. tularensis isolates, including accurate subspecies identification. F. tularensis subsp. tularensis (type A) isolates showed great diversity at VNTR loci, while F. tularensis subsp. holarctica (type B) isolates showed much lower levels despite a much broader geographical prevalence. The resolution of two distinct clades within F. tularensis subsp. tularensis (designated A.I and A.II) revealed a previously unrecognized genetic division within this highly virulent subspecies. F. tularensis subsp. holarctica appears to have recently spread globally across continents from a single origin, while F. tularensis subsp. tularensis has a long and complex evolutionary history almost exclusively in North America. The sole non-North American type A isolates (Slovakian) were closely related to the SCHU S4 strain. Significant linkage disequilibrium was detected among VNTR loci of F. tularensis consistent with a clonal population structure. Overall, this work greatly augments the study of tularemia ecology and epidemiology, while providing a framework for future forensic analysis of F. tularensis isolates.