Deciphering the pathogenesis of tendinopathy: a three-stages process

Our understanding of the pathogenesis of "tendinopathy" is based on fragmented evidences like pieces of a jigsaw puzzle. We propose a "failed healing theory" to knit these fragments together, which can explain previous observations. We also propose that albeit "overuse injury" and other insidious "micro trauma" may well be primary triggers of the process, "tendinopathy" is not an "overuse injury" per se. The typical clinical, histological and biochemical presentation relates to a localized chronic pain condition which may lead to tendon rupture, the latter attributed to mechanical weakness. Characterization of pathological "tendinotic" tissues revealed coexistence of collagenolytic injuries and an active healing process, focal hypervascularity and tissue metaplasia. These observations suggest a failed healing process as response to a triggering injury. The pathogenesis of tendinopathy can be described as a three stage process: injury, failed healing and clinical presentation. It is likely that some of these "initial injuries" heal well and we speculate that predisposing intrinsic or extrinsic factors may be involved. The injury stage involves a progressive collagenolytic tendon injury. The failed healing stage mainly refers to prolonged activation and failed resolution of the normal healing process. Finally, the matrix disturbances, increased focal vascularity and abnormal cytokine profiles contribute to the clinical presentations of chronic tendon pain or rupture. With this integrative pathogenesis theory, we can relate the known manifestations of tendinopathy and point to the "missing links". This model may guide future research on tendinopathy, until we could ultimately decipher the complete pathogenesis process and provide better treatments

Mechanisms of viral entry: sneaking in the front door

Recent developments in methods to study virus internalisation are providing clearer insights into mechanisms used by viruses to enter host cells. The use of dominant negative constructs, specific inhibitory drugs and RNAi to selectively prevent entry through particular pathways has provided evidence for the clathrin-mediated entry of hepatitis C virus (HCV) as well as the caveolar entry of Simian Virus 40. Moreover, the ability to image and track fluorescent-labelled virus particles in real-time has begun to challenge the classical plasma membrane entry mechanisms described for poliovirus and human immunodeficiency virus. This review will cover both well-documented entry mechanisms as well as more recent discoveries in the entry pathways of enveloped and non-enveloped viruses. This will include viruses which enter the cytosol directly at the plasma membrane and those which enter via endocytosis and traversal of internal membrane barrier(s). Recent developments in imaging and inhibition of entry pathways have provided insights into the ill-defined entry mechanism of HCV, bringing it to the forefront of viral entry research. Finally, as high-affinity receptors often define viral internalisation pathways, and tropism in vivo, host membrane proteins to which viral particles specifically bind will be discussed throughout

Medium-energy shock wave therapy in the treatment of rotator cuff calcifying tendinitis

To evaluate the results of the treatment with medium-energy extracorporeal shock wave therapy (ESWT) in rotator cuff calcifying tendinitis. Fifty-four non-consecutive patients, who were referred to our institute for rotator cuff calcifying tendinitis, were managed with a standardized protocol in four sessions of medium-energy (0.11 mJ/mm2) ESWT administered with an electromagnetic lithotriptor. Pain was evaluated at the end of each session, functional state of shoulder was assessed at 1 and 6 months after the end of procedure. All patients underwent radiographs and sonography imaging. No systemic or local complications. Thirty-eight patients (70%) reported satisfactory functional results. Radiographs and sonographs showed a disappearance of calcium deposit in 29 patients (54%) and in 19 patients (35%) it appeared to be reduced more than a half. A correlation was found between residual calcium deposit and the clinical outcome, but some patients showed a reduced pain without modification of calcium deposit. These results were unmodified at 6 months follow-up. Our protocol of medium-energy ESWT provides good results overall about pain modulation

A tumor necrosis factor receptor family protein serves as a cellular receptor for the macrophage-tropic equine lentivirus

Characterization of cellular receptors for human, simian, and feline immunodeficiency viruses that are tropic for lymphocytes and macrophages have revealed a common theme of a sequential binding of viral envelope proteins with two coreceptors to mediate virus infection of target cells. In contrast to these dual tropic immunodeficiency viruses, the ungulate lentiviruses, including equine infectious anemia virus (EIAV), exclusively infect cells of the monocyte-macrophage lineage to cause progressive degenerative diseases without clinical immunodeficiency. EIAV causes a uniquely dynamic disease that is characterized by recurrent disease episodes including fever, diarrhea, lethargy, anemia, and thrombocytopenia. Although EIAV provides an important animal model for lentivirus disease resulting from macrophage infection, to date there has been no definition of the specific cellular receptor(s) used by the equine lentivirus to infect target cells. In the current study, we have identified and cloned a functional receptor for EIAV, designated equine lentivirus receptor-1 (ELR1), related to the family of TNF receptor (TNFR) proteins. ELR1 was shown to be expressed in various equine cells permissive for EIAV replication in vitro, including monocytes and macrophages. In contrast, EIAV-resistant human, murine, and simian cells were negative for ELR1 expression but became susceptible to virus infection when transduced with a recombinant murine retrovirus expressing the ELR1. Thus, these results identify a specific functional receptor for a macrophagetropic lentivirus and indicate that infection by EIAV may be mediated by a single receptor, in contrast to coreceptors used by the lymphotropic immunodeficiency lentiviruses