[Osteoarthritis of the upper ankle joint]. / Arthrose des oberen Sprunggelenks.

The majority of cases of upper ankle joint (UAJ) osteoarthritis are due to secondary causes. Clinically, osteoarthritis is usually characterized by an increasing limitation in dorsal extension of the UAJ with often relatively mild symptoms. In the course of time the full scale of the typical symptoms and the progressive restriction of the global function of the joint develop. Conservative therapy is often able to provide long-term improvement of the symptoms for the majority of patients by means of intermittent analgesics and orthoses as well as shoe modifications. Operative treatment strategies for initial stages are based on joint-sparing methods. The most frequently used therapy for progressive destruction of the UAJ is still arthrodesis. Total ankle replacement is becoming an increasingly more competitive procedure. Total ankle replacement provides a valuable extension of therapeutic possibilities for UAJ osteoarthritis.

[Lateral instability of the upper ankle joint]. / Laterale Instabilität des oberen Sprunggelenks.

Because of their frequency, ankle sprains are of major clinical and economic importance. The simple sprain with uneventful healing has to be distinguished from the potentially complicated sprain which is at risk of transition to chronic ankle instability. Conservative treatment is indicated for the acute, simple ankle sprain without accompanying injuries and also in cases of chronic instability. If conservative treatment fails, good results can be achieved by anatomic ligament reconstruction of the lateral ankle ligaments. Arthroscopic techniques offer the advantage of joint inspection and addressing intra-articular pathologies in combination with ligament repair. Accompanying pathologies must be adequately addressed during ligament repair to avoid persistent ankle discomfort. If syndesmotic insufficiency and tibiofibular instability are suspected, the objective should be early diagnosis with MRI and surgical repair.

Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways.

Heat shock proteins (HSPs) derived from tumors or virally infected cells can stimulate antigen-specific CD8(+) T cell responses in vitro and in vivo. Although this antigenicity is known to arise from HSP-associated peptides presented to the immune system by major histocompatibility complex (MHC) class I molecules, the cell biology underlying this presentation process remains poorly understood. Here we show that HSP 70 binds to the surface of antigen presenting cells by a mechanism with the characteristics of a saturable receptor system. After this membrane interaction, processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytosolic (transporter associated with antigen processing [TAP] and proteasome-dependent) or an endosomal (TAP and proteasome-independent) route, with the preferred pathway determined by the sequence context of the optimal antigenic peptide within the HSP-associated material. These findings not only characterize two highly efficient, specific pathways leading to the conversion of HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transport of HSP or HSP-associated ligands from the plasma membrane or lumen of endosomes into the cytosol.

The flagellar sigma factor FliA (sigma(28)) regulates the expression of Salmonella genes associated with the centisome 63 type III secretion system.

One of the essential features of all pathogenic strains of Salmonella enterica is the ability to enter into nonphagocytic cells. This pathogenic property is mediated by the Salmonella pathogenicity island 1 (SPI-1)-encoded type III secretion system. Expression of components and substrates of this system is subject to complex regulatory mechanisms. These mechanisms include a number of specific and global transcriptional regulatory proteins. In this study we have compared in S. enterica serovars Typhimurium and Typhi the effect of mutations in flagellar genes on the phenotypes associated with the SPI-1 type III protein secretion system. We found that serovar Typhi strains carrying a null mutation in either of the flagellar regulatory genes flhDC or fliA were severely deficient in entry into cultured epithelial cells and macrophage cytotoxicity. This defect could not be reversed by applying a mild centrifugal force, suggesting that the effects of the mutations were not due to the absence of motility. In contrast, the same mutations had no significant effect on the ability of serovar Typhimurium to enter into cultured Henle-407 cells or to induce macrophage cell death. Consistent with these observations, we found that the mutations in the flagellar regulatory proteins significantly reduced the expression of components of the SPI-1-encoded type III system in serovar Typhi but had a marginal effect in serovar Typhimurium. Our results therefore indicate that there is an overlap between regulatory mechanisms that control flagellar and type III secretion gene expression in Salmonella serovar Typhi.

Differential regulation of Salmonella typhimurium type III secreted proteins by pathogenicity island 1 (SPI-1)-encoded transcriptional activators InvF and hilA.

Salmonella enterica encodes a type III protein secretion system within a pathogenicity island (SPI-1) that is located at centisome 63 of its chromosome. This system is required for the ability of these bacteria to stimulate cellular responses that are essential for their pathogenicity. Expression of components and substrates of this system is subject to complex regulatory mechanisms. These mechanisms involve the function of HilA and InvF, two transcriptional regulatory proteins encoded within SPI-1. In this study, we examined the functional relationship between these two regulatory proteins. We found that strains carrying loss-of-function mutations in either hilA or invF differ in their ability to stimulate cellular responses. An S. typhimurium hilA mutant strain retained considerable signaling capacity that resulted in significant levels of internalization into host cells. In contrast, introduction of a nonpolar loss-of-function mutation in invF rendered S. typhimurium significantly impaired in its ability to enter host cells. Consistent with these different phenotypes, we found that HilA and InvF control the expression of different genes. HilA regulates the expression of components of the type III secretion machinery, whereas InvF controls the expression of type III secreted proteins encoded outside of SPI-1. We also found that the expression of secreted proteins encoded within SPI-1 are under the control of both HilA and InvF. Our results therefore indicate that InvF and HilA differentially control the expression of components and substrates of the invasion-associated type III secretion system.

Characterization of SprA, an AraC-like transcriptional regulator encoded within the Salmonella typhimurium pathogenicity island 1.

Pathogenicity island 1 (SPI-1) located at centisome 63 of the Salmonella chromosome encodes a type III protein secretion system that is essential for its pathogenicity. The translocation of effector proteins through this system results in the stimulation of signalling events, leading to actin cytoskeletal rearrangements and nuclear responses. These cellular responses ultimately lead to bacterial uptake, production of proinflammatory cytokines in non-phagocytic cells and the initiation of programmed cell death in macrophages. The regulation of expression of components and substrates of this type III secretion system is complex and involves the activity of several specific transcriptional regulatory proteins encoded within SPI-1. Here, we describe two additional regulatory proteins, SprA and SprB, which are encoded within SPI-1. SprA and SprB exhibit significant sequence similarity to the AraC/XylS and the LuxR/UhaP family of transcriptional regulatory proteins respectively. Insertion mutations in sprA and sprB did not significantly affect the transcription of invasion-associated genes and, consequently, did not affect the ability of Salmonella typhimurium to gain access into host cells. However, expression of sprA from an inducible heterologous promoter resulted in increased expression of genes associated with the centisome 63 type III secretion system and increased the ability of S. typhimurium to enter into host cells. Further analysis demonstrated that SprA acts either upstream or at the same level as HilA in the SPI-1 transcriptional regulatory cascade.

Molecular and functional characterization of the Salmonella typhimurium invasion genes invB and invC: homology of InvC to the F0F1 ATPase family of proteins.

Entry into intestinal epithelial cells is an essential step in the pathogenesis of Salmonella infections. Our laboratory has previously identified a genetic locus, inv, that is necessary for efficient entry of Salmonella typhimurium into cultured epithelial cells. We have carried out a molecular and functional analysis of invB and invC, two members of this locus. The nucleotide sequence of these genes indicated that invB and invC encode polypeptides with molecular masses of 15 and 47 kDa, respectively. Polypeptides with the predicted sizes were observed when these genes were expressed under the control of a T7 promoter. Strains carrying nonpolar mutations in these genes were constructed, and their phenotypes were examined in a variety of assays. A mutation in invC rendered S. typhimurium defective in their ability to enter cultured epithelial cells, while mutations in invB did not. Comparison of the predicted sequences of InvB and InvC with translated sequences in GenBank revealed that these polypeptides are similar to the Shigella spp. proteins Spa15 and Spa47, which are involved in the surface presentation of the invasion protein antigens (Ipa) of these organisms. In addition, InvC showed significant similarity to a protein family which shares sequence homology with the catalytic beta subunit of the F0F1 ATPase from a number of microorganisms. Consistent with this finding, purified preparations of InvC showed significant ATPase activity. Site-directed mutagenesis of a residue essential for the catalytical function of this family of proteins resulted in a protein devoid of ATPase activity and unable to complement an invC mutant of S. typhimurium. These results suggest that InvC may energize the protein export apparatus encoded in the inv locus which is required for the surface presentation of determinants needed for the entry of Salmonella species into mammalian cells. The role of InvB in this process remains uncertain.