[Medial foot and ankle instability]. / Mediale Fuß- und Sprunggelenkinstabilitäten.

The deltoid or medial collateral ligament consisting of superficial and deep components together with the spring ligament is the primary stabilizer of the ankle joint. Injuries of these anatomical structures are more frequent than assumed but are nevertheless often overlooked. Inadequate treatment can lead to chronic pain, instability, hindfoot deformities and ankle arthritis. Patient history and clinical assessment can help to identify injuries of the deltoid ligament. Magnetic resonance imaging (MRI) is the diagnostic method of choice. Arthroscopy of the ankle joint can be a valuable tool in the assessment of the injury. Treatment should include accompanying injuries and deformities and can range from immobilization in a cast to ligament repair up to ligament reconstruction using a free tendon graft.

The natural initiation and progression of osteoarthritis in the anterior cruciate ligament deficient feline knee.

OBJECTIVE: The aim of this study was to document the natural history of development and long-term progression of osteoarthritis (OA) in the feline knee after minimally invasive anterior cruciate ligament (ACL) transection. DESIGN: ACL transections of the left knee joint of 14 skeletally mature cats were performed. Radiographic scores, tibiofemoral and patellofemoral joint space and anterior tibial translation were assessed before, immediately and every 3 months after ACL transection (longest follow-up: 93 months). RESULTS: After 26 months, all ACL transected knees had developed definite OA. The earliest changes were observed on the tibia plateau starting as early as 2 months after ACL transection, and at 12 months signs of OA were present in more than 80% of cats in the medial and in almost 80% of cats in the lateral compartment. In the first 24 months, medial tibiofemoral joint space decreased by 0.88 mm (95% confidence interval [-0.55;-1.21] mm) and lateral tibiofemoral joint space by 0.55 mm ([-0.26;-0.85] mm). In the same interval, the joint space in the patellofemoral joint increased by 0.98 mm ([0.59; 1.37] mm). Throughout the entire observation period, the anterior tibial translation was on average 5.3 mm greater than in the contralateral knee ([4.5; 6.0]mm). CONCLUSIONS: Immediate changes in anterior tibial translation during an anterior drawer test clearly showed joint instability that persisted throughout the lifetime of the animals. Degenerative changes were observed on radiographs within 4 months of the injury only in the transected but not the contralateral limb suggesting the role of mechanical instability for the development and progression of knee OA.

Lithium insertion into silicon electrodes studied by cyclic voltammetry and operando neutron reflectometry.

Operando neutron reflectometry measurements were carried out to study the insertion of lithium into amorphous silicon film electrodes during cyclic voltammetry (CV) experiments at a scan rate of 0.01 mV s-1. The experiments allow mapping of regions where significant amounts of Li are incorporated/released from the electrode and correlation of the results to modifications of characteristic peaks in the CV curve. High volume changes up to 390% accompanied by corresponding modifications of the neutron scattering length density (which is a measure of the average Li fraction present in the electrode) are observed during electrochemical cycling for potentials below 0.3 V (lithiation) and above 0.2 V (delithiation), leading to a hysteretic behaviour. This is attributed to result from mechanical stress as suggested in the literature. Formation and modification of a surface layer associated with the solid electrolyte interphase (SEI) were observed during cycling. Within the first lithiation cycle the SEI grows to 120 Å for potentials below 0.5 V. Afterwards a reversible and stable modification of the SEI between 70 Å (delithiated state) and 120 Å (lithiated state) takes place.

[Total ankle arthroplasty in valgus ankle osteoarthritis]. / Sprunggelenkprothese bei Valgusarthrose.

Ankle osteoarthritis (OA) is often associated with deformities. Valgus OA is less frequent than varus OA and causes of valgus OA include medial ligament instability, flat foot and posttraumatic situations, e.g. fractures of the fibula or lateral tibial plafond. The importance of the mechanical axis is generally accepted in orthopedic surgery. In cases of implantation of total ankle replacements the normal biomechanics need to be restored in order to have a correct and pain-free functioning total ankle replacement both in the short and long-term. The two most important criteria are (1) an anterior tibio-talar angle of about 90° and (2) a neutral hindfoot position. The hindfoot position is measured with the hindfoot alignment view according to Saltzman. In this view, healthy feet are in neutral or minimal varus position of 1-2° and not in a valgus position as generally assumed. The following operative steps are performed depending on the degree and localization of the valgus deformity: (1) total ankle replacement, (2) supramalleolar or (3) inframalleolar osteotomy/arthrodesis, (4) medial ligament repair, (5) fibula osteotomy and (6) syndesmotic reconstruction.

[Femoroacetabular impingement of the hip in sports - a review for sports physicians]. / Femoroacetabuläres Impingement der Hüfte beim Sportler - ein Review für Sportärzte.

Recently the relevance of femoroacetabular impingement as a cause of hip and groin pain in sportsmen has been recognized. The entity often poses diagnostic and therapeutic problems to the sports physician. The patients go through an odyssey of different diagnostic and therapeutic modalities before the correct diagnosis is made and an adequate therapy is implemented. Not seldom, patients get even operated at another site which is thought to cause the problems. The present review analyzes the current literature concerning diagnostic standards and therapy of femoroacetabular impingement focussing on their relevance for sports medicine. It is aimed to help the sports physician to recognise this entity as a cause for groin and hip pain in the athlete and realise its importance for the short term performance of the athlete and its long term significance in terms of development of early hip osteoarthrosis.

Polarization analysis in soft X-ray diffraction to study magnetic and orbital ordering.

An experimental approach to the analysis of charge, magnetic and orbital ordering in 3d transition-metal oxides is presented. The technique combines two important components: azimuthal rotations around the Bragg wavevector and polarization analysis of the Bragg intensities in the range 500-900 eV. The polarization analysis is performed using graded multilayers, which are translated and rotated in the vacuum chamber. It is shown why these two components are important to determine the origin of the Bragg scattered signals and how they allow us to separate the different contributions. Examples are given for the oxygen K and the Mn, Co, Ni and Cu L(2,3)-edges, and the advantages and drawbacks of this experimental technique are discussed.

[The HINTEGRA ankle: short- and mid-term results]. / Die HINTEGRA-sprunggelenkprothese: kurz- und mittelfristige erfahrungen.

The HINTEGRA ankle was developed as an attempt to specifically address the needs of minimal bone resection, extended bone support, proper ligament balancing, and minimal contact stresses within and around the prosthesis. The purpose of this article was to present the design and rationale of this prosthesis, and to analyze the clinical and radiological short- to mid-term results particularly with respect to the revisions and learning curve. Of the 278 total ankle replacements (between 2000 and 2004) with the HINTEGRA ankle, 271 ankles [patients: 261, males: 133, females: 128, age: 58.4 years (range: 25-90 years)] were clinically and radiographically assessed after 36.1 months (range: 12-64 months). The preoperative diagnosis was post-traumatic osteoarthrosis in 206 cases (76.0%), systemic arthritis in 34 cases (12.5%), and a primary osteoarthrosis in 31 cases (11.5%). Beside 4 perioperative and 19 early postoperative complications, a late complication occurred in 40 cases (14.8%). Of these, 22 complications (8.2%) were not related to implants, and 18 complications (6.6%) were related to implants. In all, 39 cases (14.4%) were revised; of these, 5 cases (1.8%) were revised to ankle arthrodesis. All other 34 revision arthroplasties were successful and did not evidence any differences in the outcome to the non-revised ankles. The AOFAS hindfoot score improved from 40.3 (range: 14-61) to 85.0 (range: 44-100) points at last follow-up. Radiographically, the tibial component was stable in all remaining 266 ankles, and no tilting of the component occurred since surgery. The talar component was positioned too posteriorly in 12 ankles (4.4%). The concept of minimal bone resection and wide bony support was shown to be successful on the tibial and talar sides. Most complications occurred in the early cases of this series, and the learning curve was found to be short and steep. Despite the high amount of post-traumatic cases with limited soft tissue quality, the obtained function, pain relief, and patient satisfaction were promising and, compared with other devices, the results mostly were superior. This may support the belief that anatomically shaped surfaces, as is the case in the HINTEGRA ankle, may advance success in total ankle replacement.

In vivo and in vitro induction of MxA protein in peripheral blood mononuclear cells from patients chronically infected with hepatitis C virus.

To test whether (HCV) persistence is related to interferon (IFN) hyporesponsiveness, peripheral blood monuclear cells from 29 patients and 11 controls were studied for MxA protein expression. In vitro, only IFN-alpha (P<.001) and interleukin-2 (P<.05) induced MxA protein expression above unstimulated levels. Forty patients were treated with IFN-alpha2b. Patients showed higher basal levels of MxA protein (P<.02) and 2',5'-oligoadenylate synthase (2-5A) activity (P<.05) than controls. During therapy, MxA protein levels (P<.001) and 2-5A activity (P<.05) increased; after 1 month, MxA levels remained high, whereas 2-5A activity declined to initial levels. Increases in MxA were inversely correlated with decreases in serum alanine aminotransferase levels, and MxA induction was greater among virological responders. Thus, the IFN system seems to be activated in chronic HCV infection, but HCV appears to modulate these two components of the IFN system differentially. These results suggest that an inefficient response may contribute to virus persistence and affect the therapeutic outcome.

Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Chronic hepatitis B treatment has been significantly improved by interferon (IFN) treatment. However, some studies have suggested that hepatitis B virus (HBV) might have a direct effect on the resistance to IFN. Defective particles, generated by spliced HBV RNA and associated with chronic hepatitis B, have been previously characterized; expression of these particles leads to cytoplasmic accumulation of the capsid protein. The aim of this study was to investigate the role of these defective genomes in IFN resistance. The global antiviral activity of IFN was studied by virus yield reduction assays, the expression of three IFN-induced antiviral proteins was analysed by Western blotting and confocal microscopy, and the regulation of MxA gene expression was studied by Northern blotting and the luciferase assay, in Huh7 cells transfected with a complete or the defective HBV genome. Results showed that the expression of the defective genome reduces the antiviral activity of IFN and that this modulation involves a selective inhibition of MxA protein induction by the HBV capsid protein. Our results also show the trans-suppressive effect of the HBV capsid on the MxA promoter, which might participate in this phenomenon. In conclusion, this study shows a direct interplay between the IFN-sensitive pathway and the capsid protein and might implicate this defective HBV genome in virus persistence.

Transcriptional activation of CYP2C, MxA and Fas in sudden infant death syndrome.

The expression of cytochrome P4502C has been shown to be upregulated in sudden infant death syndrome (SIDS) and could be linked to viral infection through the release of interferon alpha and interleukins. MxA is a reliable marker of IFNalpha release and its level was significantly enhanced in SIDS reflecting the release of IFNalpha in response to viral infection. Similarly, the concentration of Fas protein was increased in SIDS (2.6x control) and indicated a stimulation of the Fas gene expression. Accumulation of MxA and Fas proteins were visible in liver and to a lesser extent in lung and kidney. The amount of RNA encoding CYP2C9 (4.4x control), 2C8 (2.5x) and 2C18 (2.3x) was markedly higher in SIDS than in age-matched children and would suggest a transcriptional activation of CYP2C gene expression. Finally, CYP2C genes were shown to be adjacent to two IFN-inducible genes (IFI54 and IFI56) on chromosome 10. We conclude that in SIDS a viral infection leads to the release of IFNalpha which could activate a battery of IFN-inducible genes. This might modify the chromatin structure and facilitate the accessibility to promoter/regulatory sequences of CYP2C and Fas genes close to IFN-inducible gene on chromosome 10.

The proximal interferon-stimulated response elements are essential for interferon responsiveness: a promoter analysis of the antiviral MxA gene.

Interferon (IFN)-inducible human MxA protein mediates resistance against influenza and several other RNA viruses. The MxA gene is under the control of type I IFN and, in certain cell types, is also directly activated by viruses. Here we show that in human macrophages, MxA mRNA levels are upregulated by very low doses of IFN-alpha in a dose-dependent manner. A similar, albeit much weaker, dose-dependent induction was seen with IFN-gamma. The induction was rapid and independent of protein synthesis. Interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) did not influence MxA mRNA levels alone or in combination with IFNs, in spite of the presence of putative response elements of these cytokines in the MxA promoter. We show that the promoter of the MxA gene contains two functional IFN-stimulated response elements (ISRE) near the transcription start site and one homologous ISRE-like element, which is apparently nonfunctional, further upstream. The two proximal ISRE sites are essential for IFN-alpha-induced transcription and appear to be binding sites for IFN-stimulated gene factor 3 complex. In addition, EMSA and DNAse I footprinting analysis demonstrated that Spl binds with high affinity to a region encompassing nucleotides -25 and -50 and, thus, may provide means of interaction with the basal transcriptional machinery.

W/C, W/Ti, Ni/Ti, and Ni/V Multilayers for the Soft-X-ray Range: Experimental Investigation with Synchrotron Radiation.

An experimental investigation of W/C, W/Ti, Ni/Ti, and Ni/V multilayers is presented that uses synchrotron radiation in the soft-x-ray energy region between 100 and 1500 eV with special emphasison the water window. The multilayers were designed as normal incidence reflectors and for polarimetry purposes around the Brewster angle. Both reflection and transmission multilayers were prepared for use as linear polarizers and phase retarders, respectively, to produce or analyze circularly polarized light. Their period was optimized to achieve maximum reflectance at the 1s absorption edge of C (284 eV) and the 2p edges of Ti (454 eV) and V (512 eV), respectively. At these edges the multilayers show an enhancement of reflectance and energy resolution that is in accordance with theoretical calculations.

Impaired interferon induction of human MxA protein in chronic hepatitis B virus infection.

MxA protein is interferon inducible, and its role as an antiviral mediator is being studied in various viral diseases. Several cytokines, including type 1 interferons (alpha and beta), interleukins 2 and 12, and granulocyte, macrophage, and granulocyte-macrophage colony-stimulating factors, were tested for their ability to induce human MxA protein synthesis in peripheral blood mononuclear cells from 15 chronic hepatitis B virus-infected patients and 6 healthy subjects as controls. Constitutive MxA expression was scarce in patients and controls but increased significantly in response to type I interferons. MxA responsiveness to interferon alpha was diminished significantly in chronic hepatitis B patients, compared with healthy donors (P < 0.05); this effect was more marked in patients with high viremia levels. Interleukins 2 and 12, and none of the colony-stimulating factors tested, induced low, but detectable, MxA protein levels. These results indicate that chronic infection by hepatitis B virus may impair activation of the immune cells and their capacity to respond to type 1 interferons.

The unglycosylated extracellular domain of type-II receptor for transforming growth factor-beta. A novel assay for characterizing ligand affinity and specificity.

The activation of the human transforming growth factor (TGF-beta) system begins with the cytokine-induced association of the extracellular domains of two structurally related receptor subunits. To study the protein-protein interactions between TGF-beta and the ligand-specific receptor subunit, the extracellular domain of the human TGF-beta receptor type II (T beta R-II) has been expressed as an intracellular protein in insect cells using the baculovirus expression system. The cDNA construct was engineered to encode amino acids 24-159 (the signal sequence 1-23 was lacking) preceded by one initiator methionine residue and six histidine residues added at the carboxy terminus. The soluble receptor accumulated in the cytoplasm of infected cells and was purified by one-step nickel-chelate affinity chromatography. The purified protein was not glycosylated; it migrated as a single band of apparent mass 19.5 kDa in SDS/polyacrylamide gels, and had a homogeneous N-terminal sequence. We have established a solid-phase binding assay using radioiodinated TGF-beta 3 and capture antibodies to immobilize the soluble receptor. In this assay, the apparent dissociation constant of the TGF-beta type-II receptor ectodomain for TGF-beta 3 was approximately 150 nM (this value is approximately 1000-fold higher than that of the cell-membrane receptor complex of living cells). The affinity of TGF-beta 3 for the unglycosylated ectodomain of T beta R-II from insect cells was lower than the affinity for the recombinant glycosylated ectodomain T beta R-II from mouse cells. The novel assay has been used to characterize affinities and specificities of TGF-beta 3, TGF-beta 2, corresponding mutants and hybrid proteins, as well as a related protein, BMP-2. The assay could also be used to search for inhibitors.

Treatment strategies for early-stage chronic lymphocytic leukemia: can interferon-inducible MxA protein and tumor necrosis factor play a role as predictive markers for response to interferon therapy?

The potential benefit of interferon (IFN)-alpha therapy in early-stage B cell chronic lymphocytic leukemia (B-CLL) patients is still under discussion, and no assays are available to distinguish potential responders from nonresponders. Herein we analyzed the usefulness of serum tumor necrosis factor (TNF, a cytokine released by CLL cells) and MxA protein (an intracellular marker for biologic activity of endogenous IFN) concentrations as predictive measurements for evolution and response to IFN therapy in early-stage CLL patients. TNF levels and MxA expression were determined at diagnosis in 21 CLL patients. A statistically significant correlation was found between low TNF levels and MxA expression and between high TNF levels and no measurable MxA expression. The patients were then randomized to receive IFN-alpha or no therapy and were evaluated for response and evolution. When response to IFN-alpha therapy was considered, it became apparent that early-stage CLL patients with higher TNF levels and no measurable MxA expression were more likely to benefit from IFN therapy, whereas those patients with lower TNF levels and MxA expression could be considered CLL candidates for longer survival without therapy. More patients have to be tested to strengthen the value of MxA expression and TNF concentrations for subsequent response to IFN-alpha therapy.

Ligand-induced dimerization of the extracellular domain of the TGF-beta receptor type II.

Transforming growth factor-beta (TGF-beta) signals by mediating the association of two distinct transmembrane serine/threonine kinase receptors, the type I (T beta RI) and II (T beta RII). Here, we took advantage of recombinant human T beta RII extracellular domain (T beta RII-ED) to analyze TGF-beta/T beta RII complex formation which is the initial event in the construction of a signaling complex. We found that recombinant T beta RII-ED binds TGF-beta 3 more efficiently than TGF-beta 2 and therefore maintains the native T beta RII binding selectivity for the different TGF-beta isoforms. Biochemical analysis showed that free T beta RII-ED is expressed as a monomer. Upon ligand binding, both TGF-beta 3 and -beta 2 isoforms induce homodimerization of T beta RII-ED, each TGF-beta subunit being able to bind one T beta RII-ED molecule. These results suggested that ligand dependent receptor dimerization may be an important early step in the TGF-beta signaling complex formation.

Interferons, Mx genes, and resistance to influenza virus.

Human influenza is primarily an infection of the upper respiratory tract and central airways. The interferon (IFN) system appears to have a role in limiting viral spread and initiating recovery before the development of T-cell and B-cell responses in primary infection. All cellular responses to IFNs result from interaction with cell surface receptors that trigger the expression of a number of cellular genes. Among the IFN-inducible gene products, the Mx proteins have attracted much attention because they have potential activity against influenza virus and possibly against other viruses. Mx proteins are guanosine triphosphate (GTP)-binding proteins with intrinsic GTPase activity. They seem to act indirectly against viruses by modifying cellular functions needed along the viral replication pathway. In mice the Mx1 protein has been shown to be necessary and sufficient to protect against influenza virus infection because the resistance does not require a functioning immune system. In humans the MxA protein has antiviral activities against influenza viruses. The MxA protein is encoded on the distal part of the long arm of chromosome 21 together with several other proteins implicated in the IFN system. Patients with Down's syndrome (trisomy 21) have an increased expression of MxA protein, and their cells display an increased sensitivity to IFNs in vitro because of gene dosage effects. These patients, however, are more susceptible to upper respiratory infection than normal individuals. This susceptibility has been related to deficiencies in the immune system. Therefore, induction of MxA in man does not sem sufficient to prevent influenza spreading, and, in contrast to the murine Mx system, a functioning immune system is necessary for protection.

Interferon-alpha hybrids.

The alpha-interferons (IFN-alpha) belong to a family of polypeptides comprising several subtypes. Using recombinant DNA technology, it has been possible to create IFN hybrids that provide novel combinations of the amino acid residues from the parental protein sequences. They have been used to study structure-activity relationships of IFN-alpha and interactions with the IFN-alpha receptor, and to create analogs of natural IFNs with novel properties for potential therapeutic application. The biological data obtained with these hybrids are now evaluated in terms of the published structural and homology models of IFN-beta and -alpha.

Interferon-alpha-induced biologic modifications in patients with chronic myelogenous leukemia.

Serum neopterin (Np), beta 2-microglobulin (beta 2-M), and 2',5'-adenylate (2',5'A) levels and intracellular 2',5'A and human Mx (Hu-Mx) protein synthesis were measured in 20-24 chronic myeloid leukemia patients before and during 1 year of IFN-alpha treatment and in a further 8-9 patients before and at the end of the first and second treatment weeks only. Univariate analysis showed that IFN-alpha increased Np and 2',5'A serum levels and intracellular concentrations of 2',5'A and Hu-Mx significantly from the end of the first week to month 12 of therapy. The biologic marker profiles were similar in cytogenetic responders and nonresponders, as well as in patients treated with IFN-alpha early (< 12 months from diagnosis) or late (after > 12 months standard chemotherapy). Further, there were no differences in the short-term (first 14 days) or long-term (during 12 month therapy) induction of the biologic markers irrespective of whether IFN-alpha 2a or IFN-alpha 2b was given. Because multivariate analysis revealed no significant interactions between cytogenetic response, time to treatment, and type of IFN-alpha used, increments in intracellular 2',5'A and Hu-Mx protein were similar at all study times for all factor combinations tested. Np levels varied significantly only during the first 14 therapy days; changes in serum 2',5'A were never statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)