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Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling. DecryptM profiling of 31 cancer drugs in 13 cell lines demonstrates the broad applicability of the approach. The resulting 1.8 million dose-response curves are provided as an interactive molecular resource in ProteomicsDB.

We have used a mass spectrometry-based proteomic approach to compile an atlas of the thermal stability of 48,000 proteins across 13 species ranging from archaea to humans and covering melting temperatures of 30-90 °C. Protein sequence, composition and size affect thermal stability in prokaryotes and eukaryotic proteins show a nonlinear relationship between the degree of disordered protein structure and thermal stability. The data indicate that evolutionary conservation of protein complexes is reflected by similar thermal stability of their proteins, and we show examples in which genomic alterations can affect thermal stability. Proteins of the respiratory chain were found to be very stable in many organisms, and human mitochondria showed close to normal respiration at 46 °C. We also noted cell-type-specific effects that can affect protein stability or the efficacy of drugs. This meltome atlas broadly defines the proteome amenable to thermal profiling in biology and drug discovery and can be explored online at http://meltomeatlas.proteomics.wzw.tum.de:5003/ and http://www.proteomicsdb.org.

Background: There are case descriptions of pronounced peri-implant inflammatory reactions and necrosis in non-infectious knee joint replacements with metal-polyethylene pairing., Objectives: Due to the histopathological similarities to the dysfunctional metal-on-metal (MoM) hip joint replacement, MoM-like reactions in knee joint arthroplasty ("ARMD-KEP") are proposed and a histopathological comparison is made., Materials and Methods: This analysis evaluates five cases of "ARMD-KEP" using: (1) the SLIM consensus classification, (2) the particle algorithm, (3) the CD3 focus score and (4) the AVAL score. The comparison groups consist of 11 adverse cases of MoM hip and 20 cases of knee joint arthroplasty without adverse reaction., Results: The ARMD-KEP cases were identified as SLIM type VI. Their median ALVAL score was 10. The CD3 focus score confirmed an adverse reaction. Particle corrosion was found in two of five cases., Conclusions: This data indicates that, in rare cases, an adverse MoM-like reaction may be present in knee replacements, with inflammatory and immunological expression similar to that of the adverse MoM reaction in the hip. The pathomechanisms can be discussed as follows: (1) secondary metal-metal contact, (2) dysfunctional loading of the coupling mechanism and (3) corrosion of the metal components. Much like trunnionosis in the hip, the term "hingiosis" is proposed for corrosion phenomena in dysfunctional conditions of coupled knee endoprosthetic systems.

Because the blood-brain barrier (BBB) is an obstacle for drug-delivery, carrier systems such as polybutylcyanoacrylate (PBCA) nanoparticles (NPs) have been studied. Yet, little is known of how physiochemical features such as size, surfactants and surface charge influence BBB passage in vivo. We now used a rat model of in vivo imaging of the retina - which is brain tissue and can reflect the situation at the BBB - to study how size and surface charge determine NPs' ability to cross the blood-retina barrier (BRB). Interestingly, for poloxamer 188-modified, DEAE-dextran-stabilised, fluorescent PBCA NPs, decreasing the average zeta-size from 272 nm to 172 nm by centrifugation reduced the BRB passage of the NPs substantially. Varying the zeta potential within the narrow range of 0-15 mV by adding different amounts of stabiliser revealed that 0 mV and 15 mV were less desirable than 5 mV which facilitated the BRB passage. Moreover, whether the fluorescent marker was adsorbed or incorporated also influenced the transport into the retina tissue. Thus, minor changes in design of nano-carriers can alter physicochemical parameters such as size or zeta potential, thus substantially influencing NPs' biological distribution in vivo, possibly by interactions with blood constituents and peripheral organs.

Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even for highly expressed mRNAs, that few proteins show tissue-specific expression, that strong differences between mRNA and protein quantities within and across tissues exist and that protein expression is often more stable across tissues than that of transcripts. Only 238 of 9,848 amino acid variants found by exome sequencing could be confidently detected at the protein level showing that proteogenomics remains challenging, needs better computational methods and requires rigorous validation. Many uses of this resource can be envisaged including the study of gene/protein expression regulation and biomarker specificity evaluation., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2-fold. A reporter assay provided functional support for two novel UTR motifs, and an immobilized mRNA affinity competition-binding assay identified motif-specific bound proteins for one motif. Moreover, our integrative model led to a new metric of codon optimality that captures the effects of codon frequency on protein synthesis and degradation. Altogether, this study shows that a large fraction of PTR ratio variation in human tissues can be predicted from sequence, and it identifies many new candidate post-transcriptional regulatory elements., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Immunogenicity is a major problem during the development of biotherapeutics since it can lead to rapid clearance of the drug and adverse reactions. The challenge for biotherapeutic design is therefore to identify mutants of the protein sequence that minimize immunogenicity in a target population whilst retaining pharmaceutical activity and protein function. Current approaches are moderately successful in designing sequences with reduced immunogenicity, but do not account for the varying frequencies of different human leucocyte antigen alleles in a specific population and in addition, since many designs are non-functional, require costly experimental post-screening. Here, we report a new method for de-immunization design using multi-objective combinatorial optimization. The method simultaneously optimizes the likelihood of a functional protein sequence at the same time as minimizing its immunogenicity tailored to a target population. We bypass the need for three-dimensional protein structure or molecular simulations to identify functional designs by automatically generating sequences using probabilistic models that have been used previously for mutation effect prediction and structure prediction. As proof-of-principle we designed sequences of the C2 domain of Factor VIII and tested them experimentally, resulting in a good correlation with the predicted immunogenicity of our model.

Several different synthetic methods have been developed to fabricate tungsten oxide (WO(3)) nanostructures, but most of them require exotic reagents or are unsuitable for mass production. In this paper, we present a systematic investigation demonstrating that arc discharge is a fast and inexpensive synthesis method which can be used to produce high quality tungsten oxide nanostructures for NO(2) gas sensing measurements. The as-synthesized WO(3) nanostructures are characterized by x-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), finger-print Raman spectroscopy and proton induced x-ray emission (PIXE). The analysis shows that spheroidal-shaped monoclinic WO(3) crystal nanostructures were produced with an average diameter of 30 nm (range 10-100 nm) at an arc discharge current of 110 A and 300 Torr oxygen partial pressure. It is found that the morphology is controlled by the arc discharge parameters of current and oxygen partial pressure, e.g. a high arc discharge current combined with a low oxygen partial pressure results in small WO(3) nanostructures with improved conductivity. Sensors produced from the WO(3) nanostructures show a strong response to NO(2) gas at 325 °C. The ability to tune the morphology of the WO(3) nanostructures makes this method ideal for the fabrication of gas sensing materials.

We have developed a novel technique based on the selective desorption of an oxide film in order to grow ordered arrays of silicon carbide nanocrystals on a silicon surface. These nanocrystals form as a byproduct of void nucleation in the oxide during the high-temperature vacuum annealing of silicon, a process which normally produces a random distribution of nanocrystals across the silicon surface after its oxide layer has been fully desorbed. By the pre-deposition of a thin layer of excess silicon on the oxide surface through a patterned lithography mask, site-specific nucleation of voids in the silicon oxide can instead be achieved during the annealing step, leading to the growth of silicon carbide nanocrystals in regular patterns over the silicon surface.

The durability of endoprosthetic implants of the large joints has increased over the last decades. North American studies have shown a 10-year durability of 94% for prosthetic hip implants, and European studies have shown 10-year durabilities of 88-95%. Pathologists differentiate three etiological disease patterns for the"pathology of endoprosthetics" that lead to reduction of implant durability: 1) periprosthetic particle disease (aseptic loosening), 2) infection, and 3) arthrofibrosis. Four types of neosynovitis/periprosthetic membrane have been determined in a consensus classification: particle-induced type (type I), with a mean prosthesis durability (MPD) of 12 years; infectious type (type II), MPD 2.5 years; combined type (type III), MPD 4.2 years; and indeterminate type (type IV), MPD 5.5 years. There are three histopathologic degrees of arthrofibrosis; grade 1 always needs clinical information for diagnosis, whereas grades 2 and 3 are distinct histopathologic entities.

The diagnosis of infections in patients with arthritis and/or joint prostheses requires interdisciplinary cooperation and the use of up-to-date methods. Massive bacterial infection can be identified by bacterial culture, and minimal infection can be detected by molecular pathological methods. These processes include specific enrichment of bacterial and fungal DNA, amplification, and identification of the DNA by gel electrophoresis, sequencing techniques, and chip technologies.Anamnesis (enteral or urogenital infection), the clinical picture (oligoarthritis), and further parameters (e.g., HLA B27 status) are important for the diagnosis of reactive arthritis. In many cases of reactive arthritis, molecular methods allow detection of bacterial DNA or RNA in synovial fluid or tissue. Molecular pathological methods allow the fast and reliable differential diagnosis of granulomatous synovialitis without prior cultivation of bacteria or fungi. The development of new molecular pathological methods for detecting bacterial and fungal nucleic acids will increase diagnostic accuracy.

Histopathological assessment of synovial biopsies has an established value. The value for inflammatory joint diseases without standardized rating mechanisms was, however, unknown until recently. The exemplary use of the synovitis score in four cases all including recurrent bruises of the knee joint portrays its value for diagnosis and therapy. Usage of the score includes assessing the enlargement of the lining layer, cellular density of synovial stroma and leucocyte infiltration by giving each a score of 0-3 points and adding them. Presence of high-grade synovitis (>or=4 points) in all cases displayed the reason for the joint bruises within a primarily inflammatory, rheumatoid circle. In this report we show the broad variety of uses for the synovitis score dealing with cases of Lyme arthritis, rheumatoid arthritis, seronegative monarthritis and HLA-B27-positive peripheral arthritis.

Monostotic manifestation of fibrous dysplasia in the spine is exceedingly rare. We report the case of a 30 year-old woman suffering from slowly increasing low back pain. Radiologically a polycyclic, slightly gadolinium-enhancing, solitary lesion within the first lumbar vertebral body was detected. The lesion was removed and stabilized with bone marrow transplant. We describe the radiological and histopathological findings.

The objective of this study was to measure the resultant force in the human bone-patellar tendon-bone graft after reconstruction of the anterior cruciate ligament under various conditions in vitro. Seven fresh-frozen cadaver lower extremities were used. Force measurement was made with a quartz force transducer mounted in a specially designed load cell. The effect of passive extension movement, quadriceps pull, varus torque, and valgus torque on the resultant force in the ligament were investigated. Passive extension of the joint generated a rapid increase of force in the graft between 30 degrees and 0 degrees of flexion, reaching its maximum (128+/-25 N) at full extension. When quadriceps pull was applied to extend the joint, resultant force increased at 50 degrees of flexion and reached its maximum (219+/-25 N) at full extension. Additional resistance applied to the level of the ankle joint generated an additional load of the graft. Increase of forces in the ligament resulted from both varus and valgus applied moments.

Objective: To test whether a rigid or a flexible ankle orthosis affects postural sway in single-limb stance as quantified by stabilometry., Design: Crossover trial., Setting: University laboratory., Participants: Twenty-two athletes with functional ankle instability (consecutive sample of patients with recurrent ankle sprains but without mechanical instability) and 22 healthy athletes (control group of volunteers matched to age, height, weight, physical activity)., Interventions: Stabilometry in single-limb stance on a force platform. Participants were tested on each leg with and without a rigid or a flexible ankle orthosis. The order of test conditions was randomized., Main Outcome Measures: Sway velocities, sway pattern, and sway area as calculated from center of pressure movements. The two groups were compared by Mann-Whitney test, and the different orthoses within each group were compared by Wilcoxon test, paired samples (type I error 5%, Bonferroni adjustment)., Results: In athletes with functional ankle instability, both a rigid and a flexible ankle orthosis significantly reduced mediolateral sway velocity. A flexible ankle orthosis also changed sway pattern significantly, by reducing the percentage of linear movements of less than 5 degrees per .01 sec., Conclusions: In athletes with functional ankle instability, ankle orthoses reduce mediolateral sway velocity, possibly because of improved mediolateral proprioception.

The aim of this study was to examine whether color Doppler imaging can be used to assess vascular patency after use of pedicle pelvic bone grafts in the operative treatment of avascular necrosis of the femoral head. We performed color Doppler imaging and selective angiography in 10 consecutive patients (12 hip joints) treated for avascular necrosis of the femoral head. In comparison to angiographic results, nine patent and two occluded grafts were demonstrated correctly by color Doppler imaging. In one case, a graft confirmed as patent by angiography was not demonstrable by color Doppler imaging. Accuracy, sensitivity, and specificity of color Doppler imaging were high when compared to angiography as a standard. Color Doppler imaging is suited to evaluate vascular patency after use of vascularized pedicle bone grafts in the treatment of avascular necrosis of the femoral head.

Objective: A new 3-dimensional cell culture system was established to examine the invasion of rheumatoid synovial cells into cartilage., Methods: Synovial cells from 20 patients with rheumatoid arthritis (RA) and 15 patients with osteoarthritis (OA) were co-cultured as multicellular spheroids with cartilage fragments., Results: After 4 weeks the rheumatoid spheroids eroded the cartilage. The destruction of cartilage was supported by a high expression level of cathepsin D and matrix metalloproteinases. In contrast, the OA tissue showed attachment to the cartilage only., Conclusion: Our results indicate that spheroid/cartilage co-cultures seem to be a suitable in vitro model for the study of destructive cellular mechanisms that occur in RA.

In 20 patients with a fracture of femur or tibia 5.2 years after arthroplasty of knee the results of the operative treatment are presented. The results show that especially bone damaging diseases as rheumatoid arthritis, osteoporosis and the loosening of the endoprosthesis are favorable for the fracture during the follow-up. The conclusion of the investigation shows that in younger patients the external fixation by plates and screws is the preferential treatment, in elderly people or comminuted fracture an internal fixation, also in combination with an additional osteosynthesis, allows a fast mobilization. The number of observed complications is higher than in primary knee arthroplasty, the full weight bearing 1st delayed. The rate of further operations and unsatisfactory results is also higher being affected by the high mean age of the operated patients (73.4 years). The possible use of a total femur implant must be discussed critically because only an individual production can avoid further damage of the parts of the joint that were not concerned by the fracture.

The analysis of rearranged antibody-encoding genes from B cell foci in rheumatoid synovial tissue has characterized these cells as highly mutated memory B cells with a high proportion of members of the VH4 family. In order to characterize further the VH4 response in one patient, B cell-rich areas from different sections of synovial membrane (SM) were identified by CD20 staining, isolated by microdissection and pooled, in order to analyse highly enriched B cells without selection by in vitro culture procedures. From DNA of about 5 x 10(3) B cells rearranged VH genes were amplified by polymerase chain reaction (PCR) and cloned. Sequencing of 11 clones containing rearranged VH4 gene products revealed that seven were potentially functional, and all were mutated with 84-96% homology to known germ-line (gl) genes and VH4 gl genes amplified from the patient's genomic DNA. Analysis of the complementarity determining region (CDR) 3 revealed that two products represented members of one B cell clone which differed by five nucleotide changes. Three of the five mutations encoded amino acid replacements in CDRs indicating antigen-driven expansion of one specific clone. Additional analyses of 25 members of three B cell clones from isolated aggregates showing intraclonal diversity in one of three clones provided further evidence that antigen selection takes place in the SM. Overall, the pattern of mutations and the replacement to silent (R:S) ratios were diverse, with six products indicating antigen selection by their high R:S ratios in CDRs. Although DNA analysis does not allow a characterization of antibody specificities, we can conclude from our analysis does not allow a characterization of antibody specificities, we can conclude from our analysis of antibody-encoding genes that selection by antigen and expansion of specific clones occur in the SM against the background of polyclonal activation.

In acute anterior cruciate ligament (ACL) lesions with effusion of the knee joint it is often difficult to realize a positive Lachman sign. It was suggested that the tension of the joint capsule may reduce tibial displacement although the ACL is completely disrupted. In 10 cadaver knee joints the ACL was dissected and the capsule was closed again. By a canula the knee joints were filled with isotonic saline solution in steps of 20 ml up to 100 ml. Before and after dissection of the ACL and during filling the joint we measured the anterior tibial displacement by use of the MEDmetric KT 1000 arthrometer. In a second series we examined 5 patients with acute effusion of the knee joint before and after puncture of the effusion. We detected the electromyographic activity of the quadriceps muscle end and the hamstrings during the KT 1000 test and patellar reflex. In the cadaver tests we found no reduction of the anterior tibial translation while filling the joint with saline solution. The electromyographic examinations showed a reflectory action in the quadriceps muscle and in the hamstrings when the Lachman test was performed. In the quadriceps muscle the electromyographic amplitude was reduced after puncture; the hamstrings showed a drastically reduced amplitude and duration of the signal. When patellar reflex was performed we recorded an electromyographic action in both muscle groups, too. Puncture could only reduce the signals of the hamstrings. Our results suggest that the reduction of the anterior drawer and the Lachman test in acute effusion is caused not mechanically by the tension of the capsule but by a reflectory muscle action of the hamstrings.

Objectives: To identify genes that are involved in the development and progression of rheumatoid arthritis (RA)., Methods: We used a multiple gene analysis system and a set of available genes participating in processes such as proliferation, differentiation, tumour progression, and metastasis, to identify their RA related expression. Synovial tissues from 22 patients with RA were evaluated in comparison with those from six patients with osteoarthritis and two patients with non-inflamed joints as controls, using northern blot and reverse transcriptase polymerase chain reaction experiments., Results: Our data confirm the role of c-fos and c-jun as constitutive signal transmitters in solid RA tissues, thus demonstrating the potential of the approach. Activation of both genes persisted through multiple passages of the cells in tissue cultures derived from the synovial lining of RA tissues. There was an increased expression of ets-2 in 30% of RA samples and an up to 30-fold decreased expression of the potential metastasis suppressor gene nm23-H1 in 90% of RA tissues, compared with control tissues., Conclusions: The data presented show for the first time a significant decrease of nm23-H1 expression in RA, which is possibly involved in local invasiveness, and a strong activation of the ets-2 nuclear oncogene in about one third of RA tissues, which may also be part of a pathway leading to advanced disease stages. The constitutive expression of c-fos and c-jun in RA tissue most probably results from a continuing inflammatory stimulus. These findings with cell cultures suggest an intrinsic activation mechanism of these early response genes in RA.

Fat embolism syndrome (FES) during implantation of an uncemented resurfacing type of total knee replacement is the leading cause of postoperative mortality. A possible explanation might be the insertion of a solid intramedullary alignment rod, resulting in an intrafemoral pressure increase. On 45 cadaveric human femora we measured the resulting intramedullary pressure during insertion of three different alignment rods: a solid rod and a hollow shaped guiding rod, both 10 mm in diameter, and a fluted alignment rod of 8.5 mm in diameter. The highest intramedullary pressures occurred after placement of a solid 10 mm alignment rod (3.77 +/- 0.44 bar), followed by a fluted 8.5 mm rod (2.53 +/- 0.28 bar). In both cases, the increased pressure led to an extrusion of bone marrow contents through the venous system of the proximal femur. The least increase occurred after insertion of a hollow shaped alignment rod (0.26 +/- 0.03 bar) without any fat extrusion. Our study confirms the hypothesis that insertion of solid intramedullary alignment rods during preparation of the femoral shaft results in a dangerous pressure increase, so that embolization can occur. To minimize the risk of a FES, instruments should be modified in a manner, that only hollow shaped alignment rods are used.

A comparison between intramedullary (n = 13) and extramedullary (n = 37) stabilization was performed in 50 patients (mean age 67.4 years) after fractures of the femoral shaft following knee or hip arthroplasty. Fracture of the femoral shaft (mean 5.5 years after the implantation) is observed especially often in patients with osteoporosis, loosening of the prosthesis, and rheumatoid arthritis. The ratio between cemented and uncemented endoprosthesis was 4:1. The investigation shows that extramedullary stabilization by means of plates and screws is the preferred treatment for younger patients and in the case of distal fractures, while in older people intramedullary fixation in combination with an additional osteosynthesis allows early mobilization. The number of complications observed is higher than with primary arthroplasty. The frequency of further operations, postoperative fractures and unsatisfactory results is significantly higher than in primary hip and knee surgery or uncomplicated fracture of the femur.

The activity of knee-related muscles was registered via exercising on a bicycle ergometer by 17 patients with clinically diagnosed chondropathia patellae. M. quadriceps activity was shorter and the hamstring activity longer in the chondropathy group compared with a matched healthy control group. The changes in m. quadriceps occurred to an almost equal extent in lateral and medial sections. In five patients with unilateral complaints, the electromyographic changes were nevertheless noted on both sides. The study shows that chondropathia patellae involves a change in muscle control affecting not only the knee extensors but also the hamstrings. Through the changed innervation pattern the coactivation phase, i.e. the phase of simultaneous activation of knee flexors and extensors at the end of the extension phase, takes place at a higher angle of flexion. Physiotherapy should involve all knee-related muscles and should include not only isometric but also dynamic exercises.

Mosaic trisomy of chromosome 7 is known to occur in a variety of non-neoplastic hyperproliferative disorders. In long-term cell cultures established from rheumatic synovium with mosaic trisomy 7, we observed a continuous increase in the proportion of cells with trisomy 7 to over 50% by the 10th in vitro passage. Simultaneous in situ hybridization with a repetitive chromosome-7-specific DNA probe and fluorescent Ki-67 labelling showed a strong correlation between trisomy 7 and an elevated proliferation index in cultured rheumatic synovial cells. Moreover, we observed a fraction of rapidly proliferating cells with up to eight copies of chromosome 7 as the sole cytogenetic change. Frequent somatic pairing of centromeres of two chromosomes 7 in interphase nuclei suggests either atypical non-disjunction with a persisting centromere or selective endoreduplication of chromosome 7.

Fifty-eight patients had a prospective follow-up examination 1 year after arthroscopic ACL replacement. Stability measurement was done using a KT-1000 arthrometer. The side-to-side difference was less than 2 mm in 40 patients, 2-4 mm in 11 patients and more than 4 mm in 7 patients. The position of the tibial and femoral tunnels and interference screw was measured from the postoperative X-ray. The positions of screws and tunnels were highly variable. However, there was no statistical correlation between the position of the femoral interference screw and stability measurement or between the position of the femoral interference screw and flexion contracture or between the position of the tibial interference screw and the extension contracture. However, out of six patients with the femoral tunnel in an extremely anterior position (> 20 mm anterior of the over the top position), only one patient had a stable joint (< 2 mm difference in KT 1000 with 89 N anterior shear load) at follow-up. A screw divergence of more than 10 degrees was found in 18 patients. A tibial interference screw with more than 30 degrees of divergence was seen in seven patients. The primary fixation strength of the bone block could be diminished in these cases. This may have an impact on the early rehabilitation protocol.

The objective was to study prevalence and underlying pathology of "swimmer's shoulder". Twenty-two competitive swimmers of national "D-Kader" (elite development swimmers) were evaluated by means of questionnaire, clinical examination and isokinetic testing of external rotation and internal rotation. At the examination current interfering pain necessitating a cessation or reduction of practice was found in 5 (23%) athletes. At isokinetic testing 8 (36%) athletes complained of shoulder pain. Any history of pain was seen in 14 (64%) swimmers. A positive impingement sign was noted in 11 (50%) athletes. Apprehension sign which is indicative of anterior instability was found in 11 (50%) swimmers. Clinical equivalents of dysfunction of scapulothoracic muscles such as scapular winging (5 athletes) and shoulder protraction (12 athletes) were noted. For comparison of results of isokinetic testing a control group of non-swimmers was selected matching the group of swimmers exactly in terms of age, sex and dominant side. External rotation/internal rotation ratio of peak torque and total work at 60 deg/sec and 180 deg/sec was significantly lower in swimmers than in controls. The ratio was independent of sex, dominant side, history of pain and pain at examination. During internal rotation competitive swimmers produced significantly higher peak torques and total work than controls. There was no significant difference in external rotation. In conclusion there are several different abnormalities of function contributing to the pathology of "swimmer's shoulder":--Laxity of anterior-inferior capsuloligamentous structures with atruamatic anterior instability due to repetitive overload.--Impingement with rotator cuff tendinitis.--Muscular imbalance of the rotator cuff muscles and scapulothoracic dysfunction.

The participation of the humoral immune system in rheumatoid arthritis (RA) is characterized by the production of rheumatoid factors (RF). RF are autoantibodies against the Fc part of IgG which are encoded by diverse germ-line genes. Most of the RF-encoding genes are unmutated, but in RA, a substantial quantity is encoded by somatically mutated genes. In addition, the synovial membranes (SM) of the diseased joints of RA patients are infiltrated by B lymphocytes which form germinal center-like aggregates. To analyze the local immune response, B cell foci from two RA SM were isolated by micromanipulation. From DNA of these foci, the rearranged kappa light chain variable region (V kappa) genes were amplified by polymerase chain reaction (PCR), cloned and sequenced. The amplification of different V kappa-J kappa combinations of different foci suggested oligoclonal expansion of B lymphocytes, which was confirmed by sequence analysis: each PCR product contained members of a single B cell clone. The sequence analysis of 29 different clones revealed rearrangements of diverse V kappa genes. Both frequent representatives of the V kappa 3 and the V kappa 1 family, as well as rarely used genes such as the L10 and B2 genes of the V kappa 2 and V kappa 5 families were found. Of the eleven potentially functional gene rearrangements, eight were significantly mutated, indicating their derivation from antigen-selected B cells. Intraclonal diversity in one of these clones may suggest ongoing mutation in the diseased synovial membrane of patients with RA.

It was suggested that the ACL has not only mechanical functions but also acts as proprioceptive organ. In cruciate deficient knees pathological patterns of muscle control were found. These findings could be caused by a disturbed afferent signal from the disrupted ACL or by secondary changes in muscle innervation, which shall protect the instable knee against subluxation. 33 patients with unilateral operative ACL repair (21 cases with primary suture, 12 cases with autogenous ligamentum-patellae-reconstruction; average post op 36.5 yr) were examined clinically and with the KT 1000 arthrometer (MEDMETRIC Inc.). Patients history was evaluated by using the LYSHOLM score. During a cycling task the electromyographic activity was monitored from the thigh muscles (M. vastus lat. and med., lat. and med. hamstrings). In comparison to the ACL deficient patients, we tested 25 healthy subjects of same age and activity level. In the ACL group the following differences to the normals were found: the M. vastus lat. showed a significantly delayed onset, earlier end and shorter duration. M. vastus med. had the same pattern; the delayed begin of activity and the shorter duration were statistically significant. M. biceps femoris showed a significant later onset and shorter duration. So did the medial hamstrings; the differences, however, were not statistically significant. There was no significant difference between operated and healthy leg in the ACL group. By comparing the primary sutures and the ligamentum-patellae-reconstructions no significant differences were found. The instable patients (KT 1000 > 3 mm) of the ACL group showed more distinct differences in the EMG pattern than the patients with stable knee joints.(ABSTRACT TRUNCATED AT 250 WORDS)

The object of this study was to find out whether an arthrotomy of the knee would damage joint proprioception. Twenty patients who underwent arthrotomy, and 20 patients after arthroscopy, were tested on a modified ergometer and the electromyographic action of their quadriceps and hamstrings recorded. The quadriceps action started later and had a shorter duration (20 ms) after arthrotomy. The differences are statistically significant in intra-individual comparison both for vastus lateralis and medialis, in comparison with the normal group for only the vastus medialis. There were no significant differences in muscle control after arthroscopy. These results are in favor of preferring arthroscopy to arthrotomy whenever possible.

The patellar tendon graft replacing the anterior cruciate ligament undergoes histomorphological and biomechanical changes. From literature we can estimate a force of 200 N to be a critical limit of graft load after ACL-plasty in humans. The comparison with the graft loads under various conditions provided the following conclusions: Unlimited passive motion of the knee joint can be done without risk. Early weight bearing is possible. Active extension exercise against gravity could damage the graft in the range of 0 to 20 degrees of flexion in some patients. A rehabilitation protocol has to regard these biomechanical principles. In a prospective study 74 patients underwent rehabilitation according to the protocol described. An extension contracture of more than 10 degrees was seen in 9 patients. In all cases it was due to a notch-impingement or a cyclops. One year after operation 57 patients had a follow up. The side to side-difference in anterior drawer measured with a KT-1000-arthrometer was less than 2 mm in 45 patients. Six patients had difference between 2 and 4 mm. In six patients the difference was more than 4 mm.

The objective of the study was to assess prospectively the percentage of patients with restricted range of motion (arthrofibrosis) after ACL-plasty and to assess the clinical benefit of arthroscopic surgery. We had arthrofibrosis in 9 out of 74 cases (12%). In 8 cases there was a combined lag of flexion and extension and in one case there was only a lag of extension. In all patients range of motion could be improved by arthroscopic surgery. There was a significant raise in extension (13.3 degrees) and in flexion (28.7 degrees). In the arthrofibrosis-group more patients had undergone surgery for acute ACL-rupture (66%) than in the group without arthrofibrosis (32%).

Fat embolism syndrome occurs in only 0.9-4% of patients with long bone fractures and especially with intramedullary nailing. Earlier publications have shown that intramedullary manipulation, e.g. reaming and nailing, can produce high pressures of up to 1 bar. The design of the new non-slotted interlocking compressions nails seems to increase the pressure in the femoral cavity. We measured the intramedullary pressure during reaming of the marrow cavity and insertion of compression nails (OSTEO), using cadaver femora and a piezo pressure transducer. We simulated a proximal fracture and performed 30 drilling and 20 nailing procedures. On average we detected a maximum pressure of 0.26 bar during drilling and 0.63 bar during nailing. During reaming the pressure increased when the reamer had passed the narrow diaphysis and reached the metaphysis. When the tried to enlarge the femoral canal by pushing and pulling the reamer repeatedly we measured high pressure peaks. During nailing we detected short impulses lasting a few milliseconds. The results show that the new compression nail do not produce higher intramedullary pressure than slotted nails. It is possible to avoid a dangerous pressure level by using a careful operative technique.

Avulsion fractures of the lateral tibial plateau, known as the lateral capsular sign, are increasingly associated with anterior cruciate ligament (ACL) ruptures. This phenomenon, known as the Ségond fracture, is a bony avulsion of the menisco-tibial ligament. Stress, which can lead to an avulsion of this kind, almost always occurs during knee flexion and internal tibial rotation, and in most cases only after damage to the primary ACL stabilizer. Examination of 151 ACL ruptures revealed a Ségond fracture in 9% of patients. Nearly all were caused by sports injuries and, understandably, the accident mechanism always included knee flexion and internal rotation of the tibial. In a similarly large number of other knee injuries without damage to the ACL, only one case of a Ségond fracture was found. This phenomenon, which is easy to detect by radiograph, can thus be regarded as a strong indication of the presence of a ligament injury.

Cytogenetic analysis of primary cell cultures and/or passages 1-3 of synovial tissue from seven patients with rheumatoid arthritis was performed. As the only recurrent chromosome aberration, trisomy 7 was found in six of seven cultures. In four cultures, trisomy 7 occurred as a clonal change in up to 20% of the analyzed cells, with an increase of the proportion of cells with +7 with the duration of the in vitro culture. Apart from this recurrent change, a variety of partly clonal, partly nonclonal numerical and structural chromosome aberrations were observed in all cases. These findings support the view that clonal chromosome aberrations may play a role in the pathogenesis of invasive growth of the synovial tissue in rheumatoid arthritis although the localized synovial hyperproliferation is not a true neoplastic process.

In normal cortical screws the thread must be cut by a separate thread-cutter. So a high stability of the connection is achieved. On the other hand thread cutting needs time, which may be assumed to several minutes during a plate osteosynthesis. To avoid thread-cutting, self-tapping screws were used 20 years ago. These old self-tapping screws had a reduced stability and a lower torque at the final screw driving so that they tended to destroy the thread. By a modification of the cutting edges at the tip of the screw the tapping quality is increased decisively. The microscopic examination showed a better cutting of the new screws with little difference to a thread-cutter. In biomechanical tests the final torque and the maximum tension force of the self-tapping screws were at the same level as in usual pre-cut screws. In the practical use the new self-tapping screws have a good handling and save time during operation. In osteoporosis, they should be used carefully in order to meet the opposite corticalis' hole and not to destroy the ipsilateral corticalis' thread.

Flat contact of the collar of the stem with the resection area of the femur in total hip replacement can often not be achieved even when the operation technique is very precise. Uneven bone patches or deviations in the resection angle lead to points of contact. If this contact area is localized to the lateral part of the collar, considerable varus torque acts on the prosthesis stem. By a simple modification, removal of the lateral area of the collar, medical bone - collar contact is achieved. It is independent from deviations in the operative procedure. In biomechanical experiments, drastic reduction in harmful torque was demonstrated by this modification. Thus, more "physiological" force transmission from the prosthesis to the bone can be expected.

A simple aid for reposition of spondylolisthesis with the Fixateur interne is presented. The modification consists of a metric thread, which is cut in the end of the SCHANZ screw, a fitting butterfly nut and a distance tube. This instrument allows a well-dosed and controlled extension and reposition of the dislocated vertebra in all planes. No other instruments or implants, which may hinder the operation, are necessary. After the reposition the bone graft may be inserted from ventral or from dorsal. The dorsal intercorporal spondylodesis saves time, means a lower trauma for the patient and has the possibility for interfragmental compression.

Various PMMA bone cements containing zirconium oxide (ZrO2) as an X-ray contrast medium and zirconium oxides of several manufacturers were tested for their radioactivity by means of a gamma spectrometer. All the bone cements tested (Implast, Palacos R, and Sulfix-6) showed a certain degree of radioactivity. The radiation source in the bone cement is the added zirconium oxide, which is polluted by radioactive elements. The examination of various zirconium oxides showed some high radioactive emissions. The risk of radiation-induced cancer seems to be small, because the cements are normally implanted in humans older than 60 years. In view of the fact that these X-ray contrast media remain in the body for decades as components of the bone cement, the radioactive zirconium oxides should be replaced by high-purity radiation-free zirconium oxide or barium sulphate as soon as possible.

In order to overcome the problems of stress protection and pressure atrophy of bone, which are associated with the traditional plating technique, in Poland a modified type of plating, ZESPOL has been, developed. In this procedure, the plate is not screwed onto the surface of the bone, but is fixed above the bone by special platform screw bolts in a comblike construction. This paper describes an experimental biomechanical investigation, using cadaver tibia, which compares the stability of the ZESPOL principle with that of the traditionally applied autocompression plate (ACP). In order to make the system biomechanically comparable, instead of the original ZESPOL plates, which are different in dimension, an ACP was used that was specially adapted to fit the ZESPOL criteria. Compared to the ACP, the bending stability of the ZESPOL osteosynthesis was found to be significantly less. When the same stress was applied, the total bending capacity of the ZESPOL system was found to be between 9% and 1348% higher, depending on the position of the plate and the direction of the force applied. In addition, the gap of the osteotomy site was between 6% and 923% greater with the ZESPOL system. Deformation of the bone adjacent to the osteotomy site was more closely approximate to intact bone with ACP than with ZESPOL plate. Our evaluations show that the ZESPOL system has less bending stability than ACP, without having the advantage of a more physiological bone-bending curve. However, the stability of the new system can be regarded as being overall sufficient.

In a comparative study the tissue reaction of several X-ray contrast materials was examined by subcutaneous and intraperitoneal application on rats. There were tested Bariumsulphate (BaSO4) and three Zircondioxyde (ZrO2) samples of several manufactures (cubic and monocline ZrO2-Feldmühle; Optipur-Merck). In the histologic evaluation no inflammatory signs could be seen. In case of BaSO4 the tissue reaction was more distinct than in the ZrO2 samples. Within the tested ZrO2 samples the differences were small; the cubic ZrO2 showed the slightest, the monocline one the relatively strongest cellular reaction. We also measured the radioactive emission by the contrast media. Here the monocline and--first of all--the cubic ZrO2 showed an alarming radioactive emission (radium 3000-11,500 Bq/kg). Only the Optipur (Merck) was free of radiation and can so be recommended for human implantation. Also the BaSO4 had no measurable radioactive Emission. Therefore only these two X-ray contrast media can be recommended for human implantation.

Creatine-Kinase-BB (CK-BB) is a brain specific enzyme, with a prognostic value for the patient's outcome after head-injury. We have investigated 76 brain injured patients and attempted to show a correlation of the concentrations of CK-BB and the Glasgow-Outcome-Scale (GOS). Patients with a CK-BB concentration of more than 50 ng/ml died. Patients, who had a CK-BB concentration less than 25 ng/ml showed only minimal neurological deficits. Intracerebral contusions and acute subdural haematomas showed the highest CK-BB concentration, indicating a high degree of braintissue-damage. CK-BB seems to have no correlation with the age of patients. Normalisation of elevated CK-BB levels do not correlate with recovery from neurological deficit.

The mechanical superiority of carbon fiber reinforced PMMA containing additional apatite was shown previously. For further improvement these carbon fibers were now submitted to a superficial oxidation treatment by HNO3. A closer contact between the carbon fibers and PMMA and even trabeculae-like adhesions were detected by Scanning Electron Microscopy. The fatigue strength of the carbon fiber reinforced bone cement could be increased at 17% by this oxidation treatment. This increase, however, is less than that observed in the case of other fiber reinforced composites. Most likely this is caused by the pronounced polymerisation contraction of PMMA. Further improvement of the adhesion of the fibers to cement may be achieved by different oxidation techniques, further extraction of foreign substances or graft polymerization of the carbon fibers by PMMA or other polymers.

Osteosynthesis with modern self-contracting plates has a few fundamental drawbacks apart from its undisputably good points. Among these drawbacks we have the pressure strain on the bone surface; the traction strain exercised by the screw thread in the bone; and, chiefly, spongiotisation and bone atrophy due to so-called stress protection. A new modification of this process, called Zespol, in which the plate is no longer fastened direct to the bone but is fastened floating over the bone surface to so-called platform screws, tries to solve these problems. In a comparative animal experiment tibial transverse osteotomies in the rabbit were treated by osteosynthesis using small fragmentary ACP and Zespol plates. In respect of healing of the fracture none of the two methods showed any advantage. Histological evaluation of the plated bone sections were characterised in both plate systems by increasing spongiotisation and bone atrophy that increased with the length of application. Degradation processes were about equal with both systems. A special feature with the Zespol animals was that the cleft originally existing between the plate and the bone was filled up with newly formed spongy and later cortical bone. Due to this process the original cortex layer lost its function and atrophied severely. After 12 to 18 weeks the bone surface had reached the lower side of the Zespol plate and there was contact by touch. This restored similar biomechanical conditions as those existing in conventional plates after this period.

Apart from the advantages of plate osteosynthesis, like primary bone healing and immediate post-operative mobilisation treatment, the disadvantages of this method must be mentioned. First of all these are the high pressure on the surface of the bone by the plate and the high tension stress on the bone by the thread of the screws, which can lead to bone atrophy. Besides the splinting by the plate is accompanied by a functional lack of the bone. The bone reacts on this "stress protection" by reduction of material, especially under the plate. These disadvantages shall be avoided by a new osteosynthesis system, called ZESPOL, which has been developed in Poland. Here the plate does not contact directly the bone, but is fixed above the periost by special screw bolts. Although this method is used in Poland clinically with success, until now no experimental examinations concerning the stability of this osteosynthesis have been published. In the following biomechanical tests we examined, whether the new method achieves a comparable interfragmental compression like common selfcompressing plate systems. We measured the maximal interfragmental compression with an interposed piezo-electric element on human cadaver tibiae. Because the original ZESPOL plates have greater dimensions than common plates, we did not use these original plates. In order to get a comparability between the two systems, we modified small Autocompression plates (ACP) by milling a slot in the underside, so that they could be used with the original ZESPOL screw bolts. These modified ZESPOL plates we compared with common 6-hole Autocompression plates and cortical screws.(ABSTRACT TRUNCATED AT 250 WORDS)

In oblique fractures of the shaft of the tibia, plate osteosynthesis is combined with an interfragmentary traction screw to enhance the stability. Depending on the position of the fracture, the screw is introduced separately or via a plate hole near to the fracture. The maximum resistance to bending and the plastic deformation of plate osteosyntheses were studied in the tibiae of human corpses, with or without traction screw; in some cases, pure traction screw osteosyntheses were used in this study. It was found that the additional traction screw enhanced the stability by 52%, whereas plastic deformation was markedly reduced. Furthermore, the traction screw more than doubled the rigidity of the osteosynthesis, facilitating early healing of the fracture. Theoretical considerations show that a traction screw will greatly reduce the harmful shear stress of the fracture and increase interfragmentary compression, depending on the direction of the screw. If the screw is introduced, as recommended by Danis, in the bisector of the angle between the perpendicular on the fracture fissure and the perpendicular on the bone axis, one obtains high interfragmentar compression and reduction of shear stress by one-half. If the traction screw progresses perpendicularly to the bone axis, however, interfragmentary compression will be less, whereas the shear forces are fully compensated. Hence, the procedure according to Danis is meaningful in low-tension plate osteosyntheses (e.g. neutralisation plates), whereas transverse positioning of the screw appears to yield more favourable results in osteosyntheses applied under high tension.