[Conservative treatment of atraumatic femoral head necrosis]. / Konservative Therapie der atraumatischen Hüftkopfnekrose.

BACKGROUND: Femoral head necrosis is a progressive disease that can progress within a relatively short time. Therefore, an early and clear diagnosis including stage classification and treatment is necessary to prevent or delay the onset of the femoral head and joint destruction. TREATMENT: In addition to the identification of possible risk factors and treatment, the question of the available treatment options arises. The present article deals with conservative treatment options and presents the published results in the sense of the currently available evidence and against the background of the S3 guideline on atraumatic femoral head necrosis. The results of physical therapy, drug therapy (iloprost and bisphosphonates ), electrotherapy, shockwave therapy, etc. are presented. In the early stages of femoral head necrosis with low expansion, alendronate gives positive results. Iloprost is also a successful conservative treatment option in the early stages of atraumatic femoral head necrosis (ARCO I and II). In stages ARCO III and IV, Ilomedin is no longer indicated. Anticoagulants, such as enoxaparin, have demonstrated an arthroprotective effect.

[Prevalence, comorbidity and interdisciplinary treatment of rheumatoid arthritis - Insurance data on outpatient and inpatient care in Baden-Württemberg]. / Prävalenz, Komorbidität und interdisziplinäre Versorgung der Rheumatoiden Arthritis ­ Versicherungsdaten zur ambulanten und stationären Versorgung in Baden-Württemberg.

BACKGROUND: Rheumatoid arthritis (RA) has an increased number of comorbidities compared with the general population. OBJECTIVE: Study aim was to collect epidemiological data on prevalence, incidence and comorbidities of RA as well as utilization of outpatient and inpatient care services. MATERIAL AND METHODS: In an age and gender-adjusted case control study, a total of 3.4 million patients insured by the AOK Baden-Württemberg were analysed with respect to visits to physicians, prevalence, incidence and comorbidities of RA. The study was based on out- and inpatient diagnoses from 2013. RESULTS: The RA prevalence was 0.64% (n = 26,919), the incidence was 0.04%. Patients with RA have significant more comorbidities in almost all diagnosis groups, especially in musculoskeletal and cardiovascular diseases, compared to a control group (n = 181,209). 22.8% of RA patients had not contacted an internist rheumatologist, orthopedist or orthopedic surgeon. Biological disease-modifying anti-rheumatic drugs (DMARDs) were almost exclusively prescribed by internist rheumatologists, while conventional DMARDs were equally prescribed by general practitioners and rheumatologists. Of the RA patients 32.6% were hospitalized at least once a year and were nearly twice as frequently inpatient as the control group. CONCLUSION: RA patients need more in- and outpatient healthcare services and suffer significantly more often from comorbidities. The general practitioner is the most frequently visited physician. Other consulted physicians are rheumatologists, ophthalmologists, orthopedists/orthopedic surgeons and internists not specialized in rheumatology. The study highlights the need to create consensus treatment algorithms and maintain a close interdisciplinary and intersectoral cooperation and communication.

[Incidence of knee injuries : Numbers for outpatient and inpatient care in Germany]. / Inzidenz von Kniegelenkverletzungen : Zahlen für die ambulante und stationäre Versorgung in Deutschland.

BACKGROUND: Musculoskeletal illnesses and injuries are among the most common ailments in the Federal Republic of Germany. In 2008 they generated costs of nearly 29 billion euros. Figures about their incidence and prevalence are necessary for a demand-oriented planning of future patient-centred care. METHOD: Pseudonymised data of 3.8 million people insured by AOK Baden-Württemberg between 2008 and 2013 were evaluated. The diagnoses were assigned to nine injury groups. For outpatient care confirmed diagnoses were considered, and for inpatient care both primary and secondary diagnoses were considered. For all patients with structural knee injuries, it was evaluated whether they made use of one of five eligible treatment paradigms either in the quarter in which they were injured or in the following quarter. RESULTS: 418,257 patients were treated in 2013 for at least one new-onset injury (10.9 % of all insurees); 86,783 insurees (2.3 % of all insurees) had a newly occurring knee injury. The vast majority of the patients were treated by specialist doctors. While magnetic resonance imaging clearly increased during the observation period, the incidence of surgical therapy did not change. Striking are the different age distributions regarding the types of injuries, with a high injury incidence amongst young men and a significant increase in injuries between 2008 and 2013, especially amongst women. CONCLUSION: For the first time, the data quantify the knee injury incidences of a large cohort in Germany. They show which inpatient and outpatient health care services have been claimed and that an age- and gender-adapted prevention and an increased awareness are needed.

Culture of chondrocytes in alginate gel: variations in conditions of gelation influence the structure of the alginate gel, and the arrangement and morphology of proliferating chondrocytes.

Sodium alginate, which gels in the presence of calcium ions, is commonly used for culture of anchorage-independent cells, such as chondrocytes. Normally, the gel appears microscopically homogeneous but, depending on the conditions of gelation, it may contain a varying number of small channels that extend inward from the surface. We have examined the influence of these channels on the morphology of cultured chondrocytes entrapped in alginate beads. Growth-plate or articular chondrocytes cultured in alginate normally proliferate and form rounded cell clusters but, in alginate beads containing numerous channels, many chondrocytes become aligned and form columns similar to those in the growth plate in vivo. As the pattern of cellular growth and morphology in alginate is profoundly influenced by the presence of channels in the gel, further studies were conducted to determine what specific conditions of gelation affect their formation. The channels are especially numerous when both the alginate and the gelling solutions lack sodium ions or other monovalent cations. The channels are cavities in the gel formed by particulate blocking of the rapid diffusion of calcium ions from the gelling solution into the boundary of the calcium alginate solution, and hence they extend inward from cells at the surface of the alginate gel. An understanding of the conditions under which these channels develop makes it possible either to avoid their formation or, alternatively, to enhance the number of channels in order to encourage proliferating cells to grow in radial columns, rather than in a less organized pattern characteristic of most culture systems.

Expression of membrane type 1 matrix metalloproteinase in human articular cartilage.

OBJECTIVE: To detect the message for membrane type 1 (MT1) matrix metalloproteinase (MMP) in articular cartilage and chondrosarcoma cells, to study its expression in osteoarthritis (OA), and to determine whether interleukin-1beta (IL-1beta) influences its expression. METHODS: Reverse transcription-polymerase chain reaction methods were used to detect message. Cloning and sequencing were applied to confirm the sequence. Northern blotting was used to quantify the message for MT1-MMP and to compare its expression in OA cartilage with or without IL-1beta treatment. In situ hybridization was utilized to show MT1-MMP transcripts in cartilage and to study the influence of IL-1beta. RESULTS: The results show that MT1-MMP messenger RNA (mRNA) is expressed in chondrosarcoma cells and OA chondrocytes. Results of the in situ hybridization confirmed the expression in OA cartilage as well as in normal cartilage. The level of mRNA was not modulated following IL-1beta stimulation. CONCLUSION: This study shows that MT1-MMP is expressed by chondrocytes. The similarities in mRNA levels in OA and normal chondrocytes suggest that regulation of MT1-MMP mRNA may not be a primary factor in OA.

Complexity of IL-1 beta induced gene expression pattern in human articular chondrocytes.

The mRNA fingerprinting technique, differential display reverse transcription polymerase chain (DDRT-PCR), was used to detect changes in the overall pattern of gene expression in human articular knee chondrocytes-induced by interleukin-1 beta (IL-1 beta), the prototypical inducer of catabolic responses in degenerate joint diseases. One hundred different primer combinations generated approximately 10,000 different PCR fragments for IL-1 beta treated, as well as for untreated human chondrocytes, cultivated in alginate beads. This represented 53% of all expressed chondrocyte genes as based on statistical considerations. Side by side comparisons of differential display patterns originating from two different donor tissues yielded 44 reproducibly, differentially-displayed cDNA fragments, which were subcloned and sequenced. Sequence homology searches revealed sequence identities to the human necrosis factor alpha (TNF-alpha) and IL-1 regulated gene TSG-6, fibronectin, osteopontin, calnexin, and the DNA repair enzyme ERCC5. The differential expression was confirmed with Northern and quantitative PCR analyses. The known function of these genes and their known IL-1 responsiveness indicate that the employed model system reflects the pleiotropic effects of IL-1 on the overall gene expression in human articular chondrocytes and identifies genes involved in very different biochemical pathways. Twenty-seven cDNAs lacked sequence homologies to known genes and may represent novel genes.

Effects of recombinant human osteogenic protein 1 on the production of proteoglycan, prostaglandin E2, and interleukin-1 receptor antagonist by human articular chondrocytes cultured in the presence of interleukin-1beta.

OBJECTIVE: Recombinant human osteogenic protein 1 (OP-1) is an effective stimulator of human cartilage 35S-proteoglycan synthesis. The present study was conducted to determine whether stimulation of human articular chondrocytes with OP-1 can help overcome interleukin-1beta (IL-1beta)-induced suppression of 35S-proteoglycan synthesis. METHODS: Human articular chondrocytes in alginate beads were maintained for 3 days in the absence (control) or presence of IL-1beta at 0.1-100 pg/ml with or without OP-1 at 50 ng/ml, in medium containing 10% fetal bovine serum (FBS). Incorporation of 35S-sulfate into proteoglycans was quantified during the last 4 hours of culture and reported as counts per minute per microg DNA. Release of interleukin-1 receptor antagonist (IL-1Ra) and prostaglandin E2 into the medium was monitored by immunoassay. RESULTS: IL-1beta at 10 pg/ml caused a 60% decrease in 35S-proteoglycan synthesis. This could be blocked by including 500 ng/ml IL-1Ra in the medium. The presence of 50 ng/ml OP-1 in the IL-1beta-containing medium was effective in restoring 35S-proteoglycan synthesis to the level of that found in cultures not treated with IL-1beta. The restorative effects of OP-1 and IL-1Ra were cumulative. The rate of release of prostaglandin E2 and IL-1Ra into the medium was not affected by the presence of OP-1. CONCLUSION: Treatment of human articular chondrocytes with OP-1 cultured in the presence of FBS is effective in overcoming the down-regulation of proteoglycan synthesis induced by low doses of IL-1beta.

Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes.

OBJECTIVE: To study the effects of recombinant human osteogenic protein-1 (rHuOP-1; bone morphogenetic protein-7) on proteoglycan and collagen synthesis by human articular chondrocytes. METHODS: Articular chondrocytes from fetal, adolescent, and adult human donors were cultured in alginate beads for 4 days in a mixture of Ham's F-12, Dulbecco's modified Eagle's medium, 10% fetal bovine serum (FBS), then for an additional 3-10 days in the presence and absence of rHuOP-1, with and without FBS. Chondrocyte synthetic activity was measured as the amount of incorporation of 35S-sulfate into proteoglycans and 3H-proline into hydroxyproline. Sieve chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were performed to identify specific proteoglycans and collagens. RESULTS: Recombinant human OP-1 markedly stimulated the synthesis of proteoglycans (mostly aggrecan) and collagens (predominantly type II) by all chondrocyte preparations. This did not require the presence of FBS and was associated with continued expression of the chondrocyte phenotype. CONCLUSION: Recombinant human OP-1 is a more potent stimulator of the synthesis of cartilage-specific molecules by human articular chondrocytes than are other factors tested for comparison, including TGF beta 1 and activin A.

[Do calcium and zinc ions influence matrix molecule synthesis of chondrocytes?]. / Haben Kalzium- und Zinkionen einen Einfluss auf die Matrixmolekülsynthese von Chondrozyten?

The experiments described here tested the effect of various calcium (Ca) and Zinc (Zn) concentrations on cell proliferation and matrix molecule synthesis of fetal and adult bovine chondrocytes in monolayer cultures. Levels of Ca < 0.2 mM in a culture medium or the addition of Zn (0.1-50 microM) selectively promoted the production of collagen but did not affect significantly synthesis of proteoglycans. No change in proliferation of fetal and adult chondrocytes could be observed. In contrast 10 mM Ca promoted the hypertrophic differentiation of chondrocytes (e.g. expression of collagen type X). The results are related to calcium channel configurations in chondrocytes in the discussion.

The superficial layer of human articular cartilage is more susceptible to interleukin-1-induced damage than the deeper layers.

OBJECTIVE: To compare the responses of chondrocytes from superficial and deep layers of normal human articular cartilage to interleukin-1 (IL-1) and IL-1 receptor antagonist protein (IRAP), and to evaluate the binding sites for IL-1 on these cells. METHODS: Cartilage and chondrocytes from superficial and deeper layers of human femoral condyles were cultured with and without IL-1 in the presence and absence of IRAP. The effect of these agents on 35S- proteoglycan synthesis and catabolism and production of stromelysin and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by biochemical and immunologic assays. Receptor binding was evaluated using 125I-labeled IL-1. RESULTS: IL-1 induced more severe inhibition of proteoglycan synthesis and a lower ratio of secreted TIMP-l:stromelysin in chondrocytes from superficial cartilage than those from deeper cartilage. IRAP blocked responses to IL-1 more effectively in chondrocytes from deep cartilage than those from superficial cartilage. Chondrocytes from the articular surface showed approximately twice the number of high-affinity b!nding sites for IL-1 as did cells from deep cartilage. CONCLUSION: Chondrocytes from the surface of articular cartilage show a greater vulnerability to the harmful effects of IL-1 and are less responsive to the potential therapeutic effects of IRAP than cells in the deeper layers of the tissue.

Collagen and proteoglycan production by bovine fetal and adult chondrocytes under low levels of calcium and zinc ions.

The experiments described herein tested the effects of CaCl2 and ZnCl2, added at various concentrations in the culture medium, upon the synthesis of collagen and proteoglycan by adult and fetal (articular, epiphyseal and hypertrophic) bovine chondrocytes maintained in high density multilayer cultures. CaCl2 concentrations below 0.5 mM or the addition of 1-50 microM ZnCl2 to the medium selectively promoted the production of collagen by all four populations of chondrocytes but had no effect on fibroblasts. Further, these changes had no statistically significant effect on the incorporation of 35S-sulfate into macromolecules or on the synthesis of gelatinase A, measured by gelatin zymography. The addition of CaCl2 and ZnCl2 at these concentrations did not result in a change in the relative proportion of non-crosslinked 3H-collagen molecules (synthesized in the presence of beta-aminopropionitrile) partitioning in the cell layer and medium compartments, and did not appreciably alter the pattern of collagens synthesized by any of the cell populations. The hypertrophic cells synthesized high levels of collagen type X in the presence as well as absence of exogenously added cations. However, CaCl2 at 10 mM caused a marked upregulation of collagen type X synthesis by a preparation of chondrocytes derived from the entire growth plate, consistent with the view that calcium at that concentration stimulated the differentiation of some of the cells into hypertrophic chondrocytes.

Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma.

An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATVs) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects, and 2-year survival rates. For vaccine preparation, the tumor-derived freshly isolated and cryopreserved cells were thawed, purified by Percoll density centrifugation, and depleted of tumor-infiltrating lymphocytes by immunomagnetic beads. After inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle disease virus (NDV) or they were admixed with Bacillus Calmette Guérin (BCG) organisms. Vaccination was performed in the arm beginning 6-8 weeks after operation, three times at 2-week intervals. Of 57 patients that received ASI, 48 were treated by virus-infected ATV (ATV-NDV) and 9 were treated with the BCG-admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions from ATV-NDV-treated patients was 18 mm for the first vaccination and 26 and 29 mm for the succeeding ones. Although the application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine led to long-lasting ulcers and to more serious side effects. The 2-year survival rate obtained with ATV-NDV was 97.9%, whereas the survival rate with ATV/BCG was 66.7%. The mean survival of 661 patients from a historical control was 73.8%. These data suggest that the type and quality of the tumor vaccine for ASI treatment is important. The findings with ATV-NDV necessitate corroboration in a prospective, randomized controlled study.

Resection for adenocarcinoma of the body and tail of the pancreas.

Adenocarcinoma of the pancreatic body and tail often presents late and is widely regarded as incurable by surgical resection; long-term survivors are rare. Thirteen patients underwent left resection (n = 7) or total pancreatectomy (n = 6) in a consecutive series of 105 patients with carcinoma of the body or tail of the pancreas. Comparison was made with 17 patients with locally advanced or metastatic disease. Preoperative computed tomography predicted irresectable disease when a large perivascular lymph node mass was demonstrated. Preoperative angiography predicted irresectable disease when there was encasement or obliteration of the coeliac axis or its major branches, or of the superior mesenteric artery or vein. Splenic vessel involvement was sometimes compatible with resection. After resection, median survival was 13 (range 3-50) months, with a minimum follow-up of 2 years. Five patients survived more than 2 years, and three are still alive 30, 43 and 50 months after resection. Resection of carcinoma of the body or tail of the pancreas was possible in 12 per cent of patients and long-term survival was observed in some of these.

[Are pathohistological studies helpful in the clinical differential diagnosis of chronic arthritis?]. / Ist die pathohistologische Untersuchung bei der klinischen Differentialdiagnose chronischer Arthritiden hilfreich?

We have evaluated the diagnostic and therapeutic consequences of histopathological examinations of knee synovium from 216 patients with chronic arthropathies. We were able to differentiate between non-rheumatic etiologies, such as tuberculous arthritis, villonodular synovitis, crystal arthropathies and chondromatosis. This resulted in the establishment of a diagnosis and often a guide to therapy as well. It is rarely possible however to conclusively differentiate among the different inflammatory rheumatic diseases or osteo-arthroses by the histopathology of the joint lesions seen.