Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure.

CD18 integrins are adhesion molecules expressed on the cell surface of leukocytes and play a central role in the molecular mechanisms supporting leukocyte migration to zones of inflammation. Recently, it was discovered that CD11a/CD18 is shed from the leukocyte surface in models of inflammation. In this study, we show that shedding of human CD11/CD18 complexes is a part of synovial inflammation in rheumatoid arthritis and spondyloarthritis but not in osteoarthritis. In vivo and in vitro data suggest that the shedding is driven by TNF-α, which links the process to central events in the inflammatory response. The shed complexes contain multiple heterodimers of CD11/CD18, are variable in size, and differ according to the type of synovial inflammation. Furthermore, the differential structures determine the avidity of binding of the complexes to the ICAM-1. With the estimated concentrations of CD11/CD18 in plasma and synovial fluid a significant coverage of binding sites in ICAM-1 for CD18 integrins is expected. Based on cell adhesion experiments in vitro, we hypothesize that the large soluble complexes of CD11/CD18 act in vivo to buffer leukocyte adhesion by competing with the membrane-bound receptors for ICAM-1 binding sites. As reported here for synovial inflammation changes in the concentration or structure of these complexes should be considered as likely contributors to disease activity.

Acupuncture for a patient with whiplash-type injury.

A 69 year-old woman presented in the surgery because of a whiplash-type injury. Because of progressive headache and dizziness since the accident, and because she had developed rhinitis and intermittent flashes of the left visual field, she was admitted to the neurological department on suspicion of subdural haematoma and possible fracture of the skull. Neurological examination and a CT scan were normal and she was discharged. Because of persisting headaches, and dizziness, her own general practitioner decided to use acupuncture treatment. Acupuncture was given at points GB20 GB21 and SI16 bilaterally and directly over the site in the forehead, where she fell. After 6 weeks treatment, the dizziness disappeared, and after two additional treatments the rhinitis and headache disappeared. At follow-up 6 months after cessation of treatment, the patient had only intermittent dizziness, with no headaches, visual disturbances or rhinitis.

Temporomandibular dysfunction can contribute to aggravation of tension-type headache: a case report.

A 15-year-old girl, who had had occasional tension-type headache, developed, rather suddenly and without any obvious reason, severe headache. She was admitted to hospital, where examination including CT and magnetic resonance scans did not show any abnormality. A visit to her own general practitioner 7 months later showed tenderness in the muscle of mastication. The patient was referred to a dentist, who diagnosed temporomandibular dysfunction and tension-type headache. After three acupuncture treatments, the patient was without headache and remained free of headache during the following 6 months.

Long-term trends in the incidence of type 1 diabetes in Denmark: the seasonal variation changes over time.

There is a worldwide increase of type 1 diabetes mellitus (T1DM). In 1996, the Danish population-based registry was initiated including all newly diagnosed children aged 0-15 yr. This is the report of incidence and seasonal variation for the first 10 yr of the registry. The data was analyzed using Poisson's regression analysis. A total of 2166 children with diabetes were diagnosed before the age of 15 yr between 1996 and 2005. In this period, the annual increase in childhood T1DM was 3.43% (95% confidence interval: 1.91-4.97), which was unaffected by age and gender. Seasonal variation in incidence rates varied by year but not by age and gender. In conclusion, there is a steep increase in incidence of childhood T1DM in Denmark; the increase is comparable with the increase seen in other European countries. There is a significant seasonal variation that changes on a year-to-year basis. The observed variations in cadence rates may be associated with viral epidemics, sunshine exposure, or vitamin D levels and suggest further exploration of these relations.

A description of children and adolescents in Danish chiropractic practice: results from a nationwide survey.

OBJECTIVE: The purpose of this study was to describe Danish chiropractic patients younger than 18 years. METHODS: Questionnaires were mailed to all chiropractic clinics in Denmark during a randomly assigned month between September 2007 and September 2008. All patients younger than 18 years or their parents were asked to complete a questionnaire collecting information on age, presenting complaint, duration and consequences of this complaint, referral mode, and use of pain medication. RESULTS: Babies were the most common pediatric patients with about one third being between 0 and 4 months of age. Infantile colic was the most common presenting complaint in this age group. For the older children, musculoskeletal problems were the most dominant complaint, ranging from 33% among the preschool children to 75% among the teenagers. These complaints were often chronic and about a third of the children older than 2 years had experienced symptoms for more than 1 year before seeing the chiropractor. These health complaints were reported to restrict activity as well as alter mood, and 39% of the 2- to 17-year olds used analgesics. There was limited referral of patients from other health care professionals. CONCLUSIONS: Babies made up most of the Danish chiropractic patients younger than 18 years. Among the older children and the adolescents, musculoskeletal complaints were most common and mostly of a chronic nature. The large number of pediatric patients in chiropractic practices and the paucity of evidence of treatment effectiveness indicate the need for further research in these age groups.

The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy.

The purpose of this study was to analyze the expression of the two proinflammatory cytokines IL-20 and IL-24 and their shared receptors in rheumatoid arthritis and spondyloarthropathy. IL-20 was increased in plasma of rheumatoid arthritis patients compared with osteoarthritis patients and IL-24 was increased in synovial fluid and plasma of rheumatoid arthritis and spondyloarthropathy patients compared with osteoarthritis patients. IL-20 and IL-24 mRNA was only present at low levels in the synovium. In the synovial membrane, IL-20 protein was present in mononuclear cells and neutrophil granulocytes whereas IL-24 protein was observed in endothelial cells and mononuclear cells. IL-20 receptor type 1 and IL-22 receptor were expressed by granulocytes in the synovial fluid. In synovial fluid mononuclear cell cultures, stimulation with recombinant human IL-20 or recombinant human IL-24 induced monocyte chemoattractant protein 1 (CCL2/MCP-1) secretion, but not tumour necrosis factor alpha mRNA synthesis or IL-6 secretion. Both IL-20 and IL-24 showed correlations to CCL2/MCP-1 in plasma from rheumatoid arthritis and spondyloarthropathy patients. This study associates IL-20 and IL-24 to the synovium of rheumatoid arthritis and spondyloarthropathy and results indicate that the two cytokines contribute to disease pathogenesis through recruitment of neutrophil granulocytes and induction of CCL2/MCP-1.

Good clinical practice is now obligatory in academic clinical drug research in the European Union.

By May 2004, all clinical trials in the European Union (EU) on medicinal products have to be initiated and conducted in compliance with the principles in the new directive on Good Clinical Practice (GCP). This requirement will also apply to non-commercial trials involving registered drugs and may therefore restrain the academic clinical drug research. In Denmark, three public GCP units connected in a national network and associated with the university hospitals in Copenhagen, Odense and Aarhus have been established. The GCP units offer academic researchers the necessary quality assurance and quality control systems to ensure that clinical drug research can be performed according to GCP. The Danish initiative is presented here as a contribution to the future work with implementation of the principles of GCP in academic clinical drug research in the European Union.

[Public GCP unit--experiences from the Aarhus University Hospital]. / GCP i offentligt regi--erfaringer fra Arhus Universitetshospital.

According to the EU GCP-directive, all clinical trials involving medical products must adhere to the GCP-standards by May 2004. This may entail difficulties for investigator-initiated trials not sponsored by the industry. A public GCP-unit was established at Aarhus University Hospital in 1995. The unit offers researchers a monitoring system including discussion of the protocol, check of formalities, and verification of data and protocol compliance. As a contribution to the future work with GCP, experience from the GCP-unit at Aarhus University Hospital is presented here.

[Simplification of procedures for clinical drug trials in the EU is coming up]. / Forenkling af procedurer for klinisk lægemiddelforskning i EU på vej.

A proposal for a new regulation on clinical trials that will replace the Clinical Trials Directive has been launched by the EU Commission the 17 July 2012. The proposal contains ideas that undoubtedly will lead to a greater harmonisation within the EU, a more smooth approval procedure, and a lowering of the administrative burden. Details are still to be discussed, and waiting until 2016 when the new rules are adopted is definitely a problem, but all together the new proposal is to be regarded as good news for clinical drug research.

Human retinal pigment epithelial cells inhibit proliferation and IL2R expression of activated T cells.

The purpose of this study was to characterize the effects of human retinal pigment epithelial (RPE) cells on activated T cells. Activated T cells were cocultured with adult and foetal human RPE cells whereafter apoptosis and proliferation were determined by flow cytometry and (3)H-Thymidine incorporation assay, respectively. T cells and RPE cells were cultured directly together or in a transwell system for determination of the effect of cell contact. The importance of cell surface molecules was examined by application of a panel of blocking antibodies (CD2, CD18, CD40, CD40L, CD54, CD58) in addition to use of TCR negative T cell lines. The expression of IL2R-alpha -beta and -gamma chains of activated T cells was analysed by flow cytometry after incubation of T cells alone or with RPE cells. Human RPE cells were found to inhibit the proliferation of activated T cells by a cell contact-dependent mechanism. The RPE cells inhibitory abilities were not affected by blocking of any of the tested surface molecules. The inhibition of the T cells' proliferation correlates with a decreased expression of IL2R-beta and -gamma chains. The T cells regain their ability to proliferate and increase their IL2R-beta and -gamma chain expression within 24 hr after removal from the coculture. It is concluded that the cultured human adult and foetal RPE cells inhibit the proliferation of activated T cells by a process that does not involve apoptosis. It depends on cell contact but the involved surface molecules were not revealed. The proliferation inhibition correlates with a modulation of the T cells' expression of IL2R, and is reversible.