Type 2 diabetes is associated with the accumulation of senescent T cells.

Type 2 diabetes is a global health priority, given that it is driven, in part, by an ageing population, the role of immune senescence has been overlooked. This is surprising, as the functional impairments of senescent T cells show strong similarities to patients with hyperglycaemia. Immune senescence is typified by alterations in T cell memory, such as the accumulation of highly differentiated end-stage memory T cells, as well as a constitutive low-grade inflammation, which drives further immune differentiation. We show here in a preliminary study that people living with type 2 diabetes have a higher circulating volume of senescent T cells accompanied with a higher level of systemic inflammation. This inflammatory environment drives the expression of a unique array of chemokine receptors on senescent T cells, most notably C-X-C motif chemokine receptor type 2. However, this increased expression of migratory markers does not translate to improved extravasation owing to a lack of glucose uptake by the T cells. Our results therefore demonstrate that the presence of senescent T cells has a detrimental impact on immune function during type 2 diabetes.

Clinical medical sciences for undergraduate dental students in the United Kingdom and Ireland - a curriculum.

The technical aspects of dentistry need to be practised with insight into the spectrum of human diseases and illnesses and how these impact upon individuals and society. Application of this insight is critical to decision-making related to the planning and delivery of safe and appropriate patient-centred healthcare tailored to the needs of the individual. Provision for the necessary training is included in undergraduate programmes, but in the United Kingdom and Ireland there is considerable variation between centres without common outcomes. In 2009 representatives from 17 undergraduate dental schools in the United Kingdom and Ireland agreed to move towards a common, shared approach to meet their own immediate needs and that might also be of value to others in keeping with the Bologna Process. To provide a clear identity the term 'Clinical Medical Sciences in Dentistry' was agreed in preference to other names such as 'Human Disease' or 'Medicine and Surgery'. The group was challenged to define consensus outcomes. Contemporary dental education documents informed, but did not drive the process. The consensus curriculum for undergraduate Clinical Medical Sciences in Dentistry teaching agreed by the participating centres is reported. Many of the issues are generic and it includes elements that are likely to be applicable to others. This document will act as a focus for a more unified approach to the outcomes required by graduates of the participating centres and act as a catalyst for future developments that ultimately aim to enhance the quality of patient care.

Health-related quality of life, smoking and carotid atherosclerosis in white British women with systemic lupus erythematosus.

We tested the hypothesis that carotid atherosclerosis in systemic lupus erythematosus (SLE) is associated with poor health-related quality of life (HRQOL), which is independent of any association with traditional risk factors (TRFs), lifestyle and socioeconomic factors. Women with SLE completed the RAND Medical Outcome Study 36-Item Short-Form Health Survey version 1 (MOS SF-36). B-mode Doppler examination of the carotid arteries determined the presence of atherosclerotic plaque. The association between carotid plaque and HRQOL domains was analysed using logistic regression models with sequential adjustments for age, TRFs, education level and employment status. We studied 181 women, 47 (26%) of whom had carotid plaque. Carotid plaque was significantly associated with lower levels of physical functioning (p = 0.047), vitality (p = 0.04), role emotional (p = 0.04) and mental health subscales (p = 0.01) and lower mental component summary score (MCS) (p = 0.03). These associations were no longer significant after adjustment for age and TRFs, especially smoking. Smokers had lower physical functioning, vitality and mental health and more bodily pain. The association between carotid plaque and HRQOL was not independent of TRFs and smoking was a key mediator of the associations found. Poor HRQOL in smokers will need addressing as part of any smoking cessation strategies in SLE patients.

Subclinical atherosclerosis in systemic lupus erythematosus (SLE): the relative contribution of classic risk factors and the lupus phenotype.

OBJECTIVES: We aimed to examine the strength of association between traditional cardiovascular risk factors and carotid plaque development in systemic lupus erythematosus (SLE) patients and controls. We also aimed to determine which lupus-related factors are associated with carotid plaque and whether SLE sensitizes patients to the effects of traditional factors. METHODS: We studied 200 women with SLE and 100 controls. Demographic and risk factor data were collected and SLE features, including autoantibody profiles and therapy were noted. All subjects had B- mode ultrasound of their carotid arteries examined for the presence and distribution of plaque. RESULTS: SLE patients <55 years old had more plaque (21% vs 3% P < 0.01) and more SLE patients had plaque in the internal carotid artery (11% vs 4%; P < 0.05). Traditional risk factor models performed less well in SLE compared with controls [area under Receiver Operator Characteristic curves (AUC ROC) = 0.76 vs 0.90; P < 0.01]. A multivariable model using SLE factors only, performed significantly better (AUC ROC = 0.87; P < 0.01). The final model in SLE included age and cigarette pack-years smoking as well as azathioprine exposure ever, antiphospholipid antibodies (APLA) and previous arterial events (AUC ROC = 0.88). CONCLUSIONS: SLE patients have a higher prevalence and different distribution of carotid plaque than controls. SLE factors perform significantly better than traditional risk factors in their association with atherosclerosis in SLE and these factors add to the influence of traditional risk factors rather than sensitizing lupus patients to traditional factors. The SLE phenotype helps identify patients at increased risk of atherosclerosis.

The role of fear of physical movement and activity in chronic fatigue syndrome.

OBJECTIVE: To examine beliefs in relation to avoidance of activity in chronic fatigue syndrome (CFS) patients. METHODS: The first phase consisted of modifying an existing chronic pain measure of kinesiophobia-fear of physical movement and activity-and validating it on the CFS population [Tampa Scale of Kinesiophobia-Fatigue (TSK-F); n=129; test-retest: r=.89, P<.001; alpha=.68]. Subscales of Illness Beliefs (alpha=.78) and Beliefs about Activity (alpha=.70) were identified. The second phase consisted of evaluating whether behavioural persistence was predicted by the TSK-F (n=33). Participants were asked to ride an exercise bike for as long as they felt able. RESULTS: Analyses indicated that behavioural persistence did not correlate with maximal heart rate or resting heart rate, level of tiredness, symptom severity, illness identity or emotional distress. However, the TSK-F did correlate highly with distance travelled and added a significant 15% of the variance in distance after adjustments for gender and physical functioning (PF). The TSK-F Beliefs about Activity subscale appears to be the predictive factor, explaining 12% of the variance in excise performance or rather 12% of the avoidance of exercise. CONCLUSION: Beliefs about Activity appear to be an important variable in predicting behaviour and avoidance of exercise. As avoidance has been suggested as a key to the maintenance of symptoms, disability and distress in CFS patients, this research has important theoretical, clinical and research implications.

Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis.

The aim of this study was to determine the comparative efficacy and safety of intra-articular (i/a) triamcinolone. hexacetonide (TH) and i/a hyaluronic acid (HA) in inflammatory knee osteoarthritis. A randomized double-blind comparative trail was carried out in a rheumatology outpatient department. There were 63 patients (24 male, 39 female, mean age 70.5 years) with bilateral symptomatic knee osteoarthritis with effusion. Each was given five HA injections at weekly intervals; or 20 mg TH followed by four placebo (saline) injections. Patients were examined weekly during the treatment period and then at monthly intervals for a further 6 months. Assessment included recording of: visual analog scores (VAS) for pain; duration of stiffness; range of movement; joint effusion; local heat; synovial thickening; joint-line and periarticular tenderness. The principal outcome measure was pain on a self-selected activity assessed by Vas. The two groups were comparable at entry and no significant differences between the groups developed at any time during the treatment period. However, there was a high drop-out rate and intention to treat analysis failed to demonstrate statistically significant differences between the groups. In patients remaining in the study, significantly less pain was experienced by the HA group during the 6 month follow-up period. Other parameters showed a similar trend in favor of experienced by the HA group during the 6 month follow-up period. Other parameters showed a similar trend in favor of HA. We could not, however, demonstrate significant differences between the placebo and active treatments. HA may therefore be a useful additional therapy for symptomatic knee osteoarthritis and may have a long duration of action.

Association of radiographic changes of osteoarthritis, symptoms, and synovial fluid particles in 300 knees.

Associations between compartmental distribution of radiographic changes of osteoarthritis (OA), individual features of OA (joint space loss, sclerosis, cyst, osteophyte; each scored 0-3), and presence of synovial fluid calcium particles (calcium pyrophosphate dihydrate (CPPD) crystals identified by polarised light microscopy and other calcium particles by alizarin red positivity (ARP) were sought in 300 osteoarthritic knees (178 patients; mean age 72, range 33-96 years). Patients whose knees were symptom free as well as those with symptoms were included. Osteoarthritis of two or three compartments but not unicompartmental OA was associated with the presence of CPPD or ARP. Involvement of any compartment (not just patellofemoral), and higher mean scores for both total and individual osteoarthritis changes (except cysts) was associated with CPPD and ARP; CPPD, but not ARP, was associated with symptoms: knees reported as having symptoms had higher mean total OA scores. Femoral cortical erosion, found more often in women, was associated with higher mean total OA score at the patellofemoral compartment but not with the presence of particles. Attrition, remodelling, and chondrocalcinosis (each scored as present or absent) occurred more often in knees with CPPD. Age did not correlate with any aspect of the OA score. This study confirms the association of calcium particles with the process of OA. Unlike previous studies confined to symptomatic knees, a radiographic pattern specific to CPPD ('pyrophosphate arthropathy') did not emerge.

Chlormezanone in primary fibromyalgia syndrome: a double blind placebo controlled study.

Primary fibromyalgia syndrome (PFS) is a common condition that often proves resistant to health interventions. Chlormezanone combines corrective effects on disturbed sleep with muscle-relaxant properties, and therefore could be of potential benefit in PFS. Forty-two female patients with PFS (mean age 49, range 24-72 years) were randomly and blindly allocated either chlormezanone 400 mg nocte or placebo. Patients were assessed by single observer at 0, 3 and 6 weeks of treatment; assessments included sleep quality, inactivity and morning stiffness, morning alertness, tender point score, mood change and global opinion (patient and observer). No beneficial therapeutic effect could be attributed to chlormezanone. Although there are problems in assessing severity of a predominantly subjective condition, this essentially negative finding is of interest in respect to the pathogenesis of PFS.

High-performance liquid chromatographic determination of naproxen, ibuprofen and diclofenac in plasma and synovial fluid in man.

High-performance liquid chromatographic assay procedures have been developed for naproxen, ibuprofen and diclofenac in human plasma and synovial fluid samples. A single liquid-liquid extraction procedure was used to isolate each compound from acidified biological matrix prior to the quantitative analysis. A Spherisorb ODS column (12.5 cm x 4.6 mm I.D.) was used for all the chromatography. Naproxen was eluted with a mobile phase of methanol-Sörensen's buffer at pH 7 (37:63, v/v). Ibuprofen and diclofenac were eluted using mobile phases of methanol-water at pH 3.3 (65:35, v/v and 63:37, v/v, respectively). Diphenylacetic acid was used as the internal standard for the assay of naproxen and flurbiprofen was used in the analysis of ibuprofen and diclofenac. Inter- and intra-day coefficients of variation were less than 7%. The assays were used in clinical studies of the three drugs in osteo- and rheumatoid arthritis patients.

Tophaceous pyrophosphate deposition with extensor tendon rupture.

Tophaceous deposition of calcium pyrophosphate dihydrate (CPPD) crystals is considered unusual as is deposition within tendon sheaths. Associated tendon rupture is described but is rare. We report a lady with tophaceous CPPD deposition at the wrist, a previously unreported site. Contrary to previous cases, this occurred in the setting of symptomatic, polyarticular, pyrophosphate arthropathy. An additional point of interest was development of associated extensor tendon rupture with features favouring a non-inflammatory mechanism of tendon damage.

Evaluation of a method for clinically assessing osteoarthritis of the knee.

A system for assessing symptoms (pain, stiffness, gelling) and signs (local temperature, effusion, tenderness, synovial swelling, popliteal cyst, crepitus) of osteoarthritis of the knee has been developed. The system has been assessed for intra- and interobserver variation using normal and osteoarthritic knees. Intraobserver variability is low for all indices but interobserver variability is high for physical signs. It is suggested that the components within this system, when applied by a single observer, may provide a reasonable framework for clinical assessment of osteoarthritis of the knee.

Absence of autoimmunity to type II collagen in generalised nodal osteoarthritis.

A cardinal feature of generalised nodal osteoarthritis is the loss of articular cartilage. To determine if autoimmunity to these cartilage collagens occurred, serum antibodies to native and denatured type II collagen were measured by enzyme linked immunosorbent assay (ELISA) in 96 patients (90 women, six men, aged 47-91 years) with generalised nodal osteoarthritis. Generalised nodal osteoarthritis was diagnosed by typical clinical and radiological features. Serum samples from 42 blood donors were assayed as controls. No significant difference was found between the patients with generalised nodal osteoarthritis and the controls. Furthermore, the 20 patients who were HLA-A1, B8 positive had similar antibody levels to the group as a whole. One woman patient with generalised nodal osteoarthritis (HLA-A1, B8 negative) had markedly increased antibody levels to native and denatured type II collagen in a pattern similar to that seen in patients with rheumatoid arthritis. This patient did not develop super added rheumatoid arthritis during a three year follow up period. Autoimmunity to type II collagen is therefore rare in generalised nodal osteoarthritis. A lack of collagen antibodies in a condition characterised by hyaline cartilage loss suggests that the presence of such antibodies in rheumatoid arthritis is more than a secondary event to joint damage.

A limited association of generalized osteoarthritis with alleles at the type II collagen locus: COL2A1.

A significant genetic influence in osteoarthritis has been observed in the combination of Heberden's nodes and generalized osteoarthritis. We examined whether mutation in the gene encoding the major cartilage matrix protein type II collagen was responsible by comparing allele frequencies at the locus (COL2A1) in a group of 61 patients with nodal GOA with a control population and by analysing the COL2A1 genotypes of 21 affected sibling pairs. There were no significant allele differences but a slightly increased tendency over chance alone for affected siblings to have inherited the same COL2A1 alleles from their parents.

Inorganic pyrophosphate, nucleoside triphosphate pyrophosphatase, and cartilage fragments in normal human synovial fluid.

The association between calcium pyrophosphate dihydrate (CPPD) crystal deposition and ageing is unexplained. Levels of inorganic pyrophosphate (PPi) and activity of nucleoside triphosphate pyrophosphatase (NTPP) were estimated in synovial fluid from 91 asymptomatic normal knees, including five with isolated CPPD crystal deposition (70 subjects; median age 47, range 22-83 years). In non-crystal fluids, PPi levels and NTPP activities were low (median, interquartile range: 9.5, 7.6-12.3 microM, and 1, 0.4-2 microM/30 min/mg protein, respectively: n = 50) and a generalized increase with age was not demonstrated. Higher values for PPi and NTPP in all five subjects with isolated CPPD deposition supports involvement of altered PPi metabolism, unrelated to ageing per se, in crystal formation. Presumed cartilage fragments were identified by morphological characteristics in 70% of normal fluids: metachromatic staining and electron microscopy, undertaken in a limited number, supported identification of such particles as cartilage. This finding supports dynamic turnover of healthy matrix, and questions the usefulness of identification, without quantification, cartilage fragments as a measure of cartilage damage.

Synovial fluid pyrophosphate and nucleoside triphosphate pyrophosphatase: comparison between normal and diseased and between inflamed and non-inflamed joints.

Deposition of intra-articular calcium pyrophosphate is associated with both aging and arthropathy; increased concentrations of free pyrophosphate (PPi) may contribute to such deposition. Free pyrophosphate and nucleoside triphosphate pyrophosphatase (NTPase) were estimated in synovial fluids from 50 subjects with normal knees and from 44 patients with rheumatoid arthritis, 61 with pyrophosphate arthropathy, and 59 with osteoarthritis. For arthropathic knees clinically assessed inflammation was classified as active or inactive using a summated score of six clinical features. The order of PPi (mumol/l) and NTPase (mumol PPi/30 min/mg protein) was pyrophosphate arthropathy greater than osteoarthritis greater than rheumatoid arthritis (median PPi, NTPase respectively: for pyrophosphate arthropathy 15.9, 0.45; for osteoarthritis 9.3, 0.25; for rheumatoid arthritis 4.4, 0.18), with significant differences between all groups. In pyrophosphate arthropathy both PPi (mumol/l) and NTPase (mumol PPi/30 min/mg protein) were higher than normal (15.9, 0.45 v 8.6, 0.2 respectively), but findings in osteoarthritis did not differ from normal. The inflammatory state of the knee had a distinct but variable effect on synovial fluid findings in rheumatoid arthritis and pyrophosphate arthropathy, but not in osteoarthritis. There was no correlation of either PPi or NTPase with age, or between PPi and NTPase in any group. This study provides in vivo data for synovial fluid PPi and NTPase. It suggests that factors other than PPi need to be considered in a study of crystal associated arthropathy. Clinical inflammation, as well as diagnosis, is important in synovial fluid studies.