A systematic review of the association between food insecurity and behaviours related to caries development in adults and children in high-income countries.

OBJECTIVES: To synthesize and appraise the evidence regarding the relationship between food insecurity and behaviours associated with dental caries development in adults and children in high-income countries. METHODS: A systematic review including observational studies assessing the association between food insecurity and selected dietary (free sugar consumption) and non-dietary factors (tooth brushing frequency; use of fluoridated toothpaste; dental visiting; oral hygiene aids; type of toothbrush used; interdental cleaning frequency and mouthwash use) related to dental caries development in adults and children in high-income countries. Studies specifically looking at food insecurity during the COVID-19 pandemic were excluded. Searches were performed in MEDLINE, Embase, Global Health and Scopus from inception to 25 May 2023. Two authors screened the search results, extracted data and appraised the studies independently and in duplicate. Study quality was assessed using the Newcastle-Ottawa Scale (with modifications for cross-sectional studies). Vote counting and harvest plots provided the basis for evidence synthesis. RESULTS: Searches identified 880 references, which led to the inclusion of 71 studies with a total of 526 860 participants. The majority were cross-sectional studies, conducted in the USA and reported free sugar consumption. Evidence for the association between food insecurity and free sugar intake from 4 cohort studies and 61 cross-sectional studies including 336 585 participants was equivocal, particularly in the sugar-sweetened beverage (SSB) consumption post-hoc subgroup, where 20 out of 46 studies reported higher SSB consumption in food insecure individuals. There was consistent, but limited, evidence for reduced dental visiting in adults experiencing food insecurity compared to food secure adults from 3 cross-sectional studies including 52 173 participants. The relationship between food insecurity and dental visiting in children was less clear (3 cross-sectional studies, 138 102 participants). A single cross-sectional study of 3275 children reported an association between food insecurity and reported failure to toothbrush the previous day. CONCLUSIONS: This review did not identify clear associations between food insecurity and behaviours commonly implicated in the development of dental caries that would explain why individuals experiencing food insecurity are more likely to have dental caries than those who have food security. There was some evidence of decreased dental visiting in adults experiencing food insecurity. Common methodological weaknesses across the evidence base related to the selection of participants or control of potentially confounding variables. Consequently, the quality of evidence for all outcomes was downgraded to very low. More research is needed to explore access to oral hygiene products and household environments conducive to habitual oral self-care in food insecure populations.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

A multi-biomarker disease activity score can predict sustained remission in rheumatoid arthritis.

BACKGROUND: Reliable assessment of remission is important for the optimal management of rheumatoid arthritis (RA) patients. In this study, we used the multi-biomarker disease activity (MBDA) test to explore the role of biomarkers in predicting point remission and sustained remission. METHODS: RA patients on > 6 months stable therapy in stable low disease activity (DAS28-ESR ≤ 3.2) were assessed every 3 months for 1 year. Baseline, intermittent (IR) and sustained (SR) remission were defined by DAS28-ESR, DAS28-CRP, simple disease activity index (SDAI), clinical disease activity index (CDAI) and ACR/EULAR Boolean criteria. Patients not fulfilling any remission criteria at baseline were classified as 'low disease activity state' (LDAS). Patients not fulfilling any remission criteria over 1 year were classified as 'persistent disease activity' (PDA). MBDA score was measured at baseline/3/6 months. The baseline MBDA score, the 6-month time-integrated MBDA score and MBDA biomarkers were used for analyses. The area under the receiver operating characteristic curve (AUROC) assessed the ability of the MBDA score to discriminate between remission and non-remission. Biomarkers were analysed at baseline using the Mann-Whitney test and over time using the Jonckheere-Terpstra trend test. RESULTS: Of 148 patients, 27% were in the LDAS, 65% DAS28-ESR remission, 51% DAS28-CRP remission, 40% SDAI remission, 43% CDAI remission and 25% ACR/EULAR Boolean remission at baseline. Over 1 year, 9% of patients were classified as PDA. IR and SR were achieved in 42%/47% by DAS28-ESR, 46%/29% by DAS28-CRP, 45%/20% by SDAI, 44%/21% by CDAI and 35%/9% by ACR/EULAR Boolean criteria, respectively. By all remission criteria, baseline MBDA score discriminated baseline remission (AUROCs 0.68-0.75) and IR/SR (AUROCs 0.65-0.74). The 6-month time-integrated MBDA score discriminated IR/SR (AUROCs 0.65-0.79). Baseline MBDA score and concentrations of IL-6, leptin, SAA and CRP were significantly lower in all baseline remission criteria groups vs LDAS. They and the 6-month time-integrated values were lower among patients who achieved IR/SR vs PDA over 1 year. CONCLUSIONS: This study demonstrated that the MBDA score and its biomarkers IL-6, leptin, SAA and CRP differentiated between small differences in disease activity (i.e. between low disease activity and remission states). They were also predictors of remission over 1 year.

Mechanisms of checkpoint inhibition-induced adverse events.

Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non-small-cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self-tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune-related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field.

Exploring the feasibility of using routinely collected data to produce antibiotic prescribing profiles for general dental practitioners in Wales.

This article describes a project that assessed whether routinely collected antibiotic prescribing and NHS dental treatment data could be linked to produce personalised prescribing profiles for general dental practitioners working in Wales, UK. Dental public health competencies required for this work included: Multi-agency working to develop a sustainable system of monitoring antibiotic prescribing in primary dental care in Wales, Dental public health intelligence, Development of dental service quality indicators.

The frequency of remission and low disease activity in patients with rheumatoid arthritis, and their ability to identify people with low disability and normal quality of life.

OBJECTIVE: Treat-to-target in rheumatoid arthritis (RA) recommends targeting remission, with low disease activity (LDA) being an alternative goal. When deciding to target remission or LDA, important considerations are the likelihood of attaining them, and their impacts on function and health-related quality of life (HRQoL). We have addressed this by studying: (a) the frequency of remission and LDA/remission; (b) DAS28-ESR trends after remission; (c) ability of remission vs. LDA to identify patients with normal function (HAQ ≤ 0.5) and HRQoL (EQ-5D ≥ the normal population). METHODS: We studied 571 patients in two clinical trials, and 1693 patients in a 10-year routine care cohort. We assessed the frequency and sustainability of remission and LDA/remission, variability in DAS28-ESR after remission, and sensitivity/specificity of remission and LDA/remission at identifying patients with low disability levels and normal HRQoL using Receiver Operator Characteristic (ROC) curves. RESULTS: Point remission and remission/LDA were common (achieved by 35-58% and 49-74% of patients, respectively), but were rarely sustained (sustained remission and remission/LDA achieved by 5-9% and 9-16% of patients, respectively). Following attaining remission, DAS28-ESR levels varied substantially. Despite this, of those patients attaining point remission, the majority (53-61%) were in remission at study end-points. Whilst remission was highly specific at identifying patients with low disability (85-91%) it lacked sensitivity (51-57%); similar findings were seen for normal HRQoL (specificity 78-86%; sensitivity 52-59%). The optimal DAS28-cut-off to identify individuals with low disability and normal HRQoL was around the LDA threshold. CONCLUSIONS: Our findings support both the treat-to-target goals. Attaining remission is highly specific for attaining low disability and normal HRQoL, although many patients with more active disease also have good function and HRQoL. Attaining a DAS28-ESR ≤ 3.2 has a better balance of specificity and sensitivity for attaining these outcomes, with the benefit of being more readily achievable. Although sustaining these targets over time is rare, even attaining them on a one-off basis leads to better function and HRQoL outcomes for patients.

Why might patients in the UK consult a general medical practitioner when experiencing dental problems? A literature review of patients' perspectives.

OBJECTIVE: to systematically appraise and synthesise the existing evidence regarding the reasons why patients in the UK may consult a general medical practitioner (GMP) when experiencing a dental problem. BASIC RESEARCH DESIGN: a systematic review of the scientific and grey literature published between 1996 and 2017. PARTICIPANTS: dental service users (adults or children) from the UK and/or their carers who were seeking, or had sought, care for a dental problem from a GMP. MAIN OUTCOMES: patients' perspectives on reasons for consulting a GMP were qualitatively synthesised according to Levesque et al.'s conceptual framework of access to health care. RESULTS: Out of 1,232 references screened, 2 studies met the inclusion criteria for the review. They identified the following factors that can influence care-seeking for dental problems: patients' interpretation of their symptoms; their understanding of practitioners' scope of practice; the availability of timely dental care; and the affordability of care. Both studies had weaknesses with regard to either their conduct and/or reporting. CONCLUSIONS: Choice of practitioner for dental problems is likely to be influenced by both the beliefs and attitudes of the individual patient and the organisation and attributes of the providers of dental and medical care. However, in light of the quality of the existing evidence base, there is a need for high-quality studies exploring the reasons why patients in the UK may seek care from a GMP when experiencing dental problems.

Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial.

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers.

SpineCreator: a Graphical User Interface for the Creation of Layered Neural Models.

There is a growing requirement in computational neuroscience for tools that permit collaborative model building, model sharing, combining existing models into a larger system (multi-scale model integration), and are able to simulate models using a variety of simulation engines and hardware platforms. Layered XML model specification formats solve many of these problems, however they are difficult to write and visualise without tools. Here we describe a new graphical software tool, SpineCreator, which facilitates the creation and visualisation of layered models of point spiking neurons or rate coded neurons without requiring the need for programming. We demonstrate the tool through the reproduction and visualisation of published models and show simulation results using code generation interfaced directly into SpineCreator. As a unique application for the graphical creation of neural networks, SpineCreator represents an important step forward for neuronal modelling.

Antimicrobial prescribing by dentists in Wales, UK: findings of the first cycle of a clinical audit.

Objective To describe the findings of the first cycle of a clinical audit of antimicrobial use by general dental practitioners (GDPs).Setting General dental practices in Wales, UK.Subjects and methods Between April 2012 and March 2015, 279 GDPs completed the audit. Anonymous information about patients prescribed antimicrobials was recorded. Clinical information about the presentation and management of patients was compared to clinical guidelines published by the Scottish Dental Clinical Effectiveness Programme (SDCEP).Results During the data collection period, 5,782 antimicrobials were prescribed in clinical encounters with 5,460 patients. Of these 95.3% were antibiotic preparations, 2.7% were antifungal agents, and 0.6% were antivirals. Of all patients prescribed antibiotics, only 37.2% had signs of spreading infection or systemic involvement recorded, and 31.2% received no dental treatment. In total, 79.2% of antibiotic, 69.4% of antifungal, and 57.6% of antiviral preparations met audit standards for dose, frequency, and duration. GDPs identified that failure of previous local measures, patient unwillingness or inability to receive treatment, patient demand, time pressures, and patients' medical history may influence their prescribing behaviours.Conclusions The findings of the audit indicate a need for interventions to support GDPs so that they may make sustainable improvements to their antimicrobial prescribing practices.

Improving medication adherence in rheumatoid arthritis (RA): a pilot study.

The aim of this exploratory pilot study was to adapt a psychological intervention to improve adherence to medication for patients with rheumatoid arthritis (RA). The approach draws on cognitive behavioural therapy (CBT) techniques, including motivational interviewing . The current study aimed to (i) adapt the intervention for patients with RA, (ii) assess its effectiveness in improving adherence to medication and (iii) evaluate patients' experience of the intervention. Participants were randomly allocated to either the 'intervention group' (N = 10), receiving up to six weekly sessions of 'Compliance Therapy', or to the 'wait-list control' group (N = 8), who received standard care. Data was collected pre intervention (baseline), post intervention and at six weeks post intervention (follow-up). Eighteen female participants with a mean age of 48.78 years (SD 15.12) took part in the study. Comparisons across the two time points for each group found that only those in the 'intervention' group demonstrated significant improvement in mean scores on adherence measures. Between-group comparisons were not significant. The pilot study suggests that an intervention based on CBT may improve adherence in patients with RA, but further research is required.

General dental practitioners' perceptions of antimicrobial use and resistance: a qualitative interview study.

BACKGROUND: Dentists are responsible for 9-10% of all antibiotics dispensed in primary care in the UK, many of which may be provided contrary to clinical guidelines. Since antibiotic consumption has been identified as a major cause of antibiotic resistance, dental prescribing may be a significant contributor to this important public health problem.Objective This study aims to explore general dental practitioners' (GDPs) perceptions and attitudes towards antibiotic use and resistance. METHOD: Qualitative interview study with 19 purposively sampled GDPs working in Wales. A set of open-ended questions were developed and amended during semi-structured telephone interviews. Interviews were recorded, transcribed verbatim and codes were developed using thematic analysis. RESULTS: Perceptions of antibiotic use and resistance varied widely between practitioners, particularly with respect to the prevalence and impact of resistant strains on the management of dentoalveolar infection, and the impact of dental prescribing on the emergence of resistance. GDPs reported that their antibiotic prescribing decisions were driven by both clinical pressures and wider public health considerations. CONCLUSIONS: Interventions to enhance the quality of antibiotic prescribing in primary care dentistry should address issues associated with inappropriate prescribing as well as providing education about the causes, prevalence and impact of antibiotic resistance.

Precipitating and perpetuating factors of rheumatoid arthritis immunopathology: linking the triad of genetic predisposition, environmental risk factors and autoimmunity to disease pathogenesis.

Rheumatoid arthritis (RA) is considered to occur when genetic and environmental factors interact to trigger immunopathological changes and consequently an inflammatory arthritis. Over the last few decades, epidemiological and genetic studies have identified a large number of risk factors for RA development, the most prominent of which comprise cigarette smoking and the shared epitope alleles. These risks appear to differ substantially between anti-cyclic citrullinated peptide (ACPA)-positive and ACPA-negative disease. In this article, we will summarise the risk factors for RA development that have currently been identified, outlining the specific gene-environment and gene-gene interactions that may occur to precipitate and perpetuate autoimmunity and RA. We will also focus on how this knowledge of risk factors for RA may be implemented in the future to identify individuals at a high risk of disease development in whom preventative strategies may be undertaken.

Functional autoantibodies against serpin E2 in rheumatoid arthritis.

OBJECTIVE: To search for novel autoantibodies in patients with rheumatoid arthritis (RA) in an effort to better understand the processes of joint destruction in this disease. METHODS: Using a modified SEREX technique and complementary DNA derived from RA synovium, serpin E2 was identified as a novel autoantigen and was analyzed by immunohistochemistry. Levels of anti-serpin E2 autoantibodies in serum and synovial fluid from patients with RA, osteoarthritis (OA), psoriatic arthritis, and ankylosing spondylitis, and/or from healthy individuals were assessed by enzyme-linked immunosorbent assay. Since serpin E2 is an inhibitor of serine proteases, we studied the inhibitory activity of serpin E2 toward its target, urokinase plasminogen activator (uPA), in vitro in the presence of isolated anti-serpin E2 autoantibodies and in vivo using the uPA activity assay. RESULTS: We identified autoantibodies against serpin E2 by the SEREX technique. Serpin E2 was overexpressed in RA synovial tissues as compared with OA synovial tissues. Significantly higher levels of anti-serpin E2 autoantibodies were present in samples of synovial fluid (28%) and serum (22%) from RA patients as compared with OA patients (0 and 6%, respectively) or with healthy individuals (6% of sera). Most importantly, anti-serpin E2 autoantibodies isolated from RA sera reversed the inhibitory activity of serpin E2 by 70%. Furthermore, the levels of anti-serpin E2 autoantibodies correlated with the uPA activity in vivo. CONCLUSION: This study characterizes a functional property of a novel autoantibody in RA. Since anti-serpin E2 autoantibodies interfere with the inhibitory activity of serpin E2 toward serine proteases, they might facilitate the joint destruction in RA.

Repeated vaginal administration of trimeric HIV-1 clade C gp140 induces serum and mucosal antibody responses.

Vaccine-mediated prevention of primary infection with human immunodeficiency virus (HIV) may require the sustained production of antibody at mucosal portals of entry. Here, we describe a novel approach of repeated mucosal immunization by delivering an HIV-1 envelope glycoprotein (gp) in a gel formulated for intravaginal delivery. Rabbits were immunized over one to three 19-day cycles of intravaginal dosing with soluble recombinant trimeric HIV-1 clade C gp140 administered in Carbopol gel. The formulation was well tolerated. A single immunization cycle induced immunoglobulin G (IgG) antibody detected in the serum and female genital tract, and titers were boosted on further immunization. Vaccine-induced serum antibodies neutralized the infectivity of a pseudovirus carrying a heterologous clade C envelope. Our data prove the concept that repeated exposure of the female genital tract to HIV envelope can induce mucosally detectable antibody.

The central role of T cells in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory syndromes. As such, RA is often considered the prototype disease for defining both the molecular and pathological basis of immune-mediated chronic inflammatory disease, and for validating targeted therapies. The immunogenetics of RA suggest a key role for aberrant pathways of T-cell activation in the initiation and/or perpetuation of disease. In the T-cell activation process, CD4+ T-cells are engaged by antigenic peptide fragments in a complex with HLA class II molecules, in addition to co-stimulatory molecules, such as CD80/CD86, expressed on the surface of professional antigen presenting cells. The strongest evidence supporting a role for CD4+ T cells in disease pathogenesis is the association between RA and HLA-DRB1; however, the functional role of this association has yet to be defined. Susceptibility to RA may also be linked with several RA-associated allelic variants of genes, especially PTPN22, but also CTLA4, IL2RA, IL-2RB, STAT4, PTPN2 and PADI4, many of which encode molecules directly implicated in pathways of T-cell activation.The presence of inflammatory infiltrates, such as follicular structures, in the synovial membrane provides compelling evidence of ongoing immune reactions in moderate to severe RA. These structures likely play a key role in T cell - B cell cooperation and the local generation of specific autoantibodies; as such, chronically activated synovial T cells represent key cellular targets for therapy. Evidence also supports a role for T-helper (Th) cells, Th17 cells, and impaired CD4+CD25(hi) regulatory T cell (Treg) function in the pathogenesis of RA. In addition to discussing a range of issues regarding T-cell activation in RA, this review describes how therapeutic modulation of T-cell function, as opposed to profound immunosuppression or immunodepletion, has been associated with better disease outcomes in clinical trials. Ultimately, elucidation of the distinct effects of co-stimulation modulation with abatacept on T cells should provide key insights into understanding how to restore immune homeostasis in patients with RA.

The use of adjuvant granulocyte-macrophage colony-stimulating factor in HIV-related disseminated atypical mycobacterial infection.

Mycobacterium avium complex (MAC) continues to be a challenging problem in some patients with advanced human immunodeficiency virus (HIV) infection despite the availability of potent chemotherapeutic agents. The use of adjunctive immunomodulatory therapy has shown promise in vitro, but there is currently limited supportive clinical evidence [Kemper CA, Bermudez LE, Derenski SC. Immunomodulatory treatment of Mycobacterium avium complex bacteraemia in patients with AIDS by use of recombinant granulocyte-macrophage colony-stimulating factor. J Infect Dis 1998;177:914-20; Kedzierska K, Johnson M, Mijch A, Cooke I, Rainbird M, Roberts S, et al. Granulocyte-macrophage colony-stimulating factor augments phagocytosis of Mycobacterium avium complex by human immunodeficiency virus type-1 infected monocytes/macrophages in vitro and in vivo. J Infect Dis 2000;181:390-94]. We report the resolution of MAC disease resistant to traditional therapy, in an HIV-infected individual, following the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF).

What does tumour necrosis factor excess do to the immune system long term?

Members of the tumour necrosis factor (TNF)/TNF-receptor (TNF-R) superfamily coordinate the immune response at multiple levels. For example, TNF, LTalpha, LTbeta and RANKL provide signals required for lymphoid neogenesis, CD27, OX-40, 4-1BB and CD30 deliver costimulatory signals to augment immune responses, while pro-apoptotic members such as TNF, CD95L and TRAIL may contribute to the termination of the response. Biological identity of individual family members has been revealed through studies of gain of function or gene deficient mutants. Most notable are the development of spontaneous inflammatory polyarthritis in human TNF-globin transgenic mice, the auto-inflammatory syndromes resulting from mutations in the 55-kDa TNF-R, and, in particular, the obligatory role for the RANKL/RANK axis in osteoclastogenesis and bone remodelling. A growing appreciation of the molecular basis of signalling pathways transduced by TNF-R has provided a framework for better understanding the biology of this expanding family. For while the rapid and robust activation of NF-kappaB and MAPK pathways is typical of acute TNF-R engagement, the molecular basis of sustained receptor signalling remains a mystery, in spite of its relevance to chronic inflammatory and immune responses. Focusing on T cells, this report describes some of the molecular footprints of sustained TNF-R engagement and illustrates how these may influence immune function. A common theme arising is that prolonged TNF stimulation alters signalling thresholds over time. The authors propose that one major outcome of long term exposure to TNF is a state of localised IL-2 deficiency at sites of inflammation. The implications of this deficiency are discussed.