The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus.

Introduction: Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. Methods: We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras. Results: GC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Discussion: We identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.

Assessment and management of chronic pain.

Chronic pain can have significant physical, psychological and social effects on a person's life, as well as on their families and friends. However, it is often not well-recognised or understood, which can lead to further harm. Therefore, an individualised, person-centred approach to chronic pain is essential to accurately assess pain and to develop an appropriate treatment plan. This article outlines the biomedical and psychosocial factors that can influence an individual's pain experience that should be considered as part of the assessment and management of chronic pain, and explores the assessment tools available to assist in this process. It also discusses the management options available for chronic pain, including neural blockade and analgesics, as well as non-pharmacological options such as psychological approaches, physical activity and exercise, and complementary and alternative therapies.

Evaluation of the impact of nurse consultant roles in the United Kingdom: a mixed method systematic literature review.

AIM: This paper reports a mixed methods systematic review examining the impact of nurse consultant roles in adult healthcare settings, with a view to identifying indicators for demonstrating their impact on patient and professional outcomes. BACKGROUND: Nurse consultants were introduced in England in 2000 with the intention to achieve better outcomes for patients by improving quality and services. Previous studies have investigated the impact of nurse consultants, but attempts to amalgamate this evidence have been methodologically limited. Since these reviews were published, the importance of demonstrating the contribution of nurse consultants has prompted new research. A robust review of the evidence is now required. DATA SOURCES: A broad search strategy was adapted for eight databases. Grey literature was sought from various sources. REVIEW METHODS: Quantitative and qualitative studies were included. Study quality was assessed using appropriate instruments. Cross-study synthesis combined the quantitative and qualitative findings in relation to the dimensions of impact identified. Measures of impact were mapped against a framework for assessing clinical and professional outcomes. RESULTS: Thirty-six studies were included. The findings suggest a largely positive influence of nurse consultants on a range of clinical and professional outcomes, which map onto the proposed framework of impact. However, there was very little robust evidence and the methodological quality of studies was often weak. CONCLUSION: Further robust research is required to explore nurse consultants' impact on patient and professional outcomes. The proposed framework for assessing impact could be used to guide future research and assist nurse consultants assess their impact.

Spontaneous regression of human cancer cells in vitro: potential role of disruption of Cdk1/Cdk4 co-expression.

BACKGROUND: Although well-acknowledged in vivo, spontaneous death of cancer cells in vitro is less widely appreciated. MATERIALS AND METHODS: Colony formation was studied in untreated control plates of standard clonogenic assays and measurements of actual and potential doubling times performed in asynchronous cultures of human cancer cells lines. Western blotting of lung large cell carcinoma, COR-L23 cells actively undergoing spontaneous cell death was also carried out. RESULTS: Catastrophic disintegration of mature colonies could be seen in the untreated plates of lung large cell carcinoma, H460 and colon adenocarcinoma, SW620 human cancer cell lines and a significant cell loss factor was present in the cell lines growing as adherent cells in continuous culture. Western blotting demonstrated alterations of relative cyclin dependent kinase (Cdk)1 to Cdk4 protein expression in dying COR-L23 cells. CONCLUSION: The phenomenon of spontaneous cell death should be considered a hallmark of cancer and may be the result of failure to stabilise unstable, fully developed cancer cells due to the disruption of Cdk1/Cdk4 co-expression in those cells.

Dynamic heterogeneity of proteomic expression in human cancer cells does not affect Cdk1/Cdk4 co-expression.

Tumour heterogeneity is becoming increasingly important as an obstacle to genomic and proteomic technologies designed to improve the diagnosis and treatment of human cancer. In a panel of 19 human in-vitro cancer cell lines, we show marked heterogeneity of proteomic expression of key genes responsible for the control of cell division and death. Patterns of expression of these proteins were unique for each cell line. In addition, dynamic heterogeneity of proteomic expression of Cyclin D1, Cdk1, Cdk4 and even actin was detected. The relative levels of each protein fluctuated independently from experiment to experiment separated only by short passages in tissue culture. Cdk1 and Cdk4 proteomic co-expression (Seabra, 2007) was not, however, affected by dynamic heterogeneity, or, in 4 cell lines, by treatment with D0.1 doses of CDDP. Cdk1/Cdk4 may thus provide a complex molecular target for anti-cancer drug development which is unaffected by tumour heterogeneity and is not disrupted by conventional chemotherapy.

Theranostic proteomic profiling of cyclins, cyclin dependent kinases and Ras in human cancer cell lines is dependent on p53 mutational status.

Despite major advances in the molecular biology of the cancer cell over the past two decades, the great majority of patients are still treated by conventional cytotoxic drugs. The chemotherapy regimens employed frequently include platinating agents, taxanes, intercalating agents and topoisomerase inhibitors. Attempts to predict the therapeutic efficacy of such drugs by molecular profiling (theranostics) have up to the present time had limited success. Genes responsible for the control of cell division, senescence and apoptosis whose normal functions become corrupted during carcinogenesis, might potentially play a part in determining chemotherapeutic response. Here we have examined the relationships between the chemoresponsiveness of 18 human in vitro cancer cell lines and proteomic expression of Ras, cyclins B1 and D1 and cyclin-dependent kinases Cdk1 and Cdk4. When all 18 cell lines were examined as a single group, proteomic expression did not provide any helpful theranostic predictors. Clear relationships between proteomic expression and drug efficacy emerged, however, when Ras, cyclin B1, cyclin D1, Cdk1 and Cdk4 were examined separately in p53 wild-type and p53 mutant cell subsets. We suggest that the theranostic relationships we have detected in vitro may have potential relevance in vivo and should prompt clinical theranostic studies which take account of p53 mutational status.

Nurse of the year 2002. An interview with Amanda Howarth.

Dawn Freshwater interviews Nurse of the Year (2002) Amanda Howarth and asks her about her work as a Clinical Nurse Specialist in Pain Management where she is using Complementary Therapies to help patients with Multiple Sclerosis cope with chronic pain.

Will aromatherapy be a useful treatment strategy for people with multiple sclerosis who experience pain?

This paper outlines the use of massage and aromatherapy for pain management and how it might work, concentrating specifically on patients with multiple sclerosis who have long-standing pain. The services currently offered to these patients are discussed to include the assessment procedure, the treatments undertaken and the range of essential oils used. The review procedure, and continuation of the treatments are also outlined with a brief summary of audit results being presented. Plans for future service development and research are also proposed.