The lymphotoxin axis is important for the maintenance of several specialized lymphoid microenvironments in secondary lymphoid tissue. Lymphoid-tissue architecture is highly plastic and requires continual homeostatic signaling to maintain its basal functional state. The cellularity of lymph nodes in adult mice was reduced by systemic blockade of lymphotoxin-beta receptor (LTbeta R) signaling with a soluble decoy receptor both in resting and reactive settings. This reduction in cellularity resulted from greatly impaired lymphocyte entry into lymph nodes due to decreased levels of peripheral lymph node addressing (PNAd) and MAdCAM on high endothelial venules (HEV). LTbeta R signaling was required to maintain normal levels of RNA expression of MAdCAM, and also of PNAd by regulating the expression of key enzymes and scaffold proteins required for its assembly. Thus, the homeostatic maintenance of functional HEV status in adult mice relies largely on LTbeta R signaling.

SUMMARYVascular endothelial growth factor (VEGF) is abundant in synovium and synovial fluids, where it probably contributes to vascular permeability and angiogenesis in arthritic joints. To investigate the probable sources of VEGF in synovium, we compared the ability of several cytokines (TGF-b, plateletderived growth factor (PDGF), IL-1, tumour necrosis factor (TNF), basic fibroblast growth factor (bFGF) that are associated with arthritis and angiogenesis, to stimulate secretion of VEGF protein by human synovial fibroblasts. TGF-b was the strongest inducer of VEGF secretion; six times more VEGF was secreted when cells were stimulated by TGF-b than when stimulated by PDGF or IL-1 for 24 h. TNF-a and bFGF did not stimulate any secretion of VEGF. The stimulatory effects of TGF-b and IL-1 on VEGF secretion were additive. Hypoxic culture alone also stimulated VEGF secretion, but more importantly, hypoxic culture conditions doubled the rate of VEGF secretion stimulated by the cytokines TGF-b and IL-1. When dermal and synovial fibroblasts were stimulated identically by hypoxia and cytokines (TGF-b and IL-1), synovial fibroblasts secreted four times more VEGF than did dermal fibroblasts. Thus in rheumatoid arthritis, the capacity of synovial fibroblasts in the hypoxic environment to secrete large amounts of VEGF in response to cytokines such as TGF-b probably contributes significantly to angiogenesis in the synovium.

The creative research method 'draw and write' has been used in health, social care and education research for several decades. A literature search of studies utilising this method was conducted during the planning stages of a study exploring primary school children's perceptions of infant feeding. A review of this literature noted a range of benefits of 'draw and write' in enabling child participation. However, it also identified that the method has been used inconsistently, and found that there are issues for researchers in relation to interpretation of creative work and analysis of data. As a result of this an improvement on this method, entitled 'draw, write and tell', was developed in an attempt to provide a more child orientated and consistent approach to data collection, interpretation and analysis. This article identifies the issues relating to 'draw and write' and describes the development and application of 'draw, write and tell' as a case study, noting its limitations and benefits. KeywordsChildren, draw and write, draw write and tell, creative methods, infant feeding, breastfeeding 2 of 26The creative research method known as 'draw and write' has been widely used by researchers working with children to explore a range of social and health related subjects. A literature review of studies in the United Kingdom, which have used 'draw and write', was undertaken recently as part of research exploring children's perceptions of infant feeding. This article reports the findings of this literature review and comments on the use of the method across a range of studies. It also describes and discusses the rationale for 'draw, write and tell', which was developed for the research study (Author 2011a) in an attempt to resolve some of the issues relating to 'draw and write' identified during the literature review.

Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0•9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0•9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.

A lymphotoxin-β (LTβ) receptor-Ig fusion protein (LTβR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTβR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTβR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTβR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.

Background: There are no published empirical research studies exploring transgender people's experiences of seeking and receiving counselling or psychotherapy outside of gender identity clinics within the UK. As a result, counsellors know little about why transgender people seek counselling, who they seek counselling from, and what their experiences are of receiving counselling. Aim: To address this gap in the literature, this study investigated transgender people's experiences of seeking and receiving counselling or psychotherapy outside of gender identity clinics within the UK. Funding for this study was provided by a BACP Seedcorn grant. Method: A mixed method small‐scale qualitative research design was employed, comprising an online survey and five semi‐structured interviews. Findings: Participants tended to seek counselling on two or more occasions and received between 2 and 12 sessions. Participants sought counselling for common psychological concerns as well as gender identity and coming out issues. A fear of being discriminated against and exploring gender for the first time were significant barriers in seeking help. Participants reported mixed experiences of counselling but valued a therapeutic relationship in which they felt affirmed, listened to and understood. Discussion: The findings from this study mirror aspects of previous research conducted in the USA concerning transgender clients' experiences of counselling. However, these findings point to the importance of recognising the potential vulnerability transgender clients experience when seeking counselling and the need for therapists to develop greater awareness, knowledge and competence regarding working with transgender clients.

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The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-alpha. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-alpha. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity.