Clinical trials and basic research: defining mechanisms and improving treatment in connective tissue disease

Despite advances in elucidating the pathogenic factors responsible for its development, systemic sclerosis remains complex and poorly understood, and treatment options are limited. Multidisciplinary collaborative efforts are needed to better characterize clinical and prognostic parameters and to design and implement large-scale clinical trials in well defined populations with therapies that target potential disease modulators

Systemic sclerosis and related connective tissue diseases: present and future

Greece, to discuss systemic sclerosis (SSc) and related connective tissue diseases (CTDs). SSc is a clinically heterogeneous and complex disease that is characterized by vascular dysfunction, vascular and extravascular fibrosis, and characteristic immune derangements, and for which few treatment options are available. The aims of the CTD International Scientific Advisory Board were threefold: to define the role of local mediators in CTDs, in particular to identify the nature of the initial insult in CTDs and to consider the role of genetic perturbations in CTDs; to translate what has been learned from clinical trials into clinical practice and to evaluate current treatment options for CTDs and their complications; and to address future directions for the management of CTDs and associated rare diseases, based on the biologic mechanisms elucidated. This supplemen

Tumour necrosis factor-α production in fibrosing alveolitis is macrophage subset specific

BACKGROUND: Previous studies have revealed that tumour necrosis factor (TNF)-α is upregulated in fibrosing alveolitis (FA) in humans. The aim of this study was to compare the TNF-α secretory profile of alveolar macrophages (AMs) and peripheral blood monocytes (Mos) of patients with cryptogenic FA and systemic sclerosis (SSc), a rheumatological disorder in which lung fibrosis can occur. In particular, we wished to assess whether TNF-α levels differ between SSc patients with FA (FASSc) and a nonfibrotic group. METHODS: The reverse haemolytic plaque assay was used to evaluate the secretion of cytokine at a single cell level while immunostaining allowed subtyping of AMs and Mos. RESULTS: This study demonstrated a difference in total TNF-α levels produced by AMs when the levels in subjects with FA (cryptogenic FA and FASSc) were compared to levels in either SSc patients without FA (P = 0.0002) or normal healthy controls (P < 0.001). In addition, AMs from patients with FASSc secreted more TNF-α than those of patients with no FA (P = 0.003). In contrast, there were no significant differences in Mo TNF-α secretion between the groups. A positive correlation was found between total TNF-α level and number of neutrophils obtained by bronchoalveolar lavage from patients with FA (r = 0.49, P < 0.04). Finally, it was demonstrated that there was significant heterogeneity of TNF-α secretion and that a numerically significant subset of mononuclear phagocytes, RFD7, was responsible for more than 80% of TNF-α production. CONCLUSION: By demonstrating the primary cell source of TNF-α in FASSc, more accurately targeted, possibly localized, anti-TNF strategies might be employed with success in the future

Nxt1 Is Necessary for the Terminal Step of Crm1-Mediated Nuclear Export

Soluble factors are required to mediate nuclear export of protein and RNA through the nuclear pore complex (NPC). These soluble factors include receptors that bind directly to the transport substrate and regulators that determine the assembly state of receptor–substrate complexes. We recently reported the identification of NXT1, an NTF2-related export factor that stimulates nuclear protein export in permeabilized cells and undergoes nucleocytoplasmic shuttling in vivo (Black, B.E., L. Lévesque, J.M. Holaska, T.C. Wood, and B.M. Paschal. 1999. Mol. Cell. Biol. 19:8616–8624). Here, we describe the molecular characterization of NXT1 in the context of the Crm1-dependent export pathway. We find that NXT1 binds directly to Crm1, and that the interaction is sensitive to the presence of Ran-GTP. Moreover, mutations in NXT1 that reduce binding to Crm1 inhibit the activity of NXT1 in nuclear export assays. We show that recombinant Crm1 and Ran are sufficient to reconstitute nuclear translocation of a Rev reporter protein from the nucleolus to an antibody accessible site on the cytoplasmic side of the NPC. Further progress on the export pathway, including the terminal step of Crm1 and Rev reporter protein release, requires NXT1. We propose that NXT1 engages with the export complex in the nucleoplasm, and that it facilitates delivery of the export complex to a site on the cytoplasmic side of NPC where the receptor and substrate are released into the cytoplasm

Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis

BACKGROUND: Systemic sclerosis is a disease of unknown origin which often occurs in women after their childbearing years. It has many clinical and histopathological similarities to chronic graft-versus-host disease. Recent studies indicate that fetal stem cells can survive in the maternal circulation for many years post partum. This finding suggests that fetal cells persisting in the maternal circulation or tissues could be involved in the pathogenesis of systemic sclerosis by initiating a graft-versus-host reaction. METHODS: We used the polymerase chain reaction (PCR) to identify Y-chromosome sequences in DNA extracted from peripheral-blood cells and skin lesions from women with systemic sclerosis of recent onset. To confirm the PCR findings, we used fluorescence in situ hybridization of peripheral-blood cells and cells within chronic inflammatory-cell infiltrates in biopsy specimens of affected skin. RESULTS: Y-chromosome sequences were found in DNA from peripheral-blood cells in 32 of 69 women with systemic sclerosis (46 percent), as compared with 1 of 25 normal women (4 percent, P\u3c0.001), and in T lymphocytes from 3 women with systemic sclerosis who had male offspring. Furthermore, Y-chromosome sequences were identified in skin-biopsy specimens from 11 of 19 women with systemic sclerosis (58 percent); 9 of the 11 were known to have carried male fetuses. Nucleated cells containing Y chromosomes were detected by fluorescence in situ hybridization in paraffin-embedded sections of skin lesions from all seven women we tested whose skin-biopsy specimens contained Y-chromosome sequences. CONCLUSIONS: Fetal antimaternal graft-versus-host reactions may be involved in the pathogenesis of systemic sclerosis in some women

Community-Guided Focus Group Analysis to Examine Cancer Disparities

Accountability for Cancer Care through Undoing Racism and Equity (ACCURE) is a systems-change intervention addressing disparities in treatment initiation and completion and outcomes for early stage Black and White breast and lung cancer patients. Using a community-based participatory research approach, ACCURE is guided by a diverse partnership involving academic researchers, a non-profit community-based organization, its affiliated broader-based community coalition, and providers and staff from two cancer centers

Reducing Youth Access to Alcohol: Findings from a Community-Based Randomized Trial

Underage drinking continues to be an important public health problem and a challenge to the substance abuse prevention field. Community-based interventions designed to more rigorously control underage access to alcohol through retailer education and greater enforcement of underage drinking laws have been advocated as potentially effective strategies to help address this problem, but studies designed to evaluate such interventions are sparse. To address this issue we conducted a randomized trial involving 36 communities to test the combined effectiveness of five interrelated intervention components designed to reduce underage access to alcohol. The intervention was found to be effective in reducing the likelihood that retail clerks would sell alcohol to underage-looking buyers, but did not reduce underage drinking or the perceived availability of alcohol among high school students. Post hoc analyses, however, revealed significant associations between the level of underage drinking law enforcement in the intervention communities and reductions in both 30-day use of alcohol and binge drinking. The findings highlight the difficulty in reducing youth drinking even when efforts to curtail retail access are successful. Study findings also suggest that high intensity implementation of underage drinking law enforcement can reduce underage drinking. Any such effects of enhanced enforcement on underage drinking appear to be more directly attributable to an increase in perceived likelihood of enforcement and the resultant perceived inconveniences and/or sanctions to potential drinkers, than to a reduction in access to alcohol per se

Indicators of injury recovery identified by patients, family members and clinicians

Introduction A focus on what is important to patients has been recognized as an essential pillar in care to ensure safe patient care that focuses on outcomes identified as important by patients. Despite this, asking trauma patients and their families what they consider should be the priorities of care and recovery has been neglected. Methods Adult trauma patients admitted to two centers in Australia for ≥24 h for the treatment of physical injury, and family members of injured patients and clinicians caring for injured patients were invited to participate. Individual interviews were conducted with the patient and family members prior to hospital discharge, and again one and three months post discharge. Individual interviews or focus groups were conducted with clinicians at one point in time. Content analysis of all transcripts was undertaken to determine the indicators of successful recovery over time. Results Participants in the three stakeholder groups were enrolled (patients − 33; family members—22; clinicians—40). Indicators of recovery focused on five main categories including returning to work, resuming family roles, achieving independence, recapturing normality and achieving comfort. Other categories that were less frequently identified included maintaining one’s household, restoring emotional stability, cosmetic considerations and appearance, realignment of life goals, psychological recovery and development of self. Indicators of recovery after physical injury were similar across the three stakeholder groups, although with greater detail identified by patients. In addition, indicators evolved over time with increasing recognition of the importance of the overall impact of the injury in general and on activities of daily living and an unfolding appreciation that life could not be taken for granted. Conclusions Description of the indicators of recovery after traumatic injury that matter to patients, family members and clinicians enable an understanding of similarities and differences. Further testing in a broader cohort of participants is essential to identify patient reported outcome measures that might be used in trauma care and associated research

The effectiveness of interventions to change six health behaviours: a review of reviews

Background: Several World Health Organisation reports over recent years have highlighted the high incidence of chronic diseases such as diabetes, coronary heart disease and cancer. Contributory factors include unhealthy diets, alcohol and tobacco use and sedentary lifestyles. This paper reports the findings of a review of reviews of behavioural change interventions to reduce unhealthy behaviours or promote healthy behaviours. We included six different health-related behaviours in the review: healthy eating, physical exercise, smoking, alcohol misuse, sexual risk taking (in young people) and illicit drug use. We excluded reviews which focussed on pharmacological treatments or those which required intensive treatments (e. g. for drug or alcohol dependency). Methods: The Cochrane Library, Database of Abstracts of Reviews of Effectiveness (DARE) and several Ovid databases were searched for systematic reviews of interventions for the six behaviours (updated search 2008). Two reviewers applied the inclusion criteria, extracted data and assessed the quality of the reviews. The results were discussed in a narrative synthesis. Results: We included 103 reviews published between 1995 and 2008. The focus of interventions varied, but those targeting specific individuals were generally designed to change an existing behaviour (e. g. cigarette smoking, alcohol misuse), whilst those aimed at the general population or groups such as school children were designed to promote positive behaviours (e. g. healthy eating). Almost 50% (n = 48) of the reviews focussed on smoking (either prevention or cessation). Interventions that were most effective across a range of health behaviours included physician advice or individual counselling, and workplace- and school-based activities. Mass media campaigns and legislative interventions also showed small to moderate effects in changing health behaviours. Generally, the evidence related to short-term effects rather than sustained/longer-term impact and there was a relative lack of evidence on how best to address inequalities. Conclusions: Despite limitations of the review of reviews approach, it is encouraging that there are interventions that are effective in achieving behavioural change. Further emphasis in both primary studies and secondary analysis (e.g. systematic reviews) should be placed on assessing the differential effectiveness of interventions across different population subgroups to ensure that health inequalities are addressed.</p