Group mindfulness based cognitive therapy vs group support for self-injury among young people: Study protocol for a randomised controlled trial

Background: Non-suicidal self-injury (NSSI) is a transdiagnostic behaviour that can be difficult to treat; to date no evidence based treatment for NSSI exists. Mindfulness Based Cognitive Therapy (MBCT) specifically targets the mechanisms thought to initiate and maintain NSSI, and thus appears a viable treatment option. The aims of the current study are to test the ability of MBCT to reduce the frequency and medical severity of NSSI, and explore the mechanisms by which MBCT exerts its effect. Methods/Design: We will conduct a parallel group randomised controlled trial of Mindfulness Based Cognitive Therapy (MBCT) versus Supportive Therapy (ST) in young people aged 18-25 years. Computerised block randomisation will be used to allocate participants to groups. All participants will meet the proposed DSM-5 criteria for NSSI (i.e. five episodes in the last twelve months). Participants will be excluded if they: 1) are currently receiving psychological treatment, 2) have attempted suicide in the previous 12 months, 3) exhibit acute psychosis, 4) have a diagnosis of borderline personality disorder, or 5) have prior experience of MBCT. Our primary outcome is the frequency and medical severity of NSSI. As secondary outcomes we will assess changes in rumination, mindfulness, emotion regulation, distress tolerance, stress, and attentional bias, and test these as mechanisms of change. Discussion: This is the first randomised controlled trial to test the efficacy of MBCT in reducing NSSI. Evidence of the efficacy of MBCT for self-injury will allow provision of a brief intervention for self-injury that can be implemented as a stand-alone treatment or integrated with existing treatments for psychiatric disorders

Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis.

Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P=0.001-0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P=0.002-0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD

Tumor-DCs accumulate lipid and reduce numerically with disease progression.

<p>Mice were inoculated with 5 x 10⁵ AE17 mesothelioma cells and tumors allowed to develop into small (< 40 mm²) or large (> 80 mm²) tumors. Total CD11c⁺ DCs within tumors and lymphoid organs were identified (A) and lipid levels measured using BODIPY staining shown as MFIs of CD11c⁺ DCs; representative samples shown (B). Pooled data show the proportions of CD11c⁺ DCs within tumors (C), spleens (D), dLN (E) and ndLN (F). Pooled data show the lipid content of CD11c⁺ DCs in AE17 tumors (G), spleens (H), dLN (I) and ndLN (J). Lymphoid organs from tumor-bearing mice were compared to those from healthy mice: n = 18 mice with small tumors, n = 9 mice with large tumors and n = 8 healthy control mice. All pooled data are shown as mean ± SEM.</p

Tumor-antigen-specific CD8⁺ T cell proliferation in draining lymph nodes decreases with increasing tumor burden.

<p>C57BL/6J mice were inoculated with 5 x10⁵ AE17 tumor cells, which were used as negative controls (B) or with AE17sOVA tumor cells (growth rate shown in A; n = 10 mice; data shown as mean ± SEM) on day 0. CFSE-labelled, CD8⁺, class I restricted, OVA-specific T cells from OT-1 mice were adoptively transferred at days 4, 11, 18 and 25 into the tumor-bearing mice. The dLNs were harvested from recipient mice three days post transfer such that FACS analysis was on days 7 (C, G), 14 (D, G), 21 (E, G) and 28 (F, G) post tumor cell inoculation. The lymph nodes were prepared as single cell suspensions and stained for CD8 for re-isolation of CFSE-labelled OT-1 cells. FACS analysis was performed by gating on CD8⁺ T cells. Representative FACS profiles shown in B-F. Results from individual mice from 1 experiment with 3–6 mice/group (G).</p

Mesothelioma tumor cells modulate human MoDC lipid content and function.

<p>Human blood monocytes cultured with GM-CSF and IL-4 were exposed to varying ratios of JU77 mesothelioma tumor cells (A). At day 7, iMoDCs stained for CD11c expression and lipid levels using BODIPY were analysed by flow cytometry. Large cells were first gated (B) and CD11c⁺ DCs identified (unfilled line), relative to the isotype control (shaded area; C). The BODIPY mean fluorescence intensity (MFI) of CD11c⁺ DCs is proportional to intracellular lipid content (D). Pooled data shows lipid levels of iMoDCs co-cultured with varying ratios of JU77 tumor cells (E). During differentiation, DCs were also exposed to Met5A cells (at a ratio of 1DC: 10Met5A cells), and DC lipid content measured as BODIPY MFI (F). The DQ-OVA assay was used to measure the antigen processing ability of iMoDCs exposed to JU77 tumor cells (G). Data in (E) and (G) is from 6 individuals and data in (F) is from 2 individuals; all data shown as mean ± SEM. * = p < 0.05; ** = p < 0.005; *** = p < 0.0005.</p

Mesothelioma tumor cells promote partial DC maturation.

<p>Differentiating iMoDCs exposed to varying ratios of JU77 cells were stained for CD11c and maturation markers for flow cytometric analysis. CD11c⁺ DCs were identified as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123563#pone.0123563.g001" target="_blank">Fig 1</a>. Expression of each surface marker was analyzed on gated CD11c⁺ cells; representative gating strategy is shown (A). Pooled data of the percent of iMoDCs expressing CD1a (B), CD86 (C), HLA-DR (E) and CD80 (G) and surface expression levels (shown as MFIs) of CD86 (D), HLA-DR (F) and CD80 (H) on iMoDCs is from 6 individuals and shown as mean ± SEM. * = p < 0.05; ** = p < 0.005.</p