Staying well after depression: trial design and protocol

<p>Abstract</p> <p>Background</p> <p>Depression is often a chronic relapsing condition, with relapse rates of 50-80% in those who have been depressed before. This is particularly problematic for those who become suicidal when depressed since habitual recurrence of suicidal thoughts increases likelihood of further acute suicidal episodes. Therefore the question how to prevent relapse is of particular urgency in this group.</p> <p>Methods/Design</p> <p>This trial compares Mindfulness-Based Cognitive Therapy (MBCT), a novel form of treatment combining mindfulness meditation and cognitive therapy for depression, with both Cognitive Psycho-Education (CPE), an equally plausible cognitive treatment but without meditation, and treatment as usual (TAU). It will test whether MBCT reduces the risk of relapse in recurrently depressed patients and the incidence of suicidal symptoms in those with a history of suicidality who do relapse. It recruits participants, screens them by telephone for main inclusion and exclusion criteria and, if they are eligible, invites them to a pre-treatment session to assess eligibility in more detail. This trial allocates eligible participants at random between MBCT and TAU, CPE and TAU, and TAU alone in a ratio of 2:2:1, stratified by presence of suicidal ideation or behaviour and current anti-depressant use. We aim to recruit sufficient participants to allow for retention of 300 following attrition. We deliver both active treatments in groups meeting for two hours every week for eight weeks. We shall estimate effects on rates of relapse and suicidal symptoms over 12 months following treatment and assess clinical status immediately after treatment, and three, six, nine and twelve months thereafter.</p> <p>Discussion</p> <p>This will be the first trial of MBCT to investigate whether MCBT is effective in preventing relapse to depression when compared with a control psychological treatment of equal plausibility; and to explore the use of MBCT for the most severe recurrent depression - that in people who become suicidal when depressed.</p> <p>Trial Registration</p> <p>Current Controlled Trials: ISRCTN97185214.</p

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

L

Context-Dependent Regulation of Epithelial Growth by Echinoid

The size of an animal is determined by the growth, proliferation, and survival of every cell in its body. Individual cells must respond to local cues and properly adjust their growth behavior to collectively generate tissues and organs of the proper size. How cells regulate their growth, and how they coordinate to regulate the size of the organs, are two fundamental questions which have long captivated developmental biologists, and which remain incompletely understood. Much of what is already known about growth regulation has been learned from the study of mutants. Mutations affecting multiple signaling pathways can lead to overgrowth or undergrowth. However, the study of genetic mosaics has shown that outcome of growth-disrupting mutations depends not only on the properties of affected cells, but also on the interactions those cells have with their neighbors. For example, cells heterozygous for a class of mutations called Minute are slow growing but viable when all cells carry the mutation, but are eliminated in the presence of wild type neighbors. This phenomenon, termed cell competition, highlights how cells can non-autonomously influence growth and survival within a mosaic tissue.I conducted a genetic screen in Drosophila to identify new genes which regulate growth in mosaics, focusing specifically on cell adhesion genes. The screen identified 9 genes which, when knocked down in clones in the wing imaginal disc, alter the size, shape, or number of clones which are recovered later in development. Of particular interest was the gene echinoid (ed): clones of cells lacking ed are small, round, and underrepresented, but ed mutations affecting large populations of cells can cause tissue overgrowth. My dissertation work is aimed at understanding the mechanistic basis of these seemingly contradictory phenotypes and to clarify the role of ed in regulating cellular and tissue growth. I demonstrate that cells lacking ed die by apoptosis at increased rates, at least in part because they express lower levels of the anti-apoptotic protein Diap1. This contributes to the elimination of ed-deficient clones in mosaic tissues. I also confirm that organs which are mostly or entirely deficient of ed overgrow because of a failure to terminate growth when the organ has reached its appropriate final size. Ed has been previously shown to have a function in restricting growth via its interactions with the Hippo pathway, which regulates the expression of pro-growth and anti-apoptotic genes downstream of the transcription factor Yorkie (Yki). I show that this prevailing model cannot account for many of the phenotypes observed in ed-depleted tissues. Contrary to other reports, I found that many—but not all—Yki target genes are expressed at lower levels in ed-depleted cells. In mosaics, many of these same Yki targets are expressed at higher levels in the wild-type neighbors of ed clones. These observations are consistent with clonal elimination but inconsistent ed having a simple, growth-inhibitory effect via the Hippo pathway. To understand why ed mutant organs overgrow, I screened for dominant modifiers of the overgrowth phenotype caused by Gal4-driven knockdown of ed in the wing. The top hit in this screen was upd2Δ, which suppressed overgrowth and enhanced cell death. While characterizing these modification phenotypes, I determined that they were ed-independent artifacts of a UAS construct present in the upd2Δ allele which interacts with Gal4. Although ultimately uninformative to the overgrowth phenotype associated with ed, this line of inquiry uncovered important information about the properties of the upd2Δ allele which may be of interest to researchers who use this allele, or other alleles generated in a similar manner.Overall, this work advances our understanding of how growth is regulated by echinoid, highlights the context-dependence of ed’s effects on growth, and paints a more complicated picture of how ed interacts with the Hippo pathway than previously appreciated

A flagellate-to-amoeboid switch in the closest living relatives of animals.

Amoeboid cell types are fundamental to animal biology and broadly distributed across animal diversity, but their evolutionary origin is unclear. The closest living relatives of animals, the choanoflagellates, display a polarized cell architecture (with an apical flagellum encircled by microvilli) that resembles that of epithelial cells and suggests homology, but this architecture differs strikingly from the deformable phenotype of animal amoeboid cells, which instead evoke more distantly related eukaryotes, such as diverse amoebae. Here, we show that choanoflagellates subjected to confinement become amoeboid by retracting their flagella and activating myosin-based motility. This switch allows escape from confinement and is conserved across choanoflagellate diversity. The conservation of the amoeboid cell phenotype across animals and choanoflagellates, together with the conserved role of myosin, is consistent with homology of amoeboid motility in both lineages. We hypothesize that the differentiation between animal epithelial and crawling cells might have evolved from a stress-induced switch between flagellate and amoeboid forms in their single-celled ancestors

RARα and RARγ reciprocally control K5+ progenitor cell expansion in developing salivary glands

Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RARα and RARγ have opposing effects on K5+ cell cycle progression and cell distribution. RARα negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RARγ is necessary but not sufficient to positively maintain K5+ cells, as agonism of RARγ alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RARα agonism and RARγ inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RARα and RARγ reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RARα may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool.Summary statementRARα and RARγ reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically restricted, evolutionarily conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but why only a subset of cell polarize LGN is not known. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light on how spindle orientation influences epidermal stratification

AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis

Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically restricted, evolutionarily conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but why only a subset of cell polarize LGN is not known. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light on how spindle orientation influences epidermal stratification