The mammalian innate immune system is activated by foreign nucleic acids. Detection of double-stranded DNA (dsDNA) in the cytoplasm triggers characteristic antiviral responses and macrophage cell death. Cytoplasmic dsDNA rapidly activated caspase 3 and caspase 1 in bone marrow-derived macrophages. We identified the HIN-200 family member and candidate lupus susceptibility factor, p202, as a dsDNA binding protein that bound stably and rapidly to transfected DNA. Knockdown studies showed p202 to be an inhibitor of DNA-induced caspase activation. Conversely, the related pyrin domain-containing HIN-200 factor, AIM2 (p210), was required for caspase activation by cytoplasmic dsDNA. This work indicates that HIN-200 proteins can act as pattern recognition receptors mediating responses to cytoplasmic dsDNA.

Macrophages are the main components of inflammation during skin wound healing. They are critical in wound closure and in excessive inflammation, resulting in defective healing observed in chronic wounds. Given the heterogeneity of macrophage phenotypes and functions, we here hypothesized that different subpopulations of macrophages would have different and sometimes opposing effects on wound healing. Using multimarker flow cytometry and RNA expression array analyses on macrophage subpopulations from wound granulation tissue, we identified a Ly6c(lo)MHCII(hi) "noninflammatory" subset that increased both in absolute number and proportion during normal wound healing and was missing in Ob/Ob and MYD88-/- models of delayed healing. We also identified IL17 as the main cytokine distinguishing this population from proinflammatory macrophages and demonstrated that inhibition of IL17 by blocking Ab or in IL17A-/- mice accelerated normal and delayed healing. These findings dissect the complexity of the role and activity of the macrophages during wound inflammation and may contribute to the development of therapeutic approaches to restore healing in chronic wounds.

Interfollicular epidermal (IFE) homeostasis is a major physiological process allowing maintenance of the skin barrier function. Despite progress in our understanding of stem cell populations in different hair follicle compartments, cellular mechanisms of IFE maintenance, in particular, whether a hierarchy of progenitors exists within this compartment, have remained controversial. We here used multicolour lineage tracing with Brainbow transgenic labels activated in the epidermis to track individual keratinocyte clones. Two modes of clonal progression could be observed in the adult murine dorsal skin. Clones attached to hair follicles showed rapid increase in size during the growth phase of the hair cycle. On the other hand, clones distant from hair follicles were slow cycling, but could be mobilized by a proliferative stimulus. Reinforced by mathematical modelling, these data support a model where progenitor cycling characteristics are differentially regulated in areas surrounding or away from growing hair follicles. Thus, while IFE progenitors follow a non-hierarchical mode of development, spatiotemporal control by their environment can change their potentialities, with far-reaching implications for epidermal homeostasis, wound repair and cancer development.

Hair follicles (HFs) upon development enter a lifelong cycle of growth, regression, and resting. These phases have been extensively studied at the cellular and molecular levels for individual HFs. However, HFs group into domains with coordinated cycling strongly influenced by their environment. These macroscopic hair domains have been difficult to study and can be influenced by physiological or pathological conditions, such as pregnancy or skin wounds. To robustly address this issue, we generated a mouse model for quantitative monitoring of β-catenin activity reflecting HF cycle dynamics macroscopically by using live bioluminescence imaging. These mice allowed live tracking of HF cycles and development, and highlighted hair regenerative patterns known to occur through macro-environmental cues, including initiation events, propagating anagen and border stability, and allowed refinement of a mechanistic mathematical model that integrates epidermal cell population dynamics into an excitable reaction-diffusion model. HF cycling could be studied in situations of pregnancy, wound healing, hair plucking, as well as in response to cyclosporine or Wnt3a stimulation. In conclusion, we developed a model for analysis of HF cycling at the macroscopic level that will allow refined analysis of hair cycle kinetics as well as its propagation dynamics.

Young and Ensing (1999) developed a model of the recovery process based on the views of mental health consumers. Recovery is a process of acknowledging and accepting the disorder, discovering and fostering self-empowerment, learning and self-definition, returning to basic functioning and improving quality of life. Forming relationships is a problem for people with enduring mental health disorders. According to Mayers (2000), this appeared to be the area that had the most negative effect on their quality of life because it affected their wish to be involved in leisure activities and to attempt to seek employment.People with a dual diagnosis experience disruption in carrying out their daily occupations. This article describes a study in which an occupational therapist explored the leisure participation of clients with a dual diagnosis. In-depth, semi-structured interviews were conducted with four outpatients from an alcohol and drug rehabilitation programme. Inductive analysis of the informants' interviews identified two main themes: leisure as part of the recovery process and the barriers to leisure participation.This study provides support for the need to understand the leisure occupations of the clients with whom occupational therapists work. Further research is required to examine the interventions that assist clients with a dual diagnosis to develop meaningful leisure activities.

No abstract

Introduction: Isolated local recurrence of prostate cancer following primary radiotherapy or brachytherapy may be treated with focal salvage high dose rate brachytherapy, although there remains an absence of high quality evidence to support this approach. Methods: Men with prostate cancer treated consecutively between 2015 and 2018 using 19 Gy in a single fraction high dose rate brachytherapy (HDR) for locally recurrent prostate cancer were identified from an institutional database. Univariable analysis was performed to evaluate the relationship between patient, disease and treatment factors with biochemical progression free survival (bPFS). Results: 43 patients were eligible for evaluation. Median follow up duration was 26 months (range 1-60). Median bPFS was 35 months (95% confidence interval 25.6-44.4). Kaplan-Meier estimates for bPFS at 1, 2 and 3 years post salvage were 95.2%, 70.6% and 41.8% respectively. On univariable Cox regression analysis, only nadir PSA was significantly associated with bPFS although the majority of patients were also treated with androgen deprivation therapy. Only one late grade 3 genitourinary toxicity was observed. Conclusion: Focal salvage HDR brachytherapy may provide good biochemical control with a low risk of severe toxicity. Further evaluation within clinical trials are needed to establish its role in the management of locally recurrent prostate cancer.

Accidental or deliberate dispersion of plutonium (Pu) and americium (Am) into the public environment could contaminate large numbers of people by inhalation. If measures to reduce the internal dose are considered appropriate, oral administration of either calcium (Ca) or zinc (Zn) diethylenetriaminepenta-acetic acid (DTPA) would be the simplest treatment. Published experimental data from rats on the effects of oral DTPA on the retention of inhaled Pu and Am show that: (1) orally administered Zn-DTPA is as effective as repeated intravenous injection for the decorporation of Pu and Am inhaled as nitrates, although higher dosages are required; (2) oral Zn-DTPA appears to be an effective treatment for Am dioxide but not Pu dioxide; (3) maximum decorporation of Pu, by oral or intravenous administration, requires a large molar excess of Zn-DTPA over Pu (>1 x 10(6)); (4) neither oral nor injected Zn-DTPA are likely to be effective for Pu oxides, nor when Pu and Am nitrates are mixed with other dusts. It is concluded that oral administration of a simple aqueous solution of Zn-DTPA could be an important treatment in accident or emergency scenarios after intake of pure chemical forms of Pu and Am, which are highly or moderately soluble in biological fluids. However, more research is needed on the efficacy of treatment when these forms are mixed with other materials. Importantly, studies designed to increase the efficiency of uptake of DTPA from the gastrointestinal tract could appreciably reduce the dosage.