Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice

Androgens have profound effects on T cell homeostasis, including regulation of thymic T lymphopoiesis (thymopoiesis) and production of recent thymic emigrants (RTEs), i. e., immature T cells that derive from the thymus and continue their maturation to mature naive T cells in secondary lymphoid organs. Here we investigated the androgen target cell for effects on thymopoiesis and RTEs in spleen and lymph nodes. Male mice with a general androgen receptor knockout (G-ARKO), T cell-specific (T-ARKO), or epithelial cell-specific (E-ARKO) knockout were examined. G-ARKO mice showed increased thymus weight and increased numbers of thymic T cell progenitors. These effects were not T cell-intrinsic, since T-ARKO mice displayed unaltered thymus weight and thymopoiesis. In line with a role for thymic epithelial cells (TECs), E-ARKO mice showed increased thymus weight and numbers of thymic T cell progenitors. Further, E-ARKO mice had more CD4(+)and CD8(+)T cells in spleen and an increased frequency of RTEs among T cells in spleen and lymph nodes. Depletion of the androgen receptor in epithelial cells was also associated with a small shift in the relative number of cortical (reduced) and medullary (increased) TECs and increased CCL25 staining in the thymic medulla, similar to previous observations in castrated mice. In conclusion, we demonstrate that the thymic epithelium is a target compartment for androgen-mediated regulation of thymopoiesis and consequently the generation of RTEs

mTORC1-S6K Activation by Endotoxin Contributes to Cytokine Up-Regulation and Early Lethality in Animals

Background: mTORC1 (mammalian target of rapamycin complex 1) activation has been demonstrated in response to endotoxin challenge, but the mechanism and significance are unclear. We investigated the effect of mTORC1 suppression in an animal model of endotoxemia and in a cellular model of endotoxin signaling. Methodology/Principal Findings: Mice were treated with the mTORC1 inhibitor rapamycin or vehicle prior to lethal endotoxin challenge. Mortality and cytokine levels were assessed. Cultured macrophage-like cells were challenged with endotoxin with or without inhibitors of various pathways known to be upstream of mTORC1. Activated pathways, including downstream S6K pathway, were assessed by immunoblots. We found that mTORC1-S6K suppression by rapamycin delayed mortality of mice challenged with lethal endotoxin, and was associated with dampened circulating levels of VEGF, IL-1b, IFN-c and IL-5. Furthermore, in vitro cellular studies demonstrated that LPS (lipopolysaccharide) activation of mTORC1-S6K still occurs in the presence of PI3K-Akt inhibition alone, but can be suppressed by concurrent inhibition of PI3K-Akt and MEK-ERK pathways. Conclusions/Significance: We conclude that cellular activation of mTORC1-S6K contributes to cytokine up-regulation an

Elderly persons in the risk zone. Design of a multidimensional, health-promoting, randomised three-armed controlled trial for "prefrail" people of 80+ years living at home

Background The very old (80+) are often described as a "frail" group that is particularly exposed to diseases and functional disability. They are at great risk of losing the ability to manage their activities of daily living independently. A health-promoting intervention programme might prevent or delay dependence in activities of daily life and the development of functional decline. Studies have shown that those who benefit most from a health-promoting and disease-preventive programme are persons with no, or discrete, activity restrictions. The three-armed study "Elderly in the risk zone" is designed to evaluate if multi-dimensional and multi-professional educational senior meetings are more effective than preventive home visits, and if it is possible to prevent or delay deterioration if an intervention is made when the persons are not so frail. In this paper the study design, the intervention and the outcome measures as well as the baseline characteristics of the study participants are presented. Methods/Design The study is a randomised three-armed single-blind controlled trial with follow-ups 3 months, 1 and 2 years. The study group should comprise a representative sample of pre-frail 80-year old persons still living at home in two municipalities of Gothenburg. To allow for drop-outs, it was estimated that a total of about 450 persons would need to be included in the study. The participants should live in their ordinary housing and not be dependent on the municipal home help service or care. Further, they should be independent of help from another person in activities of daily living and be cognitively intact, having a score of 25 or higher as assessed with the Mini Mental State Examination (MMSE). Discussion We believe that the design of the study, the randomisation procedure, outcome measurements and the study protocol meetings should ensure the quality of the study. Furthermore, the multi-dimensionality of the intervention, the involvement of both the professionals and the senior citizens in the planning of the intervention should have the potential to effectively target the heterogeneous needs of the elderly. Trial registration ClinicalTrials.gov, NCT0087705

Fidelity and moderating factors in complex interventions: a case study of a continuum of care program for frail elderly people in health and social care

<p>Abstract</p> <p>Background</p> <p>Prior studies measuring fidelity of complex interventions have mainly evaluated adherence, and not taken factors affecting adherence into consideration. A need for studies that clarify the concept of fidelity and the function of factors moderating fidelity has been emphasized. The aim of the study was to systematically evaluate implementation fidelity and possible factors influencing fidelity of a complex care continuum intervention for frail elderly people.</p> <p>Methods</p> <p>The intervention was a systematization of the collaboration between a nurse with geriatric expertise situated at the emergency department, the hospital ward staff, and a multi-professional team with a case manager in the municipal care services for older people. Implementation was evaluated between September 2008 and May 2010 with observations of work practices, stakeholder interviews, and document analysis according to a modified version of The Conceptual Framework for Implementation Fidelity.</p> <p>Results</p> <p>A total of 16 of the 18 intervention components were to a great extent delivered as planned, while some new components were added to the model. No changes in the frequency or duration of the 18 components were observed, but the dose of the added components varied over time. Changes in fidelity were caused in a complex, interrelated fashion by all the moderating factors in the framework, i.e., context, staff and participant responsiveness, facilitation, recruitment, and complexity.</p> <p>Discussion</p> <p>The Conceptual Framework for Implementation Fidelity was empirically useful and included comprehensive measures of factors affecting fidelity. Future studies should focus on developing the framework with regard to how to investigate relationships between the moderating factors and fidelity over time.</p> <p>Trial registration</p> <p>ClinicalTrials.gov, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01260493">NCT01260493</a>.</p

Design of a randomized controlled study of a multi-professional and multidimensional intervention targeting frail elderly people

<p>Abstract</p> <p>Background</p> <p>Frail elderly people need an integrated and coordinated care. The two-armed study "Continuum of care for frail elderly people" is a multi-professional and multidimensional intervention for frail community-dwelling elderly people. It was designed to evaluate whether the intervention programme for frail elderly people can reduce the number of visits to hospital, increase satisfaction with health and social care and maintain functional abilities. The implementation process is explored and analysed along with the intervention. In this paper we present the study design, the intervention and the outcome measures as well as the baseline characteristics of the study participants.</p> <p>Methods/design</p> <p>The study is a randomised two-armed controlled trial with follow ups at 3, 6 and 12 months. The study group includes elderly people who sought care at the emergency ward and discharged to their own homes in the community. Inclusion criteria were 80 years and older <it>or </it>65 to 79 years with at least one chronic disease and dependent in at least one activity of daily living. Exclusion criteria were acute severely illness with an immediate need of the assessment and treatment by a physician, severe cognitive impairment and palliative care. The intention was that the study group should comprise a representative sample of frail elderly people at a high risk of future health care consumption. The intervention includes an early geriatric assessment, early family support, a case manager in the community with a multi-professional team and the involvement of the elderly people and their relatives in the planning process.</p> <p>Discussion</p> <p>The design of the study, the randomisation procedure and the protocol meetings were intended to ensure the quality of the study. The implementation of the intervention programme is followed and analysed throughout the whole study, which enables us to generate knowledge on the process of implementing complex interventions. The intervention contributes to early recognition of both the elderly peoples' needs of information, care and rehabilitation and of informal caregivers' need of support and information. This study is expected to show positive effects on frail elderly peoples' health care consumption, functional abilities and satisfaction with health and social care.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01260493">NCT01260493</a></p