Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

A quantitative risk assessment of waterborne infectious disease in the inundation area of a tropical monsoon region

Flooding and inundation are annual events that occur during the rainy season in Cambodia, and inundation has a strong relationship with human health. This study simulated the coliform bacteria distribution using a hydraulic model and estimated the impact of inundation on public health using a dose–response model. The model parameters were calibrated using field survey data from Cambodia and obtained good agreement with the coliform group count distribution. The results suggest that the impact of inundation on human health is most noticeable in residential areas. The annual average risk of infection during medium-sized flood events is 0.21. The risk due to groundwater use ranges from 0.12 to 0.17 in inundation areas and reaches as high as 0.23 outside the inundation areas. The risk attributed to groundwater use is therefore higher than that for surface water use (0.02–0.06), except in densely populated areas at the city center. There is a high risk for infection with waterborne disease in residential areas, and the annual average risk during small flood events is 0.94. An assessment of possible countermeasures to reduce the risk shows that the control of inundation may bring more risk to public health in Cambodia. Shallower inundation water (<0.3 m) leads to a higher risk of infection, but if the depth is greater than 2 m, the risk is low in residential areas.The simulated results explain the spatial distributions of infection risk, which are vitally important for determining the highest priority places with relatively high risk and will be helpful for decision makers when considering the implementation of countermeasures

Acute medical unit comprehensive geriatric assessment intervention study (AMIGOS)

<p>Abstract</p> <p>Background</p> <p>Many older people presenting to Acute Medical Units (AMU) are discharged after only a short stay (< 72 hours), yet many re-present to hospital or die within 1 year. Comprehensive Geriatric Assessment may improve patient outcomes for this group.</p> <p>Method</p> <p>Participants</p> <p>Patients aged > 70 years and scoring positive on a risk screening tool ('Identification of Seniors At Risk') who are discharged within 72 hours of attending an AMU with a medical crisis, recruited prior to discharge. Sample size is 400. Carers of participants will also be recruited.</p> <p>Intervention</p> <p>Assessment on the AMU and further out-patient management by a specialist physician in geriatric medicine. Assessment and further management will follow the principles of Comprehensive Geriatric Assessment, providing advice and support to primary care services.</p> <p>Design</p> <p>Multi-centre, individual patient randomised controlled trial comparing intervention with usual care.</p> <p>Outcome measurement</p> <p>Follow up is by postal questionnaire 90 days after randomisation, and data will be entered into the study database by a researcher blind to allocation. The primary outcome is the number of days spent at home (for those admitted from home), or days spent in the same care home (if admitted from a care home). Secondary outcomes include mortality, institutionalisation, health and social care resource use, and scaled outcome measures, including quality of life, disability, mental well-being. Carer strain and well being will also be measured at 90 days.</p> <p>Analyses</p> <p>Comparisons of outcomes and costs, and a cost utility analysis between the intervention and control groups will be carried out.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN21800480">ISRCTN21800480</a></p

Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development

<p>Abstract</p> <p>Background</p> <p>Human clinical studies and mouse models clearly demonstrate that cytomegalovirus (CMV) disrupts normal organ and tissue development. Although CMV is one of the most common causes of major birth defects in humans, little is presently known about the mechanism(s) underlying CMV-induced congenital malformations. Our prior studies have demonstrated that CMV infection of first branchial arch derivatives (salivary glands and teeth) induced severely abnormal phenotypes and that CMV has a particular tropism for neural crest-derived mesenchyme (NCM). Since early embryos are barely susceptible to CMV infection, and the extant evidence suggests that the differentiation program needs to be well underway for embryonic tissues to be susceptible to viral infection and viral-induced pathology, the aim of this study was to determine if first branchial arch NCM cells are susceptible to mCMV infection prior to differentiation of NCM derivatives.</p> <p>Results</p> <p>E11 mouse mandibular processes (MANs) were infected with mouse CMV (mCMV) for up to 16 days <it>in vitr</it>o. mCMV infection of undifferentiated embryonic mouse MANs induced micrognathia consequent to decreased Meckel's cartilage chondrogenesis and mandibular osteogenesis. Specifically, mCMV infection resulted in aberrant stromal cellularity, a smaller, misshapen Meckel's cartilage, and mandibular bone and condylar dysmorphogenesis. Analysis of viral distribution indicates that mCMV primarily infects NCM cells and derivatives. Initial localization studies indicate that mCMV infection changed the cell-specific expression of FN, NF-κB2, RelA, RelB, and Shh and Smad7 proteins.</p> <p>Conclusion</p> <p>Our results indicate that mCMV dysregulation of key signaling pathways in primarily NCM cells and their derivatives severely disrupts mandibular morphogenesis and skeletogenesis. The pathogenesis appears to be centered around the canonical and noncanonical NF-κB pathways, and there is unusual juxtaposition of abnormal stromal cells and surrounding matrix. Moreover, since it is critically important that signaling molecules are expressed in appropriate cell populations during development, the aberrant localization of components of relevant signaling pathways may reveal the pathogenic mechanism underlying mandibular malformations.</p

Multi-Target Drugs: The Trend of Drug Research and Development

Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target–target and drug–drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future

Developing an agenda for research about policies to improve access to healthy foods in rural communities: a concept mapping study

Background Policies that improve access to healthy, affordable foods may improve population health and reduce health disparities. In the United States most food access policy research focuses on urban communities even though residents of rural communities face disproportionately higher risk for nutrition-related chronic diseases compared to residents of urban communities. The purpose of this study was to (1) identify the factors associated with access to healthy, affordable food in rural communities in the United States; and (2) prioritize a meaningful and feasible rural food policy research agenda. Methods This study was conducted by the Rural Food Access Workgroup (RFAWG), a workgroup facilitated by the Nutrition and Obesity Policy Research and Evaluation Network. A national sample of academic and non-academic researchers, public health and cooperative extension practitioners, and other experts who focus on rural food access and economic development was invited to complete a concept mapping process that included brainstorming the factors that are associated with rural food access, sorting and organizing the factors into similar domains, and rating the importance of policies and research to address these factors. As a last step, RFAWG members convened to interpret the data and establish research recommendations. Results Seventy-five participants in the brainstorming exercise represented the following sectors: non-extension research (n = 27), non-extension program administration (n = 18), “other� (n = 14), policy advocacy (n = 10), and cooperative extension service (n = 6). The brainstorming exercise generated 90 distinct statements about factors associated with rural food access in the United States; these were sorted into 5 clusters. Go Zones were established for the factors that were rated highly as both a priority policy target and a priority for research. The highest ranked policy and research priorities include strategies designed to build economic viability in rural communities, improve access to federal food and nutrition assistance programs, improve food retail systems, and increase the personal food production capacity of rural residents. Respondents also prioritized the development of valid and reliable research methodologies to measure variables associated with rural food access. Conclusions This collaborative, trans-disciplinary, participatory process, created a map to guide and prioritize research about polices to improve healthy, affordable food access in rural communities