Augmented TLR2 Expression on Monocytes in both Human Kawasaki Disease and a Mouse Model of Coronary Arteritis

BACKGROUND: Kawasaki disease (KD) of unknown immunopathogenesis is an acute febrile systemic vasculitis and the leading cause of acquired heart diseases in childhood. To search for a better strategy for the prevention and treatment of KD, this study compared and validated human KD immunopathogenesis in a mouse model of Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis. METHODS: Recruited subjects fulfilled the criteria of KD and were admitted for intravenous gamma globulin (IVIG) treatment at the Kaohsiung Chang Gung Memorial Hospital from 2001 to 2009. Blood samples from KD patients were collected before and after IVIG treatment, and cardiovascular abnormalities were examined by transthoracic echocardiography. Wild-type male BALB/c mice (4-week-old) were intraperitoneally injected with LCWE (1 mg/mL) to induce coronary arteritis. The induced immune response in mice was examined on days 1, 3, 7, and 14 post injections, and histopathology studies were performed on days 7 and 14. RESULTS: Both human KD patients and LCWE-treated mice developed coronary arteritis, myocarditis, valvulitis, and pericarditis, as well as elevated plasma levels of interleukin (IL)-2, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α in acute phase. Most of these proinflammatory cytokines declined to normal levels in mice, whereas normal levels were achieved in patients only after IVIG treatment, with a few exceptions. Toll-like receptor (TLR)-2, but not TLR4 surface enhancement on circulating CD14+ monocytes, was augmented in KD patients before IVIG treatment and in LCWE-treated mice, which declined in patients after IVIG treatment. CONCLUSION: This result suggests that that not only TLR2 augmentation on CD14+ monocytes might be an inflammatory marker for both human KD patients and LCWE-induced CAL mouse model but also this model is feasible for studying therapeutic strategies of coronary arteritis in human KD by modulating TLR2-mediated immune activation on CD14+ monocytes

Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

Environment Orientation : a structured simulation approach for agent-based complex systems

Complex systems are collections of independent agents interacting with each other and with their environment to produce emergent behaviour. Agent-based computer simulation is one of the main ways of studying complex systems. A naive approach to such simulation can fare poorly, due to large communication overhead, and due to the scope for deadlock between the interacting agents sharing a computational platform. Agent interaction can instead be considered entirely from the point of view of the environment(s) within which the agents interact. Structuring a simulation using such Environment Orientation leads to a simulation that reduces communication overhead, that is effectively deadlock-free, and yet still behaves in the manner required. Additionally the Environment Orientation architecture eases the development of more sophisticated large-scale simulations, with multiple kinds of complex agents, situated in and interacting with multiple kinds of environments. We describe the Environment Orientation simulation architecture. We report on a number of experiments that demonstrate the effectiveness of the Environment Orientation approach: a simple flocking system, a flocking system with multiple sensory environments, and a flocking system in an external environment

Temperature, recreational fishing and diapause egg connections : dispersal of spiny water fleas (Bythotrephes longimanus)

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in Biological Invasions 13 (2011): 2513-2531, doi:10.1007/s10530-011-0078-8.The spiny water flea (Bythotrephes longimanus) is spreading from Great Lakes coastal waters into northern inland lakes within a northern temperature-defined latitudinal band. Colonization of Great Lakes coastal embayments is assisted by winds and seiche surges, yet rapid inland expansion across the northern states comes through an overland process. The lack of invasions at Isle Royale National Park contrasts with rapid expansion on the nearby Keweenaw Peninsula. Both regions have comparable geology, lake density, and fauna, but differ in recreational fishing boat access, visitation, and containment measures. Tail spines protect Bythotrephes against young of the year, but not larger fish, yet the unusual thick-shelled diapausing eggs can pass through fish guts in viable condition. Sediment traps illustrate how fish spread diapausing eggs across lakes in fecal pellets. Trillions of diapausing eggs are produced per year in Lake Michigan and billions per year in Lake Michigamme, a large inland lake. Dispersal by recreational fishing is linked to use of baitfish, diapausing eggs defecated into live wells and bait buckets, and Bythothephes snagged on fishing line, anchor ropes, and minnow seines. Relatively simple measures, such as on-site rinsing of live wells, restricting transfer of certain baitfish species, or holding baitfish for 24 h (defecation period), should greatly reduce dispersal.Study of Lakes Superior and Michigan was funded from NSF OCE-9726680 and OCE-9712872 to W.C.K., OCE-9712889 to J. Churchill. Geographic survey sampling and Park studies in the national parks during 2008-2010 were funded by a grant from the National Park Service Natural Resource Preservation Program GLNF CESU Task Agreement No. J6067080012

The ubiquitin proteasome system in neuropathology

The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed

Translocation of Threatened New Zealand Falcons to Vineyards Increases Nest Attendance, Brooding and Feeding Rates

Anthropogenic landscapes can be rich in resources, and may in some cases provide potential habitat for species whose natural habitat has declined. We used remote videography to assess whether reintroducing individuals of the threatened New Zealand falcon Falco novaeseelandiae into a highly modified agricultural habitat affected the feeding rates of breeding falcons or related breeding behavior such as nest attendance and brooding rates. Over 2,800 recording hours of footage were used to compare the behavior of falcons living in six natural nests (in unmanaged, hilly terrain between 4 km and 20 km from the nearest vineyard), with that of four breeding falcon pairs that had been transported into vineyards and nested within 500 m of the nearest vineyard. Falcons in vineyard nests had higher feeding rates, higher nest attendance, and higher brooding rates. As chick age increased, parents in vineyard nests fed chicks a greater amount of total prey and larger prey items on average than did parents in hill nests. Parents with larger broods brought in larger prey items and a greater total sum of prey biomass. Nevertheless, chicks in nests containing siblings received less daily biomass per individual than single chicks. Some of these results can be attributed to the supplementary feeding of falcons in vineyards. However, even after removing supplementary food from our analysis, falcons in vineyards still fed larger prey items to chicks than did parents in hill nests, suggesting that the anthropogenic habitat may be a viable source of quality food. Although agricultural regions globally are rarely associated with raptor conservation, these results suggest that translocating New Zealand falcons into vineyards has potential for the conservation of this species