Impaired insulin signaling in the B10.D2-Hc0 H2d H2-T18c/oSnJ mouse model of complement factor 5 deficiency.

Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2-Hc0 H2d H2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin-sensitizing function of C5.

Ethics and HIV prevention research: An analysis of the early tenofovir PrEP trial in Nigeria.

In 2004, the first ever multi-sited clinical trials studied the prospect of HIV biomedical prevention (referred to as pre-exposure prophylaxis-'PrEP'). The trials were implemented at several international sites, but many officially closed down before they completed. At most sites, both scientists and community AIDS advocates raised concerns over the ethics and scientific rationales of the trial. Focusing on the Nigerian trial site, we detail the controversy that emerged among mostly Nigerian research scientists who scrutinized the research design and protocol. While some of the disputes, especially those pertaining to community engagement mechanisms, were ultimately resolved in international fora and implemented in later PrEP trials, concerns over science rationales and assumptions were never addressed. We argue that scientific rationales should be treated as ethical concerns and suggest that such concerns should be deliberated at host sites before the trial protocol is finalized.

Macrophage-Targeted Therapeutics for Metabolic Disease.

Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.

Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments.

OBJECTIVE: Obesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness. METHODS: C57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity. RESULTS: Eosinophils were increased ∼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils. CONCLUSIONS: We have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate.

Iron homeostasis: a new job for macrophages in adipose tissue?

Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron-handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity.

The use of 14C-FIAU to predict bacterial thymidine kinase presence: implications for radiolabeled FIAU bacterial imaging.

UNLABELLED: Currently available infectious disease imaging techniques cannot differentiate between infection and sterile inflammation or between different types of infections. Recently, radiolabeled FIAU was found to be a substrate for the thymidine kinase (TK) enzyme of multiple pathogenic bacteria, leading to its translational use in the imaging of bacterial infections. Patients with immunodeficiencies, however, are susceptible to a different group of pathogenic bacteria when compared to immunocompetent subjects. In this study, we wanted to predict the usefulness of radiolabeled FIAU in the detection of bacterial infections commonly occurring in patients with immunodeficiencies, in vitro, prior to attempting in vivo imaging with (124)I-FIAU-PET. METHODS: We obtained representative strains of bacterial pathogens isolated from actual patients with genetic immunodeficiencies. We evaluated the bacterial susceptibility of different strains to the effect of incubation with FIAU, which would implicate the presence of the thymidine kinase (TK) enzyme. We also incubated the bacteria with (14)C-FIAU and consequently measured its rate of incorporation in the bacterial DNA using a liquid scintillation counter. RESULTS: Unlike the other bacterial strains, the growth of Pseudomonas aeruginosa was not halted by FIAU at any concentration. All the tested clinical isolates demonstrated different levels of (14)C-FIAU uptake, except for P. aeruginosa. CONCLUSION: Radiolabeled FIAU has been successful in delineating bacterial infections, both in preclinical and pilot translational studies. In patients with immunodeficiencies, Pseudomonas infections are commonly encountered and are usually difficult to differentiate from fungal infections. The use of radiolabeled FIAU for in vivo imaging of those patients, however, would not be useful, considering the apparent lack of TK enzyme in Pseudomonas. One has to keep in mind that not all pathogenic bacteria possess the TK enzyme and as such will not all retain FIAU. Our technique is simple, and can be easily used to assess whether a certain bacterial strain of interest can or cannot be visualized using radiolabeled FIAU.

Creating a learning healthcare system in surgery: Washington State's Surgical Care and Outcomes Assessment Program (SCOAP) at 5 years.

There are increasing efforts towards improving the quality and safety of surgical care while decreasing the costs. In Washington state, there has been a regional and unique approach to surgical quality improvement. The development of the Surgical Care and Outcomes Assessment Program (SCOAP) was first described 5 years ago. SCOAP is a peer-to-peer collaborative that engages surgeons to determine the many process of care metrics that go into a "perfect" operation, track on risk adjusted outcomes that are specific to a given operation, and create interventions to correct under performance in both the use of these process measures and outcomes. SCOAP is a thematic departure from report card oriented QI. SCOAP builds off the collaboration and trust of the surgical community and strives for quality improvement by having peers change behaviors of one another. We provide, here, the progress of the SCOAP initiative and highlight its achievements and challenges.

The Ascomycota tree of life: a phylum-wide phylogeny clarifies the origin and evolution of fundamental reproductive and ecological traits.

We present a 6-gene, 420-species maximum-likelihood phylogeny of Ascomycota, the largest phylum of Fungi. This analysis is the most taxonomically complete to date with species sampled from all 15 currently circumscribed classes. A number of superclass-level nodes that have previously evaded resolution and were unnamed in classifications of the Fungi are resolved for the first time. Based on the 6-gene phylogeny we conducted a phylogenetic informativeness analysis of all 6 genes and a series of ancestral character state reconstructions that focused on morphology of sporocarps, ascus dehiscence, and evolution of nutritional modes and ecologies. A gene-by-gene assessment of phylogenetic informativeness yielded higher levels of informativeness for protein genes (RPB1, RPB2, and TEF1) as compared with the ribosomal genes, which have been the standard bearer in fungal systematics. Our reconstruction of sporocarp characters is consistent with 2 origins for multicellular sexual reproductive structures in Ascomycota, once in the common ancestor of Pezizomycotina and once in the common ancestor of Neolectomycetes. This first report of dual origins of ascomycete sporocarps highlights the complicated nature of assessing homology of morphological traits across Fungi. Furthermore, ancestral reconstruction supports an open sporocarp with an exposed hymenium (apothecium) as the primitive morphology for Pezizomycotina with multiple derivations of the partially (perithecia) or completely enclosed (cleistothecia) sporocarps. Ascus dehiscence is most informative at the class level within Pezizomycotina with most superclass nodes reconstructed equivocally. Character-state reconstructions support a terrestrial, saprobic ecology as ancestral. In contrast to previous studies, these analyses support multiple origins of lichenization events with the loss of lichenization as less frequent and limited to terminal, closely related species.

Familial adenomatous polyposis in children younger than age ten years: a multidisciplinary clinic experience.

PURPOSE: Children with familial adenomatous polyposis have a greater mortality and morbidity in the first decade of life compared with the general population. Some children with a more severe disease phenotype present early with colorectal adenomata and may require colectomy at an early age. We present our multidisciplinary clinic experience with familial adenomatous polyposis in children younger than age ten years at the time of presentation. METHODS: A cross-sectional analysis was performed on all patients with suspected or confirmed familial adenomatous polyposis presenting in the first decade of life and followed by the multidisciplinary Pediatric Hereditary Polyposis Clinic at our institutions. Analysis included demographics, clinical presentation and course, gene mutation testing, endoscopic-histologic findings, and surgical outcome. RESULTS: Twenty-two children (11 males) presented with suspected or confirmed familial adenomatous polyposis. Two were discharged from follow-up after negative adenomatous polyposis coli gene mutation testing. The rest underwent annual hepatoblastoma surveillance through age ten years with negative findings. Twelve patients presented with symptoms: six had de novo familial adenomatous polyposis. Seven had gastrointestinal hemorrhage and went on to colonoscopy. Four patients with adenomatous polyposis coli gene mutation at codon 1309 were referred for colectomy before age ten years. Referral to colectomy was earlier in patients with 1309 mutation and with de novo familial adenomatous polyposis. CONCLUSIONS: Children with familial adenomatous polyposis younger than age ten years may present presymptomatically for disease surveillance. Familial adenomatous polyposis with adenomatous polyposis coli gene mutation at codon 1309 entails a risk of a more aggressive phenotype; early colectomy may be indicated in children harboring this gene mutation.