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Adipose tissue, which is crucial for the regulation of energy within the body, contains both white and brown adipocytes. White adipose tissue (WAT) primarily stores energy, while brown adipose tissue (BAT) plays a critical role in energy dissipation as heat, offering potential for therapies aimed at enhancing metabolic health. Regulation of the RhoA/ROCK pathway is crucial for appropriate specification, differentiation and maturation of both white and brown adipocytes. However, our knowledge of how this pathway is controlled within specific adipose depots remains unclear, and to date a RhoA regulator that selectively controls adipocyte browning has not been identified. Our study shows that GRAF1, a RhoGAP, is highly expressed in metabolically active tissues, and closely correlates with brown adipocyte differentiation in culture and in vivo. Mice with either global or adipocyte-specific GRAF1 deficiency exhibit impaired BAT maturation and compromised cold-induced thermogenesis. Moreover, defects in differentiation of human GRAF1-deficient brown preadipocytes can be rescued by treatment with a Rho kinase inhibitor. Collectively, these studies indicate that GRAF1 can selectively induce brown adipocyte differentiation and suggest that manipulating GRAF1 activity may hold promise for the future treatment of diseases related to metabolic dysfunction., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Tolerance and resistance are two host eco-immunological strategies in response to microparasite invasion. In the strategy of "resistance", host responses are induced to decrease microparasite replication while the "tolerance" strategy allows hosts coexistence with microparasites by minimizing responses to avoid immune-mediated damage. The causative agent of Lyme disease is a group of genotypically diverse bacterial species, Borrelia burgdorferi sensu lato (Bb), which is transmitted by Ixodes ticks and persists in different reservoir animals. In North America, eastern fence lizards (Sceloporus undulatus) can be fed on by Ixodes ticks but are incompetent to one genotype of Bb (i.e., ospC type A). However, field-collected lizards showed evidence of previous infection by Bb strains with undefined genotypes. Supporting this evidence, we introduced three genotypically different Bb strains individually to eastern fence lizards and found a Bb genotype-dependent manner of infectivity. We compared liver transcriptomics and observed elevated immune responses triggered by a lizard-incompetent Bb strain (strain B31). We showed two lizard-competent strains with one having no immunomodulation (strain B379) but the other developing upregulated immune responses (strain 297). These results suggest that genetic variation in microparasites both induces different host strategies for dealing with infection and determines microparasite fitness in the hosts. These findings demonstrate that Bb and eastern fence lizards can serve as a model to investigate the mechanisms underlying eco-immunological strategies of tolerance vs. resistance during host-microparasite interaction., Competing Interests: Declarations of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Ultrasonography is an excellent investigative tool that can assist with the diagnosis of soft tissue conditions. In human medicine, ultrasonography is a fundamental diagnostic tool for the investigation of suspected vegetal foreign bodies (VFB), with protocol-based ultrasonography providing increased accuracy compared to lesion-focused examinations. Protocol-based ultrasonography is an emerging tool within the veterinary field, however, compared to human medicine is not routinely employed. The objective of this study was to develop a systematic ultrasound protocol to examine the distal limb for the visualization of vegetal foreign bodies (SUEDVEG). A 12 MHz linear and an 18 MHz high-frequency small-footprint linear array transducer was used on cadaver forelimbs ( n  = 6) and hindlimbs ( n  = 6) with images obtained from three common foreign body locations within the distal limb; 1; the interdigital webbing, 2; the palmar/plantar aspect of the phalanges and metacarpus and 3; the dorsal region of the phalanges and metacarpus. From these images, a 13-step systematic musculoskeletal protocol was developed and utilized on eight clinical cases or 10 limbs that had signs typical of distal limb VFB to preliminarily validate the proposed method. Vegetal foreign bodies were successfully identified and retrieved in seven ( n  = 8) clinical cases with method steps 9 and 11 (orthogonal views) identifying the majority of VFBs. The described ultrasound method appears highly useful for visualizing soft tissue locations of the canine distal limb known for tracking foreign bodies. Further studies are required to validate the described systematic examination method as the preferred clinical protocol over currently used lesion-focused exploration techniques., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schoenfeld, Combs, Callcott, Jermyn and Rotne.)

Menthol cigarette use is disproportionately higher among sexual- and gender-minoritized (SGM; 36%) individuals compared to cisgender, heterosexual (29%), individuals. The FDA has announced intentions to ban menthol in cigarettes, citing these use and health disparities as partial motivation. This study identified potential outcomes of a menthol cigarette ban among SGM individuals who smoke menthol cigarettes (N = 72). Potential outcomes were identified via concept mapping using the prompt: "If menthol in cigarettes was banned, a specific action I would take related to my tobacco use is…" Participants generated 82 response statements, sorted them, and rated them on personal relevance. Eight thematic clusters were identified: (1) Thoughtful Consideration of the Ban, (2) Negative Reactions to the Ban, (3) Positive Aspects of the Ban, (4) Strategies to Reduce Cravings, (5) Intent to Quit and Cessation Strategies, (6) Support-Seeking and Engagement in Positive Behaviors, (7) Strategies to Maintain Menthol-Flavored Product Use, and (8) Substance Use Alternatives to Menthol Cigarettes. Cluster differences based on sociodemographic factors, smoking behavior, and quitting interest were identified. Results provide insight into potential responses to a menthol cigarette ban and can contribute to public health prevention and intervention efforts, messaging campaigns, and support services for SGM people who smoke menthol cigarettes, specifically.

Alternative splicing is an RNA processing mechanism involved in skeletal muscle development and pathology. Muscular diseases exhibit splicing alterations and changes in mechanobiology leading us to investigate the interconnection between mechanical forces and RNA processing. We performed deep RNA-sequencing after stretching muscle cells. First, we uncovered transcriptional changes in genes encoding proteins involved in muscle function and transcription. Second, we observed that numerous mechanosensitive genes were part of the MAPK pathway which was activated in response to stretching. Third, we revealed that stretching skeletal muscle cells increased the proportion of alternatively spliced cassette exons and their inclusion. Fourth, we demonstrated that the serine and arginine-rich proteins exhibited stronger transcriptional changes than other RNA-binding proteins and that SRSF4 phosphorylation is mechanosensitive. Identifying SRSF4 as a mechanosensitive RNA-binding protein that might contribute to crosstalk between mechanotransduction, transcription, and splicing could potentially reveal novel insights into muscular diseases, particularly those with unknown etiologies., (© 2022. The Author(s).)

Host association-the selective adaptation of pathogens to specific host species-evolves through constant interactions between host and pathogens, leaving a lot yet to be discovered on immunological mechanisms and genomic determinants. The causative agents of Lyme disease (LD) are spirochete bacteria composed of multiple species of the Borrelia burgdorferi sensu lato complex, including B. burgdorferi ( Bb ), the main LD pathogen in North America-a useful model for the study of mechanisms underlying host-pathogen association. Host adaptation requires pathogens' ability to evade host immune responses, such as complement, the first-line innate immune defense mechanism. We tested the hypothesis that different host-adapted phenotypes among Bb strains are linked to polymorphic loci that confer complement evasion traits in a host-specific manner. We first examined the survivability of 20 Bb strains in sera in vitro and/or bloodstream and tissues in vivo from rodent and avian LD models. Three groups of complement-dependent host-association phenotypes emerged. We analyzed complement-evasion genes, identified a priori among all strains and sequenced and compared genomes for individual strains representing each phenotype. The evolutionary history of ospC loci is correlated with host-specific complement-evasion phenotypes, while comparative genomics suggests that several gene families and loci are potentially involved in host association. This multidisciplinary work provides novel insights into the functional evolution of host-adapted phenotypes, building a foundation for further investigation of the immunological and genomic determinants of host association. IMPORTANCE Host association is the phenotype that is commonly found in many pathogens that preferential survive in particular hosts. The Lyme disease (LD)-causing agent, B. burgdorferi ( Bb ), is an ideal model to study host association, as Bb is mainly maintained in nature through rodent and avian hosts. A widespread yet untested concept posits that host association in Bb strains is linked to Bb functional genetic variation conferring evasion to complement, an innate defense mechanism in vertebrate sera. Here, we tested this concept by grouping 20 Bb strains into three complement-dependent host-association phenotypes based on their survivability in sera and/or bloodstream and distal tissues in rodent and avian LD models. Phylogenomic analysis of these strains further correlated several gene families and loci, including ospC , with host-specific complement-evasion phenotypes. Such multifaceted studies thus pave the road to further identify the determinants of host association, providing mechanistic insights into host-pathogen interaction.

Predicting pathogen emergence and spillover risk requires understanding the determinants of a pathogens' host range and the traits involved in host competence. While host competence is often considered a fixed species-specific trait, it may be variable if pathogens diversify across hosts. Balancing selection can lead to maintenance of pathogen polymorphisms (multiple-niche-polymorphism; MNP). The causative agent of Lyme disease, Borrelia burgdorferi ( Bb ), provides a model to study the evolution of host adaptation, as some Bb strains defined by their outer surface protein C ( ospC ) genotype, are widespread in white-footed mice and others are associated with non-rodent vertebrates (e.g. birds). To identify the mechanisms underlying potential strain × host adaptation, we infected American robins and white-footed mice, with three Bb strains of different ospC genotypes. Bb burdens varied by strain in a host-dependent fashion, and strain persistence in hosts largely corresponded to Bb survival at early infection stages and with transmission to larvae (i.e. fitness). Early survival phenotypes are associated with cell adhesion, complement evasion and/or inflammatory and antibody-mediated removal of Bb, suggesting directional selective pressure for host adaptation and the potential role of MNP in maintaining OspC diversity. Our findings will guide future investigations to inform eco-evolutionary models of host adaptation for microparasites.

Brown rats (Rattus norvegicus) thrive in urban environments by navigating the anthropocentric environment and taking advantage of human resources and by-products. From the human perspective, rats are a chronic problem that causes billions of dollars in damage to agriculture, health, and infrastructure. Did genetic adaptation play a role in the spread of rats in cities? To approach this question, we collected whole-genome sequences from 29 brown rats from New York City (NYC) and scanned for genetic signatures of adaptation. We tested for 1) high-frequency, extended haplotypes that could indicate selective sweeps and 2) loci of extreme genetic differentiation between the NYC sample and a sample from the presumed ancestral range of brown rats in northeast China. We found candidate selective sweeps near or inside genes associated with metabolism, diet, the nervous system, and locomotory behavior. Patterns of differentiation between NYC and Chinese rats at putative sweep loci suggest that many sweeps began after the split from the ancestral population. Together, our results suggest several hypotheses on adaptation in rats living in proximity to humans., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

As the rate of urbanization continues to increase globally, a growing body of research is emerging that investigates how urbanization shapes the movement-and consequent gene flow-of species in cities. Of particular interest are native species that persist in cities, either as small relict populations or as larger populations of synanthropic species that thrive alongside humans in new urban environments. In this study, we used genomic sequence data (SNPs) and spatially explicit individual-based analyses to directly compare the genetic structure and patterns of gene flow in two small mammals with different dispersal abilities that occupy the same urbanized landscape to evaluate how mobility impacts genetic connectivity. We collected 215 white-footed mice ( Peromyscus leucopus ) and 380 big brown bats ( Eptesicus fuscus ) across an urban-to-rural gradient within the Providence, Rhode Island (U.S.A.) metropolitan area (population =1,600,000 people). We found that mice and bats exhibit clear differences in their spatial genetic structure that are consistent with their dispersal abilities, with urbanization having a stronger effect on Peromyscus mice. There were sharp breaks in the genetic structure of mice within the Providence urban core, as well as reduced rates of migration and an increase in inbreeding with more urbanization. In contrast, bats showed very weak genetic structuring across the entire study area, suggesting a near-panmictic gene pool likely due to the ability to disperse by flight. Genetic diversity remained stable for both species across the study region. Mice also exhibited a stronger reduction in gene flow between island and mainland populations than bats. This study represents one of the first to directly compare multiple species within the same urban-to-rural landscape gradient, an important gap to fill for urban ecology and evolution. Moreover, here we document the impacts of dispersal capacity on connectivity for native species that have persisted as the urban landscape matrix expands., Competing Interests: None declared., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Urban Norway rats ( Rattus norvegicus ) carry several pathogens transmissible to people. However, pathogen prevalence can vary across fine spatial scales (i.e., by city block). Using a population genomics approach, we sought to describe rat movement patterns across an urban landscape and to evaluate whether these patterns align with pathogen distributions. We genotyped 605 rats from a single neighborhood in Vancouver, Canada, and used 1,495 genome-wide single nucleotide polymorphisms to identify parent-offspring and sibling relationships using pedigree analysis. We resolved 1,246 pairs of relatives, of which only 1% of pairs were captured in different city blocks. Relatives were primarily caught within 33 meters of each other leading to a highly leptokurtic distribution of dispersal distances. Using binomial generalized linear mixed models, we evaluated whether family relationships influenced rat pathogen status with the bacterial pathogens Leptospira interrogans , Bartonella tribocorum , and Clostridium difficile , and found that an individual's pathogen status was not predicted any better by including disease status of related rats. The spatial clustering of related rats and their pathogens lends support to the hypothesis that spatially restricted movement promotes the heterogeneous patterns of pathogen prevalence evidenced in this population. Our findings also highlight the utility of evolutionary tools to understand movement and rat-associated health risks in urban landscapes., Competing Interests: None declared., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Urbanization exposes species to novel environments and selection pressures that may change morphological traits within a population. We investigated how the shape and size of crania and mandibles changed over time within a population of brown rats ( Rattus norvegicus ) living in Manhattan, New York, USA, a highly urbanized environment. We measured 3D landmarks on the cranium and mandible of 62 adult individuals sampled in the 1890s and 2010s. Static allometry explained approximately 22% of shape variation in crania and mandible datasets, while time accounted for approximately 14% of variation. We did not observe significant changes in skull size through time or between the sexes. Estimating the P-matrix revealed that directional selection explained temporal change of the crania but not the mandible. Specifically, rats from the 2010s had longer noses and shorter upper molar tooth rows, traits identified as adaptive to colder environments and higher quality or softer diets, respectively. Our results highlight the continual evolution to selection pressures. We acknowledge that urban selection pressures impacting cranial shape likely began in Europe prior to the introduction of rats to Manhattan. Yet, our study period spanned changes in intensity of artificial lighting, human population density, and human diet, thereby altering various aspects of rat ecology and hence pressures on the skull., Competing Interests: The authors have no conflicts of interest., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Regulation of cellular death is central to nearly all physiological routines and is dysregulated in virtually all diseases. Cell death occurs by two major processes, necrosis which culminates in a pervasive inflammatory response and apoptosis which is largely immunologically inert. As necrosis has long been considered an accidental, unregulated form of cellular death that occurred in response to a harsh environmental stimulus, it was largely ignored as a clinical target. However, recent elegant studies suggest that certain forms of necrosis can be reprogrammed. However, scant little is known about the molecules and pathways that orchestrate calcium-overload-induced necrosis, a main mediator of ischemia/reperfusion (IR)-induced cardiomyocyte cell death. To rectify this critical gap in our knowledge, we performed a novel genome-wide siRNA screen to identify modulators of calcium-induced necrosis in human muscle cells. Our screen identified multiple molecular circuitries that either enhance or inhibit this process, including lysosomal calcium channel TPCN1, mitophagy mediatorTOMM7, Ran-binding protein RanBP9, Histone deacetylase HDAC2, chemokine CCL11, and the Arp2/3 complex regulator glia maturation factor-γ (GMFG). Notably, a number of druggable enzymes were identified, including the proteasome β5 subunit (encoded by PSMB5 gene), which controls the proteasomal chymotrypsin-like peptidase activity. Such findings open up the possibility for the discovery of pharmacological interventions that could provide therapeutic benefits to patients affected by myriad disorders characterized by excessive (or too little) necrotic cell loss, including but not limited to IR injury in the heart and kidney, chronic neurodegenerative disorders, muscular dystrophies, sepsis, and cancers., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

In Australia, compulsory microchipping legislation requires that animals are microchipped before sale or prior to 3 months in the Australian Capital Territory, New South Wales, Queensland and Victoria, and by 6 months in Western Australia and Tasmania. Describing the implementation of microchipping in animals allows the data guardians to identify individual animals presenting to differing veterinary practices over their lifetimes, and to evaluate compliance with legislation. VetCompass Australia (VCA) collates electronic patient records from primary care veterinary practices into a database for epidemiological studies. VCA is the largest companion animal clinical data repository of its kind in Australia, and is therefore the ideal resource to analyse microchip data as a permanent unique identifier of an animal. The current study examined the free-text 'examination record' field in the electronic patient records of 1000 randomly selected dogs and cats in the VCA database. This field may allow identification of the date of microchip implantation, enabling comparison with other date fields in the database, such as date of birth. The study revealed that the median age at implantation for dogs presented as individual patients, rather than among litters, was 74.4 days, significantly lower than for cats (127.0 days, p = 0.003). Further exploration into reasons for later microchipping in cats may be useful in aligning common practice with legislative requirements.

The neuroactive mycotoxin lolitrem B causes a neurological syndrome in grazing livestock resulting in hyperexcitability, muscle tremors, ataxia and, in severe cases, clonic seizures and death. To define the effects of the major toxin lolitrem B in the brain, a functional metabolomic study was undertaken in which motor coordination and tremor were quantified and metabolomic profiling undertaken to determine relative abundance of both toxin and key neurotransmitters in various brain regions in male mice. Marked differences were observed in the duration of tremor and coordination between lolitrem B pathway members, with some showing protracted effects and others none at all. Lolitrem B was identified in liver, kidney, cerebral cortex and thalamus but not in brainstem or cerebellum which were hypothesised previously to be the primary site of action. Metabolomic profiling showed significant variation in specific neurotransmitter and amino acid profiles over time. This study demonstrates accumulation of lolitrem B in the brain, with non-detectable levels of toxin in the brainstem and cerebellum, inducing alterations in metabolites such as tyrosine, suggesting a dynamic catecholaminergic response over time. Temporal characterisation of key pathways in the pathophysiological response of lolitrem B in the brain were also identified.

Urbanization often substantially influences animal movement and gene flow. However, few studies to date have examined gene flow of the same species across multiple cities. In this study, we examine brown rats ( Rattus norvegicus ) to test hypotheses about the repeatability of neutral evolution across four cities: Salvador, Brazil; New Orleans, USA; Vancouver, Canada; and New York City, USA. At least 150 rats were sampled from each city and genotyped for a minimum of 15 000 genome-wide single nucleotide polymorphisms. Levels of genome-wide diversity were similar across cities, but varied across neighbourhoods within cities. All four populations exhibited high spatial autocorrelation at the shortest distance classes (less than 500 m) owing to limited dispersal. Coancestry and evolutionary clustering analyses identified genetic discontinuities within each city that coincided with a resource desert in New York City, major waterways in New Orleans, and roads in Salvador and Vancouver. Such replicated studies are crucial to assessing the generality of predictions from urban evolution, and have practical applications for pest management and public health. Future studies should include a range of global cities in different biomes, incorporate multiple species, and examine the impact of specific characteristics of the built environment and human socioeconomics on gene flow., (© 2018 The Author(s).)

VetCompass Australia is veterinary medical records-based research coordinated with the global VetCompass endeavor to maximize its quality and effectiveness for Australian companion animals (cats, dogs, and horses). Bringing together all seven Australian veterinary schools, it is the first nationwide surveillance system collating clinical records on companion-animal diseases and treatments. VetCompass data service collects and aggregates real-time, clinical records for researchers to interrogate, delivering sustainable and cost-effective access to data from hundreds of veterinary practitioners nationwide. Analysis of these clinical records will reveal geographical and temporal trends in the prevalence of inherited and acquired diseases, identify frequently prescribed treatments, revolutionize clinical auditing, help the veterinary profession to rank research priorities, and assure evidence-based companion-animal curricula in veterinary schools. VetCompass Australia will progress in three phases: (1) roll-out of the VetCompass platform to harvest Australian veterinary clinical record data; (2) development and enrichment of the coding (data-presentation) platform; and (3) creation of a world-first, real-time surveillance interface with natural language processing (NLP) technology. The first of these three phases is described in the current article. Advances in the collection and sharing of records from numerous practices will enable veterinary professionals to deliver a vastly improved level of care for companion animals that will improve their quality of life., Competing Interests: The authors declare no conflicts of interest.

Aim: Differences in children's development and susceptibility to diseases and exposures have been observed by sex, yet human studies of sex differences in miRNAs are limited., Materials & Methods: The genome-wide miRNA expression was characterized by sequencing-based EdgeSeq assay in cord blood buffy coats from 89 newborns, and 564 miRNAs were further analyzed., Results: Differential expression of most miRNAs was higher in boys. Neurodevelopment, RNA metabolism and metabolic ontology terms were enriched among miRNA targets. The majority of upregulated miRNAs (86%) validated by nCounter maintained positive-fold change values; however, only 21% reached statistical significance by false discovery rate., Conclusion: Accounting for host factors like sex may improve the sensitivity of epigenetic analyses for epidemiological studies in early childhood., Competing Interests: Financial & competing interests disclosure This work was supported by grants 1R01ES023067 and PO1 ES009605 from the National Institute of Environmental Health Science (NIEH) and RD83451301 from the US Environmental Protection Agency (EPA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Native to China and Mongolia, the brown rat (Rattus norvegicus) now enjoys a worldwide distribution. While black rats and the house mouse tracked the regional development of human agricultural settlements, brown rats did not appear in Europe until the 1500s, suggesting their range expansion was a response to relatively recent increases in global trade. We inferred the global phylogeography of brown rats using 32 k SNPs, and detected 13 evolutionary clusters within five expansion routes. One cluster arose following a southward expansion into Southeast Asia. Three additional clusters arose from two independent eastward expansions: one expansion from Russia to the Aleutian Archipelago, and a second to western North America. Westward expansion resulted in the colonization of Europe from which subsequent rapid colonization of Africa, the Americas and Australasia occurred, and multiple evolutionary clusters were detected. An astonishing degree of fine-grained clustering between and within sampling sites underscored the extent to which urban heterogeneity shaped genetic structure of commensal rodents. Surprisingly, few individuals were recent migrants, suggesting that recruitment into established populations is limited. Understanding the global population structure of R. norvegicus offers novel perspectives on the forces driving the spread of zoonotic disease, and aids in development of rat eradication programmes., (© 2016 The Author(s).)

Background: Rapid uptake of vitamin C into blood and retention in tissues are important indicators of the efficacy of vitamin C supplementation and its immune-supporting role. The objective of this study was to evaluate the bioavailability of vitamin C in plasma (reflective of recent intake) and leukocytes (reflective of tissue stores and influences on immune function) from a novel vitamin C formulation, Ester-C(®)., Methods: The study was a double-blind, placebo-controlled, crossover trial. Thirty-six subjects, 18-60 years of age, were randomized to receive placebo (PL, 0 mg vitamin C), ascorbic acid (AA, 1000 mg vitamin C), and Ester-C(®) (EC, 1000 mg vitamin C). Plasma and leukocyte vitamin C were measured baseline and at 2, 4, 8 and 24 h postdose., Results: The concentration and percent change from baseline in plasma were significantly higher with EC at all time points when compared to PL. No significant differences between EC and AA were observed in plasma concentration. Maximum plasma concentration was higher for EC compared to AA (P = 0.039) and PL (P < 0.001). Plasma area under the curve (AUC0-24h) was higher for EC (P < 0.001) compared to PL. The concentration change from baseline in leukocyte vitamin C was increased with EC at 24 h post-dose (P = 0.036) while no significant within-group changes were observed in AA or PL at any time point. The percent change in leukocyte vitamin C concentration was higher for EC at 8 and 24 h compared to AA (P = 0.028 and P = 0.034, respectively) and PL (P = 0.042 and P = 0.036, respectively)., Conclusions: A single dose of EC resulted in favorable percent change in leukocyte vitamin C concentration compared to AA and PL, indicating EC is retained longer within leukocytes. Trial registration ClinicalTrials.gov Identifier NCT01852903.

Objective: This article describes the process of adapting and implementing a complex, multicomponent intervention for a new population. Specifically, the article delineates the development and implementation of the Fostering Healthy Futures for Teens (FHF-T) program, which is an adaptation and extension of the Fostering Healthy Futures ® (FHF) preventive intervention. FHF is a 9-month mentoring and skills group program for 9 to 11 year olds recently placed in foster care. Following the designation of FHF as an evidence-based intervention, there was increasing demand for the program. However, the narrow population for which FHF had demonstrated efficacy limited broader implementation of the existing intervention. FHF-T was designed to extend the reach of the program by adapting the FHF intervention for adolescents in the early years of high school who have a history of out-of-home care. Specifically, this adaptation recognizes key developmental differences between preadolescent and adolescent populations., Method: After designing a program model and adapting the program components, the FHF-T mentoring program was implemented with 42 youth over 2 program years., Results: Of the teens who were offered the program, 75% chose to enroll, and 88% of those graduated 9 months later. Although the program evidenced high rates of uptake and participant satisfaction, some unexpected challenges were encountered that will need to be addressed in future iterations of the program., Conclusions: Too often program adaptations are made without careful consideration of important contextual issues, and too infrequently, these adapted programs are studied. Our process of program adaptation with rigorous measurement of program implementation provides a useful model for other evidence-based programs seeking thoughtful adaptation.

Objective: The aim was to identify clinical parameters and immunohistochemical markers predictive of recurrence and overall survival (OS) in a community cohort of patients with primary uterine leiomyosarcoma (ULMS)., Methods/materials: All patients with new diagnosis of ULMS from 1999 to 2007 were identified from the Kaiser Permanente Northern California pathology database. A retrospective chart review was performed to gather demographic and clinical data. The primary outcomes were recurrence-free survival and OS. In addition, a subset of tumor samples was available to analyze 3 immunohistochemical markers using tissue microarray techniques; these are as follows: estrogen receptor (ER) alpha, epidermal growth factor receptor (EGFR), and Ki-67., Results: Seventy-five patients with ULMS were identified, of which 63 had adequate tumor tissue available for immunohistochemical evaluation. The median follow-up for all stages was 28 months. The rate of recurrence or progressive disease was 76% for stage I patients compared with 85% for stage II to IV patients. At 3 years, 37% of stage I patients were recurrence free compared with 27% of stage II to IV patients. Overall survival for stage I patients declined from 64% to 38% between 3 and 5 years while remaining stable at 30% for stage II to IV patients. In multivariable analysis, increasing mitotic counts were associated with increased risk of recurrence (hazards ratio [HR], 3.2; P = 0.013) and a trend toward decreased OS (HR, 2.2; P = 0.10). Expression of ER (HR, 1.0), EGFR expression (HR, 1.0), and Ki-67 expression (HR, 1.0) were not predictive of recurrence or OS., Conclusions: Recurrence rate of 76% for patients with stage I ULMS was higher than previously published cohorts. Mitotic counts were associated with increased recurrence and decreased OS. Expressions of ER, EGFR, and Ki-67 were not useful for predicting overall recurrence or survival.

Purpose: FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down-regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine transition in the FAS promoter region (position -1377) is thought to reduce stimulatory protein 1 transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. The same authors have shown that the presence of an adenine residue rather than a guanine residue at -1,377 bp significantly attenuates transcription factor stimulatory protein 1 binding and may contribute to a reduction in FAS expression and ultimately to the enrichment of apoptosis-resistant clones in AML. We hypothesized that FAS genotype by altering susceptibility to apoptosis might affect outcome of childhood AML therapy., Experimental Design: Four hundred forty-four children treated for de novo AML on a uniform protocol were genotyped for FAS 1377., Results: There were no significant differences in overall survival, event-free survival, treatment-related mortality, or relapse rate between patients with FAS 1377GG genotype versus 1377GA/1377AA genotypes., Conclusions: FAS 1377 genotype does not alter outcome of de novo AML in children.

Aims: Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at > or =0.5 but <3 microg ml(-1). It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg(-1) day(-1). The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented., Methods: Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg(-1)) and 16 in a multiple-dose study [6 mg kg(-1) day(-1) once daily for 5 days or twice daily (12 mg kg(-1) day(-1)) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed., Results: The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg(-1) day(-1)) in the multiple-dose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg(-1) day(-1) group achieved trough concentrations that were within the therapeutic window. Conclusions Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg(-1) day(-1) range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.

Objective: The authors investigate the recovery of gastrointestinal motility in the fed and fasted state after laparoscopic and open cholecystectomy., Summary Background Data: Clinical recovery after laparoscopic cholecystectomy is known to be more rapid than after conventional open cholecystectomy. However, the actual effect of a laparoscopic approach on gastrointestinal motility, particularly fed-state motility, is not well investigated., Methods: Laparoscopic (LAP, n=6) or open (OPEN, n=6) cholecystectomy was performed in 12 dogs. Bipolar recording electrodes were placed on the antrum, small intestine, and the transverse and descending colon, and fasting myoelectric data were recorded after operation. Solid meal gastric emptying studies were performed before surgery and on postoperative days 1 and 2. Transit time studies were performed using 10 radiopaque markers., Results: Gastric emptying was significantly delayed in the OPEN group at 120 minutes on postoperative day 1 compared with pre-operative emptying (p<0.05), but was not delayed on postoperative day 2. Gastric emptying was not delayed in the LAP group after operation. Transit time was the same between groups. Gastric dysrhythmias were more frequent on postoperative day 3 (p<0.05) in the OPEN group. There were no significant differences in the presence, cycle length, or propagation velocity of the migrating motor complex on any postoperative day. Discrete or continuous electrical response activity in the colon was observed by postoperative day 1 in both groups., Conclusions: Fed-state motility is the only parameter for which laparoscopic cholecystectomy showed an improvement in postoperative recovery. Recovery of fasted gastrointestinal motility in dogs is equally rapid after either operation.

Background: Recent studies show that depending on the type of shock morphology used, 5% to 15% of patients requiring implantable defibrillators cannot be treated with a nonthoracotomy system. In these cases, an epicardial patch-based system becomes necessary. In this study, we investigated a newly developed epicardial carbon electrode as an alternative to a standard epicardial titanium patch., Methods and Results: A tubular epicardial braided carbon electrode of 7F diameter and 14-cm length applied in a U-shape to the epicardium was compared with a standard left ventricular epicardial 15-cm2 titanium mesh patch (CPI Inc). As cathode, a CPI endocardial lead, a Medtronic lead, or a carbon-platinum-iridium prototype electrode was used. Ventricular fibrillation was induced with a 60-Hz generator and allowed to continue for 10 seconds before a shock was given. Two different biphasic shock waveforms (3.2/2- and 6/6-millisecond) were delivered by the six electrode configurations. Eight dogs (weight, 24.5 +/- 1.3 kg) underwent an up-down defibrillation protocol. The order of testing the epicardial electrodes, the endocardial cathodes, and the waveform was randomized. With the epicardial carbon electrode, the mean defibrillation threshold (DFT) energy decreased 39% to 56% and the voltage decreased 24% to 35% compared with the titanium patch: from 8.3 +/- 2.5 to 4.9 +/- 3.6 J with the CPI lead and the 3.2/2-millisecond waveform, from 6.2 +/- 2.5 to 2.9 +/- 2.1 J with the carbon-platinum-iridium prototype, and from 6.4 +/- 3.4 J to 3.5 +/- 2.6 J with the Medtronic lead (P < or = .05). The DFT determinations with the 6/6-millisecond biphasic waveform showed a similar trend with slightly higher values., Conclusions: Compared with a titanium patch, the new braided epicardial electrode significantly decreases the defibrillation energy requirements. This effect can be maximized by using an endocardial carbon-platinum-iridium prototype as cathode and a short duration biphasic waveform.

A large research literature suggests that modelling in the absence of reinforcement for either the model's or the observer's behavior is a potent source of social learning. This literature is based entirely, however, on experiments using models that always display the critical behaviors. It is possible, therefore, that results obtained in these experiments would not generalize to natural settings in which modelling is intermittent. The effects of intermittent modelling were examined using three groups of 15 four- and five-year-old children. Male and female children from middle-income families were individually exposed to an adult model who alternated descriptions of pictures of common objects. With one group, the model used no descriptive adjectives (color or number) in her descriptions after baseline; she used descriptive adjectives with 50% of the pictures with a second group, and 100% of the pictures with a third. Analyses of the data showed that the children substantially increased their use of descriptive adjectives in both modelling groups, but not in the no-modelling group. The fact that there were no significant differences between the 50% and 100% modelling groups suggests that results obtained in studies using consistent modelling can be generalized to natural settings.