Sensory deprivation and motor restriction associated with extensive oxygen therapy may lead to poor oromotor control in preterm infants. Non-nutritive suck is one of the first complex oromotor behaviors infants perform. This study determined the spatiotemporal variability of non-nutritive suck (NNS) pressure trajectories in three preterm groups with differing oxygen histories—one control group with minimal or no O2 therapy, and two Respiratory Distress Syndrome (RDS) groups with either a mild/moderate (RDS1) or moderate/severe (RDS2) O2 history. The Non-nutritive Suck Spatiotemporal Index (NNS STI) quantifies spatial and temporal variability across kinematic trajectories, and was calculated from digital representations of infants’ suck pressure signals. An ANCOVA revealed a significant effect for group (p < .001) on the NNS STI measure, with RDS2 infants showing highly variable NNS patterning, and thus relatively underdeveloped suck. Extensive oxygen therapy, which alters the oral sensory environment and reduces motor experiences, disrupts the development of coordinated NNS in preterm infants.

Background

Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.

Methods

We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor–positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction–based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results

No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).

Conclusions

CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.

Research on language and aging typically shows that language comprehension is preserved across the life span. Recent neuroimaging results suggest that this good performance is underpinned by age-related neural reorganization [e.g., Tyler, L. K., Shafto, M. A., Randall, B., Wright, P., Marslen-Wilson, W. D., & Stamatakis, E. A. Preserving syntactic processing across the adult life span: The modulation of the frontotemporal language system in the context of age-related atrophy. Cerebral Cortex, 20, 352–364, 2010]. The current study examines how age-related reorganization affects the balance between component linguistic processes by manipulating semantic and phonological factors during spoken word recognition in younger and older adults. Participants in an fMRI study performed an auditory lexical decision task where words varied in their phonological and semantic properties as measured by degree of phonological competition and imageability. Older adults had a preserved lexicality effect, but compared with younger people, their behavioral sensitivity to phonological competition was reduced, as was competition-related activity in left inferior frontal gyrus. This was accompanied by increases in behavioral sensitivity to imageability and imageability-related activity in left middle temporal gyrus. These results support previous findings that neural compensation underpins preserved comprehension in aging and demonstrate that neural reorganization can affect the balance between semantic and phonological processing.

Pleiotropy across the 8q24 region is perhaps the most intriguing of the genome-wide association findings relating to cancer. This region of chromosome 8 is a gene desert, far from any recognized genes. Guarrera et al., whose work is reported in this issue (Am J Epidemiol. 2012;175(6):479–487), took an epidemiologic approach to learn more about the 8q24 region. They capitalized on their ascertainment of other endpoints in members of the cohort at the Turin site of the European Prospective Investigation Into Cancer and Nutrition to investigate multiple outcomes for additional pleiotropic effects in the 8q24 region. Alternative design options might involve genotyping of more variants, incorporation of more cases, or use of a single control group close to the size of the most common case group. Their analytic methods reflect the uncertainty of the underlying biology. The findings sharpen the scientific question about how variation in the 8q24 region affects pathogenesis. The genome-wide association effort is possible because of the economy of scale afforded by extremely dense genotyping. Strict adherence to the hypothesis-driven approach would ignore information that is obtainable at a trivial cost. The genome-wide association strategy tests whether agnostic data-mining methods can advance knowledge alongside or even in place of the standard hypothesis-driven approach, which is the conventional scientific method children learn in kindergarten and onward, even through graduate school and beyond.

Background

We evaluated factors associated with long-term dependence on percutaneous endoscopic gastrostomy (PEG) tubes.

Methods

154 patients receiving treatment at the University of Alabama at Birmingham between 2002 and 2004 who underwent PEG tube placement were identified through retrospective review of medical records. Using binary logistic regression, we evaluated the association of various factors on long-term dependence on PEG tubes.

Results

25.3% of survivors remained PEG tube dependent at 12 months. The odds of long-term PEG-tube dependence were greater for those who did not have partners compared with those who had partners (OR 3.33, p=0.004), for patients who received radiation therapy (OR 6.21, p=0.018), and for those who had a tracheotomy in place for longer than thirty days (OR 4.328, p=0.035).

Conclusions

Data suggest that interventions targeted at reducing long-term dependence on PEG tubes take into account not only treatment-related factors, but also the important role that social support plays.

Diseases transmitted by mosquitoes have a devastating impact on global health and the situation is complicated due to difficulties with both existing control measures and the impact of climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. The Streptomyces phage phiC31 integrase system has been successfully adapted for site-directed transgene integration in a range of insects, thus overcoming many limitations due to size constraints and random integration associated with transposon-mediated transformation. Using this technology, we previously published the first site-directed transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 docking site at a defined genomic location. A second phase of genetic modification then achieved site-directed integration of an anti-malarial effector gene. In the current publication we report improved efficiency and utility of the phiC31 integrase system following the generation of Anopheles gambiae self-docking strains. Four independent strains, with docking sites at known locations on three different chromosome arms, were engineered to express integrase under control of the regulatory regions of the nanos gene from Anopheles gambiae. The resulting protein accumulates in the posterior oocyte to provide integrase activity at the site of germline development. Two self-docking strains, exhibiting significantly different levels of integrase expression, were assessed for site-directed transgene integration and found to demonstrate greatly improved survival and efficiency of transformation. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters to regulate their expression, enabling those offering maximum effect with minimum fitness cost to be identified. The improved technology we describe here will facilitate comparative studies of effector transgenes, allowing informed choices to be made that potentially lead to transmission blockade.

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC50 = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC50: PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials.

New technologies may be required to integrate the National Institutes of Health’s Patient Reported Outcome Management Information System (PROMIS) into multi-center clinical trials. To better understand this need, we identified likely PROMIS reporting formats, developed a multi-center clinical trial process model, and identified gaps between current capabilities and those necessary for PROMIS. These results were evaluated by key trial constituencies. Issues reported by principal investigators fell into two categories: acceptance by key regulators and the scientific community, and usability for researchers and clinicians. Issues reported by the coordinating center, participating sites, and study subjects were those faced when integrating new technologies into existing clinical trial systems. We then defined elements of a PROMIS Tool Kit required for integrating PROMIS into a multi-center clinical trial environment. The requirements identified in this study serve as a framework for future investigators in the design, development, implementation, and operation of PROMIS Tool Kit technologies.

Purpose

A minority of early invasive breast cancers show a pattern of central necrosis and fibrosis (CNF). Previous studies have documented an adverse prognostic impact and association with other adverse pathological features, but its predictive importance for therapy selection is unknown.

Methods

We examined the prognostic and predictive value of CNF in two randomized clinical trials comparing chemoendocrine therapy with endocrine therapy alone in patients with node-negative breast cancer. A total of 1850 patients randomly assigned to treatment groups comparing endocrine with chemoendocrine therapy, and with centrally-assessed CNF, ER, PgR and HER2 were included in the analytic cohort. The median follow up was 10 years.

Results

CNF was present in 84 of 1850 trial patients (4.5%). It was associated with tumor characteristics suggesting poor outcome, but was an independent adverse factor for disease-free survival. In the presence of CNF outcome was worse regardless of tumor grade, whereas in the absence of CNF, patients with grade 3 tumors had poorer outcome than those with grade 1-2 tumors. Among patients with estrogen receptor-absent tumors chemoendocrine therapy was superior to endocrine therapy alone only in the absence of CNF [HR (chemoendocrine:endocrine)=0.46 in CNF-absent, 0.90 in CNF-present], while among those with receptor-positive disease chemoendocrine therapy was beneficial only in the presence of CNF [HR=0.34 CNF-present, 0.96 CNF-absent].

Conclusion

The results suggest that the presence of CNF reflects a biological difference in early breast cancer that is important in modulating the efficacy of standard therapies. Accordingly we believe that its presence should be routinely reported.

Objective

There are data suggesting that blood product transfusions increase the risk of developing acute lung injury (ALI) in adults, and may be associated with increased mortality in adults with ALI. A possible association between transfusions and adverse outcomes of pediatric patients with ALI has not been studied previously. We tested the hypothesis that blood product transfusions to pediatric patients with ALI within the first 72 hours of the diagnosis would be associated with increased mortality and prolonged mechanical ventilation.

Design

An epidemiologic database of pediatric ALI prospectively gathered from July 1996 to May 2000 was analyzed.

Setting

Children were enrolled from both a tertiary referral hospital and a major community children's hospital.

Patients

Three hundred fifteen patients who met the 1994 American European Consensus Committee definition of ALI between the ages of 36 weeks corrected gestational age and 18 years.

Main Outcome Measure

Mortality in the pediatric intensive care unit.

Results

Multivariate analyses indicated that the transfusion of fresh-frozen plasma (FFP) was associated with increased mortality, independent of the severity of hypoxemia (Pao2/Fio2), presence of multiple organ system failure or disseminated intravascular coagulation (odds ratio = 1.08, 95% confidence interval = 1.00–1.17, p = 0.04). FFP transfusion was analyzed as a continuous variable, so that for each milliliter of FFP transfused per kilogram patient body weight per day, the odds of death increased by 1.08. There was a trend toward an association of the transfusion of FFP with a fewer number of days of unassisted ventilation (regression coefficient = −0.21, 95% confidence interval = −0.42–0.01, p = 0.06).

Conclusions

The transfusion of FFP is associated with an increased risk of mortality in children with ALI. The association between FFP and mortality in children with ALI should be investigated further.

Objective

Von Willebrand factor antigen (vWF-Ag) is a marker of pulmonary and systemic endothelial activation and injury. Adult studies indicate that patients with plasma vWF-Ag levels ≥450% of control early in the course of acute lung injury (ALI) have an increased risk of death. The objective of this study was to evaluate whether vWF-Ag is elevated in the early phase of ALI in children and whether the magnitude of the increase was predictive of two important outcomes: mortality or duration of mechanical ventilation.

Design

Two-center, prospective observational study.

Setting

Two pediatric intensive care units: one in an academic university setting and one in a major community children's hospital.

Patients

After appropriate consent, plasma was collected from 48 pediatric patients on day 1 of ALI, 45 patients on day 2 of ALI, and four intubated controls.

Interventions

None.

Measurements and Main Results

Mean Pao2/Fio2 at the onset of ALI was 140 ± 70, and mortality rate was 17%. vWF-Ag levels on day 1 of ALI were higher in patients compared with controls (287 ±183 vs. 87 ± 84% of control [mean ± sd], p < .05). Patients with vWF-Ag levels ≥450% of control on day 1 of ALI had a markedly greater risk of death (odds ratio, 7.0; confidence interval, 1.31, 37.30; p < .05). Multivariate analysis revealed that elevated vWF-Ag level and either presence of multiple organ system failure or Pediatric Risk of Mortality III score independently predict increased risk of death. vWF-Ag levels on day 2 of ALI were significantly higher in patients who required prolonged mechanical ventilation (316 ±173 vs. 191 ± 89% of control, p < .05).

Conclusions

Early injury to the systemic and pulmonary endothelium, as measured by plasma vWF-Ag levels, is associated with an increased risk of death and prolonged mechanical ventilation in pediatric patients with ALI. (Pediatr Crit Care Med 2007; 8:96–101)

The complement system plays an important role in inflammatory and immune responses, and recent evidence has suggested that it may also play a role in lymphomagenesis. We evaluated the association between genetic variation in complement system genes and risk of non-Hodgkin lymphoma (NHL) in a population-based case–control study conducted among women in Connecticut. Tag SNPs in 30 complement genes were genotyped in 432 Caucasian incident cases and 494 frequency-matched controls. A gene-based analysis that adjusted for the number of tag SNPs genotyped in each gene showed a significant association with NHL overall (P = 0.04) as well as with diffuse large B-cell lymphoma (DLBCL) (P = 0.01) for the C1RL gene. A SNP-based analysis showed that a C>T base substitution for C1RL rs3813729 (odds ratio (OR)CT = 0.60, 95% confidence interval (CI) = 0.42–0.87, Ptrend = 0.0062) was associated with a decreased risk of overall NHL, as well as for DLBCL (ORCT = 0.39, 95% CI = 0.20–0.73; Ptrend = 0.0034). Additionally, SNPs (C2 rs497309, A>C and C3 rs344550, G>C) in two complement genes were positively associated with marginal zone lymphoma (MZL) and C1QG was associated with CLL/SLL, but these results were based on a limited number of cases. Our results suggest a potential role of the complement system in susceptibility to NHL; however, our results should be viewed as exploratory and further replication is needed to clarify these preliminary findings.

Recent studies have linked dopamine to differences in behavior and brain activity in normal individuals. We explored these relationships in older and younger adults by investigating how functional connectivity between the striatum and prefrontal cortex is related to caudate dopamine and verbal working memory task performance. We studied 12 young and 18 older participants with functional magnetic resonance imaging (fMRI) during this task, and used positron emission tomography with the tracer 6-[18F]-fluoro-L-m-tyrosine (FMT) to assess dopamine synthesis capacity. Younger adults had a greater extent of frontal-caudate functional connectivity during the load-dependent delay period of the working memory task than the older participants. Across all subjects, the extent of this functional connectivity was negatively correlated with dopamine synthesis capacity, such that participants with the greatest connectivity had the lowest caudate FMT signal. Additionally, the extent of functional connectivity was positively correlated with working memory performance. Overall these data suggest interdependencies exist between fronto-striatal functional connectivity, dopamine, and working memory performance and that this system is functioning suboptimally in normal aging.

INTRODUCTION

Adult survivors of childhood lower-extremity sarcoma are largely physically inactive, a behavior which potentially compounds their health burden. Altering this behavior requires understanding those factors that contribute to their physical inactivity. Therefore, this investigation sought to identify factors associated with inactivity in this subpopulation of cancer survivors.

METHODS

Demographic, personal, treatment and physical activity information from adult survivors of childhood lower-extremity sarcomas was obtained from the Childhood Cancer Survivor Study (CCSS) cohort. Generalized linear models were used to identify variables that best identified those individuals who were physically inactive.

RESULTS

Only 41% of survivors met Center for Disease Control (CDC) activity guidelines. Survivors were 1.20 (95% CI 1.11–1.30) more likely compared to CCSS sibling cohort and 1.12 (95% CI 1.10–1.15) times more likely than the general population to fail to meet CDC guidelines. Significant predictors of physical inactivity included female sex, hemipelvectomy surgery, and platinum and vinca alkaloid chemotherapy.

CONCLUSIONS

The primary findings of this study are that survivors of childhood onset lower-extremity sarcoma are 1) highly likely to be physically inactive and 2) less likely than their siblings or the general population to regularly exercise. This study has identified treatment related risk factors associated with inactivity that will help health and wellness practitioners develop successful exercise interventions to help these survivors achieve recommended levels of physical activity for health.

IMPLICATIONS FOR CANCER SURVIVORS

These results suggest that physical activity interventions for adult survivors of childhood lower-extremity sarcomas should be sex specific and responsive to unique physical late effects experienced by these survivors.

Children vary widely in the rate at which they acquire words—some start slow and speed up, others start fast and continue at a steady pace. Do early developmental variations of this sort help predict vocabulary skill just prior to kindergarten entry? This longitudinal study starts by examining important predictors (SES, parent input, child gesture) of vocabulary growth between 14 and 46 months (n=62), and then uses growth estimates to predict children's vocabulary at 54 months. Velocity and acceleration in vocabulary development at 30 months predicted later vocabulary, particularly for children from low socioeconomic backgrounds. Understanding the pace of early vocabulary growth thus improves our ability to predict school readiness, and may help identify children at risk for starting behind.

Objective

ICU nurses are repeatedly exposed to work related stresses resulting in the development of psychological disorders including posttraumatic stress disorder and burnout syndrome. Resilience is a learnable multidimensional characteristic enabling one to thrive in the face of adversity. In a national survey, we sought to determine whether resilience was associated with healthier psychological profiles in intensive care unit nurses.

Design

Surveys were mailed to 3500 randomly selected ICU nurses across the United States and included: demographic questions, the Posttraumatic Diagnostic Scale, Hospital Anxiety and Depression Scale, Maslach Burnout Inventory and the Connor-Davidson Resilience Scale.

Measurements and Main Results

Overall, 1239 of the mailed surveys were returned for a response rate of 35%, and complete data was available on a total of 744 nurses. Twenty-two percent of the intensive care unit nurses were categorized as being highly resilient. The presence of high resilience in these nurses was significantly associated with a lower prevalence of posttraumatic stress disorder, symptoms of anxiety or depression, and burnout syndrome (<0.001 for all comparisons). In independent multivariable analyses adjusting for five potential confounding variables, the presence of resilience was independently associated with a lower prevalence of posttraumatic stress disorder (p < 0.001), and a lower prevalence of burnout syndrome (p < 0.001).

Conclusions

The presence of psychological resilience was independently associated with a lower prevalence of posttraumatic stress disorder and burnout syndrome in intensive care unit nurses. Future research is needed to better understand coping mechanisms employed by highly resilient nurses and how they maintain a healthier psychological profile.

In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10−8, per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17–1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10−14) and rs12617313 (P = 7.48 × 10−12), both highly correlated with rs9679290 (r2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r2 < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10−9, per-allele OR = 1.28, 95% CI: 1.18–1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.

Background

One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent SNP markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer and age.

Methods

We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.

Results

The best risk model (C-statistic=0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P=0.009), with highest accuracy in men younger than 60 years (C-statistic=0.679). The absolute ten-year risk for 50-year old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).

Conclusions

Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from PSA screening.

Impact

Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.

Constipation is a common clinical problem. Initial management of chronic constipation should include lifestyle maneuvers, and increased fiber and fluids. Polyethylene glycol, sodium picosulfate, bisacodyl, prucalopride, lubiprostone, and linaclotide were all more effective than placebo for treating chronic idiopathic constipation. Many commonly used agents lack quality evidence supporting their use.

Edentulous mandible fractures present a unique and challenging surgical problem, particularly because of lack of occlusive dental surfaces to capitalize upon maxillomandibular fixation (MMF). We present a novel technique to achieve MMF using rigid plates spanning the oral cavity to fixate the maxilla to the mandible. The process is rapid and allows stability using the established principles of rigidity, external fixation, and osteosynthesis. This technique allows for a faster MMF than with a Gunning splint and allows for easier oral hygiene. An illustrative case and pre- and postoperative imaging are provided.

The TgCRND8 mouse model of Alzheimer’s disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse.

T cell trafficking between the blood and lymphoid organs is a complex, multistep process that requires several highly dynamic and coordinated changes in cyto-architecture. Members of the ezrin, radixin and moesin (ERM) family of actin-binding proteins have been implicated in several aspects of this process, but studies have yielded conflicting results. Using mice with a conditional deletion of ezrin in CD4+ cells and moesin-specific siRNA, we generated T cells lacking ERM proteins, and investigated the effect on specific events required for T cell trafficking. ERM-deficient T cells migrated normally in multiple in vitro and in vivo assays, and could undergo efficient diapedesis in vitro. However, these cells were impaired in their ability to adhere to the β1 integrin ligand fibronectin, and to polarize appropriately in response to fibronectin and VCAM-1 binding. This defect was specific for β1 integrins, as adhesion and polarization in response to ICAM-1 were normal. In vivo, ERM-deficient T cells showed defects in homing to lymphoid organs. Taken together, these results show that ERM proteins are largely dispensable for T cell chemotaxis, but are important for β1 integrin function and homing to lymphoid organs.

Conventional DCs from mice lacking zDC (also known as Zbtb46) express more MHCII and produce more VEGF in the steady state.

Classical dendritic cells (cDCs) process and present antigens to T cells. Under steady-state conditions, antigen presentation by cDCs induces tolerance. In contrast, during infection or inflammation, cDCs become activated, express higher levels of cell surface MHC molecules, and induce strong adaptive immune responses. We recently identified a cDC-restricted zinc finger transcription factor, zDC (also known as Zbtb46 or Btbd4), that is not expressed by other immune cell populations, including plasmacytoid DCs, monocytes, or macrophages. We define the zDC consensus DNA binding motif and the genes regulated by zDC using chromatin immunoprecipitation and deep sequencing. By deleting zDC from the mouse genome, we show that zDC is primarily a negative regulator of cDC gene expression. zDC deficiency alters the cDC subset composition in the spleen in favor of CD8+ DCs, up-regulates activation pathways in steady-state cDCs, including elevated MHC II expression, and enhances cDC production of vascular endothelial growth factor leading to increased vascularization of skin-draining lymph nodes. Consistent with these observations, zDC protein expression is rapidly down-regulated after TLR stimulation. Thus, zDC is a TLR-responsive, cDC-specific transcriptional repressor that is in part responsible for preventing cDC maturation in the steady state.

The effective dissemination and implementation of evidence-based health interventions within community settings is an important cornerstone to expanding the availability of quality health and mental health services. Yet it has proven a challenging task for both research and community stakeholders. This paper presents the current framework developed by the UCLA/RAND NIMH Center to address this research-to-practice gap by: 1) providing a theoretically-grounded understanding of the multi-layered nature of community and healthcare contexts and the mechanisms by which new practices and programs diffuse within these settings; 2) distinguishing among key components of the diffusion process—including contextual factors, adoption, implementation, and sustainment of interventions—showing how evaluation of each is necessary to explain the course of dissemination and outcomes for individual and organizational stakeholders; 3) facilitating the identification of new strategies for adapting, disseminating, and implementing relatively complex, evidence-based healthcare and improvement interventions, particularly using a community-based, participatory approach; and 4) enhancing the ability to meaningfully generalize findings across varied interventions and settings to build an evidence base on successful dissemination and implementation strategies.