Context-driven automatic subgraph creation for literature-based discovery.
Literature-based discovery (LBD) is characterized by uncovering hidden associations in non-interacting scientific literature. Prior approaches to LBD include use of: (1) domain expertise and structured background knowledge to manually filter and explore the literature, (2) distributional statistics and graph-theoretic measures to rank interesting connections, and (3) heuristics to help eliminate spurious connections. However, manual approaches to LBD are not scalable and purely distributional approaches may not be sufficient to obtain insights into the meaning of poorly understood associations. While several graph-based approaches have the potential to elucidate associations, their effectiveness has not been fully demonstrated. A considerable degree of a priori knowledge, heuristics, and manual filtering is still required. In this paper we implement and evaluate a context-driven, automatic subgraph creation method that captures multifaceted complex associations between biomedical concepts to facilitate LBD. Given a pair of concepts, our method automatically generates a ranked list of subgraphs, which provide informative and potentially unknown associations between such concepts. To generate subgraphs, the set of all MEDLINE articles that contain either of the two specified concepts (A, C) are first collected. Then binary relationships or assertions, which are automatically extracted from the MEDLINE articles, called semantic predications, are used to create a labeled directed predications graph. In this predications graph, a path is represented as a sequence of semantic predications. The hierarchical agglomerative clustering (HAC) algorithm is then applied to cluster paths that are bounded by the two concepts (A, C). HAC relies on implicit semantics captured through Medical Subject Heading (MeSH) descriptors, and explicit semantics from the MeSH hierarchy, for clustering. Paths that exceed a threshold of semantic relatedness are clustered into subgraphs based on their shared context. Finally, the automatically generated clusters are provided as a ranked list of subgraphs. The subgraphs generated using this approach facilitated the rediscovery of 8 out of 9 existing scientific discoveries. In particular, they directly (or indirectly) led to the recovery of several intermediates (or B-concepts) between A- and C-terms, while also providing insights into the meaning of the associations. Such meaning is derived from predicates between the concepts, as well as the provenance of the semantic predications in MEDLINE. Additionally, by generating subgraphs on different thematic dimensions (such as Cellular Activity, Pharmaceutical Treatment and Tissue Function), the approach may enable a broader understanding of the nature of complex associations between concepts. Finally, in a statistical evaluation to determine the interestingness of the subgraphs, it was observed that an arbitrary association is mentioned in only approximately 4 articles in MEDLINE on average. These results suggest that leveraging the implicit and explicit semantics provided by manually assigned MeSH descriptors is an effective representation for capturing the underlying context of complex associations, along multiple thematic dimensions in LBD situations.


Adrenomedullin blockade suppresses growth of human hormone-independent prostate tumor xenograft in mice.
To study the role of the adrenomedullin system [adrenomedullin and its receptors (AMR), CLR, RAMP2, and RAMP3] in prostate cancer androgen-independent growth. Androgen-dependent and -independent prostate cancer models were used to investigate the role and mechanisms of adrenomedullin in prostate cancer hormone-independent growth and tumor-associated angiogenesis and lymphangiogenesis. Adrenomedullin and AMR were immunohistochemically localized in the carcinomatous epithelial compartment of prostate cancer specimens of high grade (Gleason score >7), suggesting a role of the adrenomedullin system in prostate cancer growth. We used the androgen-independent Du145 cells, for which we demonstrate that adrenomedullin stimulated cell proliferation in vitro through the cAMP/CRAF/MEK/ERK pathway. The proliferation of Du145 and PC3 cells is decreased by anti-adrenomedullin antibody (αAM), supporting the fact that adrenomedullin may function as a potent autocrine/paracrine growth factor for prostate cancer androgen-independent cells. In vivo, αAM therapy inhibits the growth of Du145 androgen-independent xenografts and interestingly of LNCaP androgen-dependent xenografts only in castrated animals, suggesting strongly that adrenomedullin might play an important role in tumor regrowth following androgen ablation. Histologic examination of αAM-treated tumors showed evidence of disruption of tumor vascularity, with depletion of vascular as well as lymphatic endothelial cells and pericytes, and increased lymphatic endothelial cell apoptosis. Importantly, αAM potently blocks tumor-associated lymphangiogenesis, but does not affect established vasculature and lymphatic vessels in normal adult mice. We conclude that expression of adrenomedullin upon androgen ablation in prostate cancer plays an important role in hormone-independent tumor growth and in neovascularization by supplying/amplifying signals essential for pathologic neoangiogenesis and lymphangiogenesis. Clin Cancer Res; 19(22); 6138-50. ©2013 AACR.


The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort.
The association between saturated fatty acid (SFA) intake and ischemic heart disease (IHD) risk is debated. We sought to investigate whether dietary SFAs were associated with IHD risk and whether associations depended on 1) the substituting macronutrient, 2) the carbon chain length of SFAs, and 3) the SFA food source. Baseline (1993-1997) SFA intake was measured with a food-frequency questionnaire among 35,597 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. IHD risks were estimated with multivariable Cox regression for the substitution of SFAs with other macronutrients and for higher intakes of total SFAs, individual SFAs, and SFAs from different food sources. During 12 y of follow-up, 1807 IHD events occurred. Total SFA intake was associated with a lower IHD risk (HR per 5% of energy: 0.83; 95% CI: 0.74, 0.93). Substituting SFAs with animal protein, cis monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs), or carbohydrates was significantly associated with higher IHD risks (HR per 5% of energy: 1.27-1.37). Slightly lower IHD risks were observed for higher intakes of the sum of butyric (4:0) through capric (10:0) acid (HRSD: 0.93; 95% CI: 0.89, 0.99), myristic acid (14:0) (HRSD: 0.90; 95% CI: 0.83, 0.97), the sum of pentadecylic (15:0) and margaric (17:0) acid (HRSD: 0.91: 95% CI: 0.83, 0.99), and for SFAs from dairy sources, including butter (HRSD: 0.94; 95% CI: 0.90, 0.99), cheese (HRSD: 0.91; 95% CI: 0.86, 0.97), and milk and milk products (HRSD: 0.92; 95% CI: 0.86, 0.97). In this Dutch population, higher SFA intake was not associated with higher IHD risks. The lower IHD risk observed did not depend on the substituting macronutrient but appeared to be driven mainly by the sums of butyric through capric acid, the sum of pentadecylic and margaric acid, myristic acid, and SFAs from dairy sources. Residual confounding by cholesterol-lowering therapy and trans fat or limited variation in SFA and PUFA intake may explain our findings. Analyses need to be repeated in populations with larger differences in SFA intake and different SFA food sources.


Arterial Therapies of Non-Colorectal Liver Metastases.
The unique situation of the liver with arterial and venous blood supply and the dependency of the tumor on the arterial blood flow make this organ an ideal target for intrahepatic catheter-based therapies. Main forms of treatment are classical bland embolization (TAE) cutting the blood flow to the tumors, chemoembolization (TACE) inducing high chemotherapy concentration in tumors, and radioembolization (TARE) without embolizing effect but very high local radiation. These different forms of therapies are used in different centers with different protocols. This overview summarizes the different forms of treatment, their indications and protocols, possible side effects, and available data in patients with non-colorectal liver tumors. A research in PubMed was performed. Mainly clinical controlled trials were reviewed. The search terms were 'embolization liver', 'TAE', 'chemoembolization liver', 'TACE', 'radioembolization liver', and 'TARE' as well as 'chemosaturation' and 'TACP' in the indications 'breast cancer', 'neuroendocrine', and 'melanoma'. All reported studies were analyzed for impact and reported according to their clinical relevance. The main search criteria revealed the following results: 'embolization liver + breast cancer', 122 results, subgroup clinical trials 16; 'chemoembolization liver + breast cancer', 62 results, subgroup clinical trials 11; 'radioembolization liver + breast cancer', 37 results, subgroup clinical trials 3; 'embolization liver + neuroendocrine', 283 results, subgroup clinical trials 20; 'chemoembolization liver + neuroendocrine', 202 results, subgroup clinical trials 9; 'radioembolization liver + neuroendocrine', 64 results, subgroup clinical trials 9; 'embolization liver + melanoma', 79 results, subgroup clinical trials 15; 'chemoembolization liver + melanoma', 60 results, subgroup clinical trials 14; 'radioembolization liver + melanoma', 18 results, subgroup clinical trials 3. The term 'chemosaturation liver' was tested without indication since only few publications exist and provided us with five results and only one clinical trial. Despite many years of clinical use and documented efficacy on intra-arterial treatments of the liver, there are still only a few prospective multicenter trials with many different protocols. To guarantee the future use of these efficacious therapies, especially in the light of many systemic or surgical therapies in the treatment of non-colorectal liver metastases, further large randomized trials and transparent guidelines need to be established.


Chromatic-distortion compensation in splitting and focusing of femtosecond pulses by use of a pair of diffractive optical elements.
We propose a simple optical system to compensate for chromatic distortion that occurs during fan-out of femtosecond pulses by diffractive optics. The proposed system comprises a pair of diffractive elements, one for splitting an incoming pulse and the other for focusing the split pulses. With an appropriate separation between the elements, chromatic distortion resulting from the spectral bandwidth of a femtosecond pulse is removed, and an array of focused pulses with the same dimensions can be obtained. The theory has been verified through optical and processing experiments with 100-fs, 800-nm pulses.


Novel computed tomography-based tools reliably quantify plant reproductive investment.
The flower is a bisexual reproductive unit where both genders compete for resources. Counting pollen and ovules in flowers is essential to understand how much is invested in each gender. Classical methods to count very numerous pollen grains and ovules are inefficient when pollen grains are tightly aggregated, and when fertilization rates of ovules are unknown. In this study we have therefore developed novel counting techniques based on computed tomography. In order to demonstrate the potential of our methods in very difficult cases, we counted pollen and ovules across inflorescences of deceptive and rewarding species of European orchids, which possess both very large numbers of pollen grains (tightly aggregated) and ovules. Pollen counts did not significantly vary across inflorescences and pollination strategies, whereas deceptive flowers had significantly more ovules than rewarding flowers. The within-inflorescence variance of pollen-to-ovule ratios in rewarding flowers was four times higher than in deceptive flowers, possibly demonstrating differences in the constraints acting on both pollination strategies. We demonstrate the inaccuracies and limitations of previously established methods, and the broad applicability of our new techniques: they allow measurement of reproductive investment without restriction on object number or aggregation, and without specimen destruction.


Cis-regulation in the Drosophila Bithorax Complex.
The discovery of the first homeotic mutation by Calvin Bridges in 1915 profoundly influenced the way we think about developmental processes. Although many mutations modify or deform morphological structures, homeotic mutations cause a spectacular phenotype in which a morphological structure develops like a copy of a structure that is normally found elsewhere on an organism's body plan. This is best illustrated in Drosophila where homeotic mutations were first discovered. For example, Antennapedia mutants have legs developing on their head instead of antennae. Because a mutation in a single gene creates such complete structures, homeotic genes were proposed to be key "selector genes" regulating the initiation of a developmental program. According to this model, once a specific developmental program is initiated (i.e., antenna or leg), it can be executed by downstream "realizator genes" independent of its location along the body axis. Consistent with this idea, homeotic genes have been shown to encode transcription factor proteins that control the activity of the many downstream targets to "realize" a developmental program. Here, we will review the first and perhaps, best characterized homeotic complex, the Bithorax Complex (BX-C).


Variation in target and distractor heterogeneity impacts performance in the centroid task.
In a selective centroid task, the participant views a brief cloud of items of different types-some of which are targets, the others distractors-and strives to mouse-click the centroid of the target items, ignoring the distractors. Advantages of the centroid task are that multiple target types can appear in the same display and that influence functions, which estimate the weight of each stimulus type in the cloud on the perceived centroid for each participant, can be obtained easily and efficiently. Here we document the strong, negative impact on performance that results when the participant is instructed to attend to target dots that consist of two or more levels of a single feature dimension, even when those levels differ categorically from those of the distractor dots. The results also show a smaller, but still observable decrement in performance that results when there is heterogeneity in the distractor dots.


Validation of AclarusDx™, a blood-based transcriptomic signature for the diagnosis of Alzheimer's disease.
Biomarkers have gained an increased importance in the past years in helping physicians to diagnose Alzheimer's disease (AD). This study was designed to identify a blood-based, transcriptomic signature that can differentiate AD patients from control subjects. The performance of the signature was then evaluated for robustness in an independent blinded sample population. RNA was extracted from 177 blood samples (90 AD patients and 87 controls) and gene expression profiles were generated using the human Genome-Wide Splice Array™. These profiles were used to establish a signature to differentiate AD patients from controls. Subsequently, prediction results were optimized by establishing grey zone boundaries that discount prediction scores near the disease status threshold. Signature validation was then performed on a blinded independent cohort of 209 individuals (111 AD and 98 controls). The AclarusDx™ signature consists of 170 probesets which map to 136 annotated genes, a significant number of which are associated with inflammatory, gene expression, and cell death pathways. Additional signature genes are known to interact with pathways involved in amyloid and tau metabolism. The validation sample set, after removal of 45 individuals with prediction profile scores within the grey zone, consisted of 164 subjects. The AclarusDx™ performance on this validation cohort had a sensitivity of 81.3% (95% CI: [73.3%; 89.3%]); and a specificity of 67.1% (95% CI: [56.3%; 77.9%]). AclarusDx™ is a non-invasive blood-based transcriptomic test that, in combination with standard assessments, can provide physicians with objective information to support the diagnosis of AD.


Compressed vertebrae in Atlantic salmon Salmo salar: evidence for metaplastic chondrogenesis as a skeletogenic response late in ontogeny.
Anterior/posterior (a/p) compression of the vertebral column, referred to as 'short tails', is a recurring event in farmed Atlantic salmon. Like other skeletal deformities, the problem usually becomes evident in a late life phase, too late for preventive measures, making it difficult to understand the aetiology of the disease. We use structural, radiological, histological, and mineral analyses to study 'short tail' adult salmon and to demonstrate that the study of adult fish can provide important insights into earlier developmental processes. 'Short tails' display a/p compressed vertebrae throughout the spine, except for the first post-cranial vertebrae. The vertebral number is unaltered, but the intervertebral space is reduced and the vertebrae are shorter. Compressed vertebrae are characterized by an unchanged central part, altered vertebral end plates (straight instead of funnel-shaped), an atypical inward bending of the vertebral edges, and structural alterations in the intervertebral tissue. The spongiosa is unaffected. The growth zones of adjacent vertebrae fuse and blend towards the intervertebral space into chondrogenic tissue. This tissue produces different types of cartilage, replacing the notochord. The correspondence in location of intervertebral cartilage and deformed vertebral end plates, and the clearly delimited, unaltered, central vertebral parts suggest that the a/p compression of vertebral bodies is a late developmental disorder that may be related to a metaplastic shift of osteogenic tissue into chondrogenic tissue in the vertebral growth zone. Given the lack of evidence for infections, metabolic disorders and/or genetic disorders, we propose that an altered mechanical load could have caused the transformation of the bone growth zones and the concomitant replacement of the intervertebral (notochord) tissue by cartilaginous tissues in the 'short tails' studied here. This hypothesis is supported by the role that notochord cells are known to play in spine development and in maintaining the structure of the intervertebral disk.


Adolescent bullying, cannabis use and emerging psychotic experiences: a longitudinal general population study.
Using longitudinal and prospective measures of psychotic experiences during adolescence, we assessed the risk of developing psychosis in three groups showing low, increasing and elevated psychotic experiences associated with bullying by peers and cannabis use in a UK sample of adolescents. Method Data were collected by self-report from 1098 adolescents (mean age 13.6 years; 60.9% boys) at five separate time points, equally separated by 6 months, across a 24-month period. General growth mixture modelling identified three distinct trajectories of adolescents reporting psychotic experiences: elevated, increasing and low. Controlling for cannabis use, bullying by peers significantly predicted change in psychotic experiences between Time 2 and Time 5 in adolescents belonging to the increasing group. No effect was found for the elevated or low groups. Controlling for bullying, an earlier age of cannabis use and cannabis use more than twice significantly predicted change in psychotic experiences in adolescents belonging to the increasing group. Cannabis use at any age was significantly associated with subsequent change in psychotic experiences in the low group. Reverse causal associations were examined and there was no evidence for psychotic experiences at Time 1 predicting a subsequent change in cannabis use between Times 2 and 5 in any trajectory group. Bullying by peers and cannabis use are associated with adolescents' reports of increasing psychotic experiences over time. Further research into the longitudinal development of psychosis in adolescence and the associated risk factors would allow for early intervention programmes to be targeted more precisely.


Reinterpretation, reclassification, and its downstream effects: challenges for clinical laboratory geneticists.
In recent years, the amount of genomic data produced in clinical genetics services has increased significantly due to the advent of next-generation sequencing. This influx of genomic information leads to continuous changes in knowledge on how genetic variants relate to hereditary disease. These changes can have important consequences for patients who have had genetic testing in the past, as new information may affect their clinical management. When and how patients should be recontacted after new genetic information becomes available has been investigated extensively. However, the issue of how to handle the changing nature of genetic information remains underexplored in a laboratory setting, despite it being the first stage at which changes in genetic data are identified and managed. The authors organized a 7-day online focus group discussion. Fifteen clinical laboratory geneticists took part. All (nine) Dutch clinical molecular genetics diagnostic laboratories were represented. Laboratories in our study reinterpret genetic variants reactively, e.g. at the request of a clinician or following identification of a previously classified variant in a new patient. Participants currently deemed active, periodic reinterpretation to be unfeasible and opinions differed on whether it is desirable, particularly regarding patient autonomy and the main responsibilities of the laboratory. The efficacy of reinterpretation was questioned in the presence of other strategies, such as reanalysis and resequencing of DNA. Despite absence of formal policy regarding when to issue a new report for clinicians due to reclassified genetic data, participants indicated similar practice across all laboratories. However, practice differed significantly between laboratory geneticists regarding the reporting of VUS reclassifications. Based on the results, the authors formulated five challenges needing to be addressed in future laboratory guidelines: 1. Should active reinterpretation of variants be conducted by the laboratory as a routine practice? 2. How does reinterpretation initiated by the laboratory relate to patient expectations and consent? 3. When should reinterpreted data be considered clinically significant and communicated from laboratory to clinician? 4. Should reinterpretation, reanalysis or a new test be conducted? 5. How are reclassifications perceived and how might this affect laboratory practice?


A retrosynthetic biology approach to metabolic pathway design for therapeutic production.
Synthetic biology is used to develop cell factories for production of chemicals by constructively importing heterologous pathways into industrial microorganisms. In this work we present a retrosynthetic approach to the production of therapeutics with the goal of developing an in situ drug delivery device in host cells. Retrosynthesis, a concept originally proposed for synthetic chemistry, iteratively applies reversed chemical transformations (reversed enzyme-catalyzed reactions in the metabolic space) starting from a target product to reach precursors that are endogenous to the chassis. So far, a wider adoption of retrosynthesis into the manufacturing pipeline has been hindered by the complexity of enumerating all feasible biosynthetic pathways for a given compound. In our method, we efficiently address the complexity problem by coding substrates, products and reactions into molecular signatures. Metabolic maps are represented using hypergraphs and the complexity is controlled by varying the specificity of the molecular signature. Furthermore, our method enables candidate pathways to be ranked to determine which ones are best to engineer. The proposed ranking function can integrate data from different sources such as host compatibility for inserted genes, the estimation of steady-state fluxes from the genome-wide reconstruction of the organism's metabolism, or the estimation of metabolite toxicity from experimental assays. We use several machine-learning tools in order to estimate enzyme activity and reaction efficiency at each step of the identified pathways. Examples of production in bacteria and yeast for two antibiotics and for one antitumor agent, as well as for several essential metabolites are outlined. We present here a unified framework that integrates diverse techniques involved in the design of heterologous biosynthetic pathways through a retrosynthetic approach in the reaction signature space. Our engineering methodology enables the flexible design of industrial microorganisms for the efficient on-demand production of chemical compounds with therapeutic applications.


One minute analysis of 200 histone posttranslational modifications by direct injection mass spectrometry.
DNA and histone proteins define the structure and composition of chromatin. Histone posttranslational modifications (PTMs) are covalent chemical groups capable of modeling chromatin accessibility, mostly due to their ability in recruiting enzymes responsible for DNA readout and remodeling. Mass spectrometry (MS)-based proteomics is the methodology of choice for large-scale identification and quantification of protein PTMs, including histones. High sensitivity proteomics requires online MS coupling with relatively low throughput and poorly robust nano-liquid chromatography (nanoLC) and, for histone proteins, a 2-d sample preparation that includes histone purification, derivatization, and digestion. We present a new protocol that achieves quantitative data on about 200 histone PTMs from tissue or cell lines in 7 h from start to finish. This protocol includes 4 h of histone extraction, 3 h of derivatization and digestion, and only 1 min of MS analysis via direct injection (DI-MS). We demonstrate that this sample preparation can be parallelized for 384 samples by using multichannel pipettes and 96-well plates. We also engineered the sequence of a synthetic "histone-like" peptide to spike into the sample, of which derivatization and digestion benchmarks the quality of the sample preparation. We ensure that DI-MS does not introduce biases in histone peptide ionization as compared to nanoLC-MS/MS by producing and analyzing a library of synthetically modified histone peptides mixed in equal molarity. Finally, we introduce EpiProfileLite for comprehensive analysis of this new data type. Altogether, our workflow is suitable for high-throughput screening of >1000 samples per day using a single mass spectrometer.


Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization.
GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl- load. Under high Cl- load or heightened synaptic drive, lower Cl- extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl- lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl- extrusion across laminae critically shapes plasticity for selective nociceptive modalities.


Genes regulated in metastatic osteosarcoma: evaluation by microarray analysis in four human and two mouse cell line systems.
Osteosarcoma (OS) is a rare bone neoplasm that affects mainly adolescents. It is associated with poor prognosis in case of metastases formation. The search for metastasis predicting markers is therefore imperative to optimize treatment strategies for patients at risk and important for the search of new drugs for the treatment of this devastating disease. Here, we have analyzed by microarray the differential gene expression in four human and two mouse OS cell line systems consisting of parental cell lines with low metastatic potential and derivatives thereof with increased metastatic potential. Using two osteoblastic cell line systems, the most common OS phenotype, we have identified forty-eight common genes that are differentially expressed in metastatic cell lines compared to parental cells. The identified subset of metastasis relevant genes in osteoblastic OS overlapped only minimally with differentially expressed genes in the other four preosteoblast or nonosteoblastic cell line systems. The results imply an OS phenotype specific expression pattern of metastasis regulating proteins and form a basis for further investigation of gene expression profiles in patients' samples combined with survival analysis with the aim to optimize treatment strategies to develop new drugs and to consequently improve the survival of patients with the most common form of osteoblastic OS.


Introducing considerations in the Translation of Chinese Medicine.
This article introduces the document, Considerations in the Translation of Chinese Medicine, published in PDF form online in both Chinese and English. This 20-page document includes several sections describing why the Considerations is necessary, the specificity of texts in Chinese medicine; the history of translation in Chinese medicine; who constitutes an ideal translator of Chinese medicine; what types of language exist in Chinese medicine; and specific issues in the translation of Chinese medicine, such as domestication versus foreignization, technical terminology, period-specific language, style, polysemy, and etymological translation. The final section offers a brief advisory for consumers, and concludes with a call to further discussion, and action, specifically in the development of international collaborative efforts towards the creation of more rigorous guidelines for the translation of Chinese medicine. The current article provides an overview of several of these sections, and includes links to the original document.


The association of mavenism and pleasure with food involvement in older adults.
Food involvement is concerned with the involvement people have in the preparation and consumption of food. Little is known about older people's food involvement or about the factors which may influence it. Therefore the main aim of this study was to examine food involvement and its associations among older Australians. An Internet-based nationwide survey of 1,041 people aged 55 years and over (M = 66 years, SD 6.99) was conducted in 2012. Quota sampling was used to ensure that the age, gender and state of residence of the respondents were representative of the Australian population aged over 55 years. Bell and Marshall's Food Involvement Scale was administered, along with questions pertaining to socio-demographic, social and hedonic factors. Overall predictor variables explained 45% (p = <0.0001) of variance in food involvement. Food mavenism and pleasure motivation for food were the factors most strongly associated with food involvement (β = .36; 95% CI .46, .61; p = < 0.0001 and β = .31; 95% CI .78, 1.08; p = < 0.0001, respectively). The predictive ability of demographic factors was reasonably poor. Food mavenism and pleasure motivation are stronger predictors of Food Involvement than demographic factors. This suggests communication and health promotion opportunities among older people.


Impact of a Patient Navigator Program on Hospital-Based and Outpatient Utilization Over 180 Days in a Safety-Net Health System.
With emerging global payment structures, medical systems need to understand longer-term impacts of care transition strategies. To determine the effect of a care transition program using patient navigators (PNs) on health service utilization among high-risk safety-net patients over a 180-day period. Randomized controlled trial conducted October 2011 through April 2013. Patients admitted to the general medicine service with ≥1 readmission risk factor: (1) age ≥ 60; (2) in-network inpatient admission within prior 6 months; (3) index length of stay ≥ 3 days; or (4) admission diagnosis of heart failure or (5) chronic obstructive pulmonary disease. The analytic sample included 739 intervention patients, 1182 controls. Through hospital visits and 30 days of post-discharge telephone outreach, PNs provided coaching and assistance with medications, appointments, transportation, communication with primary care, and self-care. Primary outcomes: (1) hospital-based utilization, a composite of ED visits and hospital admissions; (2) hospital admissions; (3) ED visits; and (4) outpatient visits. We evaluated outcomes following an index discharge, stratified by patient age (≥ 60 and < 60 years), using a 180-day time frame divided into six 30-day periods. The PN program produced starkly different outcomes by patient age. Among older PN patients, hospital-based utilization was consistently lower than controls, producing an 18.7% cumulative decrease at 180 days (p = 0.038); outpatient visits increased in the critical first 30-day period (p = 0.006). Among younger PN patients, hospital-based utilization was 31.7% (p = 0.038) higher at 180 days, largely reflecting sharply higher utilization in the initial 30 days (p = 0.002), with non-significant changes thereafter; outpatient visits experienced no significant changes. A PN program serving high-risk safety-net patients differentially impacted patients based on age, and among younger patients, outcomes varied over time. Our findings highlight the importance for future research to evaluate care transition programs among different subpopulations and over longer time periods.


Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages.
Tissue-resident macrophages, such as microglia, Kupffer cells, and Langerhans cells, derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident macrophages self-renew locally, independently of circulating monocytes and HSCs. In contrast, adult blood monocytes, as well as infiltrating, gut, and dermal macrophages, derive from Myb-dependent HSCs. These findings are derived from the mouse, using gene knockouts and lineage tracing, but their applicability to human development has not been formally demonstrated. Here, we use human induced pluripotent stem cells (iPSCs) as a tool to model human hematopoietic development. By using a CRISPR-Cas9 knockout strategy, we show that human iPSC-derived monocytes/macrophages develop in an MYB-independent, RUNX1-, and SPI1 (PU.1)-dependent fashion. This result makes human iPSC-derived macrophages developmentally related to and a good model for MYB-independent tissue-resident macrophages, such as alveolar and kidney macrophages, microglia, Kupffer cells, and Langerhans cells.


The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane.
Polarization of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel to the apical plasma membrane in epithelial cells is critical for vectorial chloride transport. Previously, we reported that the C terminus of CFTR constitutes a PDZ-interacting domain that is required for CFTR polarization to the apical plasma membrane and interaction with the PDZ domain-containing protein EBP50 (NHERF). PDZ-interacting domains are typically composed of the C-terminal three to five amino acids, which in CFTR are QDTRL. Our goal was to identify the key amino acid(s) in the PDZ-interacting domain of CFTR with regard to its apical polarization, interaction with EBP50, and ability to mediate transepithelial chloride secretion. Point substitution of the C-terminal leucine (Leu at position 0) with alanine abrogated apical polarization of CFTR, interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. Point substitution of the threonine (Thr at position -2) with alanine or valine had no effect on the apical polarization of CFTR, but reduced interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane as well as chloride secretion. By contrast, individual point substitution of the other C-terminal amino acids (Gln at position -4, Asp at position -3 and Arg at position -1) with alanine had no effect on measured parameters. We conclude that the PDZ-interacting domain, in particular the leucine (position 0) and threonine (position -2) residues, are required for the efficient, polarized expression of CFTR in the apical plasma membrane, interaction of CFTR with EBP50, and for the ability of CFTR to mediate chloride secretion. Mutations that delete the C terminus of CFTR may cause cystic fibrosis because CFTR is not polarized, complexed with EBP50, or efficiently expressed in the apical membrane of epithelial cells.


Spatial reference frames of visual, vestibular, and multimodal heading signals in the dorsal subdivision of the medial superior temporal area.
Heading perception is a complex task that generally requires the integration of visual and vestibular cues. This sensory integration is complicated by the fact that these two modalities encode motion in distinct spatial reference frames (visual, eye-centered; vestibular, head-centered). Visual and vestibular heading signals converge in the primate dorsal subdivision of the medial superior temporal area (MSTd), a region thought to contribute to heading perception, but the reference frames of these signals remain unknown. We measured the heading tuning of MSTd neurons by presenting optic flow (visual condition), inertial motion (vestibular condition), or a congruent combination of both cues (combined condition). Static eye position was varied from trial to trial to determine the reference frame of tuning (eye-centered, head-centered, or intermediate). We found that tuning for optic flow was predominantly eye-centered, whereas tuning for inertial motion was intermediate but closer to head-centered. Reference frames in the two unimodal conditions were rarely matched in single neurons and uncorrelated across the population. Notably, reference frames in the combined condition varied as a function of the relative strength and spatial congruency of visual and vestibular tuning. This represents the first investigation of spatial reference frames in a naturalistic, multimodal condition in which cues may be integrated to improve perceptual performance. Our results compare favorably with the predictions of a recent neural network model that uses a recurrent architecture to perform optimal cue integration, suggesting that the brain could use a similar computational strategy to integrate sensory signals expressed in distinct frames of reference.


Colles fracture, spine fracture, and subsequent risk of hip fracture in men and women. A meta-analysis.
In postmenopausal women, a history of any fracture is an important risk factor for a future hip fracture. Whether similar findings apply to aging men remains to be established. We conducted a systematic review and meta-analysis of the literature to compare men and women with respect to the relative risk of hip fracture after a wrist or spine fracture. Studies published in full from January 1982 through September 2002 in English, French, or German were identified from the PubMed database and from reference lists of retrieved articles. We included cohort studies that reported fractures associated with minimal trauma of the wrist or spine as a risk factor for a subsequent hip fracture among (white) women and men who were fifty years old or older. Data were extracted by two independent reviewers and were checked for accuracy in a second review. Differences in assessments were resolved by consensus of the two reviewers. Nine cohort studies were included in this meta-analysis: five studies were conducted in the United States and four, in Europe. After homogeneity of association was demonstrated across all studies, a fixed-effects meta-analysis was used to calculate pooled relative risks with 95% confidence intervals. Among postmenopausal women, the relative risks for a future fracture of the hip after a fracture of the wrist or spine were 1.53 (95% confidence interval, 1.34 to 1.74; p < 0.001) and 2.20 (95% confidence interval, 1.92 to 2.51; p < 0.001), respectively. In older men, these relative risks were 3.26 (95% confidence interval, 2.08 to 5.11; p < 0.001) and 3.54 (95% confidence interval, 2.01 to 6.23; p < 0.001), respectively. Fractures of the distal part of the radius increased the relative risk of hip fracture significantly more in men than in women (p = 0.002). The impact of a spine fracture, conversely, did not differ between genders (p = 0.11). Sensitivity analyses with use of random-effects methodology confirmed these findings to be robust. This meta-analysis suggests that a previous spine fracture has an equally important impact on the risk of a subsequent hip fracture in both genders. The prospective association between a Colles fracture and a subsequent hip fracture, however, is significantly stronger among men than among postmenopausal women. Men with a Colles fracture are at high risk for a future hip fracture and should be evaluated as candidates for preventive measures.


Anticipating the species jump: surveillance for emerging viral threats.
Zoonotic disease surveillance is typically triggered after animal pathogens have already infected humans. Are there ways to identify high-risk viruses before they emerge in humans? If so, then how and where can identifications be made and by what methods? These were the fundamental questions driving a workshop to examine the future of predictive surveillance for viruses that might jump from animals to infect humans. Virologists, ecologists and computational biologists from academia, federal government and non-governmental organizations discussed opportunities as well as obstacles to the prediction of species jumps using genetic and ecological data from viruses and their hosts, vectors and reservoirs. This workshop marked an important first step towards envisioning both scientific and organizational frameworks for this future capability. Canine parvoviruses as well as seasonal H3N2 and pandemic H1N1 influenza viruses are discussed as exemplars that suggest what to look for in anticipating species jumps. To answer the question of where to look, prospects for discovering emerging viruses among wildlife, bats, rodents, arthropod vectors and occupationally exposed humans are discussed. Finally, opportunities and obstacles are identified and accompanied by suggestions for how to look for species jumps. Taken together, these findings constitute the beginnings of a conceptual framework for achieving a virus surveillance capability that could predict future species jumps.


A randomized trial of A.C.T. (asthma care training) for kids.
A randomized control trial of a curriculum, A.C.T. (Asthma Care Training) for Kids, was conducted. Seventy-six children between the ages of 8 and 12 years, whose asthma required treatment with medications at least 25% of the days per month, were randomly assigned to control and experimental groups. The control group received 4 1/2 hours of lecture presentations on asthma and its management. The experimental groups (consisting of four to seven children and their parents) received five 1-hour sessions comprising "the treatment." Children and their parents were interviewed before the sessions and 3, 6, and 12 months after the completion of the experimental treatment. Use of emergency rooms and hospitals was determined by reviewing the records of these patients (all members of the Los Angeles Kaiser Permanente health care system) for the period of 1 year before and 1 year after the treatment. Results include (1) equivalent increases in knowledge and changes in beliefs in both groups, (2) significant changes in the self-reported compliance behaviors of the experimental group only, and (3) significant reductions in emergency room visits and days of hospitalization among those receiving the experimental treatment, compared with the control group. These changes represent an estimated savings of approximately $180 per child per year for those in the experimental group.


Primary orthostatic tremor is an exaggeration of a physiological response to instability.
Primary orthostatic tremor (POT) is a rare disorder characterised by an intense sense of unsteadiness upon standing and a 16-Hz tremor in which the timing between tremor bursts in different muscles (unilateral and bilateral) remains constant. Hitherto, similar EMG activity has not been described in healthy subjects and it has been postulated that the oscillations seen in POT are primarily pathological. In this study, EMG was recorded from tibialis anterior in healthy subjects who were made unsteady through vestibular galvanic stimulation or leaning backwards. Under these conditions, a peak at approximately 16 Hz was seen in the coherence between the left and right tibialis anterior. This bilateral coherence was absent when the subjects activated the same muscles when not unsteady. These data indicate the existence of a physiological system involved in organising postural responses under circumstances of imbalance and characterised by a highly synchronised output at approximately 16 Hz. In addition, the results suggest that the core abnormality in POT may be an exaggerated sense of unsteadiness when standing still, which then elicits activity from a 16-Hz oscillator normally engaged in postural responses.


Why Some Mastectomy Patients Opt to Undergo Delayed Breast Reconstruction: Results of a Long-Term Prospective Study.
Delayed breast reconstruction is an option for women who have undergone mastectomy; however, uptake is low. The purpose of this study was to identify premastectomy and postmastectomy demographic, clinical, and psychosocial predictors of uptake of delayed breast reconstruction in the long-term survivorship period. This was a prospective longitudinal survey study of mastectomy patients in which a repeated measures design was used to evaluate uptake of delayed breast reconstruction. Demographic, clinical, and psychosocial variables were collected before mastectomy and 1 year after mastectomy. Information regarding uptake of delayed breast reconstruction was collected at approximately 6 years after mastectomy. A predictive model was designed using a multivariate logistic regression model and Akiake information criterion stepwise algorithm. Ninety-six mastectomy patients were followed from before mastectomy to 75.2 months after mastectomy, and 35 women (36.5 percent) underwent delayed breast reconstruction. Women who elected for delayed breast reconstruction experienced worsening of body concerns from before mastectomy to 1 year after mastectomy, compared with women who did not elect to undergo delayed breast reconstruction (p = 0.03). Mean scores for psychological distress were significantly worse both before mastectomy and 1 year after mastectomy in women who went on to undergo delayed breast reconstruction compared with those who did not undergo delayed breast reconstruction (p = 0.034 and p = 0.022, respectively). A predictive model for the uptake of delayed breast reconstruction was developed using demographic, clinical, and psychosocial characteristics. The area under the receiver operating characteristic curve was 85 percent, indicating good precision. Women who are experiencing higher levels of distress, anxiety, and body concerns both before and after mastectomy appear to be significantly likely to select delayed breast reconstruction. This may have implications for postreconstruction satisfaction and psychosocial functioning. Risk, III.


Identification of two imidazole binding sites and key residues for substrate specificity in human primary amine oxidase AOC3.
Human membrane primary amine oxidase (hAOC3; also known as vascular adhesion protein-1, VAP-1) is expressed upon inflammation in most tissues, where its enzymatic activity plays a crucial role in leukocyte trafficking. We have determined two new structures of a soluble, proteolytically cleaved form of hAOC3 (sAOC3), which was extracted from human plasma. In the 2.6 Å sAOC3 structure, an imidazole molecule is hydrogen bonded to the topaquinone (TPQ) cofactor, which is in an inactive on-copper conformation, while in the 2.95 Å structure, an imidazole molecule is covalently bound to the active off-copper conformation of TPQ. A second imidazole bound by Tyr394 and Thr212 was identified in the substrate channel. We furthermore demonstrated that imidazole has an inhibitory role at high concentrations used in crystallization. A triple mutant (Met211Val/Tyr394Asn/Leu469Gly) of hAOC3 was previously reported to change substrate preferences toward those of hAOC2, another human copper-containing monoamine oxidase. We now mutated these three residues and Thr212 individually to study their distinct role in the substrate specificity of hAOC3. Using enzyme activity assays, the effect of the four single mutations was tested with four different substrates (methylamine, benzylamine, 2-phenylethylamine, and p-tyramine), and their binding modes were predicted by docking studies. As a result, Met211 and Leu469 were shown to be key residues for substrate specificity. The native structures of sAOC3 and the mutational data presented in this study will aid the design of hAOC3 specific inhibitors.


Prevention of heat strain by immersing the hands and forearms in water.
The effectiveness of hand immersion in water at 10 degrees C, 20 degrees C and 30 degrees C as a technique for reducing heat strain in Royal Navy (RN) personnel has been investigated at the Institute of Naval Medicine (INM). Four subjects exercised at a moderate work rate, whilst wearing fire fighting clothing in an environmental chamber at 40 degrees C. The subjects reached heat strain safety limits within 45 minutes of commencing work at which point they rested in the heat for 30 minutes whilst they underwent one of four experimental conditions: without intervention (control); or with their hands immersed in water at 10 degrees C, 20 degrees C or 30 degrees C. The experiment was repeated on a further three days so that the subjects undertook each experimental condition in a balanced randomised order. During the control condition without hand immersion the subjects were unable to cool. Immersion of the hands in water (at 10 degrees C, 20 degrees C or 30 degrees C) significantly (P < 0.05) lowered body core (auditory canal) temperature within ten minutes. Assessing the effectiveness of this technique by the initial rates of core temperature reduction, revealed that immersion of the hands was more effective the colder the water. Following 20 minutes of hand immersion mean core temperature had dropped from 38.5C to: 36.9(standard deviation 0.19) degrees C, 37.3(0.18) degrees C, and 37.8(0.10) degrees C, in 10 degrees C, 20 degrees C and 30 degrees C water respectively. Cooling powers estimated from changes in mean body temperature were 334, 307 and 113 watts using 10 degrees C, 20 degrees C and 30 degrees C water respectively. These results indicate that hand immersion in water at a temperature of between 10 degrees C and 30 degrees C is an efficient means of cooling heat stressed personnel who have been exercising. This simple and effective technique may be applied to many industrial and military tasks to reduce heat strain, lower the risk of heat injury, and increase safe total work times in the heat. For the RN, hand immersion could be used in fire fighting, damage control and NBC operations where personnel alternately work and rest.


Effects of cross-training. Transfer of training effects on VO2max between cycling, running and swimming.
Cross-training is a widely used approach for structuring a training programme to improve competitive performance in a specific sport by training in a variety of sports. Despite numerous anecdotal reports claiming benefits for cross-training, very few scientific studies have investigated this particular type of training. It appears that some transfer of training effects on maximum oxygen uptake (VO2max) exists from one mode to another. The nonspecific training effects seem to be more noticeable when running is performed as a cross-training mode. Swim training, however, may result in minimum transfer of training effects on VO2max. Cross-training effects never exceed those induced by the sport-specific training mode. The principles of specificity of training tend to have greater significance, especially for highly trained athletes. For the general population, cross-training may be highly beneficial in terms of overall fitness. Similarly, cross-training may be an appropriate supplement during rehabilitation periods from physical injury and during periods of overtraining or psychological fatigue.


Sensitivity and ex vivo validation of finite element models of the domestic pig cranium.
A finite element (FE) validation and sensitivity study was undertaken on a modern domestic pig cranium. Bone strain data were collected ex vivo from strain gauges, and compared with results from specimen-specific FE models. An isotropic, homogeneous model was created, then input parameters were altered to investigate model sensitivity. Heterogeneous, isotropic models investigated the effects of a constant-thickness, stiffer outer layer (representing cortical bone) atop a more compliant interior (representing cancellous bone). Loading direction and placement of strain gauges were also varied, and the use of 2D membrane elements at strain gauge locations as a method of projecting 3D model strains into the plane of the gauge was investigated. The models correctly estimate the loading conditions of the experiment, yet at some locations fail to reproduce correct principal strain magnitudes, and hence strain ratios. Principal strain orientations are predicted well. The initial model was too stiff by approximately an order of magnitude. Introducing a compliant interior reported strain magnitudes more similar to the ex vivo results without notably affecting strain orientations, ratios or contour patterns, suggesting that this simple heterogeneity was the equivalent of reducing the overall stiffness of the model. Models were generally insensitive to moderate changes in loading direction or strain gauge placement, except in the squamosal portion of the zygomatic arch. The use of membrane elements made negligible differences to the reported strains. The models therefore seem most sensitive to changes in material properties, and suggest that failure to model local heterogeneity in material properties and structure of the bone may be responsible for discrepancies between the experimental and model results. This is partially attributable to a lack of resolution in the CT scans from which the model was built, and partially due to an absence of detailed material properties data for pig cranial bone. Thus, caution is advised when using FE models to estimate absolute numerical values of breaking stress and bite force unless detailed input parameters are available. However, if the objective is to compare relative differences between models, the fact that the strain environment is replicated well means that such investigations can be robust.


Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells.
Natural Killer (NK) cells can engage multiple virally infected or tumor cells sequentially and deliver perforin for cytolytic killing of these targets. Using microscopy to visualize degranulation from individual NK cells, we found that repeated activation via the Fc receptor CD16 decreased the amount of perforin secreted. However, perforin secretion was restored upon subsequent activation via a different activating receptor, NKG2D. Repeated stimulation via NKG2D also decreased perforin secretion, but this was not rescued by stimulation via CD16. These different outcomes of sequential stimulation could be accounted for by shedding of CD16 being triggered by cellular activation. The use of pharmacological inhibitors and NK cells transfected to express a noncleavable form of CD16 revealed that CD16 shedding also increased NK cell motility and facilitated detachment of NK cells from target cells. Disassembly of the immune synapse caused by CD16 shedding aided NK cell survival and boosted serial engagement of target cells. Thus, counterintuitively, shedding of CD16 may positively impact immune responses.


Clinical significance of human kallikrein 10 gene expression in colorectal cancer and gastric cancer.
Recent evidence suggests that the human kallikrein 10 (KLK10) gene is differentially regulated in endocrine-related tumors and has potential as diagnostic and/or prognostic marker; however, KLK10 expression has never been investigated in gastrointestinal cancers. The aims of this study were to demonstrate expression and single nucleotide polymorphisms of KLK10 in colorectal cancer (CRC) and gastric cancer (GC), and to correlate the relative KLK10 expression level with clinicopathological factors of CRC and GC. Between March 2004 and January 2005, 63 patients with histologically confirmed CRC and 36 with GC were recruited into the study. Using quantitative real-time (qRT) RT-PCR and Western blot, KLK10 expression in tumor and non-tumor colorectal and gastric tissues was determined at the mRNA and protein levels. KLK10 protein was localized by immunohistochemistry. The KLK10 genomic DNA from 16 cases of paired normal/cancerous colorectal tissues was PCR-amplified and examined for single nucleotide polymorphisms by direct sequencing. KLK10 mRNA expression was detected by qRT in 61 of 63 (96.8%) CRC specimens and in all GC specimens. KLK10 expression was much higher in tumor tissue than in the corresponding normal mucosal tissue at the mRNA and protein levels (P<0.01). The KLK10 mRNA expression level significantly correlated with lymphatic invasion (P=0.034) and clinical stage of CRC (P=0.025). The KLK10 mRNA expression level significantly correlated with the depth of GC invasion (P=0.018), clinical stage (P=0.045), patient sex (P=0.027) and Lauren type of gastric cancer (P=0.028). No mutations or polymorphisms were detected in exon 1, 2 and 5 of KLK10 gene in CRC. Single nucleotide polymorphisms were identified in codon 50 of exon 3, GCC (alanine) to TCC (serine). The genetic changes of exon 4 were located at codon 106 [GGC (glysine) to GGA (glysine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and codon 149 [CCG (proline) to CTG (leucine)]. All were identical in tumor and corresponding normal tissue DNA from the same individuals. KLK10 expression is up-regulated in CRC and GC and higher expression of KLK10 closely correlates with advanced disease stage, which predicts a poorer prognosis; however, further follow-up study is needed.


Variable suites of non-effector genes are co-regulated in the type III secretion virulence regulon across the Pseudomonas syringae phylogeny.
Pseudomonas syringae is a phylogenetically diverse species of Gram-negative bacterial plant pathogens responsible for crop diseases around the world. The HrpL sigma factor drives expression of the major P. syringae virulence regulon. HrpL controls expression of the genes encoding the structural and functional components of the type III secretion system (T3SS) and the type three secreted effector proteins (T3E) that are collectively essential for virulence. HrpL also regulates expression of an under-explored suite of non-type III effector genes (non-T3E), including toxin production systems and operons not previously associated with virulence. We implemented and refined genome-wide transcriptional analysis methods using cDNA-derived high-throughput sequencing (RNA-seq) data to characterize the HrpL regulon from six isolates of P. syringae spanning the diversity of the species. Our transcriptomes, mapped onto both complete and draft genomes, significantly extend earlier studies. We confirmed HrpL-regulation for a majority of previously defined T3E genes in these six strains. We identified two new T3E families from P. syringae pv. oryzae 1_6, a strain within the relatively underexplored phylogenetic Multi-Locus Sequence Typing (MLST) group IV. The HrpL regulons varied among strains in gene number and content across both their T3E and non-T3E gene suites. Strains within MLST group II consistently express the lowest number of HrpL-regulated genes. We identified events leading to recruitment into, and loss from, the HrpL regulon. These included gene gain and loss, and loss of HrpL regulation caused by group-specific cis element mutations in otherwise conserved genes. Novel non-T3E HrpL-regulated genes include an operon that we show is required for full virulence of P. syringae pv. phaseolicola 1448A on French bean. We highlight the power of integrating genomic, transcriptomic, and phylogenetic information to drive concise functional experimentation and to derive better insight into the evolution of virulence across an evolutionarily diverse pathogen species.


Multimodality Molecular Imaging-Guided Tumor Border Delineation and Photothermal Therapy Analysis Based on Graphene Oxide-Conjugated Gold Nanoparticles Chelated with Gd.
Tumor cell complete extinction is a crucial measure to evaluate antitumor efficacy. The difficulties in defining tumor margins and finding satellite metastases are the reason for tumor recurrence. A synergistic method based on multimodality molecular imaging needs to be developed so as to achieve the complete extinction of the tumor cells. In this study, graphene oxide conjugated with gold nanostars and chelated with Gd through 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA) (GO-AuNS-DOTA-Gd) were prepared to target HCC-LM3-fLuc cells and used for therapy. For subcutaneous tumor, multimodality molecular imaging including photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) and the related processing techniques were used to monitor the pharmacokinetics process of GO-AuNS-DOTA-Gd in order to determine the optimal time for treatment. For orthotopic tumor, MRI was used to delineate the tumor location and margin in vivo before treatment. Then handheld photoacoustic imaging system was used to determine the tumor location during the surgery and guided the photothermal therapy. The experiment result based on orthotopic tumor demonstrated that this synergistic method could effectively reduce tumor residual and satellite metastases by 85.71% compared with the routine photothermal method without handheld PAI guidance. These results indicate that this multimodality molecular imaging-guided photothermal therapy method is promising with a good prospect in clinical application.


Saccades to somatosensory targets. II. motor convergence in primate superior colliculus.
1. We examined cells with saccade-related activity in the superior colliculus (SC) of monkeys performing saccades to both somatosensory and visual targets. Our goals were 1) to determine whether signals from these separate sensory systems have converged onto a common motor pathway by the level of the SC; 2) to determine the frame of reference of somatosensory saccade signals in the SC; and 3) to relate collicular motor activity to the behavioral characteristics of somatosensory saccades. 2. Somatosensory targets consisted of vibrotactile stimuli delivered to the hands, which were held in fixed spatial positions. Saccades of different directions and amplitudes were elicited from different initial eye positions. Of 86 cells with motor-related activity, 85 (99%) discharged for saccades to both visual and somatosensory targets. The remaining cell was active only for visual saccades. 3. Cells with saccade-related activity had movement fields representing the direction and amplitude of saccades to both visual and somatosensory targets. We found no cells that discharged for saccades to a particular somatosensory target regardless of the vector of the saccade. 4. Small modality-dependent differences in the spatial tuning of the movement fields were observed, but these variations formed no clear pattern. Given the large population of cells active in conjunction with each saccade, these small tuning differences may have no net effect. Because the visual and somatosensory movement fields of individual cells were similar to each other, the inaccuracy of somatosensory saccades is likely to be the result of inaccurate signals reaching the SC, rather than an error signal added downstream. 5. The peak discharge frequency of collicular motor cells was lower for somatosensory saccades than for visual saccades, although the number of spikes in the discharge was about the same. 6. The latency of the onset of the prelude of motor activity following the cue to initiate a saccade was about the same for somatosensory and visual trials, even though somatosensory saccades have longer reaction times than visual saccades. However, the peak of the motor activity was delayed on somatosensory trials such that the timing of the peak was the same with respect to the movement on somatosensory and visual trials. 7. We conclude that the same population of saccade-related neurons in the SC that represents saccades to visual targets also represents saccades to somatosensory targets. Somatosensory saccades are encoded by these cells as the change in eye position necessary to bring the target onto the fovea, rather than the location of the stimulus on the body surface. Modality-dependent differences in the frequency and timing of collicular motor activity may contribute to velocity and reaction time differences.


Sarcomatous transformation in a cellular angiofibroma: a case report.
Cellular angiofibroma is a rare benign mesenchymal tumour of middle-aged adults. This tumour is usually located in the vulvovaginal or inguinoscrotal region. This report describes the case of a patient with a 3.5 cm subcutaneous mass, 2 cm below the left anterior superior iliac spine. Grossly, the mass had tan-white cut surface with a 1.5 cm tan-yellow, whorled, well-delineated nodule. Histologically, the tumour was composed primarily of cytologically bland spindle cells set in a collagenous stroma, with multiple dilated vessels. Other areas showed an abrupt transition to hypercellular sarcomatous elements, including pleomorphic cells with high mitotic activity. The tumour cells were diffusely positive for vimentin and factor XIIIa, and weakly positive for CD34. The patient did not develop any recurrences or metastases, and expired 3 years later of metastatic poorly differentiated carcinoma of unknown origin. This is believed to be the first reported case of sarcomatous transformation in a cellular angiofibroma.


Temporary cardiac pacing.
The use of temporary cardiac pacing in critical care and stepdown units has grown tremendously over the past 10 years. While the concept of artificial pacing is simple, improvements in generator technology and lead design, along with broader clinical applications, have made temporary cardiac pacing more complex. Consequently, the critical care nurse is required to maintain an advanced level of knowledge regarding modes and complications of temporary pacing, and assessment skills related to recognizing pacemaker hemodynamic effects and pacemaker problems.


Exploring biogeochemical and ecological redundancy in phytoplankton communities in the global ocean.
Climate-change-induced alterations of oceanic conditions will lead to the ecological niches of some marine phytoplankton species disappearing, at least regionally. How will such losses affect the ecosystem and the coupled biogeochemical cycles? Here, we couch this question in terms of ecological redundancy (will other species be able to fill the ecological roles of the extinct species) and biogeochemical redundancy (can other species replace their biogeochemical roles). Prior laboratory and field studies point to a spectrum in the degree of redundancy. We use a global three-dimensional computer model with diverse planktonic communities to explore these questions further. The model includes 35 phytoplankton types that differ in size, biogeochemical function and trophic strategy. We run two series of experiments in which single phytoplankton types are either partially or fully eliminated. The niches of the targeted types were not completely reoccupied, often with a reduction in the transfer of matter from autotrophs to heterotrophs. Primary production was often decreased, but sometimes increased due to reduction in grazing pressure. Complex trophic interactions (such as a decrease in the stocks of a predator's grazer) led to unexpected reshuffling of the community structure. Alterations in resource utilization may cause impacts beyond the regions where the type went extinct. Our results suggest a lack of redundancy, especially in the 'knock on' effects on higher trophic levels. Redundancy appeared lowest for types on the edges of trait space (e.g. smallest) or with unique competitive strategies. Though highly idealized, our modelling findings suggest that the results from laboratory or field studies often do not adequately capture the ramifications of functional redundancy. The modelled, often counterintuitive, responses-via complex food web interactions and bottom-up versus top-down controls-indicate that changes in planktonic community will be key determinants of future ocean global change ecology and biogeochemistry.


Role of interleukin-8 and transforming growth factor-beta1 in enhancement of human cytomegalovirus replication by human T cell leukemia-lymphoma virus type I in macrophages coinfected with both viruses.
Human cytomegalovirus (HCMV) is one of the most frequent opportunistic agents causing severe illness in chronic human T cell leukemia-lymphoma virus type I (HTLV-I) infection. Our previous studies have shown that coinfection of macrophages with HCMV and HTLV-I significantly enhances HCMV replication, resulting in release of infectious HCMV from dually infected cells. We found that double infection of macrophages with HCMV and HTLV-I induced a rapid production of substantial amounts of interleukin-8 (IL-8) and transforming growth factor-beta1 (TGF-beta1). Results of transfection studies demonstrated that the tax gene product of HTLV-I was able to induce secretion of IL-8 and TGF-beta1. In addition to its cytokine-inducing effect, the Tax protein could interact with HCMV synergistically to result in production of much higher levels of IL-8 and TGF-beta1 than expected on the basis of their separate activities. Treatment of dually infected macrophage cultures with neutralizing antibodies to IL-8 and TGF-beta1 led to a nearly 1000-fold decrease in release of infectious HCMV from coinfected cells. Similar results were obtained when anti-IL-8 and anti-TGF-beta1 treatments were combined in macrophage cultures transfected with the tax gene before HCMV infection. Our results suggest that the stimulatory effect of HTLV-I Tax protein on HCMV replication in coinfected macrophages is largely mediated by high levels of IL-8 and TGF-beta1 production.


Trends in substance use among US military personnel: the impact of changing demographic composition.
This paper examines the impact of the military population's changing demographic composition on observed changes in substance use by military personnel. Cross-sectional data are drawn from the six Department of Defense Worldwide Surveys of Substance Abuse and Health Behaviors Among Military Personnel conducted in 1980, 1982, 1985, 1988, 1992, and 1995. Using the method of direct standardization to adjust for changes in demographic composition, trends in substance use are examined. Changes in heavy alcohol use were more affected by demographic changes in the military population than were changes in illicit drug use or cigarette use. Findings indicate that changes in demographic composition may need to be controlled when assessing trends from cross-sectional surveys.


The aged care pain chart: an innovative approach to assessing, managing and documenting pain in older people.
This article presents the development and initial testing of a comprehensive pain chart for the assessment, management and documentation of pain in older people in subacute and residential aged care. The pain chart was developed from existing assessment scales and pain indicators, and is targeting needs of older people in residential care and geriatric hospital settings with high prevalence of cognitive impairments. The chart is based on self-report of pain but allows for observation of pain-related behaviours for those unable to report pain. The chart consists of one evaluative and one documentation dimension, and was evaluated by a group of clinicians in geriatric hospital care (n = 15) and residential aged care (n = 6). The chart was found to be content valid, informative and easy to use, facilitating clinical assessments and monitoring, and assisting visual readings of patients' temporal pain trends.


The 2016 American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) Database: Characteristics and Methods.
To describe the characteristics of the patient population included in the 2016 IRIS® Registry (Intelligent Research in Sight) database for analytic aims. Description of a clinical data registry. The 2016 IRIS Registry database consists of 17 363 018 unique patients from 7200 United States-based ophthalmologists in the United States. Electronic health record (EHR) data were extracted from the participating practices and placed into a clinical database. The approach can be used across dozens of EHR systems. Demographic characteristics. The 2016 IRIS Registry database includes data about patient demographics, top-coded disease conditions, and visit rates. The IRIS Registry is a unique, large, real-world data set that is available for analytics to provide perspectives and to learn about current ophthalmic care and treatment outcomes. The IRIS Registry can be used to answer questions about practice patterns, use, disease prevalence, clinical outcomes, and the comparative effectiveness of different treatments. Limitations of the data are the same limitations associated with EHR data in terms of documentation errors or missing data and the lack of images. Currently, open access to the database is not available, but there are opportunities for researchers to submit proposals for analyses, for example through a Research to Prevent Blindness and American Academy of Ophthalmology Award for IRIS Registry Research.


Consumption profile and factors associated with the ingestion of beer and distilled beverages among elderly Brazilians: Gender differences.
To estimate the prevalence of the consumption of beer and distilled beverages and associated factors among Brazilian older adults residing in a highly populated city in Brazil, highlighting the factors associated with frequent consumption and differences in consumption between men and women. It was a cross-sectional, analytic study carried out by means of probability samples of conglomerates of older adults (aged 65-74 years). Descriptive analysis, univariate analysis and estimates of multivariate models through logistic regression (OR, 95% CI) were realized. 500 of the 736 evaluated seniors were included in the present analysis. 128 (27.3%), 103 (21.3%) and 167 (34.9%) of the seniors indicate past or current use of beer, distilled beverages and frequent use of alcohol, respectively. The consumption of beer was associated with use of tobacco between women; and with marital status and schooling between men. The consumption of distilled beverages was associated with schooling and use of tobacco between women; and age and use of tobacco in men. Daily or weekly use was associated with schooling and use of tobacco between women; age and the use of tobacco between men. In the elderly population studied, a noteworthy prevalence of the consumption of beer and distilled beverages was identified, and this use was associated with personal and behavioral determinants. Similar associations related to frequent (daily or weekly) consumption were also identified. Significant differences in the profile of consumption were identified between men and women, with more abusive use among men. Geriatr Gerontol Int 2016; 16: 810-820.


Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group.
Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival. We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060). We integrated genomic markers with clinical data. We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair-associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status. This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.


Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study.
Purpose To perform an updated analysis of the randomized phase III GADOLIN trial in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated with obinutuzumab (GA101; G) and bendamustine (B). Patients and Methods Patients with histologically documented, rituximab-refractory CD20+ indolent non-Hodgkin lymphoma received G 1,000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2 to 6) plus B 90 mg/m2/d (days 1 and 2, all cycles) or B 120 mg/m2/d monotherapy. Patients who did not experience disease progression with G-B received G maintenance (1,000 mg every 2 months) for up to 2 years. The primary end point was progression-free survival (PFS). Results Of 413 randomly assigned patients (intention-to-treat [ITT]: G-B, n = 204; B monotherapy, n = 209), 335 had follicular lymphoma (FL; G-B, n = 164; B monotherapy, n = 171). After a median follow-up of 31.8 months, median PFS in ITT patients was 25.8 months (G-B) and 14.1 months (B monotherapy; hazard ratio [HR], 0.57; 95% CI, 0.44 to 0.73; P < .001). Overall survival (OS) also was prolonged (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027). PFS and OS benefits were similar in patients with FL. Grade 3 to 5 adverse events (AEs) were reported by 148 (72.5%) and 133 (65.5%) patients in the G-B and B monotherapy arms, respectively, most commonly neutropenia (G-B, 34.8%; B monotherapy, 27.1%), thrombocytopenia (10.8% and 15.8%), anemia (7.4% and 10.8%), and infusion-related reactions (9.3% and 3.4%). Serious AEs occurred in 89 G-B patients (43.6%) and 75 B monotherapy patients (36.9%); fatal AEs occurred in 16 (7.8%) and 13 (6.4%), respectively. Conclusion This updated analysis confirms the PFS benefit for G-B shown in the primary analysis. A substantial OS benefit also was demonstrated in the ITT population and in patients with FL. Toxicity was similar for both treatments.


Lifetime distribution of spontaneous emission from emitter(s) in three-dimensional woodpile photonic crystals.
Spontaneous emission lifetime distribution in the basic unit cell or on a plane of the excited emitters embedded in woodpile photonics crystals with low refractive index contrast are investigated. It is found that the spontaneous emission lifetime distribution strongly depends on the position and transition frequency of the emitters, and has the same symmetry as that of the unit cell. The lifetimes of emitters near the upper gap edge are longer than that in the center of the pseudo-gap, which is quite a contrast to the conventional concept. Furthermore, it is revealed that the polarization orientation of the emitters has significant influence on the lifetime distribution, and may result in a high anisotropy factor (defined as the difference between the maximum and minimum values of the lifetime) up to 4.2. These results may be supplied in probing the lifetime distribution or orientation-dependent local density of states in future experiments.


Does greater low frequency EEG activity in normal immaturity and in children with epilepsy arise in the same neuronal network?
Greater low frequency power (<8 Hz) in the electroencephalogram (EEG) at rest is normal in the immature developing brain of children when compared to adults. Children with epilepsy also have greater low frequency interictal resting EEG activity. Whether these power elevations reflect brain immaturity due to a developmental lag or the underlying epileptic pathophysiology is unclear. The present study addresses this question by analyzing spectral EEG topographies and sources for normally developing children and children with epilepsy. We first compared the resting EEG of healthy children to that of healthy adults to isolate effects related to normal brain immaturity. Next, we compared the EEG from 10 children with generalized cryptogenic epilepsy to the EEG of 24 healthy children to isolate effects related to epilepsy. Spectral analysis revealed that global low (delta: 1-3 Hz, theta: 4-7 Hz), medium (alpha: 8-12 Hz) and high (beta: 13-25 Hz) frequency EEG activity was greater in children without epilepsy compared to adults, and even further elevated for children with epilepsy. Topographical and tomographic EEG analyses showed that normal immaturity corresponded to greater delta and theta activity at fronto-central scalp and brain regions, respectively. In contrast, the epilepsy-related activity elevations were predominantly in the alpha band at parieto-occipital electrodes and brain regions, respectively. We conclude that lower frequency activity can be a sign of normal brain immaturity or brain pathology depending on the specific topography and frequency of the oscillating neuronal network.


Causes and consequences of song amplitude adjustment in a territorial bird: a case study in nightingales.
Vocal amplitude, one of the crucial factors for the exchange of acoustic signals, has been neglected in studies of animal communication, but recent studies on song variation in Common Nightingales Luscinia megarhynchos have revealed new insights into its importance in the singing behavior of territorial birds. In nightingales song amplitude is not maximized per se, but is individually regulated according to the level of masking background noise. Also, birds adjust their vocal intensity according to social variables, as in male-male interactions. Moreover, during such interactions, males exploited the directionality of their songs to broadcast them in the direction of the intended receivers ensuring the most effective signal transmission. Studies of the development of this typical long-range signaling suggest that sound level is highly interrelated with overall developmental progression and learning, and thus should be viewed as an integral part of song ontogeny. I conclude that song amplitude is a dynamic feature of the avian signal system, which is individually regulated according to the ecological demands of signal transmission and the social context of communication.


Ultradeep bisulfite sequencing analysis of DNA methylation patterns in multiple gene promoters by 454 sequencing.
We developed a novel approach for conducting multisample, multigene, ultradeep bisulfite sequencing analysis of DNA methylation patterns in clinical samples. A massively parallel sequencing-by-synthesis method (454 sequencing) was used to directly sequence >100 bisulfite PCR products in a single sequencing run without subcloning. We showed the utility, robustness, and superiority of this approach by analyzing methylation in 25 gene-related CpG rich regions from >40 cases of primary cells, including normal peripheral blood lymphocytes, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). A total of 294,631 sequences was generated with an average read length of 131 bp. On average, >1,600 individual sequences were generated for each PCR amplicon far beyond the few clones (<20) typically analyzed by traditional bisulfite sequencing. Comprehensive analysis of CpG methylation patterns at a single DNA molecule level using clustering algorithms revealed differential methylation patterns between diseases. A significant increase in methylation was detected in ALL and FL samples compared with CLL and MCL. Furthermore, a progressive spreading of methylation was detected from the periphery toward the center of select CpG islands in the ALL and FL samples. The ultradeep sequencing also allowed simultaneous analysis of genetic and epigenetic data and revealed an association between a single nucleotide polymorphism and the methylation present in the LRP1B promoter. This new generation of methylome sequencing will provide digital profiles of aberrant DNA methylation for individual human cancers and offers a robust method for the epigenetic classification of tumor subtypes.


Automated nuclear analysis of Leishmania major telomeric clusters reveals changes in their organization during the parasite's life cycle.
Parasite virulence genes are usually associated with telomeres. The clustering of the telomeres, together with their particular spatial distribution in the nucleus of human parasites such as Plasmodium falciparum and Trypanosoma brucei, has been suggested to play a role in facilitating ectopic recombination and in the emergence of new antigenic variants. Leishmania parasites, as well as other trypanosomes, have unusual gene expression characteristics, such as polycistronic and constitutive transcription of protein-coding genes. Leishmania subtelomeric regions are even more unique because unlike these regions in other trypanosomes they are devoid of virulence genes. Given these peculiarities of Leishmania, we sought to investigate how telomeres are organized in the nucleus of Leishmania major parasites at both the human and insect stages of their life cycle. We developed a new automated and precise method for identifying telomere position in the three-dimensional space of the nucleus, and we found that the telomeres are organized in clusters present in similar numbers in both the human and insect stages. While the number of clusters remained the same, their distribution differed between the two stages. The telomeric clusters were found more concentrated near the center of the nucleus in the human stage than in the insect stage suggesting reorganization during the parasite's differentiation process between the two hosts. These data provide the first 3D analysis of Leishmania telomere organization. The possible biological implications of these findings are discussed.


Fully programmable two-dimensional pulse shaper for broadband line-by-line amplitude and phase control.
We introduce a fully programmable two-dimensional (2D) pulse shaper, able to simultaneously control the amplitude and phase of very fine spectral components over a broad bandwidth. This is achieved by aligning two types of spectral dispersers in a cross dispersion setup: a virtually imaged phased array for accessing fine resolution and a transmission grating for achieving broad bandwidth. We take advantage of the resultant 2D dispersion profile as well as introduce programmability by adding a 2D liquid crystal on silicon spatial light modulator at the masking plane. Our shaper has a resolution of ~3 GHz operating over the entire 'C' band of >5.8 THz. Experimental evidence is provided that highlights the full programmability, fine spectral control, and broad bandwidth operation (limited currently by the bandwidth of the input light). We also show line-by-line manipulation of record 836 comb lines over the C-band.


The effect of antibiotic stewardship interventions with stakeholder involvement in hospital settings: a multicentre, cluster randomized controlled intervention study.
There is limited evidence from multicenter, randomized controlled studies to inform planning and implementation of antibiotic stewardship interventions in hospitals. A cluster randomized, controlled, intervention study was performed in selected specialities (infectious diseases, pulmonary medicine and gastroenterology) at three emergency care hospitals in Western Norway. Interventions applied were audit with feedback and academic detailing. Implementation strategies included co-design of interventions with stakeholders in local intervention teams and prescribers setting local targets for change in antibiotic prescribing behaviour. Primary outcome measures were adherence to national guidelines, use of broad-spectrum antibiotics and change in locally defined targets of change in prescribing behaviour. Secondary outcome measures were length of stay, 30-day readmission, in-hospital- and 30-day mortality. One thousand eight hundred two patients receiving antibiotic treatment were included. Adherence to guidelines had an absolute increase from 60 to 66% for all intervention wards (p = 0.04). Effects differed across specialties and pulmonary intervention wards achieved a 14% absolute increase in adherence (p = 0.003), while no change was observed for other specialties. A pulmonary ward targeting increased use of penicillin G 2 mill IU × 4 for pneumonia and COPD exacerbations had an intended increase of 30% for this prescribing behaviour (p < 0.001). Pulmonary wards had a higher increase in adherence, independent of applied intervention. The effect of antibiotic stewardship interventions is dependent on how and in which context they are implemented. Additional effects of interventions are seen when stakeholders discuss ward prescribing behaviour and agree on specific targets for changes in prescribing practice.


Ultrastructure of the adenohypophysis in the larval anadromous sea lamprey, Petromyzon marinus L.
The ultrastructure of the adenohypophysis (AH) in the larval anadromous sea lamprey, Petromyzon marinus L., was examined. The AH is subdivided into three regions, the pro-, meso-, and meta-AH. Cells of the nasopharyngeal stalk extend directly beneath the pro- and meso-AH to form the ventral surface of the gland. Some cells in the pro- and meso-AH are arranged into small follicles. Each region of the AH is characterized by a single granulated (secretory) cell type. Granulated cells constitute 80-90% of the pro-AH and contain secretory granules that range from 800 to 2400 A in diameter. Only 10-20% of the cells in the meso-AH are granulated and they contain much smaller secretory granules (400 to 1250 A diameter) than those in the pro-AH. Granulated cells constitute 80-90% of the meta-AH and contain only a few secretory granules, ranging from 1000 to 2500 A in diameter, and many vesicles containing either a loose flocculent or dense granular material. Non-granulated (stellate) cells are found in all regions. They are characterized by their long cell processes, abundant cytoplasmic filaments, and variable electron density. The appearance of organelles in these cells suggests they are nonsecretory. They may play a role in maintaining the structural integrity of the gland and the regulation of granule release in the pro-AH. Two types of nongranulated cells make up 80-90% of the meso-AH. Type I are stellate cells, type II may be undifferentiated cells. The functional significance of the secretory cells in the larval AH is discussed.


Behavioral influences on prescription inhaler acquisition for persistent asthma in a patient-centered medical home.
Medication adherence can be said to begin with the patient acquiring, or picking up their prescribed medications. There has been considerable study of asthma patients' adherence beliefs once they have possessed medication; however, little is known about attitudes that facilitate or impede their acquisition of such medication. The purpose of this study was to examine the behavioral influences, motivation, and self-efficacy that may guide a patient's decision to pick up asthma controller medications from the pharmacy for the treatment of persistent asthma. A chart review of patients with an asthma diagnosis treated at an academic family medicine practice identified 582 English-speaking adults prescribed an asthma medication. Participants were contacted in a randomized order via telephone and asked to complete an investigator-developed survey based upon the Theory of Planned Behavior. Descriptive statistics, chi square and t-tests were used for data analysis. 240 individuals were contacted, and 27 individuals consented and completed a survey. Eighteen individuals (67%) were prescribed a controller inhaler in the past year, fourteen of whom picked up their prescription from the pharmacy. Individuals who did not pick up their prescription reported more strongly than those who did that using their inhaler is important (P = 0.01). No other statistically significant differences were identified. Use of an inhaler is important to the patient based upon survey results; however, this belief did not correlate with adherence. Future studies that investigate patient-specific motivators would allow practitioners to better target clinical interventions to improve medication adherence in patients with asthma.


Genetic Analysis of the Henry Mountains Bison Herd.
Wild American plains bison (Bison bison) populations virtually disappeared in the late 1800s, with some remnant animals retained in what would become Yellowstone National Park and on private ranches. Some of these private bison were intentionally crossbred with cattle for commercial purposes. This forced hybridization resulted in both mitochondrial and nuclear introgression of cattle genes into some of the extant bison genome. As the private populations grew, excess animals, along with their history of cattle genetics, provided founders for newly established public bison populations. Of the US public bison herds, only those in Yellowstone and Wind Cave National Parks (YNP and WCNP) appear to be free of detectable levels of cattle introgression. However, a small free-ranging population (~350 animals) exists on public land, along with domestic cattle, in the Henry Mountains (HM) of southern Utah. This isolated bison herd originated from a founder group translocated from YNP in the 1940s. Using genetic samples from 129 individuals, we examined the genetic status of the HM population and found no evidence of mitochondrial or nuclear introgression of cattle genes. This new information confirms it is highly unlikely for free-living bison to crossbreed with cattle, and this disease-free HM bison herd is valuable for the long-term conservation of the species. This bison herd is a subpopulation of the YNP/WCNP/HM metapopulation, within which it can contribute significantly to national efforts to restore the American plains bison to more of its native range.