Neuro-endocrine basis for altered plasma glucose homeostasis in the Fragile X mouse.
The fragile X mouse model shows an increase in seizure susceptibility, indicating an involvement of the GABAergic system via an alteration in cellular excitability. In the brain, we have previously described a reduction in GABAA receptor expression as a likely basis for this susceptibility. In the brains of fragile X mice, this reduction in receptor expression culminates with a concomitant increase in the expression of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. Further, voltage-sensitive calcium channel expression is reduced in the pancreas of the fragile X mouse. Since there are considerable similarities in the GABAergic system in the brain and pancreas, we evaluated the protective role of taurine in pancreatic islet development in both wild type (WT) and fragile X mice (KO). One-month-old FVB/NJ males or age-matched fmr1-knockout (KO) mice were supplemented with taurine in drinking water (0.05% w/v) for four weeks. Age-matched controls were fed water only for the same duration. At four weeks, mice were sacrificed and pancreases processed for histology and immunohistochemical studies on changes of insulin, glucagon and somatostatin expression. Additional mice were subjected to a glucose tolerance test. Taurine treatment resulted in a significant increase in the number and size of islets. WT taurine-fed mice, slightly hypoglycemic prior to glucose injection, showed significantly reduced plasma glucose at 30 min post-injection when compared to control mice. KO mice had normal baseline plasma glucose concentration; however, following glucose injection they had higher plasma glucose levels at 30 min when compared to controls. Supplementation of taurine to KO mice resulted in reduced baseline levels of plasma glucose. After glucose injection, the taurine-fed KO mice had reduced plasma glucose at 30 min compared to KO. Concomitant with the increased islets size and glucose tolerance observed in taurine-fed mice there was an increase in insulin, glucagon and somatostatin immunoreactivity in the islets of WT mice. In the KO mice however, insulin levels were not affected whereas glucagon and somatostatin levels were reduced. Exocytosis of these hormones is calcium-dependent, therefore any exacerbation of calcium homeostasis could affect hormone release. We found the expression of the voltage sensitive calcium channels (VSCC) is drastically reduced in the pancreas of fragile X mice. During early development, the VSCC play an important role in calcium-dependent gene expression. Since these channels are also involved in depolarization and calcium-mediated vesicular release of neurotransmitters and pancreatic hormones, alterations in the expression of VSCC not only will affect calcium-mediated gene expression but also hormonal and neurotransmitter release creating therefore a neuroendocrine perturbation in the fragile X that may potentially affect other organ systems. We find that in the fragile X mouse, taurine treatment may partially restore functionality of the neuro-endocrine pancreas.


Biomineralization changes with food supply confer juvenile scallops (Argopecten purpuratus) resistance to ocean acidification.
Future ocean acidification (OA) will affect physiological traits of marine species, with calcifying species being particularly vulnerable. As OA entails high energy demands, particularly during the rapid juvenile growth phase, food supply may play a key role in the response of marine organisms to OA. We experimentally evaluated the role of food supply in modulating physiological responses and biomineralization processes in juveniles of the Chilean scallop, Argopecten purpuratus, that were exposed to control (pH ~ 8.0) and low pH (pH ~ 7.6) conditions using three food supply treatments (high, intermediate, and low). We found that pH and food levels had additive effects on the physiological response of the juvenile scallops. Metabolic rates, shell growth, net calcification, and ingestion rates increased significantly at low pH conditions, independent of food. These physiological responses increased significantly in organisms exposed to intermediate and high levels of food supply. Hence, food supply seems to play a major role modulating organismal response by providing the energetic means to bolster the physiological response of OA stress. On the contrary, the relative expression of chitin synthase, a functional molecule for biomineralization, increased significantly in scallops exposed to low food supply and low pH, which resulted in a thicker periostracum enriched with chitin polysaccharides. Under reduced food and low pH conditions, the adaptive organismal response was to trade-off growth for the expression of biomineralization molecules and altering of the organic composition of shell periostracum, suggesting that the future performance of these calcifiers will depend on the trajectories of both OA and food supply. Thus, incorporating a suite of traits and multiple stressors in future studies of the adaptive organismal response may provide key insights on OA impacts on marine calcifiers.


Early life adversity increases foraging and information gathering in European starlings, Sturnus vulgaris.
Animals can insure themselves against the risk of starvation associated with unpredictable food availability by storing energy reserves or gathering information about alternative food sources. The former strategy carries costs in terms of mass-dependent predation risk, while the latter trades off against foraging for food; both trade-offs may be influenced by an individual's developmental history. Here, we consider a possible role of early developmental experience in inducing different mass regulation and foraging strategies in European starlings. We measured the body mass, body condition, foraging effort, food consumption and contrafreeloading (foraging for food hidden in sand when equivalent food is freely available) of adult birds (≥10 months old) that had previously undergone a subtle early life manipulation of food competition (cross-fostering into the highest or lowest ranks in the brood size hierarchy when 2-12 days of age). We found that developmentally disadvantaged birds were fatter in adulthood and differed in foraging behaviour compared with their advantaged siblings. Disadvantaged birds were hyperphagic compared with advantaged birds, but only following a period of food deprivation, and also spent more time contrafreeloading. Advantaged birds experienced a trade-off between foraging success and time spent contrafreeloading, whereas disadvantaged birds faced no such trade-off, owing to their greater foraging efficiency. Thus, developmentally disadvantaged birds appeared to retain a phenotypic memory of increased nestling food competition, employing both energy storage and information-gathering insurance strategies to a greater extent than their advantaged siblings. Our results suggest that subtle early life disadvantage in the form of psychosocial stress and/or food insecurity can leave a lasting legacy on foraging behaviour and mass regulation even in the absence of food insufficiency during development or adulthood.


Combining paleo-data and modern exclosure experiments to assess the impact of megafauna extinctions on woody vegetation.
Until recently in Earth history, very large herbivores (mammoths, ground sloths, diprotodons, and many others) occurred in most of the World's terrestrial ecosystems, but the majority have gone extinct as part of the late-Quaternary extinctions. How has this large-scale removal of large herbivores affected landscape structure and ecosystem functioning? In this review, we combine paleo-data with information from modern exclosure experiments to assess the impact of large herbivores (and their disappearance) on woody species, landscape structure, and ecosystem functions. In modern landscapes characterized by intense herbivory, woody plants can persist by defending themselves or by association with defended species, can persist by growing in places that are physically inaccessible to herbivores, or can persist where high predator activity limits foraging by herbivores. At the landscape scale, different herbivore densities and assemblages may result in dynamic gradients in woody cover. The late-Quaternary extinctions were natural experiments in large-herbivore removal; the paleoecological record shows evidence of widespread changes in community composition and ecosystem structure and function, consistent with modern exclosure experiments. We propose a conceptual framework that describes the impact of large herbivores on woody plant abundance mediated by herbivore diversity and density, predicting that herbivore suppression of woody plants is strongest where herbivore diversity is high. We conclude that the decline of large herbivores induces major alterations in landscape structure and ecosystem functions.


Phospholipase C-related, but catalytically inactive protein (PRIP) up-regulates osteoclast differentiation via calcium-calcineurin-NFATc1 signaling.
Phospholipase C-related, but catalytically inactive protein (PRIP) was previously identified as a novel inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-δ but lacking phospholipase activity. We recently showed that PRIP gene knock-out (KO) in mice increases bone formation and concomitantly decreases bone resorption, resulting in increased bone mineral density and trabecular bone volume. However, the role of PRIP in osteoclastogenesis has not yet been fully elucidated. Here, we investigated the effects of PRIP on bone remodeling by investigating dynamic tooth movement in mice fitted with orthodontic devices. Morphological analysis indicated that the extent of tooth movement was smaller in the PRIP-KO mice than in wild-type mice. Histological analysis revealed fewer osteoclasts on the bone-resorption side in maxillary bones of PRIP-KO mice, and osteoclast formation assays and flow cytometry indicated lower osteoclast differentiation in bone marrow cells isolated from these mice. The expression of genes implicated in bone resorption was lower in differentiated PRIP-KO cells, and genes involved in osteoclast differentiation, such as the transcription factor NFATc1, exhibited lower expression in immature PRIP-KO cells initiated by M-CSF. Moreover, calcineurin expression and activity were also lower in the PRIP-KO cells. The PRIP-KO cells also displayed fewer M-CSF-induced changes in intracellular Ca2+ and exhibited reduced nuclear localization of NFATc1. Up-regulation of intracellular Ca2+ restored osteoclastogenesis of the PRIP-KO cells. These results indicate that PRIP deficiency impairs osteoclast differentiation, particularly at the early stages, and that PRIP stimulates osteoclast differentiation through calcium-calcineurin-NFATc1 signaling via regulating intracellular Ca2.


Species-specific activity of antibacterial drug combinations.
The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine1,2. Drug combinations can help to fight multi-drug-resistant bacterial infections, yet they are largely unexplored and rarely used in clinics. Here we profile almost 3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in six strains from three Gram-negative pathogens-Escherichia coli, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa-to identify general principles for antibacterial drug combinations and understand their potential. Despite the phylogenetic relatedness of the three species, more than 70% of the drug-drug interactions that we detected are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process. We provide mechanistic insights into this dichotomy and further dissect the interactions of the food additive vanillin. Finally, we demonstrate that several synergies are effective against multi-drug-resistant clinical isolates in vitro and during infections of the larvae of the greater wax moth Galleria mellonella, with one reverting resistance to the last-resort antibiotic colistin.


Ultrafast Electron Transfer in a Self-Assembling Sulfonated Aluminum Corrole-Methylviologen Complex.
Photoinduced electron transfer systems can mimic certain features of natural photosynthetic reaction centers, which are crucial for solar energy production. Among other tetra-pyrroles, the versatile chemical and photophysical properties of corroles make them very promising donors applicable in donor-acceptor complexes. Here, we present a first comprehensive study of ultrafast photoinduced electron transfer in a self-assembling sulfonated aluminum corrole-methylviologen complex combining visible and mid-IR transient absorption spectroscopy. The noncovalent D-A association of the corrole-methylviologen complex has the great advantage that photoinduced charge separation becomes possible even though the back electron transfer (BET) rate is large. Initial forward electron transfer from corrole to methylviologen is observed on an ∼130 fs time scale. Subsequent back electron transfer takes place with τBET = (1.8 ± 0.5) ps, revealing very complex relaxation dynamics. Direct probing in the mid-IR allows us to unravel the back electron transfer and cooling dynamics/electronic reorganization. Upon tracing the dynamics of the methylviologen-radical marker band at 1640 cm-1 and the C═C stretching of corrole at around 1500 cm-1, we observe that large amounts of excess energy survive the back transfer, leading to the formation of hot ground state absorption. A closer examination of the signal after 300 ps, surviving the back transfer, exhibits a charge-separation yield of 10-15%.


The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability.
The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.


Understanding usage of a hybrid website and smartphone app for weight management: a mixed-methods study.
Advancements in mobile phone technology offer huge potential for enhancing the timely delivery of health behavior change interventions. The development of smartphone-based health interventions (apps) is a rapidly growing field of research, yet there have been few longitudinal examinations of how people experience and use these apps within their day-to-day routines, particularly within the context of a hybrid Web- and app-based intervention. This study used an in-depth mixed-methods design to examine individual variation in (1) impact on self-reported goal engagement (ie, motivation, self-efficacy, awareness, effort, achievement) of access to a weight management app (POWeR Tracker) when provided alongside a Web-based weight management intervention (POWeR) and (2) usage and views of POWeR Tracker. Thirteen adults were provided access to POWeR and were monitored over a 4-week period. Access to POWeR Tracker was provided in 2 alternate weeks (ie, weeks 1 and 3 or weeks 2 and 4). Participants' goal engagement was measured daily via self-report. Mixed effects models were used to examine change in goal engagement between the weeks when POWeR Tracker was and was not available and whether the extent of change in goal engagement varied between individual participants. Usage of POWeR and POWeR Tracker was automatically recorded for each participant. Telephone interviews were conducted and analyzed using inductive thematic analysis to further explore participants' experiences using POWeR and POWeR Tracker. Access to POWeR Tracker was associated with a significant increase in participants' awareness of their eating (β1=0.31, P=.04) and physical activity goals (β1=0.28, P=.03). The level of increase varied between individual participants. Usage data showed that participants used the POWeR website for similar amounts of time during the weeks when POWeR Tracker was (mean 29 minutes, SD 31 minutes) and was not available (mean 27 minutes, SD 33 minutes). POWeR Tracker was mostly accessed in short bursts (mean 3 minutes, SD 2 minutes) during convenient moments or moments when participants deemed the intervention content most relevant. The qualitative data indicated that nearly all participants agreed that it was more convenient to access information on-the-go via their mobiles compared to a computer. However, participants varied in their views and usage of the Web- versus app-based components and the informational versus tracking tools provided by POWeR Tracker. This study provides evidence that smartphones have the potential to improve individuals' engagement with their health-related goals when used as a supplement to an existing online intervention. The perceived convenience of mobile access to information does not appear to deter use of Web-based interventions or strengthen the impact of app access on goal engagement. A mixed-methods design enabled exploration of individual variation in daily usage of the app-based tools.


Design and Feasibility Testing of the truth FinishIt Tobacco Countermarketing Brand Equity Scale.
The original truth campaign was a branded, national smoking prevention mass media effort focused on at-risk youth ages 12-17. Today the truth brand focuses on the goal of finishing tobacco (truth FinishIt). There have been significant changes in the tobacco control landscape, leading FinishIt to focus on 15- to 21-year-olds. The present article reports on formative research and media monitoring data collected to pilot test a new truth FinishIt brand equity scale. The goals of this study were to (a) content analyze truth FinishIt mass media ads, (b) assess truth's social media and followers' perceptions of truth's digital brand identity, and (c) develop and feasibility test a new version of the truth FinishIt brand equity scale using data from an existing Truth Initiative media monitoring study. Through factor analysis, we identified a brand equity scale, as in previous research, consisting of 4 main constructs: brand loyalty, leadership/satisfaction, personality, and awareness. Targeted truth attitudes and beliefs about social perceptions, acceptability, and industry-related beliefs were regressed on the higher order factor and each of the 4 individual brand equity factors. Ordinary least squares regression models generally showed associations in the expected directions (positive for anti-tobacco and negative for pro-tobacco) between targeted attitudes/beliefs and truth FinishIt brand equity. This study succeeded in developing and validating a new truth FinishIt brand equity scale. The scale may be a valuable metric for future campaign evaluation. Future studies should examine the effects of truth FinishIt brand equity on tobacco use behavioral outcomes over time.


Drug voyager: a computational platform for exploring unintended drug action.
The dominant paradigm in understanding drug action focuses on the intended therapeutic effects and frequent adverse reactions. However, this approach may limit opportunities to grasp unintended drug actions, which can open up channels to repurpose existing drugs and identify rare adverse drug reactions. Advances in systems biology can be exploited to comprehensively understand pharmacodynamic actions, although proper frameworks to represent drug actions are still lacking. We suggest a novel platform to construct a drug-specific pathway in which a molecular-level mechanism of action is formulated based on pharmacologic, pharmacogenomic, transcriptomic, and phenotypic data related to drug response ( http://databio.gachon.ac.kr/tools/ ). In this platform, an adoption of three conceptual levels imitating drug perturbation allows these pathways to be realistically rendered in comparison to those of other models. Furthermore, we propose a new method that exploits functional features of the drug-specific pathways to predict new indications as well as adverse reactions. For therapeutic uses, our predictions significantly overlapped with clinical trials and an up-to-date drug-disease association database. Also, our method outperforms existing methods with regard to classification of active compounds for cancers. For adverse reactions, our predictions were significantly enriched in an independent database derived from the Food and Drug Administration (FDA) Adverse Event Reporting System and meaningfully cover an Adverse Reaction Database provided by Health Canada. Lastly, we discuss several predictions for both therapeutic indications and side-effects through the published literature. Our study addresses how we can computationally represent drug-signaling pathways to understand unintended drug actions and to facilitate drug discovery and screening.


Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4.
CD4 is an integral membrane glycoprotein which is known as the human immunodeficiency virus (HIV) receptor for infection of human cells. The protein is synthesized in the endoplasmic reticulum (ER) and subsequently transported to the cell surface via the Golgi complex. HIV infection of CD4+ cells leads to downmodulation of cell surface CD4, due at least in part to the formation of stable intracellular complexes between CD4 and the HIV type 1 (HIV-1) Env precursor polyprotein gp160. This process "traps" both proteins in the ER, leading to reduced surface expression of CD4 and reduced processing of gp160 to gp120 and gp41. We have recently demonstrated that the presence of the HIV-1-encoded integral membrane protein Vpu can reduce the formation of Env-CD4 complexes, resulting in increased gp160 processing and decreased CD4 stability. We have studied the effect of Vpu on CD4 stability and found that Vpu induces rapid degradation of CD4, reducing the half-life of CD4 from 6 h to 12 min. By using a CD4-binding mutant of gp160, we were able to show that this Vpu-induced degradation of CD4 requires retention of CD4 in the ER, which is normally accomplished through its binding to gp160. The involvement of gp160 in the induction of CD4 degradation is restricted to its function as a CD4 trap, since, in the absence of Env, an ER retention mutant of CD4, as well as wild-type CD4 in cultures treated with brefeldin A, a drug that blocks transport of proteins from the ER, is degraded in the presence of Vpu.


Telomere dysfunction increases mutation rate and genomic instability.
The increased tumor incidence in telomerase null mice suggests that telomere dysfunction induces genetic instability. To test this directly, we examined mutation rate in the absence of telomerase in S. cerevisiae. The mutation rate in the CAN1 gene increased 10- to 100-fold in est1Delta strains as telomeres became dysfunctional. This increased mutation rate resulted from an increased frequency of terminal deletions. Chromosome fusions were recovered from est1Delta strains, suggesting that the terminal deletions may occur by a breakage-fusion-bridge type mechanism. At one locus, chromosomes with terminal deletions gained a new telomere through a Rad52p-dependent, Rad51p-independent process consistent with break-induced replication. At a second locus, more complicated rearrangements involving multiple chromosomes were seen. These data suggest that telomerase can inhibit chromosomal instability.


Oxaliplatin as a radiosensitiser for upper and lower gastrointestinal tract malignancies: what have we learned from a decade of translational research?
Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies should be designed, the pre-clinical evidence for the use of oxaliplatin chemotherapy as a radiosensitising agent is appraised. Particular focus is placed on oxaliplatin's biological mechanisms of action, including cell cycle effects, the formation of DNA adducts and interstrand cross-links and the role of DNA repair proteins. At a clinical level, there is currently no evidence to suggest that oxaliplatin provides an additional benefit to concurrent chemo-radiation regimes that utilise fluoropyrimidines; we evaluate the reasons for this observation, the limitations of clinical trial design and the opportunities that currently exist to design clinical trials which are underpinned by an understanding of the basic biology.


Public choice in health: problems, politics and perspectives on formulating national health policy.
Development of health policy goals necessitates a choice among normative premises--an accommodation of conflicting values. Any debate that does not identify underlying assumptions or link policy prescriptions to a theoretical perspective is destined to degenerate into uncommunicative and unproductive rhetorical posturing. A sensible approach toward formulating national health policy requires that competing values be identified and discussed explicitly. This article will examine the effect that selection of different theoretical perspectives can have on the identification of problems and on the formulation of prescriptive policies in the health field. It will also focus on the different values that are promoted by different policy perspectives and consider alternative models for implementing value choices.


Clonal instability of V region hypermutation in the Ramos Burkitt's lymphoma cell line.
Affinity maturation of the humoral immune response is caused by single base changes that are introduced into the V regions of the Ig genes during a brief period of B cell differentiation. It has recently become possible to study V region mutation in some human Burkitt's lymphoma cell lines that mutate their V regions and express surface markers that suggest they arose from the malignant transformation of germinal center B cells. Ramos Burkitt's cells constitutively mutate their V regions at a rate of approximately 2 x 10(-5) mutations/bp/generation. However, the sequencing of unselected V regions suggested that our Ramos cell line was progressively losing its ability to undergo V region hypermutation. To accurately quantify this process, subclones with different nonsense mutations in the mu heavy chain V region were identified. Reversion analysis and sequencing of unselected V regions were used to examine the clonal stability of V region hypermutation. Even after only 1 month in culture, stable and unstable subclones could be identified. The identification of mutating and non-mutating subclones of Ramos provided a unique opportunity to identify factors involved in the mutational process. Differential gene expression between mutating and non-mutating Ramos clones was examined by RT-PCR and cDNA microarray analyses. We found that the expression of activation-induced cytidine deaminase (AID), a putative cytidine deaminase, correlated with mutation rates in Ramos subclones. These results suggest that the hypermutation phenotype is inherently unstable in Ramos and that long culture periods favor outgrowth of non-mutating cells that express lower levels of AID.


Demographic expansion of an African opportunistic carnivore during the Neolithic revolution.
The diffusion of Neolithic technology together with the Holocene Climatic Optimum fostered the spread of human settlements and pastoral activities in North Africa, resulting in profound and enduring consequences for the dynamics of species, communities and landscapes. Here, we investigate the demographic history of the African wolf (Canis lupaster), a recently recognized canid species, to understand if demographic trends of this generalist and opportunistic carnivore reflect the increase in food availability that emerged after the arrival of the Neolithic economy in North Africa. We screened nuclear and mitochondrial DNA in samples collected throughout Algeria and Tunisia, and implemented coalescent approaches to estimate the variation of effective population sizes from present to ancestral time. We have found consistent evidence supporting the hypothesis that the African wolf population experienced a meaningful expansion concurring with a period of rapid population expansion of domesticates linked to the advent of agricultural practices.


Improving the trustworthiness, usefulness, and ethics of biomedical research through an innovative and comprehensive institutional initiative.
The reproducibility crisis triggered worldwide initiatives to improve rigor, reproducibility, and transparency in biomedical research. There are many examples of scientists, journals, and funding agencies adopting responsible research practices. The QUEST (Quality-Ethics-Open Science-Translation) Center offers a unique opportunity to examine the role of institutions. The Berlin Institute of Health founded QUEST to increase the likelihood that research conducted at this large academic medical center would be trustworthy, useful for scientists and society, and ethical. QUEST researchers perform "science of science" studies to understand problems with standard practices and develop targeted solutions. The staff work with institutional leadership and local scientists to incentivize and support responsible practices in research, funding, and hiring. Some activities described in this paper focus on the institution, whereas others may benefit the national and international scientific community. Our experience, approaches, and recommendations will be informative for faculty leadership, administrators, and researchers interested in improving scientific practice.


Safety of audiology direct access for medicare patients complaining of impaired hearing.
Allowing Medicare beneficiaries to self-refer to audiologists for evaluation of hearing loss has been advocated as a cost-effective service delivery model. Resistance to audiology direct access is based, in part, on the concern that audiologists might miss significant otologic conditions. To evaluate the relative safety of audiology direct access by comparing the treatment plans of audiologists and otolaryngologists in a large group of Medicare-eligible patients seeking hearing evaluation. Retrospective chart review study comparing assessment and treatment plans developed by audiologists and otolaryngologists. 1550 records comprising all Medicare eligible patients referred to the Audiology Section of the Mayo Clinic Florida in 2007 with a primary complaint of hearing impairment. Assessment and treatment plans were compiled from the electronic medical record and placed in a secured database. Records of patients seen jointly by audiology and otolaryngology practitioners (Group 1: 352 cases) were reviewed by four blinded reviewers, two otolaryngologists and two audiologists, who judged whether the audiologist treatment plan, if followed, would have missed conditions identified and addressed in the otolaryngologist's treatment plan. Records of patients seen by audiology but not otolaryngology (Group 2: 1198 cases) were evaluated by a neurotologist who judged whether the patient should have seen an otolaryngologist based on the audiologist's documentation and test results. Additionally, the audiologist and reviewing neurotologist judgments about hearing asymmetry were compared to two mathematical measures of hearing asymmetry (Charing Cross and AAO-HNS [American Academy of Otolaryngology-Head and Neck Surgery] calculations). In the analysis of Group 1 records, the jury of four judges found no audiology discrepant treatment plans in over 95% of cases. In no case where a judge identified a discrepancy in treatment plans did the audiologist plan risk missing conditions associated with significant mortality or morbidity that were subsequently identified by the otolaryngologist. In the analysis of Group 2 records, the neurotologist judged that audiology services alone were all that was required in 78% of cases. An additional 9% of cases were referred for subsequent medical evaluation. The majority of remaining patients had hearing asymmetries. Some were evaluated by otolaryngology for hearing asymmetry in the past with no interval changes, and others were consistent with noise exposure history. In 0.33% of cases, unexplained hearing asymmetry was potentially missed by the audiologist. Audiologists and the neurotologist demonstrated comparable accuracy in identifying Charing Cross and AAO-HNS pure-tone asymmetries. Of study patients evaluated for hearing problems in the one-year period of this study, the majority (95%) ultimately required audiological services, and in most of these cases, audiological services were the only hearing health-care services that were needed. Audiologist treatment plans did not differ substantially from otolaryngologist plans for the same condition; there was no convincing evidence that audiologists missed significant symptoms of otologic disease; and there was strong evidence that audiologists referred to otolaryngology when appropriate. These findings are consistent with the premise that audiology direct access would not pose a safety risk to Medicare beneficiaries complaining of hearing impairment.


Erythropoiesis: development and differentiation.
Through their oxygen delivery function, red blood cells are pivotal to the healthy existence of all vertebrate organisms. These cells are required during all stages of life--embryonic, fetal, neonatal, adolescent, and adult. In the adult, red blood cells are the terminally differentiated end-product cells of a complex hierarchy of hematopoietic progenitors that become progressively restricted to the erythroid lineage. During this stepwise differentiation process, erythroid progenitors undergo enormous expansion, so as to fulfill the daily requirement of ~2 × 10(11) new erythrocytes. How the erythroid lineage is made has been a topic of intense research over the last decades. Developmental studies show that there are two types of red blood cells--embryonic and adult. They develop from distinct hemogenic/hematopoietic progenitors in different anatomical sites and show distinct genetic programs. This article highlights the developmental and differentiation events necessary in the production of hemoglobin-producing red blood cells.


Development of chewing in children from 12 to 48 months: longitudinal study of EMG patterns.
Developmental changes in the coordinative organization of masticatory muscles were examined longitudinally in four children over 49 experimental sessions spanning the age range of 12-48 mo. Electromyographic (EMG) records were obtained for right and left masseter muscles, right and left temporalis muscles, and the anterior belly of the digastric. Two independent analytic processes were employed, one that relied on identification of onset and offset of muscle activation and a second that used pairwise cross-correlational techniques. The results of these two analyses, which were found to be consistent with each other, demonstrated that the basic chewing pattern of reciprocally activated antagonistic muscle groups is established by 12 mo of age. Nevertheless, chewing efficiency appears to be improved through a variety of changes in the chewing pattern throughout early development. Coupling of activity among the jaw elevator muscles was shown to strengthen with maturation, and the synchrony of onset and offset of these muscles also increased. Coactivation of antagonistic muscles decreased significantly with development. This decrease in antagonistic coactivation and increase in synchrony among jaw elevators, and a parallel decrease in EMG burst duration, were taken as evidence of increased chewing efficiency. No significant differences in the frequency of chewing were found across the ages studied. Additional considerations include the appropriateness of this coordinative infrastructure for other developing oromotor skills, such as speech production. It is suggested that the relatively fixed coordinative framework for chewing exhibited by these children would not be suitable for adaptation to speech movements, which have been shown to rely on a much more variable and adjustable coordinative organization.


Climate-Smart Design for Ecosystem Management: A Test Application for Coral Reefs.
The interactive and cumulative impacts of climate change on natural resources such as coral reefs present numerous challenges for conservation planning and management. Climate change adaptation is complex due to climate-stressor interactions across multiple spatial and temporal scales. This leaves decision makers worldwide faced with local, regional, and global-scale threats to ecosystem processes and services, occurring over time frames that require both near-term and long-term planning. Thus there is a need for structured approaches to adaptation planning that integrate existing methods for vulnerability assessment with design and evaluation of effective adaptation responses. The Corals and Climate Adaptation Planning project of the U.S. Coral Reef Task Force seeks to develop guidance for improving coral reef management through tailored application of a climate-smart approach. This approach is based on principles from a recently-published guide which provides a framework for adopting forward-looking goals, based on assessing vulnerabilities to climate change and applying a structured process to design effective adaptation strategies. Work presented in this paper includes: (1) examination of the climate-smart management cycle as it relates to coral reefs; (2) a compilation of adaptation strategies for coral reefs drawn from a comprehensive review of the literature; (3) in-depth demonstration of climate-smart design for place-based crafting of robust adaptation actions; and (4) feedback from stakeholders on the perceived usefulness of the approach. We conclude with a discussion of lessons-learned on integrating climate-smart design into real-world management planning processes and a call from stakeholders for an "adaptation design tool" that is now under development.


Identifying diazotrophs by incorporation of nitrogen from (15)N(2) into RNA.
The diversity and abundance of active diazotrophs was investigated in a New Zealand pulp and paper wastewater by enrichment with (15)N(2). Purified (15)N-RNA was analysed by reverse transcription, molecular cloning and sequence analysis of 16S rRNA to reveal a diverse community of bacteria as indicated by a Shannon Weaver Index value of > 2.8. The major class represented in the enriched culture were the gamma-Proteobacteria at 85% with a secondary group of the phylum Firmicutes present at 8.2%, the remaining sequences were affiliated with the alpha- and beta-Proteobacterial classes (1.4% and 4.3%, respectively). Three dominant genera, Aeromonas, Pseudomonas and Bacillus, were identified by comparison with published sequences and phylogenetic analysis. To confirm that representatives of the taxonomic groups identified from the active enriched nitrogen-fixing community were capable of fixing nitrogen Aeromonas and Pseudomonas species were cultivated and shown to possess nifH genes. In wastewater, fluorescence in situ hybridisation probing revealed that the dominant nitrogen-fixing population identified in this study were present in the population, but at lower levels. The population is, therefore, reliant on a small sub-population of diazotrophs to supply the community's nitrogen needs above that already present in the wastewater.


Comparative overview of ST-elevation myocardial infarction epidemiology, demographics, management, and outcomes in five Asia-Pacific countries: a meta-analysis.
The aim of this study is to gain insight into the differences in demographics of ST-elevation myocardial infarction (STEMI) patients in Asia-Pacific, as well as inter-country variation in treatment and mortality outcomes. Systematic review of published studies and reports from known registries in Australia, Japan, Korea, Singapore, and Malaysia that began data collection after the year 2000. Supplementary self-report survey questionnaire on public health data answered by representative cardiologists working in these countries. Twenty studies comprising of 158 420 patients were included in the meta-analysis. The mean age was 61.6 years. Chronic kidney disease prevalence was higher in Japan, while dyslipidaemia was low in Korea. Use of aspirin, P2Y12 inhibitors, and statins were high throughout, but ACEi/ARB and β-blocker prescriptions were lower in Japan and Malaysia. Reperfusion strategies varied greatly, with high rates of primary percutaneous coronary intervention (pPCI) in Korea (91.6%), whilst Malaysia relies far more on fibrinolysis (72.6%) than pPCI (9.6%). Similarly, mortality differed, with 1-year mortality from STEMI was considerably greater in Malaysia (17.9%) and Singapore (11.2%) than in Korea (8.1%), Australia (7.8%), and Japan (6.2%). The countries were broadly similar in development and public health indices. Singapore has the highest gross national income and total healthcare expenditure per capita, whilst Malaysia has the lowest. Primary PCI is available in all countries 24/7/365. Despite broadly comparable public health systems, differences exist in patient profile, in-hospital treatment, and mortality outcomes in these five countries. Our study reveals areas for improvements. The authors advocate further registry-based multi-country comparative studies focused on the Asia-Pacific region.


Surgical repair of the incompetent femoral vein valve.
Incompetent femoral vein valves are identified by reflux femoral phlebography in selected patients with postphlebitic syndrome. In addition to conventional stripping of varices and subfascial interruption of communicating veins, 14 patients with 17 involved extremities have undergone surgical repair of an incompetent valve in the superficial femoral veins. Pathologic condition of the valve consisted of elongation of the cusp edge. Repair was achieved by a series of tucking sutures shortening the cusp and restoring competence to the valve. Healing of ulcers and relief of swelling occurred in 90% of the patients. This rate was maintained up to seven years. These cases demonstrate the feasibility of surgery on the femoral vein valve. The relative importance of conventional stripping, subfascial communicating vein interruption, and femoral valve repair will have to be established by way of further clinical experience.


The incidence of soft tissue injury in operative tibial plateau fractures: a magnetic resonance imaging analysis of 103 patients.
The goal of this study was to determine the incidence of injury to soft tissue structures of the knee in tibial plateau fractures scheduled for surgery. Prospective cohort. Level I academic medical center. One hundred three consecutive patients with acute tibial plateau fractures indicated for operative intervention. Standard x-ray examinations, including anteroposterior, lateral, and oblique views, were performed in the emergency department. Subsequently all patients had magnetic resonance imaging performed. The Schatzker and AO/OTA classifications were used to classify each fracture pattern based solely on the x-rays. Soft tissue injuries were assessed by magnetic resonance imaging. Fifteen categories of injury were determined as positive or negative on each magnetic resonance imaging, which included tears of the cruciates, collateral ligaments, menisci, and posterolateral corner. The overall incidence of injury to soft tissues was higher than previously reported. Only 1 patient (1%) in the series had complete absence of any soft tissue injury. Seventy-nine patients (77%) sustained a complete tear or avulsion of 1 or more cruciate or collateral ligaments. Ninety-four patients (91%) had evidence of lateral meniscus pathology. Forty-five patients (44%) had medial meniscus tears. Seventy patients (68%) had tears of 1 or more of the posterolateral corner structures of the knee. The most frequent fracture pattern was a lateral plateau split-depression (Schatzker II) (60%). No pure depression injuries (Schatzker III, AO/OTA 41-B2) were seen. The incidence of complete ligamentous or meniscal disruption associated with operative tibial plateau fractures was higher than previously reported. Though the clinical importance of injury to each of these structures is unknown, the treating surgeon should be aware that a variety of soft tissue injuries are common in these fractures. In addition, all fractures had at least 1 cortical split visible on magnetic resonance imaging, implying that pure depression patterns are very rare or may not exist.


Mitochondrial localization of Dictyostelium discoideum dUTPase mediated by its N-terminus.
The nuclear and mitochondrial genomes of Dictyostelium discoideum, a unicellular eukaryote, have relatively high A+T-contents of 77.5% and 72.65%, respectively. To begin to investigate how the pyrimidine biosynthetic pathway fulfills the demand for dTTP, we determined the catalytic properties and structure of the key enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) that hydrolyzes dUTP to dUMP, the precursor of dTTP. The annotated genome of D. discoideum identifies a gene encoding a polypeptide containing the five conserved motifs of homotrimeric dUTPases. Recombinant proteins, comprised of either full-length or core polypeptides with all conserved motifs but lacking residues 1-37 of the N-terminus, were active dUTPases. Crystallographic analyses of the core enzyme indicated that the C-termini, normally flexible, were constrained by interactions with the shortened N-termini that arose from the loss of residues 1-37. This allowed greater access of dUTP to active sites, resulting in enhanced catalytic parameters. A tagged protein comprised of the N-terminal forty amino acids of dUTPase fused to green fluorescent protein (GFP) was expressed in D. discoideum cells. Supporting a prediction of mitochondrial targeting information within the N-terminus, localization and subcellular fractionation studies showed GFP to be in mitochondria. N-terminal sequencing of immunoprecipitated GFP revealed the loss of the dUTPase sequence upon import into the organelle.


Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.
Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD+, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD+ repletion.


[Skin bioengineering: preclinical and clinical applications].
Regenerative Medicine is an emerging field that combines basic research and clinical observations in order to identify the elements required to replace damaged tissues and organs in vivo and to stimulate the body's intrinsic regenerative capacity. Great benefits are expected in this field as researchers take advantage of the potential regenerative properties of both embryonic and adult stem cells, and more recently, of induced pluripotent stem cells. Bioengineered skin emerged mainly in response to a critical need for early permanent coverage of extensive burns. Later this technology was also applied to the treatment of chronic ulcers. Our group has established a humanized mouse model of skin grafting that involves the use of bioengineered human skin in immunodeficient mice. This model is suitable for the study of physiologic and pathologic cutaneous processes and the evaluation of treatment strategies for skin diseases, including protocols for gene and cell therapy and tissue engineering.


A Cut-Stem Inoculation Technique to Evaluate Soybean for Resistance to Macrophomina phaseolina.
Charcoal rot of soybean is caused by the fungal pathogen Macrophomina phaseolina. Effective and reliable techniques to evaluate soybean for resistance to this fungus are needed to work toward a management scheme that would utilize host resistance. Three experiments were conducted to investigate the use of a cut-stem inoculation technique to evaluate soybean genotypes for resistance to M. phaseolina. The first experiment compared aggressiveness of M. phaseolina isolates collected from soybean on different soybean genotypes. Significant (P < 0.05) differences among the isolates and genotypes for relative area under disease progress curve (RAUDPC) were found without a significant isolate-genotype interaction. The second experiment compared 14 soybean genotypes inoculated with M. phaseolina in multiple trials conducted in two environments, the greenhouse and growth chamber. Significant (P < 0.05) differences among environments and highly significant (P < 0.001) differences among soybean genotypes for RAUDPC were found. The environment-genotype interaction was nonsignificant (P > 0.05). Soybean genotypes DT97-4290, DT98-7553, DT98-17554, and DT99-16864 had significantly (P < 0.05) lower RAUDPC than 7 of the 14 genotypes. The third experiment evaluated resistance in selected Phaseolus spp. and soybean genotypes. The range of RAUDPC for Phaseolus spp. was similar to that of soybean. The Phaseolus lunatus 'Bush Baby Lima' had significantly (P < 0.05) lower RAUDPC than P. vulgaris genotypes evaluated. The cut-stem inoculation technique, which has several advantages over field tests, successfully distinguished differences in aggressiveness among M. phaseolina isolates and relative differences among soybean genotypes for resistance to M. phaseolina comparable with results of field tests.


Cytoplasmic intermediate filaments mediate actin-driven positioning of the nucleus.
The localization of the nucleus is precisely regulated, and defects in nuclear positioning are observed in diseases such as lissencephaly, cerebellar ataxia and dysplasia. We show here that cytoplasmic intermediate filaments are essential players in actin-dependent positioning of the nucleus. The actin retrograde flow is relayed by a flow of intermediate filaments that accumulate asymmetrically around the nuclear envelope. Perturbations of the intermediate filament network alter positioning of the nucleus in both migrating and immobile astrocytes. This function of intermediate filaments might be crucial for regulating cell motility, in particular in tumor cells expressing high levels of cytoplasmic intermediate filaments.


Optical fiber in-line Mach-Zehnder interferometer based on dual internal mirrors formed by a hollow sphere pair.
We demonstrate a fiber in-line Mach-Zehnder interferometer based on dual internal mirrors formed by a hollow sphere pair and fabricated by femtosecond laser micromachining together with the fusion splicing technique. The hollow sphere surface adjacent to the fiber core can reflect part of the incident light beam to the air-cladding interface, where the light beam is reflected again before returning to the fiber core by another hollow sphere surface and recombining with the light beam remaining in the fiber core. Such an interferometer is miniature and robust, and is sensitive to environmental variations and allows simultaneous surrounding refractive index, temperature, and curvature measurement.


A manganese-dependent dioxygenase from Arthrobacter globiformis CM-2 belongs to the major extradiol dioxygenase family.
Almost all bacterial ring cleavage dioxygenases contain iron as the catalytic metal center. We report here the first available sequence for a manganese-dependent 3,4-dihydroxyphenylacetate (3,4-DHPA) 2,3-dioxygenase and its further characterization. This manganese-dependent extradiol dioxygenase from Arthrobacter globiformis CM-2, unlike iron-dependent extradiol dioxygenases, is not inactivated by hydrogen peroxide. Also, ferrous ions, which activate iron extradiol dioxygenases, inhibit 3,4-DHPA 2,3-dioxygenase. The gene encoding 3,4-DHPA 2,3-dioxygenase, mndD, was identified from an A. globiformis CM-2 cosmid library. mndD was subcloned as a 2.0-kb SmaI fragment in pUC18, from which manganese-dependent extradiol dioxygenase activity was expressed at high levels in Escherichia coli. The mndD open reading frame was identified by comparison with the known N-terminal amino acid sequence of purified manganese-dependent 3,4-DHPA 2,3-dioxygenase. Fourteen of 18 amino acids conserved in members of the iron-dependent extradiol dioxygenase family are also conserved in the manganese-dependent 3,4-DHPA 2,3-dioxygenase (MndD). Thus, MndD belongs to the extradiol family of dioxygenases and may share a common ancestry with the iron-dependent extradiol dioxygenases. We propose the revised consensus primary sequence (G,T,N,R)X(H,A)XXXXXXX(L,I,V,M,F)YXX(D,E,T,N,A)PX(G,P) X(2,3)E for this family. (Numbers in brackets indicate a gap of two or three residues at this point in the sequence.) The suggested common ancestry is also supported by sequence obtained from genes flanking mndD, which share significant sequence identity with xylJ and xylG from Pseudomonas putida.


A single analytical model for sparkle and graininess patterns in texture of effect coatings.
Flakes in effect coatings, which are responsible for its color shift, are not perfectly horizontally oriented, producing a non uniform texture when observed from a distance of around one meter or less. If the coating is illuminated by a diffuse source, a granular appearance is observed, called graininess. But when the coating is illuminated by unidirectional light, some luminous spots on a dark background appear, effect that is known as sparkle. The characterization of these two textures is getting more important for automotive industry because of the high percentage of cars with effect coatings and because improvements in imaging technology allows this effect to be measured by, for instance, commercial instruments as BYK-mac. A single analytical model to understand and radiometrically characterize both sparkle and graininess in effect coatings is presented and studied in this work. It allows both patterns to be explained and, despite its simplicity, includes variables related to the optical system (Point Spread Function (PSF) and size of the entrance pupil), its distance to the coating, the diffusion grade of the illumination, the illumination and observation directions, and coating parameters.


Asymmetric Cancer Hallmarks in Breast Tumors on Different Sides of the Body.
During the last decades it has been established that breast cancer arises through the accumulation of genetic and epigenetic alterations in different cancer related genes. These alterations confer the tumor oncogenic abilities, which can be resumed as cancer hallmarks (CH). The purpose of this study was to establish the methylation profile of CpG sites located in cancer genes in breast tumors so as to infer their potential impact on 6 CH: i.e. sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, genome instability and invasion and metastasis. For 51 breast carcinomas, MS-MLPA derived-methylation profiles of 81 CpG sites were converted into 6 CH profiles. CH profiles distribution was tested by different statistical methods and correlated with clinical-pathological data. Unsupervised Hierarchical Cluster Analysis revealed that CH profiles segregate in two main groups (bootstrapping 90-100%), which correlate with breast laterality (p = 0.05). For validating these observations, gene expression data was obtained by RealTime-PCR in a different cohort of 25 tumors and converted into CH profiles. This analyses confirmed the same clustering and a tendency of association with breast laterality (p = 0.15). In silico analyses on gene expression data from TCGA Breast dataset from left and right breast tumors showed that they differed significantly when data was previously converted into CH profiles (p = 0.033). We show here for the first time, that breast carcinomas arising on different sides of the body present differential cancer traits inferred from methylation and expression profiles. Our results indicate that by converting methylation or expression profiles in terms of Cancer Hallmarks, it would allow to uncover veiled associations with clinical features. These results contribute with a new finding to the better understanding of breast tumor behavior, and can moreover serve as proof of principle for other bilateral cancers like lung, testes or kidney.


Ultra-low dose CT attenuation correction for PET/CT: analysis of sparse view data acquisition and reconstruction algorithms.
For PET/CT systems, PET image reconstruction requires corresponding CT images for anatomical localization and attenuation correction. In the case of PET respiratory gating, multiple gated CT scans can offer phase-matched attenuation and motion correction, at the expense of increased radiation dose. We aim to minimize the dose of the CT scan, while preserving adequate image quality for the purpose of PET attenuation correction by introducing sparse view CT data acquisition.We investigated sparse view CT acquisition protocols resulting in ultra-low dose CT scans designed for PET attenuation correction. We analyzed the tradeoffs between the number of views and the integrated tube current per view for a given dose using CT and PET simulations of a 3D NCAT phantom with lesions inserted into liver and lung. We simulated seven CT acquisition protocols with {984, 328, 123, 41, 24, 12, 8} views per rotation at a gantry speed of 0.35 s. One standard dose and four ultra-low dose levels, namely, 0.35 mAs, 0.175 mAs, 0.0875 mAs, and 0.043 75 mAs, were investigated. Both the analytical Feldkamp, Davis and Kress (FDK) algorithm and the Model Based Iterative Reconstruction (MBIR) algorithm were used for CT image reconstruction. We also evaluated the impact of sinogram interpolation to estimate the missing projection measurements due to sparse view data acquisition. For MBIR, we used a penalized weighted least squares (PWLS) cost function with an approximate total-variation (TV) regularizing penalty function. We compared a tube pulsing mode and a continuous exposure mode for sparse view data acquisition. Global PET ensemble root-mean-squares-error (RMSE) and local ensemble lesion activity error were used as quantitative evaluation metrics for PET image quality.With sparse view sampling, it is possible to greatly reduce the CT scan dose when it is primarily used for PET attenuation correction with little or no measureable effect on the PET image. For the four ultra-low dose levels simulated, sparse view protocols with 41 and 24 views best balanced the tradeoff between electronic noise and aliasing artifacts. In terms of lesion activity error and ensemble RMSE of the PET images, these two protocols, when combined with MBIR, are able to provide results that are comparable to the baseline full dose CT scan. View interpolation significantly improves the performance of FDK reconstruction but was not necessary for MBIR. With the more technically feasible continuous exposure data acquisition, the CT images show an increase in azimuthal blur compared to tube pulsing. However, this blurring generally does not have a measureable impact on PET reconstructed images.Our simulations demonstrated that ultra-low-dose CT-based attenuation correction can be achieved at dose levels on the order of 0.044 mAs with little impact on PET image quality. Highly sparse 41- or 24- view ultra-low dose CT scans are feasible for PET attenuation correction, providing the best tradeoff between electronic noise and view aliasing artifacts. The continuous exposure acquisition mode could potentially be implemented in current commercially available scanners, thus enabling sparse view data acquisition without requiring x-ray tubes capable of operating in a pulsing mode.


Multiple paternity and hybridization in two smooth-hound sharks.
Multiple paternity appears to be a common trait of elasmobranch mating systems, with its occurrence likely driven by convenience, due to females seeking to minimize the stress of male harassment. Here we use molecular markers to analyse the frequency of multiple paternity in two related viviparous sharks, Mustelus mustelus and Mustelus punctulatus. We first applied molecular methods to assign pregnant females, embryos and additional reference adults (N = 792) to one of the two species. Paternity analysis was performed using a total of 9 polymorphic microsatellites on 19 females and 204 embryos of M. mustelus, and on 13 females and 303 embryos of M. punctulatus. Multiple paternity occurs in both species, with 47% of M. mustelus and 54% of M. punctulatus litters sired by at least two fathers. Female fecundity is not influenced by multiple mating and in 56% of polyandrous litters paternity is skewed, with one male siring most of the pups. Genetic analyses also revealed hybridization between the two species, with a M. punctulatus female bearing pups sired by a M. mustelus male. The frequency of polyandrous litters in these species is consistent with aspects of their reproductive biology, such as synchronous ovulation and possible occurrence of breeding aggregations.


A systematic review assessing the effectiveness of interventions to improve persistence with anti-resorptive therapy in women at high risk of clinical fracture.
despite availability of effective treatments for osteoporosis, impact on fracture rates may be suboptimal because of failure to adhere to recommended anti-resorptive therapy. to identify randomized controlled trials (RCTs) evaluating interventions intended to improve persistence with anti-resorptive therapy for treating women with osteoporosis or osteopenia. The design of the study is a systematic review and meta-analysis of RCTs. included trials were those reporting interventions to improve persistence with or adherence to anti-resorptive treatment compared to a control medication or usual care. A search of MEDLINE, EMBASE, CINAHL and the Cochrane Library was supplemented by review of cited literature. Reports were reviewed and data pooled where appropriate. The primary outcome was duration of persistence with medication. six trials met inclusion criteria, including four reporting persistence as an outcome measure indicating a relative reduction in non-persistence of 22% (pooled relative risk: 0.78, 95% confidence interval 0.65-0.95) for active compared to control interventions. Heterogeneity between the trial effects was present but not significant (I(2) = 47%, P = 0.11). Interventions were varied in design, and some measurements of adherence were subject to self-report bias. Two trials included the majority of participants (3386/3497), accounting for >90% of the weight in the pooled estimate. trials to date suggest potential for improving persistence with medication taking thus improving treatment outcomes and reducing fracture risk. More precise measurement of medication taking and promoting fidelity to a precisely defined intervention protocol may lead to better assessment of impact on clinically important outcomes.


Identification of the glycosylation sites utilized on the V1a vasopressin receptor and assessment of their role in receptor signalling and expression.
Most of the large family of G-protein-coupled receptors (GPCRs) possess putative N-glycosylation sites within their N-termini. However, for the vast majority of GPCRs, it has not been determined which, if any, of the consensus glycosylation sites are actually utilized or what the functional ramifications are of modification by oligosaccharide. The occurrence and function of glycosylation of the V(1a) vasopressin receptor (V(1a)R) has been investigated in this study. Using a combination of translation systems that are either glycosylation-competent or do not support glycosylation, we established that of the four putative N-glycosylation sites at Asn(14), Asn(27), Asn(198) and Asn(333) only the first three sites are actually modified by carbohydrate. This was confirmed by disruption of consensus sites by site-directed mutagenesis, individually and in combination. The V(1a)R is not O-glycosylated. The functionality of a series of glycosylation-defective V(1a)R constructs was characterized after expression in HEK 293T cells. It was found that carbohydrate moieties are not required for the receptor to bind any of the four classes of ligand available, or for intracellular signalling. The glycosylation status of the V(1a)R did, however, regulate the level of total receptor expression and also the abundance of receptor at the cell surface. Furthermore, the nature of this regulation (increased or decreased expression) was dictated by the locus of the oligosaccharide modification. Modification of any one of the consensus sites alone, however, was sufficient for wild-type expression, indicating a redundancy within the glycosylation sites. A role for the carbohydrate in the correct folding or stabilization of the V(1a)R is indicated. Glycosylation is not required, however, for efficient trafficking of the receptor to the cell surface. This study establishes the functional importance of N-glycosylation of the V(1a)R.


Distribution of secretoneurin, a peptide derived from secretogranin II, in rat brain: an immunocytochemical and radioimmunological study.
The distribution of secretoneurin, a peptide derived from its precursor secretogranin II by proteolytic processing, was studied in the central nervous system of the rat by immunocytochemistry and radioimmunoassay and compared to the distribution of secretogranin II messenger RNA by using in situ hybridization. With a specific antiserum a distinct staining of fibers and to a lesser extent also of perikarya was observed throughout the central nervous system. A high density of immunoreactive fibers and terminals was found in several brain areas, i.e. the lateral septum, the medial parts of the amygdala, some medial thalamic nuclei, the hypothalamus, habenula, nucleus interpeduncularis, locus coeruleus, nucleus tractus solitarii, the substantiae gelatinosae of the caudal trigeminal nucleus and of the spinal cord. The quantitative distribution as measured by a radioimmunoassay agreed well with the varying densities of immunoreactivity found by immunocytochemistry. The highest concentrations of this peptide were present in the hypothalamus, in particular, in the median eminence and are comparable to those of the most highly concentrated neuropeptides. The distribution of immunopositive perikarya corresponded well with that of secretogranin II messenger RNA obtained by in situ hybridization. The pattern of secretoneurin expression in rat brain was widespread and unique, partially overlapping with established chemical transmitters and neuropeptides. The functional significance of this new brain peptide remains to be established.


Regulation of protein phosphatase type 1 and cell cycle progression by PfLRR1, a novel leucine-rich repeat protein of the human malaria parasite Plasmodium falciparum.
The protein called 'suppressor of the dis2 mutant (sds22+)' is an essential regulator of cell division in fission and budding yeasts, where its deletion causes mitotic arrest. Its role in cell cycle control appears to be mediated through the activation of protein phosphatase type 1 (PP1) in Schizosaccharomyces pombe. We have identified the Plasmodium falciparum Sds22 orthologue, which we designated PfLRR1 as it belongs to the leucine-rich repeat protein family. We showed by glutathione-S-transferase pull-down assay that the PfLRR1 gene product interacts with PfPP1, that the PfLRR1-PfPP1 complex is present in parasite extracts and that PfLRR1 inhibits PfPP1 activity. Functional studies in Xenopus oocytes revealed that PfLRR1 interacted with endogenous PP1 and overcame the G2/M cell cycle checkpoint by promoting progression to germinal vesicle breakdown (GVBD). Confirmatory results showing the appearance of GVBD were observed when oocytes were treated with anti-PP1 antibodies or okadaic acid. Taken together, these observations suggest that PfLRR1 can regulate the cell cycle by binding to PP1 and regulating its activity.


Gastrointestinal stem cells and cancer: bridging the molecular gap.
Cancer is believed to be a disease involving stem cells. The digestive tract has a very high cancer prevalence partly owing to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes including familial adenomatous polyposis (FAP) has led to significant advances, including the adenoma-carcinoma sequence. The initial mutation involved in this stepwise progression is in the "gatekeeper" tumor suppressor gene adenomatous polyposis coli (APC). In FAP somatic, second hits in this gene are nonrandom events, selected for by the position of the germ-line mutation. Extensive work in both the mouse and human has shown that crypts are clonal units and mutated stem cells may develop a selective advantage, eventually forming a clonal crypt population by a process called "niche succession." Aberrant crypt foci are then formed by the longitudinal division of crypts into two daughter units--crypt fission. The early growth of adenomas is contentious with two main theories, the "top-down" and "bottom-up" hypotheses, attempting to explain the spread of dysplastic tissue in the bowel. Initial X chromosome inactivation studies suggested that colorectal tumors were monoclonal; however, work on a rare XO/XY human patient with FAP and chimeric Min mice showed that 76% of adenomas were polyclonal. A reduction in tumor multiplicity in the chimeric mouse model has been achieved by the introduction of a homozygous tumor resistance allele. This model has been used to suggest that short-range interaction between adjacent initiated crypts, not random polyp collision, is responsible for tumor polyclonality.


Carotid artery stenting--current status and future directions.
Carotid endarterectomy has been the standard of therapy for carotid occlusive disease in stroke prevention. More recently, carotid angioplasty and stenting became an important alternative in the treatment of carotid occlusive disease. The widespread use of cerebral protection devices has substantially decreased the morbidity of the procedure. As the experience with carotid stenting increases, so does the enthusiasm for the potential of this minimally invasive carotid intervention to become the main treatment option for the high risk patients, as well as for the average asymptomatic patient. Although current available data indicate that the results regarding success and complication rates are similar between carotid stenting and endarterectomy, several prospective clinical trials are currently in progress to evaluate the efficacy of carotid artery stenting in different patient populations and definitively establish its role in the treatment of carotid disease. This paper reviews the current status of carotid stenting, including results from clinical trials, technical aspects and controversial issues and strategies to provide cerebral protection from embolization.


Nanoindentation analysis of the micromechanical anisotropy in mouse cortical bone.
Studies investigating micromechanical properties in mouse cortical bone often solely focus on the mechanical behaviour along the long axis of the bone. Therefore, data on the anisotropy of mouse cortical bone is scarce. The aim of this study is the first-time evaluation of the anisotropy ratio between the longitudinal and transverse directions of reduced modulus and hardness in mouse femurs by using the nanoindentation technique. For this purpose, nine 22-week-old mice (C57BL/6) were sacrificed and all femurs extracted. A total of 648 indentations were performed with a Berkovich tip in the proximal (P), central (C) and distal (D) regions of the femoral shaft in the longitudinal and transverse directions. Higher values for reduced modulus are obtained for indentations in the longitudinal direction, with anisotropy ratios of 1.72 ± 0.40 (P), 1.75 ± 0.69 (C) and 1.34 ± 0.30 (D). Hardness is also higher in the longitudinal direction, with anisotropic ratios of 1.35 ± 0.27 (P), 1.35 ± 0.47 (C) and 1.17 ± 0.19 (D). We observed a significant anisotropy in the micromechanical properties of the mouse femur, but the correlation for reduced modulus and hardness between the two directions is low (r2 < 0.3) and not significant. Therefore, we highly recommend performing independent indentation testing in both the longitudinal and transverse directions when knowledge of the tissue mechanical behaviour along multiple directions is required.


Nature of Excitons in Bidimensional WSe₂ by Hybrid Density Functional Theory Calculations.
2D tungsten diselenide (2D-WSe₂) is one of the most successful bidimensional materials for optoelectronic and photonic applications, thanks to its strong photoluminescence properties and to a characteristic large exciton binding energy. Although these optical properties are widely recognized by the scientific community, there is no general understanding of the atomistic details of the excitonic species giving rise to them. In this work, we present a density functional theory investigation of excitons in 2D-WSe₂, where we compare results obtained by standard generalized gradient approximation (GGA) methods (including spin-orbit coupling) with those by hybrid density functionals. Our study provides information on the size of the self-trapped exciton, the number and type of atoms involved, the structural reorganization, the self-trapping energy, and the photoluminescence energy, whose computed value is in good agreement with experimental measurements in the literature. Moreover, based on the comparative analysis of the self-trapping energy for the exciton with that for isolated charge carriers (unbound electrons and holes), we also suggest a simplified approach for the theoretical estimation of the excitonic binding energy, which can be compared with previous estimates from different approaches or from experimental data.


The location and function of vitamin E in membranes (review).
Vitamin E is a fat-soluble vitamin that consists of a group of tocols and tocotrienols with hydrophobic character, but possessing a hydroxyl substituent that confers an amphipathic character on them. The isomers of biological importance are the tocopherols, of which alpha-tocopherol is the most potent vitamin. Vitamin E partitions into lipoproteins and cell membranes, where it represents a minor constituent of most membranes. It has a major function in its action as a lipid antioxidant to protect the polyunsaturated membrane lipids against free radical attack. Other functions are believed to be to act as membrane stabilizers by forming complexes with the products of membrane lipid hydrolysis, such as lysophospholipids and free fatty acids. The main experimental approach to explain the functions of vitamin E in membranes has been to study its effects on the structure and stability of model phospholipid membranes. This review describes the function of vitamin E in membranes and reviews the current state of knowledge of the effect of vitamin E on the structure and phase behaviour of phospholipid model membranes.


Support in everyday activities with a home-based electronic memory aid for persons with memory impairments.
The purposes of this study was to examine the possibilities of a home-based electronic memory aid with sensors for persons with memory impairments, as support to carry out everyday activities in their own home environments. The method involved a single-subject study with a multiple baseline AB design. Five participants identified three activities each that they usually forget to carry out. An electronic memory aid with individually spoken reminders was installed in the participant's home. There were automatic computer registrations of completed activities during the study phase of 12 weeks. Assessments of functioning and quality of life (QoL) were conducted before and after the intervention and at follow-up after 2 months. Four participants improved in completing most of the self-chosen activities when the electronic memory aid was used. Performance and satisfaction with performance and QoL improved, but there was no memory function improvement. There were technical problems with the aid, which had a negative effect for users. Electronic memory aids have a large potential for supporting persons with cognitive impairments. It is important to conduct follow-up afterwards, because the use of an aid and the need of support change over time and put high demands on technical reliability of the electronic memory aid.


Antidepressants with a high serotonin reuptake transporter affinity and serum lipid levels in a population-based study in older adults.
We aimed to investigate the association between antidepressants and serum lipid levels in a population-based study in older adults. We included participants from the prospective Rotterdam Study with data on lipid levels (total, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, and triglycerides). We classified antidepressants based on binding affinity to the serotonin transporter (low/intermediate- and high-affinity antidepressants). We compared lipid levels in users of these groups of antidepressants with lipid levels in non-users. Furthermore, we studied effect modification by the 102 C>T polymorphism (HTR2A gene), which is associated with antidepressant drug response and metabolic outcomes. Compared with non-users (N = 6438), LDL cholesterol level was higher (2.9 versus 3.1 mmol/L, respectively; p = 0.05) in users of high-affinity antidepressants (N = 89). Similar levels of the other lipids were observed between the groups for the other lipids. The mean difference in serum LDL cholesterol level between non-users and users of high-affinity antidepressants was largest in participants with the CC genotype compared with the other genotypes (notably 0.47 mmol/L), indicative of effect modification (p-value for interaction = 0.03). Antidepressants with a high serotonin reuptake transporter affinity were associated with higher LDL cholesterol levels, which were modified by a common genetic variation in the HTR2A gene.


Trihalomethanes in public water supplies and adverse birth outcomes.
We conducted a retrospective cohort study to evaluate the relation between the level of total trihalomethanes in drinking water and adverse birth outcomes. The study population comprised women residing in an area with municipal surface water who had a singleton birth in Nova Scotia between January 1, 1988, and December 31, 1995, or a pregnancy termination for a major fetal anomaly. We found little association between trihalomethane level and the outcomes related to fetal weight or gestational age, but we found an elevated relative risk for stillbirths for average trihalomethane levels during pregnancy of 100 microg/liter or greater (adjusted relative risk = 1.66; 95% confidence interval = 1.09-2.52) relative to women exposed to trihalomethane levels of 0-49 microg/liter. We saw little evidence of an elevated prevalence or dose-response pattern for congenital anomalies, with the possible exception of chromosomal abnormalities (adjusted prevalence ratio = 1.38 and 95% confidence interval = 0.73-2.59 for women exposed to trihalomethane levels of 100 microg/liter or greater).


Building bridges to evidence-based practice: the MacArthur Foundation Child System and Treatment Enhancement Projects (Child STEPs).
The papers in this special issue describe research undertaken by the MacArthur Foundation-funded Research Network on Youth Mental Health. The project is designed to understand the challenges of implementing evidence-based treatments in community-based mental health practices. This Introduction and the following articles describe the impetus and conceptual framework underlying one cluster of the Network's activity-i.e., the Clinic Systems Project (CSP). The CSP studies examined the organizational and service system environments in a large national sample of community mental health and affiliated organizations that provide services to children. The main goal is to identify leverage points for, and barriers to, the adoption and implementation of evidence-based practices for children.


The effect of dietary restriction on reproduction: a meta-analytic perspective.
Dietary restriction (DR), a reduction in the amount of food or particular nutrients eaten, is the most consistent environmental manipulation to extend lifespan and protect against age related diseases. Current evolutionary theory explains this effect as a shift in the resolution of the trade-off between lifespan and reproduction. However, recent studies have questioned the role of reproduction in mediating the effect of DR on longevity and no study has quantitatively investigated the effect of DR on reproduction across species. Here we report a comprehensive comparative meta-analysis of the effect of DR on reproduction. In general, DR reduced reproduction across taxa, but several factors moderated this effect. The effect of DR on reproduction was greater in well-studied model species (yeast, nematode worms, fruit flies and rodents) than non-model species. This mirrors recent results for longevity and, for reproduction, seems to result from a faster rate of decline with decreasing resources in model species. Our results also suggested that not all reproductive traits are affected equally by DR. High and moderate cost reproductive traits suffered a significant reduction with DR, but low cost traits, such as ejaculate production, did not. Although the effect of DR on reproduction was stronger in females than males, this sex difference reduced to near zero when accounting for other co-factors such as the costliness of the reproductive trait. Thus, sex differences in the effect of DR on longevity may be due to a failure to expose males to as complete a range of the costs of reproduction as females. We suggest that to better understand the generality of the effect of DR, future studies should attempt to address the cause of the apparent model species bias and ensure that individuals are exposed to as many of the costs of reproduction as possible. Furthermore, our meta-analytic approach reveals a general shortage of DR studies that record reproduction, particularly in males, as well as a lack of direct side-by-side comparisons of the effect of DR on males and females.


From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation.
Studies on monocyte and macrophage biology and differentiation have revealed the pleiotropic activities of these cells. Macrophages are tissue sentinels that maintain tissue integrity by eliminating/repairing damaged cells and matrices. In this M2-like mode, they can also promote tumor growth. Conversely, M1-like macrophages are key effector cells for the elimination of pathogens, virally infected, and cancer cells. Macrophage differentiation from monocytes occurs in the tissue in concomitance with the acquisition of a functional phenotype that depends on microenvironmental signals, thereby accounting for the many and apparently opposed macrophage functions. Many questions arise. When monocytes differentiate into macrophages in a tissue (concomitantly adopting a specific functional program, M1 or M2), do they all die during the inflammatory reaction, or do some of them survive? Do those that survive become quiescent tissue macrophages, able to react as naïve cells to a new challenge? Or, do monocyte-derived tissue macrophages conserve a "memory" of their past inflammatory activation? This review will address some of these important questions under the general framework of the role of monocytes and macrophages in the initiation, development, resolution, and chronicization of inflammation.


Refractive index profile measurements of diffused optical waveguides.
Refractive index profiles resulting from the fabrication of optical waveguides by diffusion techniques are measured using a reflection interferometric technique. In Cd-diffused ZnSe waveguides, the index variations are found to be complementary error functions that closely follow the composition changes for deep (>5 microm) diffusions. Shallow (<5 microm) diffusions produce waveguides in which the index profile is a complementary error function that differs significantly from the composition profile. The relationship between composition and refractive index is determined for Cd compositions less than 10%. Refractive index profiles in commercially available diffused glass waveguides (SELFOC rod and fibers) are also described.


Mapping Catalytically Relevant Edge Electronic States of MoS2.
Molybdenum disulfide (MoS2) is a semiconducting transition metal dichalcogenide that is known to be a catalyst for both the hydrogen evolution reaction (HER) as well as for hydro-desulfurization (HDS) of sulfur-rich hydrocarbon fuels. Specifically, the edges of MoS2 nanostructures are known to be far more catalytically active as compared to unmodified basal planes. However, in the absence of the precise details of the geometric and electronic structure of the active catalytic sites, a rational means of modulating edge reactivity remain to be developed. Here we demonstrate using first-principles calculations, X-ray absorption spectroscopy, as well as scanning transmission X-ray microscopy (STXM) imaging that edge corrugations yield distinctive spectroscopic signatures corresponding to increased localization of hybrid Mo 4d states. Independent spectroscopic signatures of such edge states are identified at both the S L2,3 and S K-edges with distinctive spatial localization of such states observed in S L2,3-edge STXM imaging. The presence of such low-energy hybrid states at the edge of the conduction band is seen to correlate with substantially enhanced electrocatalytic activity in terms of a lower Tafel slope and higher exchange current density. These results elucidate the nature of the edge electronic structure and provide a clear framework for its rational manipulation to enhance catalytic activity.


Molecular evidence for increased regulatory conservation during metamorphosis, and against deleterious cascading effects of hybrid breakdown in Drosophila.
Speculation regarding the importance of changes in gene regulation in determining major phylogenetic patterns continues to accrue, despite a lack of broad-scale comparative studies examining how patterns of gene expression vary during development. Comparative transcriptional profiling of adult interspecific hybrids and their parental species has uncovered widespread divergence of the mechanisms controlling gene regulation, revealing incompatibilities that are masked in comparisons between the pure species. However, this has prompted the suggestion that misexpression in adult hybrids results from the downstream cascading effects of a subset of genes improperly regulated in early development. We sought to determine how gene expression diverges over development, as well as test the cascade hypothesis, by profiling expression in males of Drosophila melanogaster, D. sechellia, and D. simulans, as well as the D. simulans (female) x D. sechellia (male) male F1 hybrids, at four different developmental time points (3rd instar larval, early pupal, late pupal, and newly-emerged adult). Contrary to the cascade model of misexpression, we find that there is considerable stage-specific autonomy of regulatory breakdown in hybrids, with the larval and adult stages showing significantly more hybrid misexpression as compared to the pupal stage. However, comparisons between pure species indicate that genes expressed during earlier stages of development tend to be more conserved in terms of their level of expression than those expressed during later stages, suggesting that while Von Baer's famous law applies at both the level of nucleotide sequence and expression, it may not apply necessarily to the underlying overall regulatory network, which appears to diverge over the course of ontogeny and which can only be ascertained by combining divergent genomes in species hybrids. Our results suggest that complex integration of regulatory circuits during morphogenesis may lead to it being more refractory to divergence of underlying gene regulatory mechanisms--more than that suggested by the conservation of gene expression levels between species during earlier stages. This provides support for a 'developmental hourglass' model of divergence of gene expression in Drosophila resulting in a highly conserved pupal stage.


Radial velocity studies of cool stars.
Our current view of exoplanets is one derived primarily from solar-like stars with a strong focus on understanding our Solar System. Our knowledge about the properties of exoplanets around the dominant stellar population by number, the so-called low-mass stars or M dwarfs, is much more cursory. Based on radial velocity discoveries, we find that the semi-major axis distribution of M dwarf planets appears to be broadly similar to those around more massive stars and thus formation and migration processes might be similar to heavier stars. However, we find that the mass of M dwarf planets is relatively much lower than the expected mass dependency based on stellar mass and thus infer that planet formation efficiency around low-mass stars is relatively impaired. We consider techniques to overcome the practical issue of obtaining good quality radial velocity data for M dwarfs despite their faintness and sustained activity and emphasize (i) the wavelength sensitivity of radial velocity signals, (ii) the combination of radial velocity data from different experiments for robust detection of small amplitude signals, and (iii) the selection of targets and radial velocity interpretation of late-type M dwarfs should consider Hα behaviour.


Frailty Intervention Trial (FIT).
Frailty is a term commonly used to describe the condition of an older person who has chronic health problems, has lost functional abilities and is likely to deteriorate further. However, despite its common use, only a small number of studies have attempted to define the syndrome of frailty and measure its prevalence. The criteria Fried and colleagues used to define the frailty syndrome will be used in this study (i.e. weight loss, fatigue, decreased grip strength, slow gait speed, and low physical activity). Previous studies have shown that clinical outcomes for frail older people can be improved using multi-factorial interventions such as comprehensive geriatric assessment, and single interventions such as exercise programs or nutritional supplementation, but no interventions have been developed to specifically reverse the syndrome of frailty.We have developed a multidisciplinary intervention that specifically targets frailty as defined by Fried et al. We aim to establish the effects of this intervention on frailty, mobility, hospitalisation and institutionalisation in frail older people. A single centre randomised controlled trial comparing a multidisciplinary intervention with usual care. The intervention will target identified characteristics of frailty, functional limitations, nutritional status, falls risk, psychological issues and management of chronic health conditions. Two hundred and thirty people aged 70 and over who meet the Fried definition of frailty will be recruited from clients of the aged care service of a metropolitan hospital. Participants will be followed for a 12-month period. This research is an important step in the examination of specifically targeted frailty interventions. This project will assess whether an intervention specifically targeting frailty can be implemented, and whether it is effective when compared to usual care. If successful, the study will establish a new approach to the treatment of older people at risk of further functional decline and institutionalisation. The strategies to be examined are readily transferable to routine clinical practice and are applicable broadly in the setting of aged care health services. Australian New Zealand Clinical Trails Registry: ACTRN12608000250336.


Assessing country-level efforts to link research to action.
We developed a framework for assessing country-level efforts to link research to action. The framework has four elements. The first element assesses the general climate (how those who fund research, universities, researchers and users of research support or place value on efforts to link research to action). The second element addresses the production of research (how priority setting ensures that users' needs are identified and how scoping reviews, systematic reviews and single studies are undertaken to address these needs). The third element addresses the mix of four clusters of activities used to link research to action. These include push efforts (how strategies are used to support action based on the messages arising from research), efforts to facilitate "user pull" (how "one-stop shopping" is provided for optimally packaged high-quality reviews either alone or as part of a national electronic library for health, how these reviews are profiled during "teachable moments" such as intense media coverage, and how rapid-response units meet users' needs for the best research), "user pull" efforts undertaken by those who use research (how users assess their capacity to use research and how structures and processes are changed to support the use of research) and exchange efforts (how meaningful partnerships between researchers and users help them to jointly ask and answer relevant questions). The fourth element addresses approaches to evaluation (how support is provided for rigorous evaluations of efforts to link research to action).


Effect of Intrathecal Baclofen on Pain and Quality of Life in Poststroke Spasticity.
Background and Purpose- Intrathecal baclofen (ITB) is an effective treatment for managing patients with severe poststroke spasticity, who can experience continued pain and decline in their quality of life (QoL). SISTERS (Spasticity In Stroke-Randomized Study) was a randomized, controlled, open-label, multicenter, phase 4 study to evaluate ITB therapy versus conventional medical management (CMM) with oral antispastic medications for treatment of poststroke spasticity. Methods- Poststroke patients with spasticity in ≥2 extremities and an Ashworth Scale score of ≥3 in ≥2 affected lower extremity muscle groups were randomized (1:1) to ITB (N=31) or CMM (N=29). Both treatment arms received physiotherapy throughout. The primary outcome was the change in average Ashworth Scale score in the lower extremities of the affected side from baseline to month 6. Here, we report results for secondary outcomes: pain via the Numeric Pain Rating Scale, health-related QoL by the EuroQol-5 dimensional 3 level utility score and health status visual analog scale score, stroke-specific QoL, and patient satisfaction. Analyses were performed on an intention-to-treat basis. Results- We observed significant treatment effects in favor of ITB over CMM for changes from baseline to month 6 in Numeric Pain Rating Scale scores for actual pain (ITB versus CMM: mean, -1.17 [SD, 3.17] versus 0.00 [3.29]; median, -1.00 versus 0.00; P=0.0380) and least pain (mean, -1.61 [2.29] versus 0.24 [3.07]; median, -1.00 versus 0.00; P=0.0136), and EuroQol-5 dimensional 3 level utility scores (mean, +0.09 [0.26] versus +0.01 [0.16]; median, +0.07 versus 0.00; P=0.0197). Between-group differences were not statistically significant for EuroQol-5 dimensional 3 level visual analog scale, stroke-specific QoL summary, or Numeric Pain Rating Scale worst pain scores, although ITB patients showed greater numeric improvements from baseline during follow-up. More ITB patients than CMM patients (73% versus 48%) were satisfied with the spasticity reduction at month 6. Conclusions- These data support that ITB therapy is associated with improvements in pain and QoL in poststroke patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01032239.