Televised obesity-prevention advertising across US media markets: exposure and content, 2010-2011.
To examine levels of exposure and content characteristics for recent televised obesity-prevention campaigns sponsored by state and community health departments, federal agencies, non-profit organizations and television stations in the USA. Nielsen television ratings for obesity-prevention advertising were collected for the top seventy-five US media markets and were used to calculate household exposure levels for 2010 and 2011. Governmental advertisements were coded for content. United States. Average household exposure to obesity-prevention campaigns was 2·6 advertisements per month. Exposure increased by 31 % between 2010 and 2011, largely driven by increases in federal advertisements. In 2011, the federal government accounted for 62 % of obesity-prevention exposure, non-profit organizations for 9 %, community departments for 8 %, state departments for 3 %, and television station-sponsored public-service announcements for 17 %. The greatest percentage increase between 2010 and 2011 was in community advertising, reflecting efforts funded by the Communities Putting Prevention to Work (CPPW) programme. Among thirty-four state and community campaigns, the majority advocated both healthy eating and physical activity (53 %). Campaigns typically had positive or neutral emotional valence (94 %). Obesity or overweight was mentioned in 47 % of campaigns, but only 9 % specifically advocated weight loss. Exposure to televised obesity-prevention advertising increased from 2010 to 2011 and was higher than previously found in 1999-2003, apart from in 2003 during the federal VERB campaign. Nevertheless, exposure remains low relative to advertising for unhealthy foods. New federal campaigns have increased exposure to obesity-prevention advertising nationally, while CPPW grants have increased exposure for targeted areas.


Adaptation with gene flow across the landscape in a dune sunflower.
Isolation by adaptation increases divergence at neutral loci when natural selection against immigrants reduces the rate of gene flow between different habitats. This can occur early in the process of adaptive divergence and is a key feature of ecological speciation. Despite the ability of isolation by distance (IBD) and other forms of landscape resistance to produce similar patterns of neutral divergence within species, few studies have used landscape genetics to control for these other forces. We have studied the divergence of Helianthus petiolaris ecotypes living in active sand dunes and adjacent non-dune habitat, using landscape genetics approaches, such as circuit theory and multiple regression of distance matrices, in addition to coalescent modelling. Divergence between habitats was significant, but not strong, and was shaped by IBD. We expected that increased resistance owing to patchy and unfavourable habitat in the dunes would contribute to divergence. Instead, we found that landscape resistance models with lower resistance in the dunes performed well as predictors of genetic distances among subpopulations. Nevertheless, habitat class remained a strong predictor of genetic distance when controlling for isolation by resistance and IBD. We also measured environmental variables at each site and confirmed that specific variables, especially soil nitrogen and vegetation cover, explained a greater proportion of variance in genetic distance than did landscape or the habitat classification alone. Asymmetry in effective population sizes and numbers of migrants per generation was detected using coalescent modelling with Bayesian inference, which is consistent with incipient ecological speciation being driven by the dune habitat.


Superior Capsule Reconstruction: What Do We Know?
The management of irreparable rotator cuff tears remains challenging. Since its introduction by Mihata in 2012, superior capsule reconstruction (SCR) has grown in popularity at an astonishingly rapid rate. The aim of this article is to provide a comprehensive review of the available literature, in order to highlight what has so far been published on SCR, covering all aspects including biomechanical, clinical and radiological studies as well as descriptions of the various techniques for performing the procedure. The short-term clinical results of SCR are promising, but there is need for further long-term studies, as well as randomised controlled trials comparing SCR to other treatment modalities for irreparable rotator cuff tears. Further imaging studies looking at graft healing rates are also required as the healing rates published so far are variable. Additionally, the mechanism of action by which SCR delivers good short-term functional outcomes needs further clarification, as does the importance of the choice of graft type and thickness.


Sociodemographic and socioeconomic differences in sleep duration and insomnia-related symptoms in Finnish adults.
Poor sleep tends to be patterned by sociodemographic and socioeconomic factors. The aim of this study was to examine the associations of sociodemographic and socioeconomic factors with sleep duration and insomnia-related symptoms across life course. We used cross-sectional Health 2000 Survey (2000-2001) among a total of 5,578 adult Finns, aged 30-79 years, representative of adult Finnish population. Data about sociodemographic and socioeconomic circumstances, insomnia-related symptoms over the previous month as well as average sleep duration were collected by questionnaires. Multinomial logistic regression models were adjusted first for gender and age, second for sociodemographic factors, third additionally for socioeconomic factors, and fourth for all covariates and self-perceived health simultaneously. On average 70% of Finnish adults slept 7-8 hours a day. Frequent insomnia-related symptoms were more prevalent among women (14%) than men (10%). Not being married, not having children, having low education, low income, being unemployed, and being a disability retiree were associated with frequent insomnia-related symptoms. Similar factors were associated with short and long sleep duration. However, childhood socioeconomic position was mostly unrelated to sleep in adulthood except parental education had some associations with short sleep duration. Disadvantaged socioeconomic position in adulthood, in particular income and employment status, is associated with poorer sleep. When promoting optimal sleep duration and better sleep quality, families with low incomes, unemployed people, and disability retirees should be targeted.


Expression of the axon growth-related neural adhesion molecule TAG-1/axonin-1 in the adult mouse brain.
TAG-1/axonin-1 is a neuronal cell adhesion molecule of the immunoglobulin superfamily. It is predominantly expressed during neural development and has been reported to be involved in axonal growth and pathfinding. Here, the expression of TAG-1/axonin-1 was investigated anatomically in the adult mouse brain by in situ hybridization using digoxigenin-labeled cRNA probes. Low levels of TAG-1/axonin-1 could be detected in cerebellar granule cells, in tufted and mitral cells of the olfactory bulb, and in pyramidal cells of area CA1 and CA3 of the hippocampus. We suspect that the expression of TAG-1/axonin-1 in these structures of the adult brain may serve neural plasticity.


[BMS: S for syndrome or S for symptom? A reappraisal of the burning mouth syndrome].
In this article, some nosological and ethiopathogenetic aspects of Burning Mouth Syndrome (BMS) are critically evaluated. Despite the number of papers frequently published on this subject, there is still no universally accepted definition of this disorder. Therefore, a premise on which to base an experimental approach is missing. This also leads to a lack of parameters for comparing the clinical-experimental experiences reported in various studies in this field. Moreover, it makes it rather easy to verify the absence of definitive scientific proof as well. Such proof would allow researches to consider the etiological aspects presented in the literature thus far as certain. Due to this lack of certainty, it might be prudent to introduce the concept of idiopathic (or essential) BMS to indicate a burning sensation in the oral cavity when the etiology is unknown and not correlated to noticeable local or systemic alterations. This would be true BMS. In other words, many local and/or systemic anomalies could lead to a burning type of symptomatology localised in the oral cavity but this does not constitute a sufficient requisite to indicate a diagnosis of BMS, according to the authors.


Krestin (PSK).
A polysaccharide preparation isolated from Coriolus versicolor (Fr.) Quél. of Basidiomycetes (PSK) predominantly consists of glucan and approximately 25% tightly bound protein. PSK was effective against various allogeneic and syngeneic animal tumors and has been given orally to cancer patients. Various suppressed or enhanced immune responses of tumor-bearing animals were restored to normal levels by the administration of PSK in the tumor models tested. The killer T cell activity was augmented in tumor-bearing mice by intraperitoneal or oral administration of PSK, and there was correlation between the PSK associated antitumor effect and the killer T cell activity. It was found that PSK competed with immunosuppressive substances isolated from tumor-bearing mice and that the intestinal immune system appeared to be modulated by oral administration of PSK. After oral administration of 14C- or 35S-labeled PSK to normal rats, it was found that small or large molecular substances appeared in the serum depending on the time elapsed after administration, an indication that large molecular size products were from the digestive tract.


Redefining secondary injury after subarachnoid hemorrhage in light of multimodal advanced neuroimaging, intracranial and transcranial neuromonitoring: beyond vasospasm.
The classic idea that arterial narrowing, called vasospasm (VSP), represents the hallmark of secondary injury after subarachnoid hemorrhage, has been challenged. The more complex and pleiotropic pathophysiological repercussions from the irruption of arterial blood into the subarachnoid layers go beyond the ascribed VSP. Putting adjectives in front of this term, such as "symptomatic," "microdialytic," or "angiographic" VSP, is misleading. Delayed cerebral ischemia (DCI) is a better term but remains restrictive to severe hypoperfusive injury and neglects oligemia, edema, and metabolic nonischemic injuries. In recognition of these issues, the international conference on VSP integrated "neurovascular events" into its name ( www.vasospasm2013.com ) and a multidisciplinary research group was formed in 2010 to study subgroups of DCI/VSP and their respective significance.In three parts, this tiered article provides a broader definitional envelope for DCI and secondary neurovascular insults after SAH, with a rubric for each subtype of delayed neuronal dysfunction. First, it pinpoints the need for nosologic precision and covers current terminological inconsistency. Then, it highlights the input of neuroimaging and neuromonitoring in defining secondary injurious processes. Finally, a new categorization of deteriorating patients is proposed, going beyond a hierarchical or dichotomized definition of VSP/DCI, and common data elements are suggested for future trials.


Strategies against human papillomavirus infection and cervical cancer.
Papillomaviruses infect a wide variety of animals, including humans. The human papillomavirus (HPV), in particular, is one of the most common causes of sexually transmitted disease. More than 200 types of HPV have been identified by DNA sequence data, and 85 HPV genotypes have been well characterized to date. HPV can infect the basal epithelial cells of the skin or inner tissue linings, and are, accordingly, categorized as either cutaneous or mucosal type. HPV is associated with a panoply of clinical conditions, ranging from innocuous lesions to cervical cancer. In the early 1980s, studies first reported a link between cervical cancer and genital HPV infection. Genital HPV infections are now recognized to be a major risk factor in at least 95% of cervical cancers. 30 different HPV genotypes have been identified as causative of sexually transmitted diseases, most of which induce lesions in the cervix, vagina, vulva, penis, and anus, as the result of sexual contact. There is also direct evidence demonstrating that at least four of these genotypes are prerequisite factors in cervical cancer. The main aim of this review was to evaluate the current literature regarding the pathovirology, diagnostics, vaccines, therapy, risk groups, and further therapeutic directions for HPV infections. In addition, we reviewed the current status of HPV infections in South Korean women, as evidenced by our data.


Identification of complex metabolic states in critically injured patients using bioinformatic cluster analysis.
Advances in technology have made extensive monitoring of patient physiology the standard of care in intensive care units (ICUs). While many systems exist to compile these data, there has been no systematic multivariate analysis and categorization across patient physiological data. The sheer volume and complexity of these data make pattern recognition or identification of patient state difficult. Hierarchical cluster analysis allows visualization of high dimensional data and enables pattern recognition and identification of physiologic patient states. We hypothesized that processing of multivariate data using hierarchical clustering techniques would allow identification of otherwise hidden patient physiologic patterns that would be predictive of outcome. Multivariate physiologic and ventilator data were collected continuously using a multimodal bioinformatics system in the surgical ICU at San Francisco General Hospital. These data were incorporated with non-continuous data and stored on a server in the ICU. A hierarchical clustering algorithm grouped each minute of data into 1 of 10 clusters. Clusters were correlated with outcome measures including incidence of infection, multiple organ failure (MOF), and mortality. We identified 10 clusters, which we defined as distinct patient states. While patients transitioned between states, they spent significant amounts of time in each. Clusters were enriched for our outcome measures: 2 of the 10 states were enriched for infection, 6 of 10 were enriched for MOF, and 3 of 10 were enriched for death. Further analysis of correlations between pairs of variables within each cluster reveals significant differences in physiology between clusters. Here we show for the first time the feasibility of clustering physiological measurements to identify clinically relevant patient states after trauma. These results demonstrate that hierarchical clustering techniques can be useful for visualizing complex multivariate data and may provide new insights for the care of critically injured patients.


Application of magnetic separation to steelmaking slags for reclamation.
Integrated iron and steel plants generate large amounts of metallurgical slag, which usually contains some quantity of metals or mixtures of oxides that could be treated to be recycled in various applications. The conventional method for disposal of slags is dumping. However, it is possible to process the slags to be used in the production of metallic iron, or as an additive in cement making. In this study, a basic oxygen furnace (BOF) steelwork slag obtained from the Kardemir integrated iron and steel works, Karabuk, Turkey is used. A drum magnetic separator system with pre-engineered crucial processing parameters of drum revolution speed, drum radius, drum flesh thickness, and magnitude of the magnetic field applied is utilized, as these parameters have a competing influence on the results. Subsequently, the effects of slag grain size and the drum-blade gap are investigated in the separation efficiency of magnetic grains. It is found that collection of magnetic grains is improved by decreasing the grain size of slags and moreover, the collection of magnetic grains fraction is increased with an increase in the gap between the blades and drum.


Role of Gene Interactions in Hybrid Speciation: Evidence from Ancient and Experimental Hybrids
The origin of a new diploid species by means of hybridization requires the successful merger of differentiated parental species' genomes. To study this process, the genomic composition of three experimentally synthesized hybrid lineages was compared with that of an ancient hybrid species. The genomic composition of the synthesized and ancient hybrids was concordant (rs = 0.68, P < 0.0001), indicating that selection to a large extent governs hybrid species formation. Further, nonrandom rates of introgression and significant associations among unlinked markers in each of the three synthesized hybrid lineages imply that interactions between coadapted parental species' genes constrain the genomic composition of hybrid species.


Use of benzoctamine as sedative in patients with respiratory failure.
Benzoctamine (Tacitin) was given by mouth as night sedation to patients admitted to hospital with respiratory failure. Fourteen patients had chronic obstructive bronchitis and six had acute severe asthma. One patient with asthma needed intravenous sedation with benzoctamine. No adverse effects were observed, and there was no significant change of forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), or Pco(2) in any patient after benzoctamine. Nevertheless, further clinical experience of the drug is required before its use can be safely recommended in respiratory failure.


optix drives the repeated convergent evolution of butterfly wing pattern mimicry.
Mimicry--whereby warning signals in different species evolve to look similar--has long served as a paradigm of convergent evolution. Little is known, however, about the genes that underlie the evolution of mimetic phenotypes or to what extent the same or different genes drive such convergence. Here, we characterize one of the major genes responsible for mimetic wing pattern evolution in Heliconius butterflies. Mapping, gene expression, and population genetic work all identify a single gene, optix, that controls extreme red wing pattern variation across multiple species of Heliconius. Our results show that the cis-regulatory evolution of a single transcription factor can repeatedly drive the convergent evolution of complex color patterns in distantly related species, thus blurring the distinction between convergence and homology.


Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.
To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and 68.9 +/- 3.5 from 2.5 h onward; and hexameric insulin 20.7 +/- 1.9 from 0 to 2 h, 45.6 +/- 5.0 from 2.5 to 5 h, and 70.6 +/- 6.3 from 5 h onward. Association state is a major determinant of rates of absorption of insulin and insulin analogues. The lag phase and the subsequent increasing rate of subcutaneous soluble insulin absorption can be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process.


Risk perception, trust, and factors related to a planned new nuclear power plant in Taiwan after the 2011 Fukushima disaster.
After the Fukushima nuclear disaster in March 2011, an international review of nuclear safety indicated that two of the three nuclear power plants (NPPs) operating in Taiwan were listed as the most dangerous in the world. To understand the perception of NPP risks by the public in Taiwan and their attitudes regarding a planned fourth NPP after the Fukushima nuclear incident in 2011, a study was conducted in August 2011. A sample of 2819 individuals responded to the survey, with 66% perceiving that Taiwan's safety management of NPPs was inferior to Japan's, while 40% perceived a higher possibility of nuclear accidents like that in Japan. On average, a 'safe' distance of 94 km from an NPP was expected. 56% opposed the planned fourth NPP, with females (adjusted odd ratios (aOR) 2.03; 95% confidence interval (CI) 1.71-2.41), residence near the planned fourth NPP (aOR/CI 13.90/7.79-24.80), distrust of safety management (aOR/CI 1.98/1.45-2.69) and emergency planning (aOR/CI 1.89/1.49-2.40) as the main determinants. Others included those who expected larger safe distances from an NPP (trend test, p < 0.001), perceived excess cancer risks of living within 30 km of an NPP (aOR/CI 2.74/2.02-3.71), and projection of no electric shortage without NPPs (aOR/CI 1.93/1.50-2.49). Given that Taiwan's large population lives close to the existing NPPs and long-term concerns about the safety of these nuclear plants, the Fukushima incident in Japan likely augmented public risk perceptions on nuclear power in general and on the planned fourth NPP.


Cortical brain mapping of peripheral nerves using functional magnetic resonance imaging in a rodent model.
The regions of the body have cortical and subcortical representation in proportion to their degree of innervation. The rat forepaw has been studied extensively in recent years using functional magnetic resonance imaging (fMRI), typically by stimulation using electrodes directly inserted into the skin of the forepaw. Here we stimulate the nerve directly using surgically implanted electrodes. A major distinction is that stimulation of the skin of the forepaw is mostly sensory, whereas direct nerve stimulation reveals not only the sensory system but also deep brain structures associated with motor activity. In this article, we seek to define both the motor and sensory cortical and subcortical representations associated with the four major nerves of the rodent upper extremity. We electrically stimulated each nerve (median, ulnar, radial, and musculocutaneous) during fMRI acquisition using a 9.4-T Bruker scanner (Bruker BioSpin, Billerica, MA). A current level of 0.5 to 1.0 mA and a frequency of 5 Hz were used while keeping the duration constant. A distinct pattern of cortical activation was found for each nerve that can be correlated with known sensorimotor afferent and efferent pathways to the rat forepaw. This direct nerve stimulation rat model can provide insight into peripheral nerve injury.


WHO's Service Availability and Readiness Assessment of primary health care services of commune health centers in a rural district of Northern Vietnam.
The objective of this study was to assess the availability and readiness of the primary health care (PHC) services of commune health centers (CHCs) in Quoc Oai, a rural district of Northern Vietnam based on the World Health Organization's Service Availability and Readiness Assessment (SARA) tool. The study was done in 2 steps. First, the heads of the 21 CHCs of Quoc Oai district were interviewed using SARA, a quantitative survey, and the responses were then validated by direct observations of each facility. The results showed that although the average number of health staffs in each CHC met the national standards (at least 5 staffs per CHC), its allocation within each CHC was not properly met because some CHCs had only 2 health staffs. Several health equipment and facilities were not fully available in many CHCs, and although the majority of the PHC services were available at the CHCs, their readiness remained limited. Several significant correlates between the availability of health care workers and the availability of the facilities and the PHC services were observed, suggesting that they depend upon and affect one another in the health system. Using the SARA-based inventory, the study helps health managers and policy makers to prioritize efforts and allocate resources more appropriately. To be effective, attention should be given to how to make facilities, services, and human resources for health ready for PHC activities-more investment and support from the system (from higher to lower level) and the government.


Lactobacillus reuteri DSM 17938 for managing infant colic: protocol for an individual participant data meta-analysis.
Infant colic, or excessive crying of unknown cause in infants less than 3 months old, is common and burdensome. Its aetiology is undetermined, and consensus on its management is still lacking. Recent studies suggest a possible link between infant colic and gut microbiota, indicating probiotics to be a promising treatment. However, only a few strains have been tested, and results from randomised controlled trials are conflicting. It is important to clarify whether probiotics are effective for treating infant colic in general, and to identify whether certain subgroups of infants with colic would benefit from particular strains of probiotics. Through an individual participant data meta-analysis (IPDMA), we aim to identify whether the probiotic Lactobacillus reuteri DSM 17938 is effective in the management of infant colic, and to clarify whether its effects differ according to feeding method (breast vs formula vs combined), proton pump inhibitor exposure, and antibiotic exposure. The primary outcomes are infant crying duration and treatment success (at least 50% reduction in crying time from baseline) at 21 days postintervention. Individual participant data from all studies will be modelled simultaneously in multilevel generalised linear mixed-effects regression models to account for the nesting of participants within studies. Subgroup analyses of participant-level and intervention-level characteristics will be undertaken on the primary outcomes to assess if the intervention effect differs between certain groups of infants. Approved by the Royal Children's Hospital Human Research Ethics Committee (HREC 34081). Results will be reported in a peer-reviewed journal in 2015. PROSPERO CRD42014013210.


A single nutrient feed supports both chemically defined NS0 and CHO fed-batch processes: Improved productivity and lactate metabolism.
A chemically defined nutrient feed (CDF) coupled with basal medium preloading was developed to replace a hydrolysate-containing feed (HCF) for a fed-batch NS0 process. The CDF not only enabled a completely chemically defined process but also increased recombinant monoclonal antibody titer by 115%. Subsequent tests of CDF in a CHO process indicated that it could also replace the hydrolysate-containing nutrient feed in this expression system as well as providing an 80% increase in product titer. In both CDF NS0 and CHO processes, the peak lactate concentrations were lower and, more interestingly, lactate metabolism shifted markedly from net production to net consumption when cells transitioned from exponential to stationary growth phase. Subsequent investigations of the lactate metabolic shift in the CHO CDF process were carried out to identify the cause(s) of the metabolic shift. These investigations revealed several metabolic features of the CHO cell line that we studied. First, glucose consumption and lactate consumption are strictly complementary to each other. The combined cell specific glucose and lactate consumption rate was a constant across exponential and stationary growth phases. Second, Lactate dehydrogenase (LDH) activity fluctuated during the fed-batch process. LDH activity was at the lowest when lactate concentration started to decrease. Third, a steep cross plasma membrane glucose gradient exists. Intracellular glucose concentration was more than two orders of magnitude lower than that in the medium. Fourth, a large quantity of citrate was diverted out of mitochondria to the medium, suggesting a partially truncated tricarboxylic acid (TCA) cycle in CHO cells. Finally, other intermediates in or linked to the glycolytic pathway and the TCA cycle, which include alanine, citrate, isocitrate, and succinate, demonstrated a metabolic shift similar to that of lactate. Interestingly, all these metabolites are either in or linked to the pathway downstream of pyruvate, but upstream of fumarate in glucose metabolism. Although the specific mechanisms for the metabolic shift of lactate and other metabolites remain to be elucidated, the increased understanding of the metabolism of CHO cultures could lead to future improvements in medium and process development.


Clustering of trauma and associations with single and co-occurring depression and panic attack over twenty years.
Individuals who experience one type of trauma often experience other types, yet few studies have examined the clustering of trauma. This study examines the clustering of traumatic events and associations of trauma with risk for single and co-occurring major depressive disorder (MDD) and panic attack for 20 years after first trauma. Lifetime histories of MDD, panic attack, and traumatic events were obtained from participants in an Australian twin sample. Latent class analysis was used to derive trauma classes based on each respondent's trauma history. Associations of the resulting classes and of parental alcohol problems and familial effects with risk for a first onset of single and co-occurring MDD and panic attack were examined from the year of first trauma to 20 years later. Traumatic events clustered into three distinct classes characterized by endorsement of little or no trauma, primarily nonassaultive, and primarily assaultive events. Individuals in the assaultive class were characterized by a younger age at first trauma, a greater number of traumatic events, and high rates of parental alcohol problems. Members of the assaultive trauma class had the strongest and most enduring risk for single and co-occurring lifetime MDD and panic attack. Assaultive trauma outweighed associations of familial effects and nonassaultive trauma with risk for 10 years following first trauma.


Larval ecology of mosquitoes in sylvatic arbovirus foci in southeastern Senegal.
Although adult mosquito vectors of sylvatic arbovirus [yellow fever (YFV), dengue-2 (DENV-2) and chikungunya (CHIKV)] have been studied for the past 40 years in southeastern Senegal, data are still lacking on the ecology of larval mosquitoes in this area. In this study, we investigated the larval habitats of mosquitoes and characterized their seasonal and spatial dynamics in arbovirus foci. We searched for wet microhabitats, classified in 9 categories, in five land cover classes (agriculture, forest, savannah, barren and village) from June, 2010 to January, 2011. Mosquito immatures were sampled monthly in up to 30 microhabitats of each category per land cover and bred until adult stage for determination. No wet microhabitats were found in the agricultural sites; in the remaining land covers immature stages of 35 mosquito species in 7 genera were sampled from 9 microhabitats (tree holes, fresh fruit husks, decaying fruit husks, puddles, bamboo holes, discarded containers, tires, rock holes and storage containers). The most abundant species was Aedes aegypti formosus, representing 30.2% of the collections, followed by 12 species, representing each more than 1% of the total, among them the arbovirus vectors Ae. vittatus (7.9%), Ae. luteocephalus (5.7%), Ae. taylori (5.0%), and Ae. furcifer (1.3%). Aedes aegypti, Cx. nebulosus, Cx. perfuscus, Cx. tritaeniorhynchus, Er. chrysogster and Ae. vittatus were the only common species collected from all land covers. Aedes furcifer and Ae. taylori were collected in fresh fruit husks and tree holes. Species richness and dominance varied significantly in land covers and microhabitats. Positive associations were found mainly between Ae. furcifer, Ae. taylori and Ae. luteocephalus. A high proportion of potential enzootic vectors that are not anthropophilic were found in the larval mosquito fauna. In southeastern Senegal, Ae. furcifer and Ae. taylori larvae showed a more limited distribution among both land cover and microhabitat types than the other common species. Uniquely among vector species, Ae. aegypti formosus larvae occurred at the highest frequency in villages. Finally, a high proportion of the potential non-anthropophilic vectors were represented in the larval mosquito fauna, suggesting the existence of unidentified sylvatic arbovirus cycles in southeastern Senegal.


Sicily statement on evidence-based practice.
A variety of definitions of evidence-based practice (EBP) exist. However, definitions are in themselves insufficient to explain the underlying processes of EBP and to differentiate between an evidence-based process and evidence-based outcome. There is a need for a clear statement of what Evidence-Based Practice (EBP) means, a description of the skills required to practise in an evidence-based manner and a curriculum that outlines the minimum requirements for training health professionals in EBP. This consensus statement is based on current literature and incorporating the experience of delegates attending the 2003 Conference of Evidence-Based Health Care Teachers and Developers ("Signposting the future of EBHC"). Evidence-Based Practice has evolved in both scope and definition. Evidence-Based Practice (EBP) requires that decisions about health care are based on the best available, current, valid and relevant evidence. These decisions should be made by those receiving care, informed by the tacit and explicit knowledge of those providing care, within the context of available resources. Health care professionals must be able to gain, assess, apply and integrate new knowledge and have the ability to adapt to changing circumstances throughout their professional life. Curricula to deliver these aptitudes need to be grounded in the five-step model of EBP, and informed by ongoing research. Core assessment tools for each of the steps should continue to be developed, validated, and made freely available. All health care professionals need to understand the principles of EBP, recognise EBP in action, implement evidence-based policies, and have a critical attitude to their own practice and to evidence. Without these skills, professionals and organisations will find it difficult to provide 'best practice'.


The PediPump: a versatile, implantable pediatric ventricular assist device--update IV.
Cleveland Clinic's PediPump (Cleveland, OH, USA) is a ventricular assist device designed for the support of pediatric patients. The PediPump is a mixed-flow ventricular assist device with a magnetically suspended impeller measuring 10.5 mm in diameter by 64.5 mm in length. Progress and achievements for the PediPump program are considered according to the development project's three primary objectives: Basic engineering: along with size reductions, substantial design improvements have been incorporated in each design iteration including the motor, magnetic bearings, axial touch points, and heat transfer path; Anatomic modeling and device fitting studies: Techniques based on computed tomography and magnetic resonance imaging have been developed to create three-dimensional anatomic-modeling and device-fitting tools to facilitate device implantation and to assist in preoperative planning. For in vivo testing, to date, six acute (6-h duration) and nine chronic (30-day target duration) implantations have been performed in sheep; the implantation of the PediPump appears to be relatively easy with excellent hemodynamic performance and minimal hemolysis during support. Cleveland Clinic's PediPump program supported by the National Heart, Lung and Blood Institute's Pediatric Circulatory Support Program has led to the development of a pediatric ventricular assist device that has satisfactory performance in preclinical evaluation and appears to be ready to support a program of clinical testing.


Crystal Structures of the Global Regulator DasR from Streptomyces coelicolor: Implications for the Allosteric Regulation of GntR/HutC Repressors.
Small molecule effectors regulate gene transcription in bacteria by altering the DNA-binding affinities of specific repressor proteins. Although the GntR proteins represent a large family of bacterial repressors, only little is known about the allosteric mechanism that enables their function. DasR from Streptomyces coelicolor belongs to the GntR/HutC subfamily and specifically recognises operators termed DasR-responsive elements (dre-sites). Its DNA-binding properties are modulated by phosphorylated sugars. Here, we present several crystal structures of DasR, namely of dimeric full-length DasR in the absence of any effector and of only the effector-binding domain (EBD) of DasR without effector or in complex with glucosamine-6-phosphate (GlcN-6-P) and N-acetylglucosamine-6-phosphate (GlcNAc-6-P). Together with molecular dynamics (MD) simulations and a comparison with other GntR/HutC family members these data allowed for a structural characterisation of the different functional states of DasR. Allostery in DasR and possibly in many other GntR/HutC family members is best described by a conformational selection model. In ligand-free DasR, an increased flexibility in the EBDs enables the attached DNA-binding domains (DBD) to sample a variety of different orientations and among these also a DNA-binding competent conformation. Effector binding to the EBDs of DasR significantly reorganises the atomic structure of the latter. However, rather than locking the orientation of the DBDs, the effector-induced formation of β-strand β* in the DBD-EBD-linker segment merely appears to take the DBDs 'on a shorter leash' thereby impeding the 'downwards' positioning of the DBDs that is necessary for a concerted binding of two DBDs of DasR to operator DNA.


Uncommon bovine viral diarrhea virus subtype 1e associated with abortions in cattle in southern Brazil.
We characterized bovine viral diarrhea virus (BVDV)-related abortions in cattle and identified the species and subgenotypes in the state of Santa Catarina, southern Brazil. Our RT-PCR assay was positive for BVDV in 5 fetuses from different farms; however, 3 of the 5 fetuses were also PCR-positive for Neospora caninum. In the 5 BVDV-positive fetuses, gross lesions included fetal mummification (1), hepatomegaly (1), subcutaneous edema (1), and perirenal edema (1). Predominant histologic lesions included epicarditis and mild-to-moderate lymphoplasmacytic myocarditis (5), mild multifocal lymphoplasmacytic interlobular pneumonia (4), nephrosis associated with moderate multifocal interstitial nephritis (1), moderate multifocal lymphoplasmacytic necrotic hepatitis (1), and mild multifocal lymphoplasmacytic meningitis (1). The amplification products from the Pestivirus 5'UTR region of 4 of the 5 fetuses had 96.3-100% similarity between fetal strains and reference strains. The samples were distributed into 2 branches of the phylogenetic tree; strains UDESC:01, UDESC:02, and UDESC:05 clustered in the BVDV-1e branch, uncommon in the Americas, and strain UDESC:04 clustered in the BVDV-2b branch. The three 1e strains had 96.9-97.4% similarity.


Supplementation with L-Glutamine and L-Alanyl-L-Glutamine Changes Biochemical Parameters and Jejunum Morphophysiology in Type 1 Diabetic Wistar Rats.
We evaluated the effects of the supplementation with L-glutamine and glutamine dipeptide (GDP) on biochemical and morphophysiological parameters in streptozotocin-diabetic rats. For this purpose, thirty animals were distributed into six groups treated orally (gavage) during thirty days: non diabetic rats (Control) + saline, diabetic + saline; Control + L-glutamine (248 mg/kg), Diabetic + L-glutamine (248 mg/kg), Control + GDP (400 mg/kg), Diabetic + GDP (400 mg/kg). Diabetes was induced by an intravenous injection of streptozotocin (60 mg/kg) and confirmed by fasting glucose ≥ 200 mg/dL. Physiological parameters, i.e., body mass, food intake, blood glucose, water intake, urine and faeces were evaluated during supplementation. After the period of supplementation, the animals were euthanized. The blood was collected for biochemical assays (fructosamine, transaminases, lipid profile, total protein, urea, ammonia). Moreover, the jejunum was excised and stored for morphophysiological assays (intestinal enzyme activity, intestinal wall morphology, crypt proliferative index, number of serotoninergic cells from the mucosa, and vipergic neurons from the submucosal tunica). The physiological parameters, protein metabolism and intestinal enzyme activity did not change with the supplementation with L-glutamine or GDP. In diabetic animals, transaminases and fructosamine improved with L-glutamine and GDP supplementations, while the lipid profile improved with L-glutamine. Furthermore, both forms of supplementation promoted changes in jejunal tunicas and wall morphometry of control and diabetic groups, but only L-glutamine promoted maintenance of serotoninergic cells and vipergic neurons populations. On the other hand, control animals showed changes that may indicate negative effects of L-glutamine. Thus, the supplementation with L-glutamine was more efficient for maintaining intestinal morphophysiology and the supplementation with GDP was more efficient to the organism as a whole. Thus, we can conclude that local differences in absorption and metabolism could explain the differences between the supplementation with L-glutamine or GDP.


Evaluating the association of allergies with multiple sclerosis susceptibility risk and disease activity in a pediatric population.
Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.


Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis.
We conducted a systematic review and economic analysis to ascertain the efficacy of eradication therapy in the treatment of H. pylori positive peptic ulcer disease. Comprehensive search of electronic databases, bibliographies of retrieved articles, contact with pharmaceutical companies, and experts in the field to identify published and unpublished literature from 1966 to the present. The data were incorporated into a Monte Carlo simulation Markov model that incorporated all the uncertainty in the estimates to evaluate cost-effectiveness. Fifty-two trials were included in the final metaanalysis. In duodenal ulcer healing, H. pylori eradication therapy was superior to ulcer healing drug (relative risk (RR) of ulcer persisting = 0.66; 95% confidence interval (CI) = 0.58 to 0.76) and no treatment (RR = 0.37; 95% CI 0.26 to 0.53). In gastric ulcer healing, H. pylori eradication therapy was not statistically superior to ulcer healing drug (RR = 1.32; 95% CI = 0.92 to 1.90). In preventing duodenal ulcer recurrence, H. pylori eradication therapy was not statistically superior to maintenance therapy with ulcer healing drug (RR of ulcer recurring = 0.73; 95% CI = 0.42 to 1.25), but was superior to no treatment (RR = 0.19; 95% CI = 0.15 to 0.26). In preventing gastric ulcer recurrence, H. pylori eradication was superior to no treatment (RR = 0.31; 95% CI 0.19 to 0.48). The Markov model suggested H. pylori eradication is cost-effective for duodenal ulcer over 1 year and gastric ulcer over 2 years with over 95% confidence despite the uncertainty in the data. H. pylori eradication therapy reduces the recurrence of peptic ulcer disease and is cost-effective.


Rotation covariant image processing for biomedical applications.
With the advent of novel biomedical 3D image acquisition techniques, the efficient and reliable analysis of volumetric images has become more and more important. The amount of data is enormous and demands an automated processing. The applications are manifold, ranging from image enhancement, image reconstruction, and image description to object/feature detection and high-level contextual feature extraction. In most scenarios, it is expected that geometric transformations alter the output in a mathematically well-defined manner. In this paper we emphasis on 3D translations and rotations. Many algorithms rely on intensity or low-order tensorial-like descriptions to fulfill this demand. This paper proposes a general mathematical framework based on mathematical concepts and theories transferred from mathematical physics and harmonic analysis into the domain of image analysis and pattern recognition. Based on two basic operations, spherical tensor differentiation and spherical tensor multiplication, we show how to design a variety of 3D image processing methods in an efficient way. The framework has already been applied to several biomedical applications ranging from feature and object detection tasks to image enhancement and image restoration techniques. In this paper, the proposed methods are applied on a variety of different 3D data modalities stemming from medical and biological sciences.


Structure and topology of microbial communities in the major gut compartments of Melolontha melolontha larvae (Coleoptera: Scarabaeidae).
Physicochemical gut conditions and the composition and topology of the intestinal microbiota in the major gut compartments of the root-feeding larva of the European cockchafer (Melolontha melolontha) were studied. Axial and radial profiles of pH, O2, H2, and redox potential were measured with microsensors. Terminal restriction fragment length polymorphism (T-RFLP) analysis of bacterial 16S rRNA genes in midgut samples of individual larvae revealed a simple but variable and probably nonspecific community structure. In contrast, the T-RFLP profiles of the hindgut samples were more diverse but highly similar, especially in the wall fraction, indicating the presence of a gut-specific community involved in digestion. While high acetate concentrations in the midgut and hindgut (34 and 15 mM) corroborated the presence of microbial fermentation in both compartments, methanogenesis was confined to the hindgut. Methanobrevibacter spp. were the only methanogens detected and were restricted to this compartment. Bacterial 16S rRNA gene clone libraries of the hindgut were dominated by clones related to the Clostridiales. Clones related to the Actinobacteria, Bacillales, Lactobacillales, and gamma-Proteobacteria were restricted to the lumen, whereas clones related to the beta- and delta-Proteobacteria were found only on the hindgut wall. Results of PCR-based analyses and fluorescence in situ hybridization of whole cells with group-specific oligonucleotide probes documented that Desulfovibrio-related bacteria comprise 10 to 15% of the bacterial community at the hindgut wall. The restriction of the sulfate-reducer-specific adenosine-5'-phosphosulfate reductase gene apsA to DNA extracts of the hindgut wall in larvae from four other populations in Europe suggested that sulfate reducers generally colonize this habitat.


Structure of the archaeal pab87 peptidase reveals a novel self-compartmentalizing protease family.
Self-compartmentalizing proteases orchestrate protein turnover through an original architecture characterized by a central catalytic chamber. Here we report the first structure of an archaeal member of a new self-compartmentalizing protease family forming a cubic-shaped octamer with D(4) symmetry and referred to as CubicO. We solved the structure of the Pyrococcus abyssi Pab87 protein at 2.2 A resolution using the anomalous signal of the high-phasing-power lanthanide derivative Lu-HPDO3A. A 20 A wide channel runs through this supramolecular assembly of 0.4 MDa, giving access to a 60 A wide central chamber holding the eight active sites. Surprisingly, activity assays revealed that Pab87 degrades specifically d-amino acid containing peptides, which have never been observed in archaea. Genomic context of the Pab87 gene showed that it is surrounded by genes involved in the amino acid/peptide transport or metabolism. We propose that CubicO proteases are involved in the processing of d-peptides from environmental origins.


Ezrin/NF-κB Pathway Regulates EGF-induced Epithelial-Mesenchymal Transition (EMT), Metastasis, and Progression of Osteosarcoma.
BACKGROUND Epithelial-mesenchymal transition (EMT) is responsible for metastasis of cancers, and NF-κB can promote tumor progression. Ezrin is an important molecule participating in EMT. However, whether Ezrin mediates NF-κB in EGF-induced osteosarcoma is unknown. MATERIAL AND METHODS Ezrin phosphorylation, NF-κB activation, and EGF-induced EMT were studied in MG63 and U20S cells with NF-κB inhibition, silencing, or over-expressing Ezrin. Cell morphology, proliferation, migration, and motility were analyzed. An osteosarcoma model was established in mice by injecting MG63 and U20S and reducing Ezrin. RESULTS With EGF induction in vitro, Ezrin Tyr353 and Thr567 were phosphorylated, and EMT, proliferation, migration, and motility of osteosarcoma cells were promoted. Silencing Ezrin suppressed and over-expressing Ezrin promoted the nuclear translocation of p65 and phosphorylated IκBα (p-IκBα) in EGF-induced osteosarcoma cells. NF-κB inhibitor blocked EGF-induced EMT in both cell types, as well as reserving cell morphology and suppressing proliferation, migration, and motility. In vivo, reducing Ezrin significantly suppressed metastasis of osteosarcoma xenografts, increased liver and lung weights, and activated NF-κB, which were both induced by EGF. CONCLUSIONS Ezrin/NF-κB regulated EGF-induced EMT, as well as progression and metastasis of osteosarcoma in vivo and in vitro. Ezrin/NF-κB may be a new therapeutic target to prevent osteosarcoma from deterioration.


Catch me if I fall! Enacted uncertainty avoidance and the social safety net as country-level moderators in the job insecurity-job attitudes link.
Job insecurity is related to many detrimental outcomes, with reduced job satisfaction and affective organizational commitment being the 2 most prominent reactions. Yet, effect sizes vary greatly, suggesting the presence of moderator variables. On the basis of Lazarus's cognitive appraisal theory, we assumed that country-level enacted uncertainty avoidance and a country's social safety net would affect an individual's appraisal of job insecurity. More specifically, we hypothesized that these 2 country-level variables would buffer the negative relationships between job insecurity and the 2 aforementioned job attitudes. Combining 3 different data sources, we tested the hypotheses in a sample of 15,200 employees from 24 countries by applying multilevel modeling. The results confirmed the hypotheses that both enacted uncertainty avoidance and the social safety net act as cross-level buffer variables. Furthermore, our data revealed that the 2 cross-level interactions share variance in explaining the 2 job attitudes. Our study responds to calls to look at stress processes from a multilevel perspective and highlights the potential importance of governmental regulation when it comes to individual stress processes.


Acute insomnia: current conceptualizations and future directions.
Despite significant contributions made in the area of persistent/chronic insomnia, especially with regard to the underlying mechanisms driving its maintenance, the area of acute insomnia has received comparatively little attention. The aim of this paper is to review the literature with regard to understanding the situational and personaological circumstances that surround the development of acute insomnia. The review begins by examining how the existing diagnostic systems conceptualise acute insomnia. Theoretical models that explain, or inferentially explain, the transition between normal sleep and acute insomnia are then explored and evaluated. The review then examines the current evidence base in terms of the pathogenesis of acute insomnia from naturalistic and experimental studies. Overall, the findings from the review confirm the paucity of evidence available but perhaps more importantly highlight the need for a structured diagnosis of acute insomnia as the first step in a research and treatment strategy. To this end a diagnostic system, drawing on the existing literature on stress and the systems used to diagnose depression, is forwarded and justified and a research agenda advanced.


Racial/Ethnic and Gender Disparities in Health Care Use and Access.
To document racial/ethnic and gender differences in health service use and access after the Affordable Care Act went into effect. Secondary data from the 2006-2014 National Health Interview Survey. Linear probability models were used to estimate changes in health service use and access (i.e., unmet medical need) in two separate analyses using data from 2006 to 2014 and 2012 to 2014. Adult respondents aged 18 years and older (N = 257,560). Results from the 2006-2014 and 2012-2014 analyses show differential patterns in health service use and access by race/ethnicity and gender. Non-Hispanic whites had the greatest gains in health service use and access across both analyses. While there was significant progress among Hispanic respondents from 2012 to 2014, no significant changes were found pre-post-health care reform, suggesting access may have worsened before improving for this group. Asian men had the largest increase in office visits between 2006 and 2014, and although not statistically significant, the increase continued 2012-2014. Black women and men fared the worst with respect to changes in health care access. Ongoing research is needed to track patterns of health service use and access, especially among vulnerable racial/ethnic and gender groups, to determine whether existing efforts under health care reform reduce long-standing disparities.


An update of the WCRF/AICR systematic literature review on esophageal and gastric cancers and citrus fruits intake.
The 2007 World Cancer Research Fund/American Institute for Cancer Research expert report concluded that foods containing vitamin C probably protect against esophageal cancer and fruits probably protect against gastric cancer. Most of the previous evidence was from case-control studies, which may be affected by recall and selection biases. More recently, several cohort studies have examined these associations. We conducted a systematic literature review of prospective studies on citrus fruits intake and risk of esophageal and gastric cancers. PubMed was searched for studies published until 1 March 2016. We calculated summary relative risks and 95 % confidence intervals (95 % CI) using random-effects models. With each 100 g/day increase of citrus fruits intake, a marginally significant decreased risk of esophageal cancer was observed (summary RR 0.86, 95 % CI 0.74-1.00, 1,057 cases, six studies). The associations were similar for squamous cell carcinoma (RR 0.87, 95 % CI 0.69-1.08, three studies) and esophageal adenocarcinoma (RR 0.93, 95 % CI 0.78-1.11, three studies). For gastric cancer, the nonsignificant inverse association was observed for gastric cardia cancer (RR 0.75, 95 % CI 0.55-1.01, three studies), but not for gastric non-cardia cancer (RR 1.02, 95 % CI 0.90-1.16, four studies). Consistent summary inverse associations were observed when comparing the highest with lowest intake, with statistically significant associations for esophageal (RR 0.77, 95 % CI 0.64-0.91, seven studies) and gastric cardia cancers (RR 0.62, 95 % CI 0.39-0.99, three studies). Citrus fruits may decrease the risk of esophageal and gastric cardia cancers, but further studies are needed.


Heightened stress responsivity and emotional reactivity during pubertal maturation: Implications for psychopathology.
This commentary reviews and reflects on the studies of this special section: studies that collectively provide compelling evidence for meaningful changes in stress- and emotionally reactive psychophysiological systems with the transition from middle childhood into adolescence. The observed changes were complex and often overlaid upon ontogenetic differences in basal levels of activation of these systems. Maturational increases in responsiveness to stressors were stressor dependent and differentially expressed across autonomic and hormonal measures. Pubertal status increased the impact of some affective valence manipulations, although not significantly influencing others, including negative affect-related potentiation of startle/reflexes. Such ontogenetic increases in stressor and affect sensitivity may have implications for developmental psychopathology. Developmental increases in stressor reactivity may normally aid youth in responding adaptively to the challenges of adolescence, but may result in stress dysregulation among at-risk adolescents, increasing further their vulnerability for psychopathology. Pubertal-related increases in sensitivity to emotionally laden stimuli may exacerbate individual predispositions for exaggerated affective processing, perhaps contributing to the emergence of psychological disorders in these youth. Together, these studies, with their innovative use of autonomic, reflexive, and hormonal measures to index age- and pubertal-related changes in reactivity to stressors and affective stimuli, provide promising directions for future research. Some of these, along with a few cautionary notes, are outlined.


A pilot study of a family focused, psychosocial intervention with war-exposed youth at risk of attack and abduction in north-eastern Democratic Republic of Congo.
Rural communities in the Haut-Uele Province of northern Democratic Republic of Congo live in constant danger of attack and/or abduction by units of the Lord's Resistance Army operating in the region. This pilot study sought to develop and evaluate a community-participative psychosocial intervention involving life skills and relaxation training and Mobile Cinema screenings with this war-affected population living under current threat. 159 war-affected children and young people (aged 7-18) from the villages of Kiliwa and Li-May in north-eastern DR Congo took part in this study. In total, 22% of participants had been abduction previously while 73% had a family member abducted. Symptoms of post-traumatic stress reactions, internalising problems, conduct problems and pro-social behaviour were assessed by blinded interviewers at pre- and post-intervention and at 3-month follow-up. Participants were randomised (with an accompanying caregiver) to 8 sessions of a group-based, community-participative, psychosocial intervention (n=79) carried out by supervised local, lay facilitators or a wait-list control group (n=80). Average seminar attendance rates were high: 88% for participants and 84% for caregivers. Drop-out was low: 97% of participants were assessed at post-intervention and 88% at 3 month follow-up. At post-test, participants reported significantly fewer symptoms of post-traumatic stress reactions compared to controls (Cohen's d=0.40). At 3 month follow up, large improvements in internalising symptoms and moderate improvements in pro-social scores were reported, with caregivers noting a moderate to large decline in conduct problems among the young people. Trial Registration clinicalTrials.gov, Identifier: NCT01542398.


Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs.
D(2)-like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D(2)-like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-n-propyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D(2)-producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems, effects blocked by D(2), but not D(1), antagonists. In the MN9D cells, quinpirole and R-(-)-N-propylnorapomorphine (NPA) also inhibited the K(+)-stimulated release of [(3)H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K(+)-stimulated [(3)H]dopamine release, although they antagonized the effects of quinpirole. S-(+)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D(2L) receptors coupled to inhibition of dopamine release, but a weak partial agonist at D(2L) receptor-mediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D(2) receptors coupled to G protein-coupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D(2) receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D(2L) receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".


Two months of endurance training does not alter diastolic function evaluated by TDI in 9-11-year-old boys and girls.
Superior global cardiac performance (ie stroke volume) is classically reported after training in children. Current knowledge of the impact of exercise training on myocardial relaxation, a major component of left ventricular (LV) filling and subsequently stroke volume, is, however, limited in the paediatric population. This study aimed to investigate the effect of aerobic training on LV wall motion velocities by tissue Doppler imaging (TDI) in healthy children. 25 children (11 girls, 14 boys) were enrolled in a 2 month high-intensity aerobic training programme and 25 (12 girls and 13 boys) served as controls. The children (9-11 years old) performed a graded maximal exercise test on a treadmill to evaluate maximal oxygen uptake. Standard Doppler echocardiography and TDI measurements were performed at baseline and end of the study. Tissue Doppler systolic, early and late myocardial velocities were obtained at the mitral annulus in the septal, lateral, inferior and posterior walls. Maximal oxygen uptake increased by 6.5% (before: 51.6 (SD 4.2), after: 55.0 (4.5) ml/min/kg p<0.001) after training. A modest but significant increase in left ventricular end-diastolic diameter was also noticed (before: 46.1 (3.4), after: 48.3 (4.3) mm.BSA(-1/2), p<0.001), whereas left ventricular wall thickness and mass were unchanged. Neither transmitral inflow velocities nor early and late wall motion (Em: before = 18.4 (2.7), after = 18.0 (2.3) cm/s, Am: before = 6.8 (1.2), after = 6.7 (1.3) cm/s) were affected by training. Shortening fraction and regional systolic function (Sm: before = 10.1 (1.6), after = 10.2 (1.4) cm/s) by TDI were also unchanged. High-intensity aerobic sessions repeated over a 2 month period failed to improve regional diastolic function assessed by TDI in healthy young children.


Statistical reporting in the BJH: some dos and don'ts.
Statistics provides an important tool to enable large amounts of data from an experiment to be summarised and conclusions drawn. To be informative statistics need to serve the experimenter appropriately and give clear and understandable answers. It is important that the reader can clearly understand the methodology used, and that that methodology is appropriate to the situation. We present here some issues to be considered when writing for publication in the British Journal of Haematology (BJH).


Origin and evolution of arthropod hemocyanins and related proteins.
Arthropod hemocyanins are large, multimeric, (n x 6) copper-containing proteins that deliver oxygen in the haemolymph of many chelicerate, crustacean, myriapod, and also possibly some insect species. The arthropod hemocyanins belong to a large protein superfamily that also includes the arthropod phenoloxidases, certain crustacean and insect storage proteins (pseudo-hemocyanins and hexamerins), and the insect hexamerin receptors. Here I summarise the present knowledge of the origin, functional adaptations, and evolution of these proteins. Arthropod and mollusc hemocyanins are, if at all, only distantly related. As early as in the arthropod stem line, the hemocyanins emerged from a phenoloxidase-like enzyme. The evolution of distinct hemocyanin subunits, as well as the formation of multi-hexamers occurred independently within the arthropod subphyla. Hemocyanin subunit evolution is strikingly different in the Chelicerata, Myriapoda and Crustacea. Hemocyanins individually gave rise to two distinct copper-less storage proteins, the insect hexamerins and the crustacean pseudo-hemocyanins (cryptocyanins). The receptor responsible for the uptake of hexamerin by the larval fat body of the insects emerged from a hexamerin-precursor. Molecular phylogenetic analyses show a close relationship of the crustacean and insect proteins, providing strong support for a pancrustacean taxon, while structural data suggest a myriapod-chelicerate clade.


Factors influencing the success of aerial rabies vaccination of foxes.
Sylvatic rabies has been eradicated from most of Central Europe, but cases still occur in the Balkans. Oral rabies vaccination of foxes is an effective method for controlling the disease. The aim of this study was to evaluate the success of aerial vaccination campaigns conducted in Montenegro by identifying ecological, environmental and climatic factors that influenced the prevalence of antibodies to the rabies vaccine. To monitor the bait uptake and the serological responses to vaccination, foxes were shot by hunters. Of 175 shot foxes, 142 foxes (81.1%) had consumed baits. Of these only a total of 81 (57.0%) tested positive for rabies vaccine antibodies, possibly, due to the delayed uptake of bait in which the rabies vaccine was already inactivated. We found that low vaccination responses were associated with high fox density and bait delivery in open areas. In high fox density habitat, bait uptake might be delayed as other food and prey options for foxes are abundant. Similarly, delayed bait uptake probably occurred in open areas as such areas are less frequently used by foxes. The findings of this study suggest that efficacy of oral rabies vaccination by aerial delivery is associated with landscape features.


Effects of beta-blockade on neurohumoral responses and neurochemical markers in pacing-induced heart failure.
We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.


Conservation and utilization of African Oryza genetic resources.
Africa contains a huge diversity of both cultivated and wild rice species. The region has eight species representing six of the ten known genome types. Genetic resources of these species are conserved in various global germplasm repositories but they remain under collected and hence underrepresented in germplasm collections. Moreover, they are under characterized and therefore grossly underutilized. The lack of in situ conservation programs further exposes them to possible genetic erosion or extinction. In order to obtain maximum benefits from these resources, it is imperative that they are collected, efficiently conserved and optimally utilized. High throughput molecular approaches such as genome sequencing could be employed to more precisely study their genetic diversity and value and thereby enhance their use in rice improvement. Oryza sativa was the first crop plant to have its reference genome sequence released marking a major milestone that opened numerous opportunities for functional characterization of the entire rice genome. Studies have however demonstrated that one reference genome sequence is not enough to fully explore the genetic variation in the Oryza genus, hence the need to have reference sequences for other species in the genus. An overview of the state of conservation and utilization of African Oryza is hereby presented. Progress in the release of reference genome sequences for these species is also highlighted.


Chronic whiplash and whiplash-associated disorders: an evidence-based approach.
Whiplash is neck pain experienced as a result of a motor vehicle collision or similar trauma. Following a motor vehicle collision, 15% to 40% of patients with acute neck pain develop chronic neck pain. The cervical facet joint is the most common source of chronic neck pain after whiplash injury, followed by disk pain. Some patients experience pain from both structures. Initial management recommendations need not be directed toward an exact structural cause, but treatment includes advising the patient to remain active, prescribing medications when necessary, and providing advice regarding the generally favorable outcome. When neck pain persists, the physician should recommend medial branch blocks of the dorsal rami of the spinal nerves that supply the putative painful facet joint or joints; this is done to determine whether the facet joints are the cause of pain. When significant relief occurs on two occasions, radiofrequency neurotomy typically provides substantial relief for approximately 8 to 12 months and can be repeated indefinitely as needed. Occasionally, long-term treatment with medication may be indicated. Anterior cervical diskectomy and fusion is necessary on rare occasions.


Yersinia pseudotuberculosis-induced calcium signaling in neutrophils is blocked by the virulence effector YopH.
Pathogenic species of the genus Yersinia evade the bactericidal functions of phagocytes. This evasion is mediated through their virulence effectors, Yops, which act within target cells. In this study we investigated the effect of Yersinia pseudotuberculosis on Ca2+ signaling in polymorphonuclear neutrophils. The intracellular free calcium concentration in single adherent human neutrophils was monitored during bacterial infection and, in parallel, the encounter between the bacteria and cells was observed. When a plasmid-cured strain was used for infection, adherence of a single bacterium to the cellular surface induced a beta1 integrin-dependent transient increase in the intracellular concentration of free calcium. This was, however, not seen with Yop-expressing wild-type bacteria, which adhered to the cell surface without generating any Ca2+ signal. Importantly, the overall Ca2+ homeostasis was not affected by the wild-type strain; the Ca2+ signal mediated by the G-protein-coupled formyl-methionyl-leucyl-phenylalanine receptor was still functioning. Hence, the blocking effect was restricted to certain receptors and their signaling pathways. The use of different Yop mutant strains revealed that the protein tyrosine phosphatase YopH was responsible for the inhibition. This virulence determinant has previously been implicated in very rapid Yersinia-mediated effects on target cells as the key effector in the blockage of phagocytic uptake. The present finding, that Y. pseudotuberculosis, via YopH, specifically inhibits a self-induced immediate-early Ca2+ signal in neutrophils, offers more-detailed information concerning the effectiveness of this virulence effector and implies an effect on Ca2+-dependent, downstream signals.


Cohort Differences in Cognitive Aging in the Longitudinal Aging Study Amsterdam.
This study aims to examine cohort differences in cognitive performance and rates of change in episodic memory, processing speed, inductive reasoning, and general cognitive performance and to investigate whether these cohort effects may be accounted for by education attainment. The first cohort (N = 705) was born between 1920 and 1930, whereas the second cohort (N = 646) was born between 1931 and 1941. Both birth cohorts were aged 65 to 75 years at baseline and were followed up 3 and 6 years later. Data were analyzed using linear mixed models. The later born cohort had better general cognitive performance, inductive reasoning, and processing speed at baseline, but cohort differences in inductive reasoning and general cognitive performance disappeared after adjusting for education. The later born cohort showed steeper decline in processing speed. Memory decline was steeper in the earlier born cohort but only from Time 1 to Time 3 when the same memory test was administered. Education did not account for cohort differences in cognitive decline. The later born cohort showed better initial performance in certain cognitive abilities, but no better preservation of cognitive abilities overtime compared with the earlier born cohort. These findings carry implications for healthy cognitive aging.


Auxiliary α2δ1 and α2δ3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development.
VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct α2δ subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that α2δ1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of α2δ3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that α2δ1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on α2δ1 knockdown. Overexpression of α2δ3 increases the excitatory synaptic density as well but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonaloutgrowth in immature interneurons. Together, our findings demonstrate that α2δ1 and α2δ3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in α2δ surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity.SIGNIFICANCE STATEMENT The computational capacity of neuronal networks is determined by their connectivity. Chemical synapses are the main interface for transfer of information between individual neurons. The initial formation of network connectivity requires spontaneous electrical activity and the calcium channel-mediated signaling. We found that, in early development, auxiliary α2δ3 subunits of calcium channels foster presynaptic release of GABA, trigger formation of inhibitory synapses, and promote axonal outgrowth in inhibitory interneurons. In contrast, later in development, α2δ1 subunits promote the glutamatergic neurotransmission and synaptogenesis, as well as strongly enhance neuronal network activity. We propose that formation of connectivity in neuronal networks is associated with a concerted interplay of α2δ1 and α2δ3 subunits of calcium channels.


Ambiguities in helical reconstruction.
Helical polymers are found throughout biology and account for a substantial fraction of the protein in a cell. These filaments are very attractive for three-dimensional reconstruction from electron micrographs due to the fact that projections of these filaments show many different views of identical subunits in identical environments. However, ambiguities exist in defining the symmetry of a helical filament when one has limited resolution, and mistakes can be made. Until one reaches a near-atomic level of resolution, there are not necessarily reality-checks that can distinguish between correct and incorrect solutions. A recent paper in eLife (Xu et al., 2014) almost certainly imposed an incorrect helical symmetry and this can be seen using filament images posted by Xu et al. A comparison between the atomic model proposed and the published three-dimensional reconstruction should have suggested that an incorrect solution was found.


The genetics of feeding in Caenorhabditis elegans.
The pharynx of Caenorhabditis elegans is a nearly self-contained neuromuscular organ responsible for feeding. To identify genes involved in the development or function of the excitable cells of the pharynx, I screened for worms with visible defects in pharyngeal feeding behavior. Fifty-two mutations identified 35 genes, at least 22 previously unknown. The genes broke down into three broad classes: 2 pha genes, mutations in which caused defects in the shape of the pharynx, 7 phm genes, mutations in which caused defects in the contractile structures of the pharyngeal muscle, and 26 eat genes, mutants in which had abnormal pharyngeal muscle motions, but had normally shaped and normally birefringent pharynxes capable of vigorous contraction. Although the Eat phenotypes were diverse, most resembled those caused by defects in the pharyngeal nervous system. For some of the eat genes there is direct evidence from previous genetic mosaic and pharmacological studies that they do in fact affect nervous system. In eat-5 mutants the motions of the different parts of the pharynx were poorly synchronized. eat-6 and eat-12 mutants failed to relax their pharyngeal muscles properly. These pharyngeal motion defects are most easily explained as resulting from abnormal electrical excitability of the pharyngeal muscle membrane.


Association of Depression With All-Cause and Cardiovascular Disease Mortality Among Adults in China.
Depression is associated with increased disease burden worldwide and with higher risk of mortality in Western populations. To investigate whether depression is a risk factor for all-cause and cardiovascular disease (CVD) mortality in adults in China. This cohort study prospectively followed adults aged 30 to 79 years in the China Kadoorie Biobank (CKB) study from June 1, 2004, to December 31, 2016, and adults aged 32 to 104 years in the Dongfeng-Tongji (DFTJ) study from September 1, 2008, to December 31, 2016. Data analysis was conducted from June 1, 2018, to March 31, 2019. Depression was evaluated using the Chinese version of the World Health Organization Composite International Diagnostic Interview-Short Form in the CKB cohort and a 7-item symptoms questionnaire modified from the Composite International Diagnostic Interview-Short Form in the DFTJ cohort. Multivariable-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for the association of depression with mortality. Covariates in the final models included sociodemographic characteristics, lifestyle factors, and personal and family medical history. Among 512 712 individuals (mean [SD] age, 52.0 [10.7] years; 302 509 [59.0%] women) in the CKB cohort, there were 44 065 deaths, including 18 273 CVD deaths. The 12-month prevalence of major depressive episode in the CKB cohort was 0.64%, and the 1-month prevalence of clinically significant depressive symptoms was 17.96% in the DFTJ cohort. Among 26 298 individuals (mean [SD] age, 63.6 [7.8] years; 14 508 [55.2%] women) in the DFTJ cohort, there were 2571 deaths, including 1013 CVD deaths. In the multivariable-adjusted model, depression was associated with increased risk of all-cause mortality (CKB cohort: HR, 1.32 [95% CI, 1.20-1.46]; P < .001; DFTJ cohort: HR, 1.17 [95% CI, 1.06-1.29]; P = .002) and CVD mortality (CKB cohort: HR, 1.22 [95% CI, 1.04-1.44]; P = .02; DFTJ cohort: HR, 1.32 [95% CI, 1.14-1.54]; P < .001). In both cohorts, men had statistically significantly higher risk of all-cause mortality (CKB cohort: HR, 1.53 [95% CI, 1.32-1.76]; DFTJ cohort: HR, 1.24 [95% CI, 1.10-1.41]) and CVD mortality (CKB cohort: HR, 1.39 [95% CI, 1.10-1.76]; DFTJ cohort: HR, 1.49 [95% CI, 1.23-1.80]), while the association of depression with mortality among women was only significant for all-cause mortality in the CKB cohort (HR, 1.19 [95% CI, 1.03-1.37]). These findings suggest that depression is associated with an increased risk of all-cause and CVD mortality in adults in China, particularly in men. These findings highlight the importance and urgency of depression management as a measure for preventing premature deaths in China.


Integrating semianalytical and genetic algorithms to retrieve the constituents of water bodies from remote sensing of ocean color.
This work presents a novel GA-SA approach to retrieve the constituents of water bodies from remote sensing of ocean color. This approach is validated and compared to the existing algorithms using the same synthetic and in-situ datasets compiled by the International Ocean Color Coordinate Group. Comparing to the other methods, the GA-SA approach provides better retrievals for both the inherent optical properties and various water constituents. This novel approach is successfully applied in processing the images taken by MODerate resolution Imaging Spectroradiometer (MODIS) and generates regional maps of chlorophyll-a concentration, total suspended matter, and the absorption coefficient of color dissolved organic matter at 443nm.


Medical Thoracoscopy, Computed Tomography-guided Biopsy, and Ultrasound-guided Biopsy for Malignant Pleural Mesothelioma: A Systematic Review.
Although surgical thoracoscopy is recommended in the diagnosis of malignant pleural mesothelioma (MPM), the invasiveness of this procedure is of strong concern. Our review aimed to evaluate the accuracies of medical thoracoscopy (MT), computed tomography (CT)-guided biopsy, and ultrasound (US)-guided biopsy in the diagnosis of MPM among patients with pleural effusion. We searched the MEDLINE, Embase, Central, and International Clinical Trials Registry Platform databases for studies evaluating the diagnostic accuracy of at least one of the biopsy procedures among patients with pleural effusion of unknown aetiology who had undergone thoracentesis and/or blind biopsy. A hierarchical summary receiver operating curve was created for MT. Following full-text screening, 15 studies were included. MT studies had a high risk of bias and low applicability concern; however, hierarchical summary receiver operating curve revealed that MT had a high sensitivity. MT might be a useful rule-in test for guiding the use of more invasive diagnostic procedures.


Kaempferol induced apoptosis via endoplasmic reticulum stress and mitochondria-dependent pathway in human osteosarcoma U-2 OS cells.
Kaempferol is a natural flavonoid. Previous studies have reported that kaempferol has anti-proliferation activities and induces apoptosis in many cancer cell lines. However, there are no reports on human osteosarcoma. In this study, we investigate the anti-cancer effects and molecular mechanisms of kaempferol in human osteosarcoma cells. Our results demonstrate that kaempferol significantly reduces cell viabilities of U-2 OS, HOB and 143B cells, especially U-2 OS cells in a dose-dependent manner, but exerts low cytotoxicity on human fetal osteoblast progenitor hFOB cells. Comet assay, DAPI staining and DNA gel electrophoresis confirm the effects of DNA damage and apoptosis in U-2 OS cells. Flow cytometry detects the increase of cytoplasmic Ca(2+) levels and the decrease of mitochondria membrane potential. Western blotting and fluorogenic enzymatic assay show that kaempferol treatment influences the time-dependent expression of proteins involved in the endoplasmic reticulum stress pathway and mitochondrial signaling pathway. In addition, pretreating cells with caspase inhibitors, BAPTA or calpeptin before exposure to kaempferol increases cell viabilities. The anti-cancer effects of kaempferol in vivo are evaluated in BALB/c(nu/nu) mice inoculated with U-2 OS cells, and the results indicate inhibition of tumor growth. In conclusion, kaempferol inhibits human osteosarcoma cells in vivo and in vitro.


Cancer therapy-related cardiac dysfunction: is endothelial dysfunction at the heart of the matter?
Significant improvements in cancer survival have brought to light unintended long-term adverse cardiovascular effects associated with cancer treatment. Although capable of manifesting a broad range of cardiovascular complications, cancer therapy-related cardiac dysfunction (CTRCD) remains particularly common among the mainstay anthracycline-based and human epidermal growth factor receptor-targeted therapies. Unfortunately, the early asymptomatic stages of CTRCD are difficult to detect by cardiac imaging alone, and the initiating mechanisms remain incompletely understood. More recently, circulating inflammatory markers, cardiac biomarkers, microRNAs, and extracellular vesicles (EVs) have been considered as early markers of cardiovascular injury. Concomitantly, the role of the endothelium in regulating cardiac function in the context of CTRCD is starting to be understood. In this review, we highlight the impact of breast cancer therapies on the cardiovascular system with a focus on the endothelium, and examine the status of circulating biomarkers, including inflammatory markers, cardiac biomarkers, microRNAs, and endothelial cell-derived EVs. Investigation of these emerging biomarkers may uncover mechanisms of injury, detect early stages of cardiovascular damage, and elucidate novel therapeutic approaches.


Dinosaurs and the Cretaceous Terrestrial Revolution.
The observed diversity of dinosaurs reached its highest peak during the mid- and Late Cretaceous, the 50 Myr that preceded their extinction, and yet this explosion of dinosaur diversity may be explained largely by sampling bias. It has long been debated whether dinosaurs were part of the Cretaceous Terrestrial Revolution (KTR), from 125-80 Myr ago, when flowering plants, herbivorous and social insects, squamates, birds and mammals all underwent a rapid expansion. Although an apparent explosion of dinosaur diversity occurred in the mid-Cretaceous, coinciding with the emergence of new groups (e.g. neoceratopsians, ankylosaurid ankylosaurs, hadrosaurids and pachycephalosaurs), results from the first quantitative study of diversification applied to a new supertree of dinosaurs show that this apparent burst in dinosaurian diversity in the last 18 Myr of the Cretaceous is a sampling artefact. Indeed, major diversification shifts occurred largely in the first one-third of the group's history. Despite the appearance of new clades of medium to large herbivores and carnivores later in dinosaur history, these new originations do not correspond to significant diversification shifts. Instead, the overall geometry of the Cretaceous part of the dinosaur tree does not depart from the null hypothesis of an equal rates model of lineage branching. Furthermore, we conclude that dinosaurs did not experience a progressive decline at the end of the Cretaceous, nor was their evolution driven directly by the KTR.


Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery.
Ultrasound-induced microbubble (USMB) cavitation is widely used to promote drug delivery. Our previous study investigated USMB targeting the round window membrane by applying the ultrasound transducer to the tympanic bulla. In the present study, we further extended the use of this technology to enhance drug delivery to the inner ear by introducing the ultrasound transducer into the external auditory canal (EAC) or applying it to the skull. Using a 3-dimensional-printed diffusion apparatus mimicking the pathway for ultrasound passing through and reaching the middle ear cavity in vitro, the models simulating the transcanal and transcranial approach demonstrated 4.8-fold- and 3.7-fold-higher delivery efficiencies, respectively. In an in vivo model of guinea pigs, by filling tympanic bulla with microbubbles and biotin-FITC, USMB applied transcanally and transcranially induced 2.8-fold and 1.5-fold increases in biotin-FITC delivery efficiencies, respectively. In addition, the gentamicin uptake by cochlear and vestibular hair cells and gentamicin-induced hair cell loss were significantly enhanced following transcanal application of USMB. On the 28th day after transcanal USMB, safety assessment showed no significant changes in the hearing thresholds and the integrity of cochlea. These are the first results to our knowledge to demonstrate the feasibility and support the potential clinical application of applying USMB via EAC to facilitate drug delivery into the inner ear.


HPMC capsules: current status and future prospects.
Hydroxypropyl methylcellulose (HPMC) is employed for a wide variety of pharmaceutical and food preparations. Its applications as viscolizing agent (thickening agent), coating polymer, bioadhesive, in solid dispersion to enhance solubility, binder in the process of granulation and in modified release formulations have been well documented. One other notable use is in the production of capsule shells, replacing the animal derived gelatin in conventional two-piece capsules. The aim of this review is to systemically survey published literature on the HPMC use in capsule shells and resolve questions regarding their suitability as a replacement for hard gelatin capsules. Future refinements in the production and filling of HPMC capsule shells and improvement in their in vivo/in vitro dissolution would ensure their superiority over hard gelatin capsules.


[Increased iron store and its relationship with cardiovascular disease].
In the last years, great advance has been achieved in the control of several of the classic atherogenic risk factors; nonetheless, the incidence of cardiovascular disease (CVD) still remains high. Among the disorders which are associated with CVD, increased iron stores have been described as one of them. Its study gained relevance since the "iron hypothesis", which postulates that low iron levels exert a protective effect on cardiovascular system, was elaborated. In spite of the numerous studies carried out to test this hypothesis, the results have been controversial. On the other hand, much knowledge regarding iron metabolism has been gained since the description of the regulatory hormone, hepcidin. The studies on hepcidin physiologic functions allowed the elaboration of new hypothesis that could explain the results formerly conceived as inconsistent. The aim of the present review is to describe, in light of the newest advances in iron metabolism regulation and its association with inflammation, the current state of knowledge regarding the possible role of iron overload as a risk factor of CVD.


Number and type of vertebral deformities: epidemiological characteristics and relation to back pain and height loss. European Vertebral Osteoporosis Study Group.
Vertebral deformity is the classical hallmark of osteoporosis. Three types of vertebral deformity are usually described: crush, wedge and biconcave deformities. However, there are few data concerning the descriptive epidemiology of the individual deformity types, and differences in their underlying pathogenesis and clinical impact remain uncertain. The aim of this study was to compare the epidemiological characteristics of the three types of vertebral deformity and to explore the relationships of the number and type of deformity with back pain and height loss. Age-stratified random samples of men and women aged 50 years and over were recruited from population registers in 30 European centers (EVOS study). Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. The presence, type and number of vertebral deformities was determined using the McCloskey-Kanis algorithm. A total of 13,562 men and women were studied; mean age in men was 64.4 years (SD 8.5), and in women 63.8 years (SD 8.5 years). There was evidence of variation in the occurrence of wedge, crush and biconcave deformity by age, sex and vertebral level. Wedge deformities were the most frequent deformity and tended to cluster at the mid-thoracic and thoraco-lumbar regions of the spine in both men and women. Similar predilection for these sites was observed for crush and to a lesser extent biconcave deformities though this was much less marked than for wedge deformities. In both sexes the frequency of biconcave deformities was higher in the lumbar than the thoracic spine and unlike the other deformity types it did not decline in frequency at lower lumbar vertebral levels. The prevalence of all three types of vertebral deformity increased with age and was more marked in women. There were no important differences in the effect of age on the different deformity types. All types of deformity were associated with height loss, which was greatest for individuals with crush deformity. Back pain was also associated with all types of deformity. Overall, these results do not suggest important differences in pathophysiology between the three deformity types. Biomechanical factors appear to be important in determining their distribution within the spine. All deformity types are linked with adverse outcomes, though crush deformities showed greater height loss than the other deformity types.