A Comparison of Different Approaches to Unravel the Latent Structure within Metabolic Syndrome

Background: Exploratory factor analysis is a commonly used statistical technique in metabolic syndrome research to uncover latent structure amongst metabolic variables. The application of factor analysis requires methodological decisions that reflect the hypothesis of the metabolic syndrome construct. These decisions often raise the complexity of the interpretation from the output. We propose two alternative techniques developed from cluster analysis which can achieve a clinically relevant structure, whilst maintaining intuitive advantages of clustering methodology. Methods: Two advanced techniques of clustering in the VARCLUS and matroid methods are discussed and implemented on a metabolic syndrome data set to analyze the structure of ten metabolic risk factors. The subjects were selected from the normative aging study based in Boston, Massachusetts. The sample included a total of 847 men aged between 21 and 81 years who provided complete data on selected risk factors during the period 1987 to 1991. Results: Four core components were identified by the clustering methods. These are labelled obesity, lipids, insulin resistance and blood pressure. The exploratory factor analysis with oblique rotation suggested an overlap of the loadings identified on the insulin resistance and obesity factors. The VARCLUS and matroid analyses separated these components and were able to demonstrate associations between individual risk factors. Conclusions: An oblique rotation can be selected to reflect the clinical concept of a single underlying syndrome, howeve

Identification and Characterization of Inhibitors of Human Apurinic/apyrimidinic Endonuclease APE1

APE1 is the major nuclease for excising abasic (AP) sites and particular 3′-obstructive termini from DNA, and is an integral participant in the base excision repair (BER) pathway. BER capacity plays a prominent role in dictating responsiveness to agents that generate oxidative or alkylation DNA damage, as well as certain chain-terminating nucleoside analogs and 5-fluorouracil. We describe within the development of a robust, 1536-well automated screening assay that employs a deoxyoligonucleotide substrate operating in the red-shifted fluorescence spectral region to identify APE1 endonuclease inhibitors. This AP site incision assay was used in a titration-based high-throughput screen of the Library of Pharmacologically Active Compounds (LOPAC1280), a collection of well-characterized, drug-like molecules representing all major target classes. Prioritized hits were authenticated and characterized via two high-throughput screening assays – a Thiazole Orange fluorophore-DNA displacement test and an E. coli endonuclease IV counterscreen – and a conventional, gel-based radiotracer incision assay. The top, validated compounds, i.e. 6-hydroxy-DL-DOPA, Reactive Blue 2 and myricetin, were shown to inhibit AP site cleavage activity of whole cell protein extracts from HEK 293T and HeLa cell lines, and to enhance the cytotoxic and genotoxic potency of the alkylating agent methylmethane sulfonate. The studies herein report on the identification of novel, small molecule APE1-targeted bioactive inhibitor probes, which represent initial chemotypes towards the development of potential pharmaceuticals

Attention to Speech-Accompanying Gestures: Eye Movements and Information Uptake

There is growing evidence that addressees in interaction integrate the semantic information conveyed by speakers’ gestures. Little is known, however, about whether and how addressees’ attention to gestures and the integration of gestural information can be modulated. This study examines the influence of a social factor (speakers’ gaze to their own gestures), and two physical factors (the gesture’s location in gesture space and gestural holds) on addressees’ overt visual attention to gestures (direct fixations of gestures) and their uptake of gestural information. It also examines the relationship between gaze and uptake. The results indicate that addressees’ overt visual attention to gestures is affected both by speakers’ gaze and holds but for different reasons, whereas location in space plays no role. Addressees’ uptake of gesture information is only influenced by speakers’ gaze. There is little evidence of a direct relationship between addressees’ direct fixations of gestures and their uptake

Informing research priorities for immature sea turtles through expert elicitation

This is the final version. Available from Inter Research via the DOI in this record. Although sea turtles have received substantial focus worldwide, research on the immature life stages is still relatively limited. The latter is of particular importance, given that a large proportion of sea turtle populations comprises immature individuals. We set out to identify knowledge gaps and identify the main barriers hindering research in this field. We analyzed the perceptions of sea turtle experts through an online survey which gathered their opinions on the current state of affairs on immature sea turtle research, including species and regions in need of further study, priority research questions, and barriers that have interfered with the advancement of research. Our gap analysis indicates that studies on immature leatherback Dermochelys coriacea and hawksbill Eretmochelys imbricata turtles are lacking, as are studies on all species based in the Indian, South Pacific, and South Atlantic Oceans. Experts also perceived that studies in population ecology, namely on survivorship and demography, and habitat use/behavior, are needed to advance the state of knowledge on immature sea turtles. Our survey findings indicate the need for more interdisciplinary research, collaborative efforts (e.g. data-sharing, joint field activities), and improved communication among researchers, funding bodies, stakeholders, and decision-makers

Morphological and molecular characterization of Curvularia and related species associated with leaf spot disease of rice in Peninsular Malaysia

Curvularia species are important phytopathogens reported worldwide. They are closely related; consist of major destructive pathogens mainly for grasses and cereal plants including rice (Oryza sativa). A leaf spot symptom of rice is one of the common symptoms found in the rice field and caused reduction of rice yield. However, there are no reports on Curvularia species associated with rice leaves showing spot symptoms. The objectives are to isolate and characterize Curvularia and related species from leaf spot of rice by using morphological and molecular characterization and to determine the phylogenetic relationship between the isolated fungi. Fungal isolation was done from diseased rice leaves showing leaf spot symptoms collected throughout Peninsular Malaysia. Thirty-three isolates were recovered and identified based on their morphological characteristics such as conidia morphology, colony appearance, pigmentation and growth rate for species delimitation. Internal transcribed spacer (ITS) region was amplified to confirm the species identification. The 33 isolates were identified as Bipolaris sorokiniana (10 isolates), Curvularia hawaiiensis (8 isolates), C. geniculata (6 isolates), C. eragrostidis (6 isolates), C. aeria (2 isolates) and C. lunata (1 isolate). A phylogenetic tree was constructed based on ITS sequences using neighbour-joining method. The tree grouped members of Curvularia and Bipolaris into different clades. The phylogenetic tree indicated that the presence of two groups of fungi species; highly virulent and mild pathogens. In conclusion, Curvularia species and Bipolaris sorokiniana were present in rice field in Malaysia and associated with leaf spot of rice

A multidisciplinary treatment of congenitally missing maxillary lateral incisors: a 14-year follow-up case report

Absence of the maxillary lateral incisor creates an aesthetic problem which can be managed in various ways. The condition requires careful treatment planning and consideration of the options and outcomes following either space closure or prosthetic replacement. Recent developments in restorative dentistry have warranted a re-evaluation of the approach to this clinical situation. Factors relating both to the patient and the teeth, including the presentation of malocclusion and the effect on the occlusion must be considered. The objective of this study was to describe the etiology, prevalence and alternative treatment modalities for dental agenesis and to present a clinical case of agenesis of the maxillary lateral incisors treated by the closure of excessive spaces and canine re-anatomization. A clinical case is presented to illustrate the interdisciplinary approach between orthodontics and restorative dentistry for improved esthetic results. In this report, the treatment of a girl with a Class II malocclusion of molars and canines with missing maxillary lateral incisors and convex facial profile is shown. Treatment was successfully achieved and included the space closure of the areas corresponding to the missing upper lateral incisors, through movement of the canines and the posterior teeth to mesial by fixed appliances as well as the canines transformation in the maxillary lateral incisors. This is a 14-year follow-up case report involving orthodontics and restorative dentistry in which pretreatment, posttreatment, and long-term follow-up records for the patient are presented

Talk to the Virtual Hands: Self-Animated Avatars Improve Communication in Head-Mounted Display Virtual Environments

Background When we talk to one another face-to-face, body gestures accompany our speech. Motion tracking technology enables us to include body gestures in avatar-mediated communication, by mapping one's movements onto one's own 3D avatar in real time, so the avatar is self-animated. We conducted two experiments to investigate (a) whether head-mounted display virtual reality is useful for researching the influence of body gestures in communication; and (b) whether body gestures are used to help in communicating the meaning of a word. Participants worked in pairs and played a communication game, where one person had to describe the meanings of words to the other. Principal Findings In experiment 1, participants used significantly more hand gestures and successfully described significantly more words when nonverbal communication was available to both participants (i.e. both describing and guessing avatars were self-animated, compared with both avatars in a static neutral pose). Participants ‘passed’ (gave up describing) significantly more words when they were talking to a static avatar (no nonverbal feedback available). In experiment 2, participants' performance was significantly worse when they were talking to an avatar with a prerecorded listening animation, compared with an avatar animated by their partners' real movements. In both experiments participants used significantly more hand gestures when they played the game in the real world. Conclusions Taken together, the studies show how (a) virtual reality can be used to systematically study the influence of body gestures; (b) it is important that nonverbal communication is bidirectional (real nonverbal feedback in addition to nonverbal communication from the describing participant); and (c) there are differences in the amount of body gestures that participants use with and without the head-mounted display, and we discuss possible explanations for this and ideas for future investigation

Developmental disturbances associated with agenesis of the permanent maxillary lateral incisor

The aim of this study was to characterise the intra and extra-oral phenotype associated with agenesis of the permanent maxillary lateral incisor. We compared three groups: (1) subjects with agenesis of one or both permanent maxillary lateral incisors (n=80); (2) first and second degree relatives of group 1 with no agenesis of the permanent maxillary lateral incisor and (3) subjects with no agenesis of the maxillary lateral incisor or family history of it (n=49). For each of the 201 subjects detailed clinical information was reviewed and panoramic radiographs were analysed. Considering only the sample with unilateral agenesis, microdontia of the contralateral permanent maxillary lateral incisor was significantly more frequent in group 1 (82.4%) than in group 2 (25%) and the control group (2%). This supports the theory that microdontia is a variable expression of the same developmental disturbance that causes tooth agenesis. The absence of third molars occurred more often in group 1 (36.2%) than in groups 2 and 3 (18.6% and 18.9% respectively), confirming that agenesis of third molars was markedly associated with the agenesis of the permanent maxillary lateral incisor. Agenesis of teeth other than third molars was not significantly different among subjects with agenesis of the permanent maxillary lateral incisor and their relatives. The frequencies of supernumerary teeth, permanent maxillary canine impaction, general health condition and minor anomalies were not significantly different between the three groups

Hepatic safety of antibiotics used in primary care

Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre-clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co-trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome-wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.Funding Agencies|John Curtin School of Medical Research, The Australian National University</p