Effects of load mass and size on cooperative transport in ants over multiple transport challenges.
Some ant species cooperatively transport a wide range of extremely large, heavy food objects of various shapes and materials. While previous studies have examined how object mass and size affect the recruitment of additional workers, less is understood about how these attributes affect the rest of the transport process. Using artificial baits with independently varying mass and size, we reveal their effects on cooperative transport in Paratrechina longicornis across two transport challenges: movement initiation and obstacle navigation. As expected, object mass was tightly correlated with number of porters as workers adjust group size to the task. Mass affected performance similarly across the two challenges, with groups carrying heavy objects having lower performance. Yet, object size had differing effects depending on the challenge. While larger objects led to reduced performance during movement initiation - groups took longer to start moving these objects and had lower velocities - there was no evidence for this during obstacle navigation, and the opposite pattern was weakly supported. If a group struggles to start moving an object, it does not necessarily predict difficulty navigating around obstacles; groups should persist in trying to move 'difficult' objects, which may be easier to transport later in the process. Additionally, groups hitting obstacles were not substantially disrupted, and started moving again sooner than at the start, despite the nest direction being blocked. Paratrechina longicornis transport groups never failed, performing well at both challenges while carrying widely varying objects, and even transported a bait weighing 1900 times the mass of an individual.


'Gonna make yer gorgeous': Everyday transformation, resistance and belonging in the care-based hair salon.
This paper makes a contribution to an emerging debate on dementia and citizenship through a focus on the everyday experiences of women living with dementia and in receipt of care. In particular, a link is drawn between hairdressing and citizenship in the context of dementia care. Informed by a wider debate over the importance of an emplaced, embodied and performative approach to citizenship, the authors highlight the way that intersecting forms of resistance unfold in the salon. The Hair and Care project, as the name implies, focused upon hair care and styling in the context of a wider consideration of appearance and how it is managed and what it means for people living with dementia. With a focus upon the routine, mundane and thereby often unproblematised aspects of everyday life in/with care, the discussion draws together two key ideas concerned with the interplay of power and resistance: Essed's (1991) theory of 'everyday discrimination' and Scott's (1985) notion of 'everyday resistance'. The findings illuminate the creative and collective forms of agency exercised by older women living with dementia, in the context of their relationships with one another and with the hairdressers whose services and support inspire their loyalty and patronage. Findings from the study point to the link between (inter-)personal practices of appearance management and a wider set of social conditions that are manifest in the on-going struggle over time, space and bodies in dementia care.


EULAR recommendations for the use of imaging in the clinical management of peripheral joint osteoarthritis.
The increased information provided by modern imaging has led to its more extensive use. Our aim was to develop evidence-based recommendations for the use of imaging in the clinical management of the most common arthropathy, osteoarthritis (OA). A task force (including rheumatologists, radiologists, methodologists, primary care doctors and patients) from nine countries defined 10 questions on the role of imaging in OA to support a systematic literature review (SLR). Joints of interest were the knee, hip, hand and foot; imaging modalities included conventional radiography (CR), MRI, ultrasonography, CT and nuclear medicine. PubMed and EMBASE were searched. The evidence was presented to the task force who subsequently developed the recommendations. The strength of agreement for each recommendation was assessed. 17 011 references were identified from which 390 studies were included in the SLR. Seven recommendations were produced, covering the lack of need for diagnostic imaging in patients with typical symptoms; the role of imaging in differential diagnosis; the lack of benefit in monitoring when no therapeutic modification is related, though consideration is required when unexpected clinical deterioration occurs; CR as the first-choice imaging modality; consideration of how to correctly acquire images and the role of imaging in guiding local injections. Recommendations for future research were also developed based on gaps in evidence, such as the use of imaging in identifying therapeutic targets, and demonstrating the added value of imaging. These evidence-based recommendations and related research agenda provide the basis for sensible use of imaging in routine clinical assessment of people with OA.


Identifying target populations for screening or not screening using logic regression.
Colorectal cancer remains a significant public health concern despite the fact that effective screening procedures exist and that the disease is treatable when detected at early stages. Numerous risk factors for colon cancer have been identified, but none are very predictive alone. We sought to determine whether there are certain combinations of risk factors that distinguish well between cases and controls, and that could be used to identify subjects at particularly high or low risk of the disease to target screening. Using data from the Seattle site of the Colorectal Cancer Family Registry, we fit logic regression models to combine risk factor information. Logic regression is a methodology that identifies subsets of the population, described by Boolean combinations of binary coded risk factors. This method is well suited to situations in which interactions between many variables result in differences in disease risk. We found that neither the logic regression models nor stepwise logistic regression models fit for comparison resulted in criteria that could be used to direct subjects to screening. However, we believe that our novel statistical approach could be useful in settings where risk factors do discriminate between cases and controls, and illustrate this with a simulated data set.


Gene and genon concept: coding versus regulation. A conceptual and information-theoretic analysis of genetic storage and expression in the light of modern molecular biology.
We analyse here the definition of the gene in order to distinguish, on the basis of modern insight in molecular biology, what the gene is coding for, namely a specific polypeptide, and how its expression is realized and controlled. Before the coding role of the DNA was discovered, a gene was identified with a specific phenotypic trait, from Mendel through Morgan up to Benzer. Subsequently, however, molecular biologists ventured to define a gene at the level of the DNA sequence in terms of coding. As is becoming ever more evident, the relations between information stored at DNA level and functional products are very intricate, and the regulatory aspects are as important and essential as the information coding for products. This approach led, thus, to a conceptual hybrid that confused coding, regulation and functional aspects. In this essay, we develop a definition of the gene that once again starts from the functional aspect. A cellular function can be represented by a polypeptide or an RNA. In the case of the polypeptide, its biochemical identity is determined by the mRNA prior to translation, and that is where we locate the gene. The steps from specific, but possibly separated sequence fragments at DNA level to that final mRNA then can be analysed in terms of regulation. For that purpose, we coin the new term "genon". In that manner, we can clearly separate product and regulative information while keeping the fundamental relation between coding and function without the need to introduce a conceptual hybrid. In mRNA, the program regulating the expression of a gene is superimposed onto and added to the coding sequence in cis - we call it the genon. The complementary external control of a given mRNA by trans-acting factors is incorporated in its transgenon. A consequence of this definition is that, in eukaryotes, the gene is, in most cases, not yet present at DNA level. Rather, it is assembled by RNA processing, including differential splicing, from various pieces, as steered by the genon. It emerges finally as an uninterrupted nucleic acid sequence at mRNA level just prior to translation, in faithful correspondence with the amino acid sequence to be produced as a polypeptide. After translation, the genon has fulfilled its role and expires. The distinction between the protein coding information as materialised in the final polypeptide and the processing information represented by the genon allows us to set up a new information theoretic scheme. The standard sequence information determined by the genetic code expresses the relation between coding sequence and product. Backward analysis asks from which coding region in the DNA a given polypeptide originates. The (more interesting) forward analysis asks in how many polypeptides of how many different types a given DNA segment is expressed. This concerns the control of the expression process for which we have introduced the genon concept. Thus, the information theoretic analysis can capture the complementary aspects of coding and regulation, of gene and genon.


Developing forebrain astrocytes are sensitive to thyroid hormone.
Previous studies have shown that developing neurons of the basal forebrain and hippocampus are sensitive to thyroid hormone (Gould and Butcher: J. Neurosci., 9:3347-3358, 1989; Rami et al: Neuroscience, 19:1217-1226, 1986). In order to determine whether or not thyroid hormone influences the development of astrocytes in brain regions where neurons are affected, we performed vimentin and glial fibrillary acidic protein (GFAP) immunocytochemical and single-section Golgi-impregnation analyses on the basal forebrain and hippocampus of control and neonatally thyroid hormone treated rats. For purposes of comparison, glial cells of the pontomesencephalotegmental (PMT) region, a region where developing neurons are not morphologically affected by thyroid hormone imbalances (Gould and Butcher, op. cit.), were also examined. Neonatal thyroid hormone treatment resulted in a premature disappearance of vimentin-immunoreactive radial glia in the basal forebrain and hippocampus. In addition, a premature appearance of GFAP-immunoreactive astrocytes with mature morphological characteristics was observed in the basal forebrain and hippocampus of thyroid hormone treated animals. Quantitative analyses revealed significant increases in the density of GFAP-immunostained astrocytes and in the cross-sectional cell body area and the number of primary processes in Golgi-impregnated astrocytes of the basal forebrain and hippocampus of animals treated neonatally with thyroid hormone. In contrast, no changes in any of these parameters were observed in glial cells of the PMT region with neonatal thyroid hormone treatment.


The gut microbiota and developmental programming of the testis in mice.
Nutrients and environmental chemicals, including endocrine disruptors, have been incriminated in the current increase in male reproductive dysfunction, but the underlying mechanisms remain unknown. The gastrointestinal tract represents the largest surface area exposed to our environment and thereby plays a key role in connection with exposure of internal organs to exogenous factors. In this context the gut microbiome (all bacteria and their metabolites) have been shown to be important contributors to body physiology including metabolism, cognitive functions and immunity. Pivotal to male reproduction is a proper development of the testis, including the formation of the blood-testis barrier (BTB) that encapsulates and protects germ cells from stress induced environmental cues, e.g. pathogenic organisms and xenobiotics. Here we used specific pathogen free (SPF) mice and germ-free (GF) mice to explore whether gut microbiota and/or their metabolites can influence testis development and regulation of BTB. Lumen formation in the seminiferous tubules, which coincides with the development of the BTB was delayed in the testes of GF mice at 16 days postpartum. In addition, perfusion experiments (Evans blue) demonstrated increased BTB permeability in these same mice. Reduced expressions of occludin, ZO-2 and E-cadherin in GF testis suggested that the microbiota modulated BTB permeability by regulation of cell-cell adhesion. Interestingly, exposure of GF mice to Clostridium Tyrobutyricum (CBUT), which secrete high levels of butyrate, restored the integrity of the BTB and normalized the levels of cell adhesion proteins. Moreover, the GF mice exhibited lower serum levels of gonadotropins (LH and FSH) than the SPF group. In addition, the intratesticular content of testosterone was lower in GF compared to SPF or CBUT animals. Thus, the gut microbiome can modulate the permeability of the BTB and might play a role in the regulation of endocrine functions of the testis.


Multiple-sited interaction of caldesmon with Ca(2+)-calmodulin.
The binding of Ca(2+)- and Ba(2+)-calmodulin to caldesmon and its functional consequence was investigated with three different calmodulin mutants. Two calmodulin mutants have pairs of cysteine residues substituted and oxidized to a disulphide bond in either the N- or C-terminal lobe (C41/75 and C85/112). The third mutant has phenylalanine-92 replaced by alanine (F92A). Binding measurements in the presence of Ca2+ by separation on native gels and by carbodiimide-induced cross-linking showed a lower affinity for caldesmon in all the mutants. When Ca2+ was replaced by Ba2+ the affinity of calmodulin for caldesmon was further reduced. The ability of Ca(2+)-calmodulin to release caldesmon's inhibition of the actin-tropomyosin-activated myosin ATPase was virtually abolished by mutation of phenylalanine-92 to alanine or by replacing Ba2+ for Ca2+ in native calmodulin. Both cysteine mutants retained their functional ability, but the increased concentration needed for 50% release of caldesmon inhibition reflected their decreased affinity. Ca2+ -calmodulin produced a broadening in the signals of the NMR spectrum of the 10 kDa Ca(2+)-calmodulin-binding C-terminal fragment of caldesmon arising from tryptophans -749 and -779 and caused an enhancement of maximum tryptophan fluorescence of 49% and a 16 nm blue shift of the maximum. Ca(2+)-calmodulin F92A produced a change in wavelength of 4 nm but no change in maximum, whereas Ca(2+)-calmodulin C41/75 binding produced a decrease in fluorescence with no shift of the maximum. We conclude that functional binding of Ca(2+)-calmodulin to caldesmon requires multiple interaction sites on both molecules. However, some structural modification in calmodulin does not abolish the caldesmon-related functionality. This suggests that various EF hand proteins can substitute for the calmodulin molecule.


Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach.
The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC)class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genome-wide function and relationship with underlying genetic diversity has not been resolved. We report the first genome-wide ChIP-seq map for CIITA and complement this by mapping inter-individual variation in CIITA expression as a quantitative trait. We analyse CIITA recruitment for pathophysiologically relevant primary human B cells and monocytes, resting and treated with interferon-gamma, in the context of the epigenomic regulatory landscape and DNA-binding proteins associated with the CIITA enhanceosome including RFX, CREB1/ATF1 and NFY. We confirm recruitment to proximal promoter sequences in MHC class II genes and more distally involving the canonical CIITA enhanceosome. Overall, we map 843 CIITA binding intervals involving 442 genes and find 95% of intervals are located outside the MHC and 60% not associated with RFX5 binding. Binding intervals are enriched for genes involved in immune function n and infectious disease with novel loci including major histone gene clusters. Were solve differentially expressed genes associated in trans with a CIITA intronic sequence variant, integrate with CIITA recruitment and show how this is mediated by allele-specific recruitment of NF-kB. Our results indicate a broader role for CIITA beyond the MHC involving immune-related genes.We provide new insights into allele-specific regulation of CIITA informative for understanding gene function and disease.


Environmental risk factors in pediatric psoriasis: a multicenter case-control study.
To analyze the effect of possible risk factors, including breastfeeding, on the development of childhood-onset psoriasis, a multicenter case-control study with prospective collection of data was performed. Using a standard questionnaire, personal and specific variables including family history of psoriasis, maternal and environmental tobacco smoke exposure, body mass index (BMI), exclusive and partial breastfeeding for at least 3 and 12 months, cow's milk intake before 1 year, birth delivery method, and stressful life events were collected during 2009 from 537 patients with psoriasis and 511 controls younger than 18. Overall, patients more frequently reported exposure to environmental tobacco smoke at home and stressful life events in the year preceding the diagnosis than controls. The odds ratios (OR) for smoking and stressful life events were 2.90 (95% confidence interval [CI]=2.27-3.78) and 2.94 (95% CI=2.28-3.79), respectively. In addition, children with psoriasis were more likely to have a higher BMI (>26) than controls (OR=2.52; 95% CI=1.42-4.49). High BMI, environmental tobacco smoke exposure at home, and stressful life events may influence the development of pediatric psoriasis.


Comparison of Molecular Assays for HPV Testing in Oropharyngeal Squamous Cell Carcinomas: A Population-Based Study in Northern Ireland.
Determination of human papillomavirus (HPV) status has become clinically relevant for patient stratification under UICC TNM8 staging. Within the United Kingdom, a combination of p16 IHC and HPV DNA-ISH is recommended for classifying HPV status. This study will assess a series of clinically applicable second-line molecular tests to run in combination with p16 IHC to optimally determine HPV status. The ability of HPV RNA-ISH, HPV DNA-ISH, and HPV DNA-PCR to identify p16-positive/HPV-positive patients was investigated in a population-based oropharyngeal squamous cell carcinoma (OPSCC) cohort of patients diagnosed in Northern Ireland from 2000 to 2011. Only 41% of the Northern Irish OPSCC patient population was associated with HPV-driven carcinogenesis. Both ISH assays were more specific than the DNA-PCR assay (100% and 95% vs. 67%) and were less likely to be affected by preanalytic factors such as increasing block age. A pooled HPV genotype probe for RNA-ISH was found to be the most accurate molecular assay assessed (95% accuracy) when compared with p16 positivity. Our study demonstrates the advantage of tissue-based molecular assays when determining HPV status in retrospective samples. Specifically, we demonstrate the enhanced sensitivity and specificity of ISH techniques compared with PCR-based methodology when working with formalin-fixed paraffin-embedded tissue, and found HPV RNA-ISH to be the most effective assay for determining HPV status. As p16 IHC is a relatively inexpensive, accessible, and sensitive test for stratifying patients by HPV status, this study finds that more patients would benefit from first-line p16 IHC followed by specific HPV testing using HPV RNA-ISH to confirm HPV status.


Effects of maternal alcohol consumption during breastfeeding on motor and cerebellar Purkinje cells behavior in mice.
Purkinje cells (PCs) are the sole output from the cerebellar cortex. Their electrophysiological behavior may serve as indicator of chronic ethanol effects on the cerebellum. Here, we studied the effects of ethanol consumption through breastfeeding on motor behavior, histology and PCs electrophysiology. Mice with different maternal drinking regimen (ethanol, E or sucrose, S) during prenatal (E/and S/) and postnatal period (/E and/S) were compared. Motor performance in the runway and rotarod tests was significantly worse in mice exposed to ethanol prenatally (E/E and E/S) than in mice exposed to sucrose (S/S), with a limited influence, if any, of mother regimen during lactation (E/S vs E/E). A loss of 20-25% of PCs was found for both E/S and E/E compared to S/S mice but PC numbers were similar in S/E and S/S. Mean PC spontaneous simple spike firing rate and rhythmicity were higher in E/S and E/E than in S/S but there was no difference between S/E and S/S. Complex spike frequency was similar in all groups. In contrast, complex spike duration and the related pause induced on the simple spike firing were shorter in E/E and in E/S, but no difference was found between S/E and S/S. We conclude that cerebellar dysfunction induced by maternal ethanol consumption in mice depends upon the drinking regimen during pregnancy and not during lactation.


Sustainable design of high-performance microsized microbial fuel cell with carbon nanotube anode and air cathode.
Microbial fuel cells (MFCs) are a promising alternative energy source that both generates electricity and cleans water. Fueled by liquid wastes such as wastewater or industrial wastes, the microbial fuel cell converts waste into energy. Microsized MFCs are essentially miniature energy harvesters that can be used to power on-chip electronics, lab-on-a-chip devices, and/or sensors. As MFCs are a relatively new technology, microsized MFCs are also an important rapid testing platform for the comparison and introduction of new conditions or materials into macroscale MFCs, especially nanoscale materials that have high potential for enhanced power production. Here we report a 75 μL microsized MFC on silicon using CMOS-compatible processes and employ a novel nanomaterial with exceptional electrochemical properties, multiwalled carbon nanotubes (MWCNTs), as the on-chip anode. We used this device to compare the usage of the more commonly used but highly expensive anode material gold, as well as a more inexpensive substitute, nickel. This is the first anode material study done using the most sustainably designed microsized MFC to date, which utilizes ambient oxygen as the electron acceptor with an air cathode instead of the chemical ferricyanide and without a membrane. Ferricyanide is unsustainable, as the chemical must be continuously refilled, while using oxygen, naturally found in air, makes the device mobile and is a key step in commercializing this for portable technology such as lab-on-a-chip for point-of-care diagnostics. At 880 mA/m(2) and 19 mW/m(2) the MWCNT anode outperformed the others in both current and power densities with between 6 and 20 times better performance. All devices were run for over 15 days, indicating a stable and high-endurance energy harvester already capable of producing enough power for ultra-low-power electronics and able to consistently power them over time.


Treatment of the Mal de Debarquement Syndrome: A 1-Year Follow-up.
The mal de debarquement syndrome (MdDS) is a movement disorder, occurring predominantly in women, is most often induced by passive transport on water or in the air (classic MdDS), or can occur spontaneously. MdDS likely originates in the vestibular system and is unfamiliar to many physicians. The first successful treatment was devised by Dai et al. (1), and over 330 MdDS patients have now been treated. Here, we report the outcomes of 141 patients (122 females and 19 males) treated 1 year or more ago. We examine the patient's rocking frequency, body drifting, and nystagmus. The patients are then treated according to these findings for 4-5 days. During treatment, patients' heads were rolled while watching a rotating full-field visual surround (1). Their symptom severity after the initial treatment and at the follow-up was assessed using a subjective 10-point scale. Objective measures, taken before and at the end of the week of treatment, included static posturography. Significant improvement was a reduction in symptom severity by more than 50%. Objective measures were not possible during the follow-up because of the wide geographic distribution of the patients. The treatment group consisted of 120 classic and 21 spontaneous MdDS patients. The initial rate of significant improvement after a week of treatment was 78% in classic and 48% in spontaneous patients. One year later, significant improvement was maintained in 52% of classic and 48% of spontaneous subjects. There was complete remission of symptoms in 27% (32) of classic and 19% (4) of spontaneous patients. Although about half of them did not achieve a 50% improvement, most reported fewer and milder symptoms than before. The success of the treatment was generally inversely correlated with the duration of the MdDS symptoms and with the patients' ages. Prolonged travel by air or car on the way home most likely contributed to the symptomatic reversion from the initial successful treatment. Our results indicate that early diagnosis and treatment can significantly improve results, and the prevention of symptomatic reversion will increase the long-term benefit in this disabling disorder.


A qualitative study of health care professionals' views and experiences of paediatric advance care planning.
Good end-of-life care planning is vital to ensure optimal care is provided for patients and their families. Two key factors are open and honest advance care planning conversations between the patient (where possible), family, and health care professionals, focusing on exploring what their future wishes are; and the development of an advance care plan document. However, in paediatric and neonatal settings, there has been little research to demonstrate how advance care planning conversations take place. This study explored health care professionals' views and experiences of paediatric advance care planning in hospitals, community settings and hospices. A qualitative methodology was employed using purposive sampling of health care professionals involved in the end-of-life care for children aged 0-18 years known to the hospital palliative care team, and had died at least three months before, but less than 18 months prior to the study. Ethics committee approval was obtained for the study. Located in the North of England, the study involved three hospitals, a children's hospice, and community services. Data were collected using semi-structured, digitally recorded, telephone interviews. All interviews were transcribed verbatim and subjected to thematic analysis. Twenty-one health care professionals participated, including generalist paediatric staff as well as specialist palliative care staff. Two themes were generated from the study: The timing of planning conversations, including waiting for the relationship with the family to form; the introduction of parallel planning; avoiding a crisis situation. Secondly, supporting effective conversations around advance care planning, including where to have the conversation; introducing the conversation; and how to approach the topic encompassing the value of advance care planning and documentation for families. The timing of when to start the advance care planning conversations remains an issue for health care professionals. The value of doing it in stages and considering the environment where the conversations are held was noted. Timely planning was seen as vital to avoid difficult conversations at a crisis point and for co-ordination of care. Good advance care planning is to provide the best person-centred care for the child and experience for the family.


New wheats and social progress.
Will the upward trend in all food production, so dramatically exemplified by the new wheats, be adequate to meet the needs of the growing population? Yes, for a while. No one knows for how long (14). The prophets of doom will undeniably be proved right in the long run unless their basic assumptions are nullified by concrete acts, and soon. At some point in time, either a zero population growth must be achieved or vast new sources of food must be developed, and purchasing power increased. There is nothing on the research horizon to reject "a prodigious need for mankind to practice human husbandry" (12). Our waste products have reached levels that cause major concern, and it may well be that both agricultural and social advancement will be halted by the demands dictated by population growth and the by-products of what now passes for progress but also brings environmental unbalance (15). At least, life will be different, and it may be catastrophic (16, 28). The "Three Ancients" (29) who helped plan and then, after a quarter of a century, reviewed the agricultural research and development work of the Rockefeller Foundation in developing nations concluded:


Electroporation-mediated transcatheter arterial chemoembolization in the rabbit VX2 liver tumor model.
Electropermeabilization involves the application of electrical pulses to increase cell membrane permeability. The purpose of our study was to demonstrate the potential to use electroporation-mediated transcatheter arterial chemoembolization (E-TACE) approaches to increase liver tumor drug uptake while using magnetic resonance imaging (MRI) for intraprocedural optimization of these procedures. Fourteen VX2 tumors were grown in the left hepatic lobes of 8 rabbits. Two tumors were grown in each of 6 rabbits (1 tumor serving as E-TACE-treated tumor and the other as nonelectroporated control), and solitary larger tumors were grown in 2 rabbits (half of the tumor treated with E-TACE, remaining half serving as control). Each rabbit was selectively catheterized under digital subtraction angiography guidance. Baseline MRI was performed to generate tumor contrast enhancement curves following catheter-directed infusion of gadopentetate dimeglumine to estimate the proper time delay between subsequent bolus infusion of cisplatin and application of electrical pulses (electrodes were used to deliver 8, 100-μs, 1300-V pulses at the selected delay interval postinfusion). Three hours after E-TACE, rabbits were euthanized, and tumors were sectioned for inductively coupled plasma mass spectroscopy measurements of platinum concentration (serving as reference standard of cisplatin uptake levels). Inductively coupled plasma mass spectroscopy results demonstrated significantly increased cisplatin uptake in E-TACE-treated tumor tissues, increases of 6.0 ± 3.3-fold compared with transcatheter infusion alone (P = 0.017). Our findings suggest that our E-TACE approach may significantly increase liver tumor drug uptake after targeted transcatheter infusion. MRI measurements permitted intraprocedural guidance during these catheter-directed E-TACE procedures.


Structure, organization, and sequence of alpha satellite DNA from human chromosome 17: evidence for evolution by unequal crossing-over and an ancestral pentamer repeat shared with the human X chromosome.
The centromeric regions of all human chromosomes are characterized by distinct subsets of a diverse tandemly repeated DNA family, alpha satellite. On human chromosome 17, the predominant form of alpha satellite is a 2.7-kilobase-pair higher-order repeat unit consisting of 16 alphoid monomers. We present the complete nucleotide sequence of the 16-monomer repeat, which is present in 500 to 1,000 copies per chromosome 17, as well as that of a less abundant 15-monomer repeat, also from chromosome 17. These repeat units were approximately 98% identical in sequence, differing by the exclusion of precisely 1 monomer from the 15-monomer repeat. Homologous unequal crossing-over is suggested as a probable mechanism by which the different repeat lengths on chromosome 17 were generated, and the putative site of such a recombination event is identified. The monomer organization of the chromosome 17 higher-order repeat unit is based, in part, on tandemly repeated pentamers. A similar pentameric suborganization has been previously demonstrated for alpha satellite of the human X chromosome. Despite the organizational similarities, substantial sequence divergence distinguishes these subsets. Hybridization experiments indicate that the chromosome 17 and X subsets are more similar to each other than to the subsets found on several other human chromosomes. We suggest that the chromosome 17 and X alpha satellite subsets may be related components of a larger alphoid subfamily which have evolved from a common ancestral repeat into the contemporary chromosome-specific subsets.


Building an EEG-fMRI Multi-Modal Brain Graph: A Concurrent EEG-fMRI Study.
The topological architecture of brain connectivity has been well-characterized by graph theory based analysis. However, previous studies have primarily built brain graphs based on a single modality of brain imaging data. Here we develop a framework to construct multi-modal brain graphs using concurrent EEG-fMRI data which are simultaneously collected during eyes open (EO) and eyes closed (EC) resting states. FMRI data are decomposed into independent components with associated time courses by group independent component analysis (ICA). EEG time series are segmented, and then spectral power time courses are computed and averaged within 5 frequency bands (delta; theta; alpha; beta; low gamma). EEG-fMRI brain graphs, with EEG electrodes and fMRI brain components serving as nodes, are built by computing correlations within and between fMRI ICA time courses and EEG spectral power time courses. Dynamic EEG-fMRI graphs are built using a sliding window method, versus static ones treating the entire time course as stationary. In global level, static graph measures and properties of dynamic graph measures are different across frequency bands and are mainly showing higher values in eyes closed than eyes open. Nodal level graph measures of a few brain components are also showing higher values during eyes closed in specific frequency bands. Overall, these findings incorporate fMRI spatial localization and EEG frequency information which could not be obtained by examining only one modality. This work provides a new approach to examine EEG-fMRI associations within a graph theoretic framework with potential application to many topics.


Evaluation of submucosal lesions of the large intestine: part 1. Neoplasms.
At luminal evaluation of the large intestine, any masslike protrusion that is covered by normal mucosa, whether the underlying process is intramural or extramural in origin, may be reported as a submucosal lesion. The full characterization of submucosal lesions may be difficult with optical colonoscopy alone, and endoscopic biopsy is often nondiagnostic. Cross-sectional radiologic imaging studies allow evaluation of the entire thickness of the bowel wall and surrounding tissues and often provide additional information with regard to lesion origin, internal composition, and extent of disease. Likewise, it may be difficult to distinguish submucosal lesions from mucosal polyps on radiologic images, and optical colonoscopy may provide complementary information about superficial submucosal soft-tissue lesions that are detected at computed tomographic (CT) colonography or barium imaging. Depending on the specific clinical situation, colonoscopy, CT colonography, transrectal ultrasonography, and magnetic resonance imaging all may play an important role in the diagnostic evaluation of submucosal lesions of the large intestine. It is important that radiologists be familiar with the multimodality imaging appearances of such entities so that neoplasms--especially those that are malignant--can be accurately identified and characterized and effectively managed.


Toward animal cell culture-based influenza vaccine design: viral hemagglutinin N-glycosylation markedly impacts immunogenicity.
The glycoproteins hemagglutinin (HA) and neuraminidase are the major determinants of host range and tissue tropism of the influenza virus. HA is the most abundant protein in the virus particle membrane and represents the basis of most influenza vaccines. It has been reported that influenza virus HA N-glycosylation markedly depends on the host cell line used for virus production. However, little is known about how differential glycosylation affects immunogenicity of the viral proteins. This is of importance for virus propagation in chicken eggs as well as for innovative influenza vaccine production in mammalian cell lines. In this study, we investigated the impact of the differential N-glycosylation patterns of two influenza A virus PR/8/34 (H1N1) variants on immunogenicity. Madin-Darby canine kidney cell-derived and Vero cell-derived glycovariants were analyzed for immunogenicity in a TCR-HA transgenic mouse model. Next-generation pyrosequencing validated the congruence of the potential HA N-glycosylation sites as well as the presence of the HA peptide recognized by the TCR-HA transgenic T cells. We show that differential HA N-glycosylation markedly affected T cell activation and cytokine production in vitro and moderately influenced IL-2 production in vivo. Cocultivation assays indicated that the difference in immunogenicity was mediated by CD11c(+) dendritic cells. Native virus deglycosylation by endo- and exoglycosidases dramatically reduced cytokine production by splenocytes in vitro and markedly decreased HA-specific Ab production in vivo. In conclusion, this study indicates a crucial importance of HA N-glycosylation for immunogenicity. Our findings have implications for cell line-based influenza vaccine design.


PATIENT PERSPECTIVES ON OBESITY MANAGEMENT: NEED FOR GREATER DISCUSSION OF BMI AND WEIGHT-LOSS OPTIONS BEYOND DIET AND EXERCISE, ESPECIALLY IN PATIENTS WITH DIABETES.
Objective: To identify perceptions of obesity management in patients with and without diabetes. Methods: A 48-question survey was administered in 2018 to our Endocrinology Clinic's adult patients with a body mass index (BMI) ≥30 kg/m2. Chi-squared or Fisher's exact tests were used to compare variables between groups. Results: Of 146 respondents, 105 had diabetes and 41 did not. Most respondents were female (61.4%), African American (66.4%), and with an income <$50,000 (58.6%). Those with diabetes had significantly greater comorbidities of hypertension, high cholesterol, and arthritis. Over 90% in both groups agreed that obesity is related to hypertension, diabetes, heart disease, and early death. Only 48% were aware of their BMI, and only 30.5% with diabetes and 41.5% without diabetes perceived themselves to be obese. Over 60% in each group reported discussion of diet and exercise with their providers, whereas few in both groups reported referral to a formal weight-loss program (18.9%) or to a specialty that manages obesity (4.2%), or discussion of anti-obesity medications (11.2%) or bariatric surgery (8.4%). Reported concerns with anti-obesity medications and bariatric surgery included lack of knowledge and side effects or complications. Conclusion: These findings revealed excellent patient awareness of obesity as a health problem but misperception of obese status and unawareness of BMI. Presence of diabetes and other comorbidities did not result in greater discussion of weight-loss methods beyond diet and exercise. Increased patient education and discussion of specific weight-loss services, anti-obesity medications, and bariatric surgery are needed. Abbreviations: BMI = body mass index; DM = diabetes mellitus; HbA1c = hemoglobin A1c; HCP = healthcare provider.


Spinal deformity in aged zebrafish is accompanied by degenerative changes to their vertebrae that resemble osteoarthritis.
Age-related degenerative changes within the vertebral column are a significant cause of morbidity with considerable socio-economic impact worldwide. An improved understanding of these changes through the development of experimental models may lead to improvements in existing clinical treatment options. The zebrafish is a well-established model for the study of skeletogenesis with significant potential in gerontological research. With advancing age, zebrafish frequently develop gross deformities of their vertebral column, previously ascribed to reduced trunk muscle tone. In this study, we assess degenerative changes specifically within the bone and cartilage of the vertebral column of zebrafish at 1, 2 and 3-years of age. We show increased frequency and severity of spinal deformities/curvatures with age. Underlying the most severe phenotypes are partial or complete vertebral dislocations and focal thickening of the vertebral bone at the joint margins. MicroCT examination demonstrates small defects, fractures and morphological evidence suggestive of bone erosion and remodeling (i.e. osteophytes) within the vertebrae during aging, but no significant change in bone density. Light and electron microscopic examination reveal striking age-related changes in cell morphology, suggestive of chondroptosis, and tissue remodelling of the vertebral cartilage, particularly within the pericellular micro-environment. Glycosaminoglycan analysis of the vertebral column by HPLC demonstrates a consistent, age-related increase in the yield of total chondroitin sulfate disaccharide, but no change in sulfation pattern, supported by immunohistochemical analysis. Immunohistochemistry strongly identifies all three chondroitin/dermatan sulphate isoforms (C-0-S, C-4-S/DS and C-6-S) within the vertebral cartilage, particularly within the pericellular micro-environment. In contrast, keratan sulfate immunolocalises specifically with the notochordal tissue of the intervertebral disc, and its labelling diminishes with age. In summary, these observations raise the prospect that zebrafish, in addition to modelling skeletal development, may have utility in modelling age-related degenerative changes that affect the skeleton during senescence.


Rhythmic gamma stimulation affects bistable perception.
When our brain is confronted with ambiguous visual stimuli, perception spontaneously alternates between different possible interpretations although the physical stimulus remains the same. Both alpha (8-12 Hz) and gamma (>30 Hz) oscillations have been reported to correlate with such spontaneous perceptual reversals. However, whether these oscillations play a causal role in triggering perceptual switches remains unknown. To address this question, we applied transcranial alternating current stimulation (tACS) over the posterior cortex of healthy human participants to boost alpha and gamma oscillations. At the same time, participants were reporting their percepts of an ambiguous structure-from-motion stimulus. We found that tACS in the gamma band (60 Hz) increased the number of spontaneous perceptual reversals, whereas no significant effect was found for tACS in alpha (10 Hz) and higher gamma (80 Hz) frequencies. Our results suggest a mechanistic role of gamma but not alpha oscillations in the resolution of perceptual ambiguity.


Functional assembly of AMPA and kainate receptors is mediated by several discrete protein-protein interactions.
Functional heterogeneity of ionotropic glutamate receptors arises not only from the existence of many subunits and isoforms, but also from combinatorial assembly creating channels with distinct properties. This heteromerization is subtype restricted and thought to be determined exclusively by the proximal extracellular N-terminal domain of the subunits. However, using functional assays for heteromer formation, we show that, besides the N-terminal domain, the membrane sector and the C-terminal part of S2 are critical determinants for the formation of functional channels. Our results are compatible with a model where the N-terminal domain only mediates the initial subunit associations into dimers, whereas for the assembly of the full functional tetramer, compatibility of the other regions is required.


A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi.
Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score <14 of 15), moderate/severe neurological disability (modified Rankin Score >3 of 5) and confusion (Abbreviated Mental Test Score <8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit.


Residents' views of the role of classroom-based learning in graduate medical education through the lens of academic half days.
To examine the role of classroom-based learning in graduate medical education through the lens of academic half days (AHDs) by exploring residents' perceptions of AHDs' purpose and relevance and the effectiveness of teaching and learning in AHDs. The authors invited a total of 186 residents in three programs (internal medicine, orthopedic surgery, and hematology) at the University of British Columbia Faculty of Medicine to participate in semistructured focus groups from October 2010 to February 2011. Verbatim transcripts of the interviews underwent inductive analysis. Twenty-seven residents across the three programs volunteered to participate. Two major findings emerged. Purpose and relevance of AHDs: Residents believed that AHDs are primarily for knowledge acquisition and should complement clinical learning. Classroom learning facilitated consolidation of clinical experiences with expert clinical reasoning. Social aspects of AHDs were highly valued as an important secondary purpose. Perceived effectiveness of teaching and learning: Case-based teaching engaged residents in critical thinking; active learning was valued. Knowledge retention was considered suboptimal. Perspectives on the concept of AHDs as "protected time" varied in the three programs. Findings suggest that (1) engagement in classroom learning occurs through participation in clinically oriented discussions that highlight expert reasoning processes; (2) formal classroom teaching, which focuses on knowledge acquisition, can enhance informal learning occurring during clinical activity; and (3) social aspects of AHDs, including their role in creating communities of practice in residency programs and in professional identity formation, are an important, underappreciated asset for residency programs.


Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction.
Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.


Dexamethasone induces primary amnion epithelial cell senescence through telomere-P21 associated pathway†.
Dexamethasone (Dex), a corticosteroid hormone, is used during the perinatal period to help fetal lung and other organ development. Conversely, Dex-induced cell proliferation has been associated with accelerated aging. Using primary amnion epithelial cells (AECs) from term, not in labor, fetal membranes, we tested the effects of Dex on cell proliferation, senescence, and inflammation. Primary AECs treated with Dex (100 and 200 nM) for 48 h were tested for cell viability (crystal violet dye exclusion), cell cycle progression and/or type of cell death (flow cytometry), expression patterns of steroid receptors (glucocorticoid receptor, progesterone receptor membrane component 1&2), inflammatory mediators (IL-6 and IL-8), and telomere length (quantitative RT-PCR). Mechanistic mediators of senescence (p38MAPK and p21) were determined by western blot analysis. Dex treatment did not induce AEC proliferation, cell cycle, influence viability, or morphology. However, Dex caused dependent telomere length reduction and p38MAPK-independent but p21-dependent (confirmed by treatment with p21 inhibitor UC2288). Senescence was not associated with an increase in inflammatory mediators, which is often associated with senescence. Co-treatment with RU486 produced DNA damage, cell cycle arrest, and cellular necrosis with an increase in inflammatory mediators. The effect of Dex was devoid of changes to steroid receptors, whereas RU486 increased GR expression. Dex treatment of AECs produced nonreplicative and noninflammatory senescence. Extensive use of Dex during the perinatal period may lead to cellular senescence, contributing to cellular aging associated pathologies during the perinatal and neonatal periods.


Identification of microRNA expression patterns and definition of a microRNA/mRNA regulatory network in distinct molecular groups of multiple myeloma.
To date, little evidence of miRNA expression/deregulation in multiple myeloma has been reported. To characterize miRNA in the context of the major multiple myeloma molecular types, we generated miRNA expression profiles of highly purified malignant plasma cells from 40 primary tumors. Furthermore, transcriptional profiles, available for all patients, were used to investigate the occurrence of miRNA/predicted target mRNA pair anticorrelations, and the miRNA and genome-wide DNA data were integrated in a subset of patients to evaluate the influence of allelic imbalances on miRNA expression. Differential miRNA expression patterns were identified, which were mainly associated with the major IGH translocations; particularly, t(4;14) patients showed specific overexpression of let-7e, miR-125a-5p, and miR-99b belonging to a cluster at 19q13.33. The occurrence of other lesions (ie, 1q gain, 13q and 17p deletions, and hyperdiploidy) was slightly characterized by specific miRNA signatures. Furthermore, the occurrence of several allelic imbalances or loss of heterozygosity was found significantly associated with the altered expression of miRNAs located in the involved regions, such as let-7b at 22q13.31 or miR-140-3p at 16q22. Finally, the integrative analysis based on computational target prediction and miRNA/mRNA profiling defined a network of putative functional miRNA-target regulatory relations supported by expression data.


Constructing content validity of clinical nurse specialist core competencies: exploratory sequential mixed-method study.
The demand to increase nursing competence is brought on by the requirement of safe, accessible and more effective use of healthcare provider expertise. Clinical nurse specialist competency development dates back to the late 20th century; however, an examination of the literature reveals a lack of research and discussion to support the competency development. To describe the formulation and validation process of the clinical nurse specialist core competencies. Exploratory sequential mixed-method design. This mixed-method study, conducted between 2013 and 2017 in Finland, involved four phases: I) a Policy Delphi study (n = 25, n = 22, n = 19); II) cross-mapping of preliminary competency criteria against international competency sets; III) content validity study of expanded competency criteria (n = 7, n = 10); and IV) verification of competency criteria with practicing CNSs (n = 16). Data were analysed by both qualitative and quantitative analysis methods. Seventy-four preliminary clinical nurse competency criteria were formulated in the first phase of the study. Through cross-mapping the competencies against the US and Canadian clinical nurse specialist competency sets, they were further concised to 61 criteria. The examination of Content Validity Indexes and experts' comments led to the clarification and consequent inclusion of 50 criteria to the final scale, with Scale Content Validity Index Average of 0.94. The competency criteria were evaluated to be a solid set with potential to clarify and uniform the clinical nurse specialist roles. Through a rigorous research process, validated clinical nurse specialist competency criteria were formed with a high Scale Content Validity Index Average. The results allude to the potential of formulating international competency criteria to support global role clarity and understanding. However, further research is needed to validate the content and construct of the formulated competencies with a larger population across countries.


Adrenergic influence of uterine muscle contractions stimulated by a glycoside from the root of Dalbergia saxatilis.
The mechanism of uterine muscle contraction stimulated by a triterpenoid glycoside (dalsaxin) isolated from the root of D. saxatilis was investigated by in vitro methods in the rat. Dalsaxin caused a dose-related increase in uterine muscle contraction. The contraction was single and transient and was abolished by moderate doses of isoprenaline (1.80 nmol-0.40 mumol) and salbutamol (0.13-25 mumol). Adrenaline (9.10 nmol) also caused a reversible decrease (92.6%; P < 0.01) in myometrial contraction stimulated by this glycoside (0.24 mg/ml). Uterine muscle responses to dalsaxin (0.24 mg/ml) were enhanced by the beta-adrenergic receptor antagonist, propranolol, in a dose related manner. Atipamezole (1.50 ng/ml) but not prazosin (7.72 nmol-15.60 nmol) substantially reduced (80%; P < 0.01) myometrial contractions induced by this uterine spasmogen. The results suggest that dalsaxin enhances uterine muscle contraction by stimulating post junctional alpha 2-adrenergic receptors, presumably by inhibiting plasma membrane adenylate cyclase system and its associated increase in intracellular cAMP content.


Neural Profile of Callous Traits in Children: A Population-Based Neuroimaging Study.
Callous traits during childhood, e.g., lack of remorse and shallow affect, are a key risk marker for antisocial behavior. Although callous traits have been found to be associated with structural and functional brain alterations, evidence to date has been almost exclusively limited to small, high-risk samples of boys. We characterized gray and white matter brain correlates of callous traits in over 2000 children from the general population. Data on mother-reported callous traits and brain imaging were collected at age 10 years from participants of the Generation R Study. Structural magnetic resonance imaging was used to investigate brain morphology using volumetric indices and whole-brain analyses (n = 2146); diffusion tensor imaging was used to assess global and specific white matter microstructure (n = 2059). Callous traits were associated with lower global brain (e.g., total brain) volumes as well as decreased cortical surface area in frontal and temporal regions. Global mean diffusivity was negatively associated with callous traits, suggesting higher white matter microstructural integrity in children with elevated callous traits. Multiple individual tracts, including the uncinate and cingulum, contributed to this global association. Whereas no gender differences were observed for global volumetric indices, white matter associations were present only in girls. This is the first study to provide a systematic characterization of the structural neural profile of callous traits in the general pediatric population. These findings extend previous work based on selected samples by demonstrating that childhood callous traits in the general population are characterized by widespread macrostructural and microstructural differences across the brain.


Advances in hematopoietic stem cell transplantation in the Asia-Pacific region: the second report from APBMT 2005-2015.
Between 2005 and 2015, 138,165 hematopoietic stem cell transplantation (HSCT) were reported in 18 countries/regions in the Asia-Pacific region. In this report, we describe current trends in HSCT throughout the Asia-Pacific region and differences among nations in this region and various global registries. Since 2008, more than 10,000 HSCTs have been recorded each year by the Asia-Pacific Blood and Marrow Transplantation Group Data Center. Between 2005 and 2015, the greatest increase in the number of HSCTs was observed in Vietnam. Allogeneic HSCT was performed more frequently than autologous HSCT, and a majority of cases involved related donors. Regarding allogeneic HSCT, the use of cord blood has remained steady, especially in Japan, and the number of cases involving related HLA non-identical donors has increased rapidly, particularly in China. The incidence of hemoglobinopathy, a main indication for allogeneic HSCT in India, China, Iran, and Pakistan, increased nearly six-fold over the last decade. Among the 18 participating countries/regions, the transplant rate per population varied widely according to the absolute number of HSCTs and the national/regional population size. We believe that this report will not only benefit the AP region but will also provide information about HSCT to other regions worldwide.


Interventions for treating depression after stroke.
Depression is an important consequence of stroke that impacts on recovery yet is often not detected or inadequately treated. This is an update of a Cochrane review first published in 2004. To determine whether pharmaceutical, psychological, or electroconvulsive treatment (ECT) of depression in patients with stroke can improve outcome. We searched the trials registers of the Cochrane Stroke Group (last searched October 2007) and the Cochrane Depression Anxiety and Neurosis Group (last searched February 2008). In addition, we searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2008), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), CINAHL (1982 to May 2006), PsycINFO (1967 to May 2006) and other databases. We also searched reference lists, clinical trials registers, conference proceedings and dissertation abstracts, and contacted authors, researchers and pharmaceutical companies. Randomised controlled trials comparing pharmaceutical agents with placebo, or various forms of psychotherapy or ECT with standard care (or attention control), in patients with stroke, with the intention of treating depression. Two review authors selected trials for inclusion and assessed methodological quality; three review authors extracted, cross-checked and entered data. Primary analyses were the prevalence of diagnosable depressive disorder at the end of treatment. Secondary outcomes included depression scores on standard scales, physical function, death, recurrent stroke and adverse effects. Sixteen trials (17 interventions), with 1655 participants, were included in the review. Data were available for 13 pharmaceutical agents, and four trials of psychotherapy. There were no trials of ECT. The analyses were complicated by the lack of standardised diagnostic and outcome criteria, and differing analytic methods. There was some evidence of benefit of pharmacotherapy in terms of a complete remission of depression and a reduction (improvement) in scores on depression rating scales, but there was also evidence of an associated increase in adverse events. There was no evidence of benefit of psychotherapy. A small but significant effect of pharmacotherapy (not psychotherapy) on treating depression and reducing depressive symptoms was found, as was a significant increase in adverse events. More research is required before recommendations can be made about the routine use of such treatments.


Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.
Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. Canadian Institutes of Health Research.


Characterizing the epidemiological transition in Mexico: national and subnational burden of diseases, injuries, and risk factors.
Rates of diseases and injuries and the effects of their risk factors can have substantial subnational heterogeneity, especially in middle-income countries like Mexico. Subnational analysis of the burden of diseases, injuries, and risk factors can improve characterization of the epidemiological transition and identify policy priorities. We estimated deaths and loss of healthy life years (measured in disability-adjusted life years [DALYs]) in 2004 from a comprehensive list of diseases and injuries, and 16 major risk factors, by sex and age for Mexico and its states. Data sources included the vital statistics, national censuses, health examination surveys, and published epidemiological studies. Mortality statistics were adjusted for underreporting, misreporting of age at death, and for misclassification and incomparability of cause-of-death assignment. Nationally, noncommunicable diseases caused 75% of total deaths and 68% of total DALYs, with another 14% of deaths and 18% of DALYs caused by undernutrition and communicable, maternal, and perinatal diseases. The leading causes of death were ischemic heart disease, diabetes mellitus, cerebrovascular disease, liver cirrhosis, and road traffic injuries. High body mass index, high blood glucose, and alcohol use were the leading risk factors for disease burden, causing 5.1%, 5.0%, and 7.3% of total burden of disease, respectively. Mexico City had the lowest mortality rates (4.2 per 1,000) and the Southern region the highest (5.0 per 1,000); under-five mortality in the Southern region was nearly twice that of Mexico City. In the Southern region undernutrition and communicable, maternal, and perinatal diseases caused 23% of DALYs; in Chiapas, they caused 29% of DALYs. At the same time, the absolute rates of noncommunicable disease and injury burdens were highest in the Southern region (105 DALYs per 1,000 population versus 97 nationally for noncommunicable diseases; 22 versus 19 for injuries). Mexico is at an advanced stage in the epidemiologic transition, with the majority of the disease and injury burden from noncommunicable diseases. A unique characteristic of the epidemiological transition in Mexico is that overweight and obesity, high blood glucose, and alcohol use are responsible for larger burden of disease than other noncommunicable disease risks such as tobacco smoking. The Southern region is least advanced in the epidemiological transition and suffers from the largest burden of ill health in all disease and injury groups.


Study of antibacterial mechanism of graphene oxide using Raman spectroscopy.
Graphene oxide (GO) is extensively proposed as an effective antibacterial agent in commercial product packaging and for various biomedical applications. However, the antibacterial mode of action of GO is yet hypothetical and unclear. Here we developed a new and sensitive fingerprint approach to study the antibacterial activity of GO and underlying mechanism, using Raman spectroscopy. Spectroscopic signatures obtained from biomolecules such as Adenine and proteins from bacterial cultures with different concentrations of GO, allowed us to probe the antibacterial activity of GO with its mechanism at the molecular level. Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) were used as model micro-organisms for all the experiments performed. The observation of higher intensity Raman peaks from Adenine and proteins in GO treated E. coli and E. faecalis; correlated with induced death, confirmed by Scanning electron Microscopy (SEM) and Biological Atomic Force Microscopy (Bio-AFM). Our findings open the way for future investigations of the antibacterial properties of different nanomaterial/GO composites using Raman spectroscopy.


Combating Ebola with Repurposed Therapeutics Using the CANDO Platform.
Ebola virus disease (EVD) is extremely virulent with an estimated mortality rate of up to 90%. However, the state-of-the-art treatment for EVD is limited to quarantine and supportive care. The 2014 Ebola epidemic in West Africa, the largest in history, is believed to have caused more than 11,000 fatalities. The countries worst affected are also among the poorest in the world. Given the complexities, time, and resources required for a novel drug development, finding efficient drug discovery pathways is going to be crucial in the fight against future outbreaks. We have developed a Computational Analysis of Novel Drug Opportunities (CANDO) platform based on the hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for rapid therapeutic repurposing and discovery. We used the CANDO platform to identify and rank FDA-approved drug candidates that bind and inhibit all proteins encoded by the genomes of five different Ebola virus strains. Top ranking drug candidates for EVD treatment generated by CANDO were compared to in vitro screening studies against Ebola virus-like particles (VLPs) by Kouznetsova et al. and genetically engineered Ebola virus and cell viability studies by Johansen et al. to identify drug overlaps between the in virtuale and in vitro studies as putative treatments for future EVD outbreaks. Our results indicate that integrating computational docking predictions on a proteomic scale with results from in vitro screening studies may be used to select and prioritize compounds for further in vivo and clinical testing. This approach will significantly reduce the lead time, risk, cost, and resources required to determine efficacious therapies against future EVD outbreaks.


Comparison of total mercury and methylmercury cycling at five sites using the small watershed approach.
The small watershed approach is well-suited but underutilized in mercury research. We applied the small watershed approach to investigate total mercury (THg) and methylmercury (MeHg) dynamics in streamwater at the five diverse forested headwater catchments of the US Geological Survey Water, Energy, and Biogeochemical Budgets (WEBB) program. At all sites, baseflow THg was generally less than 1ng L(-1) and MeHg was less than 0.2ng L(-1). THg and MeHg concentrations increased with streamflow, so export was primarily episodic. At three sites, THg and MeHg concentration and export were dominated by the particulate fraction in association with POC at high flows, with maximum THg (MeHg) concentrations of 94 (2.56)ng L(-1) at Sleepers River, Vermont; 112 (0.75)ng L(-1) at Rio Icacos, Puerto Rico; and 55 (0.80)ng L(-1) at Panola Mt., Georgia. Filtered (<0.7microm) THg increased more modestly with flow in association with the hydrophobic acid fraction (HPOA) of DOC, with maximum filtered THg concentrations near 5ng L(-1) at both Sleepers and Icacos. At Andrews Creek, Colorado, THg export was also episodic but was dominated by filtered THg, as POC concentrations were low. MeHg typically tracked THg so that each site had a fairly constant MeHg/THg ratio, which ranged from near zero at Andrews to 15% at the low-relief, groundwater-dominated Allequash Creek, Wisconsin. Allequash was the only site with filtered MeHg consistently above detection, and the filtered fraction dominated both THg and MeHg. Relative to inputs in wet deposition, watershed retention of THg (minus any subsequent volatilization) was 96.6% at Allequash, 60% at Sleepers, and 83% at Andrews. Icacos had a net export of THg, possibly due to historic gold mining or frequent disturbance from landslides. Quantification and interpretation of Hg dynamics was facilitated by the small watershed approach with emphasis on event sampling.


Identification of the antibiotic hops component, colupulone, as an inducer of hepatic cytochrome P-4503A in the mouse.
A higher level of cytochrome P-450 (P450)-dependent ethylmorphine (EM) N-demethylase activity was observed in hepatic microsomes from mice fed a natural-ingredient diet ("crude diet") than in those from mice fed a semi-purified diet ("purified diet"). This led to the testing of individual ingredients of the crude diet as inducers of the P-450 system. Brewers yeast proved to be the most significant inductive component of the crude diet. Further investigation revealed that hop components (lupulones) absorbed on yeast during the brewing process were responsible for the induction of the P-450 system. The induction of P-450 and several P-450-dependent monooxygenase activities (EM N-demethylation, aniline hydroxylation, benzo[a]pyrene hydroxylation) by colupulone with respect to dose and time course were investigated. The very large increase in EM N-demethylase activity elicited by colupulone suggested that P-4503A had been induced. Western blot technology verified this speculation. Western blot analysis of microsomal protein from mice fed hops, brewers yeast, or the residue of a hexane extract of hops supported the conclusion that all of these substances induced P-4503A. These substances were also relatively good inducers of P-4502B, but not as inductive of this isozyme as the crude diet. This is interpreted to mean that not all of the inductive properties of the crude diet are due to hop components. These studies question the use of crude commercial diets in studies of P-450 systems. They may also challenge some current definitions of "constitutive" and "induced" P-450s.


Assessing the predictability of nonlinear dynamics under smooth parameter changes.
Short-term forecasts of nonlinear dynamics are important for risk-assessment studies and to inform sustainable decision-making for physical, biological and financial problems, among others. Generally, the accuracy of short-term forecasts depends upon two main factors: the capacity of learning algorithms to generalize well on unseen data and the intrinsic predictability of the dynamics. While generalization skills of learning algorithms can be assessed with well-established methods, estimating the predictability of the underlying nonlinear generating process from empirical time series remains a big challenge. Here, we show that, in changing environments, the predictability of nonlinear dynamics can be associated with the time-varying stability of the system with respect to smooth changes in model parameters, i.e. its local structural stability. Using synthetic data, we demonstrate that forecasts from locally structurally unstable states in smoothly changing environments can produce significantly large prediction errors, and we provide a systematic methodology to identify these states from data. Finally, we illustrate the practical applicability of our results using an empirical dataset. Overall, this study provides a framework to associate an uncertainty level with short-term forecasts made in smoothly changing environments.


Contact allergy to neomycin sulfate: results of a multifactorial analysis.
To perform a comprehensive, multifactorial analysis of potential risk factors (demographic and clinical) for contact allergy to neomycin sulfate, a common adverse reaction resulting from the topical use of this drug; especially in some subgroups of the population. Retrospective analysis of allergy test data of the Information Network of Departments of Dermatology (IVDK, www.ivdk.org) between 1998 and 2003, including all patients patch tested with a standard screening series because of suspected allergic contact dermatitis (ACD). As one outcome, a positive (allergic) test reaction to neomycin sulfate was considered. An alternative outcome included only those patients with a positive test to neomycin sulfate and a final diagnosis of ACD. The association between outcome and potential risk factors was analyzed with Poisson regression analysis, deriving prevalence ratios (PR) as risk estimates. Of the 47,559 patients tested, 2.5% had positive reactions to neomycin sulfate, while in 1.1% ACD was additionally diagnosed. The results of the multifactorial analysis indicated that the risk of both outcomes decreased slightly during the period covered; was higher among patients with leg dermatitis; varied significantly with age and increased progressively with the number of additional positive reactions to other standard series allergens. Cross-reactivity to other, selectively tested, aminoglycoside antibiotics was substantial (kappa = 0.67; 95%CI: 0.63-0.71) for framycetin sulfate, to low (kappa = 0.33; 95%CI: 0.27-0.37) for gentamicin sulfate. The prevalence of contact sensitization to neomycin sulfate was noteworthy among patients patch tested in the IVDK centers. Supplementing clinical epidemiology, neomycin contact allergy has been estimated to be relatively common even on the level of the unselected population (prevalence approx. 1%). Hence, the topical use of neomycin sulfate by patients should be carefully monitored, considering its potential to induce ACD, with emphasis on subgroups at risk.


Modulation by general anaesthetics of rat GABAA receptors comprised of alpha 1 beta 3 and beta 3 subunits expressed in human embryonic kidney 293 cells.
1. Radioligand binding and patch-clamp techniques were used to study the actions of gamma-aminobutyric acid (GABA) and the general anaesthetics propofol (2,6-diisopropylphenol), pentobarbitone and 5 alpha-pregnan-3 alpha-ol-20-one on rat alpha 1 and beta 3 GABAA receptor subunits, expressed either alone or in combination. 2. Membranes from HEK293 cells after transfection with alpha 1 cDNA did not bind significant levels of [35S]-tert-butyl bicyclophosphorothionate ([35S]-TBPS) (< 0.03 pmol mg-1 protein). GABA (100 microM) applied to whole-cells transfected with alpha 1 cDNA and clamped at -60 mV, also failed to activate discernible currents. 3. The membranes of cells expressing beta 3 cDNAs bound [35S]-TBPS (approximately 1 pmol mg-1 protein). However, the binding was not influenced by GABA (10 nM-100 microM). Neither GABA (100 microM) nor picrotoxin (10 microM) affected currents recorded from cells expressing beta 3 cDNA, suggesting that beta 3 subunits do not form functional GABAA receptors or spontaneously active ion channels. 4. GABA (10 nM-100 microM) modulated [35S]-TBPS binding to the membranes of cells transfected with both alpha 1 and beta 3 cDNAs. GABA (0.1 microM-1 mM) also dose-dependently activated inward currents with an EC50 of 9 microM recorded from cells transfected with alpha 1 and beta 3 cDNAs, clamped at -60 mV. 5. Propofol (10 nM-100 microM), pentobarbitone (10 nM-100 microM) and 5 alpha-pregnan-3 alpha-ol-20-one (1 nM-30 microM) modulated [35S]-TBPS binding to the membranes of cells expressing either alpha 1 beta 3 or beta 3 receptors. Propofol (100 microM), pentobarbitone (1 mM) and 5 alpha-pregnan-3 alpha-ol-20-one (10 microM) also activated currents recorded from cells expressing alpha 1 beta 3 receptors. 6. Propofol (1 microM-1 mM) and pentobarbitone (1 mM) both activated currents recorded from cells expressing beta 3 homomers. In contrast, application of 5 alpha-pregnan-3 alpha-ol-20-one (10 microM) failed to activate detectable currents. 7. Propofol (100 microM)-activated currents recorded from cells expressing either alpha 1 beta 3 or beta 3 receptors reversed at the Cl- equilibrium potential and were inhibited to 34 +/- 13% and 39 +/- 10% of control, respectively, by picrotoxin (10 microM). 5 alpha-Pregnan-3 alpha-ol-20-one (100 nM) enhanced propofol (100 microM)-evoked currents mediated by alpha 1 beta 3 receptors to 1101 +/- 299% of control. In contrast, even at high concentration 5 alpha-pregnan-3 alpha-ol-20-one (10 microM) caused only a modest facilitation (to 128 +/- 12% of control) of propofol (100 microM)-evoked currents mediated by beta 3 homomers. 8. Propofol (3-100 microM) activated alpha 1 beta 3 and beta 3 receptors in a concentration-dependent manner. For both receptor combinations, higher concentrations of propofol (300 microM and 1 mM) caused a decline in current amplitude. This inhibition of receptor function reversed rapidly during washout resulting in a "surge' current on cessation of propofol (300 microM and 1 mM) application. Surge currents were also evident following pentobarbitone (1 mM) application to cells expressing either receptor combination. By contrast, this phenomenon was not apparent following applications of 5 alpha-pregnan-3 alpha-ol-20-one (10 microM) to cells expressing alpha 1 beta 3 receptors. 9. These observations demonstrate that rat beta 3 subunits form homomeric receptors that are not spontaneously active, are insensitive to GABA and can be activated by some general anaesthetics. Taken together, these data also suggest similar sites on GABAA receptors for propofol and barbiturates, and a separate site for the anaesthetic steroids.


Interventions for preventing neuropathy caused by cisplatin and related compounds.
Cisplatin and several related antineoplastic drugs used to treat many types of solid tumours are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought. To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs. On 4 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and CINAHL Plus for randomised trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related drugs among human patients. We included randomised controlled trials (RCTs) or quasi-RCTs in which the participants received chemotherapy with cisplatin or related compounds, with a potential chemoprotectant (acetylcysteine, amifostine, adrenocorticotrophic hormone (ACTH), BNP7787, calcium and magnesium (Ca/Mg), diethyldithiocarbamate (DDTC), glutathione, Org 2766, oxcarbazepine, or vitamin E) compared to placebo, no treatment, or other treatments. We considered trials in which participants underwent evaluation zero to six months after completing chemotherapy using quantitative sensory testing (the primary outcome) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary outcomes). Two review authors assessed each study, extracted the data and reached consensus, according to standard Cochrane methodology. As of 2013, the review includes 29 studies describing nine possible chemoprotective agents, as well as description of two published meta-analyses. Among these trials, there were sufficient data in some instances to combine the results from different studies, most often using data from secondary non-quantitative measures. Nine of the studies were newly included at this update. Few of the included studies were at a high risk of bias overall, although often there was too little information to make an assessment. At least two review authors performed a formal review of an additional 44 articles but we did not include them in the final review for a variety of reasons.Of seven eligible amifostine trials (743 participants in total), one used quantitative sensory testing (vibration perception threshold) and demonstrated a favourable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Furthermore the change measured was subclinical. None of the three eligible Ca/Mg trials (or four trials if a single retrospective study was included) described our primary outcome measures. The four Ca/Mg trials included a total of 886 participants. Of the seven eligible glutathione trials (387 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing but reported disparate results; meta-analyses of three of these trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. Similarly, none of the three eligible vitamin E trials (246 participants) reported quantitative sensory testing. The eligible single trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), oxcarbazepine (32 participants), and retinoic acid (92 participants) did not perform quantitative sensory testing. In all, this review includes data from 2906 participants. However, only seven trials reported data for the primary outcome measure of this review, (quantitative sensory testing) and only nine trials reported our objective secondary measure, nerve conduction test results. Additionally, methodological heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) ≥ 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766).Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity. At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results were negative and did not support the positive findings based on the qualitative measures. In summary, the present studies are limited by the small number of participants receiving any particular agent, a lack of objective measures of neuropathy, and differing results among similar trials, which make it impossible to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs.


Barriers to the use of medications to treat alcoholism.
In 1994, naltrexone became the first medication approved by the Food and Drug Administration as an adjunct in alcoholism treatment in almost fifty years. Despite evidence of its efficacy, use of naltrexone is not widespread. Patient and physician focus groups were used to identify reasons naltrexone has not been prescribed more widely. Barriers to its widespread use include a lack of awareness, a lack of evidence of efficacy in practice, side effects, time for patient management, a reluctance to take medications, medication addiction concerns, Alcoholics Anonymous (AA) philosophy, and price. The study indicates that medications to treat alcoholism must overcome numerous barriers before becoming widely accepted.


Tailoring water stability of cellulose nanopaper by surface functionalization.
Cellulose nanopaper (CNP) features appealing properties, including transparency, flatness, a low thermal expansion coefficient and thermal stability, often outperforming conventional paper. However, free-standing crystalline cellulose films usually swell in water or upon moisture sorption, compromising part of their outstanding properties. This remains a major problem whenever working in a water environment is required. Freestanding cellulose nanopaper is prepared by solution casting water suspensions of cellulose nanocrystals with an average width of 10 nm and an average aspect ratio of 28, isolated from Avicel by acid hydrolysis and extensively characterized by AFM and FE-SEM measurements and GPC detection of their degree of polymerization. We demonstrate by elemental analyses, FT-IR, Raman spectroscopy, XRD measurements and water contact angle detection that wet treatment with lauroyl chloride results in surface hydrophobization of nanopaper. The hydrophobized nanopaper, C12-CNP, shows a more compact surface morphology than the starting CNP, due to the effect of chemical functionalization, and presents enhanced resistance to water, as assessed by electrochemical permeation experiments. The new hydrophobized nanopaper is a promising substrate for thin film devices designed to work in a humid environment.


First Report of Sweet potato virus G Infecting Sweet Potato in Taiwan.
Sweet potato, Ipomoea batatas (L.) Lam., is an important root crop grown mainly in the counties of Changhua, Yunlin, Tainan, and Pingtung in Taiwan where Sweet potato feathery mottle virus (SPFMV) and Sweet potato latent virus (SPLV) have been reported. Commercial sweet potato grown in Nantou in 2009 and in Hualian in 2010 exhibited downward leaf curling and vein clearing, indicative of viral infection, yet symptoms were distinct from those caused by SPFMV, SPLV, or mixed infection of both viruses. Total RNA was extracted from two symptomatic plants from each county with RNeasy Plant Mini Kit (Qiagen, Hilden, Germany) and analyzed by reverse transcription (RT)-PCR using the potyvirusdegenerate primer Hrp5 (1) and oligo-dT18 with BamHI site at the 5' end (5'-GGATCCTTTTTTTTTTTTTTTTTT-3'). Two healthy plants served as negative controls. An approximately 1.5-kb amplicon covering the region from the 3'-end of the nuclear inclusion protein b (NIb) gene to the 3'-untranslated region (3'-UTR) was amplified from all symptomatic plants, while the healthy controls remained negative. Subsequently, one sample from each location was cloned and sequenced (GenBank Accession No. HQ171932-TW1 [Nantou] and JN205346-TW2 [Hualian]). Based on sequence comparison, the two isolates shared only 86.7% nucleotide identity. BLAST analysis of the CP gene of the isolate TW1 revealed 99% nucleotide identity with the corresponding sequence of Sweet potato virus G (SPVG)-CH2 from China (Z83314). Isolate TW2, however, only shared 86% nucleotide identity with SPVG-CH2, indicating isolate TW2 is genetically different from other isolates and probably represents a new strain of SPVG. The presence of SPVG was further confirmed in symptomatic plants by indirect ELISA using SPVG antiserum developed by Y.-H. Cheng of the Agricultural Research Institute. Since co-infection of different viruses in sweet potato can cause severe leaf symptoms and significant yield reduction (3), a preliminary field survey was also conducted to determine the extent of co-infection with more than one potyvirus using three different primer pairs, SPVGup (5'-ACCGAGCTTTACCCCAGGTAGAGAG-3')/SPVdw (5'-CGCGCAAGACTCATRTCAGTCAAAT-3') for SPVG, FM16 (5'-GAATTTAAAGATGCAGGTGTGAAC-3')/FM895 (5'-GAGGTTATGTATATTTCTAGTAAC-3') for SPFMV, and L166 (5'-GACAGAGATATCAACACTGGCACC-3')/L841 (5'-TCCAAGTAGTGTGTGTATGTTCCG-3') for SPLV. Forty-six of 128 (36%) sweet potato samples collected from Nantou, Hualian, Yunlin, Tainan, and Chiayi counties during 2010 and 2011 tested positive for SPVG. Of the 46 samples that tested positive for SPVG, six were co-infected with SPLV, 19 were co-infected with SPFMV, and two were co-infected with all three viruses. Of the samples that tested negative for SPVG, 10 were infected with SPLV, eight were infected with SPFMV, and two were infected with both SPLV and SPFMV. To date, SPVG has been detected in China, the United States, Peru, Egypt, Ethiopia, Zimbabwe, South Africa, Spain, Java, New Zealand, Hawaii, French Polynesia, and Easter Island (2). To our knowledge, this is the first report of SPVG infecting sweet potato in Taiwan. SPVG could become a new and potentially serious threat to sweet potato production in Taiwan. References: (1) C. C. Chen et al. Bot. Stud. 47:369, 2006. (2) M. Rännäli et al. Plant Dis. 92:1313, 2008. (3) M. Untiveros et al. Plant Dis. 91:669, 2007.


Tuning heterogeneous poly(dopamine) structures and mechanics: in silico covalent cross-linking and thin film nanoindentation.
Mussel-inspired synthetic poly(dopamine) thin films from dihydroxyphenylalanine (DOPA) and lysine, structurally similar to natural melanin, have drawn extensive interest as a versatile surface functionalization and coating material for use in a broad range of applications. In order to gain a better understanding of its complex and heterogeneous polymeric structure and mechanical properties, we report a computational model of poly(dopamine) by mimicking the polymerization process of the intermediate oxidized product of dopamine, 5,6-dihydroxyindole (DHI), via controlled in silico covalent cross-linking under the two most possible reaction schemes proposed in experiments. To validate our results using experiment, we synthesize poly(dopamine) thin films and perform experimental nanoindentations on the film. We observe an overall linear behavior for Young's modulus as a function of the degree of cross-linking, demonstrating the possibility of enhancing the mechanical robustness of poly(dopamine) materials by increasing the extent of polymerization. At the highest degree of polymerization considered (70%), the model mimics the linear tetrameric model for poly(dopamine) and melanin. At this degree of polymerization, we find a Young's modulus of 4.1-4.4 GPa, in agreement with our nanoindentation results of 4.3-10.5 GPa, previous experiments for natural melanin, as well as simulation results for the cyclic tetrameric melanin model (Chen et al., ACS Nano, 2013). Our results suggest that the non-covalent DHI aggregate model might not be appropriate to represent the structure of poly(dopamine) and melanin-like materials, since it gives a much smaller Young's modulus than the experimental lower bound. Our model not only nicely complements the previous computational work, but also provides new computational tools to study the heterogeneous structural and physicochemical properties of poly(dopamine) and melanin, as well as their formation pathways.


Influence of left ventricular dysfunction on flecainide therapy.
Seventy-six patients with ventricular tachyarrhythmias (40 sustained and 36 nonsustained) were treated with oral flecainide. Radionuclide left ventricular ejection fraction was 30% or less in 33 patients and greater than 30% in 43 patients. Before flecainide, compensated heart failure was present in 23 patients (ejection fraction less than or equal to 30% in 15 and greater than 30% in 8). Flecainide mean dose was 150 mg twice daily and mean plasma concentration was 720 ng/ml. New or worsened congestive heart failure occurred in seven patients on flecainide therapy, all with an ejection fraction of less than 30%; six had a previous history of compensated heart failure and of these, three died. Ejection fraction was the only independent variable that significantly influenced efficacy and tolerance of flecainide. After 1 year of therapy, efficacy and tolerance was 58% (25 of 43) in patients with an ejection fraction greater than 30% and 12% (4 of 33) in patients with an ejection fraction of 30% or less (p less than 0.001). Thus, congestive heart failure can occur during flecainide therapy, particularly in patients with a previous history of congestive heart failure and ejection fraction of less than 30%, and may particularly limit therapy in these patients. Clinical efficacy and tolerance were significantly lower in patients with an ejection fraction of less than 30%.


Predictors of microbial agents in dust and respiratory health in the Ecrhs.
Dampness and mould exposure have been repeatedly associated with respiratory health. However, less is known about the specific agents provoking or arresting health effects in adult populations. We aimed to assess predictors of microbial agents in mattress dust throughout Europe and to investigate associations between microbial exposures, home characteristics and respiratory health. Seven different fungal and bacterial parameters were assessed in mattress dust from 956 adult ECRHS II participants in addition to interview based home characteristics. Associations between microbial parameters and the asthma score and lung function were examined using mixed negative binomial regression and linear mixed models, respectively. Indoor dampness and pet keeping were significant predictors for higher microbial agent concentrations in mattress dust. Current mould and condensation in the bedroom were significantly associated with lung function decline and current mould at home was positively associated with the asthma score. Higher concentrations of muramic acid were associated with higher mean ratios of the asthma score (aMR 1.37, 95%CI 1.17-1.61). There was no evidence for any association between fungal and bacterial components and lung function. Indoor dampness was associated with microbial levels in mattress dust which in turn was positively associated with asthma symptoms.