Comparison of different solar reactors for household disinfection of drinking water in developing countries: evaluation of their efficacy in relation to the waterborne enteropathogen Cryptosporidium parvum.
Solar water disinfection (SODIS) is a type of treatment that can significantly improve the microbiological quality of drinking water at household level and therefore prevent waterborne diseases in developing countries. Cryptosporidium parvum is an obligate protozoan parasite responsible for the diarrhoeal disease cryptosporidiosis in humans and animals. Recently, this parasite has been selected by the WHO as a reference pathogen for protozoan parasites in the evaluation of household water treatment options. In this study, the field efficacy of different static solar reactors [1.5 l transparent plastic polyethylene terephthalate (PET) bottles as well as 2.5 l borosilicate glass and 25 l methacrylate reactors fitted with compound parabolic concentrators (CPC)] for solar disinfection of turbid waters experimentally contaminated with C. parvum oocysts was compared. Potential oocyst viability was determined by inclusion/exclusion of the fluorogenic vital dye propidium iodide. The results demonstrate that static solar reactors fitted with CPCs are an excellent alternative to the conventional SODIS method with PET bottles. These reactors improved the efficacy of the SODIS method by enabling larger volumes of water to be treated and, in some cases, the C. parvum oocysts were rendered totally unviable, minimising the negative effects of turbidity.


Enhancing the Velocity Data From 4D Flow MR Images by Reducing its Divergence.
Velocity measurements from 4D flow MRI are prone to be affected by several imperfections of the MR system. Assuming that blood is incompressible, we propose a novel method for enhancing the velocity field by reducing its divergence. To enhance the velocity data, we added a corrector velocity to each voxel such that the divergence is minimized. The method was validated using an analytical Womersley flow model for different settings of resolution and noise levels. The performance of the proposed method was also assessed in volunteers and patients. Results demonstrated a significant reduction of the divergence depending on the size of the regularization term, obtaining a reduction close to 50% of the mean divergence with negligible modification of flow parameters. Remarkably, we found that the reduction of the divergence, in percentage, was independent of volunteers, resolution or noise.


trans-Bis(diethanolamine-N,O)bis(saccharinato-N)cadmium(II).
The structure of the title complex consists of isolated [Cd(C7H4NO3S)2(C4H11NO2)2] units. The Cd2+ cation lies on an inversion centre and is octahedrally coordinated by two N,O-bidentate diethanolamine (dea) and two N-bonded saccharinate (sac) ligands [saccharin is 1,2-benzisothiazol-3(2H)-one 1,1-dioxide]. The dea ligands constitute the equatorial plane of the octahedron, forming two five-membered chelate rings around the Cd(II) ion, while the sac ligands are localized at the axial positions. The Cd-N(sac), Cd-N(dea) and Cd-O(dea) bond distances are 2.3879 (12), 2.3544 (14) and 2.3702 (13) A, respectively. The H atoms of the free and coordinated hydroxyl groups of the dea ligands are involved in hydrogen bonding with the carbonyl and sulfonyl O atoms of the neighbouring sac ions, while the amine H atom forms a hydrogen bond with the free hydroxyl O atom. The individual molecules are held together by strong hydrogen bonds, forming an infinite three-dimensional network.


Benthic macrofaunal assemblages of the San Francisco Estuary and Delta, USA.
The spatial and temporal distribution of macrobenthic assemblages in the San Francisco Estuary and Sacramento-San Joaquin River Delta were identified using hierarchical cluster analysis of 501 samples collected between 1994 and 2008. Five benthic assemblages were identified that were distributed primarily along the salinity gradient: (1) a polyhaline assemblage that inhabits the Central Bay, (2) a mesohaline assemblage that inhabits South Bay and San Pablo Bay, (3) a low-diversity oligohaline assemblage primarily in Suisun Bay, (4) a low-diversity sand assemblage that occurs at various locations throughout the Estuary, and (5) a tidal freshwater assemblage in the Delta. Most sites were classified within the same assemblage in different seasons and years, but a few sites switched assemblage designations in response to seasonal changes in salinity from freshwater inflows.


Sex differences in Nintendo Wii performance as expected from hunter-gatherer selection.
To test the hunter-gatherer theory of cognitive sex differences, men and women each played four video games on a Wii console: two games simulating skills necessary for hunting (navigation and shooting) and two games simulating skills necessary for gathering (fine motor and visual search). Men outperformed women on the two hunting games, whereas there were no sex differences on the gathering skill games. The findings are discussed in terms of evolutionary psychology theory.


A winter distribution model for Bicknell's Thrush (Catharus bicknelli), a conservation tool for a threatened migratory songbird.
Conservation planning and implementation require identifying pertinent habitats and locations where protection and management may improve viability of targeted species. The winter range of Bicknell's Thrush (Catharus bicknelli), a threatened Nearctic-Neotropical migratory songbird, is restricted to the Greater Antilles. We analyzed winter records from the mid-1970s to 2009 to quantitatively evaluate winter distribution and habitat selection. Additionally, we conducted targeted surveys in Jamaica (n = 433), Cuba (n = 363), Dominican Republic (n = 1,000), Haiti (n = 131) and Puerto Rico (n = 242) yielding 179 sites with thrush presence. We modeled Bicknell's Thrush winter habitat selection and distribution in the Greater Antilles in Maxent version 3.3.1. using environmental predictors represented in 30 arc second study area rasters. These included nine landform, land cover and climatic variables that were thought a priori to have potentially high predictive power. We used the average training gain from ten model runs to select the best subset of predictors. Total winter precipitation, aspect and land cover, particularly broadleaf forests, emerged as important variables. A five-variable model that contained land cover, winter precipitation, aspect, slope, and elevation was the most parsimonious and not significantly different than the models with more variables. We used the best fitting model to depict potential winter habitat. Using the 10 percentile threshold (>0.25), we estimated winter habitat to cover 33,170 km(2), nearly 10% of the study area. The Dominican Republic contained half of all potential habitat (51%), followed by Cuba (15.1%), Jamaica (13.5%), Haiti (10.6%), and Puerto Rico (9.9%). Nearly one-third of the range was found to be in protected areas. By providing the first detailed predictive map of Bicknell's Thrush winter distribution, our study provides a useful tool to prioritize and direct conservation planning for this and other wet, broadleaf forest specialists in the Greater Antilles.


Automated quantification of neurite outgrowth orientation distributions on patterned surfaces.
We have developed an image analysis methodology for quantifying the anisotropy of neuronal projections on patterned substrates. Our method is based on the fitting of smoothing splines to the digital traces produced using a non-maximum suppression technique. This enables precise estimates of the local tangents uniformly along the neurite length, and leads to unbiased orientation distributions suitable for objectively assessing the anisotropy induced by tailored surfaces. In our application, we demonstrate that carbon nanotubes arrayed in parallel bundles over gold surfaces induce a considerable neurite anisotropy; a result which is relevant for regenerative medicine. Our pipeline is generally applicable to the study of fibrous materials on 2D surfaces and should also find applications in the study of DNA, microtubules, and other polymeric materials.


Myocardial ischemia and adverse cardiac outcomes in cardiac patients undergoing noncardiac surgery with sevoflurane and isoflurane. Sevoflurane Ischemia Study Group.
Sevoflurane is associated with less tachycardia and coronary vasodilation than isoflurane and thus might be associated with less myocardial ischemia. This multicenter study examined the incidence of myocardial ischemia and adverse cardiac outcomes in adults (40-87 yr) with cardiac disease having elective noncardiac surgery. Patients were randomized to receive either sevoflurane (S) (n = 106) or isoflurane (I) (n = 108) in conjunction with sodium thiopental, vecuronium, fentanyl, and 50%-70% N2O. Intraoperative hemodynamics were maintained within 20% of awake baseline with standard drugs. A Holter monitor was applied 3-24 h before surgery and maintained until 48 h after surgery. Electrocardiograms and blood samples for analysis of the MB isoenzyme fraction of creatine phosphokinase were obtained preoperatively and daily for 48 h postoperatively. Anesthetic exposure (1.79 +/- 0.15 [mean +/- SE] minimum alveolar concentration-hour) and duration of surgery (219 +/- 13 min) did not differ between groups. The incidence of ischemia in the pre-, intra- and postoperative periods, adverse cardiac outcomes (18% occurrence), intraoperative hemodynamic variations (+/-20% change from ward baseline), and administration of adjunct cardiovascular medications were similar between groups. In cardiac patients having noncardiac surgery, sevoflurane was comparable to isoflurane with respect to the incidence of intra- and postoperative myocardial ischemia and in the frequency of adverse cardiac outcomes. Surgical patients with heart disease are at risk of heart complications, some of which could be induced by an anesthetic. We compared the incidence of cardiac complications between patients receiving sevoflurane and isoflurane. We found that the frequency of additional heart problems in cardiac patients receiving sevoflurane was not different from that associated with isoflurane.


Euroethics--a database network on biomedical ethics.
EUROETHICS is a database covering European literature on ethics in medicine. It is produced within Eurethnet, a European information network on ethics in medicine and biotechnology. The aim of Euroethics is to disseminate information on European bioethical literature that may otherwise be difficult to find. A collaboration model for pooling data from different centres was developed. The policy was to accomplish data uniformity, while still allowing for local differences in terms of software, indexing practices and resources. Records contributed to the database follow common standards in terms of data fields and indexing terms. The indexing terms derive from two thesauri, Thesaurus Ethics in the Life Sciences (TELS) and Medical Subject Headings (MeSH). Combining elements from search tools developed previously, the developers sought to find a technical solution optimized for this data model. An approach relying on a thesaurus database that is loaded along with the bibliographic database is described. The present case study offers examples of possible approaches to several tasks often encountered in database development, such as: merging data from diverse sources, getting the most out of indexing terms used in a database, and handling more than one thesaurus in the same system.


Competition between Heterochromatic Loci Allows the Abundance of the Silencing Protein, Sir4, to Regulate de novo Assembly of Heterochromatin.
Changes in the locations and boundaries of heterochromatin are critical during development, and de novo assembly of silent chromatin in budding yeast is a well-studied model for how new sites of heterochromatin assemble. De novo assembly cannot occur in the G1 phase of the cell cycle and one to two divisions are needed for complete silent chromatin assembly and transcriptional repression. Mutation of DOT1, the histone H3 lysine 79 (K79) methyltransferase, and SET1, the histone H3 lysine 4 (K4) methyltransferase, speed de novo assembly. These observations have led to the model that regulated demethylation of histones may be a mechanism for how cells control the establishment of heterochromatin. We find that the abundance of Sir4, a protein required for the assembly of silent chromatin, decreases dramatically during a G1 arrest and therefore tested if changing the levels of Sir4 would also alter the speed of de novo establishment. Halving the level of Sir4 slows heterochromatin establishment, while increasing Sir4 speeds establishment. yku70Δ and ubp10Δ cells also speed de novo assembly, and like dot1Δ cells have defects in subtelomeric silencing, suggesting that these mutants may indirectly speed de novo establishment by liberating Sir4 from telomeres. Deleting RIF1 and RIF2, which suppresses the subtelomeric silencing defects in these mutants, rescues the advanced de novo establishment in yku70Δ and ubp10Δ cells, but not in dot1Δ cells, suggesting that YKU70 and UBP10 regulate Sir4 availability by modulating subtelomeric silencing, while DOT1 functions directly to regulate establishment. Our data support a model whereby the demethylation of histone H3 K79 and changes in Sir4 abundance and availability define two rate-limiting steps that regulate de novo assembly of heterochromatin.


A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis.
Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (≥8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058).


Understanding barriers to the introduction of precision medicines in non-small cell lung cancer: A qualitative interview protocol.
Background: While precision medicines targeting genetic mutations and alterations in non-small cell lung cancer (NSCLC) have been available since 2010, their adoption into clinical practice has been slow. Evidence suggests that a number of barriers, such as insufficient clinician knowledge, a need for training of test providers, or a lack of specific clinical guidelines, may slow the implementation of precision in general. However, little attention has been given to the barriers to providing precision medicines in NSCLC. The purpose of this protocol is to outline the design for a qualitative interview study to identify the barriers and facilitators to the provision of precision medicines for NSCLC. Methods: This study will use semi-structured interviews with clinicians (n=10), test providers (n=10), and service commissioners (n=10) to identify the perceived barriers and facilitators to providing historical, current, and future precision medicines in NSCLC. Participants will be identified through mailing list advertisements and snowball sampling. Recruitment will continue until data saturation, indicated by no new themes arising from the data. Interviews will be conducted by telephone to facilitate geographical diversity. The qualitative data will be analysed using a framework analysis with themes anticipated to relate to; relevant barriers to providing precision medicines, the impact of different barriers on medicine provision, changes in the ability to provide precision medicines over time, and strategies to facilitate the provision of precision medicines. Ethics: This study has been approved by the University of Manchester Proportionate Review Research Ethics Committee (Reference number: 2017-1885-3619). Written consent will be obtained from all participants. Conclusion: This study is the first to explore the barriers and facilitators to providing precision medicines for NSCLC in the English NHS. The findings will inform strategies to improve the implementation of future precision medicines. These findings will be disseminated in peer-reviewed publications and national and international conferences.


30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study.
30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved. In this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot. Between Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040-1·132; p<0·0001; NSCLC curative: 1·045, 1·013-1·079; p=0·00033; breast palliative: 0·987, 0·977-0·996; p=0·00034; NSCLC palliative: 0·987, 0·976-0·998; p=0·0015). 30-day mortality was also significantly higher for patients receiving their first reported curative or palliative SACT versus those who received SACT previously (breast palliative: OR 2·326 99% CI 1·634-3·312; p<0·0001; NSCLC curative: 3·371, 1·554-7·316; p<0·0001; NSCLC palliative: 2·667, 2·109-3·373; p<0·0001), and for patients with worse general wellbeing (performance status 2-4) versus those who were generally well (breast curative: 6·057, 1·333-27·513; p=0·0021; breast palliative: 6·241, 4·180-9·319; p<0·0001; NSCLC palliative: 3·384, 2·276-5·032; p<0·0001). We identified trusts with mortality rates in excess of the 95% control limits; this included seven for curative breast cancer, four for palliative breast cancer, five for curative NSCLC, and seven for palliative NSCLC. Our findings show that several factors affect the risk of early mortality of breast and lung cancer patients in England and that some groups are at a substantially increased risk of 30-day mortality. The identification of hospitals with significantly higher 30-day mortality rates should promote review of clinical decision making in these hospitals. Furthermore, our results highlight the importance of collecting routine data beyond clinical trials to better understand the factors placing patients at higher risk of 30-day mortality, and ultimately improve clinical decision making. Our insights into the factors affecting risk of 30-day mortality will help treating clinicians and their patients predict the balance of harms and benefits associated with SACT. Public Health England.


Omnidirectional Transport in Fully Reconfigurable Two Dimensional Optical Ratchets.
A fully reconfigurable two-dimensional (2D) rocking ratchet system created with holographic optical micromanipulation is presented. We can generate optical potentials with the geometry of any Bravais lattice in 2D and introduce a spatial asymmetry with arbitrary orientation. Nontrivial directed transport of Brownian particles along different directions is demonstrated numerically and experimentally, including on axis, perpendicular, and oblique with respect to an unbiased ac driving. The most important aspect to define the current direction is shown to be the asymmetry and not the driving orientation, and yet we show a system in which the asymmetry orientation of each potential well does not coincide with the transport direction, suggesting an additional symmetry breaking as a result of a coupling with the lattice configuration. Our experimental device, due to its versatility, opens up a new range of possibilities in the study of nonequilibrium dynamics at the microscopic level.


Expression and phylogenetic analyses reveal paralogous lineages of putatively classical and non-classical MHC-I genes in three sparrow species (Passer).
The Major Histocompatibility Complex (MHC) plays a central role in immunity and has been given considerable attention by evolutionary ecologists due to its associations with fitness-related traits. Songbirds have unusually high numbers of MHC class I (MHC-I) genes, but it is not known whether all are expressed and equally important for immune function. Classical MHC-I genes are highly expressed, polymorphic and present peptides to T-cells whereas non-classical MHC-I genes have lower expression, are more monomorphic and do not present peptides to T-cells. To get a better understanding of the highly duplicated MHC genes in songbirds, we studied gene expression in a phylogenetic framework in three species of sparrows (house sparrow, tree sparrow and Spanish sparrow), using high-throughput sequencing. We hypothesize that sparrows could have classical and non-classical genes, as previously indicated though never tested using gene expression. The phylogenetic analyses reveal two distinct types of MHC-I alleles among the three sparrow species, one with high and one with low level of polymorphism, thus resembling classical and non-classical genes, respectively. All individuals had both types of alleles, but there was copy number variation both within and among the sparrow species. However, the number of highly polymorphic alleles that were expressed did not vary between species, suggesting that the structural genomic variation is counterbalanced by conserved gene expression. Overall, 50% of the MHC-I alleles were expressed in sparrows. Expression of the highly polymorphic alleles was very variable, whereas the alleles with low polymorphism had uniformly low expression. Interestingly, within an individual only one or two alleles from the polymorphic genes were highly expressed, indicating that only a single copy of these is highly expressed. Taken together, the phylogenetic reconstruction and the analyses of expression suggest that sparrows have both classical and non-classical MHC-I genes, and that the evolutionary origin of these genes predate the split of the three investigated sparrow species 7 million years ago. Because only the classical MHC-I genes are involved in antigen presentation, the function of different MHC-I genes should be considered in future ecological and evolutionary studies of MHC-I in sparrows and other songbirds.


Transcriptome variation along bud development in grapevine (Vitis vinifera L.).
Vegetative buds provide plants in temperate environments the possibility for growth and reproduction when environmental conditions are favorable. In grapevine, crucial developmental events take place within buds during two growing seasons in consecutive years. The first season, the shoot apical meristem within the bud differentiates all the basic elements of the shoot including flowering transition in lateral primordia and development of inflorescence primordia. These events practically end with bud dormancy. The second season, buds resume shoot growth associated to flower formation and development. Gene expression has been previously monitored at specific stages of bud development but has never been followed along the two growing seasons. Gene expression changes were analyzed along the bud annual cycle at eight different time points. Principal Components Analysis (PCA) revealed that the main factors explaining the global gene expression differences were the processes of bud dormancy and active growth as well as stress responses. Accordingly, non dormant buds showed an enrichment in functional categories typical of actively proliferating and growing cells together with the over abundance of transcripts belonging to stress response pathways. Differential expression analyses performed between consecutive time points indicated that major transcriptional changes were associated to para/endodormancy, endo/ecodormancy and ecodormancy/bud break transitions. Transcripts encoding key regulators of reproductive development were grouped in three major expression clusters corresponding to: (i) transcripts associated to flowering induction, (ii) transcripts associated to flower meristem specification and initiation and (iii) transcripts putatively involved in dormancy. Within this cluster, a MADS-box gene (VvFLC2) and other transcripts with similar expression patterns could participate in dormancy regulation. This work provides a global view of major transcriptional changes taking place along bud development in grapevine, highlighting those molecular and biological functions involved in the main events of bud development. As reported in other woody species, the results suggest that genes regulating flowering could also be involved in dormancy regulatory pathways in grapevine.


Interlaboratory evaluation of Mucorales PCR assays for testing serum specimens: A study by the fungal PCR Initiative and the Modimucor study group.
Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.


Regularized neural networks: some convergence rate results.
In a recent paper, Poggio and Girosi (1990) proposed a class of neural networks obtained from the theory of regularization. Regularized networks are capable of approximating arbitrarily well any continuous function on a compactum. In this paper we consider in detail the learning problem for the one-dimensional case. We show that in the case of output data observed with noise, regularized networks are capable of learning and approximating (on compacta) elements of certain classes of Sobolev spaces, known as reproducing kernel Hilbert spaces (RKHS), at a nonparametric rate that optimally exploits the smoothness properties of the unknown mapping. In particular we show that the total squared error, given by the sum of the squared bias and the variance, will approach zero at a rate of n(-2m)/(2m+1), where m denotes the order of differentiability of the true unknown function. On the other hand, if the unknown mapping is a continuous function but does not belong to an RKHS, then there still exists a unique regularized solution, but this is no longer guaranteed to converge in mean square to a well-defined limit. Further, even if such a solution converges, the total squared error is bounded away from zero for all n sufficiently large.


Cow, farm, and management factors during the dry period that determine the rate of clinical mastitis after calving.
The purpose of the research was to investigate cow characteristics, farm facilities, and herd management strategies during the dry period to examine their joint influence on the rate of clinical mastitis after calving. Data were collected over a 2-yr period from 52 commercial dairy farms throughout England and Wales. Cows were separated for analysis into those housed for the dry period (8,710 cow-dry periods) and those at pasture (9,964 cow-dry periods). Multilevel models were used within a Bayesian framework with 2 response variables, the occurrence of a first case of clinical mastitis within the first 30 d of lactation and time to the first case of clinical mastitis during lactation. A variety of cow and herd management factors were identified as being associated with an increased rate of clinical mastitis and these were found to occur throughout the dry period. Significant cow factors were increased parity and at least one somatic cell count > or = 200,000 cells/mL in the 90 d before drying off. A number of management factors related to hygiene were significantly associated with an increased rate of clinical mastitis. These included measures linked to the administration of dry-cow treatments and management of the early and late dry-period accommodation and calving areas. Other farm factors associated with a reduced rate of clinical mastitis were vaccination with a leptospirosis vaccine, selection of dry-cow treatments for individual cows within a herd rather than for the herd as a whole, routine body condition scoring of cows at drying off, and a pasture rotation policy of grazing dry cows for a maximum of 2 wk before allowing the pasture to remain nongrazed for a period of 4 wk. Models demonstrated a good ability to predict the farm incidence rate of clinical mastitis in a given year, with model predictions explaining over 85% of the variability in the observed data. The research indicates that specific dry-period management strategies have an important influence on the rate of clinical mastitis during the next lactation.


GROWTH OF CHLORELLA PYRENOIDOSA IN RECYCLED MEDIUM.
Bench-scale studies with Chlorella pyrenoidosa 7-11-05 were conducted in a 4-liter culture vessel with a used and recycled medium. Algal cultures were maintained for periods of several weeks by supplementing the nutrient medium with minimal amounts of certain salts. An algal strain was maintained for a period of up to 72 days with a supplemented recycled medium. No inhibition was observed as the result of any autotoxic materials. Rather dense cultures were maintained in the presence of high bacterial populations.


Wool traits of three sympatric sheep populations in Chiapas Region, México.
A total of 344 pure animals, representing seven American and South European breeds (White Chiapas Blanca, Brown Chiapas Café, Black Chiapas Negra, Churra Badana, Churra da Terra Quente, Chilean Latxa, and Spanish Merino), were randomly sampled and wool evaluated for isoalcohol scouring yield, length, and proportion for each type of fiber (long-thick, short-thin, and kemp), average of fiber diameter, and F30 (percentage of fibers with a diameter of >30 μm). The objective of this study was to characterize these breeds according to their wool traits. A low percentage of the phenotypic variability in the analyzed animals was due to differences among breeds, and that the largest part of that variability is due to differences within breeds. The obtained topology in the principal coordinates analysis showed the grouping of the three Chiapas breeds clearly separated, but the similarity with their original breed was only evident for Brown Chiapas Café. The three Chiapas sheep breeds must be regarded as clearly sympatric populations.


High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk.
Risk prediction of gastric cancers is important to implement appropriate screening procedures. Although aberrant DNA methylation is deeply involved in gastric carcinogenesis, its induction by Helicobacter pylori, a strong gastric carcinogen, is unclear. Here, we analyzed the effect of H. pylori infection on the quantity of methylated DNA molecules in noncancerous gastric mucosae and examined its association with gastric cancer risk. Gastric mucosae were collected from 154 healthy volunteers (56 H. pylori negative and 98 H. pylori positive) and 72 cases with differentiated-type gastric cancers (29 H. pylori negative and 43 H. pylori positive) by endoscopy. The numbers of DNA molecules methylated and unmethylated for eight regions of seven CpG islands (CGI) were quantified by quantitative PCR after bisulfite modification, and fractions of methylated molecules (methylation levels) were calculated. Among healthy volunteers, methylation levels of all the eight regions were 5.4- to 303-fold higher in H. pylori positives than in H. pylori negatives (P < 0.0001). Methylation levels of the LOX, HAND1, and THBD promoter CGIs and p41ARC exonic CGI were as high as 7.4% or more in H. pylori-positive individuals. Among H. pylori-negative individuals, methylation levels of all the eight regions were 2.2- to 32-fold higher in gastric cancer cases than in age-matched healthy volunteers (P < or = 0.01). Among H. pylori-positive individuals, methylation levels were highly variable, and that of only HAND1 was significantly increased in gastric cancer cases (1.4-fold, P = 0.02). It was indicated that H. pylori infection potently induces methylation of CGIs to various degrees. Methylation levels of specific CGIs seemed to reflect gastric cancer risk in H. pylori-negative individuals.


Clofarabine, cytarabine, and mitoxantrone in refractory/relapsed acute myeloid leukemia: High response rates and effective bridge to allogeneic hematopoietic stem cell transplantation.
Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18- to 65-year-old AML patients refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high-dose cytarabine consolidation, with clofarabine (30 mg/m2 /d, Days 1-5), cytarabine (750 mg/m2 /d, Days 1-5), and mitoxantrone (12 mg/m2 /d, Days 3-5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mutational profile of a 69-gene panel was evaluated. Twenty-six men and 26 women at a median age of 46 (22-65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty-two CR/CRi patients underwent allo-HSCT. The 2-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo-HSCT (P = .005), and superior RFS and EFS were associated with allo-HSCT (P < .001). Remarkably, CR after CLAM and allo-HSCT resulted in 2-year OS of 84.3% and 90%, respectively. Karyotypic aberrations and genetic mutations did not influence responses or survivals. Grade 3/4 neutropenia/thrombocytopenia and grade 3 febrile neutropenia occurred in all cases. Other nonhematologic toxicities were mild and uncommon. There was no treatment-related mortality and the performance of allo-HSCT was not compromised. Clofarabine, cytarabine, and mitoxantrone was highly effective and safe in refractory/relapsed AML. This study was registered at ClinicalTrials.gov (NCT02686593).


Modern approaches to the treatment of amyloidosis: the critical importance of early detection in surgical pathology.
The amyloidoses comprise a group of disorders of diverse etiology, in which different proteins undergo abnormal folding, leading to their deposition in tissues and concomitant tissue toxicity. This process ultimately leads to tissue destruction, with organ failure and progressive disease. Recent progress in the treatment of the systemic amyloidoses has dramatically changed the outlook for affected patients and their families. From a relatively rare and esoteric disorder that was typically diagnosed only at autopsy, or was invariably fatal if diagnosed during life, it has now become a disease for which, with modern therapies, durable responses and long-term survival can be achieved. The clinical symptoms are largely nonspecific, and therefore misdiagnosis, or late diagnosis, have been major detriments in achieving better treatment outcomes. Despite advances in laboratory medicine, amyloidoses are still diagnosed on the basis of the pathologic detection of deposits in tissues. Thus, effective primary screening for these diseases requires the active engagement of the pathology community at large, while specialized laboratories and treatment centers can offer secondary consultation and assistance with further steps. This review provides an update on pathogenesis, the clinical and pathologic features, and treatments of various amyloidoses, as well as the current terminology, classification, and practical considerations that are relevant to the diagnosis.


Middle-aged patients with an MRI-verified medial meniscal tear report symptoms commonly associated with knee osteoarthritis.
Background and purpose - No consensus exists on when to perform arthroscopic partial meniscectomy in patients with a degenerative meniscal tear. Since MRI and clinical tests are not accurate in detecting a symptomatic meniscal lesion, the patient's symptoms often play a large role when deciding when to perform surgery. We determined the prevalence and severity of self-reported knee symptoms in patients eligible for arthroscopic partial meniscectomy due to a degenerative meniscal tear. We investigated whether symptoms commonly considered to be related to meniscus injury were associated with early radiographic signs of knee osteoarthritis. Patients and methods - We included individual baseline items from the Knee injury and Osteoarthritis Outcome Score collected in 2 randomized controlled trials evaluating treatment for an MRI-verified degenerative medial meniscal tears in 199 patients aged 35-65 years. Each item was scored as no, mild, moderate, severe, extreme, and at least "mild" considering the symptoms present. Early radiographic signs of osteoarthritis, defined as a Kellgren and Lawrence grade of at least 1, were seen in 70 patients. Results - At least monthly knee pain, pain during stair walking and when twisting on the knee, and lack of confidence in knee was present in at least 80% of the patients. Median severity was at least moderate for knee pain, pain when twisting on the knee, pain walking on stairs, lack of confidence in knee, and clicking. Mechanical symptoms such as catching were rare. Early radiographic signs of osteoarthritis were associated with an increased risk of self-reported swelling, catching, and stiffness later in the day; the odds ratio was 2.4 (95% CI 1.2-4.9), 2.3 (1.2-4.3), and 2.3 (1.1-5.0), respectively. Interpretation - Middle-aged patients with a degenerative medial meniscus tear reported symptoms commonly associated with knee osteoarthritis. Frequent knee pain, presence of lack of confidence in the knee, and clicking did not distinguish those with a meniscal tear alone from those with early radiographic knee OA. Our findings support the notion that symptoms reported by those with a degenerative meniscal tear represent early signs of knee osteoarthritis.


Molecular cloning and functional characterization of the genes encoding benzoate and p-hydroxybenzoate degradation by the halophilic Chromohalobacter sp. strain HS-2.
Chromohalobacter sp. strain HS-2 was isolated from salted fermented clams and analyzed for the ability to grow on benzoate and p-hydroxybenzoate as the sole carbon and energy source. HS-2 was characterized as moderately halophilic, with an optimal NaCl concentration of 10%. The genes encoding the benzoate metabolism were cloned into a cosmid vector, sequenced, and then analyzed to reveal the benzoate (benABCD) and catechol (catBCA) catabolic genes, both of which are flanked on either side by LysR-type transcriptional regulator (catR) and membrane transport protein for benzoate (benE) in the gene order catRBCAbenABCDE. Near the large cat-ben cluster, a p-hydroxybenzoate hydroxylase gene (pobA) and two putative regulatory genes (pcaQ and pobR) were additionally detected. The HS-2 genes involved in benzoate and p-hydroxybenzoate degradation are tightly clustered within a c. 19 kb region, and show quite a different genetic organization from those of other benzoate catabolic genes. Reverse transcriptase-PCR experiments show that benzoate induces the expression of benzoate 1,2-dioxygenase, catechol 1,2-dioxygenase, and protocatechuate 3,4-dioxygenase while p-hydroxybenzoate only induced the expression of p-hydroxybenzoate hydroxylase. When expressed in Escherichia coli, benzoate 1,2-dioxygenase (BenABC) and p-hydroxybenzoate hydroxylase (PobA) transformed benzoate and p-hydroxybenzoate into cis-benzoate dihydrodiol and protocatechuate, respectively.


Protective effect of guggulsterone against cardiomyocyte injury induced by doxorubicin in vitro.
Doxorubicin (DOX) is an effective antineoplastic drug; however, clinical use of DOX is limited by its dose-dependent cardiotoxicity. It is well known that reactive oxygen species (ROS) play a vital role in the pathological process of DOX-induced cardiotoxicity. For this study, we evaluated the protective effects of guggulsterone (GS), a steroid obtained from myrrh, to determine its preliminary mechanisms in defending against DOX-induced cytotoxicity in H9C2 cells. In this study, we used a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release measurements, and Hoechst 33258 staining to evaluate the protective effect of GS against DOX-induced cytotoxicity in H9C2 cells. In addition, we observed the immunofluorescence of intracellular ROS and measured lipid peroxidation, caspase-3 activity, and apoptosis-related proteins by using Western blotting. The MTT assay and LDH release showed that treatment using GS (1-30 μM) did not cause cytotoxicity. Furthermore, GS inhibited DOX (1 μM)-induced cytotoxicity in a concentration-dependent manner. Hoechst 33258 staining showed that GS significantly reduced DOX-induced apoptosis and cell death. Using GS at a dose of 10-30 μM significantly reduced intracellular ROS and the formation of MDA in the supernatant of DOX-treated H9C2 cells and suppressed caspase-3 activity to reference levels. In immunoblot analysis, pretreatment using GS significantly reversed DOX-induced decrease of PARP, caspase-3 and bcl-2, and increase of bax, cytochrome C release, cleaved-PARP and cleaved-caspase-3. In addition, the properties of DOX-induced cancer cell (DLD-1 cells) death did not interfere when combined GS and DOX. These data provide considerable evidence that GS could serve as a novel cardioprotective agent against DOX-induced cardiotoxicity.


A data fusion environment for multimodal and multi-informational neuronavigation.
Part of the planning and performance of neurosurgery consists of determining target areas, areas to be avoided, landmark areas, and trajectories, all of which are components of the surgical script. Nowadays, neurosurgeons have access to multimodal medical imaging to support the definition of the surgical script. The purpose of this paper is to present a software environment developed by the authors that allows full multimodal and multi-informational planning as well as neuronavigation for epilepsy and tumor surgery. We have developed a data fusion environment dedicated to neuronavigation around the Surgical Microscope Neuronavigator system (Carl Zeiss, Oberkochen, Germany). This environment includes registration, segmentation, 3D visualization, and interaction-applied tools. It provides the neuronavigation system with the multimodal information involved in the definition of the surgical script: lesional areas, sulci, ventricles segmented from magnetic resonance imaging (MRI), vessels segmented from magnetic resonance angiography (MRA), functional areas from magneto-encephalography (MEG), and functional magnetic resonance imaging (fMRI) for somatosensory, motor, or language activation. These data are considered to be relevant for the performance of the surgical procedure. The definition of each entity results from the same procedure: registration to the anatomical MRI data set (defined as the reference data set), segmentation, fused 3D display, selection of the relevant entities for the surgical step, encoding in 3D surface-based representation, and storage of the 3D surfaces in a file recognized by the neuronavigation software (STP 3.4, Leibinger; Freiburg, Germany). Multimodal neuronavigation is illustrated with two clinical cases for which multimodal information was introduced into the neuronavigation system. Lesional areas were used to define and follow the surgical path, sulci and vessels helped identify the anatomical environment of the surgical field, and, finally, MEG and fMRI functional information helped determine the position of functional high-risk areas. In this short evaluation, the ability to access preoperative multi-functional and anatomical data within the neuronavigation system was a valuable support for the surgical procedure.


tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2.
Paralysis resulting from spinal cord injury is devastating and persistent. One major reason for the inability of the body to heal this type of injury ensues from the local increase of glial cells leading to the formation of a glial scar, and the upregulation of chondroitin sulfate proteoglycans (CSPGs) at the site of injury through which axons are unable to regenerate. Experimental approaches to overcome this problem have accordingly focused on reducing the inhibitory properties of CSPGs, for example by using chondroitinase to remove the sugar chains and reduce the CSPGs to their core protein constituents, although this step alone does not provide dramatic benefits as a monotherapy. Using in vitro and in vivo approaches, we describe here a potentially synergistic therapeutic opportunity based on tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen (plg) into the active protease plasmin. We show that tPA and plg both bind to the CSPG protein NG2, which functions as a scaffold to accelerate the tPA-driven conversion of plg to plasmin. The binding occurs via the tPA and plg kringle domains to domain 2 of the NG2 CSPG core protein, and is enhanced in some settings after chondroitinase-mediated removal of the NG2 proteoglycan side chains. Once generated, plasmin then degrades NG2, both in an in vitro setting using recombinant protein, and in vivo models of spinal cord injury. Our finding that the tPA and plg binding is in some instances more efficient after exposure of the NG2 proteoglycan to chondroitinase treatment suggests that a combined therapeutic approach employing both chondroitinase and the tPA/plasmin proteolytic system could be of significant benefit in promoting axonal regeneration through glial scars after spinal cord injury.


Chromosomal mapping of the genetic basis of hypertension and renal disease in FHH rats.
This study examined the genetic basis for hypertension and renal disease phenotypes in Fawn Hooded hypertensive (FHH) rats using chromosome substitution strains (consomic rats) in which each of the 20 autosomes as well as the X and Y chromosomes were transferred from the normal Brown Norway (BN) rat onto the FHH genetic background. Male and female rats of each of the parental and consomic strains were maintained for 2 wk on high-salt (8.0% NaCl) chow with N(G)-nitro-l-arginine methyl ester (l-NAME) in the drinking water (12.5 mg/l) to induce hypertension and renal disease. Mean arterial blood pressure (MAP) was significantly higher (by over 60 mmHg) in the male FHH compared with BN rats. Urinary protein and albumin excretion rates were increased by 15- and 40-fold, respectively, in the male FHH compared with the BN. Plasma renin activity was 10-fold higher in the FHH than the BN. Similar significant differences were observed between the female FHH and BN, but the degree of hypertension and proteinuria was of a lesser magnitude. Substitution of chromosome 20 from the BN to the FHH attenuated the development of l-NAME-induced hypertension, normalized plasma renin activity, and decreased plasma creatinine in male rats. In female rats, substitution of chromosome 15 decreased MAP and urinary protein excretion. Urinary excretion of albumin in males was decreased by substitution of chromosomes 1, 15, 16, and 18 from the BN into the FHH genetic background. The present data indicate that genes that can modify l-NAME-induced hypertension and proteinuria are on chromosomes 1, 15, 16, 18, and 20.


A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates.
Diets that reduce atherosclerosis risk lower levels of HDL cholesterol (HDL-C), but the significance of this is unclear. To better understand the mechanism of this phenomenon we studied the turnover of HDL apolipoproteins A-I and A-II in 13 subjects on two contrasting metabolic diets. Upon changing from high to low intake of saturated fat and cholesterol the mean HDL-C decreased 29% from 56 +/- 13 (SD) to 40 +/- 10 mg/dl, while apo A-I levels fell 23% from 139 +/- 22 to 107 +/- 22 mg/dl (both P less than 0.001). Mean apo A-II levels did not change. The fractional catabolic rate (FCR) of apo A-I increased 11% from 0.228 +/- 0.048 to 0.254 +/- 0.063 pools/d, while its absolute transport rate (TR) decreased 14% from 12.0 +/- 2.7 to 10.3 +/- 3.4 mg/kg per d (both P = 0.005). The decrease in HDL-C and apo A-I levels correlated with the decrease in apo A-I TR (r = 0.79 and 0.83, respectively; P less than 0.001), but not with the increase in apo A-I FCR (r = -0.04 and -0.02, respectively). In contrast, within each diet the HDL-C and apo A-I levels were inversely correlated with apo A-I FCR both on the high-fat (r = -0.85 and -0.77, P less than 0.001 and = 0.002, respectively) and low-fat diets (r = -0.67 and -0.48, P = 0.012 and 0.098, respectively) but not with apo A-I TR. In summary, diet-induced changes in HDL-C levels correlate with and may result from changes in apo A-I TR. In contrast, differences in HDL-C levels between people on a given diet correlate with and may result from differences in apo A-I FCR. Therefore, the mechanism of dietary effects on HDL levels differs substantially from the mechanism explaining the differences in levels between individuals on a fixed diet. In assessing coronary heart disease risk, it may be inappropriate to conclude that diet-induced decreases in HDL are equivalent to low HDL within a given diet.


Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance.
Although influenza vaccination remains the primary method for the prevention of influenza, efficacy may be limited by a poor match between the vaccine and circulating strains and the poor response of elderly patients. Hence, there is an important role for antiviral therapy in the management of influenza. While amantadine and rimantadine have been available for the treatment of influenza in some countries for several years, they are only effective against influenza A viruses, they can have neurological and gastrointestinal adverse effects, and resistant virus is rapidly generated. Neuraminidase inhibitors, a new class of drug, are potent and specific inhibitors of all strains of influenza virus, and they have minimal adverse effects. The greatest benefit is seen in those patients presenting <30 hours after development of influenza symptoms, those with severe symptoms or those in high-risk groups. In addition to treatment of the infection, both drugs are effective prophylactically and have been shown to limit spread of infection in close communities, such as families and in nursing homes. No resistant virus strains have been isolated from normal individuals treated with zanamivir. Resistant virus can be isolated from approximately 1% of adults and 5% of paediatric patients with influenza treated with oseltamivir. However, infectivity of mutant viruses is generally compromised. Governments spend millions of dollars on influenza vaccination campaigns; however, once influenza virus is circulating in the community, vaccination cannot limit the spread of disease. A greater promotion of the use of neuraminidase inhibitors for the treatment and prevention of influenza could have a significant impact on limiting its spread. This could result in saving millions of dollars, not only in direct costs associated with medical and hospital care, but also significant savings in indirect costs associated with the loss of productivity at work, school and home environments. For the benefit of all communities, there needs to be a greater awareness of the symptoms of influenza and the efficacy of neuraminidase inhibitors in disease treatment.


Ultra high frequency-electromagnetic field irradiation during pregnancy leads to an increase in erythrocytes micronuclei incidence in rat offspring.
Mobile telephones and their base stations are an important ultra high frequency-electromagnetic field (UHF-EMF) source and their utilization is increasing all over the world. Epidemiological studies suggested that low energy UHF-EMF emitted from a cellular telephone may cause biological effects, such as DNA damage and changes on oxidative metabolism. An in vivo mammalian cytogenetic test, the micronucleus (MN) assay, was used to investigate the occurrence of chromosomal damage in erythrocytes from rat offspring exposed to a non-thermal UHF-EMF from a cellular phone during their embryogenesis; the irradiated group showed a significant increase in MN occurrence. In order to investigate if UHF-EMF could also alter oxidative parameters in the peripheral blood and in the liver - an important hematopoietic tissue in rat embryos and newborns - we also measured the activity of antioxidant enzymes, quantified total sulfhydryl content, protein carbonyl groups, thiobarbituric acid-reactive species and total non-enzymatic antioxidant defense. No significant differences were found in any oxidative parameter of offspring blood and liver. The average number of pups in each litter has also not been significantly altered. Our results suggest that, under our experimental conditions, UHF-EMF is able to induce a genotoxic response in hematopoietic tissue during the embryogenesis through an unknown mechanism.


Mental tasks induce gamma EEG with reduced responsiveness in primary generalized epilepsies.
We previously revealed an interictal increase in intensity of EEG rhythms during quiescent mental activity in the 30- to 100-Hz frequency (gamma) range in primary generalized epilepsy (PGE). We have evidence that there is induction of gamma EEG in normal subjects in response to controlled mental activity. Here we test whether mental tasks further augment interictal gamma oscillations in people with PGE. We recorded interictal EEG from patients with PGE and partial epilepsy and compared EEG power spectral responses (increases over resting) during mental tasks. In partial epilepsy, mental tasks (except for alternating checkerboard visual stimulation) induced 1.5- to 2.5-fold increases in power of gamma EEG. In generalized epilepsy, generalized increases of 1.5-fold in gamma EEG were induced by only two mental tasks (reading and subtraction), and enhancement of 1- to 1.5-fold in the remaining six (checkerboard, expectancy, music, learning, recalling, and a video). Gamma EEG is less responsive to mental activation in PGE than in partial epilepsy, confirming an abnormality in gamma mechanisms in PGE. Our findings also provide a possible mechanistic link between mental activity and seizures in reading- and arithmetic-induced seizures.


Transvenous internal cardioversion for atrial fibrillation: a randomized comparison between catheters with different coil length.
The aim of this study was to evaluate the effects of 2 different right atrial electrode coil lengths on energy and voltage requirements for transvenous atrial cardioversion. Twenty-six patients (mean age 61 +/- 11 years) with chronic persistent atrial fibrillation (AF) (mean duration 11 +/- 10 months) underwent transvenous cardioversion. A 6F catheter with a 5.5-cm coil was positioned in the coronary sinus. Another catheter with either a 5.5-cm or an 8-cm coil was positioned along the lateral wall of the right atrium, according to a randomized allocation. R wave-synchronized biphasic shocks were delivered according to a step-up protocol. After cardioversion of baseline AF, AF was reinduced, the right atrial catheter was substituted, and cardioversion was repeated with the alternative right atrial coil. Successful cardioversion was obtained in all of the patients. Leading edge voltage of effective shocks was significantly lower when catheters with an 8-cm coil in right atrium were used compared with the alternative 5-cm coil catheters (301 +/- 80 volts vs 340 +/- 78 volts, P <.001), and delivered energy (6.75 +/- 4.25 joules vs 7.86 +/- 4.29 joules, P =.043) and shock impedance (60 +/- 9 ohm vs 66 +/- 10 ohm, P <.001) were lower. Moreover, shock-induced discomfort, evaluated by assessment of pain score, was reduced (3.69 +/- 1.09 vs 4.12 +/- 0.99, P =.035). The use of a longer right atrial coil results in lower shock impedance, lower energy and voltage requirements, and lower discomfort during transvenous atrial cardioversion. The results of the current study are of value either for transvenous internal cardioversion of chronic persistent AF or for implantable atrial defibrillators.


Diurnal variation and adaptation of the cough response to citric acid in normal subjects.
The lowest concentrations of citric acid were measured that caused coughing in 10 normal subjects who inhaled successively higher concentrations. Two subjects did not cough at any concentration. In the remaining eight the threshold concentration was significantly higher when measured in the afternoon than it was in the morning (p less than 0.05). The expected diurnal variation in peak expiratory flow rate (PEFR) was found (significant in the whole group--p less than 0.05); but PEFR did not change significantly when measured before and immediately after coughing caused by citric acid inhalations. In a second group of 10 normal subjects two series of citric acid inhalations were given, separated by one hour. The total number of coughs was significantly lower on the second run (p less than 0.05). Thus diurnal variation and adaptation of the cough response must be taken into account when antitussive drugs are tested.


Long-term prognostic value of dobutamine stress echocardiography in diabetic patients with limited exercise capability: a 13-year follow-up study.
To determine the incremental prognostic value of dobutamine stress echocardiography (DSE) at 13-year follow-up (SD 3.2 years) for predicting mortality and cardiac events in diabetic patients. A total of 396 diabetic patients (mean age 61 ± 11 years; 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of ischemia were studied. End points were all causes of mortality, cardiac death, and hard cardiac events (cardiac death and nonfatal myocardial infarction). During a mean follow-up of 13 years, 230 patients (58%) died (121 cardiac deaths), and 30 patients had nonfatal myocardial infarction. Cumulative survival in patients with an abnormal DSE at 5, 10, and 15 years was 68, 49, and 41%, respectively. In patients with a normal DSE, these respective numbers were 74, 57, and 44%. Multivariate analyses showed that DSE provided incremental value over clinical characteristics and stress test parameters for prediction of mortality and cardiac events. Survival analysis showed that DSE provided optimal risk stratification up to 7 years after initial testing; after that period, the risk of adverse outcome increased comparably in both normal and abnormal DSE patients. DSE provided restricted predictive value of adverse outcome in patients with diabetes who were unable to perform an adequate exercise stress test. DSE provided optimal risk stratification up to 7 years after initial testing. Repeated DSE at that time might add to its prognostic value.


Factors associated with anaemia among preschool- age children in underprivileged neighbourhoods in Antananarivo, Madagascar.
Anaemia occurs in children when the haemoglobin level in the blood is less than the normal (11 g/dL), the consequence is the decrease of oxygen quantity in the tissues. It is a prevalent public health problem in many low-income countries, including Madagascar, and data on risk factors are lacking. We used existing data collected within the pathophysiology of environmental enteric dysfunction (EED) in Madagascar and the Central African Republic project (AFRIBIOTA project) conducted in underprivileged neighbourhoods of Antananarivo to investigate the factors associated with anaemia in children 24 to 59 months of age. Children included in the AFRIBIOTA project in Antananarivo for whom data on haemoglobin and ferritin concentrations were available were included in the study. Logistic regression modelling was performed to identify factors associated with anaemia. Of the 414 children included in this data analysis, 24.4% were found to suffer from anaemia. We found that older children (adjusted OR: 0.95; 95% CI: 0.93-0.98) were less likely to have anaemia. Those with iron deficiency (adjusted OR: 6.1; 95% CI: 3.4-11.1) and those with a high level of faecal calprotectin (adjusted OR: 2.5; 95% CI: 1.4-4.4) were more likely to have anaemia than controls. To reduce anaemia in the children in this underprivileged area, more emphasis should be given to national strategies that improve children's dietary quality and micronutrient intake. Furthermore, existing measures should be broadened to include measures to reduce infectious disease burden.


Performance of direct visual inspection of the cervix with acetic acid and magnification in a previously screened population.
To assess the screening performance of direct visual inspection with acetic acid and x2 magnification (VIAM) in a previously screened population, as performed by experienced gynecologic nurses with minimal training in VIAM. Performance of VIAM was evaluated in 2,080 women from a population-based cohort in Guanacaste, Costa Rica, 5 years after they had negative enrollment results of conventional and liquid-based cytologic analysis, cervigram, and human papillomavirus DNA by Hybrid Capture Tube Test (Digene Corporation, Gaithersburg, MD). The VIAM results were compared with repeat conventional Pap smears, liquid-based cytologic examinations, and cervicography, with adjudication of differences by reference to MY09/MY11 L1 consensus primer polymerase chain reaction detection of oncogenic human papillomavirus DNA. Less than 5% of women were classified as having positive results using VIAM. The VIAM positivity was also very low among women with high-grade squamous intraepithelial lesion conventional Pap smear results (8.3%), high-grade squamous intraepithelial lesion liquid-based cytologic results (6.3%), or cervigrams suggesting cervical intraepithelial neoplasia 2,3 or cancer (30%). The VIAM positivity was not associated with human papillomavirus DNA positivity. As we practiced it, VIAM was not sensitive for detection of possibly serious incident cervical lesions in this previously screened population where cytologic screening is in place.


Years of running experience influences stride-to-stride fluctuations and adaptive response during step frequency perturbations in healthy distance runners.
The current study investigated stride-to-stride fluctuations of step rate and contact time in response to enforced step frequency perturbations as well as adaptation and de-adaptation behavior. Forty distance runners ran at a self-selected speed and were asked to match five different enforced step frequencies (150, 160, 170, 180, and 190 beats per min). The influence of experience was explored, because running is a skill that presumably gets better with practice, and increased years of running experience is protective against injury. Detrended fluctuation analysis was used to determine the strength of long-range correlations in gait fluctuations at baseline, during the perturbation, and post-perturbation. Adaptive response was measured by the ability to match, rate of matching, and aftereffect of step frequency perturbations. The structure of stride-to-stride fluctuations for step rate and contact time did not change during the perturbation or post-perturbation compared to baseline. However, fluctuations in step rate were affected by the level of perturbation. Runners with the most experience had a less persistent structural gait pattern for both step rate and contact time at baseline. Highly experienced runners also demonstrated the best adaptive response. They better matched the enforced step frequency, reached the enforced step frequency sooner, and returned to preferred step frequency more quickly following removal of the perturbation. These findings indicate baseline locomotor flexibility may be beneficial to achieve task demands and return to a stable state once the task is complete. Increased locomotor flexibility may also be a contributing factor for reduced injury risk in experienced runners.


Diversity of immune strategies explained by adaptation to pathogen statistics.
Biological organisms have evolved a wide range of immune mechanisms to defend themselves against pathogens. Beyond molecular details, these mechanisms differ in how protection is acquired, processed, and passed on to subsequent generations-differences that may be essential to long-term survival. Here, we introduce a mathematical framework to compare the long-term adaptation of populations as a function of the pathogen dynamics that they experience and of the immune strategy that they adopt. We find that the two key determinants of an optimal immune strategy are the frequency and the characteristic timescale of the pathogens. Depending on these two parameters, our framework identifies distinct modes of immunity, including adaptive, innate, bet-hedging, and CRISPR-like immunities, which recapitulate the diversity of natural immune systems.


Self-Assessment of Competence and Referral Behavior for Musculoskeletal Injections among Dutch General Practitioners.
General practitioners (GPs) are qualified and trained to administer therapeutic musculoskeletal injections when indicated. However, it is unknown to what extend Dutch GPs feel competent to administer these injections in clinical practice. Reluctance among GPs to inject might lead to unnecessary and costly referral to secondary care. An online and offline questionnaire was spread among Dutch GPs, querying demographics, GPs' self-assessment of injection competence, the number of administered/referred injections and management strategy for musculoskeletal injections. A total of 355 GPs responded. In total, 81% of the GPs considered themselves competent in administering musculoskeletal injections. Self-assessed incompetent GPs performed less injections the last month than self-assessed competent GPs (1.2 ± 1.4 vs 4.8 ± 4.6 injections, P < 0.001). Additionally, they referred four times more often to a colleague GP (0.4 ± 1.0 vs 0.1 ± 0.6 injections per month, P < 0.001) and twice as often to secondary care (1.0 ± 1.3 vs 0.5 ± 0.9 injections per month, P = 0.001). Self-assessed incompetence was associated with female sex (OR [95% CI] = 4.94 [2.39, 10.21]) and part-time work (OR [95% CI] = 2.58 [1.43, 4.66]). The most frequently addressed barriers were a lack of confidence in injection skills, lack of practical training, and uncertainty about the effectiveness and diagnosis of musculoskeletal injections. Although most GPs considered themselves competent to administer musculoskeletal injections, the referral rate to secondary care for several injections was strikingly high. To decrease secondary care referrals, addressing some of the most frequently indicated barriers is highly recommended.


Mercury in the Gulf of Mexico: sources to receptors.
Gulf of Mexico (Gulf) fisheries account for 41% of the U.S. marine recreational fish catch and 16% of the nation's marine commercial fish landings. Mercury (Hg) concentrations are elevated in some fish species in the Gulf, including king mackerel, sharks, and tilefish. All five Gulf states have fish consumption advisories based on Hg. Per-capita fish consumption in the Gulf region is elevated compared to the U.S. national average, and recreational fishers in the region have a potential for greater MeHg exposure due to higher levels of fish consumption. Atmospheric wet Hg deposition is estimated to be higher in the Gulf region compared to most other areas in the U.S., but the largest source of Hg to the Gulf as a whole is the Atlantic Ocean (>90%) via large flows associated with the Loop Current. Redistribution of atmospheric, Atlantic and terrestrial Hg inputs to the Gulf occurs via large scale water circulation patterns, and further work is needed to refine estimates of the relative importance of these Hg sources in terms of contributing to fish Hg levels in different regions of the Gulf. Measurements are needed to better quantify external loads, in-situ concentrations, and fluxes of total Hg and methylmercury in the water column, sediments, and food web.


Preparation of molecularly imprinted polymeric fibers using a single bifunctional monomer for the solid-phase microextraction of parabens from environmental solid samples.
In this study, molecularly imprinted polymer fibers for solid-phase microextraction have been prepared with a single bifunctional monomer, N,O-bismethacryloyl ethanolamine using the so-called "one monomer molecularly imprinted polymers" method, replacing the conventional combination of functional monomer and cross-linker to form high fidelity binding sites. For comparison, imprinted fibers were prepared following the conventional approach based on ethylene glycol dimethacrylate as cross-linker and methacrylic acid as monomer. The recognition performance of the new fibers was evaluated in the solid-phase microextraction of parabens, and from this study it was concluded that they provided superior performance over conventionally formulated fibers. Ultimately, real-world environmental testing on spiked solid samples was successful by the molecularly imprinted solid-phase microextraction of samples, and the relative recoveries obtained at enrichment levels of 10 ng/g of parabens were within 78-109% for soil and 83-109% for sediments with a relative standard deviation <15% (n = 3).


Global circulation patterns of seasonal influenza viruses vary with antigenic drift.
Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour.


Quality Indicators for Capsule Endoscopy and Deep Enteroscopy.
Capsule endoscopy (CE) and deep enteroscopy (DE) can be useful for diagnosing and treating suspected small-bowel disease. Guidelines and detailed recommendations exist for the use of CE/DE, but comprehensive quality indicators are lacking. The goal of this task force was to develop quality indicators for appropriate use of CE/DE by using a modified RAND/UCLA Appropriateness Method. An expert panel of 7 gastroenterologists with diverse practice experience was assembled to identify quality indicators. A literature review was conducted to develop a list of proposed quality indicators applicable to preprocedure, intraprocedure, and postprocedure periods. The panelists reviewed the literature; identified and modified proposed quality indicators; rated them on the basis of scientific evidence, validity, and necessity; and determined proposed performance targets. Agreement and consensus with the proposed indicators were verified using the RAND/UCLA Appropriateness Method. The voting procedure to prioritize metrics emphasized selecting measures to improve quality and overall patient care. Panelists rated indicators on the perceived appropriateness and necessity for clinical practice. After voting and discussion, 2 quality indicators ranked as inappropriate or uncertain were excluded. Each quality indicator was categorized by measure type, performance target, and summary of evidence. The task force identified 13 quality indicators for CE and DE. Comprehensive quality indicators have not existed for CE or DE. The task force identified quality indicators that can be incorporated into clinical practice. The panel also addressed existing knowledge gaps and posed research questions to better inform future research and quality guidelines for these procedures.


Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.
Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.


Multiplication method for sparse interferometric fringes.
Fringe analysis in the interferometry has been of long-standing interest to the academic community. However, the process of sparse fringe is always a headache in the measurement, especially when the specimen is very small. Through theoretical derivation and experimental measurements, our work demonstrates a new method for fringe multiplication. Theoretically, arbitrary integral-multiple fringe multiplication can be acquired by using the interferogram phase as the parameter. We simulate digital images accordingly and find that not only the skeleton lines of the multiplied fringe are very convenient to extract, but also the main frequency of which can be easily separated from the DC component. Meanwhile, the experimental results have a good agreement with the theoretic ones in a validation using the classical photoelasticity.


DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer.
Chemoprevention presents a major strategy for the medical management of colorectal cancer. Most drugs used for colorectal cancer therapy induce DNA-alkylation damage, which is primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Using an in silico approach, we performed a structure-based screen by docking small-molecules onto DNA polymerase β (Pol-β) and identified a potent anti-Pol-β compound, NSC-124854. Our goal was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA-alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-β by examining in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we investigated the effect of NSC-124854 on the efficacy of TMZ to inhibit the growth of mismatch repair (MMR)-deficient and MMR-proficient colon cancer cell lines using in vitro clonogenic assays. Third, we explored the effect of NSC-124854 on TMZ-induced in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic xenografts implanted in female homozygous SCID mice. Our data showed that NSC-124854 has high specificity to Pol-β and blocked Pol-β-directed SN- and LP-BER activities in in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR-proficient colon cancer cells both in vitro cell culture and in vivo xenograft models. Our findings suggest a potential novel strategy for the development of highly specific structure-based inhibitor for the prevention of colonic tumor progression.


Heterogeneous expression of E-cadherin and p53 in prostate cancer: clinical implications. BIOMED-II Markers for Prostate Cancer Study Group.
Histologic grade and tumor volume are markers of malignant phenotype. More objective markers, however, have been sought for needle biopsy specimens. The aim of this study was to evaluate how immunohistochemical expression of the potential prognostic markers E-cadherin and p53 in biopsy specimens relates to the expression of these markers in prostatectomy specimens. Therefore, we analyzed 47 prostatectomy specimens and their preoperative biopsy specimens. Fixation of surgical specimens and the immunohistochemical assay for both E-cadherin and p53 expression was optimized. All paraffin blocks containing areas of carcinoma were submitted for immunohistochemical analysis. The prevalence of abnormal p53 immunoreactivity was only 11%. In addition, abnormal p53 expression was virtually restricted to cases that were already identified as having a poor prognosis on the basis of the large volume and the high grade of their carcinomas. In 28% of the cases, we found abnormal immunoreactivity for E-cadherin. These cases revealed considerable heterogeneity in topographic distribution of abnormal expression. The level of sensitivity to the detection of abnormal E-cadherin expression or abnormal p53 in the prostatectomy specimen was 15% and 60%, respectively. In view of the inherent heterogeneity of E-cadherin expression and the low prevalence of abnormal p53 expression, we question the use of these markers for prognostic purposes in needle biopsy specimens. Unless representative sampling by needle biopsy can be assured, the use of E-cadherin expression will be of most value in prostatectomy specimens.


Effects of histamine, ethanol, and a detergent on exudation and absorption across guinea pig airway mucosa in vivo.
This study examined effects of three substances that cause mucosal provocation (histamine, ethanol, and the detergent dioctylsodium sulphosuccinate (DOSS] on the flux of solutes across airway vascular mucosal barriers in anaesthetised guinea pigs. The inward flux was assessed as absorption of iodine-131 labelled albumin (MW 69,000) from the tracheobronchial surface into the circulation and the outward flux as the exudation of two intravenously administered plasma tracers--125I albumin (MW 69,000) and fluorescein isothiocyanate conjugated (FITC) dextran (MW 70,000)--into the airway. The absorption of technetium-99m labelled DTPA (MW 492) from the tracheobronchial airways was determined in separate experiments. Histamine (5.0 nmol) dissolved in 40 microliters saline and superfused on the tracheobronchial mucosal surface caused significant and similar entry of 125I albumin and FITC dextran into the airway lumen. This dose of histamine did not, however, alter the absorption of small (99mTc DTPA) or large (131I albumin) solutes across the airway mucosa. Ethanol (0.17 mumol), superfused in the same way, also caused significant exudation of the plasma tracers into the airway lumen. In addition, ethanol increased the absorption of 131I albumin without causing change in the disappearance rate of 99mTc DTPA. The detergent, DOSS (0.28 nmol), dissolved in ethanol (0.17 mumol), caused a pronounced increase in exudation and much increased absorption of small and large tracer solutes. Thus three patterns of change in airway mucosal barriers were found. The agents that are toxic to membranes, ethanol and DOSS, caused a bidirectional increase in permeability across the mucosa, whereas histamine caused only an outward exudative flux. The results obtained with histamine are similar to those seen previously with bradykinin, capsaicin, and allergen, suggesting that endogenous inflammatory mediators have a role in mucosal defence, producing entry of plasma exudates into the airway lumen without increasing the mucosal absorption of luminal material.


MESOTIP: Phase II multicenter randomized trial evaluating the association of PIPAC and systemic chemotherapy vs. systemic chemotherapy alone as 1st-line treatment of malignant peritoneal mesothelioma.
Malignant peritoneal mesothelioma (MPM) is a rare tumoral disease characterized by the diffuse involvement of the peritoneal serosa. The standard frontline treatment of MPM is cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) unless the peritoneal disease is considered unresectable. For unresectable patients the standard frontline treatment is a combination of cisplatin and pemetrexed but the prognosis remains ominous with only 13 months of overall survival (OS). The proposed study is a multicenter randomized non-comparative study evaluating the association of Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) and systemic chemotherapy vs. systemic chemotherapy alone as first-line treatment of MPM. Patients will be randomized with a 2:1 ratio using a minimization technique. Sixty-six patients have to be enrolled. Stratification will be performed according to histology (epithelioid vs. sarcomatoid and biphasic), presence of extraperitoneal disease and center. Primary objective is OS and secondary objectives include progression-free survival (PFS), safety, compliance, feasibility, conversion to resectability, histological response to treatment and quality of life. We expect to show that intensification of the first line treatment with PIPAC for initially unresectable MPM patients increases OS. Prospective study. Clinicaltrials.gov: NCT03574493 EudraCT: 2019-001515-23.


Grafting single molecule magnets on gold nanoparticles.
The chemical synthesis and characterization of the first hybrid material composed by gold nanoparticles and single molecule magnets (SMMs) are described. Gold nanoparticles are functionalized via ligand exchange using a tetrairon(III) SMM containing two 1,2-dithiolane end groups. The grafting is evidenced by the shift of the plasmon resonance peak recorded with a UV-vis spectrometer, by the suppression of nuclear magnetic resonance signals, by X-ray photoemission spectroscopy peaks, and by transmission electron microscopy images. The latter evidence the formation of aggregates of nanoparticles as a consequence of the cross-linking ability of Fe4 through the two 1,2-dithiolane rings located on opposite sides of the metal core. The presence of intact Fe4 molecules is directly proven by synchrotron-based X-ray absorption spectroscopy and X-ray magnetic circular dichroism spectroscopy, while a detailed magnetic characterization, obtained using electron paramagnetic resonance and alternating-current susceptibility, confirms the persistence of SMM behavior in this new hybrid nanostructure.


Hip protector compliance among older people living in residential care homes.
To estimate the compliance rates for the use of hip protectors among people living in residential care homes. Population/setting: People aged 65 years and over living in residential care homes with 20 or more beds in East Kent, south east England. Seventeen homes with the highest historical frequency of hip fractures were selected. All residents were offered SAFEHIP hip protectors. Care staff recorded daily hip protector compliance on diary cards over six months. Compliance rates were estimated from the number of sessions (morning, afternoon, evening, night) that a person wore hip protectors. A total of 153 (51%) out of 299 residents agreed to wear hip protectors The 24 hour compliance rate for those who were issued with hip protectors and wore them at least once was 29%: 37% in the daytime and 3% at night. Daytime compliance rates reduced from 47% for the first month, to around 30% for months 5 and 6. This study highlights the problems of persuading older people living in residential care homes to wear hip protectors. They have been shown to prevent hip fracture in nursing home (high risk) populations, and a recent trial showed their effectiveness in a mixed geriatric population. People living in residential care homes are also at greater risk of falling and fracturing than their counterparts living in the community. Initiatives to prevent hip fracture within residential care homes are also justified.


How does the purpose of inspection influence the potency of visual salience in scene perception?
Salience-map models have been taken to suggest that the locations of eye fixations are determined by the extent of the low-level discontinuities in an image. While such models have found some support, an increasing emphasis on the task viewers are performing implies that these models must combine with cognitive demands to describe how the eyes are guided efficiently. An experiment is reported in which eye movements to objects in photographs were examined while viewers performed a memory-encoding task or one of two search tasks. The objects depicted in the scenes had known salience ranks according to a popular model. Participants fixated higher-salience objects sooner and more often than lower-salience objects, but only when memorising scenes. This difference shows that salience-map models provide useful predictions even in complex scenes and late in viewing. However, salience had no effects when searching for a target defined by category or exemplar. The results suggest that salience maps are not used to guide the eyes in these tasks, that cognitive override by task demands can be total, and that modelling top-down search is important but may not be easily accomplished within a salience-map framework.


International spread of multidrug-resistant Salmonella Schwarzengrund in food products.
We compared 581 Salmonella enterica serotype Schwarzengrund isolates from persons, food, and food animals in Denmark, Thailand, and the United States by antimicrobial drug susceptibility and pulsed-field gel electrophoresis (PFGE) typing. Resistance, including resistance to nalidixic acid, was frequent among isolates from persons and chickens in Thailand, persons in the United States, and food imported from Thailand to Denmark and the United States. A total of 183 PFGE patterns were observed, and 136 (23.4%) isolates had the 3 most common patterns. Seven of 14 isolates from persons in Denmark had patterns found in persons and chicken meat in Thailand; 22 of 390 human isolates from the United States had patterns found in Denmark and Thailand. This study suggests spread of multidrug-resistant S. Schwarzengrund from chickens to persons in Thailand, and from imported Thai food products to persons in Denmark and the United States.


Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.
Occasionally, 2 or more major neurodegenerative diseases arise simultaneously. An understanding of the genetic bases of combined disorders, such as amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), will likely provide insight into mechanisms of these and related neurodegenerative diseases. To identify loci that contain genes whose defects cause ALS. A genome-wide linkage analysis of 2 data sets from an ongoing study begun in the mid-1980s at 4 university research centers. An initial subset of 16 families (549 people) potentially informative for genetic analysis, in which 2 or more individuals were diagnosed as having ALS, identified from a Boston data set of 400 families and 4 families potentially informative (244 people) subsequently identified from a Chicago data set of more than 300 families to test a hypothesis based on findings from the Boston families. Linkage calculations assuming autosomal dominant inheritance with age-dependent penetrance (a parametric logarithm-of-odds [lod] score of 1.0 or greater required for further study of a potential locus); crossover analysis involving the ALS-FTD locus. In a set of families in which persons develop both ALS and FTD or either ALS or FTD alone, a genetic locus that is linked to ALS with FTD located between markers D9S301 and D9S167 was identified on human chromosome 9q21-q22. Families with ALS alone did not show linkage to this locus. Crossover analysis indicates this region covers approximately 17 cM. These data suggest that a defective gene located in the chromosome 9q21-q22 region may be linked to ALS with FTD. JAMA. 2000;284:1664-1669.


The development of adolescent social cognition.
Adolescence has long been considered a turbulent time; beginning with large changes in hormonal levels and consequent bodily changes, as well as changes in behavior. Recently, neuroscience studies have contributed to this picture of turbulence. We now know that the brain undergoes profound transformation during the teenage years. This paper focuses on how the social brain--the network of brain regions involved in understanding other people and self-awareness--develops during adolescence.


Carbon loss from an unprecedented Arctic tundra wildfire.
Arctic tundra soils store large amounts of carbon (C) in organic soil layers hundreds to thousands of years old that insulate, and in some cases maintain, permafrost soils. Fire has been largely absent from most of this biome since the early Holocene epoch, but its frequency and extent are increasing, probably in response to climate warming. The effect of fires on the C balance of tundra landscapes, however, remains largely unknown. The Anaktuvuk River fire in 2007 burned 1,039 square kilometres of Alaska's Arctic slope, making it the largest fire on record for the tundra biome and doubling the cumulative area burned since 1950 (ref. 5). Here we report that tundra ecosystems lost 2,016 ± 435 g C m(-2) in the fire, an amount two orders of magnitude larger than annual net C exchange in undisturbed tundra. Sixty per cent of this C loss was from soil organic matter, and radiocarbon dating of residual soil layers revealed that the maximum age of soil C lost was 50 years. Scaled to the entire burned area, the fire released approximately 2.1 teragrams of C to the atmosphere, an amount similar in magnitude to the annual net C sink for the entire Arctic tundra biome averaged over the last quarter of the twentieth century. The magnitude of ecosystem C lost by fire, relative to both ecosystem and biome-scale fluxes, demonstrates that a climate-driven increase in tundra fire disturbance may represent a positive feedback, potentially offsetting Arctic greening and influencing the net C balance of the tundra biome.


In vitro/in vivo evaluation of the efficiency of teicoplanin-loaded biodegradable microparticles formulated for implantation to infected bone defects.
Chronic osteomyelitis is still the cause of many problems in orthopaedics in terms of therapy and infection persistence. Four-to-six week systemic antibiotic therapy is required along with bone and soft tissue debridement in the therapy of chronic osteomyelitis. Prolonged-release local antibiotic therapy has been taken into consideration due to the side effects encountered in long-term high dose antibiotic use and the duration of hospitalization of the patients. Although local antibiotic therapy has been achieved by bone cement, a second surgical operation is needed for the removal of the system. On the other hand, heat generation during cement curing limits the use of heat-sensitive active ingredients. The most frequent osteomyelitis inducing micro-organism is gram (+) Staphylococcus aureus. In this study, teicoplanin, a glycopeptide antibiotic, active on gram (+) bacteria, was incorporated in a synthetic polymer in order to prepare a microsphere formulation for implantation to bone defects. Particle size, surface characteristics, loading capacity and in vitro release characteristics of the microspheres were determined as well as stability assessment of teicoplanin under accelerated conditions. In vivo studies were performed on rabbits and the microparticles were implanted intra-articularly to the lateral condylus of the femur. Antibiotic presence was detected by a microbiological assay from synovial fluid sample aspirated throughout 5 weeks. In the light of these evaluations, microspheres prepared from PLGA (75:25) (Mw 136,000) polymer were determined to be effective, and promising for obtaining prolonged local antibiotic release.


Functional characterization of the NS2B/NS3 protease complex from seven viruses belonging to different groups inside the genus Flavivirus.
The genus Flavivirus, family Flaviviridae, comprises more than 70 viruses. Many of them cause severe, potentially fatal, human diseases. Human vaccines are available for only three viruses and no effective antiviral drug is available. In order to limit the consequences of infections with flaviviruses, a promising approach consists in developing specific compounds that target the virus-encoded NS2B/NS3 protease complex, which is crucial for the viral polyprotein processing. In order to develop such compounds active as antiviral drugs against several flaviviruses, identification of biochemical properties shared by proteases from different viruses is essential. In this work, the functional similarity between the proteases from seven flaviviruses belonging to different major groups was addressed by characterizing their enzymatic properties. For each virus, a catalytically active recombinant protease was designed and expressed as a hexahistidine-tagged protein. Chromogenic and fluorogenic substrates were used to identify optimal conditions for proteolysis. Our study identified important physico-chemical properties shared by all the seven proteases we studied (high pH value requirement for optimal activity, inhibition of substrate processing by salt). However, it also evidenced slight differences in biochemical properties of the flaviviral proteases, which could sustain heterogeneous sensitivity to future inhibitors.