Spatial and temporal patterns of dengue incidence in northeastern Thailand 2006-2016.
Dengue, a viral disease transmitted by Aedes mosquitoes, is an important public health concern throughout Thailand. Climate variables are potential predictors of dengue transmission. Associations between climate variables and dengue have usually been performed on large-scale first-level national administrative divisions, i.e. provinces. Here we analyze data on a finer spatial resolution in one province, which is often more relevant for effective disease control design. The objective of this study was to investigate the effect of seasonal variations, monthly climate variability, and to identify local clusters of symptomatic disease at the sub-district level based on reported dengue cases. Data on dengue cases were retrieved from the national communicable disease surveillance system in Thailand. Between 2006 and 2016, 15,167 cases were recorded in 199 sub-districts of Khon Kaen Province, northeastern Thailand. Descriptive analyses included demographic characteristics and temporal patterns of disease and climate variables. The association between monthly disease incidence and climate variations was analyzed at the sub-district level using Bayesian Poisson spatial regression. A hotspot analysis was used to assess the spatial patterns (clustered/dispersed/random) of dengue incidence. Dengue was predominant in the 5-14 year-old age group (51.1%). However, over time, dengue incidence in the older age groups (> 15 years) gradually increased and was the most affected group in 2013. Dengue outbreaks coincide with the rainy season. In the spatial regression model, maximum temperature was associated with higher incidence. The hotspot analysis showed clustering of cases around the urbanized area of Khon Kaen city and in rural areas in the southwestern portion of the province. There was an increase in the number of reported dengue cases in older age groups over the study period. Dengue incidence was highly seasonal and positively associated with maximum ambient temperature. However, climatic variables did not explain all the spatial variation of dengue in the province. Further analyses are needed to clarify the detailed effects of urbanization and other potential environmental risk factors. These results provide useful information for ongoing prediction modeling and developing of dengue early warning systems to guide vector control operations.


Isolated supraclavicular lymph node metastasis in pancreatic adenocarcinoma: a report of three cases and review of the literature.
Supraclavicular lymph nodes represent a rare site of metastasis in pancreatic cancer. We report three cases of pancreatic adenocarcinoma with metastases to supraclavicular lymph nodes. A 51-year-old male was diagnosed with locally advanced pancreatic adenocarcinoma on computed tomography (CT) scan. He was recommended neoadjuvant chemotherapy followed by chemoradiation therapy. However, positron emission tomography (PET)/CT scans and subsequent fine needle aspiration cytology showed supraclavicular lymph node metastasis. The patient received systemic chemotherapy for metastatic pancreatic adenocarcinoma. The second patient, a 66-year-old female with pancreatic adenocarcinoma, underwent pancreaticoduodenectomy and was found to have peripancreatic lymph node involvement. She received adjuvant chemotherapy and was followed-up with surveillance CT scans, which did not reveal any metastasis. However, the patient complained of neck swelling. PET/CT scan and biopsy revealed supraclavicular lymph node metastasis from a pancreatic adenocarcinoma primary. The third patient, a 79-year-old male with a past history of thyroid carcinoma who was treated with partial thyroidectomy, developed neck swelling 4 years after his surgery. Fine needle aspiration cytology was consistent with known papillary thyroid carcinoma. Staging evaluations revealed a pancreatic mass for which he underwent subtotal pancreatectomy and splenectomy. Histopathology revealed grade 3 pancreatic adenocarcinoma. Excisional biopsy of a supraclavicular lymph node showed metastatic pancreatic adenocarcinoma. PET/CT results were consistent with these findings. In patients with pancreatic adenocarcinoma, supraclavicular lymph node metastasis represents an uncommon, but clinically significant finding that can lead to changes in treatment planning. PET imaging represents a valuable tool in the detection and follow up of these patients.


Maximum a posteriori estimator for high-contrast image composition of optical coherence tomography.
A quantitative signal amplitude estimator for optical coherence tomography (OCT) is presented. It is based on a statistical model of OCT signal and noise, using a Bayesian maximum a posteriori (MAP) estimation framework. Multiple OCT images are used for estimation, similar to the widely utilized intensity averaging method. The estimator is less biased especially at low-intensity regions, where intensity averaging approaches the noise power and hence is biased. The estimator is applied to posterior ocular OCT images and provides high-contrast visualization of pathologies. In addition, histogram analysis objectively shows the superior performance of the estimator compared with intensity averaging.


Three multidomain esterases from the cellulolytic rumen anaerobe Ruminococcus flavefaciens 17 that carry divergent dockerin sequences.
Three enzymes carrying esterase domains have been identified in the rumen cellulolytic anaerobe Ruminococcus flavefaciens 17. The newly characterized CesA gene product (768 amino acids) includes an N-terminal acetylesterase domain and an unidentified C-terminal domain, while the previously characterized XynB enzyme (781 amino acids) includes an internal acetylesterase domain in addition to its N-terminal xylanase catalytic domain. A third gene, xynE, is predicted to encode a multidomain enzyme of 792 amino acids including a family 11 xylanase domain and a C-terminal esterase domain. The esterase domains from CesA and XynB share significant sequence identity (44%) and belong to carbohydrate esterase family 3; both domains are shown here to be capable of deacetylating acetylated xylans, but no evidence was found for ferulic acid esterase activity. The esterase domain of XynE, however, shares 42% amino acid identity with a family 1 phenolic acid esterase domain identified from Clostridum thermocellum XynZ. XynB, XynE and CesA all contain dockerin-like regions in addition to their catalytic domains, suggesting that these enzymes form part of a cellulosome-like multienzyme complex. The dockerin sequences of CesA and XynE differ significantly from those previously described in R. flavefaciens polysaccharidases, including XynB, suggesting that they might represent distinct dockerin specificities.


Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction.
Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals, and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, and 6 weeks) or high-efficiency particulate absorbing-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone, and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5- to 2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.


From welcome culture to welcome limits? Uncovering preference changes over time for sheltering refugees in Germany.
Europe recently experienced a large influx of refugees, spurring much public debate about the admission and integration of refugees and migrants into society. Previous research based on cross-sectional data found that European citizens generally favour asylum seekers with high employability, severe vulnerabilities, and Christians over Muslims. These preferences and attitudes were found to be homogeneous across countries and socio-demographic groups. Here, we do not study the general acceptance of asylum seekers, but the acceptance of refugee and migrant homes in citizens' vicinity and how it changes over time. Based on a repeated stated choice experiment on preferences for refugee and migrant homes, we show that the initially promoted "welcome culture" towards refugees in Germany was not reflected in the views of a majority of a sample of German citizens who rather disapproved refugee homes in their vicinity. Their preferences have not changed between November 2015, the peak of "welcome culture," and November 2016, after political debates, media reporting and public discourse had shifted towards limiting admission of immigrants. A minority of one fifth of the sample population, who were initially rather approving of refugee and migrant homes being established in their vicinity, were more likely to change their preferences towards a rather disapproving position in 2016. Experience of contact with refugees and migrants, higher education, and general pro-immigration attitudes explain acceptance of refugee and migrant homes as well as preference stability over time. Country of origin and religion of refugees and migrants are considered less important than decent housing conditions and whether refugee and migrants arrive as families or single persons. In this respect our results highlight the importance of humanitarian aspects of sheltering and integration of refugees and other migrants into society.


Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes.
S. cerevisiae RAD50, MRE11, and XRS2 genes are required for telomere maintenance, cell cycle checkpoint signaling, meiotic recombination, and the efficient repair of DNA double-strand breaks (DSB)s by homologous recombination and nonhomologous end-joining (NHEJ). Here, we demonstrate that the complex formed by Rad50, Mre11, and Xrs2 proteins promotes intermolecular DNA joining by DNA ligase IV (Dnl4) and its associated protein Lif1. Our results show that the Rad50/Mre11/Xrs2 complex juxtaposes linear DNA molecules via their ends to form oligomers and interacts directly with Dnl4/Lif1. We also demonstrate that Rad50/Mre11/Xrs2-mediated intermolecular DNA joining is further stimulated by Hdf1/Hdf2, the yeast homolog of the mammalian Ku70/Ku80 heterodimer. These studies reveal specific functional interplay among the Hdf1/Hdf2, Rad50/Mre11/Xrs2, and Dnl4/Lif1 complexes in NHEJ.


Flexibility of Gut Microbiota in Ageing Individuals during Dietary Fiber Long-Chain Inulin Intake.
During ageing, dysbiosis in the intestinal microbiota may occur and impact health. There is a paucity of studies on the effect of fiber on the elderly microbiota and the flexibility of the aged microbiota upon prebiotic intake. It is hypothesized that chicory long-chain inulin consumption can change microbiota composition, microbial fermentation products, and immunity in the elderly. A double-blind, placebo-controlled trial is performed in healthy individuals (55-80 years), in which microbiota composition is studied before, during, and after two months of chicory long-chain inulin consumption. Fecal short chain fatty acid concentrations, T cell subsets, and antibody responses against a Hepatitis B (HB) vaccine are measured as well. Inulin consumption modified the microbiota composition, as measured by 16S rRNA sequencing. Participants consuming inulin have higher microbial diversity and a relatively higher abundance of the Bifidobacterium genus, as well as Alistipes shahii, Anaerostipes hadrus, and Parabacteroides distasonis. While the immune responses remain unchanged, the isobutyric acid levels, an undesired fermentation product, tend to be lower in the inulin group. Overall, it is shown that the gut microbiota composition is still sensitive to chicory long-chain inulin induced changes in an ageing population, although this did not translate into an improved immune response to an HB vaccine.


COMMIT: Convex optimization modeling for microstructure informed tractography.
Tractography is a class of algorithms aiming at in vivo mapping the major neuronal pathways in the white matter from diffusion magnetic resonance imaging (MRI) data. These techniques offer a powerful tool to noninvasively investigate at the macroscopic scale the architecture of the neuronal connections of the brain. However, unfortunately, the reconstructions recovered with existing tractography algorithms are not really quantitative even though diffusion MRI is a quantitative modality by nature. As a matter of fact, several techniques have been proposed in recent years to estimate, at the voxel level, intrinsic microstructural features of the tissue, such as axonal density and diameter, by using multicompartment models. In this paper, we present a novel framework to reestablish the link between tractography and tissue microstructure. Starting from an input set of candidate fiber-tracts, which are estimated from the data using standard fiber-tracking techniques, we model the diffusion MRI signal in each voxel of the image as a linear combination of the restricted and hindered contributions generated in every location of the brain by these candidate tracts. Then, we seek for the global weight of each of them, i.e., the effective contribution or volume, such that they globally fit the measured signal at best. We demonstrate that these weights can be easily recovered by solving a global convex optimization problem and using efficient algorithms. The effectiveness of our approach has been evaluated both on a realistic phantom with known ground-truth and in vivo brain data. Results clearly demonstrate the benefits of the proposed formulation, opening new perspectives for a more quantitative and biologically plausible assessment of the structural connectivity of the brain.


Epidemiology, treatment and outcome of patients with lower respiratory tract infection presenting to emergency departments with dyspnoea (AANZDEM and EuroDEM studies).
Lower respiratory tract infection (LRTI) is a frequent cause of dyspnoea in EDs, and is associated with considerable morbidity and mortality. We described and compared the management of this disease in Europe and Oceania/South-East Asia (SEA) cohorts. We conducted a prospective cohort study with three time points in Europe and Oceania/SEA. We included in this manuscript patients presenting to EDs with dyspnoea and a diagnosis of LRTI in ED. We collected comorbidities, chronic medication, clinical signs at arrival, laboratory parameters, ED management and patient outcomes. A total of 1389 patients were included, 773 in Europe and 616 in SEA. The European cohort had more comorbidities including chronic heart failure, obesity, chronic obstructive pulmonary disease and smoking. Levels of inflammatory markers were higher in Europe. There were more patients with inflammatory markers in Europe and more hypercapnia in Oceania/SEA. The use of antibiotics was higher in SEA (72.2% vs 61.8%, P < 0.001) whereas intravenous diuretics, non-invasive and invasive ventilation were higher in Europe. Intensive care unit admission rate was 9.9% in Europe cohort and 3.4% in Oceania/SEA cohort. ED mortality was 1% and overall in-hospital mortality was 8.7% with no differences between regions. More patients with LRTI in Europe presented with cardio-respiratory comorbidities, they received more adjunct therapies and had a higher intensive care unit admission rate than patients from Oceania/SEA, although mortality was similar between the two cohorts.


Kinetic and docking studies of phenol-based inhibitors of carbonic anhydrase isoforms I, II, IX and XII evidence a new binding mode within the enzyme active site.
Carbonic anhydrases (CAs, EC 126.96.36.199) are inhibited by sulfonamides, inorganic anions, phenols, coumarins (acting as prodrugs) and polyamines. A novel class of CA inhibitors (CAIs), interacting with the CA isozymes I, II (cytosolic) and IX, XII (transmembrane, tumor-associated) in a different manner, is reported here. Kinetic measurements allowed us to identify hydroxy-/methoxy-substituted benzoic acids as well as di-/tri-methoxy benzenes as submicromolar-low micromolar inhibitors of the four CA isozymes. Molecular docking studies of a set of such inhibitors within CA I and II allowed us to understand the inhibition mechanism. This new class of inhibitors binds differently compared to all other classes of inhibitors known to date: they were found between the phenol-binding site and the coumarin-binding site, filling thus the middle of the enzyme cavity. They exploit different interactions with amino acid residues and water molecules from the CA active site compared to other classes of inhibitors, offering the possibility to design CAIs with an interesting inhibition profile compared to the clinically used sulfonamides/sulfamates.


Warmer temperatures reduce the influence of an important keystone predator.
Predator-prey interactions may be strongly influenced by temperature variations in marine ecosystems. Consequently, climate change may alter the importance of predators with repercussions for ecosystem functioning and structure. In North-eastern Pacific kelp forests, the starfish Pycnopodia helianthoides is known to be an important predator of the purple sea urchin Strongylocentrotus purpuratus. Here we investigated the influence of water temperature on this predator-prey interaction by: (i) assessing the spatial distribution and temporal dynamics of both species across a temperature gradient in the northern Channel Islands, California, and (ii) investigating how the feeding rate of P. helianthoides on S. purpuratus is affected by temperature in laboratory tests. On average, at sites where mean annual temperatures were <14 °C, P. helianthoides were common, S. purpuratus was rare and kelp was persistent, whereas where mean annual temperatures exceeded 14 °C, P. helianthoides and kelp were rare and S. purpuratus abundant. Temperature was found to be the primary environmental factor influencing P. helianthoides abundance, and in turn P. helianthoides was the primary determinant of S. purpuratus abundance. In the laboratory, temperatures >16 °C (equivalent to summer temperatures at sites where P. helianthoides were rare) reduced predation rates regardless of predator and prey sizes, although larger sea urchins were consumed only by large starfishes. These results clearly demonstrate that the effect of P. helianthoides on S. purpuratus is strongly mediated by temperature, and that the local abundance and predation rate of P. helianthoides on sea urchins will likely decrease with future warming. A reduction in top-down control on sea urchins, combined with other expected impacts of climate change on kelp, poses significant risks for the persistence of kelp forests in the future.


Emergency Medical Text Classifier: New system improves processing and classification of triage notes.
Automated syndrome classification aims to aid near real-time syndromic surveillance to serve as an early warning system for disease outbreaks, using Emergency Department (ED) data. We present a system that improves the automatic classification of an ED record with triage note into one or more syndrome categories using the vector space model coupled with a 'learning' module that employs a pseudo-relevance feedback mechanism. Terms from standard syndrome definitions are used to construct an initial reference dictionary for generating the syndrome and triage note vectors. Based on cosine similarity between the vectors, each record is classified into a syndrome category. We then take terms from the top-ranked records that belong to the syndrome of interest as feedback. These terms are added to the reference dictionary and the process is repeated to determine the final classification. The system was tested on two different datasets for each of three syndromes: Gastro-Intestinal (GI), Respiratory (Resp) and Fever-Rash (FR). Performance was measured in terms of sensitivity (Se) and specificity (Sp). The use of relevance feedback produced high values of sensitivity and specificity for all three syndromes in both test sets: GI: 90% and 71%, Resp: 97% and 73%, FR: 100% and 87%, respectively, in test set 1, and GI: 88% and 69%, Resp: 87% and 61%, FR: 97% and 71%, respectively, in test set 2. The new system for pre-processing and syndromic classification of ED records with triage notes achieved improvements in Se and Sp. Our results also demonstrate that the system can be tuned to achieve different levels of performance based on user requirements.


Characterization of uptake of the new PET imaging compound 18F-fluorobenzyl triphenyl phosphonium in dog myocardium.
18F-Labeled p-fluorobenzyl triphenyl phosphonium cation (18F-FBnTP) is a member of a new class of positron-emitting lipophilic cations that may act as myocardial perfusion PET tracers. Here, we characterize the 18F-FBnTP uptake and retention kinetics, in vitro and in vivo, as well as the myocardial and whole-body biodistribution in healthy dogs, using PET. Time-dependent accumulation and retention of 18F-FBnTP in myocytes in vitro was studied. Seven anesthetized, mongrel dogs underwent dynamic PET scans of the heart after intravenous administration of 126-240 MBq 18F-FBnTP. In 4 of the 7 dogs, at the completion of a 60-min dynamic scan, whole-body scans (4 bed positions, 5-min emission and 3-min transmission per bed) were acquired. Arterial blood samples were collected at 0, 5, 10, 20, 30, and 60 min after administration, plasma activity was counted, and high-performance liquid chromatographic analyses for metabolites were performed. The extent of defluorination was assessed by measuring 18F-FBnTP bone uptake in mice, compared with 18F-fluoride. The metabolite fraction comprised <5% of total activity in blood at 5 min and gradually increased to 25% at 30 min after injection. In vivo, 18F-FBnTP myocardial concentration reached a plateau level within a few minutes, which was retained throughout the scanning time. In contrast, activity in the blood pool and lungs cleared rapidly (half-life = 19.5 +/- 4.4 and 30.7 +/- 11.6 s, respectively). Liver uptake did not exceed the activity measured in the myocardium. At 60 min, the uptake ratios of left ventricular wall to blood, lung, and liver (mean of 7 dogs) were 16.6, 12.2, and 1.2, respectively. Summation of activity from 5 to 15 min and from 30 to 60 min after injection produced high-quality cardiac images of similar contrast. Circumferential sampling and a polar plot revealed a uniform distribution, near unitary value, throughout the entire myocardium. The mean coefficient of variance, on 30- to 60-min images along the septum-to-anterior wall and the apex-to-base axes was 7.58% +/- 1.04% and 6.11% +/- 0.89% (mean +/- SD; n = 7), respectively, and on 5- to 15-min images was 7.25% +/- 1.43% and 6.12% +/- 1.88%, respectively. 18F-FBnTP whole-body distribution was highly organ specific with the kidney cortex being the major target organ, followed by the heart and the liver. 18F-FBnTP is a promising new radionuclide for cardiac imaging using PET with rapid kinetics, uniform myocardial distribution, and favorable organ biodistribution.


Domain unfolding plays a role in superfibronectin formation.
Superfibronectin (sFN) is a fibronectin (FN) aggregate that is formed by mixing FN with anastellin, a fragment of the first type III domain of FN. However, the mechanism of this aggregation has not been clear. In this study, we found that anastellin co-precipitated with FN in a ratio of approximately 4:1, anastellin:FN monomer. The primary binding site for anastellin was in the segment (III)1-3, which bound three molecules of anastellin and was able to form a precipitate without the rest of the FN molecule. Anastellin binding to (III)3 caused a conformational change in that domain that exposed a cryptic thermolysin-sensitive site. An additional anastellin binds to (III)11, where it enhances thermolysin digestion of (III)11. An engineered disulfide bond in (III)3 inhibited both aggregation and protease digestion, suggesting that the stability of (III)3 is a key factor in sFN formation. We propose a three-step model for sFN formation: 1) FN-III domains spontaneously unfold and refold; 2) anastellin binds to an unfolded domain, preventing its refolding and leaving it with exposed hydrophobic surfaces and beta-sheet edges; and 3) these exposed elements bind to similar exposed elements on other molecules, leading to aggregation. The model is consistent with our observation that the kinetics of aggregation are first order, with a reaction time of 500-700 s. Similar mechanisms may contribute to the assembly of the native FN matrix.


Melt Electrowritten In Vitro Radial Device to Study Cell Growth and Migration.
The development of in vitro assays for 3D microenvironments is essential for understanding cell migration processes. A 3D-printed in vitro competitive radial device is developed to identify preferred Matrigel concentration for glioblastoma migration. Melt electrowriting (MEW) is used to fabricate the structural device with defined and intricate radial structures that are filled with Matrigel. Controlling the printing path is necessary to account for the distance lag in the molten jet, the applied electric field, and the continuous direct-writing nature of MEW. Circular printing below a diameter threshold results in substantial inward tilting of the MEW fiber wall. An eight-chamber radial device with a diameter of 9.4 mm is printed. Four different concentrations of Matrigel are dispensed into the radial chambers. Glioblastoma cells are seeded into the center and grow into all chambers within 8 days. The cell spreading area demonstrates that 6 and 8 mg mL-1 of Matrigel are preferred over 2 and 4 mg mL-1 . Furthermore, topographical cues via the MEW fiber wall are observed to promote migration even further away from the cell seeding depot. Previous studies implement MEW to fabricate cell invasive scaffolds whereas here it is applied to 3D-print in vitro tools to study cell migration.


Survival of filamentous fungi in hypersaline Dead Sea water.
A variety of filamentous fungi have recently been isolated from the Dead Sea (340 g/L total dissolved salts). To assess the extent to which such fungi can survive for prolonged periods in Dead Sea water, we examined the survival of both spores and mycelia in undiluted Dead Sea water and in Dead Sea water diluted to different degrees with distilled water. Mycelia of Aspergillus versicolor and Chaetomium globosum strains isolated from the Dead Sea remained viable for up to 8 weeks in undiluted Dead Sea water. Four Dead Sea isolates (A. versicolor, Eurotium herbariorum, Gymnascella marismortui, and C. globosum) retained their viability in Dead Sea water diluted to 80% during the 12 weeks of the experiment. Mycelia of all species survived for the full term of the experiment in Dead Sea water diluted to 50% and 10% of its original salinity. Comparison of the survival of Dead Sea species and closely related isolates obtained from other locations showed prolonged viability of the strains obtained from the Dead Sea. Spores of isolates obtained from the terrestrial shore of the Dead Sea generally proved less tolerant to suspension in undiluted Dead Sea water than spores of species isolated from the water column. Spores of the species isolated from the control sites had lost their viability in undiluted Dead Sea water within 12 weeks. However, with the exception of Emericella spores, which showed poor survival, a substantial fraction of the spores of Dead Sea fungal isolates remained viable for that period. The difference in survival rate between spores and mycelia of isolates of the same species points to the existence of adapted halotolerant and/or halophilic fungi in the Dead Sea.


The Mutation Rate and the Age of the Sex Chromosomes in Silene latifolia.
Many aspects of sex chromosome evolution are common to both plants and animals [1], but the process of Y chromosome degeneration, where genes on the Y become non-functional over time, may be much slower in plants due to purifying selection against deleterious mutations in the haploid gametophyte [2, 3]. Testing for differences in Y degeneration between the kingdoms has been hindered by the absence of accurate age estimates for plant sex chromosomes. Here, we used genome resequencing to estimate the spontaneous mutation rate and the age of the sex chromosomes in white campion (Silene latifolia). Screening of single nucleotide polymorphisms (SNPs) in parents and 10 F1 progeny identified 39 de novo mutations and yielded a rate of 7.31 × 10-9 (95% confidence interval: 5.20 × 10-9 - 8.00 × 10-9) mutations per site per haploid genome per generation. Applying this mutation rate to the synonymous divergence between homologous X- and Y-linked genes (gametologs) gave age estimates of 11.00 and 6.32 million years for the old and young strata, respectively. Based on SNP segregation patterns, we inferred which genes were Y-linked and found that at least 47% are already dysfunctional. Applying our new estimates for the age of the sex chromosomes indicates that the rate of Y degeneration in S. latifolia is nearly 2-fold slower when compared to animal sex chromosomes of a similar age. Our revised estimates support Y degeneration taking place more slowly in plants, a discrepancy that may be explained by differences in the life cycles of animals and plants.


Glutamine-induced free radical production in cultured astrocytes.
Ammonia is a neurotoxin implicated in the pathogenesis of hepatic encephalopathy, Reye's syndrome, inborn errors of the urea cycle, glutaric aciduria, and other metabolic encephalopathies. Brain ammonia is predominantly metabolized to glutamine in astrocytes by glutamine synthetase. While the synthesis of glutamine has generally been viewed as the principal means of ammonia detoxification, this presumed beneficial effect has been questioned as growing evidence suggest that some of the deleterious effects of ammonia may be mediated by glutamine rather than ammonia per se. Since ammonia is known to induce the production of free radicals in cultured astrocytes, we investigated whether such production might be mediated by glutamine. Treatment of astrocytes with glutamine (4.5 mM) increased free radical production at 2-3 min (95%; P < 0.05), as well as at 1 and 3 h (42% and 49%, respectively; P < 0.05). Similarly treated cultured neurons failed to generate free radicals. Free radical production by glutamine was blocked by the antioxidants deferoxamine (40 microM) and alpha-phenyl-N-tert-butyl-nitrone (250 microM), as well as by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (500 microM). Free radical production was also blocked by 6-diazo-5-oxo-L-norleucine (1 mM), an inhibitor of glutaminase, suggesting that ammonia released by glutamine hydrolysis may be responsible for the generation of free radicals. Additionally, the mitochondrial permeability transition inhibitor, cyclosporin A, blocked free radical production by glutamine. The results indicate that astrocytes, but not neurons, generate free radicals following glutamine exposure. Glutamine-induced oxidative and/or nitrosative stress may represent a key mechanism in ammonia neurotoxicity.


Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection.
Secondary bacterial pneumonia following influenza virus infection is associated with high mortality, but the mechanism is largely unknown. Epigenetic gene regulation appears to play key roles in innate and adaptive immunity. We hypothesized that histone acetylation, a major epigenetic mechanism associated with transcriptionally active chromatin, might contribute to the poor outcome of postinfluenza pneumonia. Prospective experimental study. University research laboratory. C57BL/6 male mice. Mice were infected intranasally with 1.0 × 10 colony-forming units of Streptococcus pneumoniae, 7 days after intranasal inoculation with five plaque-forming units of influenza virus A/H1N1/PR8/34. The mice were intraperitoneally injected with the histone deacetylase inhibitor trichostatin A (1 mg/kg) or vehicle once a day from 1 hour after pneumococcal infection throughout the course of the experiment. The primary outcome was survival rate. Trichostatin A significantly suppressed histone deacetylase activity and significantly improved the survival rate of mice (56.3%) after postinfluenza pneumococcal infection when compared with vehicle-treated mice (20.0%), which was associated with a significant decrease in the total cell count of the bronchoalveolar lavage fluid. The interleukin-1β level in the serum and the number of natural killer cells in the lungs were significantly lower in the trichostatin A-treated group. The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.


Animal models of Alzheimer's disease and drug development.
Animal disease models are considered important in the development of drugs for Alzheimer's disease. This brief review will discuss possible reasons why their success in identifying efficacious treatments has been limited, and will provide some thoughts on the role of animal experimentation in drug development. Specifically, none of the current models of Alzheimer's disease have either construct or predictive validity, and no model probably ever will. Clearly, specific animal experiments contribute to our understanding of the disease and generate hypotheses. Ultimately, however, the hypothesis can only be tested in human patients and only with the proper tools. These tools are a pharmacologically active intervention (in humans) and a clinical trial suited to evaluate the mechanism of action. Integration of knowledge in quantitative (sub) models is considered important if not essential in this process.


The failure of rodent carcinogenesis as a model for Man.
Recent advances in our understanding of the process of carcinogenesis in Man have required revision of our thinking about the classical initiation/promotion sequence; understanding must now encompass the roles of both genetic and epigenetic change, realisation of the importance of the variable genetic backgrounds of the tumour bearers in any group and an understanding of the importance of random genetic events over time. The behavior of tumours, once established, is more complex than has been thought. Current views of the processes involved are not modelled in toxicity testing programmes.


Effects of a Major Tree Invader on Urban Woodland Arthropods.
Biological invasions are a major threat to biodiversity; however, the degree of impact can vary depending on the ecosystem and taxa. Here, we test whether a top invader at a global scale, the tree Robinia pseudoacacia (black locust or false acacia), which is known to profoundly change site conditions, significantly affects urban animal diversity. As a first multi-taxon study of this kind, we analyzed the effects of Robinia dominance on 18 arthropod taxa by pairwise comparisons of woodlands in Berlin, Germany, that were dominated by R. pseudoacacia or the native pioneer tree Betula pendula. As a negative effect, abundances of five arthropod taxa decreased (Chilopoda, Formicidae, Diptera, Heteroptera, Hymenoptera); 13 others were not affected. Woodland type affected species composition of carabids and functional groups in spiders, but surprisingly did not decrease alpha and beta diversity of carabid and spider assemblages or the number of endangered species. Tree invasion thus did not induce biotic homogenization at the habitat scale. We detected no positive effects of alien dominance. Our results illustrate that invasions by a major tree invader can induce species turnover in ground-dwelling arthropods, but do not necessarily reduce arthropod species abundances or diversity and might thus contribute to the conservation of epigeal invertebrates in urban settings. Considering the context of invasion impacts thus helps to set priorities in managing biological invasions and can illustrate the potential of novel ecosystems to maintain urban biodiversity.


The Accuracy of Pedometers in Measuring Walking Steps on a Treadmill in College Students.
Pedometers are a popular way for people to track if they have reached the recommended 10,000 daily steps. Therefore, the purpose of this study was to determine the accuracy of four brands of pedometers at measuring steps, and to determine if a relationship exists between pedometer cost and accuracy. The hypothesis was that the more expensive brands of pedometers (the Fitbit Charge™ and Omron HJ-303™) would yield more accurate step counts than less expensive brands (the SmartHealth - Walking FIT™ and Sportline™). While wearing all pedometers at once, one male and eleven female college students (mean ± SD; age = 20.8 ± 0.94 years) walked 400 meters on a treadmill for 5 minutes at 3.5 miles per hour. The pedometer step counts were recorded at the end. Video analysis of the participants' feet was later completed to count the number of steps actually taken (actual steps). When compared to the actual steps, the Sportline™ brand (-3.83 ± 22.05) was the only pedometer that was significantly similar. The other three brands significantly under-estimated steps (Fitbit™ 55.00 ± 42.58, SmartHealth™ 43.50 ± 49.71, and Omron™ 28.58 ± 33.86), with the Fitbit being the least accurate. These results suggest an inverse relationship between cost and accuracy for the four specific brands tested, and that waist pedometers are more accurate than wrist pedometers. The results concerning the Fitbit are striking considering its high cost and popularity among consumers today. Further research should be conducted to improve the accuracy of pedometers.


Paying for Sex by Young Men Who Live on the Streets in Dhaka City: Compounded Sexual Risk in a Vulnerable Migrant Community.
Dhaka City is home to thousands of migrants from Bangladesh's rural areas who often live in the streets. Prior studies examine street youth's practice of selling sex as a survival mechanism. We assess their less-studied practice of paying for sex and its association with sexual risk behaviors and outcomes. As part of the global Link Up project, trained interviewers recruited 447 young men who live on the streets, ages 15-24, from seven Dhaka City "hotspots" to participate in a survey about sexual health. Among those who ever had sex, we examined frequencies and conducted bivariate analyses of sociodemographic characteristics by paying for sex status. We then conducted bivariate and multivariate logistic regression analyses of paying for sex in the last 12 months and sexual health behaviors and outcomes. Median participant age was 18 years. Among those who ever had sex (N = 321), 80% reported paying for sex in the last 12 months and 15% reported selling sex in the last 12 months. In multivariate analyses, those who paid for sex had significantly increased odds of reporting sexually transmitted infection-related symptoms in the last six months (adjusted odds ratio = 1.76, 95% confidence interval [CI] = 1.17-2.64) and engaging in unprotected last sex with a nonprimary partner (adjusted odds ratio = 2.19, CI = 1.58-3.03). The adverse factors associated with paying for sex among young men who live on the streets in Dhaka City highlight the need for programs to educate on HIV/sexually transmitted infection prevention and promote condom use, STI screening/treatment, and HIV testing in this population.


Substantia nigra and Parkinson's disease: a brief history of their long and intimate relationship.
The substantia nigra was discovered in 1786 by Félix Vicq d'Azyr, but it took more than a century before Paul Blocq and Georges Marinesco alluded to a possible link between this structure and Parkinson's disease. The insight came from the study of a tuberculosis patient admitted in Charcot's neurology ward at la Salpêtrière because he was suffering from unilateral parkinsonian tremor. At autopsy, Blocq and Marinesco discovered an encapsulated tumor confined to the substantia nigra, contralateral to the affected side, and concluded that tremor in that particular case resulted from a midbrain lesion. This pioneering work, published in 1893, led Edouard Brissaud to formulate, in 1895, the hypothesis that the substantia nigra is the major pathological site in Parkinson's disease. Brissaud's hypothesis was validated in 1919 by Constantin Trétiakoff in a remarkable thesis summarizing a post-mortem study of the substantia nigra conducted in Marinesco's laboratory. Despite highly convincing evidence of nigral cell losses in idiopathic and post-encephalitic Parkinsonism, Trétiakoff's work raised considerable doubts among his colleagues, who believed that the striatum and pallidum were the preferential targets of parkinsonian degeneration. Trétiakoff's results were nevertheless confirmed by detailed neuropathological studies undertaken in the 1930s and by the discovery, in the 1960s, of the dopaminergic nature of the nigrostriatal neurons that degenerate in Parkinson's disease. These findings have strengthened the link between the substantia nigra and Parkinson's disease, but modern research has uncovered the multifaceted nature of this neurodegenerative disorder by identifying other brain structures and chemospecifc systems involved in its pathogenesis.


Evolutionary perspective in child growth.
Hereditary, environmental, and stochastic factors determine a child's growth in his unique environment, but their relative contribution to the phenotypic outcome and the extent of stochastic programming that is required to alter human phenotypes is not known because few data are available. This is an attempt to use evolutionary life-history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies. Transitions from one life-history phase to the next have inherent adaptive plasticity in their timing. Humans evolved to withstand energy crises by decreasing their body size, and evolutionary short-term adaptations to energy crises utilize a plasticity that modifies the timing of transition from infancy into childhood, culminating in short stature in times of energy crisis. Transition to juvenility is part of a strategy of conversion from a period of total dependence on the family and tribe for provision and security to self-supply, and a degree of adaptive plasticity is provided and determines body composition. Transition to adolescence entails plasticity in adapting to energy resources, other environmental cues, and the social needs of the maturing adolescent to determine life-span and the period of fecundity and fertility. Fundamental questions are raised by a life-history approach to the unique growth pattern of each child in his given genetic background and current environment.


Nitrofurantoin and Fosfomycin for Extended Spectrum Beta-lactamases Producing Escherichia coli and Klebsiella pneumoniae.
Urinary tract infection (UTI) is a common and painful human illness that, unfortunately not responsive to commonly used antibiotics in current practice. The role of fosfomycin and nitrofurantoin in the era of growing bacteria resistance has been widely discussed. In this study, we aimed to know the local antimicrobial susceptibilities, fosfomycin and nitrofurantoin susceptibility in particular, for urinary extended-spectrum-beta-lactamase-producing Escherichia coli and Escherichia pneumoniae (ESBL-EC and ESBL-KP) isolates in our hospital. We collected 464 urine isolates, including 384 ESBL-EC and 80 ESBL-KP isolates. Of 464 urine isolates culture positive ESBL-UTIs, EC caused 384 (82.75%), followed by Klebsiella in 80 (17.24%). Carbapenems and Colistin seems to remain as the first line therapy for the majority of ESBL-UTIs in the local setting. Colistin and fosfomycin remains the most sensitive antibiotic while nitrofurantoin still preserves the good sensitivity against ESBL and found to be an only oral sensitive antibiotic.


Affordance-controlled bifurcations of action patterns in martial arts.
Effects of participant-target distance and perceived handstriking efficiency on emergent behavior in the martial art of boxing were investigated, revealing affordance-controlled nonlinear dynamical effects (i.e. bifurcations) within the participant--target system. Results established the existence of critical values of scaled distances for emergence of first time excitations and annihilations of a diverse range of boxing actions i.e. on the appearance and dissolution of jabs, hooks and uppercuts. Reasons for the action diversity were twofold: (a) topological discontinuous changes (bifurcations) in the number of possible handstrikes, i.e. motor solutions to the hitting task; (b) fine modification of probabilities of emergence of striking patterns. Exploitation of a 'strikeability' affordance available in scaled distance-to-target information by boxers led to a diversity of emergent actions through a cascade of bifurcations in the task perceptual-motor work space. Data suggested that perceived efficiency (E) of an action changed as a function of scaled distance (D) and was correlated with the probability of occurrence of action patterns (P), exhibiting the following dependence P = P(E(D)). The implication is that probability of occurrence (P) depends on efficiency (E), which in turn depends on scaled distance (D) to the target. Accordingly, scaled distance-dependent perceived efficiency seems a viable candidate for a contextual (control) parameter to describe the nonlinear dynamics of striking actions in boxing.


Age, caste, and behavior determine the replicative activity of intestinal stem cells in honeybees (Apis mellifera L.).
Honeybees (Apis mellifera L.) display a pronounced natural aging plasticity. The differences in aging rates between the alternative phenotypes and behavioral classes could reflect differences in protection against damage or in the ability to repair vulnerable tissues. As in other animals, including humans, the gut is continually exposed to environmental insults and harbors a large population of replicating stem cells that maintain the intestinal epithelium. Through studies of the major internal organs using incorporation and immunodetection of the mitotic marker bromo-deoxyuridine, the intestine was determined to be the main site of tissue renewal in adult honeybees. Proliferative activity of the intestinal stem cells was compared among queens, workers, and males of different ages. Simultaneous attempts to assess intestinal cell loss via apoptosis yielded inconclusive results. The relationship between intestinal cell proliferation and worker life-history was evaluated in greater depth by studying diutinus winter workers, reproductive workers, and by decoupling worker behavioral status from chronological age in a single-cohort colony. Intestinal cell proliferation was abundant in all groups and showed an age-related decline in workers, queens, and males. At young ages, workers exhibited relatively more intestinal cell proliferation than did queens and queens more than drones, but the caste and sex differences decreased with age. Cell proliferation did not decrease beyond 6 weeks of age in older queens and in diutinus workers. Ovary activation did not correlate with the amount of intestinal stem cell proliferation in workers, although the queenless hive condition was associated with lower overall counts. In the single-cohort colony, nurse bees exhibited more cell proliferation than foragers, regardless of age. The overall results do not support our hypothesis that longer-lived phenotypes exhibit increased somatic repair in the form of higher replicative activity of intestinal stem cells. Instead, the observed proliferation patterns reflect differential demands for digestive activity in the different groups, which result in different requirements for replacement of lost intestinal cells. The maintenance of proliferative capacity for over 1 year suggests that queen intestinal stem cells have a relatively high replicative potential, but further studies are needed to relate honeybee lifespan differences to cellular aging.


Reduction of human prostate tumor vascularity by the alpha1-adrenoceptor antagonist terazosin.
We previously demonstrated that the quinazoline-derived a1-adrenoceptor antagonists doxazosin and terazosin suppress prostate cancer growth via apoptosis induction. The aim of this study was to determine the potential effect of a1-adrenoceptor antagonists on tumor vascularity of the human prostate. A total of 34 men with benign prostatic hyperplasia (BPH) who have been on terazosin treatment (for the obstructive symptoms) were pathologically diagnosed with prostate cancer following surgery. These patients were stratified according to the length of treatment periods with terazosin into two groups, 1 week-6 months, and 6-17 months. The control group consisted of prostatectomy specimens from 25 untreated prostate cancer patients undergoing surgery for localized disease. Formalin-fixed, paraffin-embedded prostate specimens were analyzed for apoptosis (TUNEL assay), cell proliferation (Ki-67), microvessel density (MVD) (von Willebrand factor/Factor VIII), vascular endothelial growth factor (VEGF) expression, and prostate specific antigen (PSA) immunoreactivity. A significant induction of apoptosis was observed among cancerous prostatic epithelial cells in the terazosin-treated, as compared to the untreated prostate cancer specimens, while there was no significant change in the proliferative index of the same tumor cell populations after treatment. Furthermore, terazosin resulted in a significant decrease in prostate tissue MVD compared with the untreated group (P < 0.01), that correlated with the increased apoptotic index of the cancerous areas. Tissue PSA expression in the prostatic tumor foci was also markedly reduced after terazosin treatment, while no significant changes in VEGF expression were detected. These findings provide the first evidence that terazosin, a quinazoline-based a1-blocker decreases prostate tumor vascularity. Our study has significant clinical implications in identifying selected alpha1-adrenoceptor antagonists as potential anti-tumor agents with apoptotic and anti-angiogenic effects in the human prostate that can be exploited for the treatment of advanced prostate cancer.


Metabolic impact of an NADH-producing glucose-6-phosphate dehydrogenase in Escherichia coli.
In Escherichia coli, the oxidative branch of the pentose phosphate pathway (oxPPP) is one of the major sources of NADPH when glucose is the sole carbon nutrient. However, unbalanced NADPH production causes growth impairment as observed in a strain lacking phosphoglucoisomerase (Δpgi). In this work, we studied the metabolic response of this bacterium to the replacement of its glucose-6-phosphate dehydrogenase (G6PDH) by an NADH-producing variant. The homologous enzyme from Leuconostoc mesenteroides was studied by molecular dynamics and site-directed mutagenesis to obtain the NAD-preferring LmG6PDH(R46E,Q47E). Through homologous recombination, the zwf loci (encoding G6PDH) in the chromosomes of WT and Δpgi E. coli strains were replaced by DNA encoding LmG6PDH(R46E,Q47E). Contrary to some predictions performed with flux balance analysis, the replacements caused a substantial effect on the growth rates, increasing 59 % in the Δpgi strain, while falling 44 % in the WT. Quantitative PCR (qPCR) analysis of the zwf locus showed that the expression level of the mutant enzyme was similar to the native enzyme and the expression of genes encoding key enzymes of the central pathways also showed moderate changes among the studied strains. The phenotypic and qPCR data were integrated into in silico modelling, showing an operative G6PDH flux contributing to the NADH pool. Our results indicated that, in vivo, the generation of NADH by G6PDH is beneficial or disadvantageous for growth depending on the operation of the upper Embden-Meyerhof pathway. Interestingly, a genomic database search suggested that in bacteria lacking phosphofructokinase, the G6PDHs tend to have similar preferences for NAD and NADP. The importance of the generation of NADPH in a pathway such as the oxPPP is discussed.


Evaluation of a Self-Administered Computerized Cognitive Battery in an Older Population.
The aim of this study is to assess the utility of the Cogstate self-administered computerized neuropsychological battery in a large population of older men. We invited 7,167 men (mean age of 75 years) from the Health Professionals Follow-up Study, a prospective cohort of male health professionals. We considered individual Cogstate scores and composite scores measuring psychomotor speed and attention, learning and working memory and overall cognition. Multivariate linear regression was used to assess the association between risk factors measured 4 and 28 years prior to cognitive testing and each outcome. The 1,866 men who agreed to complete Cogstate testing were similar to the 5,301 non-responders. Many expected risk factors were associated with Cogstate scores in multivariate adjusted models. Increasing age was significantly associated with worse performance on all outcomes (p < 0.001). For risk factors measured 4 years prior to testing and overall cognition, a history of hypertension was significantly associated with worse performance (mean difference of -0.08 standard units (95% CI -0.16, 0.00)) and higher consumption of nuts was significantly associated with better performance (>2 servings/week vs. <1 serving/month: 0.15 (0.03, 0.27)). The self-administered Cogstate battery showed significant associations with several risk factors known to be associated with cognitive function. Future studies of cognitive aging may benefit from the numerous advantages of self-administered computerized testing.


Platelet-activating factor and hyperacute rejection. The effect of a platelet-activating factor antagonist, SRI 63-441, on rejection of xenografts and allografts in sensitized hosts.
The pathogenesis of hyperacute transplantation reactions includes the activation of a cascade of nonspecific inflammatory reactions that precipitates the destruction of the target organ. Platelet-activating factor (PAF) represents an important component of these inflammatory cascades, and we have examined the influence of a specific PAF receptor antagonist (SRI 63-441) on the inhibition of hyperacute rejection in two experimental models, the rejection of rat cardiac allografts by presensitized recipients and guinea pig-to-rat and mouse-to-rat cardiac xenografts. Our results demonstrate that inhibition of PAF function by SRI 63-441 has a variable effect on the survival of cardiac allografts in presensitized rat recipients. In the ACI to sensitized BN cardiac allograft model, the use of SRI 63-441 alone, or in combination with CsA, FK506, or prostaglandin E2 (PGE2), does not prolong graft survival. As we have previously reported, SRI 63-441 does act as a single agent to prolong the survival of ACI to sensitized LEW grafts, and this survival effect is synergistic when combined with CsA. Here we extend these results to demonstrate that this survival is also extended when FK506 is used in the ACI-to-LEW model. Concordant mouse-to-rat cardiac xenografts are also relatively resistant to prolongation of graft survival following treatment with SRI 63-441 alone or in combination with CsA or FK506. Discordant xenografts appear to be more susceptible to inhibition of the rejection reaction with SRI 63-441. When either donor or recipient animals were treated with SRI 63-441 alone, or in combination with CsA or FK506, there was significant prolongation of guinea pig-to-rat cardiac xenograft survival. These results are consistent with our earlier description of the effectiveness of SRI 63-441 in preventing the rejection of cat-to-rabbit kidney xenografts. We believe that these results demonstrate that the use of the SRI 63-441 to specifically interfere with the function of PAF has the effect of prolonging graft survival in those systems in which performed antibody and/or complement activation are important components of the hyperacute reaction. This synthetic drug is representative of a family of compounds whose structure can be modified to balance their therapeutic and toxicity activities, and may prove to be important components of a polytherapeutic approach to the control of graft rejection in sensitized patients or following discordant xenografting.


Implantable transvenous cardioverter-defibrillators.
Implantable transvenous cardioverter-defibrillators offer a significant opportunity to decrease procedural morbidity and medical costs in the care of patients with life-threatening ventricular arrhythmias who otherwise would have required a sternotomy or thoracotomy for device insertion. The purpose of this study was to examine prospectively the safety, efficacy, and limitations associated with the use of a transvenously implanted, tiered-therapy cardioverter-defibrillator with antitachycardia pacing function in a consecutive population of 84 ventricular fibrillation (VF) and sustained ventricular tachycardia (VT) survivors. The index arrhythmia promoting transvenous cardioverter-defibrillator implantation was VF in 41 patients, VT in 27, and both VF and VT in 16. In each patient, transvenous defibrillation via a coronary sinus, a right ventricular, a superior vena caval, and/or a subcutaneous chest patch lead system was attempted. The pulsing methods used include two-electrode single-pathway pulsing or three-electrode dual-pathway simultaneous or sequential pulsing. A transvenous cardioverter-defibrillator was inserted if the defibrillation threshold (DFT) was < or = 20 J. Successful implantation of a transvenous cardioverter-defibrillator was possible in 80 of 84 (95%) patients. The mean implant DFT was 10.9 +/- 4.8 J. After cardioverter-defibrillator implantation, all patients were extubated in the operating room and sent to a standard telemetry ward for monitoring. No patient suffered a postoperative pulmonary complication or perioperative flurry of cardiac arrhythmias. Postoperative complications included lead dislodgments in eight, transient long thoracic nerve injury in one, asymptomatic left subclavian vein occlusion in two, asymptomatic small pericardial effusion in one, subcutaneous patch pocket hematomas in four, pulse generator pocket infection in one, and lead fracture in one. As experience was gained with the procedure, it was routine to discharge patients 3 days after surgery. The mean hospital stay was 6.0 +/- 2.4 days. Upon discharge, all patients returned to their prehospital activities including those with complications except for the patient with a pocket infection, who required intravenous antibiotic therapy. Patient survival using an intention-to-treat analysis was 98% over an 11 +/- 7-month follow-up period. During this time period, 31 of the 80 patients (39%) with transvenous lead systems were successfully treated by their device for sustained VT or VF. Antitachycardia pacing was used in 424 episodes of monomorphic VT and was successful in 371 (88%). All episodes of VF were aborted by the device. Antiarrhythmic drugs were used after device implantation in only eight of 80 patients (10%). Transvenous cardioverter-defibrillator implantation is practical in most candidates. Implant DFTs are usually low, surgical morbidity and postoperative complications are modest, therapy of VT and VF is efficient, and survival is excellent.


High frequency of pre-existing neutralizing antibody responses in patients with dengue during an outbreak in Central Brazil.
This study aims to identify dengue neutralizing antibody response in patients with dengue from a well-characterized cohort during an outbreak in central Brazil, 2012-2013. We analyzed paired samples from 40 patients with severe dengue and 20 patients with dengue. Eligibility criteria were: IgM, NS1Ag and/or RT-PCR positivity and positive IgG result. Plaque reduction neutralization test (PRNT50) from DENV-1 to DENV-4 was performed to identify serotype-specific NAbs response. An infecting serotype was defined as ≥4-fold increase in DENV NAbs in paired samples. Monotypic response was classified as PRNT50 ≥ 1/20 to only one DENV serotype, and multitypic response was considered to be PRNT50 ≥ 1/20 to two or more serotypes simultaneously. Patients were mainly adults. Virological dengue infection was confirmed by RT-PCR: DENV-4(n = 14) and DENV-1(n = 10). Forty-four out of 60(73.3 %) patients had NAbs to DENV-4, DENV-1(68.3 %), DENV-2(68.3 %) and DENV-3(61.6 %) respectively. Fifteen percent of the cases presented monotypic response, whereas 85 % had multitypic response. DENV-4 infected-patients presented the greatest difference in PRNT50 titers compared with other serotypes. Pre-existing DENV NAbs was not correlated with disease severity. This was the first time that DENV-4 was implicated in an epidemic in the region. Our data indicates high exposure of multiple DENV serotypes in all age groups in the pre-dengue vaccine era and also previous to Zika virus introduction in Brazil.


Comparative analysis of toxicological evaluations for dermal exposure performed under two different EU regulatory frameworks.
Dermal exposure to chemicals is highly relevant in relation to the use of cosmetic products, both in consumers and in individuals exposed occupationally. Regulatory frameworks exist within the EU to limit the dermal exposure of the general population and workers to chemicals in general, as well as to limit the use of certain substances in cosmetic products. The objective of the study was to investigate and compare toxicological evaluations of dermal exposure performed under current regulatory frameworks. The publicly disseminated hazard information under the respective regulatory frameworks was compiled and compared for the five substances resorcinol, p-phenylenediamine, p-aminophenol, N-phenyl-p-phenylenediamine, and diethylene glycol monoethyl ether. A low consistency between evaluations was observed in respect to data coverage and cited dose descriptors. No systematic differences over all five substances were identified from the viewpoint of dermal hazard assessment. The critical effect and corresponding systemic effect dose descriptor was identical for two substances, differed somewhat for two other (a factor of 2-2.5). For N-phenyl-p-phenylenediamine a critical effect was only identified under REACH.


Meteorological Controls on Local and Regional Volcanic Ash Dispersal.
Volcanic ash has the capacity to impact human health, livestock, crops and infrastructure, including international air traffic. For recent major eruptions, information on the volcanic ash plume has been combined with relatively coarse-resolution meteorological model output to provide simulations of regional ash dispersal, with reasonable success on the scale of hundreds of kilometres. However, to predict and mitigate these impacts locally, significant improvements in modelling capability are required. Here, we present results from a dynamic meteorological-ash-dispersion model configured with sufficient resolution to represent local topographic and convectively-forced flows. We focus on an archetypal volcanic setting, Soufrière, St Vincent, and use the exceptional historical records of the 1902 and 1979 eruptions to challenge our simulations. We find that the evolution and characteristics of ash deposition on St Vincent and nearby islands can be accurately simulated when the wind shear associated with the trade wind inversion and topographically-forced flows are represented. The wind shear plays a primary role and topographic flows a secondary role on ash distribution on local to regional scales. We propose a new explanation for the downwind ash deposition maxima, commonly observed in volcanic eruptions, as resulting from the detailed forcing of mesoscale meteorology on the ash plume.


Evaluating the feasibility and effect of using a hospital-wide coordinated approach to introduce evidence-based changes for pain management.
This action research project explored the feasibility and effect of implementing a hospital-wide coordinated approach to improve the management of pain. The project used a previously developed model to introduce three evidence-based changes in pain management. Part of this model included the introduction of 30 pain resource nurses (PRNs) to act as clinical champions for pain at a local level. Both quantitative and qualitative measures were used to assess the feasibility and effect of the changes introduced. Quantitative data were gathered through a hospital-wide document review and assessment of the knowledge and attitude of the PRNs at two time points: time 1 before the introduction of the PRNs and time 2 near completion of the project (11 months later). A statistically significant improvement in the documentation of pain scores on admission and each nursing shift was apparent. However, no difference was found in the percentage of patients who had been prescribed opioids for regular pain relief that had also been prescribed and dispensed a laxative/aperient. Neither were any statistically significant decreases in patient pain scores observed. An assessment of the knowledge and attitudes of the PRNs showed an improvement from time 1 to time 2 that was statistically significant. The qualitative data revealed that despite the barriers encountered, the role was satisfying for the PRNs and valued by other hospital staff. Overall, the results revealed that the new model of change incorporating PRNs was a useful and effective method for introducing and sustaining evidence-based organizational change.


Breaking of Galilean Invariance in the Hydrodynamic Formulation of Ferromagnetic Thin Films.
Microwave magnetodynamics in ferromagnets are often studied in the small-amplitude or weakly nonlinear regime corresponding to modulations of a well-defined magnetic state. However, strongly nonlinear regimes, where the aforementioned approximations are not applicable, have become experimentally accessible. By reinterpreting the governing Landau-Lifshitz equation of motion, we derive an exact set of equations of dispersive hydrodynamic form that are amenable to analytical study even when full nonlinearity and exchange dispersion are included. The resulting equations are shown to, in general, break Galilean invariance. A magnetic Mach number is obtained as a function of static and moving reference frames. The simplest class of solutions are termed uniform hydrodynamic states (UHSs), which exhibit fluidlike behavior including laminar flow at subsonic speeds and the formation of a Mach cone and wave fronts at supersonic speeds. A regime of modulational instability is also possible, where the UHS is violently unstable. The hydrodynamic interpretation opens up novel possibilities in magnetic research.


Ambiguity preferences for health.
In most medical decisions, probabilities are ambiguous and not objectively known. Empirical evidence suggests that people's preferences are affected by ambiguity. Health economic analyses generally ignore ambiguity preferences and assume that they are the same as preferences under risk. We show how health preferences can be measured under ambiguity, and we compare them with health preferences under risk. We assume a general ambiguity model that includes many of the ambiguity models that have been proposed in the literature. For health gains, ambiguity preferences and risk preferences were indeed the same. For health losses, they differed with subjects being more pessimistic in decision under ambiguity. Utility and loss aversion were the same for risk and ambiguity. Our results imply that reducing the clinical ambiguity of health losses has more impact than reducing the ambiguity of health gains, that utilities elicited with known probabilities may not carry over to an ambiguous setting, and that ambiguity aversion may impact value of information analyses if losses are involved. These findings are highly relevant for medical decision making, because most medical interventions involve losses.


From neuroprogression to neuroprotection: implications for clinical care.
Bipolar disorder follows a staged trajectory in which persistence of illness is associated with a number of clinical features such as progressive shortening of the inter-episode interval and decreased probability of treatment response. This neuroprogressive clinical process is reflected by both progressive neuroanatomical changes and evidence of cognitive decline. The biochemical foundation of this process appears to incorporate changes in inflammatory cytokines, cortisone, neurotrophins and oxidative stress. There is a growing body of evidence to suggest that these markers may differ between the early and late stages of the disorder. The presence of a series of tangible targets raises the spectre of development of rational neuroprotective strategies, involving judicious use of current therapies and novel agents. Most of the currently used mood stabilisers share effects on oxidative stress and neurotrophins, while novel potentially neuroprotective agents are being developed. These developments need to be combined with service initiatives to maximise the opportunities for early diagnosis and intervention.


Monophasic action potential recordings during acute changes in ventricular loading induced by the Valsalva manoeuvre.
The strong association between ventricular arrhythmia and ventricular dysfunction is unexplained. This study was designed to investigate a mechanism by which a change in ventricular loading could alter the time course of repolarisation and hence refractoriness. A possible mechanism may be a direct effect of an altered pattern of contraction on ventricular repolarisation and hence refractoriness. This relation has been termed contraction-excitation feedback or mechano-electric feedback. Monophasic action potentials were recorded from the left ventricular endocardium as a measure of the time course of local repolarisation. The Valsalva manoeuvre was used to change ventricular loading by increasing the intrathoracic pressure and impeding venous return, and hence reducing ventricular pressure and volume (ventricular unloading). 23 patients undergoing routine cardiac catheterisation procedures: seven with no angiographic evidence of abnormal wall motion or history of myocardial infarction (normal), five with a history of myocardial infarction but with normal wall motion, and 10 with angiographic evidence of abnormal wall motion--with or without previous infarction. One patient was a transplant recipient and was analysed separately. Tertiary referral centre for cardiology. In patients with normal ventricles during the unloading phase of the Valsalva manoeuvre (mean (SD)) monophasic action potential duration shortened from 311 (47) ms to 295 (47) ms (p less than 0.001). After release of the forced expiration as venous return was restored the monophasic action potential duration lengthened from 285 (44) ms to 304 (44) ms (p less than 0.0001). In the group with evidence of abnormal wall motion the direction of change of action potential duration during the strain phase was normal in 7/21 observations, abnormal in 6/21, and showed no clear change in 8/21. During the release phase 11/20 observations were normal, five abnormal, and four showed no clear change. In those with myocardial infarction four out of five patients had changes that resembled those with normal ventricles but the changes were less pronounced. There were no differences in any of the three groups between the changes in monophasic action potential duration in patients taking beta blockers and those who were not. The changes in monophasic action potential duration in the transplanted heart resembled those in the group with normal ventricles. Inflections on the repolarisation phase of the monophasic action potential consistent with early afterdepolarisations were seen in three of the patients with abnormal wall motion and in none of those with normal wall motion. These results are further evidence that changes in ventricular loading influence repolarisation. When wall motion was abnormal the effects on regional endocardial repolarisation were often opposite in direction to those when it was normal. Thus regional differences in wall motion could generate local electrophysiological inhomogeneity which may be relevant to the association of arrhythmia with impaired left ventricular function.


Symmetry restoring bifurcation in collective decision-making.
How social groups and organisms decide between alternative feeding sites or shelters has been extensively studied both experimentally and theoretically. One key result is the existence of a symmetry-breaking bifurcation at a critical system size, where there is a switch from evenly distributed exploitation of all options to a focussed exploitation of just one. Here we present a decision-making model in which symmetry-breaking is followed by a symmetry restoring bifurcation, whereby very large systems return to an even distribution of exploitation amongst options. The model assumes local positive feedback, coupled with a negative feedback regulating the flow toward the feeding sites. We show that the model is consistent with three different strains of the slime mold Physarum polycephalum, choosing between two feeding sites. We argue that this combination of feedbacks could allow collective foraging organisms to react flexibly in a dynamic environment.


Centralized Consensus Hemagglutinin Genes Induce Protective Immunity against H1, H3 and H5 Influenza Viruses.
With the exception of the live attenuated influenza vaccine there have been no substantial changes in influenza vaccine strategies since the 1940's. Here we report an alternative vaccine approach that uses Adenovirus-vectored centralized hemagglutinin (HA) genes as vaccine antigens. Consensus H1-Con, H3-Con and H5-Con HA genes were computationally derived. Mice were immunized with Ad vaccines expressing the centralized genes individually. Groups of mice were vaccinated with 1 X 1010, 5 X 107 and 1 X 107 virus particles per mouse to represent high, intermediate and low doses, respectively. 100% of the mice that were vaccinated with the high dose vaccine were protected from heterologous lethal challenges within each subtype. In addition to 100% survival, there were no signs of weight loss and disease in 7 out of 8 groups of high dose vaccinated mice. Lower doses of vaccine showed a reduction of protection in a dose-dependent manner. However, even the lowest dose of vaccine provided significant levels of protection against the divergent influenza strains, especially considering the stringency of the challenge virus. In addition, we found that all doses of H5-Con vaccine were capable of providing complete protection against mortality when challenged with lethal doses of all 3 H5N1 influenza strains. This data demonstrates that centralized H1-Con, H3-Con and H5-Con genes can be effectively used to completely protect mice against many diverse strains of influenza. Therefore, we believe that these Ad-vectored centralized genes could be easily translated into new human vaccines.


Predicting on-going hemorrhage and transfusion requirement after severe trauma: a validation of six scoring systems and algorithms on the TraumaRegister DGU.
The early aggressive management of the acute coagulopathy of trauma may improve survival in the trauma population. However, the timely identification of lethal exsanguination remains challenging. This study validated six scoring systems and algorithms to stratify patients for the risk of massive transfusion (MT) at a very early stage after trauma on one single dataset of severely injured patients derived from the TR-DGU (TraumaRegister DGU of the German Trauma Society (DGU)) database. Retrospective internal and external validation of six scoring systems and algorithms (four civilian and two military systems) to predict the risk of massive transfusion at a very early stage after trauma on one single dataset of severely injured patients derived from the TraumaRegister DGU database (2002-2010). Scoring systems and algorithms assessed were: TASH (Trauma-Associated Severe Hemorrhage) score, PWH (Prince of Wales Hospital/Rainer) score, Vandromme score, ABC (Assessment of Blood Consumption/Nunez) score, Schreiber score and Larsen score. Data from 56,573 patients were screened to extract one complete dataset matching all variables needed to calculate all systems assessed in this study. Scores were applied and area-under-the-receiver-operating-characteristic curves (AUCs) were calculated. From the AUC curves the cut-off with the best relation of sensitivity-to-specificity was used to recalculate sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV). A total of 5,147 patients with blunt trauma (95%) was extracted from the TR-DGU. The mean age of patients was 45.7 ± 19.3 years with a mean ISS of 24.3 ± 13.2. The overall MT rate was 5.6% (n = 289). 95% (n = 4,889) patients had sustained a blunt trauma. The TASH score had the highest overall accuracy as reflected by an AUC of 0.889 followed by the PWH-Score (0.860). At the defined cut-off values for each score the highest sensitivity was observed for the Schreiber score (85.8%) but also the lowest specificity (61.7%). The TASH score at a cut-off ≥ 8.5 showed a sensitivity of 84.4% and also a high specificity (78.4%). The PWH score had a lower sensitivity (80.6%) with comparable specificity. The Larson score showed the lowest sensitivity (70.9%) at a specificity of 80.4%. Weighted and more sophisticated systems such as TASH and PWH scores including higher numbers of variables perform superior over simple non-weighted models. Prospective validations are needed to improve the development process and use of scoring systems in the future.


Pathogens and pharmaceuticals in source-separated urine in eThekwini, South Africa.
In eThekwini, South Africa, the production of agricultural fertilizers from human urine collected from urine-diverting dry toilets is being evaluated at a municipality scale as a way to help finance a decentralized, dry sanitation system. The present study aimed to assess a range of human and environmental health hazards in source-separated urine, which was presumed to be contaminated with feces, by evaluating the presence of human pathogens, pharmaceuticals, and an antibiotic resistance gene. Composite urine samples from households enrolled in a urine collection trial were obtained from urine storage tanks installed in three regions of eThekwini. Polymerase chain reaction (PCR) assays targeted 9 viral and 10 bacterial human pathogens transmitted by the fecal-oral route. The most frequently detected viral pathogens were JC polyomavirus, rotavirus, and human adenovirus in 100%, 34% and 31% of samples, respectively. Aeromonas spp. and Shigella spp. were frequently detected gram negative bacteria, in 94% and 61% of samples, respectively. The gram positive bacterium, Clostridium perfringens, which is known to survive for extended times in urine, was found in 72% of samples. A screening of 41 trace organic compounds in the urine facilitated selection of 12 priority pharmaceuticals for further evaluation. The antibiotics sulfamethoxazole and trimethoprim, which are frequently prescribed as prophylaxis for HIV-positive patients, were detected in 95% and 85% of samples, reaching maximum concentrations of 6800 μg/L and 1280 μg/L, respectively. The antiretroviral drug emtricitabine was also detected in 40% of urine samples. A sulfonamide antibiotic resistance gene (sul1) was detected in 100% of urine samples. By coupling analysis of pathogens and pharmaceuticals in geographically dispersed samples in eThekwini, this study reveals a range of human and environmental health hazards in urine intended for fertilizer production. Collection of urine offers the benefit of sequestering contaminants from environmental release and allows for targeted treatment of potential health hazards prior to agricultural application. The efficacy of pathogen and pharmaceutical inactivation, transformation or removal during urine nutrient recovery processes is thus briefly reviewed.


Asynchronous encrypted information transmission with sub-6 fs laser system at 2.12 GHz repetition rate.
The asynchronous transmission (encoding and decoding) of 64-bit information using binary spectral phase shaping is demonstrated. The accurate introduction and retrieval of the binary information is possible by using multiphoton intrapulse interference phase scan (MIIPS) to measure and correct the spectral phase distortions of the laser and the transmission media. Experimental demonstration is achieved using a sub-6 fs Ti:Sapphire laser with 2.12-GHz repetition rate and an adaptive phase control system.


High prevalence of congenital generalized lipodystrophy in Piura, Peru.
Congenital generalized lipodystrophy (CGL) is an autosomal recessive rare disease, with a worldwide prevalence of around 1 in every 12 million people. There are several case reports of patients with CGL in Piura, a region in northern Peru; however its regional prevalence is unknown. The objective was to determine the prevalence of CGL in the region of Piura, Peru during the years 2000-2017. A descriptive, observational study was carried out. A search of clinical histories of patients with the diagnosis of CGL attended between 2000 and 2017 in the pediatric and endocrinology services of the reference hospitals of the department of Piura and in the genetic and endocrinology services of the "Instituto Nacional de Salud del Niño". A patient was considered to have CGL if they met the clinical criteria and or if they had a molecular diagnosis, in addition to patients with CGL from the department of Piura reported in previous publications. A total of 23 cases of CGL were found in Piura, the highest prevalence was in 2014 with 1.2 per 100,000 people, and by 2017 the prevalence was 0.86 per 100,000 people. In conclusion, the department of Piura has a high prevalence of CGL.


Engagement in activities revealing the body and psychosocial adjustment in adults with a trans-tibial prosthesis.
The purpose of this study was to examine the effects of the appearance of a prosthesis on social behaviour, social discomfort and psychological well-being in eleven amputees taking delivery of a prosthesis with a silicone cover. Two new scales were developed: the 'Engagement in everyday activities involving revealing the body' (EEARB); and the 'Discomfort-Engagement in everyday activities involving revealing the body' (Discomfort-EEARB) scales. The psychometric properties of these scales were determined using a sample of 101 able-bodied adults. The Hospital Anxiety and Depression Scale and the Rosenberg Self-Esteem Scale were also used to measure psychological well-being in the amputee sample. The EEARB and Discomfort-EEARB proved to have good reliability and validity. Comparison of amputees' scores prior to receiving the silicone cosmesis with those of the able-bodied adults revealed significant behavioural limitations and social discomfort, associated with low self-esteem, anxiety and depression. There was a significant increase in amputees' scores three months afier taking delivery of their prosthesis, indicating that amputees reported engaging in more activities which involved revealing their body, and that they would feel more comfortable in situations which involved revealing the body. As the amputee sample available was small and self-selected, it is not possible to generalise these findings to the amputee population as a whole. However, since there is little previous research investigating the effects of the appearance of the prosthesis, these findings demonstrate the need for further research in this area.


A hydrothermal seep on the Costa Rica margin: middle ground in a continuum of reducing ecosystems.
Upon their initial discovery, hydrothermal vents and methane seeps were considered to be related but distinct ecosystems, with different distributions, geomorphology, temperatures, geochemical properties and mostly different species. However, subsequently discovered vents and seep systems have blurred this distinction. Here, we report on a composite, hydrothermal seep ecosystem at a subducting seamount on the convergent Costa Rica margin that represents an intermediate between vent and seep ecosystems. Diffuse flow of shimmering, warm fluids with high methane concentrations supports a mixture of microbes, animal species, assemblages and trophic pathways with vent and seep affinities. Their coexistence reinforces the continuity of reducing environments and exemplifies a setting conducive to interactive evolution of vent and seep biota.


The costs of community-based psychiatric care for first-ever patients. A case register study.
Analysing costs measures in conjunction with psychiatric case register (PCR) data can provide important epidemiologically-based information on resource utilization. Costing the service use patterns of first-ever patients can indicate the shape and likely resource consequences for mental health services operating within a community-based system of care. Yearly costs were calculated for the 299 first-ever patients and 768 longer-term patients who contacted the South-Verona Psychiatric Case Register between 1 January 1992 and 31 December 1993. Bivariate and multivariate analyses were used to compare costs between these groups and to test the associations between costs and the sociodemographic and diagnostic data recorded on the PCR. For all diagnostic groups identified, first-ever patients were found to be less costly to support than longer-term patients, even after adjustment for various factors, including whether patients were single consulters. When multivariate analyses were employed, between 20% and 69% of the cost variation for first-ever patients could be explained by patient and other characteristics, and the effect of the contact (first or subsequent) variable was reduced. This study considered only the costs to the specialist psychiatric services but the methodology allows the likely annual resource implications of supporting new patients to be predicted from data collected at first contact. Such information can help ensure that services are adequately funded and that the resources are deployed appropriately between client groups.


More pistachio nuts for improving the blood lipid profile. Systematic review of epidemiological evidence.
Recent evidence suggests that regular intake of nuts may be associated with reduction of all-cause mortality, especially cardiovascular deaths. Among all types of nuts, pistachio displays the most favorable dietary composition. Therefore, we searched Medline and ISI Web of Science to identify interventional studies which evaluated changes of conventional blood lipids after replacing part of normal caloric intake with pistachio nuts in humans. Overall, 9 studies were finally included in our systematical literature review (4 randomized crossover, 3 randomized controlled and 3 prospective). In 6/9 (67%) interventional studies total cholesterol and low-density lipoprotein cholesterol (LDL-C) decreased, whereas high-density lipoprotein cholesterol (HDL-C) increased. In all studies total cholesterol/HDL-C ratio (7/7; 100%) and LDL-C/HDL-C ratio (6/6; 100%) decreased after replacing caloric intake with pistachio nuts for not less than 3 weeks. A significant reduction of triglycerides could only be observed in 2 out of 8 studies (25%). Even more importantly, in no interventional study the intake of pistachio nuts was associated with unfavorable changes of the lipid profile. The results of our literature search provide solid evidence that intake of pistachio nuts may exerts favorable effects on the traditional blood profile, provided that their consumption does not increase the habitual or recommended daily caloric intake. It seems also reasonable to suggest that further studies aimed to investigate the favorable effects of nuts on human diseases should distinguish between one type and the others, since the different nuts exhibit unique dietary composition and may hence produce distinctive biological effects in humans.


The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.


Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation.
Transplant-related mortality (TRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to be related to disease stage, duratiion of disease and type of donor. Furthermore, the outcome of transplants performed in the 1990s appears to be better than that of transplants done in the previous decade. The aims of this study were to determine whether these relationships still hold and whether the outcome of transplants is continuing to improve. We analyzed 1180 consecutive patients with leukemia (n=979) or other hematologic malignancies (n=201) undergoing HSCT in 4 time periods: before 1990, 1991-1995, 1996-2000, and 2001-2002. Changes during these eras include increasing patient age, more unrelated transplants, more patients with advanced disease, different graft-versus-host disease (GvHD) prophylaxis, and different management of infections. The actuarial 2-year transplant-related mortality (TRM) differed significantly between the transplant eras (p<0.001) with a significant interaction with disease phase (p=0.018). In patients in first remission (n=585) TRM was 34%, 25%, 21% and 6% in the four transplant eras. The reduction in TRM was less evident in patients in second remission (n=284) (37%, 35%, 30%, 25%) and absent in relapsed patients (n=311) (TRM=45%, 41%, 29%, 51%). This is a consequence of reductions in GvHD, infections and multiorgan failure among patients in remission but not among those who relapse. The actuarial 2-year survival has improved significantly in patients in first remission (54%, 66%, 72%, 78%) but not in those in second remission (38%, 46%, 52%,45%), or relapsed patients (31%, 25%, 36%, 21%). In conclusion, TRM has been significantly reduced in first remission patients, suggesting an allograft should be considered in this phase, when appropriate, without delay. There has been no improvement in survival for patients beyond first remission, due to persisting high risk of infections and organ toxicity, a possible consequence of prolonged pre-transplant chemotherapy and neutropenia.


Effect of Modulated Electrohyperthermia on the Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers.
This study aimed to determine whether changes occur in fentanyl absorption and disposition when administered in conjunction with modulated electrohyperthermia (mEHT) treatment. A randomized, single-dose, crossover, open-label study was used to investigate the effect of mEHT on the pharmacokinetic properties of fentanyl in 12 healthy volunteers. The 12 healthy volunteers were each administered a single dose of oral transmucosal fentanyl citrate (OTFC) or a single dose of OTFC with mEHT. mEHT was performed on the abdomen for 1 hour. Blood samples were collected for 24 hours after dosing. The temperature of the abdominal skin surface was assessed before dosing and at 10, 20, and 60 minutes after dosing. Geometric mean ratios (ratio of fentanyl with mEHT to fentanyl alone) for the Cmax and AUC0-last were 1.20 (90% CI, 1.09-1.32) and 1.15 (90% CI, 0.99-1.33), respectively. The mean temperature of the abdominal skin surface increased by approximately 4°C. There was an increase in the overall exposure to the drug without implications of any clinical significance. OTFC can be administered without limitations in combination with mEHT, and it is not necessary to modify the dosing regimen. cris.nih.go,kr Identifier: KCT0001286.


Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function.
B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.


Transport of DNA within cohesin involves clamping on top of engaged heads by Scc2 and entrapment within the ring by Scc3.
In addition to extruding DNA loops, cohesin entraps within its SMC-kleisin ring (S-K) individual DNAs during G1 and sister DNAs during S-phase. All three activities require related hook-shaped proteins called Scc2 and Scc3. Using thiol-specific crosslinking we provide rigorous proof of entrapment activity in vitro. Scc2 alone promotes entrapment of DNAs in the E-S and E-K compartments, between ATP-bound engaged heads and the SMC hinge and associated kleisin, respectively. This does not require ATP hydrolysis nor is it accompanied by entrapment within S-K rings, which is a slower process requiring Scc3. Cryo-EM reveals that DNAs transported into E-S/E-K compartments are 'clamped' in a sub-compartment created by Scc2's association with engaged heads whose coiled coils are folded around their elbow. We suggest that clamping may be a recurrent feature of cohesin complexes active in loop extrusion and that this conformation precedes the S-K entrapment required for sister chromatid cohesion.