Improved alliin yield in somatic embryos of Allium sativum L. (cv. Yamuna safed) as analyzed by HPTLC.
Direct somatic embryo formation (without intervening callus) from garlic clove basal tissue was induced in which the influence of plant growth regulators (PGRs) on various explants was examined. Medium added with 2.0 mg/l 6-benzylaminopurine (BAP) and 0.5 mg/l 2,4-dichlorophenoxyacetic acid (2,4-D) were the most effective PGR combination for somatic embryo induction. It induced embryos directly in 85.5% of the basal clove explant. Callus induction was also obtained from other parts of explant and 2.0 mg/l 2,4-D induced callusing in 86.5% of the inoculated explants. Protein, amino acid and alliin content were measured in callus and in embryos. Somatic embryos had more soluble protein and free amino acid compared to callus. HPTLC analysis revealed that alliin was significantly high in somatic embryos compared to undifferentiated callus tissue; the content was even more in older embryos. The present study of Allium indicates that the event of morphogenetic development including in vitro embryogeny can effectively be analysed by monitoring the changes of biochemical profiles.


Influenza virus in a natural host, the mallard: experimental infection data.
Wild waterfowl, particularly dabbling ducks such as mallards (Anas platyrhynchos), are considered the main reservoir of low-pathogenic avian influenza viruses (LPAIVs). They carry viruses that may evolve and become highly pathogenic for poultry or zoonotic. Understanding the ecology of LPAIVs in these natural hosts is therefore essential. We assessed the clinical response, viral shedding and antibody production of juvenile mallards after intra-esophageal inoculation of two LPAIV subtypes previously isolated from wild congeners. Six ducks, equipped with data loggers that continually monitored body temperature, heart rate and activity, were successively inoculated with an H7N7 LPAI isolate (day 0), the same H7N7 isolate again (day 21) and an H5N2 LPAI isolate (day 35). After the first H7N7 inoculation, the ducks remained alert with no modification of heart rate or activity. However, body temperature transiently increased in four individuals, suggesting that LPAIV strains may have minor clinical effects on their natural hosts. The excretion patterns observed after both re-inoculations differed strongly from those observed after the primary H7N7 inoculation, suggesting that not only homosubtypic but also heterosubtypic immunity exist. Our study suggests that LPAI infection has minor clinically measurable effects on mallards and that mallard ducks are able to mount immunological responses protective against heterologous infections. Because the transmission dynamics of LPAIVs in wild populations is greatly influenced by individual susceptibility and herd immunity, these findings are of high importance. Our study also shows the relevance of using telemetry to monitor disease in animals.


American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults.
The abstracted set of recommendations presented here provides essential guidance both on the prevention of postoperative delirium in older patients at risk of delirium and on the treatment of older surgical patients with delirium, and is based on the 2014 American Geriatrics Society (AGS) Guideline. The full version of the guideline, American Geriatrics Society Clinical Practice Guideline for Postoperative Delirium in Older Adults is available at the website of the AGS. The overall aims of the study were twofold: first, to present nonpharmacologic and pharmacologic interventions that should be implemented perioperatively for the prevention of postoperative delirium in older adults; and second, to present nonpharmacologic and pharmacologic interventions that should be implemented perioperatively for the treatment of postoperative delirium in older adults. Prevention recommendations focused on primary prevention (i.e., preventing delirium before it occurs) in patients who are at risk for postoperative delirium (e.g., those identified as moderate-to-high risk based on previous risk stratification models such as the National Institute for Health and Care Excellence (NICE) guidelines, Delirium: Diagnosis, Prevention and Management. Clinical Guideline 103; London (UK): 2010 July 29). For management of delirium, the goals of this guideline are to decrease delirium severity and duration, ensure patient safety and improve outcomes.


Randomized controlled trial to dismantle exposure, relaxation, and rescripting therapy (ERRT) for trauma-related nightmares.
The aim of this study was to conduct a preliminary dismantling study of exposure, relaxation, and rescripting therapy (ERRT) for nightmares. Participants (N = 70) were randomized to 1 of 2 conditions: ERRT with nightmare exposure and rescripting (full protocol; EX) or ERRT without nightmare exposure and rescripting (NEX). Participants completed follow-ups at 1 week, 3 months, and 6 months posttreatment. Both conditions yielded statistically significant improvements with medium to large effect sizes on primary outcomes related to nightmares (i.e., nights with nightmares, nightmares per week, and nightmare severity). Both conditions also yielded statistically significant improvements on secondary outcomes with medium to large effect sizes on fear of sleep, sleep quality, insomnia severity, daytime sleepiness, posttraumatic stress disorder symptom severity, and depression severity. The conditions did not differ at any time point. Findings indicate that ERRT with and without nightmare exposure and rescripting can significantly alleviate nightmares and related distress. The addition of nightmare exposure and rescription did not contribute incrementally to outcomes in this sample. It is possible that the dose of exposure was not sufficient to result in group differences or that the treatment components included in both conditions (i.e., psychoeducation about trauma, nightmares, and sleep; sleep habit modification; and relaxation training) may adequately treat factors that maintain nightmares for some individuals. Theoretical implications of findings are discussed. The reduction of symptoms of other conditions following this brief intervention provides further evidence for the primary role of nightmares and sleep disturbances posttrauma. (PsycINFO Database Record


African Primary Care Research: qualitative data analysis and writing results.
This article is part of a series on African primary care research and gives practical guidance on qualitative data analysis and the presentation of qualitative findings. After an overview of qualitative methods and analytical approaches, the article focuses particularly on content analysis, using the framework method as an example. The steps of familiarisation, creating a thematic index, indexing, charting, interpretation and confirmation are described. Key concepts with regard to establishing the quality and trustworthiness of data analysis are described. Finally, an approach to the presentation of qualitative findings is given.


Antiatherogenic potential of red wine: clinician update.
Complications of atherosclerosis remain the leading cause of morbidity and mortality in industrialized countries. Epidemiological studies have repeatedly demonstrated that moderate alcohol intake has a beneficial effect on cardiovascular disease. The purpose of this review is to examine the epidemiological and biological evidence supporting the intake of red wine as a means of reducing atherosclerosis. On the basis of epidemiological studies, moderate intake of alcoholic beverages, including red wine, reduces the risk of cardiovascular, cerebrovascular, and peripheral vascular disease in populations. In addition to the favorable biological effects of alcohol on the lipid profile, on hemostatic factors, and in reducing insulin resistance, the phenolic compounds in red wine appear to interfere with the molecular processes underlying the initiation, progression, and rupture of atherosclerotic plaques. Whether red wine is more beneficial than other types of alcohol remains unclear. Definitive data from a large-scale, randomized clinical end-point trial of red wine intake would be required before physicians can advise patients to use wine as part of preventative or medical therapies.


'Ain't nothin' like the real thing'. Motivation and study processes on a work-based project course in information systems design.
Advocates of the project method claim that project-based learning inspires student learning. However, it has been claimed that project-based learning environments demand quite a bit of self-regulation on the part of the learner. Consequently, it was tested whether students scoring low in self-regulation of learning experienced 'friction', an incompatibility between student self-regulation and the demands posed by the learning environment. This would be manifest in cognitive processing and motivation. The target group consisted of 58 mainly third-year Finnish university students taking a mandatory project course in information systems design. During the project course, student teams completed a commissioned assignment. The study also included a matched nonequivalent comparison group composed of computer science students attending study programmes without a project-based component. Data were gathered by means of a questionnaire administered at the beginning and end of the project course and it was analysed by between-groups repeated measures ANOVA. In addition, the students on the course were interviewed. Results suggest that the work-based project model in question may indeed have a substantial motivational impact, interestingly benefitting especially those students who scored low in self-regulation. It is argued that we tend to view learning environments too simplistically. In particular, a basic distinction should be made between individual and collaborative learning contexts, since peer scaffolding, group grading and choice of group roles may explain why students scoring low in self-regulation of learning did not encounter friction as expected.


Fast wideband source tuning by extra-cavity parametric process.
Fundamental and practical performance limits of continuously tunable optical sources using extra-cavity mixing process are examined. While the parametric process cannot overcome the fundamental tunable limit set by the uncertainty principle, it offers a new path in overcoming the practical performance limits associated with conventional tunable lasers. Specifically, cavity reconfiguration speed is recognized as a limiting process in all tunable lasers that cannot be circumvented by any conventional approach. Recognizing this barrier, we introduce and experimentally demonstrate a decoupling concept that relies on extra-cavity mixing to increase the tuning speed and range of any tunable laser source.


First demonstration of tuning between the Kitaev and Ising limits in a honeycomb lattice.
Recent observations of novel spin-orbit coupled states have generated interest in 4d/5d transition metal systems. A prime example is the [Formula: see text] state in iridate materials and α-RuCl3 that drives Kitaev interactions. Here, by tuning the competition between spin-orbit interaction (λSOC) and trigonal crystal field (ΔT), we restructure the spin-orbital wave functions into a previously unobserved [Formula: see text] state that drives Ising interactions. This is done via a topochemical reaction that converts Li2RhO3 to Ag3LiRh2O6. Using perturbation theory, we present an explicit expression for the [Formula: see text] state in the limit ΔT ≫ λSOC realized in Ag3LiRh2O6, different from the conventional [Formula: see text] state in the limit λSOC ≫ ΔT realized in Li2RhO3. The change of ground state is followed by a marked change of magnetism from a 6 K spin-glass in Li2RhO3 to a 94 K antiferromagnet in Ag3LiRh2O6.


Passive material properties of intact ventricular myocardium determined from a cylindrical model.
The equatorial region of the canine left ventricle was modeled as a thick-walled cylinder consisting of an incompressible hyperelastic material with homogeneous exponential properties. The anisotropic properties of the passive myocardium were assumed to be locally transversely isotropic with respect to a fiber axis whose orientation varied linearly across the wall. Simultaneous inflation, extension, and torsion were applied to the cylinder to produce epicardial strains that were measured previously in the potassium-arrested dog heart. Residual stress in the unloaded state was included by considering the stress-free configuration to be a warped cylindrical arc. In the special case of isotropic material properties, torsion and residual stress both significantly reduced the high circumferential stress peaks predicted at the endocardium by previous models. However, a resultant axial force and moment were necessary to cause the observed epicardial deformations. Therefore, the anisotropic material parameters were found that minimized these resultants and allowed the prescribed displacements to occur subject to the known ventricular pressure loads. The global minimum solution of this parameter optimization problem indicated that the stiffness of passive myocardium (defined for a 20 percent equibiaxial extension) would be 2.4 to 6.6 times greater in the fiber direction than in the transverse plane for a broad range of assumed fiber angle distributions and residual stresses. This agrees with the results of biaxial tissue testing. The predicted transmural distributions of fiber stress were relatively flat with slight peaks in the subepicardium, and the fiber strain profiles agreed closely with experimentally observed sarcomere length distributions. The results indicate that torsion, residual stress and material anisotropy associated with the fiber architecture all can act to reduce endocardial stress gradients in the passive left ventricle.


Unified pre- and postsynaptic long-term plasticity enables reliable and flexible learning.
Although it is well known that long-term synaptic plasticity can be expressed both pre- and postsynaptically, the functional consequences of this arrangement have remained elusive. We show that spike-timing-dependent plasticity with both pre- and postsynaptic expression develops receptive fields with reduced variability and improved discriminability compared to postsynaptic plasticity alone. These long-term modifications in receptive field statistics match recent sensory perception experiments. Moreover, learning with this form of plasticity leaves a hidden postsynaptic memory trace that enables fast relearning of previously stored information, providing a cellular substrate for memory savings. Our results reveal essential roles for presynaptic plasticity that are missed when only postsynaptic expression of long-term plasticity is considered, and suggest an experience-dependent distribution of pre- and postsynaptic strength changes.


First Report of Colletotrichum coccodes Causing Leaf and Neck Anthracnose on Onions (Allium cepa) in Michigan and the United States.
In July of 2010, dry, oval lesions, each with a salmon-colored center and bleached overall appearance, were observed on the leaves and neck of onions plants growing in production fields of Newaygo, Ottawa, Kent, and Ionia counties, Michigan. Acervuli and setae that are characteristic of Colletotrichum spp. were observed with a dissecting microscope, and elliptical conidia (8 to 23 × 3 to 12 μm) with attenuated ends were observed with a compound microscope. Symptomatic tissues were excised and cultured onto potato dextrose agar amended with 30 and 100 ppm of rifampicin and ampicillin, respectively. The cultures produced pale salmon-colored sporulation after growing for 5 days at 22 ± 2°C and black microsclerotia after 2 weeks. Six isolates were confirmed as C. coccodes based on sequence analysis of the internal transcribed (ITS) region of the ribosomal DNA and a 1-kb intron of the glutamine synthase gene (GS) (2). Sequences were submitted to GenBank (Accession Nos. JQ682644 and JQ682645 for ITS and GS, respectively). Pathogenicity tests were conducted on two- to three-leaved 'Stanley' and 'Cortland' onion seedlings. Prior to inoculation, seedlings were enclosed in clear plastic bags overnight to provide high relative humidity. The bags were removed, and seedlings were sprayed inoculated with a C. coccodes conidial suspension (5 × 105 conidia/ml and 25 ml/plant) in sterile double-distilled water. Control seedlings were sprayed with sterile double-distilled water. Tween (0.01%) was added to the conidial suspension and the water. Plants were enclosed in bags for 72 h postinoculation and incubated in growth chambers at 28°C day/23°C night with a 12-h photoperiod. Sunken, oval lesions were observed on the foliage of the onion seedlings inoculated with C. coccodes 4 days postinoculation. Lesions coalesced and foliage collapsed 7 days postinoculation. Control plants remained asymptomatic. When five leaf samples per replication were detached and incubated in a moist chamber for 3 days at 21 ± 2°C, abundant acervuli and setae were observed on the symptomatic tissue but not on control tissue. C. coccodes was consistently recovered from the onion seedling lesions. Six different Colletotrichum spp. have been reported to cause diseases on onions worldwide (1,4). C. circinans, which causes smudge, is an occasional onion pathogen in Michigan, while C. gloeosporioides has only been reported to be infecting onions in Georgia (3). To our knowledge, this is the first report of C. coccodes infecting and causing disease in onions plants. References: (1) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , August 6, 2010. (2) J. C. Guerber et al. Mycologia 95:872. 2003. (3) C. Nischwitz et al. Plant Dis. 92:974. 2008. (4) H. F. Schwartz, and K. S. Mohan. Compendium of Onion and Garlic Diseases and Pests, 2nd ed. The American Phytopathological Society, St. Paul, MN. 1995.


Association of Renin-Angiotensin Inhibitor Treatment With Mortality and Heart Failure Readmission in Patients With Transcatheter Aortic Valve Replacement.
Data are lacking on the effect of a renin-angiotensin system (RAS) inhibitor prescribed after transcatheter aortic valve replacement (TAVR). Treatment with a RAS inhibitor may reverse left ventricular remodeling and improve function. To investigate the association of prescription of a RAS inhibitor and outcomes after TAVR. Retrospective cohort study of TAVR procedures performed in the United States (using the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry) between July 2014 and January 2016 that were linked to Medicare claims data (final date of follow-up: March 31, 2017). To account for differences in demographics, echocardiographic findings, and in-hospital complications, 1:1 propensity matching was performed. Initial hospital discharge prescription of a RAS inhibitor after TAVR. Primary outcomes were all-cause death and readmission due to heart failure at 1 year after discharge, which were considered separately. The secondary outcome was health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ; score range: 0-100, with a higher score indicating less symptom burden and better quality of life; a small effect size was defined as 5 points) at 1 year. Among 21 312 patients who underwent TAVR at 417 US sites, 8468 patients (39.7%) were prescribed a RAS inhibitor at hospital discharge. After propensity matching, 15 896 patients were included (mean [SD] age, 82.4 [6.8] years; 48.1% were women; mean [SD] left ventricular ejection fraction [LVEF], 51.9% [11.5%]). Patients with a prescription for a RAS inhibitor vs those with no prescription had lower mortality rates at 1 year (12.5% vs 14.9%, respectively; absolute risk difference [ARD], -2.4% [95% CI, -3.5% to -1.4%]; hazard ratio [HR], 0.82 [95% CI, 0.76 to 0.90]) and lower heart failure readmission rates at 1 year (12.0% vs 13.8%; ARD, -1.8% [95% CI, -2.8% to -0.7%]; HR, 0.86 [95% CI, 0.79 to 0.95]). When stratified by LVEF, having a prescription for a RAS inhibitor vs no prescription was associated with lower 1-year mortality among patients with preserved LVEF (11.1% vs 13.9%, respectively; ARD, -2.81% [95% CI, -3.95% to -1.67%]; HR, 0.78 [95% CI, 0.71 to 0.86]), but not among those with reduced LVEF (18.8% vs 19.5%; ARD, -0.68% [95% CI, -3.52% to 2.20%]; HR, 0.95 [95% CI, 0.81 to 1.12]) (P = .04 for interaction). Of 15 896 matched patients, 4837 (30.4%) were included in the KCCQ score analysis and improvements at 1 year were greater in patients with a prescription for a RAS inhibitor vs those with no prescription (median, 33.3 [interquartile range, 14.2 to 51.0] vs 31.3 [interquartile range, 13.5 to 51.1], respectively; difference in improvement, 2.10 [95% CI, 0.10 to 4.06]; P < .001), but the effect size was not clinically meaningful. Among patients who underwent TAVR, receiving a prescription for a RAS inhibitor at hospital discharge compared with no prescription was significantly associated with a lower risk of mortality and heart failure readmission. However, due to potential selection bias, this finding requires further investigation in randomized trials.


Excitation energy-dependent nature of Raman scattering spectrum in GaInNAs/GaAs quantum well structures.
The excitation energy-dependent nature of Raman scattering spectrum, vibration, electronic or both, has been studied using different excitation sources on as-grown and annealed n- and p-type modulation-doped Ga1 - xInxNyAs1 - y/GaAs quantum well structures. The samples were grown by molecular beam technique with different N concentrations (y = 0%, 0.9%, 1.2%, 1.7%) at the same In concentration of 32%. Micro-Raman measurements have been carried out using 532 and 758 nm lines of diode lasers, and the 1064 nm line of the Nd-YAG laser has been used for Fourier transform-Raman scattering measurements. Raman scattering measurements with different excitation sources have revealed that the excitation energy is the decisive mechanism on the nature of the Raman scattering spectrum. When the excitation energy is close to the electronic band gap energy of any constituent semiconductor materials in the sample, electronic transition dominates the spectrum, leading to a very broad peak. In the condition that the excitation energy is much higher than the band gap energy, only vibrational modes contribute to the Raman scattering spectrum of the samples. Line shapes of the Raman scattering spectrum with the 785 and 1064 nm lines of lasers have been observed to be very broad peaks, whose absolute peak energy values are in good agreement with the ones obtained from photoluminescence measurements. On the other hand, Raman scattering spectrum with the 532 nm line has exhibited only vibrational modes. As a complementary tool of Raman scattering measurements with the excitation source of 532 nm, which shows weak vibrational transitions, attenuated total reflectance infrared spectroscopy has been also carried out. The results exhibited that the nature of the Raman scattering spectrum is strongly excitation energy-dependent, and with suitable excitation energy, electronic and/or vibrational transitions can be investigated.


Linked, if not the same, Mi-1 homologues confer resistance to tomato powdery mildew and root-knot nematodes.
On the short arm of tomato chromosome 6, a cluster of disease resistance (R) genes have evolved harboring the Mi-1 and Cf genes. The Mi-1 gene confers resistance to root-knot nematodes, aphids, and whiteflies. Previously, we mapped two genes, Ol-4 and Ol-6, for resistance to tomato powdery mildew in this cluster. The aim of this study was to investigate whether Ol-4 and Ol-6 are homologues of the R genes located in this cluster. We show that near-isogenic lines (NIL) harboring Ol-4 (NIL-Ol-4) and Ol-6 (NIL-Ol-6) are also resistant to nematodes and aphids. Genetically, the resistance to nematodes cosegregates with Ol-4 and Ol-6, which are further fine-mapped to the Mi-1 cluster. We provide evidence that the composition of Mi-1 homologues in NIL-Ol-4 and NIL-Ol-6 is different from other nematode-resistant tomato lines, Motelle and VFNT, harboring the Mi-1 gene. Furthermore, we demonstrate that the resistance to both nematodes and tomato powdery mildew in these two NIL is governed by linked (if not the same) Mi-1 homologues in the Mi-1 gene cluster. Finally, we discuss how Solanum crops exploit Mi-1 homologues to defend themselves against distinct pathogens.


Optimizing the power of genome-wide association studies by using publicly available reference samples to expand the control group.
Genome-wide association (GWA) studies have proved extremely successful in identifying novel genetic loci contributing effects to complex human diseases. In doing so, they have highlighted the fact that many potential loci of modest effect remain undetected, partly due to the need for samples consisting of many thousands of individuals. Large-scale international initiatives, such as the Wellcome Trust Case Control Consortium, the Genetic Association Information Network, and the database of genetic and phenotypic information, aim to facilitate discovery of modest-effect genes by making genome-wide data publicly available, allowing information to be combined for the purpose of pooled analysis. In principle, disease or control samples from these studies could be used to increase the power of any GWA study via judicious use as "genetically matched controls" for other traits. Here, we present the biological motivation for the problem and the theoretical potential for expanding the control group with publicly available disease or reference samples. We demonstrate that a naïve application of this strategy can greatly inflate the false-positive error rate in the presence of population structure. As a remedy, we make use of genome-wide data and model selection techniques to identify "axes" of genetic variation which are associated with disease. These axes are then included as covariates in association analysis to correct for population structure, which can result in increases in power over standard analysis of genetic information from the samples in the original GWA study.


Vasospasm shortens cerebral arterial time constant.
Cerebrovascular time constant (τ) estimates how fast cerebral blood arrives in cerebral arterial bed after each heart stroke. We investigate the pattern of changes in τ following subarachnoid hemorrhage (SAH), with specific emphasis on the temporal profile of changes in relation to the development of cerebral vasospasm. Simultaneous recordings of arterial blood pressure (ABP) and transcranial Doppler (TCD) blood flow velocity (CBFV) in MCA were performed daily in patients after SAH. In 22 patients (10 males and 12 females; median age: 48 years, range: 34-84 years) recordings done before spasm were compared to those done during spasm. Vasospasm was confirmed with TCD (mean CBFV in MCA > 120 cm/s and Lindegaard ratio > 3). τ was estimated as a product of compliance of cerebral arteries (C (a)) and cerebrovascular resistance (CVR). C (a) and CVR were estimated using mathematical transformations of ABP and CBFV waveforms. Vasospasm caused shortening of τ on both the spastic (before: 0.20 ± 0.05 s vs. spasm: 0.14 ± 0.04 s, P < 0.0008) and contralateral side (before: 0.22 ± 0.05 s vs. spasm: 0.16 ± 0.04 s, P < 0.0008). Before TCD signs of vasospasm were detected, τ demonstrated asymmetry with lower values on ipsilateral side to aneurysm, in comparison to contralateral side (P < 0.009), Cerebral vasospasm causes shortening of τ. Shorter τ at the side of aneurysm can be observed before formal TCD signs of vasospasm are observed, therefore, potentially reducing time to escalation of treatment.


Two-photon nitric oxide laser-induced fluorescence measurements in a diesel engine.
A two-photon nitric oxide (NO) laser-induced fluorescence (LIF) technique was developed and applied to study in-cylinder diesel combustion. The technique prevents many problems associated with in-cylinder, single-photon NO planar-laser-induced fluorescence measurements, including fluorescence interference from the Schumann-Runge bands of hot O2, absorption of a UV excitation beam by in-cylinder gases, and difficulty in rejecting scattered laser light while simultaneously attempting to maximize fluorescence signal collection. Verification that the signal resulted from NO was provided by tuning of the laser to a vibrational off-resonance wavelength that showed near-zero signal levels, which resulted from either fluorescence or interference at in-cylinder pressures of as much as 20 bar. The two-photon NO LIF signal showed good qualitative agreement with NO exhaust-gas measurements obtained over a wide range of engine loads.


A New Transport Solution for Parathyroid Allotransplantation: Effects on Cell Viability and Calcium-Sensing Receptors.
Cold ischemia protects organs and tissues by slowing their metabolism, but it also causes ischemic injury. Minimizing cold ischemia has been an important goal in parathyroid auto- and allotransplantation, as well as the transplantation of other major organs. Parathyroid glands are responsible for calcium homeostasis by releasing parathormone (PTH) into the blood circulation. Functionality of a new parathyroid transport solution (NPTS) and effects on cell viability, PTH secretion, and calcium-sensing receptor (CaSR) levels during cold ischemia were evaluated. A NPTS was prepared, and the pH was adjusted to a range of 7.2-7.4 and kept at +4°C until use. Seven patients with parathyroid hyperplasia secondary to chronic renal failure who were scheduled to undergo subtotal parathyroidectomy were enrolled in the study. Glands were cold-preserved in NPTS with different time intervals (0, 6, 12, 18, and 24 hours), and then parathyroid cell viability before and after cryopreservation, PTH secretion, and CaSR levels were determined. The mean cell viability before cryopreservation was 92.7% (range 89.2%-97.2%). There were no significant differences in cell viability rates before and after cryopreservation (p = 0.1168 and p = 0.4085, respectively), and CaSR levels (p = 0.5446) were not significant. NPTS is a solution designed specifically for parathyroid tissue transplantation. This patent pending product can support cellular viability and PTH release, as well as protect CaSR functionality for up to 24 hours of cold ischemia.


Generation and screening of a comprehensive Mycobacterium avium subsp. paratuberculosis transposon mutant bank.
Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne's Disease in ruminants. This enteritis has significant economic impact and worldwide distribution. Vaccination is one of the most cost effective infectious disease control measures. Unfortunately, current vaccines reduce clinical disease and shedding, but are of limited efficacy and do not provide long-term protective immunity. Several strategies have been followed to mine the MAP genome for virulence determinants that could be applied to vaccine and diagnostic assay development. In this study, a comprehensive mutant bank of 13,536 MAP K-10 Tn5367 mutants (P > 95%) was constructed and screened in vitro for phenotypes related to virulence. This strategy was designated to maximize identification of genes important to MAP pathogenesis without relying on studies of other mycobacterial species that may not translate into similar effects in MAP. This bank was screened for mutants with colony morphology alterations, susceptibility to D-cycloserine, impairment in siderophore production or secretion, reduced cell association, and decreased biofilm and clump formation. Mutants with interesting phenotypes were analyzed by PCR, Southern blotting and DNA sequencing to determine transposon insertion sites. These insertion sites mapped upstream from the MAP1152-MAP1156 cluster, internal to either the Mod operon gene MAP1566 or within the coding sequence of lsr2, and several intergenic regions. Growth curves in broth cultures, invasion assays and kinetics of survival and replication in primary bovine macrophages were also determined. The ability of vectors carrying Tn5370 to generate stable MAP mutants was also investigated.


Perylenetetracarboxylic anhydride as a precursor of fluorescent carbon nanoonion rings.
Thermal annealing at 400 °C of perylenetetracarboxylic anhydride in low molecular mass PEG gives rise to the formation of well defined nanoobjects of 2.5 nm height and size distribution from 10 to 65 nm (average 40 nm) after purification of the raw mixture with silicagel chromatography. TEM reveals that the flat nanoobjects are constituted of concentric graphenic rings (0.34 nm interlayer distance). The morphology of the nanoparticles resembles onion rings of nanometric dimensions (nanoonion rings C-NOR). C-NOR particles have an excitation dependent emission with λem from 430 to 570 nm and a maximum emission quantum yield of 0.49. C-NOR particles can be internalized into Hep3B human hepatoma cells as determined by confocal fluorescence microscopy and are remarkably biocompatible affecting slightly cell viability according to the MTT test.


Multimodal and multiscale optical imaging of nanomedicine delivery across the blood-brain barrier upon sonopermeation.
Rationale: The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Sonopermeation, which relies on the combination of ultrasound and microbubbles, has emerged as a powerful tool to permeate the BBB, enabling the extravasation of drugs and drug delivery systems (DDS) to and into the central nervous system (CNS). When aiming to improve the treatment of high medical need brain disorders, it is important to systematically study nanomedicine translocation across the sonopermeated BBB. To this end, we here employed multimodal and multiscale optical imaging to investigate the impact of DDS size on brain accumulation, extravasation and penetration upon sonopermeation. Methods: Two prototypic DDS, i.e. 10 nm-sized pHPMA polymers and 100 nm-sized PEGylated liposomes, were labeled with fluorophores and intravenously injected in healthy CD-1 nude mice. Upon sonopermeation, computed tomography-fluorescence molecular tomography, fluorescence reflectance imaging, fluorescence microscopy, confocal microscopy and stimulated emission depletion nanoscopy were used to study the effect of DDS size on their translocation across the BBB. Results: Sonopermeation treatment enabled safe and efficient opening of the BBB, which was confirmed by staining extravasated endogenous IgG. No micro-hemorrhages, edema and necrosis were detected in H&E stainings. Multimodal and multiscale optical imaging showed that sonopermeation promoted the accumulation of nanocarriers in mouse brains, and that 10 nm-sized polymeric DDS accumulated more strongly and penetrated deeper into the brain than 100 nm-sized liposomes. Conclusions: BBB opening via sonopermeation enables safe and efficient delivery of nanomedicine formulations to and into the brain. When looking at accumulation and penetration (and when neglecting issues such as drug loading capacity and therapeutic efficacy) smaller-sized DDS are found to be more suitable for drug delivery across the BBB than larger-sized DDS. These findings are valuable for better understanding and further developing nanomedicine-based strategies for the treatment of CNS disorders.


Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth A fibrosarcomas.
Recent studies have indicated that TNF can promote activation of the coagulation mechanism by modulating coagulant properties of endothelial cells. In this report, we demonstrate that infusion of low concentrations of TNF (3 micrograms/animal) into mice bearing meth A fibrosarcomas leads to localized fibrin deposition with formation of occlusive intravascular thrombi in close association with the endothelial cell surface. Studies with 125I-fibrinogen showed tenfold enhanced accumulation of radioactivity in tumor within 2 h after TNF infusion. Western blots of tumor extracts subjected to SDS-PAGE and visualized with a fibrin-specific mAb indicated that fibrin forms in the tumor after the TNF infusion. Electron microscopic studies demonstrated fibrin strands, based on the characteristic 21-nm periodicity, which appeared to be adherent to the endothelial cell surface. Further ultrastructural studies indicated that fibrin formation, first evident within 30 min of the TNF infusion, led to occlusive thrombi limited to the tumor vascular bed (i.e., not in the normal mouse vasculature) within 2 h and was associated with an 80% reduction in tumor perfusion based on studies with Evans blue. In view of previous work concerning TNF induction of endothelial cell procoagulant activity, the hypothesis that tumor cell products prime the response of endothelium to this cytokine was tested. Supernatants of cultured meth A fibrosarcomas obtained serum-free conditions, which had no intrinsic procoagulant activity, considerably enhanced tissue factor induction in endothelium in response to submaximal concentrations of TNF. The factor(s) in the tumor-conditioned medium appeared to be distinct from IL-1, fibroblast growth factor, IFN-gamma, TNF, endotoxin, TGF-alpha, and TGF-beta. These studies delineate a novel model of localized clot formation in which thrombosis is initiated by a pathophysiologic mediator, TNF, and provides an opportunity to examine mechanisms in the microenvironment directing clot formation to the tumor vascular bed.


Diversity of murine norovirus in wild-rodent populations: species-specific associations suggest an ancient divergence.
A survey of wild-rodent populations has revealed that murine norovirus (MNV) is present and diverse in wild-house mice Mus musculus. This virus is genetically similar to MNV infecting show mice and previously described variants circulating in laboratory mice. The detection of MNV in wild-mouse populations suggests that MNV infection of laboratory mice and show mice (from which laboratory mice are derived) derives from contact with or their origins from wild-mouse progenitors. The survey additionally identified frequent infection of wood mice (Apodemus sylvaticus) with genetically divergent variants of MNV. These viruses are distinct from previously described MNV variants, differing by 22-23 % over the complete genome sequence compared with a maximum of 13 % between M. musculus-derived strains. Comparison with other noroviruses reveals that the Apodemus MNV groups with MNV in genogroup V and shares the same overall genome organization, predicted lengths of proteins encoded by ORFs 1-3 and the existence of a conserved alternative reading frame in VP1 encoding a homologue of the MNV ORF4. Different Apodemus MNV isolates were as variable as MNV isolates and showed evidence for inter-isolate recombination. Our observation of species-specific associations of MNV variants in wild populations suggests that murine noroviruses have an ancient origin, a feature that they may share with other norovirus genogroups.


Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha.
Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.


Psychosocial interventions for smoking cessation in patients with coronary heart disease.
This is an update of a Cochrane review previously published in 2008. Smoking increases the risk of developing atherosclerosis but also acute thrombotic events. Quitting smoking is potentially the most effective secondary prevention measure and improves prognosis after a cardiac event, but more than half of the patients continue to smoke, and improved cessation aids are urgently required. This review aimed to examine the efficacy of psychosocial interventions for smoking cessation in patients with coronary heart disease in short-term (6 to 12 month follow-up) and long-term (more than 12 months). Moderators of treatment effects (i.e. intervention types, treatment dose, methodological criteria) were used for stratification. The Cochrane Central Register of Controlled Trials (Issue 12, 2012), MEDLINE, EMBASE, PsycINFO and PSYNDEX were searched from the start of the database to January 2013. This is an update of the initial search in 2003. Results were supplemented by cross-checking references, and handsearches in selected journals and systematic reviews. No language restrictions were applied. Randomised controlled trials (RCTs) in patients with CHD with a minimum follow-up of 6 months. Two authors independently assessed trial eligibility and risk of bias. Abstinence rates were computed according to an intention to treat analysis if possible, or if not according to completer analysis results only. Subgroups of specific intervention strategies were analysed separately. The impact of study quality on efficacy was studied in a moderator analysis. Risk ratios (RR) were pooled using the Mantel-Haenszel and random-effects model with 95% confidence intervals (CI). We found 40 RCTs meeting inclusion criteria in total (21 trials were new in this update, 5 new trials contributed to long-term results (more than 12 months)). Interventions consist of behavioural therapeutic approaches, telephone support and self-help material and were either focused on smoking cessation alone or addressed several risk factors (eg. obesity, inactivity and smoking). The trials mostly included older male patients with CHD, predominantly myocardial infarction (MI). After an initial selection of studies three trials with implausible large effects of RR > 5 which contributed to substantial heterogeneity were excluded. Overall there was a positive effect of interventions on abstinence after 6 to 12 months (risk ratio (RR) 1.22, 95% confidence interval (CI) 1.13 to 1.32, I² 54%; abstinence rate treatment group = 46%, abstinence rate control group 37.4%), but heterogeneity between trials was substantial. Studies with validated assessment of smoking status at follow-up had similar efficacy (RR 1.22, 95% CI 1.07 to 1.39) to non-validated trials (RR 1.23, 95% CI 1.12 to 1.35). Studies were stratified by intervention strategy and intensity of the intervention. Clustering reduced heterogeneity, although many trials used more than one type of intervention. The RRs for different strategies were similar (behavioural therapies RR 1.23, 95% CI 1.12 to 1.34, I² 40%; telephone support RR 1.21, 95% CI 1.12 to 1.30, I² 44%; self-help RR 1.22, 95% CI 1.12 to 1.33, I² 40%). More intense interventions (any initial contact plus follow-up over one month) showed increased quit rates (RR 1.28, 95% CI 1.17 to 1.40, I² 58%) whereas brief interventions (either one single initial contact lasting less than an hour with no follow-up, one or more contacts in total over an hour with no follow-up or any initial contact plus follow-up of less than one months) did not appear effective (RR 1.01, 95% CI 0.91 to 1.12, I² 0%). Seven trials had long-term follow-up (over 12 months), and did not show any benefits. Adverse side effects were not reported in any trial. These findings are based on studies with rather low risk of selection bias but high risk of detection bias (namely unblinded or non validated assessment of smoking status). Psychosocial smoking cessation interventions are effective in promoting abstinence up to 1 year, provided they are of sufficient duration. After one year, the studies showed favourable effects of smoking cessation intervention, but more studies including cost-effectiveness analyses are needed. Further studies should also analyse the additional benefit of a psychosocial intervention strategy to pharmacological therapy (e.g. nicotine replacement therapy) compared with pharmacological treatment alone and investigate economic outcomes.


Comparison of urine fibrinogen and interleukin-6 concentrations between healthy dogs and dogs with risk factors for enterococcal bacteriuria.
To compare urine concentrations of fibrinogen (uFIB) and interleukin-6 (uIL-6) between dogs with risk factors for enterococcal bacteriuria and healthy dogs. Banked urine samples with negative aerobic culture results from 8 dogs with urolithiasis, 9 dogs with anatomic abnormalities of the lower portion of the urinary tract (LUT), 10 dogs with LUT neoplasia, and 21 healthy control dogs. Urine creatinine concentration (uCrea) was determined by an automated biochemical analyzer, and uFIB and uIL-6 were determined by dog-specific ELISAs. The uFIB:uCrea and uIL-6:uCrea ratios were calculated for each sample to normalize intersample differences in urine concentration and were compared among the 4 experimental groups. Median uFIB:uCrea ratios for dogs with urolithiasis (0.72; interquartile [25th to 75 percentile] range [IQR], 0.46 to 3.48) and LUT neoplasia (6.16; IQR, 3.89 to 12.75), but not for dogs with LUT anatomic abnormalities (0.48; IQR, 0.27 to 0.69), were significantly greater than that for control dogs (0.17; IQR, 0.07 to 0.39). Median uIL-6: uCrea ratios for dogs with urolithiasis (0.48; IQR, 0.18 to 1.61), LUT anatomic abnormalities (0.25; IQR, 0.17 to 0.33), and LUT neoplasia (0.25; IQR, 0.12 to 1.01) were significantly greater than that for control dogs (0.08; IQR, 0.06 to 0.11). The uFIB and uIL-6 in dogs with risk factors for enterococcal bacteriuria were generally greater than corresponding values in control dogs. Further investigation is necessary to determine the role of fibrinogen in enterococcal colonization of the urinary tract of dogs.


Monozygotic twins discordant for Goldenhar syndrome.
To report on a pair of monozygotic female twins discordant for Goldenhar syndrome. The affected twin was a girl, who was delivered by caesarean section at 35 weeks' gestation. Her birth weight was 2,170 g, length 42.5 cm, head circumference 30 cm and her Apgar scores were 3/7. After birth the child developed severe respiratory distress and had to be moved to the neonatal intensive care unit (ICU). The other twin was a girl, born weighing 3,200 g with a length of 49 cm, head circumference of 34 cm and Apgar scores of 8/10. She was transferred to the mother-baby unit soon after birth and was discharged two days later. There was no consanguinity between the twins' parents, who were young and healthy at the time of their conception. The affected child's dysmorphic features included left hemifacial microsomia, severe micrognathia, abnormal ears, bilateral preauricular tags and epibulbar dermoid in the right eye. She developed obstructive apnea due to micrognathia and required tracheostomy. Abdominal and cranial ultrasound findings were normal, as was an ophthalmological assessment. Spine x-ray showed hemivertebra at T9 and T10. An echocardiogram showed Tetralogy of Fallot. GTG-banded karyotyping was performed on peripheral blood cells and revealed 46,XX. Zygosity testing established the pair of twins to be monozygotic with a probability greater than 99:1. Goldenhar syndrome was diagnosed in one of the twins described here. There are several reports of twins discordant for this disorder and therefore non-genetic factors may also play an important role, for instance vascular disruption during morphogenesis.


Surface association sensitizes Pseudomonas aeruginosa to quorum sensing.
In the pathogen Pseudomonas aeruginosa, LasR is a quorum sensing (QS) master regulator that senses the concentration of secreted autoinducers as a proxy for bacterial cell density. Counterintuitively, previous studies showed that saturating amounts of the LasR ligand, 3OC12-HSL, fail to induce the full LasR regulon in low-density liquid cultures. Here we demonstrate that surface association, which is necessary for many of the same group behaviors as QS, promotes stronger QS responses. We show that lasR is upregulated upon surface association, and that surface-associated bacteria induce LasR targets more strongly in response to autoinducer than planktonic cultures. This increased sensitivity may be due to surface-dependent lasR induction initiating a positive feedback loop through the small RNA, Lrs1. The increased sensitivity of surface-associated cells to QS is affected by the type IV pilus (TFP) retraction motors and the minor pilins. The coupling of physical surface responses and chemical QS responses could enable these bacteria to trigger community behaviors more robustly when they are more beneficial.


Development of "Laser Ablation Direct Analysis in Real Time Imaging" Mass Spectrometry: Application to Spatial Distribution Mapping of Metabolites Along the Biosynthetic Cascade Leading to Synthesis of Atropine and Scopolamine in Plant Tissue.
Methods for the accomplishment of small-molecule imaging by mass spectrometry are challenged by the need for sample pretreatment steps, such as cryo-sectioning, dehydration, chemical fixation, or application of a matrix or solvent, that must be performed to obtain interpretable spatial distribution data. Furthermore, these steps along with requirements of the mass analyzer such as high vacuum, can severely limit the range of sample types that can be analyzed by this powerful method. Here, we report the development of a laser ablation-direct analysis in real time imaging mass spectrometry approach which couples a 213 nm Nd:YAG solid state UV laser to a direct analysis in a real time ion source and high-resolution time-of-flight mass spectrometer. This platform enables facile determination of the spatial distribution of small-molecules spanning a range of polarities in a diversity of sample types and requires no matrix, vacuum, solvent, or complicated sample pretreatment steps. It furnishes high-resolution data, can be performed under ambient conditions on samples in their native form, and results in little to no fragmentation of analytes. We demonstrate its application through determination of the spatial distribution of molecules involved in the biosynthetic cascade leading to formation of the clinically relevant alkaloids atropine and scopolamine in Datura leichhardtii seed tissue.


Myosin I contributes to the generation of resting cortical tension.
The amoeboid myosin I's are required for cellular cortical functions such as pseudopod formation and macropinocytosis, as demonstrated by the finding that Dictyostelium cells overexpressing or lacking one or more of these actin-based motors are defective in these processes. Defects in these processes are concomitant with changes in the actin-filled cortex of various Dictyostelium myosin I mutants. Given that the amoeboid myosin I's possess both actin- and membrane-binding domains, the mutant phenotypes could be due to alterations in the generation and/or regulation of cell cortical tension. This has been directly tested by analyzing mutant Dictyostelium that either lacks or overexpresses various myosin I's, using micropipette aspiration techniques. Dictyostelium cells lacking only one myosin I have normal levels of cortical tension. However, myosin I double mutants have significantly reduced (50%) cortical tension, and those that mildly overexpress an amoeboid myosin I exhibit increased cortical tension. Treatment of either type of mutant with the lectin concanavalin A (ConA) that cross-links surface receptors results in significant increases in cortical tension, suggesting that the contractile activity of these myosin I's is not controlled by this stimulus. These results demonstrate that myosin I's work cooperatively to contribute substantially to the generation of resting cortical tension that is required for efficient cell migration and macropinocytosis.


Primary leiomyosarcoma of the kidney: a clinicopathologic study of 27 cases.
Primary leiomyosarcoma of the kidney is a rare entity that has not been well characterized. We retrieved 27 cases of primary renal leiomyosarcomas diagnosed at 3 institutions between 1986 and 2009. Mean patient age at diagnosis was 58.5 years (range 22 to 85), and 59% were female. Mean tumor size was 13.4 cm (range 4 to 26), and 59% of the tumors were identified in the right kidney. Detailed histologic examination was possible for 24 of the cases. Average mitotic count per 10 high-power fields was 11.1 (range 0 to 50), and the average extent of necrosis was 21% (range 0 to 60). Cellular pleomorphism was classified as either focal (n = 13) or extensive (n = 11) and graded as mild (n = 3), moderate (n = 7) or severe (n = 14). Tumors were either grade 2 (n = 12) or grade 3 (n = 12) using the French Federation of Cancer Centers System. Direct extension beyond the kidney capsule was identified in 55% of the cases, and lymphovascular invasion was identified in 26%. Clinical follow-up information was available for 20 of the cases, and patients were followed for an average of 2.8 years (range 0.25 to 9). Distant metastases were identified in 90% of the patients, and 75% eventually died from their tumor's burden. In conclusion, primary renal leiomyosarcomas have a grim prognosis regardless of the underlying histology.


Nanophase segregation and water dynamics in the dendrion diblock copolymer formed from the Fréchet polyaryl ethereal dendrimer and linear PTFE.
We propose a new material consisting of a dendrion copolymer formed from (a) a water-soluble dendritic polymer and (b) a hydrophobic backbone. Using molecular dynamics simulations techniques, we determine the structure and dynamics of the dendrion formed by second-generation Fréchet polyaryl ethereal dendrimer as the hydrophilic component and linear polytetrafluoroethylene (PTFE) as the hydrophobic polymer, with 5 and 10 wt % of water. We find that this material produces a well-developed nanoscale structure in which water forms a continuous nanophase, making this new family of compounds promising candidates for applications in fuel cell membranes. We find that the water molecules are incorporated into the dendrimer block of the copolymer to form a nanophase-segregated structure. The well-developed nanophase-segregated structures rendered by this material have characteristic dimensions of segregation ( approximately 30 Angstrom) and dendrimer conformational properties that are independent of water content. Calculations of water dynamics and proton transport in these nanophase-segregated structures indicate that the dendrion copolymer membrane with 10 wt % of water content has a water structure and transport properties equivalent to that of the hydrated Nafion membrane with 20 wt % of water content.


Active epithelial Hippo signaling in idiopathic pulmonary fibrosis.
Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.


Surgical compared with nonsurgical management of fractures in male veterans with chronic spinal cord injury.
Retrospective review of a clinical database. To examine treatment modalities of incident appendicular fractures in men with chronic SCI and mortality outcomes by treatment modality. United States Veterans Health Administration Healthcare System. This was an observational study of 1979 incident fractures that occurred over 6 years among 12 162 male veterans with traumatic SCI of at least 2 years duration from the Veterans Health Administration (VA) Spinal Cord Dysfunction Registry. Treatment modalities were classified as surgical or nonsurgical treatment. Mortality outcomes at 1 year following the incident fracture were determined by treatment modality. A total of 1281 male veterans with 1979 incident fractures met inclusion criteria for the study. These fractures included 345 (17.4%) upper-extremity fractures and 1634 (82.6%) lower-extremity fractures. A minority of patients (9.4%) were treated with surgery. Amputations and disarticulations accounted for 19.7% of all surgeries (1.3% of all fractures), and the majority of these were done more than 6 weeks following the incident fracture. There were no significant differences in mortality among men with fractures treated surgically compared with those treated nonsurgically. Currently, the majority of appendicular fractures in male patients with chronic SCI are managed nonsurgically within the VA health-care system. There is no difference in mortality by type of treatment.


Long-term treatment with royal jelly improves bleomycin-induced pulmonary fibrosis in rats.
This study investigated the anti-fibrotic potential of royal jelly (RJ) powder against bleomycin-induced pulmonary fibrosis in rats. The rats were given RJ orally (25, 50, and 100 mg/kg per day) for 7 consecutive days before the administration of single intratracheal instillation of bleomycin (BLM) at 7.5 IU/kg. RJ doses were continued for 21 days after BLM exposure. Fibrotic changes in the lungs were studied by cell count and analysis of cytokine levels in the bronchoalveolar lavage fluid (BALF), histopathological examination, and assaying oxidative stress biomarkers in lung tissue. The results showed that BLM administration significantly increased the fibrotic changes, collagen content, and levels of malondialdehyde and decreased total thiol and glutathione peroxidase antioxidant contents in the rats' lung tissue. An increase in the level of cell counts and pro-inflammatory and pro-fibrotic cytokines such as TNF-α and TGF-β in BALF was observed. Also, it significantly decreased IFN-γ, an anti-fibrotic cytokine, in BALF. However, RJ (50 and 100 mg/kg) reversed all of these biochemical indices as well as histopathological alterations induced by BLM. The present study demonstrates that RJ, by its antioxidant and anti-inflammatory properties, attenuates oxidative damage and fibrosis induced by BLM.


RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.


Transcriptional Activation of p53 during Cold Induced Torpor in the 13-Lined Ground Squirrel Ictidomys tridecemlineatus.
The transcription factor p53 is located at the centre of multiple pathways relating the cellular response to stress. Commonly known as a tumor suppressor, it is responsible for initiating diverse actions to protect the integrity of the genome, ranging from cell cycle arrest to apoptosis. This study investigated the regulation of p53 protein in hibernating 13-lined ground squirrel Ictidomys tridecemlineatus during multiple stages of the torpor-arousal cycle. Transcript and protein levels of p53 were both elevated in the skeletal muscle during early and late torpor stages of the hibernation cycle. Nuclear localization of p53 was also increased during late torpor, and this is associated with an increase in its DNA binding activity and expression of p53 transcriptional targets p21CIP, gadd45α, and 14-3-3σ. The increase in p53 transcriptional activity appears to be independent of its phosphorylation at Ser-15, Ser-46, and Ser-392, consistent with an absence of checkpoint kinase activation during torpor. Sequence analysis revealed unique amino acid substitutions in the ground squirrel p53 protein, which may contribute to an increase in protein stability compared to nonhibernators. Overall, the study results provided evidences for a potential role of p53 in the protection of the skeletal muscle during torpor.


The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo.
Mammalian telomerase is essential for the maintenance of telomere length [1-5]. Its catalytic core comprises a reverse transcriptase component (TERT) and an RNA component. While the biochemical role of mammalian TERT is well established [6-11], it is unknown whether it is sufficient for telomere-length maintenance, chromosome stability or other cellular processes. Cells from mice in which the mTert gene had been disrupted showed progressive loss of telomere DNA, a phenotype similar to cells in which the gene encoding the telomerase RNA component (mTR) has been disrupted [1,12]. On prolonged growth, mTert-deficient embryonic stem (ES) cells exhibited genomic instability, aneuploidy and telomeric fusions. ES cells heterozygous for the mTert disruption also showed telomere attrition, a phenotype that differs from heterozygous mTR cells [12]. Thus, telomere maintenance in mammals is carried out by a single, limiting TERT.


Political orientations are correlated with brain structure in young adults.
Substantial differences exist in the cognitive styles of liberals and conservatives on psychological measures. Variability in political attitudes reflects genetic influences and their interaction with environmental factors. Recent work has shown a correlation between liberalism and conflict-related activity measured by event-related potentials originating in the anterior cingulate cortex. Here we show that this functional correlate of political attitudes has a counterpart in brain structure. In a large sample of young adults, we related self-reported political attitudes to gray matter volume using structural MRI. We found that greater liberalism was associated with increased gray matter volume in the anterior cingulate cortex, whereas greater conservatism was associated with increased volume of the right amygdala. These results were replicated in an independent sample of additional participants. Our findings extend previous observations that political attitudes reflect differences in self-regulatory conflict monitoring and recognition of emotional faces by showing that such attitudes are reflected in human brain structure. Although our data do not determine whether these regions play a causal role in the formation of political attitudes, they converge with previous work to suggest a possible link between brain structure and psychological mechanisms that mediate political attitudes.


Polycystic kidney disease: new horizons and therapeutic frontiers.
Autosomal dominant polycystic kidney disease (ADPKD) represents the most prevalent inherited kidney disease, and an important contributor to renal and systemic morbidity. Almost 20 years after the discovery of the Pkd-1 and Pkd-2 genes, the exact molecular mechanisms of polycystic kidney disease pathogenesis still remain elusive. In the absence of a specific therapy for polycystic kidney disease, patients are treated for chronic kidney disease symptoms, like hypertension, anemia, hyperparathyroidism and pain. Intensive research on ADPKD and a variety of related complex cystic kidney disease syndromes revealed a network of intracellular signaling pathways that depend on ciliary function and include calcium- and cAMP-dependent mechanisms. Furthermore, proliferative and tissue patterning responses to mTOR, STAT, CDK and wnt signaling play an important role in various aspects of cystogenesis and represent further targets for therapy. Only a limited amount of clinical evidence from randomized controlled trials is currently available to evaluate treatment options. This includes ongoing trials of the vasopressin receptor-2 antagonist tolvaptan, as well as a set of studies that fail to show a clear therapeutic benefit of everolimus or sirolimus in PKD progression. Future research will involve the evaluation of small molecule inhibitors of growth factor receptor-, CDK- and STAT-pathways, as well as the characterization of novel biomarkers of disease progression and therapeutic response.


Janus-type dendrimer-like poly(ethylene oxide)s.
A straightforward and original methodology allowing the synthesis of Janus-type dendrimer-like poly(ethylene oxide)s (PEOs) carrying orthogonal functional groups on their surface is described. The use of 3-allyloxy-1,2-propanediol (1) as a latent AB2-type heterofunctional initiator of anionic ring-opening polymerization (AROP) of ethylene oxide (EO) and of selective branching agents of PEO chain ends served to construct the two dendrons of these dendrimer-like PEOs, following a divergent pathway. Thus, the first PEO generation of the first dendron was grown by AROP from 1 followed by the reaction of the corresponding alpha-allyl,omega,omega'-bishydroxy- heterofunctional PEO derivative with 2-(3'-chloromethybenzyloxymethyl)-2-methyl-5,5-dimethyl-1,3-dioxane (2) used as a branching agent. This afforded the dendron A with four latent peripheral hydroxyls protected in the form of two ketal rings. The remaining alpha-allylic double bond of the PEO thus prepared was transformed into two hydroxyl groups using OsO4 in order to create the first PEO generation of the dendron B by AROP of EO. Allyl chloride (3) was then used as another (latent) branching agent to react with the terminal hydroxyl of the corresponding PEO chains. Deprotection under acidic conditions of the ketal groups of dendron A, followed by AROP of EO, afforded the second PEO generation on this face. This alternate and divergent procedure, combining AROP of EO and selective branching of PEO branches, could be readily iterated, one dendron after the other up to the generation six, leading to a Janus-type dendrimer-like PEO exhibiting a total mass of around 300 kg/mol and possessing 64 peripheral groups on each face. The possibility of orthogonal functionalization of the surfaces of such Janus-type dendritic PEOs was exploited. Indeed, a dendron of generation 4 was functionalized with hydroxyl functions at its periphery, whereas the other was end-capped with either tertiary amino or disulfide groups. In a variant of this strategy, azido groups and acetylene could also be orthogonally introduced at the periphery of the fourth generation Janus-type dendrimer-like PEO and subjected to polycondensation by a 1,3-dipolar cycloaddition reaction. This afforded a necklace-like covalent assembly of dendrimer-like PEOs through the formation of stable [1,2,3]-triazole linkages.


Recuperation, rehabilitation and the residential option: the Brentwood Centre for Mothers and Children.
The place of anti-social behaviour in government policy in the United Kingdom is attracting increasing attention. Particularly interesting are residential projects aiming to rehabilitate 'problem families'. Nevertheless, to date, attempts to view these initiatives in historical perspective have been limited. This article reconstructs the history of one such institution, the Brentwood Recuperation Centre for Mothers and Children, within the broader context of the problem family debate. The argument is that, unlike in The Netherlands (whose pioneering efforts in this field were widely noted at the time), Britain tended to steer clear of residential options for families, regarding these as an expensive last resort. Nevertheless the Brentwood Centre was an important experiment, with its rise and fall mirroring broader changes in the relationship between voluntarism and the state; social work theory and practice; and attitudes to the segregation and social integration of families. Letters from the mothers also challenge the idea that stays in residential institutions were always punitive and unpleasant.


k-t FASTER: Acceleration of functional MRI data acquisition using low rank constraints.
In functional MRI (fMRI), faster sampling of data can provide richer temporal information and increase temporal degrees of freedom. However, acceleration is generally performed on a volume-by-volume basis, without consideration of the intrinsic spatio-temporal data structure. We present a novel method for accelerating fMRI data acquisition, k-t FASTER (FMRI Accelerated in Space-time via Truncation of Effective Rank), which exploits the low-rank structure of fMRI data. Using matrix completion, 4.27× retrospectively and prospectively under-sampled data were reconstructed (coil-independently) using an iterative nonlinear algorithm, and compared with several different reconstruction strategies. Matrix reconstruction error was evaluated; a dual regression analysis was performed to determine fidelity of recovered fMRI resting state networks (RSNs). The retrospective sampling data showed that k-t FASTER produced the lowest error, approximately 3-4%, and the highest quality RSNs. These results were validated in prospectively under-sampled experiments, with k-t FASTER producing better identification of RSNs than fully sampled acquisitions of the same duration. With k-t FASTER, incoherently under-sampled fMRI data can be robustly recovered using only rank constraints. This technique can be used to improve the speed of fMRI sampling, particularly for multivariate analyses such as temporal independent component analysis.


Impact of male trait exaggeration on sex-biased gene expression and genome architecture in a water strider.
Exaggerated secondary sexual traits are widespread in nature and often evolve under strong directional sexual selection. Although heavily studied from both theoretical and empirical viewpoints, we have little understanding of how sexual selection influences sex-biased gene regulation during the development of exaggerated secondary sexual phenotypes, and how these changes are reflected in genomic architecture. This is primarily due to the limited availability of representative genomes and associated tissue and sex transcriptomes to study the development of these traits. Here we present the genome and developmental transcriptomes, focused on the legs, of the water strider Microvelia longipes, a species where males exhibit strikingly long third legs compared to females, which they use as weapons. We generated a high-quality genome assembly with 90% of the sequence captured in 13 scaffolds. The most exaggerated legs in males were particularly enriched in both sex-biased and leg-biased genes, indicating a specific signature of gene expression in association with trait exaggeration. We also found that male-biased genes showed patterns of fast evolution compared to non-biased and female-biased genes, indicative of directional or relaxed purifying selection. By contrast to male-biased genes, female-biased genes that are expressed in the third legs, but not the other legs, are over-represented in the X chromosome compared to the autosomes. An enrichment analysis for sex-biased genes along the chromosomes revealed also that they arrange in large genomic regions or in small clusters of two to four consecutive genes. The number and expression of these enriched regions were often associated with the exaggerated legs of males, suggesting a pattern of common regulation through genomic proximity in association with trait exaggeration. Our findings indicate how directional sexual selection may drive sex-biased gene expression and genome architecture along the path to trait exaggeration and sexual dimorphism.


Liposomal delivery of hydrophobic RAMBAs provides good bioavailability and significant enhancement of retinoic acid signalling in neuroblastoma tumour cells.
Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid (RA) pharmacokinetics in pre-clinical neuroblastoma models. Here, we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance RA action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here, we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signalling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans.


The Role of ADHD in Predicting the Development of Violent Behavior Among Juvenile Offenders: Participation Versus Frequency.
Past research has identified attention-deficit/hyperactivity disorder (ADHD) as a risk factor for engagement in violent offending. Despite the link between the disorder and violent offending, this risk factor has yet to be examined as a predictor of heterogeneity in the development of violent offending among juvenile offenders. It is likely that the impulsivity, genetic link, and generally chronic disorder course which are characteristics of the disorder play roles in predicting violent offending, which is consistent with both self-control theory and general developmental theory related to early life deficits and life-course persistent offending. Past research has also elucidated a developmental trajectory model of violent offending, which is utilized by the present research. The present research examines ADHD as a risk factor predicting trajectory group assignment. The Pathways to Desistance data followed 1,354 juvenile offenders for 84 months following conviction for a serious offense. Using multinomial logistic regression, this study extends past research on the development of violent offending among juvenile offenders by examining ADHD as a risk factor predicting assignment to violent offending trajectory groups. Results indicate that meeting criteria for ADHD at baseline predicted membership to all trajectory groups relative to the Abstaining group when all covariates were included. This increase in risk is highest for the trajectory group characterized by the highest frequency of violent offending. This indicates the relevance of identifying and treating ADHD among juvenile offenders to best mitigate risk of violent recidivism throughout adolescence and early adulthood.


Alteration of the mu opioid receptor: Ca2+ channel signaling pathway in a subset of rat sensory neurons following chronic femoral artery occlusion.
The exercise pressor reflex, a crucial component of the cardiovascular response under physiological and pathophysiological states, is activated via metabolic and mechanical mediators that originate from contracting muscles and stimulate group III and IV afferents. We reported previously that stimulation of mu opioid receptors (MOR), expressed in both afferents, led to a significant attenuation of the reflex in rats whose femoral arteries had been occluded for 72 h. The present study examined the effect of arterial occlusion on the signaling components involved in the opioid-mediated modulation of Ca(2+) channels in rat dorsal root ganglion neurons innervating the triceps surae muscles. We focused on neurons that were transfected with cDNA coding for enhanced green fluorescent protein whose expression is driven by the voltage-gated Na(+) channel 1.8 (Na(V)1.8) promoter region, a channel expressed primarily in nociceptive neurons. With the use of a small interference RNA approach, our results show that the pertussis toxin-sensitive Gα(i3) subunit couples MOR with Ca(2+) channels. We observed a significant leftward shift of the MOR agonist [D-Ala2-N-Me-Phe4-Glycol5]-enkephalin concentration-response relationship in neurons isolated from rats with occluded arteries compared with those that were perfused freely. Femoral occlusion did not affect Ca(2+) channel density or the fraction of the main Ca(2+) channel subtype. Furthermore, Western blotting analysis indicated that the leftward shift did not result from either increased Gα(i3) or MOR expression. Finally, all neurons from both groups exhibited an inward current following exposure of the transient potential receptor vanilloid 1 (TRPV1) agonist, 8-methyl-N-vanillyl-6-nonenamide. These findings suggest that sensory neurons mediating the exercise pressor reflex express Na(V)1.8 and TRPV1 channels, and femoral occlusion alters the MOR pharmacological profile.


Polarizable density embedding: a new QM/QM/MM-based computational strategy.
We present a new QM/QM/MM-based model for calculating molecular properties and excited states of solute-solvent systems. We denote this new approach the polarizable density embedding (PDE) model, and it represents an extension of our previously developed polarizable embedding (PE) strategy. The PDE model is a focused computational approach in which a core region of the system studied is represented by a quantum-chemical method, whereas the environment is divided into two other regions: an inner and an outer region. Molecules belonging to the inner region are described by their exact densities, whereas molecules in the outer region are treated using a multipole expansion. In addition, all molecules in the environment are assigned distributed polarizabilities in order to account for induction effects. The joint effects of the inner and outer regions on the quantum-mechanical core part of the system is formulated using an embedding potential. The PDE model is illustrated for a set of dimers (interaction energy calculations) as well as for the calculation of electronic excitation energies, showing promising results.


Anaplastic thyroid cancer: cytogenetic patterns by comparative genomic hybridization.
We studied chromosomal abnormalities by comparative genomic hybridization (CGH) and flow cytometry in anaplastic thyroid cancer (ATC), and when present in coexisting or previous differentiated thyroid cancer (DTC). Overall 10 frozen tissues from patients with ATC and 5 cell lines (1 ATC and 4 DTCs) were analyzed. We found chromosomal abnormalities in 5 of 10 ATC tissues, with 24 abnormalities (22 gains and 2 losses). Among 8 ATCs that were associated with prior or concurrent DTC, more chromosomal abnormalities were found in ATC associated with follicular thyroid cancer (FTC) than those associated with PTC (median numbers 9.5 and 0.5, respectively, p = 0.046) or no associated differentiated thyroid cancer. Gain of 1q was relatively common in ATCs (30%). By flow cytometry, we found aneuploidy in 6 of 10 ATC tissues and diploidy in 4. There was concordance between DNA aneuploidy and the presence of chromosomal abnormalities by CGH in 4 of the 5 ATCs (p = 0.048). We also found 26 chromosomal abnormalities in an ATC cell line, 14.3 in 3 FTC cell line, and 3 in a PTC cell line. In conclusion, chromosomal abnormalities are frequent in ATCs associated with FTC, but uncommon in those associated with PTC and in ATCs with no associated differentiated thyroid cancer. These findings support the concept that PTC and FTC have different genetic backgrounds and, even after the transformation to ATC, they may retain some of their cytogenetic characteristics.


Predicting functional remission in patients with schizophrenia: a cross-sectional study of symptomatic remission, psychosocial remission, functioning, and clinical outcome.
New approaches to assess outcome in schizophrenia include multidimensional measures such as remission, cognition, psychosocial functioning, and quality of life. Clinical and psychosocial measures have been recently introduced to assess functional outcome. The study presented here was designed to examine the rates of symptomatic remission, psychosocial remission, global functioning, and clinical global impressions in a sample of schizophrenia outpatients in order to assess functional remission and to identify predictive factors for functional remission. A total of 168 consecutive Mexican outpatients receiving pharmacological treatment at the National Institute of Psychiatry in Mexico City were enrolled in a cross-sectional study. Symptomatic remission was assessed according to the definition and criteria proposed by the Remission in Schizophrenia Working Group using the Positive and Negative Symptom Scale. Psychosocial remission was assessed according to Barak criteria using the Psychosocial Remission in Schizophrenia scale. Functioning was measured with the Global Assessment of Functioning, and clinical outcome with the Clinical Global Impressions (CGI) Scale. Findings showed that 45.2% of patients fulfilled the symptomatic remission criteria, 32.1% achieved psychosocial remission, and 53% reported adequate functioning. However, the combination of these three outcome criteria - symptomatic, psychosocial remission, and functioning - indicated that 14.9% of the patients achieved our predefined functional remission outcome. The logistic regression model included five predictive variables for functional remission: (1) being employed, (2) use of atypical antipsychotics, (3) lower number of medications, (4) lower negative symptom severity, and (5) lower excitement symptom severity. The study demonstrated that symptomatic remission, psychosocial remission, and functioning could be achievable goals for a considerable number of patients. The outcome of functional remission was achieved by a minority of patients, less than 15%. New approaches should include multidimensional measures to assess functional outcome in schizophrenia research.


A Suboptimal Diet is Associated with Poorer Cognition: The NUDAD Project.
Nutrition is one of the modifiable risk factors for cognitive decline and Alzheimer's disease (AD) dementia, and is therefore highly relevant in the context of prevention. However, knowledge of dietary quality in clinical populations on the spectrum of AD dementia is lacking, therefore we studied the association between dietary quality and cognitive impairment in Alzheimer's disease (AD) dementia, mild cognitive impairment (MCI) and controls. We included 357 participants from the NUDAD project (134 AD dementia, 90 MCI, 133 controls). We assessed adherence to dietary guidelines (components: vegetables, fruit, fibers, fish, saturated fat, trans-fat, salt, and alcohol), and cognitive performance (domains: memory, language, visuospatial functioning, attention, and executive functioning). In the total population, linear regression analyses showed a lower vegetable intake is associated with poorer global cognition, visuospatial functioning, attention and executive functioning. In AD dementia, lower total adherence to dietary guidelines and higher alcohol intake were associated with poorer memory, a lower vegetable intake with poorer global cognition and executive functioning, and a higher trans-fat intake with poorer executive functioning. In conclusion, a suboptimal diet is associated with more severely impaired cognition-this association is mostly attributable to a lower vegetable intake and is most pronounced in AD dementia.


Effectiveness of Interventions to Improve Social Participation, Play, Leisure, and Restricted and Repetitive Behaviors in People With Autism Spectrum Disorder: A Systematic Review.
People with autism spectrum disorder (ASD) commonly experience difficulties with social participation, play, and leisure along with restricted and repetitive behaviors that can interfere with occupational performance. The objective of this systematic review was to evaluate current evidence for interventions within the occupational therapy scope of practice that address these difficulties. Strong evidence was found that social skills groups, the Picture Exchange Communication System, joint attention interventions, and parent-mediated strategies can improve social participation. The findings were less conclusive for interventions to improve play and leisure performance and to decrease restricted and repetitive behaviors, but several strategies showed promise with moderately strong supporting evidence. Occupational therapists should be guided by evidence when considering interventions to improve social participation, play, leisure, and restricted and repetitive behaviors in people with ASD. Additional research using more robust scientific methods is needed for many of the currently available strategies.


A burning issue. The Japanese "fire basin".
This article presents two deaths due to acute carbon monoxide poisoning that occurred when charcoal-burning hibachis were used as heating sources in enclosed camping facilities. In both deaths, the levels of blood carbon monoxide saturation were at or slightly below the expected lethal level. Coronary arteriosclerosis may have contributed to one death, while oxygen depletion may have been a contributing factor in the other. These cases illustrate the danger of using such heating sources in enclosed spaces, due to their carbon monoxide-generating capability. We suggest that suitable warnings be placed on the hibachis themselves.


Frequency combs and platicons in optical microresonators with normal GVD.
We predict the existence of a novel type of the flat-top dissipative solitonic pulses, "platicons", in microresonators with normal group velocity dispersion (GVD). We propose methods to generate these platicons from cw pump. Their duration may be altered significantly by tuning the pump frequency. The transformation of a discrete energy spectrum of dark solitons of the Lugiato-Lefever equation into a quasicontinuous spectrum of platicons is demonstrated. Generation of similar structures is also possible with bi-harmonic, phase/amplitude modulated pump or via laser injection locking.


Short-term Forecasting Tools for Agricultural Nutrient Management.
The advent of real-time, short-term farm management tools is motivated by the need to protect water quality above and beyond the general guidance offered by existing nutrient management plans. Advances in high-performance computing and hydrologic or climate modeling have enabled rapid dissemination of real-time information that can assist landowners and conservation personnel with short-term management planning. This paper reviews short-term decision support tools for agriculture that are under various stages of development and implementation in the United States: (i) Wisconsin's Runoff Risk Advisory Forecast (RRAF) System, (ii) New York's Hydrologically Sensitive Area Prediction Tool, (iii) Virginia's Saturated Area Forecast Model, (iv) Pennsylvania's Fertilizer Forecaster, (v) Washington's Application Risk Management (ARM) System, and (vi) Missouri's Design Storm Notification System. Although these decision support tools differ in their underlying model structure, the resolution at which they are applied, and the hydroclimates to which they are relevant, all provide forecasts (range 24-120 h) of runoff risk or soil moisture saturation derived from National Weather Service Forecast models. Although this review highlights the need for further development of robust and well-supported short-term nutrient management tools, their potential for adoption and ultimate utility requires an understanding of the appropriate context of application, the strategic and operational needs of managers, access to weather forecasts, scales of application (e.g., regional vs. field level), data requirements, and outreach communication structure.


Dendritic morphology of cardiac related medullary neurons defined by circuit-specific infection by a recombinant pseudorabies virus expressing beta-galactosidase.
The transneuronal herpesvirus tracer, pseudorabies virus (PRV) was used to determine the dendritic architecture of cardiac-related neurons. We constructed a derivative of the Bartha strain of PRV called PRV-BaBlu, that carries the lacZ gene of E. coli. Expression of beta-galactosidase by this recombinant virus enabled us to define the dendritic morphology of motoneurons and interneurons that innervate the heart. beta-galactosidase antigen filled dendritic processes that were clearly revealed by antibodies to beta-galactosidase. In contrast, the standard enzymatic reaction for detection of beta-galactosidase activity stained the cell soma well, but was inferior for labeling dendrites. Following PRV-BaBlu cardiac injection, infected neurons were clearly defined and labeled dendrites could be traced for long distances, sometimes greater than 800 microns from the cell body. Labeled dendrites of cardiomotor neurons primarily located in the nucleus ambiguus (NA) were extensive and sometimes intertwined with dendrites from other labeled motoneurons. Dendrites of labeled neurons in the dorsal motor nucleus of the vagus (DMV) typically extended in the mediolateral direction in the transverse plane. Transynaptically labeled interneurons interposed between the cardiorespiratory region of the nucleus tractus solitarius (NTS) and the NA were primarily located in the NA region and the reticular arc, the area between the DMV and NA. These interneurons had long dendrites extending along the reticular arc in the transverse plane. The dendritic arborizations of infected cardiac-related neurons in the NTS were variable in extent. We conclude that antibody detection of beta-galactosidase expressed by PRV-BaBlu after infection of neural cardiac circuits provides a superior method to define the dendrites and dendritic fields of cardiac-related motoneurons and interneurons.


Plasma glucose regulation and mortality in Korea: a pooled analysis of three community-based cohort studies.
Although diabetes is a well-known risk factor for death, its impact on cancer death is not clearly understood. Furthermore, it remains controversial whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality. We investigated the impact of diabetes or glucose tolerance categories on all cause and cause-specific mortality. Mortality analysis was conducted in three population-based cohort studies of 3,801 participants, divided according to fasting plasma glucose (FPG) (normal; stage 1 IFG [5.6≤FPG<6.1 mmol/L]; stage 2 IFG [6.1≤FPG<7.0 mmol/L]; diabetes mellitus [DM]-FPG); or 2-hour glucose after 75 g glucose loading (2hPG) (normal; IGT; DM-2hPG), or a combination of FPG and 2hPG criteria. During a median follow-up of 11.0 years, 474 subjects died from all causes. Hazard ratios (HRs) for all cause death were higher in those with diabetes as defined by either FPG or 2hPG criteria than their normal counterparts (HR, 2.2, 95% confidence interval [CI], 1.6 to 2.9 for DM-FPG; HR, 2.0, 95% CI, 1.5 to 2.7 for DM-2hPG). Similarly, diabetes defined by either FPG or 2hPG was associated with cancer death (HR, 2.9, 95% CI, 1.7 to 5.0; and HR, 2.1, 95% CI, 1.2 to 3.9, respectively). Although neither IFG nor IGT conferred higher risk for death, when combining stage 2 IFG and/or IGT, the risk of all cause death was higher than in subjects with normal glucose regulation (HR, 1.3; 95% CI, 1.0 to 1.6). Diabetes is associated with higher risk of death from all causes and cancer. In subjects without diabetes, stage 2 IFG and/or IGT confers increased risk for mortality.


Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty.
Prolonged wound drainage following total hip or total knee arthroplasty has been associated with an increased risk of postoperative morbidity. The purpose of this study was to determine the pharmacologic, surgical, and patient-specific factors that are associated with prolonged wound drainage and the relationship of this complication to the length of hospital stay and the rate of wound infections. We conducted a retrospective observational study of 1211 primary total hip arthroplasties and 1226 primary total knee arthroplasties. Prospectively collected data included body mass index, intraoperative blood loss, surgical time, type of prophylaxis against deep venous thrombosis, and length of hospital stay. The association of these factors with the duration of postoperative wound drainage was analyzed. An acute infection developed after fifteen primary total hip arthroplasties and ten primary total knee arthroplasties. The patients with an acute postoperative infection were compared with their uninfected counterparts, and an odds ratio was determined to estimate the risk of prolonged wound drainage resulting in a wound infection. Morbid obesity was strongly associated with prolonged wound drainage in the total hip arthroplasty group (p = 0.001) but not in the total knee arthroplasty group (p = 0.590). An increased volume of drain output was an independent risk factor for prolonged wound drainage in both groups. Patients who received low-molecular-weight heparin for prophylaxis against deep venous thrombosis had a longer time until the postoperative wound was dry than did those treated with aspirin and mechanical foot compression or those who received Coumadin (warfarin); this difference was significant on the fifth postoperative day (p = 0.003) but not by the eighth postoperative day. Prolonged wound drainage resulted in a significantly longer hospital stay in both groups (p < 0.001). Each day of prolonged wound drainage increased the risk of wound infection by 42% following a total hip arthroplasty and by 29% following a total knee arthroplasty. Morbid obesity, the use of low-molecular-weight heparin, and a higher drain output were associated with a prolonged time until the postoperative wound was dry following a primary total hip arthroplasty, whereas a higher drain output was the only risk factor associated with prolonged drainage following a primary total knee arthroplasty. Prolonged drainage was associated with a higher rate of infection following a primary total hip arthroplasty, whereas obesity was the only identified independent risk factor for postoperative infection following a primary total knee arthroplasty.