Enhancing activity of antibiotics against Staphylococcus aureus: Zanthoxylum capense constituents and derivatives.
Six compounds (1-6), isolated from the methanol extract of the roots of the African medicinal plant Zanthoxylum capense Thunb. (Rutaceae), and seven ester derivatives (7-13) were evaluated for their antibacterial activities and modulatory effects on the MIC of antibiotics (erythromycin, oxacillin, and tetracycline) and ethidium bromide (EtBr) against a Staphylococcus aureus reference strain (ATCC 6538). Using the same model, compounds 1-13 were also assessed for their potential as efflux pump inhibitors by a fluorometric assay that measures the accumulation of the broad range efflux pump substrate EtBr. Compounds 8 and 11 were further evaluated for their antibacterial, modulatory and EtBr accumulation effects against four additional S. aureus strains, which included two clinical methicillin-resistant S. aureus (MRSA) strains. Compounds (1-13) have not shown antibacterial activity at the concentration ranges tested. When evaluated against S. aureus ATCC 6538, oxychelerythrine (1) a benzophenanthridine alkaloid, showed the highest modulatory activity enhancing the susceptibility of this strain to all the tested antibiotics from two to four-fold. Ailanthoidiol diacetate (8) and ailanthoidiol di-2-ethylbutanoate (11) were also good modulators when combined with EtBr, increasing the bacteria susceptibility by four and two-fold, respectively. In the EtBr accumulation assay, using ATCC 6538 strain, the phenylpropanoid (+)-ailanthoidiol (6) and most of its ester derivatives (8-11) exhibited higher activity than the positive control verapamil. The highest effects were found for compounds 8 and 11 that also increased the accumulation of EtBr, using S. aureus ATCC 25923 as model. Furthermore, both compounds (8, 11) were able to enhance the ciprofloxacin activity against the MRSA clinical strains tested, causing a reduction of the antibiotic MIC values from two to four-fold. The EtBr accumulation assay revealed that this modulation activity was not due to an inhibition of efflux pumps mechanism. These results suggested that Z. capense constituents may be valuable as leads for restoring antibiotic activity against MRSA strains.


Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features.
Syphilis is a chronic disease with a waxing and waning course, the manifestations of which have been described for centuries. It occurs worldwide, and the incidence varies significantly with geographic location. Transmission is mainly by sexual contact. The causative organism, Treponema pallidum, was first described in 1905, but because of the inability to culture the organism and the limitations of direct microscopy, serologic testing is the mainstay of laboratory diagnosis. The disease has been arbitrarily divided into several stages. The primary stage is defined by a chancre at the site of inoculation. The secondary stage is characterized by a polymorphic rash, lymphadenopathy, and other systemic manifestations. A variable asymptomatic latent period follows, which for epidemiologic purposes is divided into early (<1 year) and late (>1 year) stages. The early stages (primary, secondary, and early latent) are potentially infectious. The tertiary stage is the most destructive and is marked by cardiovascular and neurologic sequelae and gummatous involvement of any organ system. Congenital infection may result in protean early or late manifestations. Unlike many other bacteria causing infectious diseases, the organism remains sensitive to penicillin, and this remains the mainstay of therapy.


Increasing incidence of endometrial carcinoma in a high-risk New Zealand community.
Endometrial carcinoma (EC) is increasing in incidence, attributed largely to the obesity epidemic. Ethnic differences in New Zealand have long been recognised, with Pacific women bearing the greater burden of disease. We hypothesise that the pooled national incidence rates underestimate the true burden of EC in our high-risk community. We aimed to: (1) determine the incidence, trends and outcome of EC in the high-risk community served by our hospital, relative to national data; and (2) examine associated demographic, and clinicopathological features with reference to risk factors, to identify potential clinical and population intervention points. All area-resident women treated for EC at Middlemore Hospital from 2000 to 2014 were identified from records, and clinicopathological data obtained. Incidence and time trend analyses were performed with reference to tumour type, age and ethnicity. The study included 588 women. Pacific, followed by Māori, women had the highest incidence of EC (relative risk = 5.11 and 2.47, respectively, relative to 'Other' women). The incidence increased for all ethnicities (annual percentage change (APC) of 7.3; 95% CI 3.6-11.1), most marked in women aged below 50 years (APC of 12.2; 95% CI 5.2-19.7). This occurred predominantly in Pacific women, who had a high prevalence of potentially reversible risk factors. Disease-specific survival was worse in Pacific, and to a lesser extent, Māori women. Prompt investigation of symptomatic, high-risk women regardless of age may detect endometrial abnormalities at an early, potentially reversible stage. The prevention and management of identifiable high-risk factors would help mitigate the risk of EC and associated diseases.


Morbidity and mortality among a cohort of human immunodeficiency virus type 1-infected and uninfected pregnant women and their infants from Malawi, Zambia, and Tanzania.
Morbidity and mortality patterns among pregnant women and their infants (before antiretroviral therapy was widely available) determines HIV-1 diagnostic, monitoring, and care interventions. Data from mothers and their infants enrolled in a trial of antibiotics to reduce mother-to-child-transmission of HIV-1 at 4 sub-Saharan African sites were analyzed. Women were enrolled during pregnancy and follow-up continued until the infants reached 12 months of age. We describe maternal and infant morbidity and mortality in a cohort of HIV-1-infected and HIV-1-uninfected mothers. Maternal and infant factors associated with mortality risk in the infants were assessed using Cox proportional hazard modeling. Among 2292 HIV-1-infected mothers, 166 (7.2%) had a serious adverse event (SAE) and 42 (1.8%) died, whereas no deaths occurred among the 331 HIV-1 uninfected mothers. Four hundred twenty-four (17.8%) of 2383 infants had an SAE and 349 (16.4%) died before the end of follow-up. Infants with early HIV-1 infection (birth to 4-6 weeks) had the highest mortality. Among infants born to HIV-1-infected women, maternal morbidity and mortality (P = 0.0001), baseline CD4 count (P = 0.0002), and baseline plasma HIV-1 RNA concentration (P < 0.0001) were significant predictors of infant mortality in multivariate analyses. The high mortality among infants with early HIV-1 infection supports access to HIV-1 diagnostics and appropriate early treatment for all infants of HIV-1-infected mothers. The significant association between stage of maternal HIV-1 infection and infant mortality supports routine CD4 counts at the time of prenatal HIV-1 testing.


Fast-moving dislocations trigger flash weakening in carbonate-bearing faults during earthquakes.
Rupture fronts can cause fault displacement, reaching speeds up to several ms(-1) within a few milliseconds, at any distance away from the earthquake nucleation area. In the case of silicate-bearing rocks the abrupt slip acceleration results in melting at asperity contacts causing a large reduction in fault frictional strength (i.e., flash weakening). Flash weakening is also observed in experiments performed in carbonate-bearing rocks but evidence for melting is lacking. To unravel the micro-physical mechanisms associated with flash weakening in carbonates, experiments were conducted on pre-cut Carrara marble cylinders using a rotary shear apparatus at conditions relevant to earthquakes propagation. In the first 5 mm of slip the shear stress was reduced up to 30% and CO2 was released. Focused ion beam, scanning and transmission electron microscopy investigations of the slipping zones reveal the presence of calcite nanograins and amorphous carbon. We interpret the CO2 release, the formation of nanograins and amorphous carbon to be the result of a shock-like stress release associated with the migration of fast-moving dislocations. Amorphous carbon, given its low friction coefficient, is responsible for flash weakening and promotes the propagation of the seismic rupture in carbonate-bearing fault patches.


Catalytic asymmetric construction of spiropyrrolidines via 1,3-dipolar cycloaddition of azomethine ylides.
Spirocyclic pyrrolidines are structural motifs frequently found in a wide variety of natural products, pharmaceuticals and biologically significant compounds. In the past few years, catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides have shown to be one of the most straightforward methods for the stereoselective preparation of diverse biologically important spiropyrrolidine heterocycles in high yields with excellent enantioselectivities under mild reaction conditions. In this review, we will discuss the recent major developments in the catalytic enantioselective synthesis of chiral spiropyrrolidine derivatives since 2009.


Surgical strategies for adenocarcinoma of the esophagogastric junction.
This chapter summarizes the surgical strategies for adenocarcinomas of the distal esophagus, gastric cardia, and subcardial gastric cancer invading the cardia+/-distal esophagus known as adenocarcinomas of the esophagogastric junction (AEG). The different surgical approaches according to the tumor origin, localization, and tumor stage are addressed with particular attention to the extent and type of resection and appropriate lymphadenectomy (LAD). The classification of AEG according to Siewert is helpful for the selection of the surgical strategy. While type I tumors benefit from a transthoracic en bloc esophagectomy including a two-field LAD, type II and III tumors can be treated by an extended total gastrectomy with a transhiatal resection of the distal esophagus and LAD of the lower mediastinum and the abdominal D2 compartment. Limited resections appear to be -possible for early tumor stages in selected cases of type I-III tumors.


Absorption-induced transparency metamaterials in the terahertz regime.
Contrary to what might be expected, when an organic dye is sputtered onto an opaque holey metal film, transmission bands can be observed at the absorption energies of the molecules. This phenomenon, known as absorption-induced transparency, is aided by a strong modification of the propagation properties of light inside the holes when filled by the molecules. Despite having been initially observed in metallic structures in the optical regime, new routes for investigation and applications at different spectral regimes can be devised. Here, to illustrate the potential use of absorption-induced transparency at terahertz, a method for molecular detection is presented and supported by a theoretical analysis.


Racing to remember: A theory of decision control in event-based prospective memory.
Event-based prospective memory (PM) requires remembering to perform intended deferred actions when particular stimuli or events are encountered in the future. We propose a detailed process theory within Braver's (2012) proactive and reactive framework of the way control is maintained over the competing demands of prospective memory decisions and decisions associated with ongoing task activities. The theory is instantiated in a quantitative "Prospective Memory Decision Control" (PMDC) architecture, which uses linear ballistic evidence accumulation (Brown & Heathcote, 2008) to model both PM and ongoing decision processes. Prospective control is exerted via decision thresholds, as in Heathcote, Loft, and Remington's (2015) "Delay Theory" of the impact of PM demands on ongoing-task decisions. However, PMDC goes beyond Delay Theory by simultaneously accounting for both PM task decisions and ongoing task decisions. We use Bayesian estimation to apply PMDC to experiments manipulating PM target focality (i.e., the extent to which the ongoing task directs attention to the features of PM targets processed at encoding) and the relative importance of the PM task. As well as confirming Delay Theory's proactive control of ongoing task thresholds, the comprehensive account provided by PMDC allowed us to detect both proactive control of the PM accumulator threshold and reactive control of the relative rates of the PM and ongoing-task evidence accumulation processes. We discuss potential extensions of PMDC to account for other factors that may be prevalent in real-world PM, such as failures of memory retrieval. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Effects of multidisciplinary integrated care on quality of care in residential care facilities for elderly people: a cluster randomized trial.
Sophisticated approaches are needed to improve the quality of care for elderly people living in residential care facilities. We determined the effects of multidisciplinary integrated care on the quality of care and quality of life for elderly people in residential care facilities. We performed a cluster randomized controlled trial involving 10 residential care facilities in the Netherlands that included 340 participating residents with physical or cognitive disabilities. Five of the facilities applied multidisciplinary integrated care, and five provided usual care. The intervention, inspired by the disease management model, consisted of a geriatric assessment of functional health every three months. The assessment included use of the Long-term Care Facility version of the Resident Assessment Instrument by trained nurse-assistants to guide the design of an individualized care plan; discussion of outcomes and care priorities with the family physician, the resident and his or her family; and monthly multidisciplinary meetings with the nurse-assistant, family physician, psychologist and geriatrician to discuss residents with complex needs. The primary outcome was the sum score of 32 risk-adjusted quality-of-care indicators. Compared with the facilities that provided usual care, the intervention facilities had a significantly higher sum score of the 32 quality-of-care indicators (mean difference - 6.7, p = 0.009; a medium effect size of 0.72). They also had significantly higher scores for 11 of the 32 indicators of good care in the areas of communication, delirium, behaviour, continence, pain and use of antipsychotic agents. Multidisciplinary integrated care resulted in improved quality of care for elderly people in residential care facilities compared with usual care. www.controlled-trials.com trial register no. ISRCTN11076857.


Scattering of targets over layered half space using a semi-analytic method in conjunction with FDTD algorithm.
Finite-difference time-domain (FDTD) algorithm with a new method of plane wave excitation is used to investigate the RCS (Radar Cross Section) characteristics of targets over layered half space. Compare with the traditional excitation plane wave method, the calculation memory and time requirement is greatly decreased. The FDTD calculation is performed with a plane wave incidence, and the RCS of far field is obtained by extrapolating the currently calculated data on the output boundary. However, methods available for extrapolating have to evaluate the half space Green function. In this paper, a new method which avoids using the complex and time-consuming half space Green function is proposed. Numerical results show that this method is in good agreement with classic algorithm and it can be used in the fast calculation of scattering and radiation of targets over layered half space.


Films of bacteria at interfaces: three stages of behaviour.
We report an investigation of the formation of films by bacteria at an oil-water interface using a combination of particle tracking and pendant drop elastometry. The films display a remarkably varied series of dynamical and mechanical properties as they evolve over the course of minutes to hours following the creation of an initially pristine interface. At the earliest stage of formation, which we interrogate using dispersions of colloidal probes, the interface is populated with motile bacteria. Interactions with the bacteria dominate the colloidal motion, and the interface displays canonical features of active matter in a quasi-two-dimensional context. This active stage gives way to a viscoelastic transition, presumably driven by the accumulation at the interface of polysaccharides and surfactants produced by the bacteria, which instill the interface with the hallmarks of soft glassy rheology that we characterize with microrheology. Eventually, the viscoelastic film becomes fully elastic with the capability to support wrinkling upon compression, and we investigate this final stage with the pendant drop measurements. We characterize quantitatively the dynamic and mechanical properties of the films during each of these three stages - active, viscoelastic, and elastic - and comment on their possible significance for the interfacial bacterial colony. This work also brings to the forefront the important role that interfacial mechanics may play in bacterial suspensions with free surfaces.


Impact of oxandrolone treatment on acute outcomes after severe burn injury.
Pharmacologic modulation of hypermetabolism clearly benefits children with major burns, however, its role in adult burns remains to be defined. Oxandrolone appears to be a promising anabolic agent although few outcome data are as yet available. We examined whether early oxandrolone treatment in severely burned adults was associated with improved outcomes during acute hospitalization. We evaluated for potential associations between oxandrolone treatment and outcomes in a large cohort of severely burned adults in the context of a multicenter observational study. Patients were dichotomized with respect to oxandrolone treatment, defined as administration within 7 days after admission, with duration of at least 7 days. Acute hospitalization outcomes were compared with univariate and multivariate analyses. One hundred seventeen patients were included in this analysis. Mean patient age was 42.6 years (range, 18-86); 77% were male, with an average TBSA of 44.1%. Baseline and injury characteristics were similar among treatment and nontreatment cohorts. Oxandrolone treatment (N = 59) did not impact length of stay but was associated with a lower mortality rate (P = .01) by univariate analysis. Oxandrolone treatment was independently associated with higher survival by adjusted analyses (P = .02). Examination of early oxandrolone treatment in this cohort of severely burned adults suggests that this therapy is safe and may be associated with improved survival. Further studies are necessary to define the exact mechanisms by which oxandrolone is beneficial during inpatient treatment.


Electrochemistry and structure of the cobalt-free Li1+xMO2 (M = Li, Ni, Mn, Fe) composite cathode.
The development of cathode materials with high capacity and cycle stability is essential to emerging electric-vehicle technologies, however, of serious environmental concern is that materials with these properties developed so far contain the toxic and expensive Co. We report here the Li-rich, Co-free Li1+xMO2 (M = Li, Ni, Mn, Fe) composite cathode material, prepared via a template-free, one-step wet-chemical method followed by conventional annealing in an oxygen atmosphere. The cathode has an unprecedented level of cation mixing, where the electrochemically-active component contains four elements at the transition-metal (3a) site and 20% Ni at the active Li site (3b). We find Ni(2+)/Ni(3+)/Ni(4+) to be the active redox-center of the cathode with lithiation/delithiation occurring via a solid-solution reaction where the lattice responds approximately linearly with cycling, differing to that observed for iso-structural commercial cathodes with a lower level of cation mixing. The composite cathode has ∼75% active material and delivers an initial discharge-capacity of ∼103 mA h g(-1) with a reasonable capacity retention of ∼84.4% after 100 cycles. Notably, the electrochemically-active component possesses a capacity of ∼139 mA h g(-1), approaching that of the commercialized LiCoO2 and Li(Ni1/3Mn1/3Co1/3)O2 materials. Importantly, our operando neutron powder-diffraction results suggest excellent structural stability of this active component, which exhibits ∼80% less change in its stacking-axis than for LiCoO2 with approximately the same capacity, a characteristic that may be exploited to enhance significantly the capacity retention of this and similar materials.


Giant intracranial aneurysms: endovascular challenges.
The treatment of giant aneurysms remains a formidable challenge for endovascular and surgical strategies. The use of endovascular techniques in a deconstructive (e.g., parent vessel occlusion) and reconstructive (e.g., stent coiling) methodology is reviewed. The results of endovascular coiling as a primary therapy for giant aneurysm occlusion have been disappointing. Hunterian strategies have had more success in published series, but recent developments in coil, glue, and stent technology show great promise in allowing parent vessel reconstruction as a primary endovascular target, with acceptable morbidity, mortality, and durability. A literature review of giant aneurysm endovascular treatment strategies was undertaken after 1994, when Guglielmi detachable coils were approved by the Food and Drug Administration. Where possible, follow-up, durability, and occlusion rates are also reviewed.


Dietary flavonoids and the prevalence and 15-y incidence of age-related macular degeneration.
The majority of research performed to date has examined the effects of commonly known antioxidants such as vitamins C, E, and A and carotenoids on age-related macular degeneration (AMD) risk and progression. To date, there is limited research on promising phytochemicals with antioxidant and anti-inflammatory properties, including flavonoids. In this exploratory study, we aimed to assess the independent associations between dietary intake of total flavonoids and common flavonoid classes with the prevalence and 15-y incidence of AMD. In this population-based cohort study, 2856 adults aged ≥49 y at baseline and 2037 followed up 15 y later were included in prevalence and incidence analyses, respectively. Dietary intake was assessed by using a semiquantitative food-frequency questionnaire (FFQ). Estimates of the flavonoid content of foods in the FFQ were assessed by using the USDA Flavonoid, Isoflavone, and Proanthocyanidin databases. AMD was assessed from retinal photographs. In cross-sectional analysis, each 1-SD increase in total overall flavonoid intake was associated with a reduced likelihood of any AMD (multivariable-adjusted OR: 0.76; 95% CI: 0.58, 0.99). Each 1-SD increase in dietary intake of total flavonols and total flavanones was associated with reduced odds of the prevalence of any AMD [multivariable-adjusted OR (95% CI): 0.75 (0.58, 0.97) and 0.77 (0.60, 0.99), respectively]. A marginally significant trend (P = 0.05) was observed between increasing the intake of total flavanone and hesperidin (from the first to the fourth quartile) and reduced likelihood of incident late AMD, after multivariable adjustment. Participants who reported ≥1 serving of oranges/d compared with those who never consumed oranges at baseline had a reduced risk of late AMD 15 y later (multivariable-adjusted OR: 0.39; 95% CI: 0.18, 0.85). Our findings suggest an independent and protective association between dietary intake of flavonoids and the likelihood of having AMD. Additional prospective cohort studies are needed to validate these findings.


Qualitative Beam Profiling of Light Curing Units for Resin Based Composites.
This study investigates two technically simple methods to determine the irradiance distribution of light curing units that governs the performance of a visible-light curing resin-based composites. Insufficient light irradiation leads to under-cured composites with poor mechanical properties and elution of residual monomers. The unknown irradiance distribution and its effect on the final restoration are the main critical issues requiring highly sophisticated experimental equipment. The study shows that irradiance distributions of LCUs can easily be determined qualitatively with generally available equipment. This significantly helps dentists in practices to be informed about the homogeneity of the curing lights.


Hydroxysafflor Yellow A Promotes Angiogenesis via the Angiopoietin 1/ Tie-2 Signaling Pathway.
The flowers of Carthamus tinctorius L. are widely used in traditional Chinese medicine to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of C. tinctorius L. flowers, is known for its multiple biological activities. The present study investigated the effects of HSYA on angiogenesis in vitro and in a mouse hindlimb ischemia model. Using human umbilical vein endothelial cells (HUVEC) in vitro and a mouse hindlimb ischemia model in vivo, the angiogenic role of HSYA was evaluated. HSYA significantly increased the capillary-like tube formation and migration of HUVEC. HSYA not only induced a rise in the expression of angiopoietin 1 and Tie-2 but it also increased phosphorylation of Tie-2, Akt, and extracellular signal-regulated kinase 1/2. Furthermore, an anti-Tie-2 neutralizing antibody significantly inhibited HSYA-induced HUVEC tube formation and migration. In vivo, the recovery of perfusion of ischemic hindlimb tissue after femoral artery interruption was significantly increased in HSYA-treated mice compared to vehicle controls. Consistent with these results, the arteriole and capillary densities in ischemic gastrocnemius muscles were significantly increased in HSYA-treated mice. These results indicate the potential utility of HSYA for the treatment of ischemic diseases.


Management and 1 year outcome for UK children with type 2 diabetes.
To report the 1-year outcome for children newly diagnosed as having type 2 diabetes in the UK. Follow-up study of a UK national cohort. All children under the age of 17 years diagnosed as having type 2 diabetes from 1 October 2004 to 31 October 2005 (inclusive). Follow-up data were available for 73 of the 76 cases. The mean age at follow-up was 14.5 years, with mean duration of diabetes 1 year. The revised incidence of type 2 diabetes in the UK in children under 17 years is 0.6/100 000/year. The mean body mass index (BMI) SDS at diagnosis was 2.89, and mean change at 1 year was -0.11 (range -1.53 to +1.37). At 1 year, only 58% achieved the American Diabetes Association/European Association for the Study of Diabetes recommended treatment target (glycated haemoglobin < or =7.0%). There was no relation between improvement in BMI and improvement in glycated haemoglobin. There was wide variation in choice of treatments and regimens. Hypertension is a common comorbidity (34%), whereas early nephropathy appears to be rare (4%). Evidence of polycystic ovarian disease was common in girls (26%). 22% of children had not been screened for nephropathy or retinopathy during the first year after diagnosis. The 3.8% mean reduction in BMI SDS in the first year after diagnosis indicates that many children find it hard to make the necessary lifestyle changes needed to positively affect metabolic health. Physicians are using a wide variety of treatment regimens, which are relatively effective in achieving glycaemic targets, but systematic screening for complications is incomplete. There is an urgent need to develop an evidence base for effective treatment and management protocols to reduce the risks of long-term microvascular and macrovascular complications.


The use of anthropogenic marine debris as a nesting material by brown boobies (Sula leucogaster).
Marine debris is pervasive worldwide, and affects biota negatively. We compared the characteristics of debris incorporated within brown booby (Sula leucogaster) nests throughout their pantropical distribution by assessing the type, colour and mass of debris items within nests and in beach transects at 18 sites, to determine if nests are indicators of the amount of debris in local marine environments. Debris was present in 14.4% of nests surveyed, with the proportion of nests with debris varying among sites (range: 0-100%). There was minimal overlap between the type or colour of debris found in nests and on adjacent beaches at individual sites. This suggests that brown boobies do not select debris uniformly across their distribution. We propose that the nests of brown boobies can be used as a sentinel of marine debris pollution of their local environment.


From direct to indirect lithium targets: a comprehensive review of omics data.
Metal ions are critical to a wide range of biological processes. Among them, lithium (Li) has been recognised for its benefit as a treatment for bipolar disorder (BD). However, we are yet to grasp the extent of its role in biological processes, despite its molecular targets having been extensively studied. Here we review a wide range of transcriptomic, proteomic and metabolomic studies in order to obtain a full picture of Li effects at various levels. Multifarious patterns of Li-regulated genes, proteins and metabolites are identified. Some of these patterns are explained as the outcomes of individual Li targets. For instance, Li inhibition of GSK-3 has a wide range of effects: axis development in embryos; cell and tissue differentiation, in particular neurogenesis and osteogenesis; or control of apoptosis. This results in neuroprotection and an attenuation of cognitive deficits. Lithium plays an important role in mitochondrial function, which it improves via its role in phospholipid metabolism and inositol depletion. This is also seen in metabolomics, where its role in the mitochondrial respiratory chain influences energy production and oxidative stress. Lithium also affects the proteins involved in the processing of APP, thus highlighting a possible involvement in Alzheimer's disease. Finally, Li also impacts lipid homeostasis, with studies showing that environmental exposure can impact lipid transport and prostaglandin synthesis. It is seldom possible to establish a causal relationship between Li targets at the molecular level and the resulting effects at the system level. For example, Li effects on adenylate cyclase regulation are not easily linked to any omic pattern despite the importance of the adenylate pathway. Nevertheless, refining our knowledge on the cellular functions of individual Li targets would improve our understanding and interpretation of omics data. This review demonstrates that Li is key to a wide range of processes at all levels, from neuroprotection to oxidative stress and energy production. A corollary of this work is the need for an increased awareness of environmental issues related to Li industrial wastes, in particular considering the widespread use of this metal in our modern society.


Comparing diversity levels in environmental samples: DNA sequence capture and metabarcoding approaches using 18S and COI genes.
Environmental DNA studies targeting multiple taxa using metabarcoding provide remarkable insights into levels of species diversity in any habitat. The main drawbacks are the presence of primer bias and difficulty in identifying rare species. We tested a DNA sequence-capture method in parallel with the metabarcoding approach to reveal possible advantages of one method over the other. Both approaches were performed using the same eDNA samples and the same 18S and COI regions, followed by high throughput sequencing. Metabarcoded eDNA libraries were PCR amplified with one primer pair from 18S and COI genes. DNA sequence-capture libraries were enriched with 3,639 baits targeting the same gene regions. We tested amplicon sequence variants (ASVs) and operational taxonomic units (OTUs) in silico approaches for both markers and methods, using for this purpose the metabarcoding data set. ASVs methods uncovered more species for the COI gene, whereas the opposite occurred for the 18S gene, suggesting that clustering reads into OTUs could bias diversity richness especially using 18S with relaxed thresholds. Additionally, metabarcoding and DNA sequence-capture recovered 80%-90% of the control sample species. DNA sequence-capture was 8x more expensive, nonetheless it identified 1.5x more species for COI and 13x more genera for 18S than metabarcoding. Both approaches offer reliable results, sharing ca. 40% species and 72% families and retrieve more taxa when nuclear and mitochondrial markers are combined. eDNA metabarcoding is quite well established and low-cost, whereas DNA-sequence capture for biodiversity assessment is still in its infancy, is more time-consuming but provides more taxonomic assignments.


V-Amylose at atomic resolution: X-ray structure of a cycloamylose with 26 glucose residues (cyclomaltohexaicosaose).
The amylose fraction of starch occurs in double-helical A- and B-amyloses and the single-helical V-amylose. The latter contains a channel-like central cavity that is able to include molecules, "iodine's blue" being the best-known representative. Molecular models of these amylose forms have been deduced by solid state 13C cross-polarization/magic angle spinning NMR and by x-ray fiber and electron diffraction combined with computer-aided modeling. They remain uncertain, however, as no structure at atomic resolution is available. We report here the crystal structure of a hydrated cycloamylose containing 26 glucose residues (cyclomaltohexaicosaose, CA26), which has been determined by real/reciprocal space recycling starting from randomly positioned atoms or from an oriented diglucose fragment. This structure provides conclusive evidence for the structure of V-amylose, as the macrocycle of CA26 is folded into two short left-handed V-amylose helices in antiparallel arrangement and related by twofold rotational pseudosymmetry. In the V-helices, all glucose residues are in syn orientation, forming systematic interglucose O(3)n...O(2)(n+l) and O(6)n...O(2)(n+6)/O(3)(n+6) hydrogen bonds; the central cavities of the V-helices are filled by disordered water molecules. The folding of the CA26 macrocycle is characterized by typical "band-flips" in which diametrically opposed glucose residues are in anti rather than in the common syn orientation, this conformation being stabilized by interglucose three-center hydrogen bonds with O(3)n as donor and O(5)(n+l), O(6)(n+l) as acceptors. The structure of CA26 permitted construction of an idealized V-amylose helix, and the band-flip motif explains why V-amylose crystallizes readily and may be packed tightly in seeds.


Tryptophan fluorescence quenching by enzyme inhibitors as a tool for enzyme active site structure investigation: epoxide hydrolase.
We present the strong fluorescence effect, a new 392 nm emission peak appearing after binding of a naphtol-urea inhibitor XIIa to the enzyme epoxide hydrolase (EH), along with the quenching of the EH tryptophan fluorescence. We have studied the quenching of the 392-nm peak (attributed to XIIa bound inside the active center of the enzyme) of the mixture EH +XIIa by various strong transparent inhibitors (competing with XIIa for binding to EH), and measured the corresponding values of the Stern-Volmer constants, K(mix)(SV). Strong EH inhibitors demonstrate different replacement behavior which can be used to distinguish them. We further demonstrate a novel fluorescent assay which allows to distinguish highly potent inhibitors and to visualize the strongest among them. We generated our assay calibration curve based on the quenching data, by plotting quenching strength K(mix)(SV) versus inhibiting strength, IC(50) values. We used moderate inhibitors for the assay plot generation. We then applied this curve to determine IC(50) values for several highly potent inhibitors, with IC(50) values at the limit of the IC(50) detection sensitivity by colorimetric enzyme assay. IC(50) values determined from our quenching assay show correlation with IC(50) values determined in the literature by more sensitive radioactive-based assay and allow differentiating the inhibitors potency in this group. To our knowledge, this is the first inhibitor assay of such kind. Chemical inhibition of EH is an important technology in the treatment of various cardiovascular diseases, therefore, this tool may play a crucial role in discovering new inhibitor structures for therapeutic EH inhibition.


Development of a federally funded demonstration colorectal cancer screening program.
Colorectal cancer is the second leading cause of cancer-related mortality among U.S. adults. In 2004, treatment costs for colorectal cancer were $8.4 billion. There is substantial evidence that colorectal cancer incidence and mortality are reduced with regular screening. The natural history of this disease is also well described: most colorectal cancers develop slowly from preexisting polyps. This slow development provides an opportunity to intervene with screening tests, which can either prevent colorectal cancer through the removal of polyps or detect it at an early stage. However, much less is known about how best to implement an effective colorectal cancer screening program. Screening rates are low, and uninsured persons, low-income persons, and persons who have not visited a physician within a year are least likely to be screened. Although the Centers for Disease Control and Prevention (CDC) has 15 years of experience supporting the National Breast and Cervical Cancer Early Detection Program for the underserved population, a similar national program for colorectal cancer is not in place. To explore the feasibility of implementing a national program for the underserved U.S. population and to learn which settings and which program models are most viable and cost-effective, CDC began a 3-year colorectal cancer screening demonstration program in 2005. This article describes briefly this demonstration program and the process CDC used to design it and to select program sites. The multiple-methods evaluation now under way to assess the program's feasibility and describe key outcomes is also detailed. Evaluation results will be used to inform future activities related to organized screening for colorectal cancer.


Helicobacter pylori in Barrett's esophagus.
Barrett's esophagus is an anatomicoclinical state in which, due to the prolonged action of gastroesophageal reflux, the squamous epithelium is replaced by columnar epithelium. Helicobacter pylori has been implicated in the pathogenesis of various gastrointestinal disorders and has occasionally been observed in Barrett's esophagus. The aim of this study is to determine the incidence of H. pylori in Barrett's esophagus and try to establish its role in the pathogenesis of this disorder. H. pylori was observed in 31 biopsies (44.3%) of the 70 studied, mainly when the epithelium is of the gastric atrophic-fundic type (p less than 0.01). Its presence shows no relation to the degree of inflammatory activity and does not seem, therefore, to play an important role in the pathogenesis of the lesion.


Metabolic Syndrome, Insulin Resistance, and Cognitive Dysfunction: Does Your Metabolic Profile Affect Your Brain?
Dementia and type 2 diabetes are both characterized by long prodromal phases, challenging the study of potential risk factors and their temporal relation. The progressive relation among metabolic syndrome, insulin resistance (IR), and dementia has recently been questioned, wherefore the aim of this study was to assess the potential association among these precursors of type 2 diabetes and cognitive dysfunction. Using data from the Prospective Epidemiological Risk Factor (PERF) Study (n = 2,103), a prospective study of elderly women in Denmark, we found that impaired fasting plasma glucose concentration was associated with 44% (9-91%) larger probability of cognitive dysfunction. In addition, subjects above the HOMA-IR threshold (HOMA-IR >2.6) had 47% (9-99%) larger odds of cognitive dysfunction. The associations could indicate that a significant proportion of dementia cases in women is likely to be preventable by effective prevention and control of the insulin homeostasis.


The effects of DNA containing CpG motif on dendritic cells.
Dendritic cells (DC) are specialized antigen-presenting cells. DC can acquire and process antigens in the periphery before maturing and migrating to secondary lymphoid tissues where they present the antigens and deliver co-stimulatory signals to T cells. We describe an immunostimulatory oligonucleotide containing a CpG motif that stimulated murine DC to up-regulate co-stimulatory molecules, induce T-cell proliferative responses and secrete interleukin-12 in vitro. Administration of this oligonucleotide, but not of a control oligonucleotide lacking this motif, to mice led to the disappearance of DC from the marginal zone and T-cell areas of spleen, but not from heart or kidney. The same CpG did not cause maturation of monocyte-derived human DC in vitro, but lipopolysaccharide-treated monocyte-derived DC showed enhanced functional activity and up-regulated co-stimulatory molecules.


Life cycle assessment of Chinese shrimp farming systems targeted for export and domestic sales.
We conducted surveys of six hatcheries and 18 farms for data inputs to complete a cradle-to-farm-gate life cycle assessment (LCA) to evaluate the environmental performance for intensive (for export markets in Chicago) and semi-intensive (for domestic markets in Shanghai) shrimp farming systems in Hainan Province, China. The relative contribution to overall environmental performance of processing and distribution to final markets were also evaluated from a cradle-to-destination-port perspective. Environmental impact categories included global warming, acidification, eutrophication, cumulative energy use, and biotic resource use. Our results indicated that intensive farming had significantly higher environmental impacts per unit production than semi-intensive farming in all impact categories. The grow-out stage contributed between 96.4% and 99.6% of the cradle-to-farm-gate impacts. These impacts were mainly caused by feed production, electricity use, and farm-level effluents. By averaging over intensive (15%) and semi-intensive (85%) farming systems, 1 metric ton (t) live-weight of shrimp production in China required 38.3 ± 4.3 GJ of energy, as well as 40.4 ± 1.7 t of net primary productivity, and generated 23.1 ± 2.6 kg of SO(2) equiv, 36.9 ± 4.3 kg of PO(4) equiv, and 3.1 ± 0.4 t of CO(2) equiv. Processing made a higher contribution to cradle-to-destination-port impacts than distribution of processed shrimp from farm gate to final markets in both supply chains. In 2008, the estimated total electricity consumption, energy consumption, and greenhouse gas emissions from Chinese white-leg shrimp production would be 1.1 billion kW·h, 49 million GJ, and 4 million metric tons, respectively. Improvements suggested for Chinese shrimp aquaculture include changes in feed composition, farm management, electricity-generating sources, and effluent treatment before discharge. Our results can be used to optimize market-oriented shrimp supply chains and promote more sustainable shrimp production and consumption.


Heavy Drinkers and the Potential Impact of Minimum Unit Pricing-No Single or Simple Effect?
To explore the potential impact of a minimum unit price (MUP: 50 pence per UK unit) on the alcohol consumption of ill Scottish heavy drinkers. Participants were 639 patients attending alcohol treatment services or admitted to hospital with an alcohol-related condition. From their reported expenditure on alcohol in their index week, and assuming this remained unchanged, we estimated the impact of a MUP (50 ppu) on future consumption. (Around 15% purchased from both the more expensive on-sale outlets (hotels, pubs, bars) and from off-sales (shops and supermarkets). For them we estimated the change in consumption that might follow MUP if (i) they continued this proportion of 'on-sales' purchasing or (ii) their reported expenditure was moved entirely to off-sale purchasing (to maintain consumption levels)). Around 69% of drinkers purchased exclusively off-sale alcohol at <50 ppu. Their drinking, post MUP, may reduce by a mean of 33%. For this group, from a population of very heavy, ill consumers, we were unable to show a differential effect across multiple deprivation quintiles. For other drinkers there might be no reduction, especially if after MUP there were many products priced close to 50 ppu. Moving away from on-sales purchases could support, for some, an increase in consumption. While a proportion of our harmed, heavy drinkers might be able to mitigate the impact of MUP by changing purchasing habits, the majority are predicted to reduce purchasing. This analysis, focusing specifically on harmed drinkers, adds a unique dimension to the evidence base informing current pricing policy. From drink purchasing data of heavy drinkers, we estimated the impact of legislating £0.50 minimum unit price. Over two thirds of drinkers, representing all multiple deprivation quintiles, were predicted to decrease alcohol purchasing; remainder, hypothetically, could maintain consumption. Our data address an important gap within the evidence base informing policy.


The UK Midwifery Study System (UKMidSS): a programme of work to establish a research infrastructure to carry out national studies of uncommon conditions and events in midwifery units.
Midwifery-led care during labour and birth in the UK is increasingly important given national commitments to choice of place of birth, reduction of unnecessary intervention and improving women's experience of care, and evidence on safety and benefits for 'low risk' women. Further evidence is needed on safety and potential benefits of midwifery-led care for some groups of 'higher risk' women and about uncommon adverse outcomes or 'near-miss' events. Uncommon obstetric events and conditions have been investigated since 2005 using the UK Obstetric Surveillance System. This programme of research will establish the UK Midwifery Study System (UKMidSS) in all UK alongside midwifery units (AMUs) and carry out the first two UKMidSS studies investigating: (i) outcomes in severely obese women admitted to AMUs, and (ii) risk factors for neonatal unit admission following birth in an AMU. We will carry out national cohort and case-control studies using UKMidSS, a national data collection platform which we will establish to collect anonymised information from all UK AMUs. Reporting midwives in each AMU will actively report cases or nil returns in response to monthly notification emails. Denominator data on the number of women admitted to and giving birth in each AMU will also be collected. Anonymised data on risk factors, management and outcomes for cases and controls/comparators as appropriate for each study, will be collected electronically using information from medical records. We will calculate incidence and prevalence with 95% confidence intervals (CIs), tabulate descriptive data using frequencies and proportions, and use logistic regression to estimate odds ratios with 95% CIs comparing specific outcomes in case and comparison women and to investigate risk factors for conditions or outcomes. As the first national infrastructure facilitating research into uncommon events and conditions in women starting labour in midwifery-led settings, UKMidSS builds on the success of other national research systems. UKMidSS studies will extend the evidence base regarding the quality and safety of midwifery-led intrapartum care and investigate extending the benefits of midwifery-led care to more women. As a national collaboration of midwives contributing to high quality research, UKMidSS will provide an infrastructure to support midwifery research capacity development.


Sporadic autonomic dysregulation and death associated with excessive serotonin autoinhibition.
Sudden infant death syndrome is the leading cause of death in the postneonatal period in developed countries. Postmortem studies show alterations in serotonin neurons in the brainstem of such infants. However, the mechanism by which altered serotonin homeostasis might cause sudden death is unknown. We investigated the consequences of altering the autoinhibitory capacity of serotonin neurons with the reversible overexpression of serotonin 1A autoreceptors in transgenic mice. Overexpressing mice exhibited sporadic bradycardia and hypothermia that occurred during a limited developmental period and frequently progressed to death. Moreover, overexpressing mice failed to activate autonomic target organs in response to environmental challenges. These findings show that excessive serotonin autoinhibition is a risk factor for catastrophic autonomic dysregulation and provide a mechanism for a role of altered serotonin homeostasis in sudden infant death syndrome.


Is the international regulation of medical complicity with torture largely window dressing? The case of Israel and the lessons of a 12-year medical ethical appeal.
This is the account of an ongoing appeal initiated in 2009 by 725 doctors from 43 countries concerning medical complicity with torture in Israel. It has been underpinned by a voluminous and still accumulating evidence base from reputable international and regional human rights organisations, quoted below, and has spanned the terms of office of four World Medical Association (WMA) presidencies and two UN special rapporteurs on torture. This campaign has been a litmus test of whether international medical codes regarding doctors and torture actually matter, and are applied rigorously and even-handededly, particularly when compelling evidence incriminates a WMA member association. Our findings in the case of Israel suggest that this is not true, and that impunity largely operates. The WMA seems in partisan violation of its mandate to be the official international watchdog on the ethical behaviour of doctors. And as the IMA case demonstrates, by their inaction national medical associations or other regulatory bodies appear to function at base as buttresses and shields of the state.


Physical activity and vascular disease in a prospective cohort study of older men: The Health In Men Study (HIMS).
The dose-response relationship between volume of physical activity and incidence of major vascular events at older age is unclear. We aimed to investigate this association in a cohort of older men. For this prospective cohort study, 7564 men aged 65-83 years and without prior vascular disease were recruited in 1996-99 from the general population in Perth, Western Australia. Men were followed up using the Western Australian Data Linkage System to identify deaths and hospitalisations. During mean follow-up of 11 (SD 4) years, there were 1557 first major vascular events: 833 ischaemic heart disease events, 551 stroke events and 173 other vascular events. Cox regression was used to calculate hazard ratios (adjusted for age, education and smoking) for incidence of major vascular events by volume of baseline recreational physical activity (measured in metabolic equivalent [MET] hours per week). Hazard ratios among men who performed 0, 1-14, 15-24, 25-39, ≥40 MET-hours per week of recreational physical activity were 1.00 (95% CI 0.91-1.10; referent), 0.88 (0.79-1.00), 0.81 (0.72-0.91), 0.81 (0.72-0.91) and 0.80 (0.71-0.89), respectively (P(trend) =0.006). The association was slightly attenuated with further adjustment for BMI. There was evidence of stronger associations at older ages and greater intensity of activity, but no evidence of effect modification by smoking, alcohol intake or BMI. There was also no evidence that the association varied by type of vascular event. Among men aged over 65 years, there was a curvilinear association between recreational physical activity and incidence of major vascular events, with an inverse association up to about 20 MET-hours per week (equivalent to 1 h of non-vigorous, or half an hour of vigorous, physical activity per day) and no evidence of further reductions in risk thereafter.


A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer.
Linking the molecular aberrations of cancer to drug responses could guide treatment choice and identify new therapeutic applications. However, there has been no systematic approach for analyzing gene-drug interactions in human cells. Here we establish a multiplexed assay to study the cellular fitness of a panel of engineered isogenic cancer cells in response to a collection of drugs, enabling the systematic analysis of thousands of gene-drug interactions. Applying this approach to breast cancer revealed various synthetic-lethal interactions and drug-resistance mechanisms, some of which were known, thereby validating the method. NOTCH pathway activation, which occurs frequently in breast cancer, unexpectedly conferred resistance to phosphoinositide 3-kinase (PI3K) inhibitors, which are currently undergoing clinical trials in breast cancer patients. NOTCH1 and downstream induction of c-MYC over-rode the dependency of cells on the PI3K-mTOR pathway for proliferation. These data reveal a new mechanism of resistance to PI3K inhibitors with direct clinical implications.


Biomechanical basis of wing and haltere coordination in flies.
The spectacular success and diversification of insects rests critically on two major evolutionary adaptations. First, the evolution of flight, which enhanced the ability of insects to colonize novel ecological habitats, evade predators, or hunt prey; and second, the miniaturization of their body size, which profoundly influenced all aspects of their biology from development to behavior. However, miniaturization imposes steep demands on the flight system because smaller insects must flap their wings at higher frequencies to generate sufficient aerodynamic forces to stay aloft; it also poses challenges to the sensorimotor system because precise control of wing kinematics and body trajectories requires fast sensory feedback. These tradeoffs are best studied in Dipteran flies in which rapid mechanosensory feedback to wing motor system is provided by halteres, reduced hind wings that evolved into gyroscopic sensors. Halteres oscillate at the same frequency as and precisely antiphase to the wings; they detect body rotations during flight, thus providing feedback that is essential for controlling wing motion during aerial maneuvers. Although tight phase synchrony between halteres and wings is essential for providing proper timing cues, the mechanisms underlying this coordination are not well understood. Here, we identify specific mechanical linkages within the thorax that passively mediate both wing-wing and wing-haltere phase synchronization. We demonstrate that the wing hinge must possess a clutch system that enables flies to independently engage or disengage each wing from the mechanically linked thorax. In concert with a previously described gearbox located within the wing hinge, the clutch system enables independent control of each wing. These biomechanical features are essential for flight control in flies.


Surgical fixation of pathologic fractures: an evaluation of evolving treatment methods.
The surgical techniques for the fixation of pathologic fractures continue to evolve. The present study examines clinical outcomes and complications associated with the use of newer generation interlocked intramedullary nails compared with open reduction and internal fixation with plates and screws for pathologic fractures in long bones. Fifty operative procedures performed on 37 patients by five community orthopaedic surgeons were retrospectively reviewed. The operative procedures were separated into two groups based upon the method of fracture fixation; the groups were compared for differences in hardware or fixation failure. The use of intramedullary devices was associated with a significantly lower number of hardware or fixation failures (p < 0.02). This data, in addition to several additional advantages of indirect reduction and intramedullary fixation of pathologic fractures, supports this method of fracture care over open reduction and internal fixation in appropriate cases.


Single cell genomics of uncultured marine alveolates shows paraphyly of basal dinoflagellates.
Marine alveolates (MALVs) are diverse and widespread early-branching dinoflagellates, but most knowledge of the group comes from a few cultured species that are generally not abundant in natural samples, or from diversity analyses of PCR-based environmental SSU rRNA gene sequences. To more broadly examine MALV genomes, we generated single cell genome sequences from seven individually isolated cells. Genes expected of heterotrophic eukaryotes were found, with interesting exceptions like presence of proteorhodopsin and vacuolar H+-pyrophosphatase. Phylogenetic analysis of concatenated SSU and LSU rRNA gene sequences provided strong support for the paraphyly of MALV lineages. Dinoflagellate viral nucleoproteins were found only in MALV groups that branched as sister to dinokaryotes. Our findings indicate that multiple independent origins of several characteristics early in dinoflagellate evolution, such as a parasitic life style, underlie the environmental diversity of MALVs, and suggest they have more varied trophic modes than previously thought.


Satellite tidal magnetic signals constrain oceanic lithosphere-asthenosphere boundary.
The tidal flow of electrically conductive oceans through the geomagnetic field results in the generation of secondary magnetic signals, which provide information on the subsurface structure. Data from the new generation of satellites were shown to contain magnetic signals due to tidal flow; however, there are no reports that these signals have been used to infer subsurface structure. We use satellite-detected tidal magnetic fields to image the global electrical structure of the oceanic lithosphere and upper mantle down to a depth of about 250 km. The model derived from more than 12 years of satellite data reveals a ≈72-km-thick upper resistive layer followed by a sharp increase in electrical conductivity likely associated with the lithosphere-asthenosphere boundary, which separates colder rigid oceanic plates from the ductile and hotter asthenosphere.


Toxoplasmosis seroprevalence in urban rodents: a survey in Niamey, Niger.
A serological survey of Toxoplasma gondii was conducted on 766 domestic and peridomestic rodents from 46 trapping sites throughout the city of Niamey, Niger. A low seroprevalence was found over the whole town with only 1.96% of the rodents found seropositive. However, differences between species were important, ranging from less than 2% in truly commensal Mastomys natalensis, Rattus rattus and Mus musculus, while garden-associated Arvicanthis niloticus displayed 9.1% of seropositive individuals. This is in line with previous studies on tropical rodents--that we reviewed here--which altogether show that Toxoplasma seroprevalence in rodent is highly variable, depending on many factors such as locality and/or species. Moreover, although we were not able to decipher statistically between habitat or species effect, such a contrast between Nile grass rats and the other rodent species points towards a potentially important role of environmental toxoplasmic infection. This would deserve to be further scrutinised since intra-city irrigated cultures are extending in Niamey, thus potentially increasing Toxoplasma circulation in this yet semi-arid region. As far as we are aware of, our study is one of the rare surveys of its kind performed in Sub-Saharan Africa and the first one ever conducted in the Sahel.


Clinical applications of cognitive event-related potentials in Alzheimer's disease.
This article has reviewed several abnormalities in the cognitive ERPs of AD patients. These abnormalities are prominent from latencies of approximately 200 msec and later. In contrast, sensory-dependent evoked potentials, such as N100, are generally normal in AD. This finding is as one familiar with the neuropathology of AD would predict. Predilection sites in early AD include the medial temporal lobe, other limbic areas, and multimodal association cortices with sparing of primary sensory areas. Unimodal association cortex is involved in AD, but not as heavily as multimodal cortex. Particular advantages of studying a given ERP paradigm or component depend largely on the specific application or hypothesis being tested. A P300 paradigm can be useful in detecting a disorder of attention or in quantifying the effects of drugs that improve attention, such as the cholinesterase inhibitors. For the early diagnosis of AD or other memory disorders, a word-repetition paradigm with an explicit recognition task or one that fosters associative learning would be recommended. This article has discussed potential use of N400 in tracking disease progression. ERPs provide a flexible and powerful technique, with superb temporal resolution, which can be used as a probe into subtle "subclinical" abnormalities of cognitive processes. Despite being applied to AD for about 25 years since the early P300 studies, the full potential of ERPs in helping diagnose and treat AD patients has yet to be realized. In this era of rapidly evolving brain-imaging techniques, electrophysiologic data are important in advancing understanding of cognition. Brain-mapping techniques that can inform where and when key cognitive processes occur are finally emerging. A final example of potential clinical application of cognitive ERPs is in the development of rational combinational treatment of cognitive enhancing drugs. Along these lines, P300 investigations in epilepsy proved helpful in ranking the cognitive side effects of anticonvulsant drugs. Drug studies that use 2 x 2 combinational designs, which compare the effects of drug A, drug B, with A + B, are currently prohibitively expensive for full-scale clinical trials in AD. It is likely that precise ERP measures could hasten drug development in several ways. Smaller samples could be used, at lower cost, to test the cognitive effects of each specific drug combination. Optimal doses of combinational therapy perhaps could be identified by repeated within-subject ERP measures. Longitudinal changes in the ERP hold promise as a marker of individual responsivity to a particular agent, which could have diagnostic utility (eg, testing response to cholinergic or dopaminergic therapy). This horizon and many others remain wide open for well-planned explorations.


Degradation of Perennial Ryegrass Leaf and Stem Cell Walls by the Anaerobic Fungus Neocallimastix sp. Strain CS3b.
The degradation of cell walls isolated from stems and leaves of perennial ryegrass by the anaerobic fungus Neocallimastix sp. strain CS3b was studied in a defined medium. The combined cellulose and hemicellulose fraction represented 53.1 (wt/wt) and 63.3% (wt/wt) of the dry weight of control grass leaf and stem cell walls, respectively. In both leaf and stem cell walls, glucose was the major neutral monosaccharide, followed by xylose, arabinose, and galactose. After 2 days of fermentation with Neocallimastix sp. strain CS3b, treated cell walls contained smaller amounts of neutral sugars compared with those of undigested cell walls. These results were more evident for glucose, xylose, and arabinose than for galactose. Furthermore, the sugar content of leaf cell walls decreased before a decline in the sugar content of stem cell walls was observed. Data from formate and hydrogen production indicated that the growth of Neocallimastix sp. strain CS3b was completed in 4 days in the culture system used. During this period, the fungus liberated about 95% of the fermentable sugars in untreated material. On a percentage basis, no significant differences were found in final extent of degradation of glucose, xylose, and arabinose. Galactose, however, was degraded to a lesser extent.


Patch use by Dipodomys deserti (Rodentia: Heteromyidae): profitability, preference, and depletion dynamics.
Granivorous desert rodents of the family Heteromyidae forage nonrandomly among "microhabitats" that vary in substrate, seed densities, and seed species composition. To explore the hypothesis that microhabitat use is sensitive to seed patch profitability, we quantified effects of seed size (1.96 vs. 5.21 mg/seed) and density (0.4-10.6 seeds/cm2) on Dipodomys deserti harvest rates, which is a measure of profitability when expressed as mg of seed taken per min. By manipulating seed density, we created large-seed and small-seed patches of known relative profitability and exposed D. deserti individuals to pairwise choices in the laboratory and field. We used three treatment classes: 1) large-seed patches that were more profitable than small-seed patches (equal seed densities); 2) large-seed and small-seed patches that were equally profitable (small-seed densities somewhat higher): and 3) large-seed patches that were less profitable than small-seed patches (small-seed densities much higher). Harvest rate increased nearly linearly with seed density, and profitability of large-seed patches was greater than small-seed patches of the same density. Cumulative harvest from a patch increased linearly with residence time up to a plateau; this "gain curve" indicates that animals move systematically within patches and hence avoid resampling already depleted areas. In the laboratory, animals visited small-seed patches first more often and visited them more frequently when they were more profitable than large-seed patches. When large-seed patches were of greater or equal profitability, large-seed patches were preferred by both measures. The expressed preference for large-seed patches, when animals were presented with equally profitable patches, suggests an underlying preference for large seeds. In the field, animals depleted all patches to a constant low profitability, in accord with qualitative predictions of optimal patch use models. These results suggest that patch preferences by D. deserti are affected by the economics of seed harvest.


Horizontal bone augmentation by means of guided bone regeneration.
The development of bone augmentation procedures has allowed placement of dental implants into jaw bone areas lacking an amount of bone sufficient for standard implant placement. Thus, the indications for implants have broadened to include jaw regions with bone defects and those with a bone anatomy that is unfavorable for implant anchorage. Of the different techniques, the best documented and the most widely used method to augment bone in localized alveolar defects is guided bone regeneration. A large body of evidence has demonstrated the successful use of guided bone regeneration to regenerate missing bone at implant sites with insufficient bone volume and the long-term success of implants placed simultaneously with, or after, guided bone regeneration. However, the influence of guided bone regeneration on implant survival and success rates, and the long-term stability of the augmented bone, remain unknown. Many of the materials and techniques currently available for bone regeneration of alveolar ridge defects were developed many years ago. Recently, various new materials and techniques have been introduced. Many of them have, however, not been sufficiently documented in clinical studies. The aim of this review was to present the scientific basis of guided bone regeneration and the accepted clinical procedures. A classification of bone defects has been presented, aiming at simplifying the decision-making process regarding the choice of strategy for bone augmentation. Finally, an outlook into actual research and the possible future options related to bone augmentation has been provided.


Reversible bridge-mediated excited-state symmetry breaking in stilbene-linked DNA dumbbells.
The excited-state behavior of synthetic DNA dumbbells possessing stilbenedicarboxamide (Sa) linkers separated by short A-tracts or alternating A-T base-pair sequences has been investigated by means of fluorescence and transient absorption spectroscopy. Electronic excitation of the Sa chromophores results in conversion of a locally excited state to a charge-separated state in which one Sa is reduced and the other is oxidized. This symmetry-breaking process occurs exclusively via a multistep mechanism-hole injection followed by hole transport and hole trapping-even at short distances. Rate constants for charge separation are strongly distance-dependent at short distances but become less so at longer distances. Disruption of the A-tract by inversion of a single A-T base pair results in a pronounced decrease in both the rate constant and efficiency of charge separation. Hole trapping by Sa is highly reversible, resulting in rapid charge recombination that occurs via the reverse of the charge separation process: hole detrapping, hole transport, and charge return to regenerate the locally excited Sa singlet state. These results differ in several significant respects from those previously reported for guanine or stilbenediether as hole traps. Neither charge separation nor charge recombination occur via a single-step superexchange mechanism, and hole trapping is slower and detrapping faster when Sa serves as the electron donor. Both the occurrence of symmetry breaking and reversible hole trapping by a shallow trap in a DNA-based system are without precedent.


Leukocyte telomere length is related to appendicular lean mass: cross-sectional data from the Berlin Aging Study II (BASE-II).
Age-related progressive loss of muscle mass is an increasing problem in our aging society, affecting physical ability, risk of falls, and need for health care. Telomere length has been recognized as a marker of biological age on the population level. The relation between muscle mass in advanced age and telomere length, however, has rarely been examined. We evaluated the relation between appendicular lean mass (ALM) and relative leukocyte telomere length (rLTL) in 1398 participants of the Berlin Aging Study II (mean ± SD age: 68.2 ± 3.7 y; 49.6% men). rLTL was determined by real-time polymerase chain reaction. Lean mass was estimated by dual X-ray absorptiometry and examined as leg lean mass (LLM), ALM, and the ratio of ALM to body mass index (ALMBMI). Weak, but highly significant (P < 0.001), correlations of rLTL with ALM (r = 0.248), ALMBMI (r = 0.254), and LLM (r = 0.263) were found. In the fully adjusted model that included age, BMI, low-grade inflammation, lifestyle factors, and morbidities as potential confounders, rLTL was associated with ALM (β = 1.11, SEM = 0.46, P = 0.017), LLM (β = 1.20, SEM = 0.36, P = 0.001), and ALMBMI (β = 0.04, SEM = 0.02, P = 0.013) in men and with LLM in women (β = 0.78, SEM = 0.35, P = 0.026). Our results suggest that short telomeres may be a risk factor for lower ALM, particularly for low LLM. To confirm the association between telomere attrition and loss of LLM and ALMBMI, which are highly relevant for physical ability, further research in a longitudinal context is needed. The medical portion of this trial was registered in the German Clinical Trials Registry (http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=start) as DRKS00009277.


A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions.
Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs. To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. PTs are useful and safe for identifying agents inducing SCAR.


Discovering differences in acoustic emission between healthy and osteoarthritic knees using a four-phase model of sit-stand-sit movements.
By performing repeated sit-stand-sit movements to create stress on knee joints, short transient bursts of high frequency acoustic emission (AE) released by the knee joints were acquired from two age matched groups consisting of healthy and osteoarthritic (OA) knees, and significant differences between these two groups were discovered from the signal analysis performed. The analysis is based on a four-phase model of sit-stand-sit movements and a two-feature descriptor of AE bursts. The four phases are derived from joint angle measurement during movement, and they consist of the ascending-acceleration and ascending-deceleration phases in the sit-to-stand movement, followed by the descending-acceleration and descending-deceleration phases in the stand-to-sit movement. The two features are extracted from AE measurement during movement, and they consist of the peak magnitude value and average signal level of each AE burst. The proposed analysis method is shown to provide a high sensitivity for differentiation of the two age matched healthy and OA groups, with the most significant difference found to come from the peak magnitude value in the ascending-deceleration phase, clear quantity and strength differences in the image based visual display of their AE feature profiles due to substantially more AE bursts from OA knee joints with higher peak magnitude values and higher average signal levels, and two well separated clusters in the space formed by the principal components. These results provide ample support for further development of AE as a novel tool to facilitate dynamic integrity assessment of knee joints in clinic and home settings.


Montelukast inhibits caspase-3 activity and ameliorates oxidative damage in the spinal cord and urinary bladder of rats with spinal cord injury.
Spinal cord injury (SCI) leads to an inflammatory response that generates substantial secondary damage within the tissue besides the primary damage. Leukotrienes are biologically active 5-lipoxygenase products of arachidonic acid metabolism that are involved in the mediation of various inflammatory disorders including SCI. In this study, we investigated the possible protective effects of montelukast, a leukotriene receptor blocker, on SCI-induced oxidative damage. Wistar albino rats (n=24) were divided randomly as control, vehicle- or montelukast (10mg/kg, ip)-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury at T10 was used. Vehicle or montelukast were administered to the injured animals 15 min after injury. At seven days post-injury, neurological examination was performed and rats were decapitated. Blood samples were taken to evaluate leukotriene B4 levels, and pro-inflmamatory cytokines (TNF-α, IL-1β) while in spinal cord and urinary bladder samples malondialdehyde (MDA), glutathione (GSH), luminol chemiluminescence (CL) levels and myeloperoxidase (MPO) and caspase-3 activities were determined. Tissues were also evaluated histologically. SCI caused significant decreases in tissue GSH, which were accompanied with significant increases in luminol CL and MDA levels and MPO and caspase-3 activities, while pro-inflammatory cytokines in the plasma were elevated. On the other hand, montelukast treatment reversed these parameters and improved histological findings. In conclusion, SCI caused oxidative tissue injury through the activation of pro-inflammatory mediators and by neutrophil infiltration into tissues, and the neuroprotective and antiapoptotic effects of montelukast are mediated by the inhibition of lipid peroxidation, neutrophil accumulation and pro-inflammatory cytokine release. Moreover, montelukast does not only exert antioxidant and antiapoptotic effects on the spinal cord, but it has a significant impact on the bladder tissue damage secondary to SCI.


Lysosomal accumulation and recycling of lipopolysaccharide to the cell surface of murine macrophages, an in vitro and in vivo study.
In this study, we detailed in a time-dependent manner the trafficking, the recycling, and the structural fate of Brucella abortus LPS in murine peritoneal macrophages by immunofluorescence, ELISA, and biochemical analyses. The intracellular pathway of B. abortus LPS, a nonclassical endotoxin, was investigated both in vivo after LPS injection in the peritoneal cavity of mice and in vitro after LPS incubation with macrophages. We also followed LPS trafficking after infection of macrophages with B. abortus strain 19. After binding to the cell surface and internalization, Brucella LPS is routed from early endosomes to lysosomes with unusual slow kinetics. It accumulates there for at least 24 h. Later, LPS leaves lysosomes and reaches the macrophage cell surface. This recycling pathway is also observed for LPS released by Brucella S19 following in vitro infection. Indeed, by 72 h postinfection, bacteria are degraded by macrophages and LPS is located inside lysosomes dispersed at the cell periphery. From 72 h onward, LPS is gradually detected at the plasma membrane. In each case, the LPS present at the cell surface is found in large clusters with the O-chain facing the extracellular medium. Both the antigenicity and heterogenicity of the O-chain moiety are preserved during the intracellular trafficking. We demonstrate that LPS is not cleared by macrophages either in vitro or in vivo after 3 mo, exposing its immunogenic moiety toward the extracellular medium.


Maximal width of the separatrix chaotic layer.
The main goal of the paper is to find the absolute maximum of the width of the separatrix chaotic layer as function of the frequency of the time-periodic perturbation of a one-dimensional Hamiltonian system possessing a separatrix, which is one of the major unsolved problems in the theory of separatrix chaos. For a given small amplitude of the perturbation, the width is shown to possess sharp peaks in the range from logarithmically small to moderate frequencies. These peaks are universal, being the consequence of the involvement of the nonlinear resonance dynamics into the separatrix chaotic motion. Developing further the approach introduced in the recent paper by Soskin [Phys. Rev. E 77, 036221 (2008)], we derive leading-order asymptotic expressions for the shape of the low-frequency peaks. The maxima of the peaks, including in particular the absolute maximum of the width, are proportional to the perturbation amplitude times either a logarithmically large factor or a numerical, still typically large, factor, depending on the type of system. Thus, our theory predicts that the maximal width of the chaotic layer may be much larger than that predicted by former theories. The theory is verified in simulations. An application to the facilitation of global chaos onset is discussed.


Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background.
The aim of this investigation was to elucidate the time-course of changes in the prevalence of fatty liver, and to analyze its clinical backgrounds over the previous 12-year period. Thirty-nine thousand one hundred and fifty-one individuals who visited the Tokai University Hospital Health Checkup Center from 1989 to 2000 were examined for the presence of fatty liver, and their clinical backgrounds were analyzed. In 1989, the prevalence of fatty liver was 12.6%, and it rose gradually thereafter, reaching 30.3% in 1998, corresponding to a 2.4-fold increase over the prevalence rate in 1989. The average prevalence was about twice as high in males (26.0%) as in females (12.7%). The prevalence was uniformly high in males in all ages, while the prevalence in females tended to rise gradually with age. Body mass index (BMI) was found to be the variable most closely related to the onset of fatty liver. On the other hand, nonobese individuals with a BMI of less than 25 kg/m(2) accounted for approximately half of all the patients with fatty liver, and this proportion remained almost unchanged during the 12-year survey period. It was therefore difficult to simply attribute the increase in the prevalence of fatty liver to the increased prevalence of obesity. In the 35 519 repeat examinees (repeaters), it was found that 5088 individuals (14.3%) developed fatty liver, and fatty liver resolved in 1248 individuals (3.5%). As fatty liver developed, the BMI increased by 1.0 +/- 1.3 kg/m(2). As fatty liver disappeared, the BMI decreased by 1.0 +/- 1.5 kg/m(2). These results suggest that the absolute value of the BMI, as well as the relative changes in the BMI in each individual, may be related to the onset of fatty liver. The aim of this investigation was to elucidate the time-course of changes in the prevalence of fatty liver, and to analyze its clinical backgrounds over the previous 12-year period.


Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries.
80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70-8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39-8·80) and upper-middle-income countries (2·06, 1·11-3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26-11·59) and upper-middle-income countries (3·89, 2·08-7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. National Institute for Health Research Global Health Research Unit.


Twenty years of ambient observations of nitrogen oxides and specified hydrocarbons in air masses dominated by traffic emissions in Germany.
The analysis of the individual composition of hydrocarbon (VOC) mixtures enables us to transform observed VOC-concentrations into their respective total VOC-reactivity versus OH radicals (RVOC = Σ(kOH+VOCi × [VOCi])). This is particularly useful because local ozone production essentially depends on this single parameter rather than on the details of the underlying hydrocarbon mixture (Klemp et al., Schriften des Forschungszentrums Jülich, Energy & Environment, 2012, 21). The VOC composition also enables us to pin down the major emission source of hydrocarbons in urban areas to be petrol cars with temporarily reduced catalyst efficiency (the so-called cold-start situation) whereas the source of nitrogen oxides (NOx = NO + NO2) is expected to be nowadays dominated by diesel cars. The observations in the vicinity of main roads in German cities show a decrease in the ratio of OH reactivities of VOC and NO2 (RVOC/RNO2) by a factor of 7.5 over the time period 1994-2014. This is larger than the expected decrease of a factor of 2.9 taking estimated trends of VOC and NOx traffic emissions in Germany (Umweltbundesamt Deutschland, National Trend Tables for the German Atmospheric Emission Reporting, 2015), during this time period. The observed reduction in the RVOC/RNO2 ratio leads to a drastic decrease in local ozone production driven by the reduction in hydrocarbons. The analysis reveals that the overall reduction of ozone production benefits from the low decrease of NOx emissions from road traffic which is a consequence of the eventual absence of catalytic converters for nitrogen oxide removal in diesel cars up to now.


Different clinical effect of several types of airborne allergens on the severity of bronchial hyperreactivity.
Atopic sensitization belongs to the most common risk factors for bronchial asthma. However, in clinical practice, it is not clear whether sensitization against pollen and perennial allergens is differently associated with the severity of bronchial hyperresponsiveness (BHR). To find out whether patients sensitized to perennial allergens differ in severity of bronchial hyperresponsiveness from patients sensitized to pollen allergens. The study includes 109 patients. Based on the results of skin prick tests, patients were divided into three groups: sensitivity to pollen allergens - group A; sensitivity to perennial allergens - group B; sensitivity to both pollen and perennial allergens - group C. Based on the histamine bronchoprovocation test, we compared the values of histamine provocative concentration causing a 20% drop in FEV1 (PC20) among particular groups of patients. Mild bronchial hyperresponsiveness was determined if the value of PC20 was >4 mg/ml, while if the value of PC20 was <4 mg/ml, the bronchial hyperresponsiveness was considered as moderate/severe. A statistically significant difference was found in the degrees of bronchial hyperresponsiveness between the three groups of patients, namely, group A with the patients sensitized only to the pollen allergens, group B comprising patients sensitized to the perennial allergens only, and group C, involving patients sensitized to the combination of both pollen and perennial allergens. The PC20 values were higher among the patients from the group A (7.46 mg/ml) compared to group B (4.25 mg/ml) and C (4.52 mg/ml). The odds ratio for moderate/severe BHR was 5.21 and 5.04 in group B and group C, respectively. Severity of bronchial hyperresponsiveness shows differences according to sensitization to particular allergens. Perennial allergens are more often associated with serious forms of bronchial hyperresponsiveness which also have an impact on the severity and prognosis of bronchial asthma.


Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection.
Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.


Co-development of manner and path concepts in language, action, and eye-gaze behavior.
In order for artificial intelligent systems to interact naturally with human users, they need to be able to learn from human instructions when actions should be imitated. Human tutoring will typically consist of action demonstrations accompanied by speech. In the following, the characteristics of human tutoring during action demonstration will be examined. A special focus will be put on the distinction between two kinds of motion events: path-oriented actions and manner-oriented actions. Such a distinction is inspired by the literature pertaining to cognitive linguistics, which indicates that the human conceptual system can distinguish these two distinct types of motion. These two kinds of actions are described in language by more path-oriented or more manner-oriented utterances. In path-oriented utterances, the source, trajectory, or goal is emphasized, whereas in manner-oriented utterances the medium, velocity, or means of motion are highlighted. We examined a video corpus of adult-child interactions comprised of three age groups of children-pre-lexical, early lexical, and lexical-and two different tasks, one emphasizing manner more strongly and one emphasizing path more strongly. We analyzed the language and motion of the caregiver and the gazing behavior of the child to highlight the differences between the tutoring and the acquisition of the manner and path concepts. The results suggest that age is an important factor in the development of these action categories. The analysis of this corpus has also been exploited to develop an intelligent robotic behavior-the tutoring spotter system-able to emulate children's behaviors in a tutoring situation, with the aim of evoking in human subjects a natural and effective behavior in teaching to a robot. The findings related to the development of manner and path concepts have been used to implement new effective feedback strategies in the tutoring spotter system, which should provide improvements in human-robot interaction.


Does lockdown reduce air pollution? Evidence from 44 cities in northern China.
Responding to the ongoing novel coronavirus (agent of COVID-19) outbreak, China implemented "the largest quarantine in human history" in Wuhan on 23 January 2020. Similar quarantine measures were imposed on other Chinese cities within days. Human mobility and relevant production and consumption activities have since decreased significantly. As a likely side effect of this decrease, many regions have recorded significant reductions in air pollution. We employed daily air pollution data and Intracity Migration Index (IMI) data form Baidu between 1 January and 21 March 2020 for 44 cities in northern China to examine whether, how, and to what extent travel restrictions affected air quality. On the basis of this quantitative analysis, we reached the following conclusions: (1) The reduction of air pollution was strongly associated with travel restrictions during this pandemic-on average, the air quality index (AQI) decreased by 7.80%, and five air pollutants (i.e., SO2, PM2.5, PM10, NO2, and CO) decreased by 6.76%, 5.93%, 13.66%, 24.67%, and 4.58%, respectively. (2) Mechanism analysis illustrated that the lockdowns of 44 cities reduced human movements by 69.85%, and a reduction in the AQI, PM2.5, and CO was partially mediated by human mobility, and SO2, PM10, and NO2 were completely mediated. (3) Our findings highlight the importance of understanding the role of green production and consumption.


Iodinated non-ionic contrast medium does not inhibit Escherichia coli growth in ex vivo inoculated canine urine.
To investigate the effect of iohexol on standardized quantitative urine culture results in dogs. The authors hypothesized that the presence of iohexol in inoculated urine samples would result in lower bacterial concentrations (CFU/mL) and, therefore, decrease culture sensitivity. Urine samples were aseptically collected during cystoscopy from a single client-owned dog untreated with antimicrobials. An experimental controlled study. The urine sample was divided into 38 aliquots (0.5 mL each) that were used as negative controls or inoculated with an equal amount of Escherichia coli (105 CFU/mL). Different volumes (0.1 and 0.5 mL) of contrast or saline were added to the aliquots and quantitative culture results were compared. Two different incubation times between the preparation of aliquots and culture were evaluated (15 minutes and 24 hours). All aliquots from samples inoculated with E. coli (positive controls and iohexol-group) had the same reported quantitative result (104 CFU/mL). No growth was reported for the negative controls. Iohexol did not show any anti-E. coli properties in canine urine cultures for dilutions up to 1:2 contrast:urine and concentrations up to 120 mgI/mL. No difference was reported when iohexol was incubated with inoculated urine for 15 minutes or 24 hours. Based on the experimental in vitro conditions described, administration of iohexol before the collection of urine during urologic procedures does not negatively impact the isolation and growth of E. coli.


Altered activation patterns by triceps surae stretch reflex pathways in acute and chronic spinal cord injury.
Spinal reflexes are modified by spinal cord injury (SCI) due the loss of excitatory inputs from supraspinal structures and changes within the spinal cord. The stretch reflex is one of the simplest pathways of the central nervous system and was used presently to evaluate how inputs from primary and secondary muscle spindles interact with spinal circuits before and after spinal transection (i.e., spinalization) in 12 adult decerebrate cats. Seven cats were spinalized and allowed to recover for 1 mo (i.e., chronic spinal state), whereas 5 cats were evaluated before (i.e., intact state) and after acute spinalization (i.e., acute spinal state). Stretch reflexes were evoked by stretching the left triceps surae (TS) muscles. The force evoked by TS muscles was recorded along with the activity of several hindlimb muscles. Stretch reflexes were abolished in the acute spinal state due to an inability to activate TS muscles, such as soleus (Sol) and lateral gastrocnemius (LG). In chronic spinal cats, reflex force had partly recovered but Sol and LG activity remained considerably depressed, despite the fact that injecting clonidine could recruit these muscles during locomotor-like activity. In contrast, other muscles not recruited in the intact state, most notably semitendinosus and sartorius, were strongly activated by stretching TS muscles in chronic spinal cats. Therefore, stretch reflex pathways from TS muscles to multiple hindlimb muscles undergo functional reorganization following spinalization, both acute and chronic. Altered activation patterns by stretch reflex pathways could explain some sensorimotor deficits observed during locomotion and postural corrections after SCI.