Monotonic Distributive Semilattices

In the study of algebras related to non-classical logics, (distributive) semilattices are always present in the background. For example, the algebraic semantic of the {→, ∧, ⊤}-fragment of intuitionistic logic is the variety of implicative meet-semilattices (Chellas 1980; Hansen 2003). In this paper we introduce and study the class of distributive meet-semilattices endowed with a monotonic modal operator m. We study the representation theory of these algebras using the theory of canonical extensions and we give a topological duality for them. Also, we show how our new duality extends to some particular subclasses.Fil: Celani, Sergio Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Departamento de Matemática; ArgentinaFil: Menchón, María Paula. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Validity of models for Dreicer generation of runaway electrons in dynamic scenarios

Runaway electron modelling efforts are motivated by the risk these energetic particles pose to large fusion devices. The sophisticated kinetic models can capture most features of the runaway electron generation but have high computational costs which can be avoided by using computationally cheaper reduced kinetic codes. In this paper, we compare the reduced kinetic and kinetic models to determine when the former solvers, based on analytical calculations assuming quasi-stationarity, can be used. The Dreicer generation rate is calculated by two different solvers in parallel in a workflow developed in the European Integrated Modelling framework, and this is complemented by calculations of a third code that is not yet integrated into the framework. Runaway Fluid, a reduced kinetic code, NORSE, a kinetic code using non-linear collision operator, and DREAM, a linearized Fokker-Planck solver, are used to investigate the effect of a dynamic change in the electric field for different plasma scenarios spanning across the whole tokamak-relevant range. We find that on time scales shorter than or comparable to the electron collision time at the critical velocity for runaway electron generation kinetic effects not captured by reduced kinetic models play an important role. This characteristic time scale is easy to calculate and can reliably be used to determine whether there is a need for kinetic modelling, or cheaper reduced kinetic codes are expected to deliver sufficiently accurate results. This criterion can be automated, and thus it can be of great benefit for the comprehensive self-consistent modelling frameworks that are attempting to simulate complex events such as tokamak start-up or disruptions

Population Pharmacokinetics of Telapristone (CDB-4124) and its Active Monodemethylated Metabolite CDB-4453, with a Mixture Model for Total Clearance

Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h−1. Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmetest) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5

Effects of deletion of the Streptococcus pneumoniae lipoprotein diacylglyceryl transferase gene lgt on ABC transporter function and on growth in vivo

Lipoproteins are an important class of surface associated proteins that have diverse roles and frequently are involved in the virulence of bacterial pathogens. As prolipoproteins are attached to the cell membrane by a single enzyme, prolipoprotein diacylglyceryl transferase (Lgt), deletion of the corresponding gene potentially allows the characterisation of the overall importance of lipoproteins for specific bacterial functions. We have used a Δlgt mutant strain of Streptococcus pneumoniae to investigate the effects of loss of lipoprotein attachment on cation acquisition, growth in media containing specific carbon sources, and virulence in different infection models. Immunoblots of triton X-114 extracts, flow cytometry and immuno-fluorescence microscopy confirmed the Δlgt mutant had markedly reduced lipoprotein expression on the cell surface. The Δlgt mutant had reduced growth in cation depleted medium, increased sensitivity to oxidative stress, reduced zinc uptake, and reduced intracellular levels of several cations. Doubling time of the Δlgt mutant was also increased slightly when grown in medium with glucose, raffinose and maltotriose as sole carbon sources. These multiple defects in cation and sugar ABC transporter function for the Δlgt mutant were associated with only slightly delayed growth in complete medium. However the Δlgt mutant had significantly reduced growth in blood or bronchoalveolar lavage fluid and a marked impairment in virulence in mouse models of nasopharyngeal colonisation, sepsis and pneumonia. These data suggest that for S. pneumoniae loss of surface localisation of lipoproteins has widespread effects on ABC transporter functions that collectively prevent the Δlgt mutant from establishing invasive infection

The hip fracture incidence curve is shifting to the right: A forecast of the age-quake

Background The number of hip fractures has doubled in the last 30–40 years in many countries. Age-adjusted incidence has been reported to be decreasing in Europe and North America, but is there a decreasing trend in all age groups

Mesenchymal Stromal Cells Improve Salivary Function and Reduce Lymphocytic Infiltrates in Mice with Sjögren's-Like Disease

Non-obese diabetic (NOD) mice develop Sjögren's-like disease (SS-like) with loss of saliva flow and increased lymphocytic infiltrates in salivary glands (SGs). There are recent reports using multipotent mesenchymal stromal cells (MSCs) as a therapeutic strategy for autoimmune diseases due to their anti-inflammatory and immunomodulatory capabilities. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund's adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD45(-)/TER119(-) cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined.Donor MSCs were isolated from bones of male transgenic eGFP mice. Eight week-old female NOD mice received one of the following treatments: insulin, CFA, MSC, or CFA+MSC (combined therapy). Mice were followed for 14 weeks post-therapy. CD45(-)/TER119(-) cells demonstrated characteristics of MSCs as they were positive for Sca-1, CD106, CD105, CD73, CD29, CD44, negative for CD45, TER119, CD11b, had high number of CFU-F, and differentiated into osteocytes, chondrocytes and adipocytes. Both MSC and MSC+CFA groups prevented loss of saliva flow and reduced lymphocytic infiltrations in SGs. Moreover, the influx of T and B cells decreased in all foci in MSC and MSC+CFA groups, while the frequency of Foxp3(+) (T(reg)) cell was increased. MSC-therapy alone reduced inflammation (TNF-α, TGF-β), but the combination of MSC+CFA reduced inflammation and increased the regenerative potential of SGs (FGF-2, EGF).The combined use of MSC+CFA was effective in both preventing saliva secretion loss and reducing lymphocytic influx in salivary glands

Diet and Physical Activity for the Prevention of Noncommunicable Diseases in Low- and Middle-Income Countries: A Systematic Policy Review

Background: Diet-related noncommunicable diseases (NCDs) are increasing rapidly in low-and middle-income countries (LMICs) and constitute a leading cause of mortality. Although a call for global action has been resonating for years, the progress in national policy development in LMICs has not been assessed. This review of strategies to prevent NCDs in LMICs provides a benchmark against which policy response can be tracked over time. Methods and Findings: We reviewed how government policies in LMICs outline actions that address salt consumption, fat consumption, fruit and vegetable intake, or physical activity. A structured content analysis of national nutrition, NCDs, and health policies published between 1 January 2004 and 1 January 2013 by 140 LMIC members of the World Health Organization (WHO) was carried out. We assessed availability of policies in 83% (116/140) of the countries. NCD strategies were found in 47% (54/116) of LMICs reviewed, but only a minority proposed actions to promote healthier diets and physical activity. The coverage of policies that specifically targeted at least one of the risk factors reviewed was lower in Africa, Europe, the Americas, and the Eastern Mediterranean compared to the other two World Health Organization regions, South-East Asia and Western Pacific. Of the countries reviewed, only 12% (14/116) proposed a policy that addressed all four risk factors, and 25% (29/116) addressed only one of the risk factors reviewed. Strategies targeting the private sector were less frequently encountered than strategies targeting the general public or policy makers. Conclusions: This review indicates the disconnection between the burden of NCDs and national policy responses in LMICs. Policy makers urgently need to develop comprehensive and multi-stakeholder policies to improve dietary quality and physical activity

Development of a framework for genotyping bovine-derived Cryptosporidium parvum, using a multilocus fragment typing tool

Background: There is a need for an integrated genotyping approach for C. parvum; no sufficiently discriminatory scheme to date has been fully validated or widely adopted by veterinary or public health researchers. Multilocus fragment typing (MLFT) can provide good differentiation and is relatively quick and cheap to perform. A MLFT tool was assessed in terms of its typeability, specificity, precision (repeatability and reproducibility), accuracy and ability to genotypically discriminate bovine-derived Cryptosporidium parvum. Methods: With the aim of working towards a consensus, six markers were selected for inclusion based on their successful application in previous studies: MM5, MM18, MM19, TP14, MS1 and MS9. Alleles were assigned according to the fragment sizes of repeat regions amplified, as determined by capillary electrophoresis. In addition, a region of the GP60 gene was amplified and sequenced to determine gp60 subtype and this was added to the allelic profiles of the 6 markers to determine the multilocus genotype (MLG). The MLFT tool was applied to 140 C. parvum samples collected in two cross-sectional studies of UK calves, conducted in Cheshire in 2004 (principally dairy animals) and Aberdeenshire/Caithness in 2011 (beef animals). Results: Typeability was 84 %. The primers did not amplify tested non-parvum species frequently detected in cattle. In terms of repeatability, within- and between-run fragment sizes showed little variability. Between laboratories, fragment sizes differed but allele calling was reproducible. The MLFT had good discriminatory ability (Simpson’s Index of Diversity, SID, was 0.92), compared to gp60 sequencing alone (SID 0.44). Some markers were more informative than others, with MS1 and MS9 proving monoallelic in tested samples. Conclusions: Further inter-laboratory trials are now warranted with the inclusion of human-derived C. parvum samples, allowing progress towards an integrated, standardised typing scheme to enable source attribution and to determine the role of livestock in future outbreaks of human C. parvum

Catheter Colonization and Abscess Formation Due to Staphylococcus epidermidis with Normal and Small-Colony-Variant Phenotype Is Mouse Strain Dependent

Coagulase-negative staphylococci (CoNS) form a thick, multilayered biofilm on foreign bodies and are a major cause of nosocomial implant-associated infections. Although foreign body infection models are well-established, limited in vivo data are available for CoNS with small-colony-variant (SCV) phenotype described as causative agents in implant-associated infections. Therefore, we investigated the impact of the Staphylococcus epidermidis phenotype on colonization of implanted PVC catheters and abscess formation in three different mouse strains. Following introduction of a catheter subcutaneously in each flank of 8- to 12-week-old inbred C57BL/6JCrl (B6J), outbred Crl:CD1(ICR) (CD-1), and inbred BALB/cAnNCrl (BALB/c) male mice, doses of S. epidermidis O-47 wild type, its hemB mutant with stable SCV phenotype, or its complemented mutant at concentrations of 106 to 109 colony forming units (CFUs) were gently spread onto each catheter. On day 7, mice were sacrificed and the size of the abscesses as well as bacterial colonization was determined. A total of 11,500 CFUs of the complemented mutant adhered to the catheter in BALB/c followed by 9,960 CFUs and 9,900 CFUs from S. epidermidis wild type in BALB/c and CD-1, respectively. SCV colonization was highest in CD-1 with 9,500 CFUs, whereas SCVs were not detected in B6J. The minimum dose that led to colonization or abscess formation in all mouse strains was 107 or 108 CFUs of the normal phenotype, respectively. A minimum dose of 108 or 109 CFU of the hemB mutant with stable SCV phenotype led to colonization only or abscess formation, respectively. The largest abscesses were detected in BALB/c inoculated with wild type bacteria or SCV (64 mm2 vs. 28 mm2). Our results indicate that colonization and abscess formation by different phenotypes of S. epidermidis in a foreign body infection model is most effective in inbred BALB/c followed by outbred CD-1 and inbred B6J mice

Dizziness reported by elderly patients in family practice: prevalence, incidence, and clinical characteristics

Background: Although dizziness in elderly patients is very common in family practice, most prevalence studies on dizziness are community-based and include a study population that is not representative of family practice. The aim of this study was to investigate the prevalence and incidence of dizziness reported by elderly patients in family practice, to describe their final diagnoses as recorded by the family physician, and to compare the clinical characteristics of dizzy patients with those of non-dizzy patients. Methods: Data were obtained from the Second Dutch National Survey of General Practice, a prospective registration study which took place over a 12-month period in 2001. We developed a search strategy consisting of 15 truncated search terms (based on Dutch synonyms for dizziness), and identified all patients aged 65 or older who visited their family physician because of dizziness (N=3,990). We used the mid-time population as denominator to calculate the prevalence and incidence, and for group comparisons we used the Student's t and Chi-square test, and logistic regression analysis. Results: The one-year prevalence of dizziness in family practice in patients aged 65 or older was 8.3%, it was higher in women than in men, and it increased with age. In patients aged 85 or older the prevalence was similar for men and women. The incidence of dizziness was 47.1 per 1000 person-years. For 39% of the dizzy patients the family physicians did not specify a diagnosis, and recorded a symptom diagnosis as the final diagnosis. Living alone, lower level of education, pre-existing cerebrovascular disease, and pre-existing hypertension were independently associated with dizziness. Conclusions: Dizziness in family practice patients increases with age. It is more common in women than in men, but this gender difference disappears in the very old. Because a large proportion of dizzy elderly patients in family practice remains undiagnosed, it would be worthwhile to carry out more diagnostic research on dizziness in a family practice setting