Eigenvalue optimisation on flat tori and lattice points in anisotropically expanding domains

This paper is concerned with the maximisation of the k'th eigenvalue of the Laplacian amongst flat tori of unit volume in dimension d as k goes to infinity. We show that in any dimension maximisers exist for any given k, but that any sequence of maximisers degenerates as k goes to infinity when the dimension is at most 10. Furthermore, we obtain specific upper and lower bounds for the injectivity radius of any sequence of maximisers. We also prove that flat Klein bottles maximising the k'th eigenvalue of the Laplacian exhibit the same behaviour. These results contrast with those obtained recently by Gittins and Larson, stating that sequences of optimal cuboids for either Dirichlet or Neumann boundary conditions converge to the cube no matter the dimension. We obtain these results via Weyl asymptotics with explicit control of the remainder in terms of the injectivity radius. We reduce the problem at hand to counting lattice points inside anisotropically expanding domains, where we generalise methods of Yu. Kordyukov and A. Yakovlev by considering domains that expand at different rates in various directions

The Steklov spectrum of cuboids

The paper is concerned with the Steklov eigenvalue problem on cuboids of arbitrary dimension. We prove a two-term asymptotic formula for the counting function of Steklov eigenvalues on cuboids in dimension d ≥ 3. Apart from the standard Weyl term, we calculate explicitly the second term in the asymptotics, capturing the contribution of the (d - 2) - dimensional facets of a cuboid. Our approach is based on lattice counting techniques. While this strategy is similar to the one used for the Dirichlet Laplacian, the Steklov case carries additional complications. In particular, it is not clear how to establish directly the completeness of the system of Steklov eigenfunctions admitting separation of variables. We prove this result using a family of auxiliary Robin boundary value problems. Moreover, the correspondence between the Steklov eigenvalues and lattice points is not exact, and hence more delicate analysis is required to obtain spectral asymptotics. Some other related results are presented, such as an isoperimetric inequality for the first Steklov eigenvalue, a concentration property of high frequency Steklov eigenfunctions and applications to spectral determination of cuboids

On Passion and Sports Fans:A Look at Football

The purpose of the present research was to test the applicability of the Dualistic Model of Passion (Vallerand et al., 2003) to being a sport (football) fan. The model posits that passion is a strong inclination toward an activity that individuals like (or even love), that they value, and in which they invest time and energy. Furthermore, two types of passion are proposed: harmonious and obsessive passion. While obsessive passion entails an uncontrollable urge to engage in the passionate activity, harmonious passion entails a sense of volition while engaging in the activity. Finally, the model posits that harmonious passion leads to more adaptive outcomes than obsessive passion. Three studies provided support for this dualistic conceptualization of passion. Study 1 showed that harmonious passion was positively associated with adaptive behaviours (e.g., celebrate the team’s victory), while obsessive passion was rather positively associated with maladaptive behaviours (e.g., to risk losing one’s employment to go to the team’s game). Study 2 used a short Passion Scale and showed that harmonious passion was positively related to the positive affective life of fans during the 2006 FIFA World Cup, psychological health (self-esteem and life satisfaction), and public displays of adaptive behaviours (e.g., celebrating one’s team victory in the streets), while obsessive passion was predictive of maladaptive affective life (e.g., hating opposing team’s fans) and behaviours (e.g., mocking the opposing team’s fans). Finally, Study 3 examined the role of obsessive passion as a predictor of partner’s conflict that in turn undermined partner’s relationship satisfaction. Overall, the present results provided support for the Dualistic Model of Passion. The conceptual and applied implications of the findings are discussed

Simultaneous Whole Mitochondrial Genome Sequencing with Short Overlapping Amplicons Suitable for Degraded DNA Using the Ion Torrent Personal Genome Machine

Whole mitochondrial (mt) genome analysis enables a considerable increase in analysis throughput, and improves the discriminatory power to the maximum possible phylo

Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease.

The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3weeks post-surgery. Importantly, we report that cystamine has neurorestorative properties 5weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing

Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology: Vascular impairments in HD

ObjectiveAlthough the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood–brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD.MethodsWe used 3‐ and 7‐Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy.ResultsWe found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction‐associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients.InterpretationTaken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications. Ann Neurol 2015;78:160–17

The complexities of breast cancer desmoplasia

The stromal, or 'desmoplastic', responses seen histologically in primary breast carcinomas can vary from being predominantly cellular (fibroblasts/myofibroblasts) with little collagen to being a dense acellular tissue. The mechanisms underlying the stromal response are complex; paracrine activation of myofibroblasts by growth factors is important but the contribution of cytokines/chemokines should not be ignored. A recent xenograft study has proposed that platelet-derived growth factor (PDGF) is the initiator of the desmoplastic response, but this has not been confirmed by (limited) analyses in vivo. Further studies are required to elaborate the mechanisms of the desmoplastic response, to determine its role in breast cancer progression and whether it is the same for all carcinomas

Analysis of 1560 inpatient and outpatient Escherichia coli isolates from across Canada - Results from the CANWARD 2007 study CANWARD 2007

OBJeCtIveS: Escherichia coli was the most common pathogen isolated in the Canadian Ward Surveillance Study (CANWARD 2007) and remains one of the most common pathogens isolated in all health care settings. An in-depth analysis of all E coli isolates was performed to determine the distribution and demographics associated with resistance to antimicrobials, presence of extended-spectrum beta-lactamases (ESBLs) and multidrug resistance (MDR; concurrent resistance to agents from three or more different antimicrobial classes). MethODS: The CANWARD 2007 study characterized pathogens isolated from inpatient (surgical and medical wards, and intensive care units) and outpatient (emergency departments and clinics) areas of 12 Canadian hospitals between January and December 2007. E coli susceptibility to 12 antimicrobials was determined, ESBL production was determined, and a multivariate nominal logistic regression model was designed to determine if sex, isolation from a sterile site, inpatient versus outpatient status, and age were significantly associated with susceptibility to the tested antimicrobials, MDR or ESBL production. ReSuLtS: In total, 1702 E coli isolates, representing 21.6% of all isolates collected in the CANWARD 2007 study, were investigated. Of these, 1560 isolates fell within the primary objective of the study and were included in the present analysis. Susceptibilities were greater than 90% for meropenem (100%), ertapenem (100%), tigecycline (99.9%), piperacillin-tazobactam (97.9%), cefepime (97.9%), ceftriaxone (95.4%), nitrofurantoin (95.2%), cefoxitin (94.8%), amoxicillinclavulanate (92.9%) and gentamicin (91.4%). Cefazolin (89.4%), the fluoroquinolones (ciprofloxacin, 79.4%; levofloxacin, 79.9%) and trimethoprim-sulfamethoxazole (75.7%) were less active agents. In the multivariate model, invasive isolates were significantly associated with lower susceptibility rates for trimethoprim-sulfamethoxazole. Increasing age was associated with lower susceptibility to fluoroquinolones, ceftriaxone, cefepime, gentamicin and nitrofurantoin, as well as ESBL production. Sex was not associated with resistance to any antimicrobial or to ESBL production. Inpatient status was associated with higher resistance rates to amoxicillin-clavulanate, cefazolin, fluoroquinolones and trimethoprim-sulfamethoxazole. Isolation of an ESBL producer was only found to be independently associated with age, being more common in older patients. MDR was not found to be associated with any variable measured when ESBL producers were excluded from analysis. CONCLuSIONS: E coli antimicrobial susceptibility varies according to patient factors. Age and inpatient status were the most important determinants in the present analysis and should be considered when prescribing empirical antimicrobial therapy. Fluoroquinolones and sulfonamides should be used cautiously and in consideration of local resistance patterns for infections caused by E coli, due to lower susceptibility rates. Independent factors associated with antimicrobial resistance were age, inpatient status and isolation from a sterile site. These factors should be considered when empirically treating infections likely caused by E coli. Local antimicrobial prescribing practices, in particular the liberal use of fluoroquinolones, and inadequate infection control practices may be reducing susceptibility rates. OBJeCtIFS : L'Escherichia coli était le pathogène le plus isolé dans l'étude CANWARD 2007 sur la surveillance des services aux hospitalisés canadiens et demeure l'un des pathogènes les plus isolés en milieu de santé. On a effectué une analyse approfondie de tous les isolats d'E coli pour déterminer la répartition et la démographie associées à la résistance aux antimicrobiens ainsi qu'à la présence de bêta-lactamases à large spectre (ESBL) et de multirésistance (résistance conjointe à au moins trois classes d'antimicrobiens). MÉthODOLOGIe : L'étude CANWARD 2007 caractérisait les pathogènes isolés de patients hospitalisés (service de chirurgie, service médical et unité de soins intensifs) et ambulatoires (urgence et cliniques) de 12 hôpitaux canadiens entre janvier et décembre 2007. On a déterminé la susceptibilité de l'E coli à 12 antimicrobiens ainsi que la production d'ESBL et conçu un modèle de régression logistique nominale multivariée pour déterminer si le sexe, l'isolement d'un foyer stérile, le statut de patient hospitalisé ou ambulatoire et l'âge s'associaient de manière significative à la susceptibilité aux antimicrobiens vérifiés, à la multirésistance ou à la production d'ESBL. RÉSuLtAtS : Au total, on a évalué 1 072 isolats d'E coli, représentant 21,6 % de tous les isolats prélevés dans le cadre de l'étude CANWARD 2007. De ce nombre, 1 560 isolats respectaient l'objectif primaire de l'étude et ont été inclus dans la présente analyse. Les susceptibilités étaient supérieures à 90 % pour le méropénem (100 %), l'ertapénem (100 %), la tigécycline (99,9 %), la pipéracilline-tazobactam (97,9 %), la céfépime (97.9 %), la ceftriaxone (95,4 %), la nitrofurantoïne (95,2 %), la céfoxitine (94,8 %), l'amoxicilline-clavulanate (92,9 %) et la gentamicine (91,4 %). La céfazoline (89,4 %), les fluoroquinolones (ciprofloxacine, 79,4 %, lévofloxacine, 79,9 %) et le triméthoprim-sulfaméthoxazole (75,7 %) étaient moins actifs. Dans le modèle multivarié, les isolats envahissants étaient associés de manière marquée à des taux de susceptibilité plus faibles pour le triméthoprim-sulfaméthoxazole. Le vieillissement s'associait à une susceptibilité plus faible aux fluoroquinolones, à la ceftriaxone, à la suite page suivante Lagacé-Wiens et al Can J Infect Dis Med Microbiol Vol 20 Suppl A Spring 2009 50A E scherichia coli is the most commonly isolated clinically relevant Gram-negative organism in most health care settings (1-3). Although most commonly associated with urinary tract infections, all body sites can be involved. Furthermore, resistance to multiple antimicrobials is increasing and multidrug resistant (MDR; concurrent resistance to agents from three or more different antimicrobial classes) isolates are common (1,4,5). Appropriate empirical antimicrobial choice must take into account local resistance patterns and other demographic variables such as patient age, site and severity of infection, sex, inpatient status as well as previous antimicrobial use, stay in hospitals or personal care homes, and colonization with antimicrobial resistant organisms (1,6). The purpose of the present study was to provide an in-depth analysis of patient factors associated with drug resistance in the most commonly isolated organism overall in Canadian hospitals. MethODS E coli isolates were obtained as part of the Canadian Ward Surveillance Study (CANWARD 2007), which collected isolates submitted to 12 clinical microbiology laboratories from tertiary care hospitals in seven provinces across Canada. Submitting sites and collection strategy are described elsewhere in the present supplement (2). Isolates had to be deemed clinically significant by the referring laboratory's current specimen work-up protocol. Demographic information collected with each isolate included patient age, sex, site of infection and the location of patient contact (surgical or medical ward, emergency room, intensive care unit [ICU] or hospital clinic). A minimum number of isolates from each hospital location and anatomical site was requested to provide more power to the study. The implication of this collection strategy is that the anatomical distribution of pathogen isolation and inpatient versus outpatient distribution does not reflect the true distribution in the population studied. Isolates were collected within both primary and secondary study objectives and only isolates collected within the primary objective were considered in this analysis. For statistical analysis, age was divided into four categories: 20 years and younger, 21 to 60 years, 61 to 80 years, and 81 years and older, and location of patient contact was divided into either inpatient (wards and ICUs) or outpatient (emergency room and clinics). Information on previous antimicrobial exposure, hospitalization duration and underlying medical conditions was not available. Antimicrobial susceptibility to amoxicillin-clavulanate, cefazolin, cefepime, ceftriaxone, ciprofloxacin, gentamicin, nitrofurantoin, levofloxacin, meropenem, ertapenem, piperacillin-tazobactam, tigecycline and trimethoprim-sulfamethoxazole was determined using broth dilution as described elsewhere in the present supplement (2). Screening for ESBL production was achieved using a 1 µg/mL or greater ceftriaxone breakpoint and confirmation was with the Clinical and Laboratory Standards Institute-recommended disk diffusion method (7). Univariate analysis using the c 2 (or Fisher's exact test where required) was undertaken to identify relationships between susceptibility to each of the antimicrobials and ESBL production; and the following variables: sex, age group, inpatient/outpatient status and isolation from a sterile site (blood, cerebrospinal fluid, synovial fluid). Relationships where the P<0.20 in the univariate analysis were included in a multivariate nominal logistic regression model to determine independent explanatory variables. Initially, a full factorial multiple logistic regression analysis was performed using the potential explanatory variables identified in the univariate analysis for each antimicrobial, and then a backward selection so that all factors remaining in the model were statistically significant at a 5% level (P<0.05). Statistical analysis was undertaken using JMP software version 7.0 (SAS Institute Inc, USA). ReSuLtS Of 7881 total organisms, 1702 E coli (21.6%) were collected from the CANWARD 2007 study, making it the most common organism isolated from patients in Canadian hospitals overall. Of these, 1560 fell within the primary objective and the remaining 142 were submitted as putative ESBL producers for separate analysis and excluded from the present analysis. The mean age of patients infected with E coli was 56.9 years; 12.3% of E coli isolates were from patients younger than 21 years, 34.7% were 21 to 60 years of age, 33.9% were 61 to 80 years of age and 19.1% were older than 80 years of age. There were more samples from women (59.3%); with both sexes combined, 50.5% were invasive isolates (all bloodstream), and 40.7% were from urine, 6.4% from respiratory sources and 2.4% from wounds. Note that the sampling strategy was biased to include a surplus of bloodstream isolates to have greater numbers of these for analysis and this does not represent the true source distribution of E coli infections. The distribution among provinces was British Columbia, 9.7%; Alberta, 7.6%; Saskatchewan, 9.1%; Manitoba, 9.2%; Ontario, 28.3%; Quebec, 29.2% and Nova Scotia, 6.9%. Isolates were not obtained from Newfoundland, Nunavut, the Northwest Territories, Yukon, New Brunswick or Prince Edward Island. Minimum inhibitory concentrations (MICs) required to inhibit 50% and 90% of organisms (MIC 50 , MIC 90 ) and percentage of isolates susceptible to the antimicrobials are provided in Resistance in E coli from Canadian inpatients and outpatients Can J Infect Dis Med Microbiol DISCuSSION Low susceptibility of ICU E coli isolates to fluoroquinolones and trimethoprim-sulfamethoxazole was not unexpected given the wide use of these antimicrobials in both inpatients and outpatients. In particular, the dramatic increase in fluoroquinolone resistance has been observed in many settings (8-10). Our observations suggest that first-generation cephalosporins and amoxicillin-clavulanate are still useful agents for infections caused by E coli in that susceptibility rates remain near 90% overall. This is particularly true of outpatient isolates where susceptibility is greater than 90% for both these agents. On the contrary, low susceptibility to fluoroquinolones even in the outpatient setting (84%) begins to bring into question the use of these agents as first line for infections commonly caused by E coli, such as urinary tract infections. Trimethoprimsulfamethoxazole susceptibility rates are below 80% in both inpatient and outpatient settings and should only be used for infections empirically in the context of supportive data from local antibiograms or definitive susceptibility data. In our multivariate model, increasing age was independently associated with reduced susceptibility to fluoroquinolones, nitrofurantoin, ceftriaxone, cefepime, gentamicin and ESBL production. The association between age and fluoroquinolone susceptibility has been demonstrated previously and is likely due to increasing exposure to fluoroquinolones over time and avoidance of fluoroquinolone use in children Predictably, inpatient isolates had lower susceptibility to several antibiotics, including amoxicillin-clavulanate, fluoroquinolones, cefazolin and trimethoprim-sulfamethoxazole. Interestingly, susceptibility to antimicrobials commonly used in the inpatient setting (ceftriaxone, cefepime, gentamicin, carbapenems and piperacillin-tazobactam) did not appear to be significantly affected by inpatient status. This is reassuring in that these antimicrobials maintain good activity overall in the hospital setting. The reason that antimicrobials commonly used in the community are most affected by inpatient status is not known, but may be due to general practitioners using these antimicrobials to treat outpatients and selection bias occurring because poor response due to antimicrobial resistance requires admission for parenteral antimicrobials. Interestingly, sex was not a predictor of susceptibility to any of the antimicrobials tested after adjusting for other factors in the multivariate model. Although large differences were seen between susceptibility to fluoroquinolones, both inpatient status and age appeared to be confounding factors in the effect of sex on fluoroquinolone resistance. The absence of a sex effect contradicts the findings of others Meropenem, ertapenem, piperacillin-tazobactam, tigecycline and cefoxitin were not significantly associated with any demographic variable in the multivariate model. Low overall resistance rates accounts for these observations. Our study had some limitations. We could not collect patient information such as length of stay, previous antimicrobial exposure and underlying disease. Although of great interest for the prediction of antimicrobial resistance, the effect of these variables cannot be determined with our data. Also, our isolates reflect only information from the 12 centres studied and our data may not reflect the antimicrobial susceptibility patterns of all hospitals in Canada. However, this study does provide valuable information about the factors predicting antimicrobial susceptibility of E coli in one of the largest of inpatient and outpatient populations in Canada studied to date

Generation of recombinant single-chain antibodies neutralizing the cytolytic activity of vaginolysin, the main virulence factor of Gardnerella vaginalis

Generated scFvs is the first example of recombinant single-chain antibodies with VLY-neutralizing activity produced in prokaryote expression system. G. vaginalis caused infections continue to be a world-wide problem, therefore neutralizing recombinant antibodies may provide novel therapeutic agents useful in the treatment of bacterial vaginosis and other diseases caused by G. vaginalis

Investigation of 3D glenohumeral displacements from 3D reconstruction using biplane X-ray images: Accuracy and reproducibility of the technique and preliminary analysis in rotator cuff tear patients

Rotator cuff (RC) tears may be associated with increased glenohumeral instability; however, this instability is difficult to quantify using currently available diagnostic tools. Recently, the three-dimensional (3D) reconstruction and registration method of the scapula and humeral head, based on sequences of low-dose biplane X-ray images, has been proposed for glenohumeral displacement assessment. This research aimed to evaluate the accuracy and reproducibility of this technique and to investigate its potential with a preliminary application comparing RC tear patients and asymptomatic volunteers. Accuracy was assessed using CT scan model registration on biplane X-ray images for five cadaveric shoulder specimens and showed differences ranging from 0.6 to 1.4 mm depending on the direction of interest. Intra- and interobserver reproducibility was assessed through two operators who repeated the reconstruction of five subjects three times, allowing defining 95% confidence interval ranging from ±1.8 to ±3.6 mm. Intraclass correlation coefficient varied between 0.84 and 0.98. Comparison between RC tear patients and asymptomatic volunteers showed differences of glenohumeral displacements, especially in the superoinferior direction when shoulder was abducted at 20 and 45 . This study thus assessed the accuracy of the low-dose 3D biplane X-ray reconstruction technique for glenohumeral displacement assessment and showed potential in biomechanical and clinical research.Fondation Paris-Tech Programme BIOMECAM Chaire ParisTech Institut de Recherche Robert-Sauvé en Santé et Sécurité du Travail du Québec Natural Science and Engineering Research Council of Canada Fonds de Recherche sur la Nature et les Technologies du Québec Fonds de Recherche en Santé du Québec, EOS Imaging, and French pôle de compétitivité MEDICEN (STEREOS + program)