Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

Cultural events and tourist development in Catalonia (Spain)

From the point of view of local development cultural tourism events represent an opportunity since they are distributed homogeneously by the Catalan territory and are experiencing a vertiginous growth as a way to differentiate the existing supply. In our study a sample of 264 telephone surveys made to organizers of events in Catalonia has been compiled, with the purpose of characterizing the existing supply, thematic typologies, management models, commercialization inputs and economic impact. The results allow us to characterize events from the point of view of their tourist potential. Finally some recommendations are set out to develop future tourism policies based on events according to product differentiation, seasonality, competitiveness and creativity.

Cultural events as tourism supply in coastal Catalan resorts

During the last three decades, the number of tourism events has been growing in Catalan coastal resorts because of the recover of Catalan cultural traditions, festivals and folklore, and also because of tourism growth. Catalan tourism resorts use events as catalysers for new supply and as a mean to differentiate and singularize themselves from their competitors. The tourism potential of cultural events is undeniable but there are some problems that prevent a more effective impact as economic and regional development agents. This paper reflects some discussions and conclusions obtained from the analysis of 264 valid responses of a survey made to different Catalan event organizers in 2008 and 2009. We describe and characterize cultural event supply in coastal resorts in order to study the events tourism importance, their capacity to generate and spread economic development, and their managerial model. The analysis is made in a geographical basis, comparing the results of the territorial organization of events of the city of Barcelona, coastal and inland municipalities. Finally some considerations about event regional tourism policy and tourism development are discussed.

Prevention and management of potential adverse events during transapical aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: Transapical transcatheter aortic valve replacement (TAVR) is a new minimally invasive technique with a known risk of unexpected intra-procedural complications. Nevertheless, the clinical results are good and the limited amount of procedural adverse events confirms the usefulness of a synergistic surgical/anesthesiological management in case of unexpected emergencies. METHODS: A review was made of the authors' four-year database and other available literature to identify major and minor intra-procedural complications occurring during transapical TAVR procedures. All implants were performed under general anesthesia with a balloon-expandable Edwards Sapien stent-valve, and followed international guidelines on indications and techniques. RESULTS: Procedural success rates ranged between 94% and 100%. Life-threatening apical bleeding occurred very rarely (0-5%), and its incidence decreased after the first series of implants. Stent-valve embolization was also rare, with a global incidence ranging from 0-2%, with evidence of improvement after the learning curve. Rates of valve malpositioning ranged from 0% to < 3%, whereas the risk of coronary obstruction ranged from 0% to 3.5%. Aortic root rupture and dissection were dramatic events reported in 0-2% of transapical cases. Stent-valve malfunction was rarely reported (1-2%), whereas the valve-in-valve bailout procedure for malpositioning, malfunctioning or severe paravalvular leak was reported in about 1.0-3.5% of cases. Sudden hemodynamic management and bailout procedures such as valve-in-valve rescue or cannulation for cardiopulmonary bypass were more effective when planned during the preoperative phase. CONCLUSION: Despite attempts to avoid pitfalls, complications during transapical aortic valve procedures still occur. Preoperative strategic planning, including hemodynamic status management, alternative cannulation sites and bailout procedures, are highly recommended, particularly during the learning curve of this technique.

A cophenetic correlation coefficient for Tocher's method

The objective of this work was to propose a way of using the Tocher's method of clustering to obtain a matrix similar to the cophenetic one obtained for hierarchical methods, which would allow the calculation of a cophenetic correlation. To illustrate the obtention of the proposed cophenetic matrix, we used two dissimilarity matrices - one obtained with the generalized squared Mahalanobis distance and the other with the Euclidean distance - between 17 garlic cultivars, based on six morphological characters. Basically, the proposal for obtaining the cophenetic matrix was to use the average distances within and between clusters, after performing the clustering. A function in R language was proposed to compute the cophenetic matrix for Tocher's method. The empirical distribution of this correlation coefficient was briefly studied. For both dissimilarity measures, the values of cophenetic correlation obtained for the Tocher's method were higher than those obtained with the hierarchical methods (Ward's algorithm and average linkage - UPGMA). Comparisons between the clustering made with the agglomerative hierarchical methods and with the Tocher's method can be performed using a criterion in common: the correlation between matrices of original and cophenetic distances.

Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study.

OBJECTIVE: To define therapeutic strategy for management of patients with ischemic stroke due to a high probability of paradoxical embolism through a Patent Foramen Ovale (PFO). METHODS: Since 1988 all consecutive patients with cerebrovascular events and PFO from the Stroke Registry of our population-based primary-care center are prospectively studied and followed. Since 1992, among 118 patients with cryptogenic embolic brain infarct or transient ischemic attack (TIA) and PFO, 32 consecutive patients younger than 60 years who presented at least two of the following criteria were admitted for surgery: history of Valsalva strain before stroke (11); multiple clinical events (13); multiple infarcts on brain Magnetic Resonance Imaging (MRI) (15); atrial septal aneurysm (ASA) (16); large right-to-left shunt (> 50 microbubbles) (12). RESULTS: Operative time 135' +/- 33'. CPB time 34' +/- 14'. Aortic crossclamping time 16' +/- 6'. Post-operative bleeding 485 +/- 170 ml. No homologous blood transfusion required. No neurological, cardiac or renal complications. All patients were followed-up corresponding to a cumulative time of 601 patient-months. This revealed no recurrent vascular events nor silent new brain lesions on brain MRI. Systematic simultaneous contrast Trans Esophageal Echocardiography (TEE)-Trans Cranial Doppler showed a small residual interatrial shunt in two patients. CONCLUSION: Surgical closure of a patent foramen ovale can be accomplished with very low morbidity and reduce efficiently the risk of stroke recurrence. It seems to be the option of choice in selected patients with a higher (> 1.5%/year) risk of stroke recurrence.

Performance of noninvasive ventilation algorithms on ICU ventilators during pressure support: a clinical study.

To evaluate the impact of noninvasive ventilation (NIV) algorithms available on intensive care unit ventilators on the incidence of patient-ventilator asynchrony in patients receiving NIV for acute respiratory failure. Prospective multicenter randomized cross-over study. Intensive care units in three university hospitals. Patients consecutively admitted to the ICU and treated by NIV with an ICU ventilator were included. Airway pressure, flow and surface diaphragmatic electromyography were recorded continuously during two 30-min periods, with the NIV (NIV+) or without the NIV algorithm (NIV0). Asynchrony events, the asynchrony index (AI) and a specific asynchrony index influenced by leaks (AIleaks) were determined from tracing analysis. Sixty-five patients were included. With and without the NIV algorithm, respectively, auto-triggering was present in 14 (22%) and 10 (15%) patients, ineffective breaths in 15 (23%) and 5 (8%) (p = 0.004), late cycling in 11 (17%) and 5 (8%) (p = 0.003), premature cycling in 22 (34%) and 21 (32%), and double triggering in 3 (5%) and 6 (9%). The mean number of asynchronies influenced by leaks was significantly reduced by the NIV algorithm (p < 0.05). A significant correlation was found between the magnitude of leaks and AIleaks when the NIV algorithm was not activated (p = 0.03). The global AI remained unchanged, mainly because on some ventilators with the NIV algorithm premature cycling occurs. In acute respiratory failure, NIV algorithms provided by ICU ventilators can reduce the incidence of asynchronies because of leaks, thus confirming bench test results, but some of these algorithms can generate premature cycling.

A new low-latitude Late Paleocene-Early Eocene radiolarian biozonation based on Unitary Associations: Applications for accreted terranes.

The late Paleocene - early Eocene sequences of DSDP Leg 10 Sites 86, 94, 95, and 96, Leg 43 Site 384 and ODP Leg 171B Hole 1051A have been re-sampled and re-examined for radiolarians. A new late Paleocene to early Eocene low-latitude radiolarian zonation suited for the correlation of accreted terranes is established by using the Unitary Association (UA) method. This method has the property of attributing equal weight to each species occurrence, which has the advantage of not being dependant on a limited set of key datums. Twenty-two UAs have been erected and correlated to the existing age models (given by nannofossils, planktonic foraminifera and radiolarians) for each site. The 22 UAs have been united into seven Unitary Associations Zones (UA Zones) (JP10-JE4) to increase lateral traceability. Herein we present the resulting composite range chart and correlation between the studied cores. The position of the UA Zones in the Paleogene timescale of.Berggren et al. (1995) have been estimated using a general consensus correlation with calcareous microfossil groups and the existing radiolarian zonation. Reproducible radiolarian events identified in the present work are bound to directly tied and compiled absolute ages given by Nigrini et al. (2006) and Sanfilippo and Nigrini (1998a). The RP zones (Sanfilippo and Nigrini 1998a) and the UA Zones are consistent. Unitary Associations permit to distinguish supplementary zonal subdivisions within RP7 and RP6. Topotypes from DSDP Leg 10 have been illustrated using mainly SEM imaging to facilitate the identification of re-crystallized forms.

Association of electrocardiogram abnormalities and incident heart failure events.

Unless effective preventive strategies are implemented, aging of the population will result in a significant worsening of the heart failure (HF) epidemic. Few data exist on whether baseline electrocardiographic (ECG) abnormalities can refine risk prediction for HF. METHODS: We examined a prospective cohort of 2,915 participants aged 70 to 79 years without preexisting HF, enrolled between April 1997 and June 1998 in the Health, Aging, and Body Composition (Health ABC) study. Minnesota Code was used to define major and minor ECG abnormalities at baseline and at year 4 follow-up. Using Cox models, we assessed (1) the association between ECG abnormalities and incident HF and (2) the incremental value of adding ECG to the Health ABC HF Risk Score using the net reclassification index. RESULTS: At baseline, 380 participants (13.0%) had minor, and 620 (21.3%) had major ECG abnormalities. During a median follow-up of 11.4 years, 485 participants (16.6%) developed incident HF. After adjusting for the Health ABC HF Risk Score variables, the hazard ratio (HR) was 1.27 (95% CI 0.96-1.68) for minor and 1.99 (95% CI 1.61-2.44) for major ECG abnormalities. At year 4, 263 participants developed new and 549 had persistent abnormalities; both were associated with increased subsequent HF risk (HR 1.94, 95% CI 1.38-2.72 for new and HR 2.35, 95% CI 1.82-3.02 for persistent ECG abnormalities). Baseline ECG correctly reclassified 10.5% of patients with HF events, 0.8% of those without HF events, and 1.4% of the overall population. The net reclassification index across the Health ABC HF risk categories was 0.11 (95% CI 0.03-0.19). CONCLUSIONS: Among older adults, baseline and new ECG abnormalities are independently associated with increased risk of HF. The contribution of ECG screening for targeted prevention of HF should be evaluated in clinical trials.

Tietoturvainformaation ja -tapahtumien hallinta PCI DSS -standardissa

Työn keskeisimpänä tavoitteena on tutkia SIEM-järjestelmien (Security Information and Event Management) käyttömahdollisuuksia PCI DSS -standardissa (Payment Card IndustryData Security Standard) lähtökohtaisesti ratkaisutoimittajan näkökulmasta. Työ on tehty Cygate Oy:ssä. SIEM on uusi tietoturvan ratkaisualue, jonka käyttöönottoa vauhdittavat erilaiset viralliset sääntelyt kuten luottokorttiyhtiöiden asettama PCI DSS -standardi. SIEM-järjestelmien avulla organisaatiot pystyvät keräämään valmistajariippumattomasti verkon systeemikomponenteista tapahtumatietoja, joiden avulla pystytään näkemään keskitetysti, mitä verkossa on tapahtunut. SIEM:ssa käsitellään sekä historiapohjaisia että reaaliaikaisia tapahtumia ja se toimii organisaatioiden keskitettynä tietoturvaprosessia tukevana hallintatyökaluna. PCI DSS -standardi on hyvin yksityiskohtainen ja sen vaatimusten täyttäminen ei ole yksinkertaista. Vaatimuksenmukaisuutta ei saavuteta hetkessä, vaan siihen liittyvä projekti voi kestää viikoista kuukausiin. Standardin yksi haasteellisimmista asioista on keskitetty lokien hallinta. Maksukorttitietoja käsittelevien ja välittävien organisaatioiden on kerättävä kaikki audit-lokit eri järjestelmistä, jotta maksukorttitietojen käyttöä pystytään luottamuksellisesti seuraamaan. Standardin mukaan organisaatioiden tulee käyttää myös tunkeutumisen ja haavoittuvuuksien havainnointijärjestelmiä mahdollisten tietomurtojen havaitsemiseksi ja estämiseksi. SIEM-järjestelmän avulla saadaan täytettyä PCI DSS -standardin vaativimpia lokien hallintaan liittyviä vaatimuksia ja se tuo samallamonia yksityiskohtaisia parannuksia tukemaan muita standardin vaatimuskohtia. Siitä voi olla hyötyä mm. tunkeutumisen ja haavoittuvuuksien havainnoinnissa. SIEM-järjestelmän hyödyntäminen standardin apuna on kuitenkin erittäin haasteellista. Käyttöönotto vaatii tarkkaa etukäteissuunnittelua ja kokonaisuuksien ymmärtämistä niin ratkaisutoimittajan kuin ratkaisun käyttöönottajan puolelta.

Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007.

To evaluate the in-hospital outcome of STEMI (ST elevation myocardial infarction) patients admitted to Swiss hospitals between 2000 and December 2007, and to identify the predictors of in-hospital mortality and major cardiac events. Data from the Swiss national registry AMIS Plus (Acute Myocardial Infarction and Unstable Angina in Switzerland) were used. All patients admitted between January 2000 and December 2007 with STEMI or a new LBBB (left bundle branch block) were included in the registry. We studied 12 026 STEMI patients admitted to 68 hospitals. The mean age was 64 +/- 13 years and 73% of the patients were male. Incidence of in-hospital death was 7.6% in 2000 and 6% in 2007. Reinfarction fell from 3.7% in 2000 to 0.9% in 2007. Thrombolysis decreased from 40.2% in 2000 to 2% in 2007. Clinical predictors of mortality were: age >65 years, Killips class III or IV, diabetes, Q wave myocardial infarction (at presentation). Patients undergoing percutaneous coronary intervention (PCI) had lower mortality and reinfarction rates (3.9% versus 11.2% and 1.1% versus 3.1% respectively, p <0.001) over time, although their numbers increased from 43% in 2000 to 85% in 2007. Patients admitted to hospitals with PCI facilities had lower mortality than patients hospitalised in hospitals without it, but the demographic characteristics differ widely between the two groups. Both in-hospital mortality and reinfarction decreased significantly over the time, parallel to an increased number of PCI. PCI was also the strongest predictor of survival. In-hospital mortality and reinfarction rate have decreased significantly in Swiss STEMI patients in the last seven years, parallel to a significant increase in the number of percutaneous coronary interventions in addition to medical therapy. Outcome is not related to the site of admission but to PCI access.

Vaccines safety; effect of supervision or SMS on reporting rates of adverse events following immunization (AEFI) with meningitis vaccine (MenAfriVac?): a randomized controlled trial.

BACKGROUND: To ensure vaccines safety, given the weaknesses of the national pharmacovigilance system in Cameroon, there is a need to identify effective interventions that can contribute to improving AEFI reporting. OBJECTIVE: To assess the effect of: (i) sending weekly SMS, or (ii) weekly supervisory visits on AEFI reporting rate during a meningitis immunization campaign conducted in Cameroon in 2012 using the meningitis A conjugate vaccine (MenAfriVac?). METHODS: Health facilities that met the inclusion criteria were randomly assigned to receive: (i) a weekly standardized SMS, (ii) a weekly standardized supervisory visits or (iii) no intervention. The primary outcome was the reported AEFI incidence rate from week 5 to 8 after the immunization campaign. Poisson regression model was used to estimate the effect of interventions after adjusting for health region, type of health facility, type and position of health workers as well as the cumulative number of AEFI reported from weeks 1 to 4. RESULTS: A total of 348 (77.2%) of 451 health facility were included, and 116 assigned to each of three groups. The incidence rate of reported AEFI per 100 health facility per week was 20.0 (15.9-24.1) in the SMS group, 40.2 (34.4-46.0) in supervision group and 13.6 (10.1-16.9) in the control group. Supervision led to a significant increase of AEFI reporting rate compared to SMS [adjusted RR=2.1 (1.6-2.7); p<0.001] and control [RR=2.8(2.1-3.7); p<0.001)] groups. The effect of SMS led to some increase in AEFI reporting rate compared to the control group, but the difference was not statistically significant [RR=1.4(0.8-1.6); p=0.07)]. CONCLUSION: Supervision was more effective than SMS or routine surveillance in improving AEFI reporting rate. It should be part of any AEFI surveillance system. SMS could be useful in improving AEFI reporting rates but strategies need to be found to improve its effectiveness, and thus maximize its benefits.

Morbillivirus glycoprotein expression induces ER stress, alters Ca2+ homeostasis and results in the release of vasostatin.

Although the pathology of Morbillivirus in the central nervous system (CNS) is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV) that we inoculated into two different cell systems: a monkey cell line (Vero) and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H) markedly accumulated in the endoplasmic reticulum (ER). This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT), another ER resident chaperon critically involved in the response to misfolded proteins and in Ca(2+) homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca(2+) homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses.