Structure of the salivary glands of the unfed male tick Amblyomma cajennense (Fabricius) (Acarina: Ixodidae)

Acini in the salivary glands of unfed male Amblyomma cajennense of different ages, were studied. The salivary glands consist of one agranular and three granular acini types. The agranular acini are directly attached to the medial and anterior portion of the main salivary duct, and to some branches of the secondary ducts. A large, clear, central cell occupies the centre and this cell is in contact with the acinar lumen. There is no valve to the lumen. Granular acini consist of approximately six to fourteen cells (type II acini) or eight to thirteen (type III acini). The type II acini have three types of granular cells ("a", "b" and "c") and a valve: the type III acini have three types of granular cells ("d", "e" and "f" and a valve.

Less frequent dosing of erythropoiesis stimulating agents in patients undergoing dialysis: a European multicentre cost study.

OBJECTIVE: To calculate the variable costs involved with the process of delivering erythropoiesis stimulating agents (ESA) in European dialysis practices. METHODS: A conceptual model was developed to classify the processes and sub-processes followed in the pharmacy (ordering from supplier, receiving/storing/delivering ESA to the dialysis unit), dialysis unit (dose determination, ordering, receipt, registration, storage, administration, registration) and waste disposal unit. Time and material costs were recorded. Labour costs were derived from actual local wages while material costs came from the facilities' accounting records. Activities associated with ESA administration were listed and each activity evaluated to determine if dosing frequency affected the amount of resources required. RESULTS: A total of 21 centres in 8 European countries supplied data for 142 patients (mean) per hospital (range 42-648). Patients received various ESA regimens (thrice-weekly, twice-weekly, once-weekly, once every 2 weeks and once-monthly). Administering ESA every 2 weeks, the mean costs per patient per year for each process and the estimates of the percentage reduction in costs obtainable, respectively, were: pharmacy labour (10.1 euro, 39%); dialysis unit labour (66.0 euro, 65%); dialysis unit materials (4.11 euro, 61%) and waste unit materials (0.43 euro, 49%). LIMITATION: Impact on financial costs was not measured. CONCLUSION: ESA administration has quantifiable labour and material costs which are affected by dosing frequency.

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells.

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E-cadherin and β-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and β-catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/β-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer.

Long-term effects of cannabis on brain structure.

The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence.

New and emerging treatment of Staphylococcus aureus infections in the hospital setting.

Methicillin-resistant Staphylococcus aureus (MRSA), both hospital-acquired and community-acquired, is a dangerous pathogen that is involved in an increasing number of serious infections with high risk for morbidity and mortality. Community-acquired MRSA strains have epidemic potential and can be particularly virulent. Vancomycin has been the standard hospital treatment for the past 40 years, but vancomycin-resistant isolates of S. aureus have emerged in the USA, and vancomycin-intermediate isolates are increasingly being reported worldwide. New antimicrobial agents with activity against multidrug-resistant S. aureus and other resistant pathogens are urgently needed. Despite great strides, further advances in our understanding of the molecular and biochemical mechanisms responsible for antimicrobial resistance are still required. Several agents have been recently approved for the treatment of serious Gram-positive infections, including linezolid, daptomycin, and tigecycline. The novel investigational cephalosporin, ceftobiprole, is one of the first penicillinase-resistant agents to target penicillin-binding protein 2a (or PBP2a), an acquired PBP with low beta-lactam-affinity that confers intrinsic beta-lactam resistance to S. aureus and other staphylococci. This mechanism of PBP binding, including inhibition of PBP2a, confers broad-spectrum activity against clinically important Gram-negative and Gram-positive pathogens, including MRSA. Phase III clinical trials comparing ceftobiprole with vancomycin alone and in combination with ceftazidime for the treatment of complicated skin and skin structure infections showed ceftobiprole to have efficacy similar to the efficacy of these comparators as evidenced by non-inferior clinical cure and microbiological eradication rates.

Subtelomeric structure of Plasmodium falciparum chromosomes

Previous studies of subtelomeric regions in Plasmodium berghei led to the identification of subtelomeric repeats (2.3kb long) present in a variable number at many chromosomal ends. Both loss and increase in 2.3kb-repeat copy number are involved in chromosome-size polymorphisms. Subtelomeric losses leading to chromosome-size polymorphisms have been described by several authors in P.falciparum where the structure of subtelomeric regions is not known in detail. We therefore undertook their characterisation, by means of chromosome walking and jumping techniques, starting from the telomere-flanking sequence present in pPftel.1, the P.falciparum telomeric clone described by Vernick and McCutchan (1988). The results indicate that at least 20 (out of 28) chromosomal ends in P.falciparum 3D7 chromosomes share a subtelomeric region, about 40kb long, covering (but not limited to) the Rep20 region. Non repetitive, AT-rich portions flanking the Rep20 region on both sides are also conserved at most chromosomal ends.

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.

Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL.

Unlike other tumor necrosis factor family members, the cytotoxic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L contains an unpaired cysteine residue (Cys(230)) in its receptor-binding domain. Here we show that the biological activity of both soluble recombinant TRAIL and cell-associated, full-length TRAIL is critically dependent on the presence of Cys(230). Mutation of Cys(230) to alanine or serine strongly affected its ability to kill target cells. Binding to its receptors was decreased by at least 200-fold, and the stability of its trimeric structure was reduced. In recombinant TRAIL, Cys(230) was found engaged either in interchain disulfide bridge formation, resulting in poorly active TRAIL, or in the chelation of one zinc atom per TRAIL trimer in the active, pro-apoptotic form of TRAIL.

Selección de péptidos sintéticos del Virus de la Hepatitis G (GBV-C/HGV) inhibidores del Péptido de Fusión HIV-I

El GB virus C (GBV-C) o virus de l'hepatitis G (HGV) es un virus format per una única cadena de RNA que pertany a la familia Flaviviridae. En els últims anys, s'han publicat nombrosos treballs en els quals s'associa la coinfecció del GBV-C i del virus de la immunodeficiència humana (VIH) amb una menor progressió de l'esmentada malaltia així com amb una major supervivència dels pacients una vegada que la SIDA s'ha desenvolupat. El mecanisme pel qual el virus GBV-C/HGV exerceix un “efecte protector” en els pacients amb VIH encara no està descrit. L’estudi de la interacció entre els virus GBVC/HGV i VIH podria donar lloc al desenvolupament de nous agents terapèutics per al tractament de la SIDA.Treballs recents mostren com la capacitat inhibitòria del virus del GBV-C/HGV és deguda a la seva glicoproteina estructural E2. S’ha vist que aquesta proteina seria capaç d’inhibir la primera fase de replicació de VIH, així com la unió i la fusió amb les membranes cel•lulars. Sobre la base d’aquests estudis, l’objectiu d’aquest treball ha estat seleccionar inhibidors del pèptid de fusió del VIH utilitzant pèptids sintètics de la proteina E2 del GBV-C/HGV. El treball realitzat ha consistit en estudiar, utilitzant assajos biofísics de leakage i de lipid mixing, la capacitat dels pèptids de la proteina estructural del virus del GBV-C/HGV per inhibir la interacció i el procés de desestabilització de membranes induïdes pel pèptid de fusió de la glicoproteina de l’embolcall, GP41, del VIH. Aquests assajos, com es descriu en treballs anteriors, han resultat útils per a la selecció i la identificació de compostos amb activitat específica anti-GP41. Es pot afirmar que efectivament els pèptids seleccionats de la proteina E2 del virus del GBV-C/HGV inhibeixen l’activitat del pèptid de fusió del VIH probablement com a consequència d’un canvi conformacional en aquest darrer.

When nightclub security agents assault clients.

In 2006, a medico-legal consultation service devoted to adult victims of interpersonal violence was set up at the Lausanne University Hospital Centre, Switzerland: the Violence Medical Unit. Most patients are referred to the consultation by the Emergency Department. They are received by forensic nurses for support, forensic examination (in order to establish medical report) and community orientation. Between 2007 and 2009, among community violence, aggressions by security agents of nightclubs on clients have increased from 6% to 10%. Most of the victims are young men who had drunk alcohol before the assault. 25.7% presented one or several fractures, all of them in the head area. These findings raise questions about the ability of security agents of nightclubs to deal adequately with obviously risky situations and ensure client security.

Modelling the distribution of bats in relation to landscape structure in a temperate mountain environment

1. Landscape modification is often considered the principal cause of population decline in many bat species. Thus, schemes for bat conservation rely heavily on knowledge about species-landscape relationships. So far, however, few studies have quantified the possible influence of landscape structure on large-scale spatial patterns in bat communities. 2. This study presents quantitative models that use landscape structure to predict (i) spatial patterns in overall community composition and (ii) individual species' distributions through canonical correspondence analysis and generalized linear models, respectively. A geographical information system (GIS) was then used to draw up maps of (i) overall community patterns and (ii) distribution of potential species' habitats. These models relied on field data from the Swiss Jura mountains. 3. Fight descriptors of landscape structure accounted for 30% of the variation in bat community composition. For some species, more than 60% of the variance in distribution could be explained by landscape structure. Elevation, forest or woodland cover, lakes and suburbs, were the most frequent predictors. 4. This study shows that community composition in bats is related to landscape structure through species-specific relationships to resources. Due to their nocturnal activities and the difficulties of remote identification, a comprehensive bat census is rarely possible, and we suggest that predictive modelling of the type described here provides an indispensable conservation tool.