Integration of molecular characterization of microorganisms in a global antimicrobial resistance surveillance program

© 2001 by the Infectious Diseases Society of America. All rights reserved.The SENTRY Antimicrobial Surveillance Program has incorporated molecular strain typing and resistance genotyping as a means of providing additional information that may be useful for understanding pathogenic microorganisms worldwide. Resistance phenotypes of interest include multidrug-resistant pathogens, extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and fluoroquinolone-resistant (FQR) strains of gram-negative bacilli and Streptococcus pneumoniae. Clusters of 2 isolates within a given resistance profile that are linked temporally and by hospital location are flagged for DNA fingerprinting. Further characterization of organisms with respect to resistance genotype is accomplished with use of polymerase chain reaction and DNA sequencing. This process has been highly successful in identifying clonal spread within clusters of multiresistant pathogens. Between 50% and 90% of MRSA clusters identified by phenotypic screening contained evidence of clonal spread. Among the Enterobacteriaceae, ESBL-producing strains of Escherichia coli and Klebsiella pneumoniae are the most common pathogens causing clusters of infection, and 50% of recognized clusters demonstrate clonal spread. Clusters of Pseudomonas aeruginosa, Acinetobacter species, and Stenotrophomonas maltophilia have been noted with clonal spread among patients with urinary tract, respiratory, and bloodstream infections. Characterization of mutations in the FQR-determining region of phenotypically susceptible isolates of E. coli and S. pneumoniae has identified first-stage mutants among as many as 40% of isolates. The ability to characterize organisms phenotypically and genotypically is extremely powerful and provides unique information that is important in a global antimicrobial surveillance program.M. A. Pfaller, J. Acar, R. N. Jones, J. Verhoef, J. Turnidge, and H. S. Sade

Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration.

Gas1 and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. Here we demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through distinct modes of Hedgehog ligand reception. Moreover, Ptch2-mediated Hedgehog signalling induces the phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a previously unknown Ptch2-specific signal pathway. We propose that although Ptch1 and Ptch2 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch2 and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche

Does maternal exposure to an environmental stressor affect offspring response to predators?

There is growing recognition of the ways in which maternal effects can influence offspring size, physiological performance, and survival. Additionally, environmental contaminants increasingly act as stressors in maternal environments, possibly leading to maternal effects on subsequent offspring. Thus, it is important to determine whether contaminants and other stressors can contribute to maternal effects, particularly under varied ecological conditions that encompass the range under which offspring develop. We used aquatic mesocosms to determine whether maternal effects of mercury (Hg) exposure shape offspring phenotype in the American toad (Bufo americanus) in the presence or absence of larval predators (dragonfly naiads). We found significant maternal effects of Hg exposure and significant effects of predators on several offspring traits, but there was little evidence that maternal effects altered offspring interactions with predators. Offspring from Hg-exposed mothers were 18% smaller than those of reference mothers. Offspring reared with predators were 23% smaller at metamorphosis than those reared without predators. There was also evidence of reduced larval survival when larvae were reared with predators, but this was independent of maternal effects. Additionally, 5 times more larvae had spinal malformations when reared without predators, suggesting selective predation of malformed larvae by predators. Lastly, we found a significant negative correlation between offspring survival and algal density in mesocosms, indicating a role for top-down effects of predators on periphyton communities. Our results demonstrate that maternal exposure to an environmental stressor can induce phenotypic responses in offspring in a direction similar to that produced by direct exposure of offspring to predators

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group

\ua9 2024. Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors

A cost-utility analysis of cervical cancer vaccination in preadolescent Canadian females

<p>Abstract</p> <p>Background</p> <p>Despite the fact that approximately 70% of Canadian women undergo cervical cancer screening at least once every 3 years, approximately 1,300 women were diagnosed with cervical cancer and approximately 380 died from it in 2008. This study estimates the effectiveness and cost-effectiveness of vaccinating 12-year old Canadian females with an AS04-adjuvanted cervical cancer vaccine. The indirect effect of vaccination, via herd immunity, is also estimated.</p> <p>Methods</p> <p>A 12-health-state 1-year-cycle Markov model was developed to estimate lifetime HPV related events for a cohort of 12-year old females. Annual transition probabilities between health-states were derived from published literature and Canadian population statistics. The model was calibrated using Canadian cancer statistics. From a healthcare perspective, the cost-effectiveness of introducing a vaccine with efficacy against HPV-16/18 and evidence of cross-protection against other oncogenic HPV types was evaluated in a population undergoing current screening practices. The base-case analysis included 70% screening coverage, 75% vaccination coverage, $135/dose for vaccine, and 3$18,672-$31,687 per QALY-gained, the lower range representing inclusion of cross-protective efficacy and herd immunity. The cost per QALY-gained was most sensitive to duration of vaccine protection, discount rate, and the correlation between probability of screening and probability of vaccination.</p> <p>Conclusion</p> <p>In the context of current screening patterns, vaccination of 12-year old Canadian females with an ASO4-ajuvanted cervical cancer vaccine is estimated to significantly reduce cervical cancer and mortality, and is a cost-effective option. However, the economic attractiveness of vaccination is impacted by the vaccine's duration of protection and the discount rate used in the analysis.</p

Untangling knowledge creation and knowledge integration in enterprise wikis

A central challenge organizations face is how to build, store, and maintain knowledge over time. Enterprise wikis are community-based knowledge systems situated in an organizational context. These systems have the potential to play an important role in managing knowledge within organizations, but the motivating factors that drive individuals to contribute their knowledge to these systems is not very well understood. We theorize that enterprise wiki initiatives require two separate and distinct types of knowledge-sharing behaviors to succeed: knowledge creation (KC) and knowledge integration (KI). We examine a Wiki initiative at a major German bank to untangle the motivating factors behind KC and KI. Our results suggest KC and KI are indeed two distinct behaviors, reconcile inconsistent findings from past studies on the role of motivational factors for knowledge sharing to establish shared electronic knowledge resources in organizations, and identify factors that can be leveraged to tilt behaviors in favor of KC or KI

Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia–ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns

Enterocyte Shedding and Epithelial Lining Repair Following Ischemia of the Human Small Intestine Attenuate Inflammation

BACKGROUND: Recently, we observed that small-intestinal ischemia and reperfusion was found to entail a rapid loss of apoptotic and necrotic cells. This study was conducted to investigate whether the observed shedding of ischemically damaged epithelial cells affects IR induced inflammation in the human small gut. METHODS AND FINDINGS: Using a newly developed IR model of the human small intestine, the inflammatory response was studied on cellular, protein and mRNA level. Thirty patients were consecutively included. Part of the jejunum was subjected to 30 minutes of ischemia and variable reperfusion periods (mean reperfusion time 120 (+/-11) minutes). Ethical approval and informed consent were obtained. Increased plasma intestinal fatty acid binding protein (I-FABP) levels indicated loss in epithelial cell integrity in response to ischemia and reperfusion (p<0.001 vs healthy). HIF-1alpha gene expression doubled (p = 0.02) and C3 gene expression increased 4-fold (p = 0.01) over the course of IR. Gut barrier failure, assessed as LPS concentration in small bowel venous effluent blood, was not observed (p = 0.18). Additionally, mRNA expression of HO-1, IL-6, IL-8 did not alter. No increased expression of endothelial adhesion molecules, TNFalpha release, increased numbers of inflammatory cells (p = 0.71) or complement activation, assessed as activated C3 (p = 0.14), were detected in the reperfused tissue. CONCLUSIONS: In the human small intestine, thirty minutes of ischemia followed by up to 4 hours of reperfusion, does not seem to lead to an explicit inflammatory response. This may be explained by a unique mechanism of shedding of damaged enterocytes, reported for the first time by our group

The role of the bronchial microvasculature in the airway remodelling in asthma and COPD

In recent years, there has been increased interest in the vascular component of airway remodelling in chronic bronchial inflammation, such as asthma and COPD, and in its role in the progression of disease. In particular, the bronchial mucosa in asthmatics is more vascularised, showing a higher number and dimension of vessels and vascular area. Recently, insight has been obtained regarding the pivotal role of vascular endothelial growth factor (VEGF) in promoting vascular remodelling and angiogenesis. Many studies, conducted on biopsies, induced sputum or BAL, have shown the involvement of VEGF and its receptors in the vascular remodelling processes. Presumably, the vascular component of airway remodelling is a complex multi-step phenomenon involving several mediators. Among the common asthma and COPD medications, only inhaled corticosteroids have demonstrated a real ability to reverse all aspects of vascular remodelling. The aim of this review was to analyze the morphological aspects of the vascular component of airway remodelling and the possible mechanisms involved in asthma and COPD. We also focused on the functional and therapeutic implications of the bronchial microvascular changes in asthma and COPD