Pneumococcal Colonization and Virulence Factors Identified Via Experimental Evolution in Infection Models

Streptococcus pneumoniae is a commensal of the human nasopharynx and a major cause of respiratory and invasive disease. We examined adaptation and evolution of pneumococcus, within nasopharynx and lungs, in an experimental system where the selective pressures associated with transmission were removed. This was achieved by serial passage of pneumococci, separately, in mouse models of nasopharyngeal carriage or pneumonia. Passaged pneumococci became more effective colonizers of the respiratory tract and we observed several examples of potential parallel evolution. The cell wall-modifying glycosyltransferase LafA was under strong selection during lung passage, whereas the surface expressed pneumococcal vaccine antigen gene pvaA and the glycerol-3-phosphate dehydrogenase gene gpsA were frequent targets of mutation in nasopharynx-passaged pneumococci. These mutations were not identified in pneumococci that were separately evolved by serial passage on laboratory agar. We focused on gpsA, in which the same single nucleotide polymorphism arose in two independently evolved nasopharynx-passaged lineages. We describe a new role for this gene in nasopharyngeal carriage and show that the identified single nucleotide change confers resistance to oxidative stress and enhanced nasopharyngeal colonization potential. We demonstrate that polymorphisms in gpsA arise and are retained during human colonization. These findings highlight how within-host environmental conditions can determine trajectories of bacterial evolution. Relative invasiveness or attack rate of pneumococcal lineages may be defined by genes that make niche-specific contributions to bacterial fitness. Experimental evolution in animal infection models is a powerful tool to investigate the relative roles played by pathogen virulence and colonization factors within different host niches

Prioritising between direct observation of therapy and case-finding interventions for tuberculosis: use of population impact measures

BACKGROUND: Population impact measures (PIMs) have been developed as tools to help policy-makers with locally relevant decisions over health risks and benefits. This involves estimating and prioritising potential benefits of interventions in specific populations. Using tuberculosis (TB) in India as an example, we examined the population impact of two interventions: direct observation of therapy and increasing case-finding. METHODS: PIMs were calculated using published literature and national data for India, and applied to a notional population of 100 000 people. Data included the incidence or prevalence of smear-positive TB and the relative risk reduction from increasing case finding and the use of direct observation of therapy (applied to the baseline risks over the next year), and the incremental proportion of the population eligible for the proposed interventions. RESULTS: In a population of 100 000 people in India, the directly observed component of the Directly Observed Treatment, Short-course (DOTS) programme may prevent 0.188 deaths from TB in the next year compared with 1.79 deaths by increasing TB case finding. The costs of direct observation are (in international dollars) I$5960 and of case finding are I$4839 or I$31702 and I$2703 per life saved respectively. CONCLUSION: Increasing case-finding for TB will save nearly 10 times more lives than will the use of the directly observed component of DOTS in India, at a smaller cost per life saved. The demonstration of the population impact, using simple and explicit numbers, may be of value to policy-makers as they prioritise interventions for their populations

Pica associated with iron deficiency or depletion: clinical and laboratory correlates in 262 non-pregnant adult outpatients

<p>Abstract</p> <p>Background</p> <p>There are many descriptions of the association of pica with iron deficiency in adults, but there are few reports in which observations available at diagnosis of iron deficiency were analyzed using multivariable techniques to identify significant predictors of pica. We sought to identify clinical and laboratory correlates of pica in adults with iron deficiency or depletion using univariable and stepwise forward logistic regression analyses.</p> <p>Methods</p> <p>We reviewed charts of 262 non-pregnant adult outpatients (ages ≥18 y) who required treatment with intravenous iron dextran. We tabulated their sex, age, race/ethnicity, body mass index, symptoms and causes of iron deficiency or depletion, serum iron and complete blood count measures, and other conditions at diagnosis before intravenous iron dextran was administered. We excluded patients with serum creatinine >133 μmol/L or disorders that could affect erythrocyte or iron measures. Iron deficiency was defined as both SF <45 pmol/L and TS <10%. Iron depletion was defined as serum ferritin (SF) <112 pmol/L. We performed univariable comparisons and stepwise forward logistic regression analyses to identify significant correlates of pica.</p> <p>Results</p> <p>There were 230 women (184 white, 46 black; ages 19-91 y) and 32 men (31 white, 1 black; ages 24-81 y). 118 patients (45.0%) reported pica; of these, 87.3% reported ice pica (pagophagia). In univariable analyses, patients with pica had lower mean age, black race/ethnicity, and higher prevalences of cardiopulmonary and epithelial manifestations. The prevalence of iron deficiency, with or without anemia, did not differ significantly between patients with and without pica reports. Mean hemoglobin and mean corpuscular volume (MCV) were lower and mean red blood cell distribution width (RDW) and platelet count were higher in patients with pica. Thrombocytosis occurred only in women and was more prevalent in those with pica (20.4% vs. 8.3%; p = 0.0050). Mean total iron-binding capacity was higher and mean serum ferritin was lower in patients with pica. Nineteen patients developed a second episode of iron deficiency or depletion; concordance of recurrent pica (or absence of pica) was 95%. Predictors of pica in logistic regression analyses were age and MCV (negative associations; p = 0.0250 and 0.0018, respectively) and RDW and platelet count (positive associations; p = 0.0009 and 0.02215, respectively); the odds ratios of these predictors were low.</p> <p>Conclusions</p> <p>In non-pregnant adult patients with iron deficiency or depletion, lower age is a significant predictor of pica. Patients with pica have lower MCV, higher RDW, and higher platelet counts than patients without pica.</p

Medical student teaching in the UK: how well are newly qualified doctors prepared for their role caring for patients with cancer in hospital?

A number of studies have identified problems with undergraduate oncology teaching. We have investigated how well prepared newly qualified doctors (first foundation year, or FY1 doctors) are for treating patients with cancer. Twenty-five FY1 doctors and 15 senior doctors participated in interviews. We turned the emergent themes into a questionnaire for all 5143 UK FY1 doctors in 2005. The response rate was 43% (2062 responses). Sixty-one percent of FY1 doctors had received oncology teaching at medical school, but 31% recalled seeing fewer than 10 patients with cancer. Forty percent of FY1 doctors felt prepared for looking after patients with cancer. Sixty-five percent felt prepared for diagnosing cancer, 15% felt they knew enough about chemotherapy and radiotherapy, and 11% felt prepared for dealing with oncological emergencies. Respondents believed medical students should learn about symptom control (71%) and communication skills (41%). Respondents who had received oncology teaching were more likely to feel prepared for looking after patients with cancer (OR 1.52; 95% CI 1.14–2.04). Preparedness also correlated with exposure to patients with cancer (OR 1.48; 95% CI 1.22–1.79). We have found worryingly low levels of exposure of medical students to patients with cancer. First foundation year doctors lack knowledge about cancer care and symptom control. Oncologists should maintain involvement in undergraduate teaching, and encourage greater involvement of patients in this teaching

Preoperative computed tomography staging of nonmetastatic colon cancer predicts outcome: implications for clinical trials

Colon cancer patients routinely undergo preoperative computed tomography (CT) scanning, but local staging is thought to be inaccurate. We aimed to determine if clinical outcome could be predicted from radiological features of the primary tumour. Consecutive patients at one hospital undergoing primary resection for colon cancer during 2000–2004 were included. Patients with visible metastases were excluded. Preoperative CT scans were reviewed independently by two radiologists blinded to histological stage and outcome. Images of the primary tumour were evaluated according to conventional TNM criteria and patients were stratified into ‘good' or ‘poor' prognosis groups. Comparison was made between prognostic group and actual clinical outcome. Hundred and twenty-six preoperative CT scans were reviewed. T-stage and nodal status was correctly predicted in only 60 and 62%, respectively. However, inter-observer agreement for prognostic group was 79% (κ=0.59) and 3-year relapse-free survival was 71 and 43% for the CT-predicted ‘good' and ‘poor' groups, respectively (P<0.0066). This compared favourably with 75 vs 43% for histology-predicted prognostic groups. Computed tomography is a robust method for stratifying patients preoperatively, with similar accuracy to histopathology for predicting outcome. Recognition of poor prognosis tumours preoperatively may permit investigation into the future use of neo-adjuvant therapy in colon cancer

Secondary contact and admixture between independently invading populations of the Western corn rootworm, diabrotica virgifera virgifera in Europe

The western corn rootworm, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae), is one of the most destructive pests of corn in North America and is currently invading Europe. The two major invasive outbreaks of rootworm in Europe have occurred, in North-West Italy and in Central and South-Eastern Europe. These two outbreaks originated from independent introductions from North America. Secondary contact probably occurred in North Italy between these two outbreaks, in 2008. We used 13 microsatellite markers to conduct a population genetics study, to demonstrate that this geographic contact resulted in a zone of admixture in the Italian region of Veneto. We show that i) genetic variation is greater in the contact zone than in the parental outbreaks; ii) several signs of admixture were detected in some Venetian samples, in a Bayesian analysis of the population structure and in an approximate Bayesian computation analysis of historical scenarios and, finally, iii) allelic frequency clines were observed at microsatellite loci. The contact between the invasive outbreaks in North-West Italy and Central and South-Eastern Europe resulted in a zone of admixture, with particular characteristics. The evolutionary implications of the existence of a zone of admixture in Northern Italy and their possible impact on the invasion success of the western corn rootworm are discussed

Multivariate Approximations to Portfolio Return Distribution

This article proposes a three-step procedure to estimate portfolio return distributions under the multivariate Gram-Charlier (MGC) distribution. The method combines quasi maximum likelihood (QML) estimation for conditional means and variances and the method of moments (MM) estimation for the rest of the density parameters, including the correlation coefficients. The procedure involves consistent estimates even under density misspecification and solves the so-called ‘curse of dimensionality’ of multivariate modelling. Furthermore, the use of a MGC distribution represents a flexible and general approximation to the true distribution of portfolio returns and accounts for all its empirical regularities. An application of such procedure is performed for a portfolio composed of three European indices as an illustration. The MM estimation of the MGC (MGC-MM) is compared with the traditional maximum likelihood of both the MGC and multivariate Student’s t (benchmark) densities. A simulation on Value-at-Risk (VaR) performance for an equally weighted portfolio at 1% and 5% confidence indicates that the MGC-MM method provides reasonable approximations to the true empirical VaR. Therefore, the procedure seems to be a useful tool for risk managers and practitioners

Profiling adult literacy facilitators in development contexts: An ethnographic study in Ethiopia

Teachers/facilitators in adult literacy learning programmes are recognised as being vital to successful learning outcomes. But little is known about them as a group. This small-scale research project comprising ethnographic-style case studies of five adult literacy facilitators (ALFs) in Ethiopia seeks to throw some light on these teachers, their backgrounds and what they bring to their teaching, with a view to improving the effectiveness of their work. The researchers found that all of the ALFs had high levels of commitment, but none of the ALFs received much in the way of training, and professional support for their role was in some cases missing. The degree (and their perception) of their own literacy practices varied greatly among them, even in their common use of mobile phones. It also emerged that while they had all fought very hard for their own education, one of the main reasons all of them stated for going into literacy teaching was not a general belief in the value of education but their priority need of a regular income. Another insight is that the female ALFs struggled more than their male counterparts in engaging learners; the women were criticised more excessively than the men. This research reveals something of the diversity of facilitators, and concludes that further such studies are needed in different contexts

Chemical and physical defense traits in two sexual forms of opuntia robusta in Central Eastern Mexico

Sexually dimorphic plants provide an excellent opportunity for examining the differences in the extent of their defense against herbivores because they exhibit sex-related differences in reproductive investment. Such differences enable comparison of the sex with high reproduction expenses with the sex that expends less. The more costly sex is usually also better defended against herbivores. Generally, females are considered more valuable than hermaphrodites in terms of fitness; however, hermaphrodites are more valuable if they can produce seed by autonomous selfing, provided that the inbreeding depression is low and pollen is limited. We studied a gynodioecious population of Opuntia robusta from Central-Eastern Mexico, which has been reported to be trioecious, dioecious, or hermaphrodite, and addressed the following questions: 1) Is the hermaphrodite's reproductive output higher than the female's, and are hermaphrodites thus better defended? 2) Are plant tissues differentially defended? 3) Do trade-offs exist among different physical defense traits? and 4) among physical and chemical defense traits? We found that 1) hermaphrodites had a higher seed output and more spines per areola than females and that their spines contained less moisture. Non-reproductive hermaphrodite cladodes contained more total phenolic compounds (TPCs) than female ones. In addition, 2) hermaphrodite reproductive cladodes bore more spines than female cladodes, and 3) and 4) we found a negative relationship between spine number per areola and areola number per cladode and a positive relationship between spine number per areola per plant and TPC concentration per plant. Non-reproductive hermaphrodite cladodes contained a higher concentration of TPCs than female cladodes, and parental cladodes contained fewer TPCs than both reproductive and empty cladodes

Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pig

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by altering the structure and function of pulmonary vessels at early disease stages. The objectives of this study were to evaluate the effects of long-term exposure to cigarette smoke on endothelial function and smooth muscle-cell proliferation in pulmonary arteries of guinea pigs.</p> <p>Methods</p> <p>19 male Hartley guinea pigs were exposed to the smoke of 7 cigarettes/day, 5 days/week, for 3 and 6 months. 17 control guinea pigs were sham-exposed for the same periods. Endothelial function was evaluated in rings of pulmonary artery and aorta as the relaxation induced by ADP. The proliferation of smooth muscle cells and their phenotype in small pulmonary vessels were evaluated by immunohistochemical expression of α-actin and desmin. Vessel wall thickness, arteriolar muscularization and emphysema were assessed morphometrically. The expression of endothelial nitric oxide synthase (eNOS) was evaluated by Real Time-PCR.</p> <p>Results</p> <p>Exposure to cigarette smoke reduced endothelium-dependent vasodilatation in pulmonary arteries (ANOVA p < 0.05) but not in the aorta. Endothelial dysfunction was apparent at 3 months of exposure and did not increase further after 6 months of exposure. Smoke-exposed animals showed proliferation of poorly differentiated smooth muscle cells in small vessels (p < 0.05) after 3 months of exposure. Prolonged exposure resulted in full muscularization of small pulmonary vessels (p < 0.05), wall thickening (p < 0.01) and increased contractility of the main pulmonary artery (p < 0.05), and enlargement of the alveolar spaces. Lung expression of eNOS was decreased in animals exposed to cigarette smoke.</p> <p>Conclusion</p> <p>In the guinea pig, exposure to cigarette smoke induces selective endothelial dysfunction in pulmonary arteries, smooth muscle cell proliferation in small pulmonary vessels and reduced lung expression of eNOS. These changes appear after 3 months of exposure and precede the development of pulmonary emphysema.</p