Investigating the role of Streptococcus pneumoniae serotype 1 virulence factors in nasopharyngeal carriage and invasive disease

Streptococcus pneumoniae serotype 1 displays some unusual epidemiological, clinical and microbiological characteristics. In Africa, serotype 1 is the leading serotype causing invasive pneumococcal diseases, including, pneumonia, meningitis and sepsis. Unusually, serotype 1 is rarely detected during routine nasopharyngeal swabbing, even in areas of high disease burden. S. pneumoniae are natural commensals of the nasopharynx and colonisation of this area has been described as a pre-requisite for invasive disease, hence little is understood about why serotype 1 carriage rates are so low, whilst burden of disease is so high. This body of work sought to identify key virulence factors associated with serotype 1 disease pathogenesis and the effect these have on nasopharyngeal colonisation and progression from carriage to invasive disease. Murine models of nasopharyngeal carriage, pneumonia and sepsis were used to study serotype 1 pathogenesis and identified the bacterial toxin pneumolysin, and autolysin as key virulence factors associated with disease pathogenesis. In addition, the influence of serotype 1 infection on the host immune responses in murine models of pneumococcal infection was also addressed. Current pneumococcal vaccines (PCV13) include serotype 1 however, the impact of this vaccination in reducing serotype 1 disease burden is still unknown. Findings here suggest that pneumolysin, not bacterial capsule should be a target for strong consideration in future vaccine design. New therapeutics should also be designed to target pneumolysin as it is in the main driver of pathogenesis in the context of pneumococcal disease, particularly in serotype 1 infection

Exposure to diesel exhaust particles increases susceptibility to invasive pneumococcal disease.

BACKGROUND: The World Health Organization estimates that air pollution is responsible for 7 million deaths per annum, with 7% of these attributable to pneumonia. Many of these fatalities have been linked to exposure to high levels of airborne particulates, such as diesel exhaust particles (DEPs). OBJECTIVES: We sought to determine whether exposure to DEPs could promote the progression of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae to invasive pneumococcal disease. METHODS: We used mouse models and in vitro assays to provide a mechanistic understanding of the link between DEP exposure and pneumococcal disease risk, and we confirmed our findings by using induced sputum macrophages isolated from healthy human volunteers. RESULTS: We demonstrate that inhaled exposure to DEPs disrupts asymptomatic nasopharyngeal carriage of S pneumoniae in mice, leading to dissemination to lungs and blood. Pneumococci are transported from the nasopharynx to the lungs following exposure to DEPs, leading to increased proinflammatory cytokine production, reduced phagocytic function of alveolar macrophages, and consequently, increased pneumococcal loads within the lungs and translocation into blood. These findings were confirmed by using DEP-exposed induced sputum macrophages isolated from healthy volunteers, demonstrating that impaired innate immune mechanisms following DEP exposure are also at play in humans. CONCLUSION: Lung inhaled DEPs increase susceptibility to pneumococcal disease by leading to loss of immunological control of pneumococcal colonisation, increased inflammation, tissue damage, and systemic bacterial dissemination

Parametric study of EEG sensitivity to phase noise during face processing

<b>Background: </b> The present paper examines the visual processing speed of complex objects, here faces, by mapping the relationship between object physical properties and single-trial brain responses. Measuring visual processing speed is challenging because uncontrolled physical differences that co-vary with object categories might affect brain measurements, thus biasing our speed estimates. Recently, we demonstrated that early event-related potential (ERP) differences between faces and objects are preserved even when images differ only in phase information, and amplitude spectra are equated across image categories. Here, we use a parametric design to study how early ERP to faces are shaped by phase information. Subjects performed a two-alternative force choice discrimination between two faces (Experiment 1) or textures (two control experiments). All stimuli had the same amplitude spectrum and were presented at 11 phase noise levels, varying from 0% to 100% in 10% increments, using a linear phase interpolation technique. Single-trial ERP data from each subject were analysed using a multiple linear regression model. <b>Results: </b> Our results show that sensitivity to phase noise in faces emerges progressively in a short time window between the P1 and the N170 ERP visual components. The sensitivity to phase noise starts at about 120–130 ms after stimulus onset and continues for another 25–40 ms. This result was robust both within and across subjects. A control experiment using pink noise textures, which had the same second-order statistics as the faces used in Experiment 1, demonstrated that the sensitivity to phase noise observed for faces cannot be explained by the presence of global image structure alone. A second control experiment used wavelet textures that were matched to the face stimuli in terms of second- and higher-order image statistics. Results from this experiment suggest that higher-order statistics of faces are necessary but not sufficient to obtain the sensitivity to phase noise function observed in response to faces. <b>Conclusion: </b> Our results constitute the first quantitative assessment of the time course of phase information processing by the human visual brain. We interpret our results in a framework that focuses on image statistics and single-trial analyses

Effects of a brief mindfulness-based intervention on emotional regulation and levels of mindfulness in senior students

Mindfulness-based interventions have been applied in diverse populations and achieved mental health benefits. This study examined the effects of a brief mindfulness program for emotional regulation and levels of mindfulness on senior students in Brazil. The intervention consisted of six weekly meetings attended by 30 participants. It is a pre-experimental research, with pre- and post-test comparative and correlation measurements. The preliminary results, which relied on parametrical and non-parametrical tests, revealed a reduction in total emotional regulation difficulties (p = 0.0001; r = − 0.55). Also, there was an increase in the levels of mindfulness in the subtests for both dimensions under evaluation: “Awareness” (p = 0.0001; d = 0.77) and “Acceptance” (p = 0.048; d = 0.37). By associating the amount of meditative practices performed by students with the variables, a significant positive correlation was found with the mindfulness dimension “Awareness” (rP = 0.422; p = 0.020), and there was a significant negative correlation with Difficulties in emotion regulation (rS = − 0.478; p = 0.008) and with its respective subscales “Non-acceptance” (rS = − 0.654; p = 0.0001) and “Clarity” (rS = − 0.463; p = 0.010). In conclusion, the application of a brief mindfulness-based intervention is promising in Brazilian university contexts; moreover, it can bring benefits to students, e.g., an increase in emotion regulation as well as in levels of mindfulness. We suggest that further research should use an experimental design and follow-up.info:eu-repo/semantics/publishedVersio

Non-consensual sterilization of women living with HIV

Women living with HIV are stigmatized and discriminated against. They often wish to have children, but they are subjected to the practice of forced (involuntary) sterilization in at least 27 countries under the guise of protecting maternal health and preventing the birth of infected infants. Some women are not asked to give consent, or a third party consents on their behalf. Others are given insufficient information or fed misinformation. The circumstances under which such women have been asked to sign consent forms for sterilization include fear, coercion, intimidation and undue influence. Courts have been clear that such practice is a breach of human rights. But, so far, it has not been formally declared in courts that such practice constitutes discrimination. More needs to be done in terms of education, sanctions against those who carry out this practice and help for victims

Evaluation of an education and activation programme to prevent chronic shoulder complaints: design of an RCT [ISRCTN71777817]

BACKGROUND: About half of all newly presented episodes of shoulder complaints (SC) in general practice are reported to last for at least six months. Early interventions aimed at the psychological and social determinants of SC are not common in general practice, although such interventions might prevent the development of chronic SC. The Education and Activation Programme (EAP) consists of an educational part and a time-contingent activation part. The aim of the EAP is to provide patients with the proper cognitions by means of education, and to stimulate adequate behaviour through advice on activities of daily living. DESIGN: The article describes the design of a randomised clinical trial (RCT) to evaluate the effectiveness and cost-effectiveness of an EAP in addition to usual care, compared to usual care only, in the prevention of chronic SC after six months. It also describes the analysis of the cost and effect balance. Patients suffering from SC for less than three months are recruited in general practice and through open recruitment. A trained general practitioner or a trained therapist administers the EAP. Primary outcome measures are patient-perceived recovery, measured by self-assessment on a seven-point scale, and functional limitations in activities of daily living. Questionnaires are used to study baseline measures, prognostic measures, process measures and outcome measures. DISCUSSION: The inclusion of patients in the study lasted until December 31(st )2003. Data collection is to end in June 2004

Value of syndromic surveillance within the Armed Forces for early warning during a dengue fever outbreak in French Guiana in 2006

<p>Abstract</p> <p>Background</p> <p>A dengue fever outbreak occured in French Guiana in 2006. The objectives were to study the value of a syndromic surveillance system set up within the armed forces, compared to the traditional clinical surveillance system during this outbreak, to highlight issues involved in comparing military and civilian surveillance systems and to discuss the interest of syndromic surveillance for public health response.</p> <p>Methods</p> <p>Military syndromic surveillance allows the surveillance of suspected dengue fever cases among the 3,000 armed forces personnel. Within the same population, clinical surveillance uses several definition criteria for dengue fever cases, depending on the epidemiological situation. Civilian laboratory surveillance allows the surveillance of biologically confirmed cases, within the 200,000 inhabitants.</p> <p>Results</p> <p>It was shown that syndromic surveillance detected the dengue fever outbreak several weeks before clinical surveillance, allowing quick and effective enhancement of vector control within the armed forces. Syndromic surveillance was also found to have detected the outbreak before civilian laboratory surveillance.</p> <p>Conclusion</p> <p>Military syndromic surveillance allowed an early warning for this outbreak to be issued, enabling a quicker public health response by the armed forces. Civilian surveillance system has since introduced syndromic surveillance as part of its surveillance strategy. This should enable quicker public health responses in the future.</p

Congenital Hypogonadotropic Hypogonadism Due to GNRH Receptor Mutations in Three Brothers Reveal Sites Affecting Conformation and Coupling

Congenital hypogonadotropic hypogonadism (CHH) is characterized by low gonadotropins and failure to progress normally through puberty. Mutations in the gene encoding the GnRH receptor (GNRHR1) result in CHH when present as compound heterozygous or homozygous inactivating mutations. This study identifies and characterizes the properties of two novel GNRHR1 mutations in a family in which three brothers display normosmic CHH while their sister was unaffected. Molecular analysis in the proband and the affected brothers revealed two novel non-synonymous missense GNRHR1 mutations, present in a compound heterozygous state, whereas their unaffected parents possessed only one inactivating mutation, demonstrating the autosomal recessive transmission in this kindred and excluding X-linked inheritance equivocally suggested by the initial pedigree analysis. The first mutation at c.845 C>G introduces an Arg substitution for the conserved Pro 282 in transmembrane domain (TMD) 6. The Pro282Arg mutant is unable to bind radiolabeled GnRH analogue. As this conserved residue is important in receptor conformation, it is likely that the mutation perturbs the binding pocket and affects trafficking to the cell surface. The second mutation at c.968 A>G introduces a Cys substitution for Tyr 323 in the functionally crucial N/DPxxY motif in TMD 7. The Tyr323Cys mutant has an increased GnRH binding affinity but reduced receptor expression at the plasma membrane and impaired G protein-coupling. Inositol phosphate accumulation assays demonstrated absent and impaired Gαq/11 signal transduction by Pro282Arg and Tyr323Cys mutants, respectively. Pretreatment with the membrane permeant GnRHR antagonist NBI-42902, which rescues cell surface expression of many GNRHR1 mutants, significantly increased the levels of radioligand binding and intracellular signaling of the Tyr323Cys mutant but not Pro282Arg. Immunocytochemistry confirmed that both mutants are present on the cell membrane albeit at low levels. Together these molecular deficiencies of the two novel GNRHR1 mutations lead to the CHH phenotype when present as a compound heterozygote

Online detection and quantification of epidemics

<p>Abstract</p> <p>Background</p> <p>Time series data are increasingly available in health care, especially for the purpose of disease surveillance. The analysis of such data has long used periodic regression models to detect outbreaks and estimate epidemic burdens. However, implementation of the method may be difficult due to lack of statistical expertise. No dedicated tool is available to perform and guide analyses.</p> <p>Results</p> <p>We developed an online computer application allowing analysis of epidemiologic time series. The system is available online at <url>http://www.u707.jussieu.fr/periodic_regression/</url>. The data is assumed to consist of a periodic baseline level and irregularly occurring epidemics. The program allows estimating the periodic baseline level and associated upper forecast limit. The latter defines a threshold for epidemic detection. The burden of an epidemic is defined as the cumulated signal in excess of the baseline estimate. The user is guided through the necessary choices for analysis. We illustrate the usage of the online epidemic analysis tool with two examples: the retrospective detection and quantification of excess pneumonia and influenza (P&I) mortality, and the prospective surveillance of gastrointestinal disease (diarrhoea).</p> <p>Conclusion</p> <p>The online application allows easy detection of special events in an epidemiologic time series and quantification of excess mortality/morbidity as a change from baseline. It should be a valuable tool for field and public health practitioners.</p