Truncated recombinant human SP-D attenuates emphysema and type II cell changes in SP-D deficient mice

BACKGROUND: Surfactant protein D (SP-D) deficient mice develop emphysema-like pathology associated with focal accumulations of foamy alveolar macrophages, an excess of surfactant phospholipids in the alveolar space and both hypertrophy and hyperplasia of alveolar type II cells. These findings are associated with a chronic inflammatory state. Treatment of SP-D deficient mice with a truncated recombinant fragment of human SP-D (rfhSP-D) has been shown to decrease the lipidosis and alveolar macrophage accumulation as well as production of proinflammatory chemokines. The aim of this study was to investigate if rfhSP-D treatment reduces the structural abnormalities in parenchymal architecture and type II cells characteristic of SP-D deficiency. METHODS: SP-D knock-out mice, aged 3 weeks, 6 weeks and 9 weeks were treated with rfhSP-D for 9, 6 and 3 weeks, respectively. All mice were sacrificed at age 12 weeks and compared to both PBS treated SP-D deficient and wild-type groups. Lung structure was quantified by design-based stereology at the light and electron microscopic level. Emphasis was put on quantification of emphysema, type II cell changes and intracellular surfactant. Data were analysed with two sided non-parametric Mann-Whitney U-test. MAIN RESULTS: After 3 weeks of treatment, alveolar number was higher and mean alveolar size was smaller compared to saline-treated SP-D knock-out controls. There was no significant difference concerning these indices of pulmonary emphysema within rfhSP-D treated groups. Type II cell number and size were smaller as a consequence of treatment. The total volume of lamellar bodies per type II cell and per lung was smaller after 6 weeks of treatment. CONCLUSION: Treatment of SP-D deficient mice with rfhSP-D leads to a reduction in the degree of emphysema and a correction of type II cell hyperplasia and hypertrophy. This supports the concept that rfhSP-D might become a therapeutic option in diseases that are characterized by decreased SP-D levels in the lung.

Alterations of alveolar type II cells and intraalveolar surfactant after bronchoalveolar lavage and perfluorocarbon ventilation. An electron microscopical and stereological study in the rat lung

BACKGROUND: Repeated bronchoalveolar lavage (BAL) has been used in animals to induce surfactant depletion and to study therapeutical interventions of subsequent respiratory insufficiency. Intratracheal administration of surface active agents such as perfluorocarbons (PFC) can prevent the alveolar collapse in surfactant depleted lungs. However, it is not known how BAL or subsequent PFC administration affect the intracellular and intraalveolar surfactant pool. METHODS: Male wistar rats were surfactant depleted by BAL and treated for 1 hour by conventional mechanical ventilation (Lavaged-Gas, n = 5) or partial liquid ventilation with PF 5080 (Lavaged-PF5080, n = 5). For control, 10 healthy animals with gas (Healthy-Gas, n = 5) or PF5080 filled lungs (Healthy-PF5080, n = 5) were studied. A design-based stereological approach was used for quantification of lung parenchyma and the intracellular and intraalveolar surfactant pool at the light and electron microscopic level. RESULTS: Compared to Healthy-lungs, Lavaged-animals had more type II cells with lamellar bodies in the process of secretion and freshly secreted lamellar body-like surfactant forms in the alveoli. The fraction of alveolar epithelial surface area covered with surfactant and total intraalveolar surfactant content were significantly smaller in Lavaged-animals. Compared with Gas-filled lungs, both PF5080-groups had a significantly higher total lung volume, but no other differences. CONCLUSION: After BAL-induced alveolar surfactant depletion the amount of intracellularly stored surfactant is about half as high as in healthy animals. In lavaged animals short time liquid ventilation with PF5080 did not alter intra- or extracellular surfactant content or subtype composition.

Do patients respect the line? Transgression of boundaries reported by Swiss general practitioners

OBJECTIVE: Transgression of boundaries in the relationship between physician and patient is commonly studied with patient as victim and physician as transgressor. A recent survey in the U.S. reported that almost 90% of physicians face transgression by patients over one year. Incidents happened mainly through verbal abuse, disregarding privacy, and overly affectionate behavior. Since this incidence seems to be alarmingly high, we were interested to analyze how often general practitioners in Switzerland experience transgression by patients. METHODS: 24% of the members of the Swiss Society of Internal Medicine (SGIM) and of the Swiss Society of General Medicine (SGAM) (n=675/2781) responded to an internet-based survey which asked for experiences of transgression by patients and for physicians' responses to transgression in the last 12 months. RESULTS: 81% of responding physicians experienced transgression over the period of one year. Analyzing the frequency of incidents per physician per year, the most common forms of transgression were 'use of physician's first name' (7.7/y), 'asking personal questions' (1.8/y), 'being verbally abusive' (1.5/y), and 'being overly affectionate' (1.4/y). Calculated incidence of transgression was 3 per 1000 patient contacts. 39% of physicians decided to ignore the incident, 37% discussed the event openly. Transgression led to dismissal of patients in 13% of events. CONCLUSION: Transgression even in mild and modest form is a rare phenomenon in Swiss practices. PRACTICE IMPLICATION: The Swiss data do not suggest that there is a specific risk for Swiss practitioners to be exposed to major transgression for which they should specifically be prepared for example in communication skills trainings.

Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

Low prevalence of atrial fibrillation in asymptomatic adults in Geneva, Switzerland

Aims To determine the prevalence of atrial fibrillation (AF) in a population-based sample of adults. Methods and results Between January 2005 and December 2007 individuals aged >/=50 years, residents of the city of Geneva, who had participated in a previous random survey were invited for follow-up examination. AF was assessed on a single resting 6-lead ECG. Reported prevalences were standardized for the age distribution of Canton Geneva. Overall participation was 72.8%. Twenty-nine cases of AF (22 men) were diagnosed among 3285 subjects (1696 men). The crude prevalence of AF (95% CI) was 0.88% (0.86, 0.90) overall, but higher in men [1.30% (1.26, 1.34)] than in women [0.44% (0.41, 0.47)]. The age-standardized AF prevalence was slightly higher [overall: 0.94% (0.91, 0.97), men: 1.23% (1.19, 1.27), women: 0.54% (0.47, 0.61)]. AF prevalence increased with age in both sexes. A 'history of suspected arterial embolism' (brain or legs) was higher in the AF cases (10.3 vs. 3.3%; P = 0.03). Conclusion This population-based survey of a general Swiss population indicates that the prevalence of AF remains below 1%. These results are less alarming than those from previous studies based on patients seeking medical care.

Intensive care medicine in Mongolia's 3 largest cities: outlining the needs

PURPOSE: To evaluate intensive care resources, support, and personnel available in Mongolia's 3 largest cities. MATERIALS AND METHODS: This prospective study was performed as a questionnaire-based survey evaluating intensive care units (ICUs) in Mongolia's 3 main cities. RESULTS: Twenty-one of 31 ICUs participated in the survey. The median number of beds per ICU was 7 (interquartile ranges, 6-10) with 0.7 (0.6-0.9) physicians and 1.5 (0.6-1.8) nurses per bed. A 24-hour physician service was available in 61.9% of the participating ICUs. A median number of 359 patients (250-500) with an average age of 39 (30-49) years were treated annually. Oxygen was available in all ICUs, but only for 60% (17-75) of beds. Pressurized air was available in 33% of the ICUs for 24% (0-15) of beds. Of the ICUs, 52.4% had a lung ventilator serving 20% (0-23) of beds. The most common admission diagnoses were sepsis, stroke, cardiac disease, postoperative or postpartum hemorrhage, and intoxication. Availability of medical equipment, disposables, and drugs was inadequate in all ICUs. CONCLUSIONS: Intensive care medicine in Mongolia's 3 largest cities is an under-resourced and underdeveloped medical specialty. The main problems encountered are insufficient training of staff as well as lack of medical equipment, disposables, and drugs.

Particles induce apical plasma membrane enlargement in epithelial lung cell line depending on particle surface area dose

Background Airborne particles entering the respiratory tract may interact with the apical plasma membrane (APM) of epithelial cells and enter them. Differences in the entering mechanisms of fine (between 0.1 μm and 2.5 μm) and ultrafine ( ≤ 0.1 μm) particles may be associated with different effects on the APM. Therefore, we studied particle-induced changes in APM surface area in relation to applied and intracellular particle size, surface and number. Methods Human pulmonary epithelial cells (A549 cell line) were incubated with various concentrations of different sized fluorescent polystyrene spheres without surface charge (∅ fine – 1.062 μm, ultrafine – 0.041 μm) by submersed exposure for 24 h. APM surface area of A549 cells was estimated by design-based stereology and transmission electron microscopy. Intracellular particles were visualized and quantified by confocal laser scanning microscopy. Results Particle exposure induced an increase in APM surface area compared to negative control (p < 0.01) at the same surface area concentration of fine and ultrafine particles a finding not observed at low particle concentrations. Ultrafine particle entering was less pronounced than fine particle entering into epithelial cells, however, at the same particle surface area dose, the number of intracellular ultrafine particles was higher than that of fine particles. The number of intracellular particles showed a stronger increase for fine than for ultrafine particles at rising particle concentrations. Conclusion This study demonstrates a particle-induced enlargement of the APM surface area of a pulmonary epithelial cell line, depending on particle surface area dose. Particle uptake by epithelial cells does not seem to be responsible for this effect. We propose that direct interactions between particle surface area and cell membrane cause the enlargement of the APM.

Action Research and Learning Analytics in Higher Education

Teaching is a dynamic activity. It can be very effective, if its impact is constantly monitored and adjusted to the demands of changing social contexts and needs of learners. This implies that teachers need to be aware about teaching and learning processes. Moreover, they should constantly question their didactical methods and the learning resources, which they provide to their students. They should reflect if their actions are suitable, and they should regulate their teaching, e.g., by updating learning materials based on new knowledge about learners, or by motivating learners to engage in further learning activities. In the last years, a rising interest in ‘learning analytics’ is observable. This interest is motivated by the availability of massive amounts of educational data. Also, the continuously increasing processing power, and a strong motivation for discovering new information from these pools of educational data, is pushing further developments within the learning analytics research field. Learning analytics could be a method for reflective teaching practice that enables and guides teachers to investigate and evaluate their work in future learning scenarios. However, this potentially positive impact has not yet been sufficiently verified by learning analytics research. Another method that pursues these goals is ‘action research’. Learning analytics promises to initiate action research processes because it facilitates awareness, reflection and regulation of teaching activities analogous to action research. Therefore, this thesis joins both concepts, in order to improve the design of learning analytics tools. Central research question of this thesis are: What are the dimensions of learning analytics in relation to action research, which need to be considered when designing a learning analytics tool? How does a learning analytics dashboard impact the teachers of technology-enhanced university lectures regarding ‘awareness’, ‘reflection’ and ‘action’? Does it initiate action research? Which are central requirements for a learning analytics tool, which pursues such effects? This project followed design-based research principles, in order to answer these research questions. The main contributions are: a theoretical reference model that connects action research and learning analytics, the conceptualization and implementation of a learning analytics tool, a requirements catalogue for useful and usable learning analytics design based on evaluations, a tested procedure for impact analysis, and guidelines for the introduction of learning analytics into higher education.

Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite

Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.

Targeted gene transfer of hepatocyte growth factor to alveolar type II epithelial cells reduces lung fibrosis in rats

Inefficient alveolar wound repair contributes to the development of pulmonary fibrosis. Hepatocyte growth factor (HGF) is a potent growth factor for alveolar type II epithelial cells (AECII) and may improve repair and reduce fibrosis. We studied whether targeted gene transfer of HGF specifically to AECII improves lung fibrosis in bleomycin-induced lung fibrosis. A plasmid encoding human HGF expressed from the human surfactant protein C promoter (pSpC-hHGF) was designed, and extracorporeal electroporation-mediated gene transfer of HGF specifically to AECII was performed 7 days after bleomycin-induced lung injury in the rat. Animals were killed 7 days after hHGF gene transfer. Electroporation-mediated HGF gene transfer resulted in HGF expression specifically in AECII at biologically relevant levels. HGF gene transfer reduced pulmonary fibrosis as assessed by histology, hydroxyproline determination, and design-based stereology compared with controls. Our results indicate that the antifibrotic effect of HGF is due in part to a reduction of transforming growth factor-β(1), modulation of the epithelial-mesenchymal transition, and reduction of extravascular fibrin deposition. We conclude that targeted HGF gene transfer specifically to AECII decreases bleomycin-induced lung fibrosis and may therefore represent a novel cell-specific gene transfer technology to treat pulmonary fibrosis.

Effects of exogenous surfactant on the non-heart-beating donor lung graft in experimental lung transplantation - a stereological study.

The use of non-heart-beating donor (NHBD) lungs may help to overcome the shortage of lung grafts in clinical lung transplantation, but warm ischaemia and ischaemia/reperfusion injury (I/R injury) resulting in primary graft dysfunction represent a considerable threat. Thus, better strategies for optimized preservation of lung grafts are urgently needed. Surfactant dysfunction has been shown to contribute to I/R injury, and surfactant replacement therapy is effective in enhancing lung function and structural integrity in related rat models. In the present study we hypothesize that surfactant replacement therapy reduces oedema formation in a pig model of NHBD lung transplantation. Oedema formation was quantified with (SF) and without (non-SF) surfactant replacement therapy in interstitial and alveolar compartments by means of design-based stereology in NHBD lungs 7 h after cardiac arrest, reperfusion and transplantation. A sham-operated group served as control. In both NHBD groups, nearly all animals died within the first hours after transplantation due to right heart failure. Both SF and non-SF developed an interstitial oedema of similar degree, as shown by an increase in septal wall volume and arithmetic mean thickness as well as an increase in the volume of peribron-chovascular connective tissue. Regarding intra-alveolar oedema, no statistically significant difference could be found between SF and non-SF. In conclusion, surfactant replacement therapy cannot prevent poor outcome after prolonged warm ischaemia of 7 h in this model. While the beneficial effects of surfactant replacement therapy have been observed in several experimental and clinical studies related to heart-beating donor lungs and cold ischaemia, it is unlikely that surfactant replacement therapy will overcome the shortage of organs in the context of prolonged warm ischaemia, for example, 7 h. Moreover, our data demonstrate that right heart function and dysfunctions of the pulmonary vascular bed are limiting factors that need to be addressed in NHBD.

BAYESIAN PHASE I DOSE FINDING IN CANCER TRIALS

This dissertation explores phase I dose-finding designs in cancer trials from three perspectives: the alternative Bayesian dose-escalation rules, a design based on a time-to-dose-limiting toxicity (DLT) model, and a design based on a discrete-time multi-state (DTMS) model. We list alternative Bayesian dose-escalation rules and perform a simulation study for the intra-rule and inter-rule comparisons based on two statistical models to identify the most appropriate rule under certain scenarios. We provide evidence that all the Bayesian rules outperform the traditional ``3+3'' design in the allocation of patients and selection of the maximum tolerated dose. The design based on a time-to-DLT model uses patients' DLT information over multiple treatment cycles in estimating the probability of DLT at the end of treatment cycle 1. Dose-escalation decisions are made whenever a cycle-1 DLT occurs, or two months after the previous check point. Compared to the design based on a logistic regression model, the new design shows more safety benefits for trials in which more late-onset toxicities are expected. As a trade-off, the new design requires more patients on average. The design based on a discrete-time multi-state (DTMS) model has three important attributes: (1) Toxicities are categorized over a distribution of severity levels, (2) Early toxicity may inform dose escalation, and (3) No suspension is required between accrual cohorts. The proposed model accounts for the difference in the importance of the toxicity severity levels and for transitions between toxicity levels. We compare the operating characteristics of the proposed design with those from a similar design based on a fully-evaluated model that directly models the maximum observed toxicity level within the patients' entire assessment window. We describe settings in which, under comparable power, the proposed design shortens the trial. The proposed design offers more benefit compared to the alternative design as patient accrual becomes slower.

Sexual Health Education from the Perspective of School Staff: Implications for Adoption and Implementation of Effective Programs in Middle School

Introduction: US teens are having sex early; however, the vast majority of schools do not implement evidence-based sexual health education (SHE) programs that could delay sexual behavior and/or reduce risky behavior. This study examines middle school staff’s knowledge, attitudes, barriers, self-efficacy, and perceived support (psychosocial factors known to influence SHE program adoption and implementation). Methods: Professional school staff from 33 southeast Texas middle schools completed an internet or paper-based survey. Prevalence estimates for psychosocial variables were computed for the total sample. Chi-square and t-test analyses examined variation by demographic factors. Results: Almost 70% of participants were female, 37% white, 42% black, 16% Hispanic; 20% administrators, 15% nurses/counselors, 31% non-physical education/non-health teachers, 28% physical education/health teachers; mean age = 42.78 years (SD = 10.9). Over 90% favored middle school SHE, and over 75% reported awareness of available SHE curricula or policies. More than 60% expressed confidence for discussing SHE. Staff perceived varying levels of administrator (28%-56%) support for SHE and varying levels of support for comprehensive sex education from outside stakeholders (e.g., parents, community leaders) (42%-85%). Overall, results were more favorable for physical education/health teachers, nurses/counselors, and administrators (when compared to non-physical education/non-health teachers) and individuals with experience teaching SHE. Few significant differences were observed by other demographic factors. Conclusions: Overall, study results were extremely positive, which may reflect a high level of readiness among school staff for adopting and implementing effective middle school SHE programs. Study results highlight the importance of several key action items for schools.

Volunteering in sport clubs

Volunteers are the most important resource for non-profit sport clubs seeking to bolster their viability (e.g. sporting programs). Although many people do voluntary work in sport clubs, stable voluntary engagement can no longer be granted. This difficulty is confirmed by existing research across various European countries. From a club management point of view, a detailed understanding of how to attract volunteers and retain them in the long term is becoming a high priority. The purpose of this study is (1) to analyse the influence of individual characteristics and corresponding organisational conditions on volunteering in sports clubs as well as (2) to examine the decision-making processes in relation to implement effective strategies for recruiting volunteers. For the first perspective a multi-level framework for the investigation of the factors of voluntary engagement in sports clubs is developed. The individual and context factors are estimated in different multi-level models based on a sample of n = 1,434 sport club members from 36 sport clubs in Switzerland. Results indicate that volunteering is not just an outcome of individual characteristics such as lower workloads, higher income, children belonging to the sport club, longer club memberships, or a strong commitment to the club. It is also influenced by club-specific structural conditions; volunteering is more probable in rural sports clubs whereas growth-oriented goals in clubs have a destabilising effect. Concerning decision-making processes an in-depth analysis of recruitment practices for volunteers was conducted in nine selected sport clubs (case study design) based on the garbage can model. Results show that the decision-making processes are generally characterised by a reactive approach in which dominant actors try to handle personnel problems of recruitment in the administration and sport domains through routine formal committee work and informal networks. In addition, it proved possible to develop a typology that deliver an overview of different decision-making practices in terms of the specific interplay of the relevant components of process control (top-down vs. bottom-up) and problem processing (situational vs. systematic). Based on the findings some recommendations for volunteer management in sport clubs are worked out.

Vocational identity achievement as a mediator of presence of calling and life satisfaction

The present study explores what mechanism might be responsible for the reported link between presence of a calling in one’s career and life satisfaction. It is proposed that vocational identity achievement acts as one important mediator of this relation and that the effects can be observed even when controlling for core self-evaluations (CSEs). The study used a short-term longitudinal design based on a sample of 269 German college students from different majors. The results confirmed the mediation model, with calling predicting vocational identity achievement 6 months later and identity serving as a stronger predictor of life satisfaction, all controlling for CSEs. However, contrary to previous research, presence of calling was not directly related to life satisfaction and even showed a negative relation when vocational identity achievement was controlled. The results are interpreted to suggest a multifaceted relation between calling and life satisfaction.