Cancer therapy-associated cardiotoxicity and signaling in the myocardium

The cardiotoxic potential of cytotoxic cancer chemotherapy is well known. Prime examples are the anthracyclines, which are highly efficacious agents for hemopoietic malignancies and solid tumors, but their clinical use is limited primarily by cardiotoxicity. Besides the conventional chemotherapeutics, new cancer drugs were developed in the last decade with the goal to specifically inhibit selected molecular targets such as growth factor receptors or intracellular tyrosine kinases in cancer cells. However, the outcome of combining conventional and newer cancer therapies could have unexpected side effects not anticipated so far and the long-term outcome is not known. Sometimes, however, unexpected side effects also shed light on previously unknown physiological functions. For example, the anti-HER2 cancer therapeutic trastuzumab (Herceptin), which can induce cardiac dysfunction, has demonstrated the importance of the ErbB/neuregulin signaling system in the adult heart. Subsequently, the role of endothelial-myocardial communication in maintaining phenotype and survival of adult cardiomyocytes has increasingly been recognized.

Structure and function of the glucose PTS transporter from Escherichia coli

The glucose transporter IICB of the Escherichia coli phosphotransferase system (PTS) consists of a polytopic membrane domain (IIC) responsible for substrate transport and a hydrophilic C-terminal domain (IIB) responsible for substrate phosphorylation. We have overexpressed and purified a triple mutant of IIC (mut-IIC), which had recently been shown to be suitable for crystallization purposes. Mut-IIC was homodimeric as determined by blue native-PAGE and gel-filtration, and had an eyeglasses-like structure as shown by negative-stain transmission electron microscopy (TEM) and single particle analysis. Glucose binding and transport by mut-IIC, mut-IICB and wildtype-IICB were compared with scintillation proximity and in vivo transport assays. Binding was reduced and transport was impaired by the triple mutation. The scintillation proximity assay allowed determination of substrate binding, affinity and specificity of wildtype-IICB by a direct method. 2D crystallization of mut-IIC yielded highly-ordered tubular crystals and made possible the calculation of a projection structure at 12Å resolution by negative-stain TEM. Immunogold labeling TEM revealed the sidedness of the tubular crystals, and high-resolution atomic force microscopy the surface structure of mut-IIC. This work presents the structure of a glucose PTS transporter at the highest resolution achieved so far and sets the basis for future structural studies.

PVR recurrence and the timing of silicon oil removal

BACKGROUND: Following vitrectomy for PVR-associated retinal detachment, placement of an encircling band, filling with silicone oil (SO) and successful retinal reattachment, a recurrence of PVR can develop. Retinal redetachment after SO removal is usually due to secondary or residual PVR. We wanted to ascertain whether the anatomical and functional outcomes of surgery in patients with a reattached retina and recurrent PVR can be improved by delaying the removal of SO. PATIENTS AND METHODS: 112 consecutive patients with PVR-associated retinal detachment who had undergone vitrectomy with SO filling, were monitored for at least 6 months after SO removal. Prior to SO removal, the retina posterior to the encircling band had to be completely reattached. Patients who developed PVR after SO filling were divided into two groups according to the duration of SO retention: 12 - 18 months (group 2: n = 48); > 18 months (group 3: n = 21). Individuals without PVR recurrence after SO filling and in whom the SO was consequently removed within 4 - 12 months served as control (group 1: n = 43). Anatomical success, intraocular pressure (IOP) and best-corrected visual acuity (BCVA) served as the primary clinical outcome parameters. RESULTS: Six months after SO removal, the anatomical success rates (86.3 %, 88.8 % and 84.6 %, in groups 1, 2 and 3, respectively; log rank = 0.794) and the BCVAs (p = 0.861) were comparable in the three groups. Mean IOP (p = 0.766), and the frequency of complications such as PVR recurrence (p = 0.936), bullous keratopathy (p = 0.981) and macular pucker (p = 0.943) were likewise similar. Patients in whom SO was retained for more than 18 months had the highest IOPs and required the heaviest dosage with anti-glaucoma drugs. CONCLUSIONS: In patients who develop a recurrence of PVR after vitrectomy and SO filling the surgeon can observe and treat retinal changes for up to 18 months without impairing the anatomical and functional outcomes. The retention of SO for more than 18 months does not improve the anatomical outcome. However, it can impair the functional outcome by precipitating the development of a persisting secondary glaucoma.

Immunogenicity and safety of aerosolized measles vaccine: Systematic review and meta-analysis

Aerosols are the most promising non-injectable method of measles vaccination studied so far and their efficacy is thought to be comparable to injected vaccine. We conducted a systematic review up to May 2006 to examine the immunogenicity and safety of aerosolized measles vaccine (Edmonston-Zagreb or Schwarz strains) 1 month or more after vaccination. Where possible we estimated pooled serological response rates and odds ratios (with 95% confidence intervals, CI) comparing aerosolized and subcutaneous vaccines in children in three age groups and adults. We included seven randomized trials, four non-randomized trials and six uncontrolled studies providing serological outcome data on 2887 individuals. In children below 10 months, the studies were heterogeneous. In four comparative studies, seroconversion rates were lower with aerosolized than with subcutaneous vaccine and in two of these the difference was unlikely to be due to chance. In children 10-36 months, the pooled seroconversion rate with aerosolized vaccine was 93.5% (89.4-97.7%) and 97.1% (92.4-100%) with subcutaneous vaccine (odds ratio 0.27, 0.04-1.62). In 5-15-year olds the studies were heterogeneous. In all comparative studies aerosolized vaccine was more immunogenic than subcutaneous. Reported side effects were mild. Aerosolized measles vaccine appears to be equally or more immunogenic than subcutaneous vaccine in children aged 10 months and older. Large randomized trials are needed to establish the efficacy and safety of aerosolized measles vaccine as primary and booster doses.

[Pediatric cardiac disease: indications for family screening and risk stratification]

In some forms of cardiac disease in childhood, familial occurrence is frequent. This implies the question whether family members should undergo cardiologic screening examinations. For cardiomyopathies the familiarity is so frequent and morbidity so important that examination by echo of all first degree relatives is recommended. As these cardiomyopathies may develop its phenotype all along a lifetime, repetitive examinations usually are indicated. For the primary electrical diseases the so called channelopathies the same is true, as for the high rate of familial occurrence and the high morbidity. Thus ECG screening of first degree relatives is recommended. In a child with congenital heart disease there are no recommendations with regard to familial screening and cardiological examinations usually are indicated only in case of clinical suspicion for heart disease.

The importance of glacier and forest change in hydrological climate-impact studies

Changes in land cover alter the water balance components of a catchment, due to strong interactions between soils, vegetation and the atmosphere. Therefore, hydrological climate impact studies should also integrate scenarios of associated land cover change. To reflect two severe climate-induced changes in land cover, we applied scenarios of glacier retreat and forest cover increase that were derived from the temperature signals of the climate scenarios used in this study. The climate scenarios were derived from ten regional climate models from the ENSEMBLES project. Their respective temperature and precipitation changes between the scenario period (2074–2095) and the control period (1984–2005) were used to run a hydrological model. The relative importance of each of the three types of scenarios (climate, glacier, forest) was assessed through an analysis of variance (ANOVA). Altogether, 15 mountainous catchments in Switzerland were analysed, exhibiting different degrees of glaciation during the control period (0–51%) and different degrees of forest cover increase under scenarios of change (12–55% of the catchment area). The results show that even an extreme change in forest cover is negligible with respect to changes in runoff, but it is crucial as soon as changes in evaporation or soil moisture are concerned. For the latter two variables, the relative impact of forest change is proportional to the magnitude of its change. For changes that concern 35% of the catchment area or more, the effect of forest change on summer evapotranspiration is equally or even more important than the climate signal. For catchments with a glaciation of 10% or more in the control period, the glacier retreat significantly determines summer and annual runoff. The most important source of uncertainty in this study, though, is the climate scenario and it is highly recommended to apply an ensemble of climate scenarios in the impact studies. The results presented here are valid for the climatic region they were tested for, i.e., a humid, mid-latitude mountainous environment. They might be different for regions where the evaporation is a major component of the water balance, for example. Nevertheless, a hydrological climate-impact study that assesses the additional impacts of forest and glacier change is new so far and provides insight into the question whether or not it is necessary to account for land cover changes as part of climate change impacts on hydrological systems.

Refugee Settlement in Australia: Policy, Scholarship and the Production of Knowledge, 1952 − 2013

Since 1947, Australia has formally resettled more than 750,000 refugees. During that time, researchers have successfully completed more than 150 Masters and doctoral theses and published more than 900 articles, books and reports about issues of refugee settlement in Australia, with about half of them being published in the past 10 years. In this paper, we discuss the development of the production of knowledge about refugee resettlement. We identify trends in the literature, such as the emergence of an ethno-specific focus, and the concern with settlement's psychological and emotional impact, and relate them to policy changes. We suggest that scholars need critically to take stock of the knowledge produced so far and be more cognisant of the international scholarly debate.

Lexical Pragmatics and Theory of Mind: The Acquisition of Connectives

The concept of theory of mind (ToM), a hot topic in cognitive psychology for the past twenty-five years, has gained increasing importance in the fields of linguistics and pragmatics. However, even though the relationship between ToM and verbal communication is now recognized, the extent, causality and full implications of this connection remain mostly to be explored. This book presents a comprehensive discussion of the interface between language, communication, and theory of mind, and puts forward an innovative proposal regarding the role of discourse connectives for this interface. The proposed analysis of connectives is tested from the perspective of their acquisition, using empirical methods such as corpus analysis and controlled experiments, thus placing the study of connectives within the emerging framework of experimental pragmatics.