Current discharge management of acute coronary syndromes: data from the Rijnmond Collective Cardiology Research (CCR) study

Background

Medical discharge management of acute coronary syndromes (ACS) remains suboptimal outside randomised trials and constitutes an essential quality benchmark for ACS. We sought to evaluate the rates of key guideline-recommended pharmacological agents after ACS and characteristics associated with optimal treatment at discharge.

Methods

The Rijnmond Collective Cardiology Research (CCR) registry is an ongoing prospective, observational study in the Netherlands that aims to enrol 4000 patients with ACS. We examined discharge and 1-month follow-up medication use among the first 1000 patients enrolled in the CCR registry. Logistic regression was performed to identify patient and hospital characteristics associated with collective guideline-recommended pharmacotherapy at hospital discharge.

Results

At discharge, 94 % of patients received aspirin, 100 % thienopyridines, 80 % angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers, 87 % β-blockers, 96 % statins, and 65 % the combination of all 5 agents. ST-segment elevation myocardial infarction, hypertension, hypercholesterolaemia, and enrolment in an interventional centre were positive independent predictors of 5-drug combination therapy at discharge. Negative independent predictors were unstable angina and advanced age.

Conclusion

Current data from the CCR registry reflect a high quality of care for ACS discharge management in the Rotterdam-Rijnmond region. However, potential still remains for further optimisation.     

Phage display of an intracellular carboxylesterase of Bacillus subtilis: comparison of Sec and Tat pathway export capabilities

Using the phage display technology, a protein can be displayed at the surface of bacteriophages as a fusion to one of the phage coat proteins. Here we describe development of this method for fusion of an intracellular carboxylesterase of Bacillus subtilis to the phage minor coat protein g3p. The carboxylesterase gene was cloned in the g3p-based phagemid pCANTAB 5E upstream of the sequence encoding phage g3p and downstream of a signal peptide-encoding sequence. The phage-bound carboxylesterase was correctly folded and fully enzymatically active, as determined from hydrolysis of the naproxen methyl ester with Km values of 0.15 mM and 0.22 mM for the soluble and phage-displayed carboxylesterases, respectively. The signal peptide directs the encoded fusion protein to the cell membrane of Escherichia coli, where phage particles are assembled. In this study, we assessed the effects of several signal peptides, both Sec dependent and Tat dependent, on the translocation of the carboxylesterase in order to optimize the phage display of this enzyme normally restricted to the cytoplasm. Functional display of Bacillus carboxylesterase NA could be achieved when Sec-dependent signal peptides were used. Although a Tat-dependent signal peptide could direct carboxylesterase translocation across the inner membrane of E. coli, proper assembly into phage particles did not seem to occur.     

Effects of nitrogen stressed algae on different Acartia species

We studied the reproductive response of two copepod species,Acartia tonsa and Acartia clausii, fed algae with differentC:N ratios (4.5 and 9.1 molar ratios respectively) in orderto investigate the influence of nutritional imbalances on calanoidcopepods egg production. Adult females were incubated with thecryptophyte Rhodomonas sp. at saturating concentrations. Thealgae were cultured under nitrogen depleted and sufficient conditions.Ingestion rates of the animals fed with different algae andtheir response in terms of egg production and hatching successof the eggs were quantified. Both species produced more eggwhen fed with nitrogen-limited algae. Ingestion rates and egghatching differed between species, but were not significantlyaffected by the quality of the food. The only difference betweenthe two species in their reaction to food quality was that A.tonsa increased the number of resting eggs, whereas no restingegg production was observed in A. clausii when fed with nitrogenlimited algae. These results support the recent suggestion thata moderately high prey C:N ratio (10–15) supports a higheregg production than a C:N ratio substantially <10.     

Agonistic behavior in wild male Magellanic penguins: when and how do they interact?

Game-theory models predict that the frequency and type of agonistic interactions should vary with the value of the resource being contested. We describe bill duels and overt fighting in male Magellanic penguins (Spheniscus magellanicus) at a breeding colony and determine whether these behaviors change with the value of the nests over which they interact. Bill duels represent low levels of aggression while overt fighting high levels of aggression. Consistent with predictions, overt fighting was more common before egg laying when nests have the highest potential value while bill duels were more common at failed nests later in the season when nests are less valuable as they could not be used for reproduction until the next season. Contrary to expectations, overt fights were shorter and resulted in fewer cuts before egg laying than after egg laying. Large size asymmetries between opponents before egg laying may enable losers to quickly assess their opponents and leave before they are hurt. As predicted, the duration and damage occurring during overt fights were positively correlated with nest cover, which is correlated with higher reproductive success. We conclude that male Magellanic penguins have rules of engagement that in the most cases follow game-theory predictions on when and how to interact.     

Models and mechanisms of metabolic regulation: genes, stress, and the HPA and HPG axes

A variety of models have been developed to better understand the mechanisms underlying individual variation in susceptibility to obesity. This review discusses several of these models and explores their role in understanding individual vulnerability to metabolic disease and the environmental factors around which metabolic perturbations occur. Recently, the focus of models has shifted towards heterogeneous populations, in which individuals characterized by a high vulnerability and individuals that are seemingly resistant can be identified. The use of these heterogeneous studies has lead to the identification of several novel biomarkers predicting obesity. This review therefore focuses on nontraditional factors, which are not directly implicated in metabolic regulation. First, the evidence from rodent knockout models for genetic factors involved in obesity is discussed. Second, the role of a stressful environment, particularly the early life environment is investigated along with a discussion of circadian disruption and metabolic disorders. Finally, the impact of sex-steroids, as exemplified by polycystic ovarian syndrome, is discussed. Overall, the data presented in our review demonstrate that in most cases interplay between genetic and environmental factors best predicts disease development. Our review shows that susceptibility to obesity may be explained by complex interactions between traditional homeostatic mechanisms, such as the hypothalamic peptide, and less studied mechanisms, like steroids and neurotrophic factors.     

Limitations of trait‐based approaches for stressor assessment: The case of freshwater invertebrates and climate drivers

The appeal of trait‐based approaches for assessing environmental vulnerabilities arises from the potential insight they provide into the mechanisms underlying the changes in populations and community structure. Traits can provide ecologically based explanations for observed responses to environmental changes, along with predictive power gained by developing relationships between traits and environmental variables. Despite these potential benefits, questions remain regarding the utility and limitations of these approaches, which we explore focusing on the following questions: (a) How reliable are predictions of biotic responses to changing conditions based on single trait–environment relationships? (b) What factors constrain detection of single trait–environment relationships, and how can they be addressed? (c) Can we use information on meta‐community processes to reveal conditions when assumptions underlying trait‐based studies are not met? We address these questions by reviewing published literature on aquatic invertebrate communities from stream ecosystems. Our findings help to define factors that influence the successful application of trait‐based approaches in addressing the complex, multifaceted effects of changing climate conditions on hydrologic and thermal regimes in stream ecosystems. Key conclusions are that observed relationships between traits and environmental stressors are often inconsistent with predefined hypotheses derived from current trait‐based thinking, particularly related to single trait–environment relationships. Factors that can influence findings of trait‐based assessments include intercorrelations of among traits and among environmental variables, spatial scale, strength of biotic interactions, intensity of habitat disturbance, degree of abiotic stress, and methods of trait characterization. Several recommendations are made for practice and further study to address these concerns, including using phylogenetic relatedness to address intercorrelation. With proper consideration of these issues, trait‐based assessment of organismal vulnerability to environmental changes can become a useful tool to conserve threatened populations into the future.     

Household Income Is Associated with the p53 Mutation Frequency in Human Breast Tumors

Background

A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation.

Methods

We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI) among 173 breast cancer patients from the greater Baltimore area, United States.

Results

p53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21%), followed by the income group between $15,000 and $60,000 (18%), while those above $60,000 HI had the fewest mutations (5%). When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05). In the adjusted logistic regression analysis with 3 income categories (trend test), the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER)-negative disease. Within this group, 42% of the low income patients (< $15,000 HI) carried a mutation, followed by the middle income group (21%), while those above $60,000 HI did not carry mutations (P _trend < 0.05).

Conclusions:

HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology.     

The microbiome of North Sea copepods

Copepods can be associated with different kinds and different numbers of bacteria. This was already shown in the past with culture-dependent microbial methods or microscopy and more recently by using molecular tools. In our present study, we investigated the bacterial community of four frequently occurring copepod species, Acartia sp., Temora longicornis, Centropages sp. and Calanus helgolandicus from Helgoland Roads (North Sea) over a period of 2 years using DGGE (denaturing gradient gel electrophoresis) and subsequent sequencing of 16S-rDNA fragments. To complement the PCR-DGGE analyses, clone libraries of copepod samples from June 2007 to 208 were generated. Based on the DGGE banding patterns of the two years survey, we found no significant differences between the communities of distinct copepod species, nor did we find any seasonality. Overall, we identified 67 phylotypes (>97 % similarity) falling into the bacterial phyla of Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria. The most abundant phylotypes were affiliated to the Alphaproteobacteria. In comparison with PCR-DGGE and clone libraries, phylotypes of the Gammaproteobacteria dominated the clone libraries, whereas Alphaproteobacteria were most abundant in the PCR-DGGE analyses.     

Bispecific designed ankyrin repeat proteins (DARPins) targeting epidermal growth factor receptor inhibit A431 cell proliferation and receptor recycling

The EGF receptor (EGFR) has been implicated in the development and progression of many tumors. Although monoclonal antibodies directed against EGFR have been approved for the treatment of cancer in combination with chemotherapy, there are limitations in their clinical efficacy, necessitating the search for robust targeting molecules that can be equipped with new effector functions or show a new mechanism of action. Designed ankyrin repeat proteins (DARPins) may provide the targeting component for such novel reagents. Previously, four DARPins were selected against EGFR with (sub)nanomolar affinity. As any targeting module should preferably be able to inhibit EGFR-mediated signaling, their effect on A431 cells overexpressing EGFR was examined: three of them were shown to inhibit proliferation by inducing G(1) arrest, as seen for the Food and Drug Administration-approved antibody cetuximab. To understand this inhibitory mechanism, we mapped the epitopes of the DARPins using yeast surface display. The epitopes for the biologically active DARPins overlapped with the EGF-binding site, whereas the fourth DARPin bound to a different domain, explaining the lack of a biological effect. To optimize the biological activity of the DARPins, we combined two DARPins binding to different epitopes with a flexible linker or with a leucine zipper, leading to a homodimer. The latter DARPin was able to reduce surface EGFR by inhibiting receptor recycling, leading to a dramatic decrease in cell viability. These results indicate that multispecific EGFR-specific DARPins are superior to cetuximab and may form the basis of new opportunities in tumor targeting and tumor therapy.     

Climate Change Increases Reproductive Failure in Magellanic Penguins

Climate change is causing more frequent and intense storms, and climate models predict this trend will continue, potentially affecting wildlife populations. Since 1960 the number of days with >20 mm of rain increased near Punta Tombo, Argentina. Between 1983 and 2010 we followed 3496 known-age Magellanic penguin (Spheniscus magellanicus) chicks at Punta Tombo to determine how weather impacted their survival. In two years, rain was the most common cause of death killing 50% and 43% of chicks. In 26 years starvation killed the most chicks. Starvation and predation were present in all years. Chicks died in storms in 13 of 28 years and in 16 of 233 storms. Storm mortality was additive; there was no relationship between the number of chicks killed in storms and the numbers that starved (P = 0.75) or that were eaten (P = 0.39). However, when more chicks died in storms, fewer chicks fledged (P = 0.05, R ² = 0.14). More chicks died when rainfall was higher and air temperature lower. Most chicks died from storms when they were 9–23 days old; the oldest chick killed in a storm was 41 days old. Storms with heavier rainfall killed older chicks as well as more chicks. Chicks up to 70 days old were killed by heat. Burrow nests mitigated storm mortality (N = 1063). The age span of chicks in the colony at any given time increased because the synchrony of egg laying decreased since 1983, lengthening the time when chicks are vulnerable to storms. Climate change that increases the frequency and intensity of storms results in more reproductive failure of Magellanic penguins, a pattern likely to apply to many species breeding in the region. Climate variability has already lowered reproductive success of Magellanic penguins and is likely undermining the resilience of many other species.