Assessment of left ventricular mechanical dyssynchrony by phase analysis of ECG-gated SPECT myocardial perfusion imaging

Cardiac resynchronization therapy (CRT) has shown benefits in patients with severe heart failure. However, at least 30% of patients selected for CRT by use of traditional criteria (New York Heart Association class III or IV, depressed left ventricular [LV] ejection fraction, and prolonged QRS duration) do not respond to CRT. Recent studies with tissue Doppler imaging have shown that the presence of LV dyssynchrony is an important predictor of response to CRT. Phase analysis has been developed to allow assessment of LV dyssynchrony by gated single photon emission computed tomography myocardial perfusion imaging. This technique uses Fourier harmonic functions to approximate regional wall thickness changes over the cardiac cycle and to calculate the regional onset-of-mechanical contraction phase. Once the onset-of-mechanical contraction phases are obtained 3-dimensionally over the left ventricle, a phase distribution map is formed that represents the degree of LV dyssynchrony. This technique has been compared with other methods of measuring LV dyssynchrony and shown promising results in clinical evaluations. In this review the phase analysis methodology is described, and its up-to-date validations are summarized.     

Targeting JNK-interacting protein 1 (JIP1) sensitises osteosarcoma to doxorubicin

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. Despite aggressive therapy, survival outcomes remain unsatisfactory, especially for patients with metastatic disease or patients with a poor chemotherapy response. Chemoresistance contributes to treatment failure. To increase the efficacy of conventional chemotherapy, essential survival pathways should be targeted concomitantly. Here, we performed a loss-of-function siRNA screen of the human kinome in SaOS-2 cells to identify critical survival kinases after doxorubicin treatment. Gene silencing of JNK-interacting-protein-1 (JIP1) elicited the most potent sensitisation to doxorubicin. This candidate was further explored as potential target for chemosensitisation in OS. A panel of OS cell lines and human primary osteoblasts was examined for sensitisation to doxorubicin using small molecule JIP1-inhibitor BI-78D3. JIP1 expression and JIP1-inhibitor effects on JNK-signalling were investigated by Western blot analysis. JIP1 expression in human OS tumours was assessed by immunohistochemistry on tissue micro arrays. BI-78D3 blocked JNK-signalling and sensitised three out of four tested OS cell lines, but not healthy osteoblasts, to treatment with doxorubicin. Combination treatment increased the induction of apoptosis. JIP1 was found to be expressed in two-thirds of human primary OS tissue samples. Patients with JIP1 positive tumours showed a trend to inferior overall survival. Collectively, JIP1 appears a clinically relevant novel target in OS to enhance the efficacy of doxorubicin treatment by means of RNA interference or pharmacological inhibition.     

Unraveling toxicological mechanisms and predicting toxicity classes with gene dysregulation networks

The use of genes for distinguishing classes of toxicity has become well established. In this paper we combine the reconstruction of a gene dysregulation network (GDN) with a classifier to assign unseen compounds to their appropriate class. Gene pairs in the GDN are dysregulated in the sense that they are linked by a common expression pattern in one class and differ in this pattern in another class. The classifier gives a quantitative measure on this difference by its prediction accuracy. As an in‐depth example, gene pairs were selected that were dysregulated between skin cells treated with either sensitizers or irritants. Pairs with known and novel markers were found such as HMOX1 and ZFAND2A, ATF3 and PPP1R15A, OXSR1 and HSPA1B, ZFP36 and MAFF. The resulting GDN proved biologically valid as it was well‐connected and enriched in known interactions, processes and common regulatory motifs for pairs. Classification accuracy was improved when compared with conventional classifiers. As the dysregulated patterns for heat shock responding genes proved to be distinct from those of other stress genes, we were able to formulate the hypothesis that heat shock genes play a specific role in sensitization, apart from other stress genes. In conclusion, our combined approach creates added value for classification‐based toxicogenomics by obtaining novel, well‐distinguishing and biologically interesting measures, suitable for the formulation of hypotheses on functional relationships between genes and their relevance for toxicity class differences. Copyright © 2012 John Wiley & Sons, Ltd.     

Assessment of myocardial viability by nuclear imaging techniques

The assessment of myocardial viability has become important in the diagnostic and prognostic work up of patients with ischemic cardiomyopathy. Patients with viable myocardium may benefit from revascularization in terms of improvement of function, symptoms, and prognosis. In contrast, patients without viable myocardium do not benefit and should be treated conservatively. Various nuclear imaging techniques are available.     

Induction of advanced glycation end products and alterations of the tensile properties of articular cartilage

OBJECTIVE: To determine whether increasing advanced glycation end products (AGEs) in bovine articular cartilage to levels present in aged human cartilage modulates the tensile biomechanical properties of the tissue. METHODS: Adult bovine articular cartilage samples were incubated in a buffer solution with ribose to induce the formation of AGEs or in a control solution. Portions of cartilage samples were assayed for biochemical indices of AGEs and tested to assess their tensile biomechanical properties, including stiffness, strength, and elongation at failure. RESULTS: Ribose treatment of cartilage induced increases in tissue fluorescence, absorbance, and pentosidine content (P < 0.001 for each comparison) by amounts similar to those that occur during aging in humans. Ribose treatment of cartilage also induced an increase in dynamic modulus (60% increase) and strength (35% increase), and a decrease (25% decrease) in strain (P < 0.001 for each comparison). CONCLUSION: The concomitant increase in AGEs and alteration of tensile properties of cartilage after ribose treatment suggest that aging-associated changes in AGEs have functional consequences for this tissue. The AGE-associated increases in strength and stiffness of cartilage may be beneficial by counteracting the decreases in these properties that are associated with degeneration. Conversely, the AGE-associated decrease in failure length, or increase in brittleness, together with increased stiffness may predispose cartilage to increased stress concentration, fracture, and aging-associated biomechanical dysfunction.     

Incorporation of simvastatin in PLLA membranes for guided bone regeneration: effect of thermal treatment on simvastatin release

Electrospun membranes based on biodegradable polymers are promising materials to be used for guided bone regeneration (GBR) therapy. The incorporation of osteostimulatory compounds can improve the biofunctionality of those membranes, making them active players in bone regeneration. Simvastatin has been shown to promote osteogenic differentiation both in vitro and in vivo. However, in most of these systems, the drug was quickly released, not matching the pace of bone regeneration. The aim of this study was to develop poly(l-lactic acid) (PLLA) membranes containing simvastatin (SV) that have a prolonged drug release rate, compatible with GBR applications. To this end, SV was mixed with PLLA and electrospun. The membranes were subjected to a thermal treatment in order to increase the crystallinity of PLLA. Morphological, structural and chemical properties of the electrospun membranes were characterized. The effect of the thermal treatment on the release profile of SV was evaluated by near physiological release experiments at 37 °C. The osteostimulatory potential was determined by in vitro culture of the membranes with rat bone marrow stromal cells (rBMSCs). The results confirmed that the thermal treatment led to an increase in polymer crystallinity and a more sustained release of SV. In vitro assays demonstrate cellular proliferation over time for all the membranes and a significant increase in osteogenic differentiation for the membranes containing SV subjected to thermal treatment.

Thermal treatment resulted in a sustained release of simvastatin and a positive response from rBMSCs.     

The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.     

The Interaction Between an Individual’s Acculturation and Community Factors on Physical Inactivity and Obesity: A Multilevel Analysis

Objectives. We examined whether the interactions between primarily speaking English at home and community-level measures (median household income and immigrant composition) are associated with physical inactivity and obesity.Methods. We pooled the 2005 and 2007 Los Angeles County Health Survey data to construct a multilevel data set, with community-level median household income and immigrant density as predictors at the community level. After controlling for individual-level demographic variables, we included the respondent’s perceived community safety as a covariate to test the hypothesis that perceived public safety mediates the association between acculturation and health outcomes.Results. The interaction between community median household income and primarily speaking English at home was associated with lower likelihoods of physical inactivity (odds ratio [OR] = 0.644; 95% confidence interval [CI] = 0.502, 0.825) and obesity (OR = 0.674; 95% CI = 0.514, 0.882). These odds remained significant after we controlled for perceived community safety.Conclusions. Resources in higher-income areas may be beneficial only to residents fully integrated into the community. Future research could focus on understanding how linguistic isolation affects community-level social learning and access to resources and whether this differs by family-level acculturation.Immigrants face the challenge of assimilating into their host country while maintaining values, beliefs, and behaviors from their homelands. Both acculturation and ethnic identity can influence health, and the construct of acculturation has been included in more and more health studies.1,2 Despite long-standing sociocultural theories of behavior that suggest that one’s behavior is the result of a dynamic interplay between internal, individual-level factors and social-cultural context,3–6 few public health studies have explored this interaction.7 A critical review noted that studies of acculturation tend to

separate culture from the larger social structure and the dynamic social processes in which behavior and beliefs are generated, and to relegate consideration of the socio-economic challenges associated with immigration, poor English language skills, and poverty, to their effects as separate or confounding variables.8^(p981)

For an immigrant, the interaction between acculturation status and the larger social structure in the host society could be important for health, as an inadequate level of acculturation in some contexts might result in reduced access to resources. In particular, undocumented immigrants have no federal coverage of health care under the Affordable Care Act. Therefore, access to resources may differ by legal status. However, in some settings, ethnic identity may buffer and even be protective against public health challenges in the United States (e.g., immigrants may maintain their dietary customs, which often include more whole foods, despite the excessive availability of processed foods in the United States).9 From a methodological perspective, multilevel models can provide a better understanding of this kind of interaction, whereby community-level factors, individual-level acculturation, and the cross-level interaction effects between the two can all be included as regressors of the outcome variable. However, very few public health studies have considered the cross-level interaction between acculturation and community-level factors on health behaviors and health outcomes. In an attempt to fill this research gap, we used population-based survey data to explore the cross-level interaction between community-level factors (median household income and immigrant composition) and individual-level linguistic acculturation (language preference at home).This study includes 2 independent variables that have been infrequently considered in previous studies of immigrant health: community immigrant composition and perceived community safety. Among various community-level factors that could influence residents’ health outcomes, community immigrant composition has begun to receive academic attention.10 Aside from individual-level acculturation indicators such as language preference and place of birth, living in a community with a high proportion of immigrants may be an independent predictor of one’s level of acculturation since people who are less acculturated may choose to live in ethnic enclaves.11 Perceived community safety has been shown to be a strong predictor of individual-level health outcomes such as having a mental health disorder or being overweight.12–15 The causal pathways between an unsafe community and negative health outcomes such as obesity could operate through reduced physical activity16–20 or through stress, which can disrupt energy metabolism and food intake regulation.21–24Because acculturation has been shown to be associated with one’s perception of community safety25 and predicts many different health behaviors and health outcomes,1,2 it is likely that an individual’s level of acculturation could modify the impact of community-level factors on health outcomes. Because understanding of these causal mechanisms is still far from conclusive, a study of the interaction between individuals’ level of acculturation and community-level factors could help reveal the complex pattern of acculturation and health. From the perspective of public health interventions, a good understanding of acculturation, perceived safety, and health could inform intersectoral collaboration between public safety, K-12 (kindergarten through 12th grade) and adult education, immigrant services, and public health agencies.