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.     

Nile Red fluorescence spectroscopy reports early physicochemical changes in myelin with high sensitivity

The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the earliest indication of myelin injury involves changes in the composition and/or polarity of its constituent lipids, we developed a sensitive spectroscopic technique for defining the chemical polarity of myelin lipids in fixed frozen tissue sections from rodent and human. The method uses a simple staining procedure involving the lipophilic dye Nile Red, whose fluorescence spectrum varies according to the chemical polarity of the microenvironment into which the dye embeds. Nile Red spectroscopy identified histologically intact yet biochemically altered myelin in prelesioned tissues, including mouse white matter following subdemyelinating cuprizone intoxication, as well as normal-appearing white matter in multiple sclerosis brain. Nile Red spectroscopy offers a relatively simple yet highly sensitive technique for detecting subtle myelin changes.

Myelin is a highly ordered, lipid-rich extension of glial cell membrane that facilitates rapid and efficient saltatory conduction of action potentials along axons in the central and peripheral nervous systems. The stability of myelin membranes critically depends on its molecular composition (1–3). Although myelin is maintained roughly at a ratio of 70:30% lipid to protein (4), lipid membranes are highly fluid; changes in lipid composition are defining characteristics of myelin development (5), homeostasis in the adult, and aging in rodents (6, 7), as well as primates (8). Shifts in lipid composition also occur in inflammatory demyelinating disorders like multiple sclerosis (MS) (9, 10). Lipids are even theorized to be targets of immune attacks in autoimmune disorders, a role previously ascribed to proteins (11). Key roles for lipids notwithstanding, tools to interrogate biochemical changes to myelin lipids have largely been restricted to in vitro systems.Once thought to be inert, myelin is now known to be a chemically and structurally dynamic element (12). Specific combinations of proteins and lipids induce formation and compaction of multilamellar vesicles that resemble myelin (13), underscoring the importance of correct chemical composition for assembly. Conversely, alterations in these molecular proportions promote decompaction and myelin vesiculation (3, 14). The polarity of lipid species in cell membranes influences their packing properties and therefore stability (15). Governed by competing thermodynamic forces of lipid curling and hydrocarbon packing (16), myelin sheaths lie at the critical edge of bilayer stability and thus are susceptible to factors in the environment. Indeed, the myelin integrity theory of MS rests on the outsized influence of environmental forces on myelin stability and function (17). Therefore, methods for detecting physicochemical changes in myelin lipid composition in situ would greatly enhance our understanding of early events in myelin development, as well as myelin damage in disease states, with important implications for therapies designed to prevent myelin loss in MS and other demyelinating disorders.The study of myelin lipid biochemistry poses unique challenges (18). Traditional analytical methods, such as thin-layer chromatography and high-performance liquid chromatography (19), depend on tissue homogenization that eliminates informative spatial relationships. Imaging lipid mass spectrometry (20) preserves spatial relationships, but submicron resolution has yet to be realized, and reproducibility at the level of sample preparation remains problematic (21). Coherent anti–Stokes Raman scattering microscopy provides high-resolution, label-free imaging of lipids in histological samples (22), but this method lacks sensitivity and requires expertise in nonlinear optics as well as highly specialized hardware. Finally, fluorescent lipophilic dyes, though widely available and easy to use, have traditionally been employed to detect lipid-rich structures in only a qualitative manner. Conventional fluorescence microscopy is therefore unable to detect subtle shifts in lipid biochemistry. By contrast, Nile Red (NR) is a fluorescent dye that is well situated to report changes in the chemical polarity of cell membranes and myelin, being both lipophilic (23, 24) and differentially fluorescent depending on solvent environment (i.e., exhibits solvatochromism) (25). The current study uses NR fluorescence spectroscopy to identify polarity shifts as an early manifestation of myelin disease prior to overt demyelination. We show that this technique reports subtle biochemical changes in myelin, resulting in a method that is a very sensitive marker of incipient myelin injury.     

The effects of cardiac resynchronization therapy on left ventricular function, myocardial energetics, and metabolic reserve in patients with dilated cardiomyopathy and heart failure

OBJECTIVES: The effects of long-term cardiac resynchronization therapy (CRT) on left ventricular (LV) energetics and metabolic reserve were evaluated. BACKGROUND: Cardiac resynchronization therapy is a new therapy for patients with drug-refractory severe heart failure (HF). METHODS: Ten patients with idiopathic dilated cardiomyopathy who had undergone implantation of biventricular pacemaker 8 +/- 5 months earlier were studied during two conditions: CRT switched on, and after CRT was switched off for 24 h. Left ventricular function was measured using echocardiography and oxidative metabolism using [(11)C]acetate positron emission tomography. Both measurements were performed at rest and during dobutamine-induced stress (5 microg/kg/min). Basal- and adenosine-stimulated (140 microg/kg/min) myocardial blood flow were quantitated using [(15)O]water. RESULTS: During CRT off, LV stroke volume was significantly reduced at rest (72 +/- 18 ml vs. 63 +/- 15 ml, p < 0.05), but LV oxidative metabolism (K(mono)) remained unchanged (0.046 +/- 0.008 vs. 0.054 +/- 0.016 min(-1)) leading to a significant deterioration of myocardial efficiency of forward work (from 48.2 +/- 16.7 to 36.6 +/- 11.7 mm Hg.l/g, p < 0.05). During dobutamine-induced stress, stroke volume and K(mono) values were not different whether CRT was on or off. However, myocardial efficiency (56.1 +/- 16.1 vs. 49.8 +/- 18.0 mm Hg.ml.g(-1).min(-1), p = 0.099) and metabolic reserve, the response of K(mono) to dobutamine (0.023 +/- 0.014 vs. 0.013 +/- 0.014 min(-1), p = 0.09), tended to reduce when CRT was switched off. Cardiac resynchronization therapy had no effects on myocardial perfusion. Natriuretic peptides increased significantly during CRT-off period. CONCLUSIONS: Long-term CRT has beneficial effects on LV function and myocardial efficiency at rest in patients with HF. These effects are not associated with changes in myocardial perfusion or oxygen consumption. During dobutamine-induced stress, CRT does not affect functional parameters, but myocardial efficiency and metabolic reserve may be increased.     

In-stent fractional flow reserve variations and related optical coherence tomography findings: the FFR–OCT co-registration study

We sought to assess in-stent variations in fractional flow reserve (FFR) in patients with previous percutaneous coronary intervention (PCI) and to associate any drop in FFR with findings by optical coherence tomography (OCT) imaging. Suboptimal post-PCI FFR values were previously associated with poor outcomes. It is not known to which extent in-stent pressure loss contributes to reduced FFR. In this single-arm observational study, 26 patients who previously underwent PCI with drug-eluting stent or scaffold implantation were enrolled. Motorized FFR pullback during continuous intravenous adenosine infusion and OCT assessments was performed. Post-PCI FFR?<?0.94 was defined as suboptimal. At a median of 63 days after PCI (interquartile range: 59–64 days), 18 out of 26 patients (72%) had suboptimal FFR. The in-stent drop in FFR was significantly higher in patients with suboptimal FFR vs. patients with optimal FFR (0.08?±?0.07 vs. 0.01?±?0.02, p?<?0.001). Receiver operating characteristic curve analysis showed that an in-stent FFR variation of >?0.03 was associated with suboptimal FFR. In patients with suboptimal FFR, the OCT analyses revealed higher mean neointimal area (respectively: 1.06?±?0.80 vs. 0.51?±?0.23 mm²; p?=?0.018) and higher neointimal thickness of covered struts (respectively 0.11?±?0.07 vs. 0.06?±?0.01 mm; p?=?0.021). Suboptimal FFR values following stent-implantation are mainly caused by significant in-stent pressure loss during hyperemia. This finding is associated to a larger neointimal proliferation.     

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.     

Direct videoscopic approach to the descending thoracic aorta for aortic arch endograft delivery: evaluation in a porcine model.

PURPOSE: To examine the feasibility of a direct videoscopic approach to the descending thoracic aorta for endograft delivery to the aortic arch. METHODS: A double purse-string suture was placed on the aorta of 3 pigs via a thoracoscopic approach. Subsequently, the aorta was cannulated in the center of the purse-string. A 22-F delivery catheter was advanced under fluoroscopic control over a guidewire via a trocar into the proximal aorta. After deployment of a tubular endograft, the catheter was withdrawn from the aorta while simultaneously tightening the purse-string suture, without aortic cross clamping. The outcome was evaluated by post implant angiography and autopsy results. RESULTS: The procedure was successfully completed in all animals, with a mean total procedure time of 126 minutes (range 118-137). Mean endograft implantation time from needle puncture to catheter extraction was 27 minutes (range 21-37). Hemostasis was obtained in all animals after withdrawal of the delivery catheter and tightening the purse-string suture. The mean blood loss was 143 mL (range 80-220). Autopsy proved all purse-string sutures to be adequately placed and all endografts deployed in the correct position. CONCLUSION: A direct videoscopic approach to the descending thoracic aorta proved a feasible technique for endograft delivery to the aortic arch in a porcine model.     

Non-occlusive mesenteric ischaemia: a common disorder in gastroenterology and intensive care

Non-occlusive mesenteric ischaemia is characterized by gastrointestinal ischaemia with normal vessels. In gastroenterology it is recognized as rare disease occasionally causing acute bowel infarction or ischaemic colitis. From intensive care literature this disorder is recognized as an early phenomenon during circulatory stress. This early mucosal ischaemia then leads to increased permeability, bacterial translocation, and further mucosal hypoperfusion. The damage is produced mainly during reperfusion following ischaemia with fresh inflow of oxygen and outflow of waste products into the systemic circulation.The mechanisms underlying non-occlusive mesenteric ischaemia include macrovascular vasoconstriction, hypoperfusion of the tips of the villi and shunting. It is very common in critically ill and perioperative patients, but also occurs in pancreatitis, renal failure and sepsis.Treatment options include aggressive fluid resuscitation and careful choice of vasoactive drugs. Control of reperfusion damage and new endothelin-antagonists are potentially useful new treatment options.     

Usefulness of hypertensive blood pressure response during a single-stage exercise test to predict long-term outcome in patients with peripheral arterial disease

The prognostic value of a hypertensive blood pressure (BP) response is still unclear. Therefore, the prognostic value of a hypertensive BP response in patients during single-stage exercise testing for peripheral arterial disease (PAD) on long-term mortality and major adverse cerebrovascular and cardiac events (MACCEs) was investigated. In addition, effects of statin, beta-blocker, and aspirin use in patients with known or suspected PAD were studied. A total of 2,109 patients were enrolled in an observational prospective study from 1993 to 2005. Hypertensive BP response was defined as an increase in systolic BP >/=55 mm Hg (95(th) percentile within our population) after a single-stage treadmill exercise test. The outcome was obtained by using the civil registries, and a questionnaire about cardiac events was sent to all survivals. Hypertensive BP response was associated with increased risk of long-term mortality (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12 to 1.80) and MACCEs (HR 1.47, 95% CI 1.09 to 1.97). After adjustments for clinical risk factors and propensity score, baseline statin use was associated with reduced risk of long-term mortality (HR 0.59, 95% CI 0.44 to 0.79), and statin, beta-blocker, and aspirin use were associated with reduced risk of MACCEs (HR 0.59, 95% CI 0.43 to 0.81; HR 0.75, 95% CI 0.60 to 0.95; HR 0.73, 95% CI, 0.57 to 0.92, respectively). In conclusion, hypertensive BP response at exercise in patients with known or suspected PAD is an important independent risk factor for all-cause long-term mortality and MACCEs, whereas statin, beta-blocker, and aspirin use were associated with an improved outcome.