Predictive Factors of Late Venous Aortocoronary Graft Failure: Ultrastructural Studies

Background

Venous aortocoronary graft arterialization may precede a preterm occlusion in some coronary artery bypass grafting (CABG) patients. The aim of the present study was to identify ultrastructural variations in the saphenous vein wall that may have an impact on the development of venous graft disease in CABG patients.

Methods

The study involved 365 consecutive patients with a mean age of 62.9±9.4 years who underwent isolated CABG. The thickness and area of the whole venous wall, the tunica intima, the tunica media and the adventitia and the number and shape (length, thickness and length/thickness ratio) of the nuclei in the medial smooth muscle cells nuclei in the distal saphenous vein segments were evaluated by ultrastructural studies. Patients were followed up for 41 to 50 months (mean 45.1±5.1). Saphenous vein graft patency was assessed by follow-up coronary angiography. Logistic regression models were used to identify independent risk factors for late graft failure.

Results

In 71 patients significant lesions in the saphenous vein grafts were observed. The whole venous wall thickness (437.5 µm vs. 405.5 µm), tunica media thickness (257.2 µm vs. 211.5 µm), whole venous wall area (2.23 mm² vs. 2.02 mm²) and tunica media area (1.09 mm² vs. 0.93 mm²) were significantly larger for this group of patients than for those without graft disease. In the latter group more elongated smooth muscle cell nuclei (higher length/thickness ratio) were found in the tunica media of the saphenous vein segments. Thickening of the saphenous vein tunica media and chunky smooth muscle cell nuclei were identified as independent risk factors for graft disease development.

Conclusions

Saphenous vein tunica media hypertrophy (resulting in wall thickening) and chunky smooth muscle cell nuclei might predict the development of venous graft disease.     

Racial Bias in Neural Empathic Responses to Pain

Recent studies have shown that perceiving the pain of others activates brain regions in the observer associated with both somatosensory and affective-motivational aspects of pain, principally involving regions of the anterior cingulate and anterior insula cortex. The degree of these empathic neural responses is modulated by racial bias, such that stronger neural activation is elicited by observing pain in people of the same racial group compared with people of another racial group. The aim of the present study was to examine whether a more general social group category, other than race, could similarly modulate neural empathic responses and perhaps account for the apparent racial bias reported in previous studies. Using a minimal group paradigm, we assigned participants to one of two mixed-race teams. We use the term race to refer to the Chinese or Caucasian appearance of faces and whether the ethnic group represented was the same or different from the appearance of the participant'' own face. Using fMRI, we measured neural empathic responses as participants observed members of their own group or other group, and members of their own race or other race, receiving either painful or non-painful touch. Participants showed clear group biases, with no significant effect of race, on behavioral measures of implicit (affective priming) and explicit group identification. Neural responses to observed pain in the anterior cingulate cortex, insula cortex, and somatosensory areas showed significantly greater activation when observing pain in own-race compared with other-race individuals, with no significant effect of minimal groups. These results suggest that racial bias in neural empathic responses is not influenced by minimal forms of group categorization, despite the clear association participants showed with in-group more than out-group members. We suggest that race may be an automatic and unconscious mechanism that drives the initial neural responses to observed pain in others.     

A Novel In Vitro Model for Microvasculature Reveals Regulation of Circumferential ECM Organization by Curvature

In microvascular vessels, endothelial cells are aligned longitudinally whereas several components of the extracellular matrix (ECM) are organized circumferentially. While current three-dimensional (3D) in vitro models for microvasculature have allowed the study of ECM-regulated tubulogenesis, they have limited control over topographical cues presented by the ECM and impart a barrier for the high-resolution and dynamic study of multicellular and extracellular organization. Here we exploit a 3D fibrin microfiber scaffold to develop a novel in vitro model of the microvasculature that recapitulates endothelial alignment and ECM deposition in a setting that also allows the sequential co-culture of mural cells. We show that the microfibers'' nanotopography induces longitudinal adhesion and alignment of endothelial colony-forming cells (ECFCs), and that these deposit circumferentially organized ECM. We found that ECM wrapping on the microfibers is independent of ECFCs'' actin and microtubule organization, but it is dependent on the curvature of the microfiber. Microfibers with smaller diameters (100–400 µm) guided circumferential ECM deposition, whereas microfibers with larger diameters (450 µm) failed to support wrapping ECM. Finally, we demonstrate that vascular smooth muscle cells attached on ECFC-seeded microfibers, depositing collagen I and elastin. Collectively, we establish a novel in vitro model for the sequential control and study of microvasculature development and reveal the unprecedented role of the endothelium in organized ECM deposition regulated by the microfiber curvature.     

Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

Background

Severe asthma is associated with T helper (T_H) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective

To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods

BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results

Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of T_H2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion

Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.     

Permeation through Phospholipid Bilayers,Skin‐Cell Penetration,Plasma Stability,and CD Spectra of α‐ and β‐Oligoproline Derivatives

After a survey of the special role, which the amino acid proline plays in the chemistry of life, the cell‐penetrating properties of polycationic proline‐containing peptides are discussed, and the widely unknown discovery by the Giralt group (J. Am. Chem. Soc. 2002 , 124, 8876) is acknowledged, according to which fluorescein‐labeled tetradecaproline is slowly taken up by rat kidney cells (NRK‐49F). Here, we describe details of our previously mentioned (Chem. Biodiversity 2004 , 1, 1111) observation that a hexa‐β³‐Pro derivative penetrates fibroblast cells, and we present the results of an extensive investigation of oligo‐L ‐ and oligo‐D ‐α‐prolines, as well as of oligo‐β²h‐ and oligo‐β³h‐prolines without and with fluorescence labels ( 1 – 8 ; Fig. 1). Permeation through protein‐free phospholipid bilayers is detected with the nanoFAST biochip technology (Figs. 2–4). This methodology is applied for the first time for quantitative determination of translocation rates of cell‐penetrating peptides (CPPs) across lipid bilayers. Cell penetration is observed with mouse (3T3) and human foreskin fibroblasts (HFF; Figs. 5 and 6–8, resp.). The stabilities of oligoprolines in heparin‐stabilized human plasma increase with decreasing chain lengths (Figs. 9–11). Time‐ and solvent‐dependent CD spectra of most of the oligoprolines (Figs. 13 and 14) show changes that may be interpreted as arising from aggregation, and broadening of the NMR signals with time confirms this assumption.     

Direct Correlation of the Organic Solar Cell Device Performance to the In‐Depth Distribution of Highly Ordered Polymer Domains in Polymer/Fullerene Films

This study correlates the device performance of organic solar cells and the electronic charge transport within polymer/fullerene films, directly to the optical order of the polymer. The optical order was measured by spectroscopic ellipsometry and evaluated by our previously derived model. We were able to determine the in‐depth distribution of higher and lower ordered poly(3‐hexylthiophene) (P3HT) domains within an [6,6]‐phenyl‐C₆₁‐butyric acid methyl ester (PCBM) matrix. The over the film thickness integrated volume fraction of highly ordered P3HT domains could be directly correlated to the corresponding solar cell device performance. We are able to describe various thermally annealing conditions between room‐temperature and 200 °C.     

Identifying Transmission Cycles at the Human-Animal Interface: The Role of Animal Reservoirs in Maintaining Gambiense Human African Trypanosomiasis

Many infections can be transmitted between animals and humans. The epidemiological roles of different species can vary from important reservoirs to dead-end hosts. Here, we present a method to identify transmission cycles in different combinations of species from field data. We used this method to synthesise epidemiological and ecological data from Bipindi, Cameroon, a historical focus of gambiense Human African Trypanosomiasis (HAT, sleeping sickness), a disease that has often been considered to be maintained mainly by humans. We estimated the basic reproduction number of gambiense HAT in Bipindi and evaluated the potential for transmission in the absence of human cases. We found that under the assumption of random mixing between vectors and hosts, gambiense HAT could not be maintained in this focus without the contribution of animals. This result remains robust under extensive sensitivity analysis. When using the distributions of species among habitats to estimate the amount of mixing between those species, we found indications for an independent transmission cycle in wild animals. Stochastic simulation of the system confirmed that unless vectors moved between species very rarely, reintroduction would usually occur shortly after elimination of the infection from human populations. This suggests that elimination strategies may have to be reconsidered as targeting human cases alone would be insufficient for control, and reintroduction from animal reservoirs would remain a threat. Our approach is broadly applicable and could reveal animal reservoirs critical to the control of other infectious diseases.     

High efficiency versus maximal performance — The cause of oxidative stress in eukaryotes: A hypothesis

Degenerative diseases are in part based on elevated production of ROS (reactive oxygen species) in mitochondria, mainly during stress and excessive work under stress (strenuous exercise). The production of ROS increases with increasing mitochondrial membrane potential (ΔΨ_m). A mechanism is described which is suggested to keep ΔΨ_m at low values under normal conditions thus preventing ROS formation, but is switched off under stress and excessive work to maximize the rate of ATP synthesis, accompanied by decreased efficiency. Low ΔΨ_m and low ROS production are suggested to occur by inhibition of respiration at high [ATP]/[ADP] ratios. The nucleotides interact with phosphorylated cytochrome c oxidase (COX), representing the step with the highest flux-control coefficient of mitochondrial respiration. At stress and excessive work neural signals are suggested to dephosphorylate the enzyme and abolish the control of COX activity (respiration) by the [ATP]/[ADP] ratio with consequent increase of ΔΨ_m and ROS production. The control of COX by the [ATP]/[ADP] ratio, in addition, is proposed to increase the efficiency of ATP production via a third proton pumping pathway, identified in eukaryotic but not in prokaryotic COX. We conclude that ‘oxidative stress’ occurs when the control of COX activity by the [ATP]/[ADP] ratio is switched off via neural signals.