Left ventricular septal and apex pacing for optimal pump function in canine hearts

OBJECTIVES: The goal of this study was to test the hypothesis that left ventricular (LV) pump function is optimal when pacing is performed at the LV near the sites where the impulses exit the Purkinje system. BACKGROUND: Pacing at the conventional site, the right ventricular (RV) apex, adversely affects hemodynamics. During normal sinus rhythm (SR), electrical activation of the working myocardium starts at the LV septal endocardium and spreads from apex to base. METHODS: Experiments were conducted in anesthetized open-chest dogs with normal ventricular conduction to investigate hemodynamic effects of pacing at various epicardial LV sites, the RV apex, and combinations of these sites (n = 11) and of RV and LV septal pacing (n = 8). The LV septal endocardium was reached via the RV by puncturing through the septum with a barbed electrode. Left ventricular systolic (LVdP/dtpos and stroke work) and diastolic (LVdP/dtneg and Tau) function were assessed using pressure-volume relations (conductance catheter technique). RESULTS: Left ventricular systolic and diastolic function were highly dependent on the site of pacing, but not on QRS duration. Left ventricular function was maintained at SR level during LV septal, LV apex, and multisite pacing, was moderately depressed during pacing at epicardial LV free wall sites, and was most severely depressed during RV apex pacing. On average, RV septal pacing did not improve LV function, compared with RV apex pacing, but in each experiment one (variable) RV pacing site was found, which only moderately reduced LV function. CONCLUSIONS: During ventricular pacing, LV pump function is maintained best (i.e., at SR level) when pacing at the LV septum or LV apex, potentially because pacing from these sites creates a physiological propagation of electrical conduction.     

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.     

Long-term health-related quality of life after pancreatic resection for malignancy in patients with and without severe postoperative complications

Background

Surgery for pancreatic cancer yields significant morbidity and mortality risks and survival is limited. Therefore, the influence of complications on quality of life (QoL) after pancreatic surgery is important. This study compares QoL in patients with and without severe complications after surgery for pancreatic (pre-)malignancy.

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.     

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.