Dependence of local left ventricular wall mechanics on myocardial fiber orientation: a model study.

The dependence of local left ventricular (LV) mechanics on myocardial muscle fiber orientation was investigated using a finite element model. In the model we have considered anisotropy of the active and passive components of myocardial tissue, dependence of active stress on time, strain and strain rate, activation sequence of the LV wall and aortic afterload. Muscle fiber orientation in the LV wall is quantified by the helix fiber angle, defined as the angle between the muscle fiber direction and the local circumferential direction. In a first simulation, a transmural variation of the helix fiber angle from +60 degrees at the endocardium through 0 degrees in the midwall layers to -60 degrees at the epicardium was assumed. In this simulation, at the equatorial level maximum active muscle fiber stress was found to vary from about 110 kPa in the subendocardial layers through about 30 kPa in the midwall layers to about 40 kPa in the subepicardial layers. Next, in a series of simulations, muscle fiber orientation was iteratively adapted until the spatial distribution of active muscle fiber stress was fairly homogeneous. Using a transmural course of the helix fiber angle of +60 degrees at the endocardium, +15 degrees in the midwall layers and -60 degrees at the epicardium, at the equatorial level maximum active muscle fiber stress varied from 52 kPa to 55 kPa, indicating a remarkable reduction of the stress range. Moreover, the change of muscle fiber strain with time was more similar in different parts of the LV wall than in the first simulation. It is concluded that (1) the distribution of active muscle fiber stress and muscle fiber strain across the LV wall is very sensitive to the transmural distribution of the helix fiber angle and (2) a physiological transmural distribution of the helix fiber angle can be found, at which active muscle fiber stress and muscle fiber strain are distributed approximately homogeneously across the LV wall.     

Dynamic capacitance of epicardial coronary arteries in vivo

The dynamic capacitance of epicardial coronary arteries (i.d. greater than or equal to 0.4 mm) in vivo was assessed from the volume stiffness and volume of these arteries. The volume stiffness was derived from the pressure wave front velocity as determined in dogs by measuring the delay time between the pressure pulses recorded proximal and distal to a segment of the anterior descending branch of the left coronary artery. The pressure pulse was generated elsewhere in the arterial system during diastole. The volume of the epicardial coronary arteries was calculated from the lengths and diameters as measured in araldite casts, making corrections for in-vitro/in-vivo differences in dimensions. The dynamic capacitance of the right coronary artery, and the anterior descending and circumflex branches of the left coronary artery at an arterial pressure of 13.3 kPa and a frequency between 7 and 30 Hz was found to be 0.0024 +/- 0.0013, 0.0062 +/- 0.0028 and 0.0079 +/- 0.0035 mL/kPa (mean +/- SD), respectively. The total capacitance of the epicardial coronary arteries was calculated to be (0.007 mL/kPa)/100 g, which is small as compared to the total capacitance of the coronary vasculature, including the intramyocardial compartment, which is in the order of (0.5 mL/kPa)/100 g [1].     

Functional changes in human leukemic cell line HL-60. A model for myeloid differentiation

Polar solvents induce terminal differentiation in the human promyelocytic leukemia cell line HL-60. The present studies describe the functional changes that accompany the morphologic progression from promyelocytes to bands and poly-morphonuclear leukocytes (PMN) over 9 d of culture in 1.3 percent dimethylsulfoxide (DMSO). As the HL-60 cells mature, the rate of O(2-) production increase 18-fold, with a progressive shortening of the lag time required for activation. Hexosemonophosphate shunt activity rises concomitantly. Ingestin of paraffin oil droplets opsonized with complement or Ig increases 10-fold over 9 d in DMSO. Latex ingestion per cell by each morphologic type does not change significantly, but total latex ingestion by groups of cells increases with the rise in the proportion of mature cells with greater ingestion capacities. Degranulation, as measured by release of β-glucuronidase, lysozyme, and peroxidase, reaches maximum after 3-6 d in DMSO, then declines. HL-60 cells contain no detectable lactoferrin, suggesting that their secondary granules are absent or defective. However, they kill staphylococci by day 6 in DMSO. Morphologically immature cells (days 1-3 in DMSO) are capable of O(2-) generation, hexosemonophosphate shunt activity, ingestion, degranulation, and bacterial killing. Maximal performance of each function by cells incubated in DMSO for longer periods of time is 50-100 percent that of normal PMN. DMSO- induced differentiation of HL-60 cells is a promising model for myeloid development.     

Uptake and metabolism of enterolactone and enterodiol by human colon epithelial cells

The enterolignans enterolactone and enterodiol are phytoestrogens that are formed from plant lignans by microorganisms in the human colon. Enterolignans circulate in plasma as conjugates. We hypothesized that conjugation of enterolignans takes place in colon epithelial cells, and studied the time course of uptake and metabolism of enterolactone and enterodiol in three human colon epithelial cell lines. In addition, the conjugates were identified by mass spectrometry with accurate mass measurement (LC/QTOFMS/MS). Intracellular levels of conjugated enterolactone and enterodiol in HT29 cells rose immediately after starting the exposure. This was accompanied by a rapid decrease in free enterolactone and enterodiol in the exposure medium of HT29 and (un)differentiated CaCo-2 but not of CCD841CoTr cells. Conjugation and excretion of enterolactone and enterodiol was complete within 8 h, except for enterodiol in CaCo-2 cells ( approximately 48 h). Enterolactone appears to be more rapidly metabolized and/or excreted than enterodiol, and also the appearance of conjugated enterolactone in medium is less affected by the presence of enterodiol than vice versa. Total (free plus conjugated) enterolignan concentrations remained constant throughout the experiments. Three conjugates were identified in exposure medium of HT29 cells: enterolactone-sulfate, enterolactone-glucuronide, and enterodiol-glucuronide.Taken together, our data suggest that phase II metabolism of enterolactone and enterodiol already may take place during uptake in the colon and that colon epithelial cells may be responsible for this metabolism.     

PSC-RANTES blocks R5 human immunodeficiency virus infection of Langerhans cells isolated from individuals with a variety of CCR5 diplotypes

Topical microbicides that effectively block interactions between CCR5(+) immature Langerhans cells (LC) residing within genital epithelia and R5 human immunodeficiency virus (HIV) may decrease sexual transmission of HIV. Here, we investigated the ability of synthetic RANTES analogues (AOP-, NNY-, and PSC-RANTES) to block R5 HIV infection of human immature LC by using a skin explant model. In initial experiments using activated peripheral blood mononuclear cells, each analogue compound demonstrated marked antiviral activity against two R5 HIV isolates. Next, we found that 20-min preincubation of skin explants with each RANTES analogue blocked R5 HIV infection of LC in a dose-dependent manner (1 to 100 nM) and that PSC-RANTES was the most potent of these compounds. Similarly, preincubation of LC with each analogue was able to block LC-mediated infection of cocultured CD4(+) T cells. Competition experiments between primary R5 and X4 HIV isolates showed blocking of R5 HIV by PSC-RANTES and no evidence of increased propagation of X4 HIV, data that are consistent with the specificity of PSC-RANTES for CCR5 and the CCR5(+) CXCR4(-) phenotype of immature LC. Finally, when CCR5 genetic polymorphism data were integrated with results from the in vitro LC infection studies, PSC-RANTES was found to be equally effective in inhibiting R5 HIV in LC isolated from individuals with CCR5 diplotypes known to be associated with low, intermediate, and high cell surface levels of CCR5. In summary, PSC-RANTES is a potent inhibitor of R5 HIV infection in immature LC, suggesting that it may be useful as a topical microbicide to block sexual transmission of HIV.     

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

1. Download high-res image (208KB)
2. Download full-size image