Dynamic Contrast-enhanced MR Imaging of Carotid Atherosclerotic Plaque: Model Selection, Reproducibility, and Validation.

Purpose: compare four known pharmacokinetic models for their ability to describe dynamic contrast material-enhanced magnetic resonance (MR) imaging of carotid atherosclerotic plaques, to determine reproducibility, and to validate the results with histologic findings. Materials and Methods: The study was approved by the institutional medical ethics committee. Written informed consent was obtained from all patients. Forty-five patients with 30%-99% carotid stenosis underwent dynamic contrast-enhanced MR imaging. Plaque enhancement was measured at 16 time points at approximately 25-second image intervals by using a gadolinium-based contrast material. Pharmacokinetic parameters (volume transfer constant, Ktrans; extracellular extravascular volume fraction, v e; and blood plasma fraction, v p) were determined by fitting a two-compartment model to plaque and blood gadolinium concentration curves. The relative fit errors and parameter uncertainties were determined to find the most suitable model. Sixteen patients underwent imaging twice to determine reproducibility. Carotid endarterectomy specimens from 16 patients who were scheduled for surgery were collected for histologic validation. Parameter uncertainties were compared with the Wilcoxon signed rank test. Reproducibility was assessed by using the coefficient of variation. Correlation with histologic findings was evaluated with the Pearson correlation coefficient. Results: The mean relative fit uncertainty (+/- standard error) for Ktrans was 10% +/- 1 with the Patlak model, which was significantly lower than that with the Tofts (20% +/- 1), extended Tofts (33% +/- 3), and extended graphical (29% +/- 3) models (P <.001). The relative uncertainty for v p was 20% 6 2 with the Patlak model and was significantly higher with the extended Tofts (46% +/- 9) and extended graphical (35% +/- 5) models (P <.001). The reproducibility (coefficient of variation) for the Patlak model was 16% for Ktrans and 26% for v p. Significant positive correlations were found between Ktrans and the endothelial microvessel content determined on histologic slices (Pearson r = 0.72, P = .005). Conclusion: The Patlak model is most suited for describing carotid plaque enhancement. Correlation with histologic findings validated Ktrans as an indicator of plaque microvasculature, and the reproducibility of Ktrans was good. (C)RSNA, 201

Cell Turnover and Detritus Production in Marine Sponges from Tropical and Temperate Benthic Ecosystems

This study describes in vivo cell turnover (the balance between cell proliferation and cell loss) in eight marine sponge species from tropical coral reef, mangrove and temperate Mediterranean reef ecosystems. Cell proliferation was determined through the incorporation of 5-bromo-2'-deoxyuridine (BrdU) and measuring the percentage of BrdU-positive cells after 6 h of continuous labeling (10 h for Chondrosia reniformis). Apoptosis was identified using an antibody against active caspase-3. Cell loss through shedding was studied quantitatively by collecting and weighing sponge-expelled detritus and qualitatively by light microscopy of sponge tissue and detritus. All species investigated displayed substantial cell proliferation, predominantly in the choanoderm, but also in the mesohyl. The majority of coral reef species (five) showed between 16.1±15.9% and 19.0±2.0% choanocyte proliferation (mean±SD) after 6 h and the Mediterranean species, C. reniformis, showed 16.6±3.2% after 10 h BrdU-labeling. Monanchora arbuscula showed lower choanocyte proliferation (8.1±3.7%), whereas the mangrove species Mycale microsigmatosa showed relatively higher levels of choanocyte proliferation (70.5±6.6%). Choanocyte proliferation in Haliclona vansoesti was variable (2.8–73.1%). Apoptosis was negligible and not the primary mechanism of cell loss involved in cell turnover. All species investigated produced significant amounts of detritus (2.5–18% detritus bodyweight-1·d-1) and cell shedding was observed in seven out of eight species. The amount of shed cells observed in histological sections may be related to differences in residence time of detritus within canals. Detritus production could not be directly linked to cell shedding due to the degraded nature of expelled cellular debris. We have demonstrated that under steady-state conditions, cell turnover through cell proliferation and cell shedding are common processes to maintain tissue homeostasis in a variety of sponge species from different ecosystems. Cell turnover is hypothesized to be the main underlying mechanism producing sponge-derived detritus, a major trophic resource transferred through sponges in benthic ecosystems, such as coral reefs

Similar matrix alterations in alveolar and small airway walls of COPD patients

BACKGROUND: Remodelling in COPD has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recent studies indicate that there is some similarity between alveolar and small airway wall matrix remodelling. The aim of this study was to characterise and assess similarities in alveolar and small airway wall matrix remodelling, and TGF-beta signalling in COPD patients of different GOLD stages. METHODS: Lung tissue sections of 14 smoking controls, 16 GOLD II and 19 GOLD IV patients were included and stained for elastin and collagens as well as hyaluronan, a glycosaminoglycan matrix component and pSMAD2. RESULTS: Elastin was significantly decreased in COPD patients not only in alveolar, but also in small airway walls. Interestingly, both collagen and hyaluronan were increased in alveolar as well as small airway walls. The matrix changes were highly comparable between GOLD stages, with collagen content in the alveolar wall increasing further in GOLD IV. A calculated remodelling index, defined as elastin divided over collagen and hyaluronan, was decreased significantly in GOLD II and further lowered in GOLD IV patients, suggesting that matrix component alterations are involved in progressive airflow limitation. Interestingly, there was a positive correlation present between the alveolar and small airway wall stainings of the matrix components, as well as for pSMAD2. No differences in pSMAD2 staining between controls and COPD patients were found. CONCLUSIONS: In conclusion, remodelling in the alveolar and small airway wall in COPD is markedly similar and already present in moderate COPD. Notably, alveolar collagen and a remodelling index relate to lung function

Early calcifications in human coronary arteries as determined with a proton microprobe

The current paradigm reads that calcifications characterize the advanced and complex lesions in the atherosclerotic process. To explore the possibility that coronary artery wall calcifications already commence at an early stage of atherosclerosis, a combination of proton beam techniques with a (sub-) micrometer resolution, i.e., micro-proton induced X-ray emission, backward and forward scattering spectroscopy, was applied on human coronary arteries with lesions preceding overt atheromas. The detection limits of phosphorus and calcium in each separate pixel, 0.88 * 0.88 µm2 in size, were approximately 150 and 80 µg/g dry weight, respectively. Calcium distributions of entire coronary artery cross section were obtained, and calcifications were demonstrated at a preatheroma stage of the atherosclerotic process. The size of the microcalcifications varied between 1 and 10 µm. The composition of the microcalcifications was deduced from the calcium-to- phosphorus ratio. In order to quantify this ratio, the thickness of the specific X-ray absorber used for PIXE had to be accurately determined. Also, thick target PIXE calculations were performed and the method was validated. The calcium-to-phosphorus ratios of the microcalcifications were assessed with good accuracy and varied from 1.62 to 2.79, which corresponds with amorphous calcium phosphate

Asynchronous electrical activation induces asymmetrical hypertrophy of the left ventricular wall

Background—Asynchronous electrical activation, induced by ventricular pacing, causes regional differences in workload, which is lower in early- than in late-activated regions. Because the myocardium usually adapts its mass and structure to altered workload, we investigated whether ventricular pacing leads to inhomogeneous hypertrophy and whether such adaptation, if any, affects global left ventricular (LV) pump function. Methods and Results—Eight dogs were paced at physiological heart rate for 6 months (AV sequential, AV interval 25 ms, ventricular electrode at the base of the LV free wall). Five dogs were sham operated and served as controls. Ventricular pacing increased QRS duration from 47.2±10.6 to 113±16.5 ms acutely and to 133.8±25.2 ms after 6 months. Two-dimensional echocardiographic measurements showed that LV cavity and wall volume increased significantly by 27±15% and 15±17%, respectively. The early-activated LV free wall became significantly (17±17%) thinner, whereas the late-activated septum thickened significantly (23±12%). Calculated sector volume did not change in the LV free wall but increased significantly in the septum by 39±13%. In paced animals, cardiomyocyte diameter was significantly (18±7%) larger in septum than in LV free wall, whereas myocardial collagen fraction was unchanged in both areas. LV pressure-volume analysis showed that ventricular pacing reduced LV function to a similar extent after 15 minutes and 6 months of pacing. Conclusions—Asynchronous activation induces asymmetrical hypertrophy and LV dilatation. Cardiac pump function is not affected by the adaptational processes. These data indicate that local cardiac load regulates local cardiac mass of both myocytes and collagen

Early calcifications in human coronary arteries as determined with a proton microprobe

The current paradigm reads that calcifications characterize the advanced and complex lesions in the atherosclerotic process. To explore the possibility that coronary artery wall calcifications already commence at an early stage of atherosclerosis, a combination of proton beam techniques with a (sub-) micrometer resolution, i.e., micro-proton induced X-ray emission, backward and forward scattering spectroscopy, was applied on human coronary arteries with lesions preceding overt atheromas. The detection limits of phosphorus and calcium in each separate pixel, 0.88 * 0.88 µm2 in size, were approximately 150 and 80 µg/g dry weight, respectively. Calcium distributions of entire coronary artery cross section were obtained, and calcifications were demonstrated at a preatheroma stage of the atherosclerotic process. The size of the microcalcifications varied between 1 and 10 µm. The composition of the microcalcifications was deduced from the calcium-to- phosphorus ratio. In order to quantify this ratio, the thickness of the specific X-ray absorber used for PIXE had to be accurately determined. Also, thick target PIXE calculations were performed and the method was validated. The calcium-to-phosphorus ratios of the microcalcifications were assessed with good accuracy and varied from 1.62 to 2.79, which corresponds with amorphous calcium phosphate

Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction

Background: Infarct rupture is a usually fatal complication of myocardial infarction (MI), for which no molecular mechanism has been described in humans. Experimental evidence in mouse models suggests that the degradation of the extracellular matrix by matrix metalloproteinases (MMPs) plays an important role in infarct rupture. The present study was designed to study the role of MMP-2, MMP-8, and MMP-9 in human infarct rupture. Methods: Heart samples were obtained from patients who died from infarct rupture and control MI patients. The MMP activity was determined by zymography and quantitative immunocapture activity assay. TIMP-1 levels were measured and immunohistochemistry for MMP-2 and MMP-9 was performed. Results: The amounts of both total and active MMP-8 and MMP-9 were significantly higher in ruptured infarct tissue than in control MI tissue, but no differences in MMP-2 activity were observed. Furthermore, the number of inflammatory cells was significantly higher in the ruptured infarcts than in control infarcts. Conclusions: These data suggest that increased MMP-8 and MMP-9 activity in the infarct area, caused by a more prominent infiltration of inflammatory cells, contribute to infarct rupture in humans. © 2009 Elsevier Inc. All rights reserved

Cell kinetics during regeneration in the sponge Halisarca caerulea: how local is the response to tissue damage?

Sponges have a remarkable capacity to rapidly regenerate in response to wound infliction. In addition, sponges rapidly renew their filter systems (choanocytes) to maintain a healthy population of cells. This study describes the cell kinetics of choanocytes in the encrusting reef sponge Halisarca caerulea during early regeneration (0-8 h) following experimental wound infliction. Subsequently, we investigated the spatial relationship between regeneration and cell proliferation over a six-day period directly adjacent to the wound, 1 cm, and 3 cm from the wound. Cell proliferation was determined by the incorporation of 5-bromo-2′-deoxyuridine (BrdU). We demonstrate that during early regeneration, the growth fraction of the choanocytes (i.e., the percentage of proliferative cells) adjacent to the wound is reduced (7.0 ± 2.5%) compared to steady-state, undamaged tissue (46.6 ± 2.6%), while the length of the cell cycle remained short (5.6 ± 3.4 h). The percentage of proliferative choanocytes increased over time in all areas and after six days of regeneration choanocyte proliferation rates were comparable to steady-state tissue. Tissue areas farther from the wound had higher rates of choanocyte proliferation than areas closer to the wound, indicating that more resources are demanded from tissue in the immediate vicinity of the wound. There was no difference in the number of proliferative mesohyl cells in regenerative sponges compared to steady-state sponges. Our data suggest that the production of collagen-rich wound tissue is a key process in tissue regeneration for H. caerulea, and helps to rapidly occupy the bare substratum exposed by the wound. Regeneration and choanocyte renewal are competing and negatively correlated life-history traits, both essential to the survival of sponges. The efficient allocation of limited resources to these life-history traits has enabled the ecological success and diversification of sponges