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Autoradiographical assessment of inflammation-targeting radioligands for atherosclerosis imaging: potential for plaque phenotype identification
EJNMMI Research volume 11, Article number: 27 (2021)
Many radioligands have been developed for the visualization of atherosclerosis by targeting inflammation. However, interpretation of in vivo signals is often limited to plaque identification. We evaluated binding of some promising radioligands in an in vitro approach in atherosclerotic plaques with different phenotypes.
Tissue sections of carotid endarterectomy tissue were characterized as early plaque, fibro-calcific plaque, or phenotypically vulnerable plaque. In vitro binding assays for the radioligands [111In]In-DOTATATE; [111In]In-DOTA-JR11; [67Ga]Ga-Pentixafor; [111In]In-DANBIRT; and [111In]In-EC0800 were conducted, the expression of the radioligand targets was assessed via immunohistochemistry. Radioligand binding and expression of radioligand targets was investigated and compared.
In sections characterized as vulnerable plaque, binding was highest for [111In]In-EC0800; followed by [111In]In-DANBIRT; [67Ga]Ga-Pentixafor; [111In]In-DOTA-JR11; and [111In]In-DOTATATE (0.064 ± 0.036; 0.052 ± 0.029; 0.011 ± 0.003; 0.0066 ± 0.0021; 0.00064 ± 0.00014 %Added activity/mm2, respectively). Binding of [111In]In-DANBIRT and [111In]In-EC0800 was highest across plaque phenotypes, binding of [111In]In-DOTA-JR11 and [67Ga]Ga-Pentixafor differed most between plaque phenotypes. Binding of [111In]In-DOTATATE was the lowest across plaque phenotypes. The areas positive for cells expressing the radioligand's target differed between plaque phenotypes for all targets, with lowest percentage area of expression in early plaque sections and highest in phenotypically vulnerable plaque sections.
Radioligands targeting inflammatory cell markers showed different levels of binding in atherosclerotic plaques and among plaque phenotypes. Different radioligands might be used for plaque detection and discerning early from vulnerable plaque. [111In]In-EC0800 and [111In]In-DANBIRT appear most suitable for plaque detection, while [67Ga]Ga-Pentixafor and [111In]In-DOTA-JR11 might be best suited for differentiation between plaque phenotypes.
Inflammation plays a crucial role in atherosclerotic plaque formation, progression, and destabilization [1, 2]. Therefore, inflammation is an attractive imaging target for plaque detection [3]. Different plaque compositions present a different likelihood of rupture and subsequent cardiovascular events like myocardial infarction or stroke [4, 5]. Hence, there is a need for (A) plaque detection, and (B) a distinction between plaques in risk of rupture and in need of treatment as opposed to plaques which do not require intervention. As inflammation is a major factor in plaque destabilization, the level of inflammation might be used to identify vulnerable, rupture-prone plaques.
2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) is taken up by metabolically active macrophages in plaque and has been shown to detect plaque inflammation in vivo [6]. However, [18F]FDG lacks specificity for inflammatory cells, and high uptake in the myocardium complicates image interpretation limiting the use of [18F]FDG in the coronary arteries [6, 7]. Therefore, recent research has focussed on the evaluation of other inflammation targeting radioligands.
A number of radioligands have shown good results for plaque detection in recent literature [8,9,10]. Especially imaging of the somatostatin subtype receptor 2 (SST2) and chemokine CXC motif receptor type 4 (CXCR4) seem promising. Coronary plaques were successfully detected by targeting SST2 on activated macrophages with [68Ga]Ga-[DOTA, Tyr3]-octreotate ([68Ga]Ga-DOTATATE) [11]. DOTA-JR11 (DOTA-Cpac[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2) also targets SST2 but has a reported five times higher uptake in tumors than DOTATATE in oncological studies, and a more favorable biodistribution resulting in a higher target to background ratio (TBR) [12,13,14,15]. Recently, we have reported on the successful use of [111In]In-DOTA-JR11 for plaque detection in atherosclerotic mice [16]. CXCR4 can be targeted with Pentixafor, which has shown favorable results for plaque visualization in a number of studies [17,18,19,20,21]. We found that targeting leukocyte function-associated antigen-1 (LFA-1) with radiolabelled DOTA-butylamino-NorBIRT (DANBIRT) was well suited for plaque detection [22, 23]. Moreover, we recently found higher uptake of radiolabelled DANBIRT than of an SST2-targeting radioligand ex vivo in human plaque tissue, as well as different levels of uptake in different plaque phenotypes [24]. Another promising radioligand is radiolabelled DOTA-Bz-EDA-folate (EC0800), which binds to the Folate Receptor (FR). We and others showed the feasibility of FR imaging for plaque detection with a number of different radioligands [25,26,27].
Previous studies mostly focused on plaque detection, and radioligand uptake is usually correlated to plaque presence, symptomatic plaque, or culprit plaque in the event of, e.g., myocardial infarction. To our knowledge, few studies relate radioligand uptake to plaque phenotype or composition (e.g., [28,29,30]). Ideally, future nuclear imaging methods relate radioligand uptake to plaque phenotype, ultimately identifying plaques requiring intervention before a major adverse cardiovascular event occurs. Therefore, we investigated radioligand binding in human plaque samples with different phenotypes. The aim of this study was to investigate which radioligands have a high potential to detect plaque, and which radioligands are most suited to differentiate between different plaque phenotypes. As PET radionuclides offer poor resolution for in vitro binding assays, we labelled the radioligands with SPECT radionuclides.
Study material
Human carotid plaques were obtained with informed consent via carotid endarterectomy from eight patients in the Erasmus MC. Sample acquisition was approved by the medical ethics committee of the Erasmus MC (MEC 2008-147). The samples were snap-frozen in liquid nitrogen and stored in − 80 °C until the experiment started to allow minimal variation between experiments due to, e.g., variations in labelling conditions. Freezing and thawing of tissue is common method of tissue storage, yet might degrade tissue quality [31,32,33]. The samples were embedded in Tissue-Tek O.C.T. compound (Sakura Finetek Europe B.V, Alpen aan den Rijn, The Netherlands) and stored in − 80 °C, after which tissue sections for in vitro binding assays and immunohistochemistry were sectioned at 4 mm intervals. All sections were included in the study (n = 37). The amount of required samples was based on an earlier study performed in our group [24].
Tissue sectioning
Tissue was sectioned at 5 µm for immunohistochemical (IHC) analysis and at 10 µm for in vitro binding assays [autoradiography (ARG)]. In vitro binding assays were performed on adjacent sections for optimal comparison. Similarly, IHC was performed on sections adjacent to the sections used for in vitro binding assays.
DOTATATE, DOTA-JR11 (provided by Helmut Maecke), DANBIRT, and EC0800 (provided by Auspep, Tullamarine, Australia) were labelled with [111In]InCl3 (Covidien, Petten, The Netherlands) with a molar activity of 200 MBq/nmol as described previously [34]. Pentixafor (provided by Hans-Jürgen Wester) was labelled with Gallium-67 (Curium, Petten, The Netherlands), as Indium-111 labelling results in reduced binding affinity [35, 36]. Although Pentixafor is regularly labelled with Ga-68, we used Ga-67 due to its preferable characteristics for autoradiography in terms of half-life and resolution. Labelling with Gallium-67 was performed with a molar activity of 100 MBq/nmol as described [37]. Radiochemical purity (> 95%) and incorporation yield (> 99%) were evaluated with high-pressure liquid chromatography and instant thin-layer chromatography on silica gel. Quenchers were added to prevent radiolysis as described previously [38, 39].
In vitro binding assays and competition binding assays
Sections were incubated for 1 h with 80 µL 10–9 M radiolabelled ligand, the incubation time was determined in our institute and the same for all investigated radioligands. Specificity of the radioligands was demonstrated previously [11, 16, 17, 40,41,42,43,44]. Additionally, we confirmed specific binding in our tissue via competition binding experiments by blocking with 10–6 M unlabelled compound (see Additional file 1: Table S1 in the data supplement). Standards (1 µL of 1:10; 1:100; and 1:1000 diluted incubation buffer in triplo) were added to normalize data. Slides were exposed to phosphor screens overnight and read with a phosphor imager (Cyclone, Perkin Elmer).
Sections were immunohistochemically stained for SST2 (ab134152, Abcam), CXCR4 (ab124824, Abcam), LFA-1 (MCA1848, AbD SeroTec), or FR (AP5032a, Abgent). In short, sections were fixed in cold acetone for 5 min (SST2, CXCR4, LFA-1) or 10% formalin for 10 min (FR), endogenous peroxidase was blocked with 0.3% H2O2 for 30 min (SST2, LFA-1, FR) or 0.15% H2O2 for 20 min (CXCR4), and non-specific binding was blocked with 1% BSA for 20 min (CXCR4) or 2% normal goat serum for 20 min (SST2, LFA-1, FR). The primary antibody was omitted from the protocol in negative controls.
Haematoxylin–eosin staining according to standard protocol was performed on the sections used for in vitro binding assays after radioactivity had sufficiently decayed. These sections were later used for plaque classification.
Plaque classification
Hematoxylin–eosin stained plaque sections where classified by two independent observers according to the criteria used in the adapted American Heart Association (AHA) classification [4, 5, 45]. Plaque phenotypes were categorized into three groups: early plaque; fibro-calcific (FCALC) as stable plaque; and phenotypically vulnerable plaque. Hematoxylin–eosin staining allows the visualization of plaque calcifications [46, 47] to classify FCALC phenotypes. Typical examples of each category are visible in Additional file 1: Figure S1 of the data supplement.
Quantification and statistical analysis
Radioactive signal in whole plaque sections was quantified with Optiquant (Perkin Elmer) by delineating the tissue section based on histology, and expressed in digital light units (DLU). Signal was corrected for radionuclide half-life and exposure time of the phosphor screen to the tissue sections. The amount of DLUs in the standards was quantified via which the percentage of added activity per incubated section was calculated by dividing the DLUs per section by the total amount of DLUs in the 80 µL incubation medium. The percentage added activity was divided by the surface area of each section (in mm2) to calculate the percentage added activity per mm2 (%AA/mm2). For immunohistochemically-stained sections, Biopix software (Biopix AB, Gothenburg, Sweden) was used to calculate the percentage DAB (3,3′-diminobenzidine) positive area per tissue section.
The data were analyzed with SPSS 21.0 (SPSS Inc, Chicago, IL). The data was tested for normality using the Shapiro–Wilk test. Differences between groups were analyzed with the Kruskal–Wallis test, with Dunn's post hoc test to account for multiple comparisons. p values below 0.05 were considered significant. Data are presented as mean ± standard deviation.
Plaque classification
Plaque sections were classified as early plaque (12 samples), stable plaque (10 samples), or phenotypically vulnerable plaque (15 samples) with an interobserver agreement of 97%.
Area of DAB positive staining and radioligand binding
Area of cells expressing radioligand targets
Figure 1a shows the average DAB-positive area for each studied radioligand target and plaque category. All radioligand targets were expressed in larger areas in more advanced plaques than in early plaques (Fig. 1a). No significant differences in areas were observed in early plaque sections. In FCALC plaque sections, the areas containing LFA-1 expressing cells were significantly higher than the areas of FR expressing cells (p < 0.05). In vulnerable plaque sections, FR was expressed in significantly less area than LFA-1 (p < 0.001) and CXCR4 (p < 0.001).
Binding of [111In]In-DANBIRT and [111In]In-EC0800 was highest across plaque phenotypes
Figure 1b shows radioligand binding of the different radioligands across plaque categories. Binding of [111In]In-DANBIRT and [111In]In-EC0800 was highest, followed by [67Ga]Ga-Pentixafor, [111In]In-DOTA-JR11, and [111In]In-DOTATATE. In sections of early plaque lesions, [111In]In-DOTATATE signal (0.00047 ± 0.00017%AA/mm2) was significantly lower than [67Ga]Ga-Pentixafor (0.0053 ± 0.0012%AA/mm2 p < 0.01), [111In]In-DANBIRT (0.026 ± 0.013%AA/mm2) and [111In]In-EC0800 (0.027 ± 0.018%AA/mm2) signal (p < 0.001). [111In]In-DOTA-JR11 signal (0.0027 ± 0.00085%AA/mm2) was also significantly lower than [111In]In-DANBIRT and [111In]In-EC0800 signals (p < 0.001).
In FCALC sections, [111In]In-DOTATATE signal (0.00053 ± 0.000076%AA/mm2) was also significantly lower compared to [67Ga]Ga-Pentixafor (0.0066 ± 0.0014%AA/mm2 p < 0.05), [111In]In-DANBIRT (0.032 ± 0.015%AA/mm2) and [111In]In-EC0800 (0.068 ± 0.050%AA/mm2) (p < 0.001). [111In]In-DOTA-JR11 signal (0.0033 ± 0.0015%AA/mm2) was also significantly lower than [111In]In-DANBIRT (p < 0.01) and [111In]In-EC0800 (p < 0.001).
In vulnerable plaque sections, [111In]In-DOTATATE signal (0.00064 ± 0.00014%AA/mm2) was again lower than that of [67Ga]Ga-Pentixafor (0.011 ± 0.003%AA/mm2 p < 0.05), [111In]In-DANBIRT (0.052 ± 0.029%AA/mm2) and [111In]In-EC0800 (0.064 ± 0.036%AA/mm2 p < 0.001). [111In]In-DOTA-JR11 signal (0.0066 ± 0.0021%AA/mm2) was significantly lower than those of [111In]In-DANBIRT (p < 0.01) and [111In]In-EC0800 (p < 0.001), whereas [111In]In-EC0800 signal was significantly higher than [67Ga]Ga-Pentixafor signal (p < 0.05).
Radioligand binding was higher in advanced plaque phenotypes than in early plaque
Figure 2 shows radioligand binding per radioligand across plaque phenotypes, Additional file 1: Figure S2 shows a more elaborate data presentation with individual data points. All radioligands showed more signal in advanced than in early plaque sections. [111In]In-DOTATATE signal was significantly higher in vulnerable sections than in sections classified as early plaque (0.00064 ± 0.00014 and 0.00047 ± 0.00017%AA/mm2 p < 0.01). [111In]In-DANBIRT and [111In]In-EC0800 also had significantly higher signal in vulnerable sections compared to early plaque (0.052 ± 0.029 vs 0.026 ± 0.013 and 0.064 ± 0.036 vs 0.027 ± 0.018%AA/mm2, respectively. p < 0.05). [111In]In-DOTA-JR11 bound significantly more to vulnerable sections compared to early (0.0066 ± 0.0021 vs 0.0027 ± 0.00085%AA/mm2 p < 0.001) and FCALC sections (0.0033 ± 0.0015%AA/mm2 p < 0.01). [67Ga]Ga-Pentixafor showed a similar binding pattern as [111In]In-DOTA-JR11, with binding in vulnerable sections being higher (0.011 ± 0.003%AA/mm2) than binding in early plaque sections (0.0053 ± 0.0012%AA/mm2 p < 0.001) and FCALC sections (0.0066 ± 0.0014%AA/mm2 p < 0.05).
[111In]In-DOTA-JR11 binding is higher than [111In]In-DOTATATE
There was a clear difference in binding amongst the SST2 targeting radioligands, but the differences were not statistically significant. [111In]In-DOTA-JR11 showed a 5.6 fold higher signal than [111In]In-DOTATATE in early plaque sections, a 6.3 fold higher signal in stable plaques, and a 10.2 fold higher signal in vulnerable plaque sections (Fig. 1b).
Location of binding differs between radioligands
Figure 1c illustrates the differences in radioligand signal and target receptor distribution in vulnerable plaque sections. Figure 2 displays representative examples of radioligand binding and target receptor distribution. Expression of SST2 and signal of [111In]In-DOTATATE and [111In]In-DOTA-JR11 was mostly located in cap areas of plaque. [67Ga]Ga-Pentixafor signal and CXCR4 expression was located in cap areas as well as around calcified nodes. [111In]In-DANBIRT signal and LFA-1 expression was visible on the medial side of the necrotic core, in cap areas, and around calcium deposits. Signal of [111In]In-EC0800 and expression of FR was mostly located at areas close to the artery lumen, and in areas at the edge of the tunica media. Signal of [67Ga]Ga-Pentixafor and [111In]In-DOTA-JR11 differed most between vulnerable plaque sections and early or stable plaque sections.
A large number of inflammation targeted radioligands has been studied for atherosclerotic plaque detection [8,9,10]. We examined the binding of several promising inflammation targeted radioligands and the distribution of cells expressing the radioligand targets in sections of different plaque phenotypes. For all radioligands, we found higher levels of binding in advanced, vulnerable plaque sections than in early plaque sections. The same pattern was visible for the portion of plaque area expressing the radioligand targets. Our key findings highlight how in vitro binding differs between these radioligands and between plaque phenotypes. The results indicate that some radioligands might be better suited for plaque detection, with a higher uptake across plaque phenotypes, whereas other radioligands appear useful to differentiate between plaque phenotypes and therefore identify plaques in need of treatment. Specifically, we found significantly higher binding of [111In]In-DANBIRT and [111In]In-EC0800 across plaque phenotypes compared to the other radioligands. Binding of [111In]In-DOTA-JR11 and [67Ga]Ga-Pentixafor differed the most between vulnerable plaque sections and sections of the other plaque phenotypes. These results could help interpret results of in vivo studies, expanding meaning of uptake in nuclear scans beyond plaque presence or identification of culprit plaque.
We studied in vitro binding of radioligands in tissue sections of atherosclerotic plaque. Binding differs strongly between in vitro assays and in vivo. The mechanisms of uptake could differ, expression of receptors might be influenced differently in vivo, and radioligands in vivo often only get a limited number of passes along tissues to reach their target receptor before being cleared from the blood. Moreover, background signal from other tissues might be high in vivo. Also, the effects of freezing or tissue degradation can play a role in in vitro binding. Despite these important differences between in vitro and in vivo, our approach provides valuable information. The targets are optimally reachable in 10 µm sections, the radioligands get sufficient time to bind to available receptors, and there are no imaging artefacts related to resolution, spill over, or attenuation. Therefore, our approach mimics the potential binding of the radioligands in the examined tissues and might give an indication of an idealized uptake that might be achieved in vivo.
We examined radioligand binding using SPECT radionuclides, as these offer a better spatial resolution in autoradiography than PET radionuclides. However, in a clinical setting PET is preferred as it has a higher spatial resolution than SPECT. Although labelling with different radionuclides can result in differences in binding affinity, all investigated targets have been examined with PET radionuclides with good results. We therefore believe our results are translatable to clinical practice.
Recent studies suggest that SST2 targeting with DOTATATE is a viable strategy for plaque detection [40, 48,49,50,51,52]. Tarkin and colleagues showed that [68Ga]Ga-DOTATATE could better discriminate between high-risk and low-risk plaques compared to [18F]FDG [11]. However, another study found that imaging with [68Ga]Ga-DOTATATE could not differentiate between symptomatic plaque and the contralateral artery, and in line with these results found no SST2 expressing cells in plaque [53]. Furthermore, the aorta to blood ratio of [68Ga]Ga-DOTATATE found by Rinne et al. [49] was lower than one, which further indicates that in vivo imaging with this radioligand requires optimization. Our in vitro results could in part explain these discrepancies. We clearly demonstrated the presence of SST2 expressing cells in human carotid tissues and found localized binding of [111In]In-DOTATATE. However, [111In]In-DOTATATE signal was much lower than signal of the other studied radioligands. Moreover, binding of [111In]In-DOTATATE between sections of different plaque phenotypes showed the least difference of all investigated radioligands. Although imaging of atherosclerosis with DOTATATE is valid for plaque detection, these results confirm the need for further optimization.
DOTA-JR11 could provide a significant improvement in SST2 imaging. Oncological studies reported a much higher uptake and TBR of DOTA-JR11 than DOTATATE, ranging from 2 to 20 fold more [12,13,14,15]. The mechanism for this difference in uptake between the SST2 targeting radioligands remains to be elucidated, it is hypothesized that antagonistic ligands such as DOTA-JR11 bind more binding sites than agonistic ligands such as DOTATATE [54]. We recently found that [111In]In-DOTA-JR11 could be used to detect atherosclerotic plaques in vivo in an animal model of atherosclerosis with high specificity [16]. Our current results showed a 10.2 fold higher signal of [111In]In-DOTA-JR11 over [111In]In-DOTATATE in vulnerable plaque sections. Moreover, binding of [111In]In-DOTA-JR11 differed significantly between plaque phenotypes, which indicates that DOTA-JR11 could be useful to discriminate between different plaque phenotypes. These results strongly suggest that imaging SST2 with DOTA-JR11 is a relevant strategy for plaque detection and characterization.
Similarly to DOTA-JR11, we found high binding of [Ga67]Ga-Pentixafor, and significantly different binding between plaque phenotypes. In line with our findings, Derlin et al. [18] found more CXCR4 expressing cells in symptomatic plaques than in asymptomatic plaque tissue. Similar findings were reported via mRNA and IHC assays, with more CXCR4 expression in late stage plaque [21, 55, 56]. Combined with our data these and other studies mark Pentixafor as an important radioligand for atherosclerosis detection and characterization [17, 19, 20, 57,58,59].
[111In]In-DANBIRT binding differed strongly from binding of [111In]In-DOTATATE, [111In]In-DOTA-JR11, and [Ga67]Ga-Pentixafor. Binding of [111In]In-DANBIRT was located at the same locations, but was in addition high at the medial side of the necrotic core. The high signal and binding in more areas compared to the other radioligands was in line with the target findings. Earlier studies showed high specificity of DANBIRT, and in vivo experiments in animal models of atherosclerosis show promising results [23, 42, 43]. Moreover, our group also found different levels of [111In]In-DANBIRT uptake in phenotypically different plaque tissues ex vivo [24]. Combined with the high binding of [111In]In-DANBIRT in our tissue sections this suggests that this radioligand is relevant for plaque detection and characterization.
[111In]In-EC0800 binding was highest across plaque phenotypes in the examined panel of radioligands, and its signal was significantly higher in sections classified as vulnerable plaque than in early plaque sections. Imaging of FR is extensively studied in atherosclerosis with different imaging probes in vivo in animal models of atherosclerosis [26, 27, 60, 61] and in vitro in human tissue [27, 62,63,64]. Müller et al. found higher FR expression and higher signal of a FR targeting radioligand in sections of plaque compared to normal arterial wall, but no significant differences between sections of plaque classified as stable or vulnerable [64]. In contrast, our group showed in vivo uptake of [111In]In-EC0800 in a mouse model of atherosclerosis and found higher [111In]In-EC0800 uptake in stable plaque compared to vulnerable plaque [26]. Jager et al. linked FR expression to presence of M1-like macrophages [62]. None of the studies examining in vitro expression or imaging of FR reported uptake or binding in the edges of tissue sections, like we observed in our study. FR staining confirmed FR expression in these locations, therefore binding of EC0800 in these locations is not an artefact. However, additional staining for CD68 (data not shown) shows no presence of macrophages in these areas. FR expression is not limited to macrophages, further studies into the binding or uptake of FR targeting radioligands are therefore recommended.
Few imaging studies make head-to-head comparisons between radioligands or relate radioligand uptake to plaque composition beyond identification of clinically identified culprit plaque. Our and various other studies can aid the development of new imaging strategies [29, 49] and are useful to translate in vivo signal to characterization of plaque status. For example, Rinne et al. examined multiple radioligands in an in vivo model of atherosclerosis, and Borchert et al. investigated uptake of multiple radioligands in vitro in different leukocyte subtypes [29, 49]. Such studies can be used to identify which radioligands are most suited for plaque detection and for identification of vulnerable plaques in need of intervention. Our results warrant further clinical translation studies of plaque imaging using these new radioligands.
This in vitro study indicates that DANBIRT and EC0800 are most suited for plaque detection given the high levels of binding. DOTA-JR11 and Pentixafor are best suited to differentiate between stable and vulnerable plaque based on the high differences in binding of these radioligands in phenotypically stable and vulnerable plaques. As in vivo studies with these radioligands show promising results for plaque detection, our findings indicate that further clinical evaluations for plaque characterization are warranted.
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This work was supported by a grant from the University Medical Center Erasmus MC.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Erasmus Medical Centre's research committee (MEC 2008-147) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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J.P. Norenberg holds patents on DANBIRT (US Patent Nos. 8,097,237; 8,435,489; 8,623,322; 8,834,838; 9,352,059; 9,546,186).
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Additional file 1: Supplemental Figure 1
. Haematoxylin-eosin stained plaque sections of typical examples of early, FCALC, and vulnerable plaque. Supplemental Figure 2. Expression of radioland targets and binding of radioligands in plaque sections. Supplemental Table 1. Results of blocking studies.
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Meester, E.J., de Blois, E., Krenning, B.J. et al. Autoradiographical assessment of inflammation-targeting radioligands for atherosclerosis imaging: potential for plaque phenotype identification. EJNMMI Res 11, 27 (2021). https://doi.org/10.1186/s13550-021-00772-z
DOI: https://doi.org/10.1186/s13550-021-00772-z


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Happy 2010!
Happy New Year, everyone!
New Years is my favorite holiday of all time. I like the feeling of shiny newness. How did you ring in the new decade? I went to the Labyrinth masquerade ball! David Bowie...fairies...and "dance, magic, dance!"
I've got a lot of plans for 2010...expect my site and blog to get some revamping later on! I've been very busy over the holidays, but there are posts coming up as I catch up on my blog work.
Here's me ready to masquerade:

subset: commoncrawl


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Pumpkin smoothie Recipe: Healthy and Nutritious
Pumpkin smoothie is the perfect breakfast on the go for the pumpkin obsessed. It is an effortless lip-smacking way to power you through the first half of the day.
Pumpkin smoothie Benefit
Pumpkin is a weight-loss-friendly food because you can consume more of it than other carb sources like rice and potatoes but, still take in fewer calories.
What's more, pumpkin is a good source of fiber, which can help curb your appetite.
Healthy pumpkin smoothie is loaded with antioxidants and vitamins, high in protein, and rich in fiber.
Simply put, this protein-packed tropical smoothie is like drinkable pumpkin pie!
If you love pumpkin pie then give this easy smoothie a try.
Fancy a slice of pumpkin pie but not in the mood for baking? This pumpkin pie smoothie is for you!
Indisputable, it's like pumpkin pie in a glass.
A smoothie that combines simple ingredients for a tasty fall treats!
You get the taste and the enjoyment without even having to put your oven on.
And guess what? It tastes like pumpkin pie! This smoothie comes together in 5 minutes and requires just 7 ingredients.
The ingredients are so simple you likely have them in your storeroom right now.
Pumpkin Smoothie Recipe: How to Make
This easy smoothie is velvety smooth, ice-cold and refreshing and combines the best fall flavors in a glass!
Pumpkin puree is the foundation of this recipe.
Make a lower-calorie smoothie by using unsweetened/unflavored pure pumpkin puree, nonfat plain yogurt, and the sweetener of your choice.
(Add vegetable like spinach and you have pumpkin pie green smoothie)
To make this smoothie you need to have some frozen bananas on hand.
Peel them, break them into quarters and freeze in a freezer bag. That way you are always set for any smoothie craving that comes your way.
And if you're not a huge banana fan, never fear! You really can't taste the banana flavor once blended with other flavors.
Frozen banana adds natural sweetness and frostiness, and the pumpkin pie spices and maple syrup transform it into a true pumpkin spice smoothie.
Vanilla protein powder is a great way of adding more protein for extra flavor and nutrition!
- 1 cup milk
- ½ cup pumpkin puree
- 1 tablespoon maple syrup
- ½ cup yogurt
- ¼ teaspoon pumpkin pie spice or cinnamon
- Splash vanilla
- 1 frozen banana
- Combine the milk, pumpkin puree, yogurt, maple syrup, pie spice, vanilla, and banana in a blender and blend until combined.
Nutrition Facts
Per Serving:
247 calories; 6.1 g total fat; 2.3 g saturated fat; 11 mg cholesterol; 120 mg sodium. 740 mg potassium; 41.9 g carbohydrates; 5.9 g fiber; 24 g sugar; 10.2 g protein; 12921 IU vitamin a iu; 14 mg vitamin c; 38 mcg folate; 343 mg calcium; 2 mg iron; 61 mg magnesium; 4 g added sugar.
Have it for breakfast, or for a snack, or a dessert or whenever you want.
Sprinkle some pumpkin pie spice on top for extra deliciousness and enjoy!
Want to Make This Recipe Vegan?
Simply sub the plain yogurt with almond milk yogurt, cashew butter (for extra creaminess), or more almond milk!


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Jennifer Allebach Joins MDA as Senior Vice President of Recreation and Camp Programs
Each year, so many MDA kids and their families can't wait for MDA Summer Camp. Jennifer Allebach, MDA's new senior vice president of Recreation and Camp Programs, can't wait to welcome them. Jennifer joined MDA in May after a long career with Girl Scouts of the USA, where she worked in adult program development, volunteer . . .


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All forms of gambling have their own myths and superstitions. People believe all kinds of different things will bring them luck or give them the best chances of making a big win. Occasionally, there's a factual basis for the belief and applying the rules will produce a better outcome. More often than not, the myth is just what the word usually means – a story we tell ourselves and hope in vain it will prove true.
Slot machines are probably the most popular of all the casino games. They are easy to play without any of the more complicated sets of rules, strategies or odds you should learn before playing some of the other games. But, just because they are easy to play does not mean there is nothing to learn about them. In reality, the design has changed dramatically over the years from relatively simple sets of mechanical reels to complicated pieces of software with a random number generator inside. The result is that the odds of winning are now better than they were. In fact, there are far worse games to play in a casino and, in some of the traditional games, there are bets you can make that have poorer odds of winning. Free online slots in Canada are a good fun way of winning a little from time to time.
The biggest myth is that there are things you can do to shade the odds in your favor. In reality, all slots are set up to maintain the house edge. The software is set up to do two things:
- To fix the odds on winning. This gives the casino enough money to pay out to all the winners and leave enough to pay the staff and bank the profits. That means, before you start, you should set yourself a budget. You can be playing for fun or playing more seriously. Either way, decide how much you can afford to lose in a session and, when you get to that amount, stop.
- The software produces "near misses" so that you are encouraged to play more. A lot of people believe that a "near miss" means a jackpot is near. This is not the case. The software will only pay out a jackpot when the casino has enough money in the bank to pay it. If you look at the Play Table, you will see that most combinations pay nothing. The majority of the winning lines only pay small amounts and only one or two lines pay out a big amount. So, as a matter of probability, you only have a few chances of winning on each spin. Now add in the fact that the random number generator is programmed to maintain the house edge.
So, when you put everything together, the basics of how to play slots are easy to learn. Once mastered, you can quickly adapt to all the new variations. The chances of multiple small wins is quite good although, in the long term, the house edge will prevail. This makes slots an exciting way of passing the time with a reasonable chance of winning a little if your luck is in.


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Below is a list of the top and leading Financial Management Services in New York. To help you find the best Financial Management Services located near you in New York, we put together our own list based on this rating points list.
New York's Best Financial Management Services:
The top rated Financial Management Services in New York are:
- Altfest Personal Wealth Management – provides comprehensive and truly objective approach to financial management.
- Earn into Wealth – offers sustainable, long-term strategies that fit your lifestyle
- Beekman Financial Planning, LLC – your partner in money decisions
- Vital Planning Group – provides a simplified financial planning
- Astra Strategic Wealth – brings your financial goals into focus
Altfest Personal Wealth Management
When you are in search for a financial advisor who will help and guide you to meet your goals, that is, to protect the financial aspects of your life, then Altfest Personal Wealth Management is an excellent choice. Whether it is about loans, credits and debt, education plans, savings or investments, Altfest is your partner in financial management. They are a team of professionals who are devoted, friendly and smart to anticipate your needs and make your life much more easier.
At Altfest, you will learn about knowledge on investments and you'll receive proper guidance on your special financial situation. Their approach is proactive by identifying the risks when it comes to financial management. Altfest makes sure that clients are happy and comfortable with them.
Financial Management, Wealth Management
Address: 445 Park Ave 6th floor, New York, NY 10022
Phone: (212) 406 0850
Website: altfest.com
"My family has been using Altfest for managing our savings and retirement investments practically since the company started. Altfest did very well by my parents, who could retire comfortably because of the company's good management of their accounts." – Barbara Krasnoff
Earn into Wealth
Earn into Wealth provides financial planning and investment management. They care especially for professionals who graduated with lots of credentials and financial accountability. This financial planner encourages clients to invest the same amount of effort to learn about managing personal finances, like the time they've invested to earn their education and credentials. They are ready to help you to achieve financial success same with the professional success you've worked for. Clients are given advice that supports the client's visions which will in turn help them attain financial independence.
Financial Planning, Investment Management
Address: 1460 Broadway, New York, NY 10036
Phone: (646) 494 6220
Website: earnintowealth.com
"It has been a pleasure partnering with Kaya for my finances. I initially went into this partnership with a different mindset of what I "needed" to do with my money, but after providing detailed analysis, Kaya showed me a different perspective. From her consistent check-ins to ensure goals are met to providing very detailed understanding of our strategy, I am confident that EIWS is helping me to reach my financial goals and I am undeniably learning so much along the way!" – Tiffany Sanders
Beekman Financial Planning, LLC
Beekman Financial Planning, LLC is composed of Certified Financial Planners who have extensive years of experience in personal financial planning, investments, retirement planning and education planning to name a few.
Their target market includes retirees, professional, business owners, executives as well as other groups. Beekman's objective is to guide and help clients to achieve their financial goals through planning finances carefully and thoroughly. Through their team's sound judgement and expertise, all your financial aspects can be integrated in one coordinated plan.
Financial Planning, Investment Management
Address: 200 Park Ave 17th Floor, New York, NY 10166
Phone: (212) 729 9244
Website: findoc1.com
"A great financial experience awaits you." – Frederick Weiner
Vital Planning Group
In the field of financial and investment management, Vital Planning Group is also one that offers a customized and comprehensive solutions. Their aim is to plan, grow, protect and preserve the interests of clients in terms of financial aspect.
Their team's approach is based on the needs of a client in its financial situation. In Vital Planning, it takes a four-step process to determine best financial management strategy to enable the clients achieve their life goals. These are analysis, recommendation, implementation and review. With this technique, you can be guaranteed to get the right strategy to attain your financial goals.
Financial Planning, Investment Management
Address: 200 Park Ave #3200b, New York, NY 10166
Phone: (888) 848 2501
Website: vitalplanning.com
"Alex was great to work with!!! I had an issue with my prior employer selling and me potentially being taxed a high amount due to a loan I took against. He was able to get me rolled over into a well performing ira within days!!! Responsive, knowledgeable & courteous!! I highly recommend!!!!" – Trevor Morris
Astra Strategic Wealth
Astra Strategic Wealth is owned by Kevin Peacock, a Certified Financial Planner. It caters various financial advisory services in financial planning and investment management. Astra believes in the uniqueness of the clients. So, the solutions that they offer are designed to suit a variety of tax situations, needs, risk tolerances and financial goals.
Before they come up with a financial strategy then make sure that excellent research is done. Also, Astra ensure that the interest of advisors and clients must be aligned. Upon hearing their client's status, they will work in collaboration to design a customized path towards financial freedom.
Investment Management, Financial Planning
Address: 99 Madison Ave #631, New York, NY 10016
Phone: (800) 805 8740
Website: astrasw.com
"Kevin Peacock and Astra Strategic Wealth create financial success – Period. The methods for investing that Kevin helped me put into place (and catering the plan to my needs of course) has proved to be so very rewarding in so many ways. If you haven't spoken with Kevin about your financial situation and the ways it can be improved, I highly recommend you do so." – Steven Kass
Alain Atkins is the senior editor for Kev's Best. Alain has been working as a journalist for nearly a decade having published pieces in many print and digital publications including the Argus Leader and the Huffing Post. Alain is based in St Louis and covers issues affecting his city and state. When he's not busy in the newsroom, Alain enjoys backpacking.


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Award Number 20-001
- and -
Orangeville Police Services Board
View full-text of this award in PDF or see Summary below
Award Date: | 2020-04-06 |
Arbitrator: |
Bendel, Michael
View awards by Bendel, Michael |
Municipality: |
View awards from Orangeville |
Region: |
View awards from Central |
Classifications: | Associations |
Grievor: | Cst. S. Fisher |
Appearances: |
K. Rowen and S. Chartrand, for the Association, for the Association
D. Mezzabotta, for the Grievor, for the Employer |
Length of Award: | 7 pp |
Collective Agreements Cit. | ---- |
Statutory Cit. | Police Services Act; Criminal Code |
Associations Duty of fair representation - Refusal to provide grievor with legal representation during investigation under Police Services Act - Association did not have exclusive power to represent employees in relation to charges under PSA - Grievance dismissed.
The grievor, a police constable with the Orangeville Police Service, was notified in August 2018 that he was being investigated for the unauthorized removal and disclosure of service property. The association offered to represent him during the investigation but it refused to provide him with legal counsel. No disciplinary charges were laid under the Police Services Act. However, in December 2018 the grievor was charged under the Criminal Code, R.S.C. 1985, c. C-46 with one count of disclosure of a private communication and one count of breach of trust by a public officer. The Criminal Code charges were based on the same facts as those at issue in the investigation under the PSA. The grievor made several requests to the association to cover his legal costs in defending the criminal charges, but the association denied his requests. In May 2019 the grievor filed a rights dispute conciliation application, alleging that the association failed to represent him fairly by refusing to provide him with legal representation in relation to the investigation under the PSA. When conciliation failed to resolve the dispute, the matter proceeded to arbitration as a grievance under the PSA. The association brought a preliminary objection, alleging that the grievance was inarbitrable by reason of its subject matter.
The association acknowledged that, pursuant to the Ontario Court of Appeal's decision in Renauld v. Lasalle (Town of) Police Association (infra), the arbitrator had jurisdiction to hear a duty of fair representation grievance. However, the association maintained that the grievance should be dismissed because the duty of fair representation did not include an obligation to represent members charged with breaches of the PSA. The grievor's representative relied on case law concerning the proper forum for a dispute between a police officer and a police association, as well as the Supreme Court of Canada's decision in Canadian Merchant Service Guild v. Gagnon (infra). She argued that the preliminary objection should be dismissed and the matter should proceed to a hearing on the merits.
Award #
In Gagnon the Supreme Court of Canada held that the duty to represent employees arises out of a bargaining agent's exclusive powers to act on behalf of employees in the bargaining unit. Subsequent case law, including Arbitrator Starkman's second award in Lafrance and North Bay Police Services Board (infra), followed the clear and obvious corollary in Gagnon: namely, that the duty applies only in respect of matters over which a bargaining agent has an exclusive power of representation. The arbitrator agreed with the conclusion in Lafrance that, because a police officer's association did not have exclusive authority to represent the officer in defence of charges under the PSA, the duty of fair representation could not be invoked in relation to charges brought under the Act. Accordingly, he upheld the association's preliminary objection and dismissed the grievance.
Authorities Cited
• Renaud v. LaSalle (Town of) Police Assn. (2006), 216 OAC 1; 154 L.A.C. (4th) 154 (ONCA) • Cumming v. Peterborough Police Assn. 2013 ONCA 670 (CanLII) • Cumming v. Peterborough (City) Police Assn., 2013 ONSC 1544 • Alessandroni and Toronto Police Assn. (unreported) Anderson; July 15, 2016 [OPAC # 16-005] • Dacosta and Brantford Police Assn. (unreported) Bendel; July 8, 2019 [OPAC # 19-004] • LaFrance and North Bay Police Services Board [2009] O.L.A.A. No. 313; (2009), 180 L.A.C. (4th) 385; OPAC # 09-001 • LaFrance and North Bay Police Assn. et al. [2009] O.L.A.A. No. 675; (2010), 187 L.A.C. (4th) 381; OPAC # 09-010 • Luis Lopez, [1989] OLRB Rep. 464 (Ontario Labour Relations Board) • Toronto District School Board, [2002] O.L.R.D. No. 2560 (OLRB) • Bruce-Grey Catholic District School Board, [2003] O.L.R.D. No. 3081 (OLRB) • Sault Ste. Marie Police Assn. and Sault Ste. Marie Police Services Board (Oct. 14, 2005) [OPAC # 15-016]; (2006) 144 L.A.C. (4th) 221 • Canadian Merchant Service Guild v. Gagnon, [1984] S.C.R. 509 ** This award has been selected for publication in Labour Arbitration Cases.
View full-text of this award in PDF


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VIDEO: Volvo Ocean Race sails into Bermuda Triangle
Published on May 4th, 2015
The lack of sounds from rattling winches and crewmembers walking the deck made sure Team Brunel's Stefan Coppers got a good night of sleep. So good actually that he woke up late for his shift to find the eerie wind of the Bermuda Triangle as his only company. Video published on May 4, 2015.


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St Paul's Catholic Primary School
A Voluntary Academy
Aspire not to have more but to be more – St Oscar Romero
Morning Oak Class!
I thought you might prefer to do online times table games instead of the 192. Have a go at the one below or search the internet for some other ones. Don't forget to finish your My Maths too.
For PE today, I thought you could choose between some Just Dance routines or get your heart pumping with a high intensity workout. If you don't like the background music you can always mute the workout and put on your own pumping tunes to get energised!
If you want to film your Just Dance routines or HIT workout I'd love to see them! Upload them to the school blog :)
Good afternoon!
The work for this afternoon is below. We will be focusing on finishing our history topic (we'll finish editing your documentaries when you are back in next week).
I hope you have a productive afternoon and I hope you have a lovely weekend too.
I look forward to seeing you all on Tuesday for Sports Day; don't forget to wear your house colour t-shirt!
As you know, our history topic is slavery. I have uploaded two PowerPoints about famous abolitionists and a famous slave who helped free lots of other slaves.
I'd like you to choose one person to research (using the PowerPoints and the internet) and create either a poster or fact file or slideshow detailing all the information you have found. You can be creative and imaginative as you want in the way you present your work!
I would like you to bring in your finished work next Friday (16th July).


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Go to the NEW FORUM
You can post a list of anywhere between 5 and 20 films (or more, but only 20 will be counted) from the year we're covering. The deciding factor in terms of release dates is the RYM list and the top 10 of each year will go on to the final top 100 round. Since Christmas and New Year are indubitably busy periods for everyone and to avoid a deadline 1 day into the new year we'll take 3 weeks for this year and the deadline is January 9th.
The points scheme is as follows:
1. 50 points
2. 40
3. 35
4. 30
5. 25
6. 20
7. 18
8. 16
9. 14
10. 12
11. 10
10. 9
20. 1
However, these are the maximum amounts of points. If you want to put certain films on your list but don't want to give them too many points, you can choose to give these less points than in this scheme (but never more) to decrease the impact on the overall results. If you don't specifically state that you want to give (some of) your films fewer points, I will assume the standard scheme.
Here are some lists to remind you of the great (or awful) films released in 1995, from a variety of sources:
Very happy about the 1994 results.
All I've really got left to see for 1995 is Dead Man, so can somebody give me 1996 recommendations? All I have on my 1996 list are Fargo, Little Dieter, Secrets & Lies, First Contact, and Beavis & Butthead. All I really have on my list of stuff to see so far is Drifting Clouds and Lone Star.
1995 is a good year (I recommend The Corridor, Fallen Angels), but 1996 seems like one of the weakest years in cinema history.
As I mentioned in another topic on the subject, 1996 is one of the weakest years in entertainment. I always try to find at least 10 8+ albums and films and 10 8.5+ songs for each year, and no year since the late '40s are as hard as 1996 (for music at least, for films I can't find more than five before the 1980s but I'm fairly certain that's more due to my own ignorance than to a lack of good films from that era).
That said, for 1996 I recommend Trainspotting (but I'm guessing you'll have already seen it) and the rather excellent Danish film Pusher.
The only films set in stone on my to-see list so far are Kusturica's Underground and Fallen Angels, but I'm already quite happy with my 1995 list so I could use some 1996 recommendations as well. I suppose I will see "When We Were Kings" and "Secrets & Lies".
1. Ulysses' Gaze / Theo Angelopoulos / Greece
2. Dead Man / Jim Jarmusch / U.S.
3. Leaving Las Vegas / Mike Figgis / U.S.
4. Underground / Emir Kusturica / Yugoslavia
5. Lumiere et Compagnie / Various
6. Clockers / Spike Lee / U.S.
7. Heat / Michael Mann / U.S.
8. Safe / Todd Haynes / U.S.
9. Xich lo / Tran Anh Hung / Vietnam
10. La cite des enfants perdus / Jean-Pierre Jeunet & Marc Caro / France
11. Maborosi / Hirokazu Kore-eda / Japan
12. Fallen Angels / Wong Kar-Wai / Hong Kong
13. Toy Story / John Lasseter / U.S.
14. Shanghai Triad / Zhang Yimou / China
15. Showgirls / Paul Verhoeven / U.S.
01. Kôkaku Kidôtai/Ghost in the Shell (Momaru Oshii)
02. Before Sunrise (Richard Linklater)
03. Se7en (David Fincher)
04. Sense and Sensibility (Ang Lee)
05. Braveheart (Mel Gibson)
06. Twelve Monkeys (Terry Gilliam)
07. Heat (Michael Mann)
08. La Cité des Enfants Perdus (Jean-Pierre Jeunet & Marc Caro)
09. Underground (Emir Kusturica)
10. The Usual Suspects (Bryan Singer)
11. Dead Man Walking (Tim Robbins)
12. La Haine (Mathieu Kassovitz)
13. Mighty Aphrodite (Woody Allen)
14. Leaving Las Vegas (Mike Figgis)
15. Dead Man (Jim Jarmusch)
For 1995, I highly recommend the movie "La Haine". A very hard film by Mathieu Kassovitz with an incredible Vincent Cassel. I think it's the kind of film who punch you !
Try...it's good !
And Zut ! I put "La cité des enfants perdus" in the 1994 list....I will reput in the 1995 list.
1. The Usual Suspects – Bryan Singer
2. Smoke – Wayne Wang & Paul Auster
3. Twelve Monkeys – Terry Gilliam
4. Jumanji – Joe Johnston
5. The Bridges of Madison County – Clint Eastwood
6. Toy Story – John Lasseter
7. Mighty Aphrodite – Woody Allen
8. Nelly et Monsieur Arnaud – Claude Sautet
9. El día de la bestia (The Day of the Beast) - Álex de la Iglesia
10. Boca a boca (Mouth to Mouth) – Manuel Gómez Pereira
11. Éxtasis (Ecstasy) – Mariano Barroso
12. The Beatles Anthology - Kevin Godley, Bob Smeaton & Geoff Wonfor
13. Flirt – Hal Hartley
14. Sostiene Pereira – Roberto Faenza
15. Dead Man – Jim Jarmusch
16. Jade – William Friedkin
17. To Die For – Gus Van Sant
18. Babe – Chris Noonan / George Miller
19. Sense and Sensibility – Ang Lee
20. Nadie hablará de nosotras cuando hayamos muerto (Nobody Will Speak of Us When We're Dead) – Agustín Díaz Yanes
1. Smoke
2. The Usual Suspects
3. Underground
4. Before Sunrise
5. La Haine (Hate)
6. Casino
7. ک سفيد [The White Balloon]
8. Heat
9. 堕落天使 [Fallen Angels]
10. Twelve Monkeys
11. Welcome to the Dollhouse
12. Dead Man
13. Se7en
14. Blue in the Face [Brooklyn Boogie]
15. Four Rooms
16. La cité des enfants perdus [The City of Lost Children]
17. Toy Story
18. Go Now
19. The Basketball Diaries
20. Desperado
The whole top 10 is amazing. Fallen Angels may be my favorite Wong Kar-Wai movie and Casino is my favorite Scorsese.
1 The Usual Suspects
2 Four Rooms
3 Seven
4 Empire Records
5 Kids
6 Angus
7 Clueless
8 Toy Story
1. A Close Shave - Nick Park
2. Les apprentis - Pierre Salvadori
3. The Usual Suspects - Bryan Singer
4. Dead Man - Jim Jarmusch
5. La cérémonie - Claude Chabrol
6. La haine [Hate] - Mathieu Kassovitz
7. Casino - Martin Scorsese
8. Nelly & Monsieur Arnaud - Claude Sautet
9. Se7en - David Fincher
10. Le péril jeune - Cédric Klapisch
11. 堕落天使 [Fallen Angels] - Wong Kar-wai
12. En avoir (ou pas) - Laetitia Masson
13. Pride and Prejudice - Andrew Davies
14. Smoke - Wayne Wang
15. To Die For - Gus Van Sant
16. Underground - Emir Kusturica
17. Le bonheur est dans le pré - Étienne Chatiliez
18. A Comédia de Deus [God's Comedy] - João César Monteiro
19. Twelve Monkeys - Terry Gilliam
1995 was a good year:
2.The Usual Supects
3.Ghost in the Shell (anime)
4.Pride and Prejudice
6.Bridges of Madison County
7.Dead Man
10.Toy Story
11.Leaving Las Vegas
12.12 Monkeys
14.Sense and Sensibility
15.Dead Man Walking
17.Strange Days
18.Memories (anime)
19.The Crossing Guard
20.The Madness of King George
1. The Corridor
2. Fallen Angels
3. The Usual Suspects
4. Before Sunrise
5. Ghost In The Shell
6. Toy Story
7. Twelve Monkeys
8. Leaving Las Vegas
9. Underground
10. Heat
11. Dead Man
12. La Ceremonie
Apollo 13 (1 point)
I got a region free player for Christmas! My horizons have been expanded.
Does anyone know a good place to look for foreign DVDs besides maybe looking at amazon.co.uk or something?
What I really like about Sarunas Bartas (The Corridor) is that I was able to watch three of his films with absolutely no subtitles and still fully understand everything that's going on. I love visual filmmaking that manages to be expressive without relying on dialog.
I also highly recommend The House from 1997.
1) Clueless
2) Leaving Las Vegas
3) Toy Story
4) Nixon - 20
5) Apollo 13 - 18
6) Pocahontas - 10
7) GoldenEye - 5
Wow, City of Lost Children is very, very good. It seriously needs some more votes. And I now really have to watch Delicatessen.
1. Leaving Las Vegas
2. A Close Shave
3. Dead Man Walking
4. 耳をすませば [Whisper of the Heart]
5. Se7en
6. Kids
7. Before Sunrise
8. The Usual Suspects
9. La haine [Hate]
10. Lust och fägring stor [All Things Fair]
11. Underground
12. Smoke
01. La Haine
02. Twelve Monkeys
03. The Beatles Anthology
04. Dead Man Walking
05. Nico Icon
06. Waterworld
07. Seven
08. Dead Man
09. Braveheart
10. Zusje (little sister)
1. The Usual Suspects
2. Toy Story
3. Heat
4. Underground
5. Seven
6. Leaving Las Vegas
7. Apollo 13
8. Before Sunrise
9. Dead Man Walking
10. Casino
1. La Haine (Matthieu Kassovitz)
2. La cérémonie (Claude Chabrol)
3. Twelve Monkeys (Terry Gilliam)
4. Undergroung (Emir Kusturica)
5. La cité des enfants perdus (Jean-Pierre Jeunet)
6. The Bridges of Madison County (Clint Eastwood)
7. Casino (Martin Scorcese)
8. Nelly et Monsieur Arnaud (Claude Sautet)
9. Dead Man (Jim Jarmush)
10. Le bonheur est dans le pré (Etienne Chatillez)
11. Die Hard 3 (John McTiernan)
12. Dead Man Walking (Tim Robbins)
13. Chacun cherche son chat (Cedric Klapisch)
14. Leaving Las-Vegas (Mike Figgis)
15. The Usual Supects (Bryan Singer)
16. L'appât (Bertand Tavernier)
17. Mighty Aphrodite (Woody Allen
18. Zusje (Robert Jan Westdijk)
Since everyone seems to have already voted, and since I was wrong about the deadline being the 1st, I suppose we could end it tonight. Yes/no?
Wait a minute, I gotta drop my list
1. Rumble in the Bronx – Jackie Chan hits a bunch of people
2. Desperado
3. Friday
4. Se7en
5. Tommy Boy
6. Heat
7. Billy Madison
8. Bad Boys
9. Die Hard With A Vengeance
10. Texas Chainsaw Massacre: The Next Generation – Stars a bionic Matthew McConaughey
My own list. Watched Underground but it was a bit too much of a mess to my liking.
1. The Usual Suspects (Bryan Singer)
2. Braveheart (Mel Gibson)
3. Heat (Michael Mann)
4. Casino (Martin Scorsese)
5. Se7en (David Fincher)
6. Before Sunrise (Richard Linklater)
7. The City of Lost Children (Marc Caro / Jean-Pierre Jeunet)
8. Twelve Monkeys (Terry Gilliam)
9. La Haine (Mathieu Kassovitz)
10. Leaving Las Vegas (Mike Figgis)
And here are the results; because of my statement of the deadline being the 9th I will leave the actual vote open for another week, but I believe every single person who has ever voted already voted (except for nj, who only participated in 1990) so I don't expect any more votes.
Title (Director) - Points/Votes/#1s
1. The Usual Suspects (Bryan Singer) - 384/11/4
2. Se7en (David Fincher) - ) - 265/10/1
3. Leaving Las Vegas (Mike Figgis) - 197/9/1
4. Twelve Monkeys (Terry Gilliam) - 187/9/0
5. La Haine [Hate] (Mathieu Kassovitz) - 182/7/2
6. Underground (Emir Kusturica) - 168/8/0
7. Heat (Michael Mann) - 159/8/0
8. Toy Story (John Lasseter) - 155/8/0
9. Before Sunrise (Richard Linklater) - 154/6/0
10. Dead Man (Jim Jarmusch) - 149/9/0
At 15 we had more participants than ever for the '90s poll, which resulted in a lot more points being needed to go to the next round. 'Smoke' would have made it in any other year after the first 6 lists, but with 120 points it just wasn't enough this year.
Richard Linklater joins the group of directors who have 2 films in the next round while Kieslowksi remains the only director with 3 films—something which is extremely likely to change in two weeks.


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With climate change at the forefront of the agenda, there's been much research and discussion into finding an alternative solution to traditional resources of energy. Here are 9 reasons why investing in photovoltaic for your home benefits both you and the environment. 1. No dangerous greenhouse or emissions gases.
Solar power is a clean, sustainable, and green source of energy. 2. PHOTOVOLTAIC technology is low maintenance, durable, and completely noiseless. Unlike wind generators there are no moving parts to break no noise pollution. Installed Once, PV panels require very little maintenance and are durable extremely. There are currently PV panels installed in Japan during the 1960s that are still producing electricity.
3. The sun is an unlimited, free source of energy that's available worldwide. PV panels only require daylight, not sunlight to produce electricity. This means that they are not effective in the summer months just, all year round but, even on cloudy days. 4. Free electricity during the day.
When your PV system is generating electricity throughout the day, you will not have to buy electricity from your supplier. The day can help you save a huge selection of pounds off your electricity expenses Therefore operating appliances during. 5. Solar PV technology is versatile. Depending on your preference, you can select from having PV panels installed onto your existing roof, or integrating the technology into the building materials themselves with solar slates or tiles. 6. PHOTOVOLTAIC is an excellent investment. With the intro of the Feed-In Tariff, homeowners are now paid for every unit of electricity they generate off their PV panels, even if they use it themselves.
- 212 Boston Scientific Corporation (NYSE:BSX) -43.7% 6.55 11.63
- After 6 months we collect 62.5/12 months times .year = 31 5.25. We've 125 + 31.25 = 156.25
- What will "open-ended pooled trust fund" suggest
- At 30, you need: $95,000
- PV = present value (initial deposit)
Solar PV not only supplies the highest payments, however the longest period also. Feed-In Tariff payments are guaranteed for 25 years, associated with inflation and tax-free. This implies your photovoltaic system would pay for itself in less than 8 years and provide comes back on investment of between 8 and 10 percent.
7. Protect yourself from increasing energy prices. The cost of traditional energy sources is is and rising likely to continue to do so. By installing a solar PV system on your home you should have your own way to obtain free electricity and therefore depend less on electricity suppliers to power your home. 8. A solar PV system could raise the value of your home. As it is a source of free income and electricity thanks to the Feed-In Tariff, a photovoltaic system could make your home more attractive to potential buyers. 9. Easy, hassle-free installation. Once a site study has been completed for your home to make sure it is suitable, the installation process is very simple.
It takes only 1 to 2 2 times and normally will not require planning permission. So you own it there, 9 reasons to go solar. Always make sure that you use a completely MCS certified company to install solar power panels on your home in any other case you won't qualify for the Feed-In Tariff. About The Author Katie Marsh can be an expert in neuro-scientific solar PV and Operations Executive for Landmark Solar. Landmark Solar is leading MCS accredited installers of photovoltaic PV panels and solar installations.


text: Release Date: July 2nd, 2007 at 8 PM by Paramount Pictures. The Cast: Shia LaBeouf, Megan Fox, Josh Duhamel, Tyrese Gibson, Rachael Taylor, Anthony Anderson, Jon Voight, John Turturro. Directed by Michael Bay. BASIC PREMISE: 16-year-old Sam (LaBeouf) and his classmate, Mikaela (Fox), join the Autobots to search for the Allspark before the Decepticons use it to destroy the world. ENTERTAINMENT VALUE: Transformers is everything you expect from an ultra-cool summer blockbuster: cool cars, exciting action scenes, slick CGI effect, comic relief, and a charismatic lead joined by a hot babe. In the opening scene, a cube called the Allspark crashes into Earth and it can wipe out the entire planet if the Decepticons get a hold of it. Way out in Qatar, U.S. soldiers lead a battle against strange machines that are actually Decepticons, while Secretary of Defense John Keller (Voight) tries to make sense of everything. Meanwhile, back in the U.S., Sam, a high school teen, just got a new car and tries, unsuccessfully to impress a hot classmate, Mikaela. The map that can locate the Allspark happens to be on ancient glasses which teenage Sam happens to be selling on Ebay, so, soon enough the Decepticons try to find him. From start to finish, it's fun to root for Sam as an underdog who must help save the world and, perhaps, win over the girl of his dreams. Co-screenwriters Alex Kurtzman, Roberto Orci add some well-needed comic relief every so often, especially with the inclusion of the offbeat Agent Simmons, played by the underrated John Turturro. Anthony Anderson also has a funny scene in a small role as a car salesman. Granted, the plot does have some plot holes toward the end and a few clichéd and awkward moments, such as a scene that almost feel like one from American Pie when Sam's parents barge in on him. Just like in Disturbia, Shia LeBeouf proves to be a solid leading man by balancing charisma and toughness without being dull or over-the-top. It also helps that the adventure itself feels exciting and thrilling, especially when Sam befriends the Autobots and realizes his purpose. Director Michael Bay includes his trademark loud explosions, pulse-pounding action scenes, slick visuals along with a fast pace and an exciting musical score. Even at a running time of 2 hours and 20 minutes, Transformers never overstays its welcome. SPIRITUAL VALUE: None is required or desired. INSULT TO YOUR INTELLIGENCE: None, as long as you suspend your disbelief and check your brain at the door. NUMBER OF TIMES I CHECKED MY WATCH: 0 IN A NUTSHELL: An ultra-cool, thrilling and crowd-pleasing summer blockbuster. Bring on Transformers 2! RECOMMENDED WAY TO WATCH: Movie Theater Main Page Alphabetical Menu Chronological Menu The "T" Menu ______________________________________________________ |


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Dreaming of warmer days and splashing water on the beach?
A bit of beach inspiration is what we need in this cold weather. And what better way to capture the beach life with the sun, sand, and sky all smiling at you than to wear coco shell beads. These glorious, stylish yet low maintenance beads are carved from the inner shell of the coconut. They are natural stunners and are just what you need to give yourself a bit of sunshine on chilly fall days.
A few facts about coconuts:
- Coconut comes from the Portuguese word cocos which means grinning face.
- The coconut tree (scientific name: cocos nucifera) is more than just a source for shells. From its leaf down to the last root fiber, each part has a particular use giving it the term "tree of life".
- Coconut husks can be used to create brushes, stuffing for mattresses, ropes, and mats.
Why should you incorporate coco shells in your jewelry designs?
Perfectly cut and sourced from coconut trees, coco shells are usually brown in tone but they can also come in a variety of colors. Even though they are lightweight, each shell is masterfully varnished with a thin coating of natural oil to make it durable. They're also carefully designed and made with a modern appeal.
Since we are already in a time where sustainability is highly practiced, you can ensure that there are no harmful levels of pollution in the creation of coco shell beads. The process apparently employs less energy than other mass-manufactured materials.
Since coco shell beads come in a variety of tones, they can work well with different materials. You can pair them with shell beads, bones, and other natural materials to enhance their organic appeal. You can also dress them up with sterling silver beads or gold-filled bead caps to make them look chic. Aside from being utilized in jewelry, coco shells can be used for macramé, crocheting, and other craft projects.
How to take care of your coco shell beads:
- Instead of using abrasive cleaners, simply wipe your coco shells with a soft wet cloth.
- Avoid using harsh chemicals to prevent the beads from cracking.
- Don't soak them in water or expose to high temperature.
- Take them off before going to bed or taking a shower.
Coco shells beads are great for incorporating into your jewelry projects. They are the "cherry on top" in a sea of sparkling gems and metal components. So go ahead and create your own coco shell jewelry and give yourself a feel of the tropics. Let's face it — who doesn't love that warm fuzzy feeling of long summer days in this cold weather.


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London's tough. We aallll know it. But we've also all stuck with it. Unless you're reading this somewhere that's not London…which is indeed possible…and totally great of course. HI NON-LONDONER! Even those of you reading this in London, we bet you've had some second thoughts about whether or not you're made for this mad city. We know we have! Every. Single. Day. Especially during rush hour. It's not a bad thing, though – always good to question your existence. But to make it easier, we've noted some signs that may just help you out…
1. You hate walking. Or anything involving using your legs.
2. You can't budget.
3. Fresh air makes you happy, and pollution tires you out. (It needs to be the other way around).
4. The sound of sirens will keep you awake at night.
5. You're claustrophobic.
6. You don't have the Fever App. (How else do you plan your social life?!)
7. You can't get yourself home after a night on the sauce.
8. You insist on wearing high heels to work/a night out.
9. You need at least 6 hours of sleep to function. Fat chance. Especially if you're a number 4 too.
10. You're a germaphobe.
11. This is what you look like on the tube whenever someone looks at you…
12. Or this…
13. Instead of this…
14. Going to a laundrette is not an option.
15. Horn beeping raises your blood pressure. (Just not worth the risk…)
16. So does running late…
17. You enjoy knowing 80% of people when you go out.
18. And being at the top of your game/social ladder.
19. You're crap at being rude to anyone.
20. You don't like cities. (Haha, we knew this one would surprise you…)
21. But we just don't get why!
Featured Image Credit: Flickr Bob Rhodes


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2022#14 Readings 🇺🇦🌻
3 minutes read | 538 words by Ruben BerenguelThis has been a really tough week.
Get started | Learning Music (Beta)
This is a very entertainingly guided tutorial to creating simple electronic music, by Ableton. Works in your browser, plenty of examples, easy UI/UX.
Mechanical Watch
A simulation of a mechanical watch, with detailed explanations about how it works. It is impressive.
🛠 Practical Pigment Mixing for Digital Painting
A very understandable paper, and the results are impressive. They have an online demo (compiled to WASM from the C sources) which is very snappy. It's not coming to Procreate though, so I'll probably forget at some point.
Being Glue
Transcribed version of a talk about glue work. I felt very identified. You probably will, too.
Know Your Customers' "Jobs to Be Done"
The JTBD (Jobs to be done) model is pretty common, and this HBR article introduces it pretty well. And from Clayton Christensen, no less.
Delegation is an art, not a science
Well, the post offers some rules and templates to do it. May not be a science, but this helps it make it paint-by-numbers.
Overview of technical writing courses (Google)
I took this… don't remember when. Long time ago. Was "ok" (nothing groundbreaking, but is decent and short), but since I'm renewing my interest in improving documentation/written material I have accumulated a lot of links I may as well share.
Kafka Streams 101
This is long (although there is a lot of code you can just skim), but very detailed. It is very focused on the Scala side of the API, but covers why you'd want to use Kafka streams, how they work and what is done behind the scenes.
🍿 Viewing collaborative editing through a databases lens
A very short talk (10 minutes) by Martin Kleppman with how to view editing via CRDTs from the standpoint of columnar databases, and what it implies for CRDT compression.
Falling Sand
A very complete walkthrough of simulating some falling material, in p5js.
The Mysterious Disappearance of a Revolutionary Mathematician
You can't go wrong by reading yet another story about Grothendieck. This comes from the New Yorker, which means the writing is top.
Some Notes on Executive Dashboards
There are some good points and food for thought in here, particularly around measuring the wrong things and not really measuring up to the future.
Three Summary Leadership Lessons From The One Minute Manager
I really like this book, and is short enough that you should probably read it instead of reading summaries. But well, here's one anyway.


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Worldwide PC shipments totaled 48.9 million units in the second quarter of 2005, a 14.8 percent increase from the same period last year, according to preliminary results by Gartner. The PC market exceeded Gartner's previous projections by 2 percentage points.
Apple Computers showed the biggest growth rate of the top five, with shipments up 31.4 percent, led by the Macintosh makers' strength in the education market, Gartner said. Latin America was the region with strongest growth in PC shipments, up 25.4 percent.
"Demand for mobile form factors accelerated sales during the second quarter," Charles Smulders, vice president of Gartner's Computing Platforms Worldwide Group, said. "Aggressive price cutting was also a significant factor in driving demand for desktop PCs."
Better Than Expected
Dell extended its lead in the worldwide market, accounting for 17.9 percent of global PC shipments. Dell experienced much higher growth rates outside of the United States, but it also grew ahead of the market rate in its domestic market, where the bulk of its shipments are made.
Hewlett-Packard's PC shipments growth rate exceeded the worldwide average, as the company performed well in the Europe, Middle East and Africa (EMEA) and Asia/Pacific regions. The quarter was a transitional time for the company, as Mark Hurd was appointed the new CEO in April, and The Personal System Group (PSG) was split from the Imaging and Printing Group after one quarter. In June, Tom Bradley was appointed as the new head of PSG.
"While the shipment picture was better than Gartner expected, it was another quarter of intense price competition for the PC vendors," Smulders said. "Even so, we expect the operating environment to get yet more difficult in the second half of 2005 as PC replacement opportunities decline."
PC shipments in the United States totaled 15.6 million units, a 10 percent increase from the second quarter of 2004. The U.S. consumer segment did well with robust mobile PC sales.
Aggressive Pricing
Dell did well in the consumer and small and midsize business segments, as its U.S. PC market share reached 32 percent in the second quarter of 2005. Apple experienced the highest growth rate among the top five vendors, as its shipments increased 31.4 percent in the quarter. Gateway increased shipments 26.6 percent, driven by sales through retail.
In the EMEA region, PC shipments increased 18.6 percent in the second quarter. Aggressive PC pricing by vendors has resulted in strong shipment growth.
In the Asia/Pacific region, shipments increased 17.3 percent in the second quarter. Mobile PC growth was very strong in the region, but China and India also attributed solid growth of desk-based PC shipments. In China, the market has been stimulated by the bundling of 17 inch LCD monitors.
Latin America showed the strongest growth in the quarter, as PC shipments increased 25.4 percent. In general, the market continues to enjoy strong macroeconomic performances.


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The way the "New GeForce RTX Family" is being presented, it sure looks like the current-gen RTX 30-series cards will sit alongside the new RTX 40-series GPUs for a good while yet.
"The best gaming platform in the world just got better," says Jen-Hsun Huang at the GeForce Beyond Special Broadcast from GTC. Introducing us to the RTX 4090 (opens in new tab) and RTX 4080 graphics cards, starting at $899 for the cheapest new Lovelace card, Nvidia is leaving a lot of PC gamers out of the next-gen mix.
But by keeping the RTX 30-series cards around alongside the RTX 40-series, it can carry on presenting the RTX Family as a complete ecosystem of GPUs.
"Our 30-series, starting at $329, are the best GPUs in the world serving mainstream gamers," says Huang. "RTX 4090 and RTX 4080 GPUs, starting at $899, deliver the ultimate performance to enthusiasts."
Interestingly, none of the Ti cards are listed on the new family slide, and neither are the RTX 3090 cards.
In light of the price and performance of the RTX 4090 and RTX 4080, there is really no room for those high-end cards, especially as there's no amount of price cutting that could really be done to make them work, given how costly those big chunks of silicon would still be to produce.
Keeping the RTX 3060, RTX 3070, and RTX 3080 around, however, can aid Nvidia to deliver on different price points all the way up to the RTX 40-series stack when it doesn't have Lovelace-based cards to do so. Yet.
We can maybe wish for some price cuts on the RTX 3070 and RTX 3080 in the days to come, but I feel they might be as cheap today as they're going to get. Fingers crossed I'm wrong.


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Yesterday I crocheted butterflies to decorate the dress of my daughter. She was pleased and I decided to share this crochet butterfly pattern with you too. This can be used not only to decorate clothes, but also as part of the decor of your room or as a magnet on your fridge.
Materials: I used yarn Bamboo (70% bamboo fiber, 30 % cotton, 50 gr/200 m) color pink and black and crochet hooks 2 mm and 1 mm.
CH – chain
SC – single crochet
DC – double crochet
TRC – treble crochet
sl.st. – slip stitch
How to crochet butterfly:
Ch 9 and join with sl st to form a ring.
Row 1: Ch 3 (count as 1 dc), 7 dc into the ring.
Row 2: Ch 2, 1 dc in first stitch, 2 dc , 2-dc into same stitch 3 times, 2 dc.
Row 3: Ch 2, 1 dc in first stitch, 3 dc, 2-trc into same stitch, 2 dc, ch 2, sl st, ch 2, 2-dc into same stitch, 2-trc into same stitch, 1 trc. Fasten off. Crochet the second wing in the same way. Starting from the same side.
Change color, I used black. Also I used a smaller crochet hook (1 mm) for tighter crochet.
Row 4: Getting crocheted from the base ring as shown in the diagram. 1 sc into the ring, 5 sc into side stitches of wing, ch 2, 4 sc into 4 dc of last row, 2-sc into same stitch, 2-sc into same stitch, 1 sc, sl st into dc, sl st into center ch-2, sl st into sl st previews row, sl st into center next ch-2, 1 sc, 1 dc, 2-trc into same stitch, 2 dc, ch2, 1 sc into same stitch, 6 sc into side stitches, 1 sc into base ring, (ch 5, picot, 5 sl st into each stitch, 1 sl st into sc) x times, 7 sc into side stitches, ch 2, 2 dc, 2-trc into same stitch, 1 dc, 1 sc, sl st into center ch-2, sl st into sl st previews row, sl st into center next ch-2, sl st into dc, 1 sc, 2-sc into same stitch, 2-sc into same stitch, 4 sc, ch 2, 5 sc into side stitches, sl st into first sc. Fasten off.
If you like my crochet butterfly pattern please share it. I also would be very pleased to know how you applied your butterflies, I am waiting for your comments.
Love, Ana (Bohemian Cat)
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