P.H.A. Mutsaers

Pentetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy

SummaryPlatinum distribution was studied in rat peritoneal tumors after i.p. treatment with equimolar doses of carboplatin and cisplatin. Low platinum concentrations (4 ppm) were detected in the periphery of the tumor after carboplatin treatment, whereas no platinum was detected 0.5 mm in from the periphery. In contrast, after cisplatin treatment, high platinum concentrations (29 ppm) were measured in the periphery of the tumor and moderate concentrations (14 ppm) were measured in the center. Only following increased carboplatin doses were low platinum concentrations detectable in the tumor. The total platinum concentration in the tumors was determined after equimolar administration of both drugs. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumors. When single cells were incubated with equimolar concentrations of carboplatin and cisplatin, 6–7 times more platinum was found in cells treated with cisplatin. However, pharmacokinetic studies favored i.p. administration of carboplatin because the clearance of this compound from the peritoneal cavity, expressed ast1/2β, was lower than that of cisplatin (239 vs 78 min), resulting in an AUC in the peritoneal cavity for both total and ultrafiltered drug that was almost 3 times higher for carboplatin than cisplatin. The AUC for ultrafiltered carboplatin in plasma was 2-fold that for cisplatin (2,801±210 vs 1,334±431 μM m). The present study demonstrated that in spite of the pharmacological advantages of carboplatin, its capacity to penetrate into peritoneal tumors and tumor cells is far lower than that of cisplatin.

Platinum distribution inintraperitoneal tumors afterintraperitoneal cisplatin treatment

SummaryThe spatial distribution of platinum (Pt) in the kidney was studied by an autoradiographic technique, in which cisplatin (CDDP) was replaced by195mPt-labeled CDDP, and by proton-induced X-ray emission (PIXE). Although both studies demonstrated comparable spatial distribution patterns, PIXE had the advantage that Pt concentrations could be determined quantitatively, in contrast to the relative information obtained by the autoradiographic technique. Using PIXE, the distribution of Pt in i.p. tumors was studied after i.p. administration of CDDP. The highest Pt concentrations were always found on the periphery of tumors, indicating that the periphery was exposed to a higher drug concentration than the center. Dose was correlated to the concentration of CDDP at both the center and the periphery (r=0.99).The Pt concentration in the periphery was usually higher by a factor of 2–3 after i.p. administration than after i.v. treatment, whereas in the center of the tumor no concentration difference could be detected. The penetration depth of CDDP lay between 1 and 2 mm and was calculated from the differences in Pt concentration after i.p. and i.v. treatment. This indicates that the effective advantage of i.p. chemotherapy with CDDP in cases of cancers limited to the peritoneal cavity is accentuated at the periphery of the tumor.

Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats

The purpose of this study was to optimise intraperitoneal chemotherapy by combining this modality with regional hyperthermia. In vitro data demonstrated that both the uptake of cisplatin into CC531 tumour cells and cytotoxicity were increased at temperatures of 40 degrees C (factor 4) and 43 degrees C (factor 6) compared to 37 degrees C. The increase of intracellular platinum concentration correlated well with the decrease in survival of these cells. In vivo, rats were treated intraperitoneally with cisplatin (5 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3) degrees C and outside the peritoneal cavity 40.5 (0.3) degrees C. Enhanced platinum concentrations were found in peritoneal tumours (factor 4.1) and kidney, liver, spleen and lung (all around a factor 2.0), after combined cisplatin-hyperthermia treatment. The platinum distribution in peritoneal tumours was more homogeneous after the combined treatment than after cisplatin alone, possibly due to increased penetration of cisplatin into peritoneal tumours. Pharmacokinetic data demonstrated an increased tumour exposure for unfiltered platinum in the peritoneal cavity (area under the curve [AUC] increased from 339 mumol/l/min to 486 mumol/l/min at 37 degrees C and 41.5 degrees C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 mumol/min and for ultrafiltered platinum from 22.2 to 107 mumol/l/min at 37 degrees C and 41.5 degrees C respectively. The latter might be due to a slower elimination of platinum from the blood. The combined treatment, intraperitoneal cisplatin and regional hyperthermia, also increased toxicity. The thermal enhancement ratio (TER) using lethality as endpoint was 1.8.

Microcalcifications in Early Intimal Lesions of Atherosclerotic Human Coronary Arteries

Although calcium (Ca) precipitation may play a pathogenic role in atherosclerosis, information on temporal patterns of microcalcifications in human coronary arteries, their relation to expression of calcification-regulating proteins, and colocalization with iron (Fe) and zinc (Zn) is scarce. Human coronary arteries were analyzed post mortem with a proton microprobe for element concentrations and stained (immuno)histochemically for morphological and calcification-regulating proteins. Microcalcifications were occasionally observed in preatheroma type I atherosclerotic intimal lesions. Their abundance increased in type II, III, and IV lesions. Moreover, their appearance preceded increased expression of calcification-regulating proteins, such as osteocalcin and bone morphogenetic protein-2. In contrast, their presence coincided with increased expression of uncarboxylated matrix Gla protein (MGP), whereas the content of carboxylated MGP was increased in type III and IV lesions, indicating delayed posttranslational conversion of biologically inactive into active MGP. Ca/phosphorus ratios of the microcalcifications varied from 1.6 to 3.0, including amorphous Ca phosphates. Approximately 75% of microcalcifications colocalized with the accumulation of Fe and Zn. We conclude that Ca microprecipitation occurs in the early stages of atherosclerosis, inferring a pathogenic role in the sequel of events, resulting in overt atherosclerotic lesions. Microcalcifications may be caused by local events triggering the precipitation of Ca rather than by increased expression of calcification-regulating proteins. The high degree of colocalization with Fe and Zn suggests a mutual relationship between these trace elements and early deposition of Ca salts.

Atherosclerosis : contrast-enhanced MR imaging of vessel wall in rabbit model-comparison of gadofosveset and gadopentetate dimeglumine

PURPOSE To investigate the potential of gadofosveset for contrast material-enhanced magnetic resonance (MR) imaging of plaque in a rabbit model of atherosclerosis. MATERIALS AND METHODS All experiments were approved by the animal ethics committee. Thirty-one New Zealand White rabbits were included in one of four study groups: animals with atherosclerosis imaged with gadofosveset (n = 10) or gadopentetate dimeglumine (n = 7) and control animals imaged with gadofosveset (n = 7) or gadopentetate dimeglumine (n = 7). Aortic atherosclerosis was induced through endothelial denudation combined with a cholesterol-enriched diet. Control rabbits underwent a sham surgical procedure and received a regular diet. After 8 weeks, pre- and postcontrast T1-weighted MR images of the aortic vessel wall were acquired. Relative signal enhancement was determined with dedicated software. Statistical analysis was performed by using a generalized linear mixed model. Immunohistochemical staining with CD31 and albumin was used to assess microvessel density and the albumin content of the vascular wall. Group differences were analyzed by using a chi(2) test. Gadofosveset spatial distribution and content within the vessel wall were determined with proton-induced x-ray emission (PIXE) analysis. RESULTS Postcontrast signal enhancement was significantly greater for atherosclerotic than for control animals imaged with gadofosveset (P = .022). Gadopentetate dimeglumine could not enable discrimination between normal and atherosclerotic vessel walls (P = .428). PIXE analysis showed higher amounts of gadopentetate dimeglumine than gadofosveset in both atherosclerotic and normal rabbit aortas. Immunohistochemical staining revealed the presence of albumin and increased microvessel density in the vascular walls of atherosclerotic rabbits. CONCLUSION These results suggest that gadofosveset can be used to differentiate between atherosclerotic and normal rabbit vessel walls. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/250/3/682/DC1.

Simulated performance of an ultracold ion source

At present, the smallest spot size which can be achieved with state-of-the-art focused ion beam (FIB) technology is mainly limited by the chromatic aberrations associated with the 4.5 eV energy spread of the liquid-metal ion source. Here we numerically investigate the performance of an ultracold ion source which has the potential for generating ion beams which combine high brightness with small energy spread. The source is based on creating very cold ion beams by near-threshold photoionization of a laser-cooled and trapped atomic gas. We present ab initio numerical calculations of the generation of ultracold beams in a realistic acceleration field and including all Coulomb interactions, i.e., both space charge effects and statistical Coulomb effects. These simulations demonstrate that with existing technology reduced brightness values exceeding 105 A m−2 sr−1 V−1 are feasible at an energy spread as low as 0.1 eV. The estimated spot size of the ultracold ion source in a FIB instrument ranges from 10 nm at ...

Direct measurement of synchronization between femtosecond laser pulses and a 3 GHz radio frequency electric field inside a resonant cavity

We demonstrate a method to measure synchronization between femtosecond laser pulses and the electric field inside a resonant 3 GHz radio frequency (RF) cavity. The method utilizes the Pockels effect in a crystal inside the RF cavity by measuring the retardation of the components of polarization as a function of RF phase. Resolution of the setup used is shown to be 29 ± 2 fs (root-mean-square, rms), with timing jitter between the laser pulses and the RF field inside the cavity of 96 ± 7 fs (rms). The method provides a tool to reduce jitter and improve time-resolution in ultrafast electron diffraction experiments.

Compact, low power radio frequency cavity for femtosecond electron microscopy

Reported here is the design, construction, and characterization of a small, power efficient, tunable dielectric filled cavity for the creation of femtosecond electron bunches in an existing electron microscope without the mandatory use of femtosecond lasers. A 3 GHz pillbox cavity operating in the TM(110) mode was specially designed for chopping the beam of a 30 keV scanning electron microscope. The dielectric material used is ZrTiO(4), chosen for the high relative permittivity (ε(r) = 37 at 10 GHz) and low loss tangent (tan δ = 2 × 10(-4)). This allows the cavity radius to be reduced by a factor of six, while the power consumption is reduced by an order of magnitude compared to a vacuum pillbox cavity. These features make this cavity ideal as a module for existing electron microscopes, and an alternative to femtosecond laser systems integrated with electron microscopes.

NUCLEAR MICROPROBE DESIGN

Abstract Nuclear microprobes with a spatial resolution in the micron or smaller range require high-quality focusing systems. Important accelerator parameters for the design are the brightness and the beam energy spread. Ion-optical calculations are necessary to support the choice of focusing device that should be used. Parasitic aberrations, such as those associated with quadrupole misalignments have to be kept low to prevent beam spot enlargement. A scanning device is used when excessive heat damage should be prevented. A versatile vacuum chamber should be built to facilitate the necessary analytical detection techniques. In this paper some aspects of nuclear microprobe design are presented.

Intra-Section Analysis of Human Coronary Arteries Reveals a Potential Role for Micro-Calcifications in Macrophage Recruitment in the Early Stage of Atherosclerosis

Background Vascular calcification is associated with poor cardiovascular outcome. Histochemical analysis of calcification and the expression of proteins involved in mineralization are usually based on whole section analysis, thereby often ignoring regional differences in atherosclerotic lesions. At present, limited information is available about factors involved in the initiation and progression of atherosclerosis. Aim of This Study This study investigates the intra-section association of micro-calcifications with markers for atherosclerosis in randomly chosen section areas of human coronary arteries. Moreover, the possible causal relationship between calcifying vascular smooth muscle cells and inflammation was explored in vitro. Technical Approach To gain insights into the pathogenesis of atherosclerosis, we performed analysis of the distribution of micro-calcifications using a 3-MeV proton microbeam. Additionally, we performed systematic analyses of 30 to 40 regions of 12 coronary sections obtained from 6 patients including histology and immuno-histochemistry. Section areas were classified according to CD68 positivity. In vitro experiments using human vascular smooth muscle cells (hVSMCs) were performed to evaluate causal relationships between calcification and inflammation. Results From each section multiple areas were randomly chosen and subsequently analyzed. Depositions of calcium crystals at the micrometer scale were already observed in areas with early pre-atheroma type I lesions. Micro-calcifications were initiated at the elastica interna concomitantly with upregulation of the uncarboxylated form of matrix Gla-protein (ucMGP). Both the amount of calcium crystals and ucMGP staining increased from type I to IV atherosclerotic lesions. Osteochondrogenic markers BMP-2 and osteocalcin were only significantly increased in type IV atheroma lesions, and at this stage correlated with the degree of calcification. From atheroma area type III onwards a considerable number of CD68 positive cells were observed in combination with calcification, suggesting a pro-inflammatory effect of micro-calcifications. In vitro, invasion assays revealed chemoattractant properties of cell-culture medium of calcifying vascular smooth muscle cells towards THP-1 cells, which implies pro-inflammatory effect of calcium deposits. Additionally, calcifying hVSMCs revealed a pro-inflammatory profile as compared to non-calcifying hVSMCs. Conclusion Our data indicate that calcification of VSMCs is one of the earliest events in the genesis of atherosclerosis, which strongly correlates with ucMGP staining. Our findings suggest that loss of calcification inhibitors and/or failure of inhibitory capacity is causative for the early precipitation of calcium, with concomitant increased inflammation followed by osteochondrogenic transdifferentiation of VSMCs.