Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice.

Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to "abortion storms" and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR-/-) mice. In WT mice, 104 PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7-11 days post infection (dpi), whereas 103 PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR-/- mice infected with 103 PFU RVFV developed hepatocellular necrosis resulting in death at 2-5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.

3D nonrigid motion correction for quantitative assessment of hepatic lesions in DCE-MRI.

PURPOSE: To provide nonrigid respiratory motion-corrected DCE-MRI images with isotropic resolution of 1.5 mm, full coverage of abdomen, and covering the entire uptake curve with a temporal resolution of 6 seconds, for the quantitative assessment of hepatic lesions. METHODS: 3D DCE-MRI data were acquired at 3 T during free breathing for 5 minutes using a 3D T1 -weighted golden-angle radial phase-encoding sequence. Nonrigid respiratory motion information was extracted and used in motion-corrected image reconstruction to obtain high-quality DCE-MRI images with temporal resolution of 6 seconds and isotropic resolution of 1.5 mm. An extended Tofts model was fitted to the dynamic data sets, yielding quantitative parametric maps of endothelial permeability using the hepatic artery as input function. The proposed approach was evaluated in 11 patients (52 ± 17 years, 5 men) with and without known hepatic lesions, undergoing DCE-MRI. RESULTS: Respiratory motion produced artifacts and misalignment between dynamic volumes (lesion average motion amplitude of 3.82 ± 1.11 mm). Motion correction minimized artifacts and improved average contrast-to-noise ratio of hepatic lesions in late phase by 47% (p < .01). Quantitative endothelial permeability maps of motion-corrected data demonstrated enhanced visibility of different pathologies (e.g., metastases, hemangiomas, cysts, necrotic tumor substructure) and showed improved contrast-to-noise ratio by 62% (p < .01) compared with uncorrected data. CONCLUSION: 3D nonrigid motion correction in DCE-MRI improves both visual and quantitative assessment of hepatic lesions by ensuring accurate alignment between 3D DCE images and reducing motion blurring. This approach does not require breath-holds and minimizes scan planning by using a large FOV with isotropic resolution.

18F-Fluoroethyl-tyrosine uptake is correlated with amino acid transport and neovascularization in treatment-naive glioblastomas.

PURPOSE: To investigate the in vivo correlation between 18F-fluoroethyl-tyrosine (18F-FET) uptake and amino acid transporter expression and vascularization in treatment-naive glioblastomas. METHODS: A total of 43 stereotactic biopsies were obtained from 13 patients with suspected glioblastoma prior to therapy. All patients underwent a dynamic 18F-FET PET/MRI scan before biopsy. Immunohistochemistry was performed using antibodies against SLC7A5 (amino acid transporter), MIB-1 (Ki67, proliferation), CD31 (vascularization) and CA-IX (hypoxia). The intensity of staining was correlated with 18F-FET uptake and the dynamic 18F-FET uptake slope at the biopsy target point. RESULTS: In all patients, the final diagnosis was IDH-wildtype glioblastoma, WHO grade IV. Static 18F-FET uptake was significantly correlated with SLC7A5 staining (r = 0.494, p = 0.001). While the dynamic 18F-FET uptake slope did not show a significant correlation with amino acid transporter expression, it was significantly correlated with the number of CD31-positive vessels (r = -0.350, p = 0.031), which is line with earlier results linking 18F-FET kinetics with vascularization and perfusion. Besides, static 18F-FET uptake also showed correlations with CA-IX staining (r = 0.394, p = 0.009) and CD31 positivity (r = 0.410, p = 0.006). While the correlation between static 18F-FET uptake and SLC7A5 staining was confirmed as significant in multivariate analysis, this was not the case for the correlation with CD31 positivity, most likely because of the lower effect size and the relatively low number of samples. No significant correlation between 18F-FET uptake and Ki67 proliferation index was observed in our cohort. CONCLUSION: Our results support the findings of preclinical studies suggesting that specific 18F-FET uptake in glioblastomas is mediated by amino acid transporters. As proposed previously, dynamic 18F-FET parameters might be more influenced by perfusion and therefore related to properties of the tumour neovascularization.

Impact of 68Ga-DOTATOC PET/MRI on robotic radiosurgery treatment planning in meningioma patients: first experiences in a single institution.

OBJECTIVEFor stereotactic radiosurgery (SRS) planning, precise contouring of tumor boundaries and organs at risk is of utmost importance. Correct interpretation of standard neuroimaging (i.e., CT and MRI) can be challenging after previous surgeries or in cases of skull base lesions with complex shapes. The aim of this study was to evaluate the impact of 68Ga-DOTATOC PET/MRI on treatment planning for image-guided SRS by CyberKnife.METHODSThe authors retrospectively identified 11 meningioma treatments in 10 patients who received a 68Ga-DOTATOC PET/MRI prior to SRS. The planning target volume (PTV) used for the patients' treatment was defined as the reference standard. This was contoured by a treating radiosurgeon (RS0) using fused planning CT and PET/MRI data sets. The same tumors were then contoured by another experienced radiosurgeon (RS1) and by a less-experienced radiosurgeon (RS2), both blinded to PET data sets. A comparison of target volumes with focus on volume-based metrics and distance to critical structures was performed. RS1 and RS2 also filled in a questionnaire analyzing the confidence level and the subjective need for the implementation of PET data sets for contouring.RESULTSAnalysis showed a subjective personal preference for PET/MRI in all cases for both radiosurgeons, particularly in proximity to critical structures. The analysis of the planning volumes per physician showed significantly smaller RS2-PTV in comparison to RS1-PTV and to RS0-PTV, whereas the median volumes were comparable between RS1-PTV and RS2-PTV (median: RS0: 4.3 cm3 [IQR 3.4-6.5 cm3] and RS1: 4.5 cm3 [IQR 2.7-6 cm3] vs RS2: 2.6 cm3 [IQR 2-5 cm3]; p = 0.003). This was also reflected in the best spatial congruency between the 2 experienced physicians (RS0 and RS1). The percentage of the left-out volume contoured by RS1 and RS2 compared to RS0 with PET/MRI demonstrated a relevant left-out-volume portion in both cases with greater extent for the less-experienced radiosurgeon (RS2) (RS1: 19.1% [IQR 8.5%-22%] vs RS2: 40.2% [IQR 34.2%-53%]). No significant differences were detected regarding investigated critical structures.CONCLUSIONSThis study demonstrated a relevant impact of PET/MRI on target volume delineation of meningiomas. The extent was highly dependent on the experience of the treating physician. This preliminary study supports the relevance of 68Ga-DOTATOC PET/MRI as a tool for radiosurgical treatment planning of meningiomas.

A multi-centre evaluation of eleven clinically feasible brain PET/MRI attenuation correction techniques using a large cohort of patients.

AIM: To accurately quantify the radioactivity concentration measured by PET, emission data need to be corrected for photon attenuation; however, the MRI signal cannot easily be converted into attenuation values, making attenuation correction (AC) in PET/MRI challenging. In order to further improve the current vendor-implemented MR-AC methods for absolute quantification, a number of prototype methods have been proposed in the literature. These can be categorized into three types: template/atlas-based, segmentation-based, and reconstruction-based. These proposed methods in general demonstrated improvements compared to vendor-implemented AC, and many studies report deviations in PET uptake after AC of only a few percent from a gold standard CT-AC. Using a unified quantitative evaluation with identical metrics, subject cohort, and common CT-based reference, the aims of this study were to evaluate a selection of novel methods proposed in the literature, and identify the ones suitable for clinical use. METHODS: In total, 11 AC methods were evaluated: two vendor-implemented (MR-ACDIXON and MR-ACUTE), five based on template/atlas information (MR-ACSEGBONE (Koesters et al., 2016), MR-ACONTARIO (Anazodo et al., 2014), MR-ACBOSTON (Izquierdo-Garcia et al., 2014), MR-ACUCL (Burgos et al., 2014), and MR-ACMAXPROB (Merida et al., 2015)), one based on simultaneous reconstruction of attenuation and emission (MR-ACMLAA (Benoit et al., 2015)), and three based on image-segmentation (MR-ACMUNICH (Cabello et al., 2015), MR-ACCAR-RiDR (Juttukonda et al., 2015), and MR-ACRESOLUTE (Ladefoged et al., 2015)). We selected 359 subjects who were scanned using one of the following radiotracers: [18F]FDG (210), [11C]PiB (51), and [18F]florbetapir (98). The comparison to AC with a gold standard CT was performed both globally and regionally, with a special focus on robustness and outlier analysis. RESULTS: The average performance in PET tracer uptake was within ±5% of CT for all of the proposed methods, with the average±SD global percentage bias in PET FDG uptake for each method being: MR-ACDIXON (-11.3±3.5)%, MR-ACUTE (-5.7±2.0)%, MR-ACONTARIO (-4.3±3.6)%, MR-ACMUNICH (3.7±2.1)%, MR-ACMLAA (-1.9±2.6)%, MR-ACSEGBONE (-1.7±3.6)%, MR-ACUCL (0.8±1.2)%, MR-ACCAR-RiDR (-0.4±1.9)%, MR-ACMAXPROB (-0.4±1.6)%, MR-ACBOSTON (-0.3±1.8)%, and MR-ACRESOLUTE (0.3±1.7)%, ordered by average bias. The overall best performing methods (MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically) showed regional average errors within ±3% of PET with CT-AC in all regions of the brain with FDG, and the same four methods, as well as MR-ACCAR-RiDR, showed that for 95% of the patients, 95% of brain voxels had an uptake that deviated by less than 15% from the reference. Comparable performance was obtained with PiB and florbetapir. CONCLUSIONS: All of the proposed novel methods have an average global performance within likely acceptable limits (±5% of CT-based reference), and the main difference among the methods was found in the robustness, outlier analysis, and clinical feasibility. Overall, the best performing methods were MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically. These methods all minimized the number of outliers, standard deviation, and average global and local error. The methods MR-ACMUNICH and MR-ACCAR-RiDR were both within acceptable quantitative limits, so these methods should be considered if processing time is a factor. The method MR-ACSEGBONE also demonstrates promising results, and performs well within the likely acceptable quantitative limits. For clinical routine scans where processing time can be a key factor, this vendor-provided solution currently outperforms most methods. With the performance of the methods presented here, it may be concluded that the challenge of improving the accuracy of MR-AC in adult brains with normal anatomy has been solved to a quantitatively acceptable degree, which is smaller than the quantification reproducibility in PET imaging.

Characterizing hypoxia in human glioma: A simultaneous multimodal MRI and PET study.

Hypoxia plays an important role for the prognosis and therapy response of cancer. Thus, hypoxia imaging would be a valuable tool for pre-therapeutic assessment of tumor malignancy. However, there is no standard validated technique for clinical application available yet. Therefore, we performed a study in 12 patients with high-grade glioma, where we directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[18 F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([18 F]-FMISO). MR-rOEF was determined from separate measurements of T2 , T2 * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [18 F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([18 F]-FMISO120-130 min ), we also analyzed the hypoxia specific uptake rate [18 F]-FMISO-k3 , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [18 F]-FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [18 F]-FMISO120-130 min concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T1 -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [18 F]-FMISO120-130 min as well as [18 F]-FMISO-k3 , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [18 F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [18 F]-FMISO-k3 was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [18 F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology.

Intra-lesional spatial correlation of static and dynamic FET-PET parameters with MRI-based cerebral blood volume in patients with untreated glioma.

PURPOSE: 18F-fluorethyltyrosine-(FET)-PET and MRI-based relative cerebral blood volume (rCBV) have both been used to characterize gliomas. Recently, inter-individual correlations between peak static FET-uptake and rCBV have been reported. Herein, we assess the local intra-lesional relation between FET-PET parameters and rCBV. METHODS: Thirty untreated glioma patients (27 high-grade) underwent simultaneous PET/MRI on a 3 T hybrid scanner obtaining structural and dynamic susceptibility contrast sequences. Static FET-uptake and dynamic FET-slope were correlated with rCBV within tumour hotspots across patients and intra-lesionally using a mixed-effects model to account for inter-individual variation. Furthermore, maximal congruency of tumour volumes defined by FET-uptake and rCBV was determined. RESULTS: While the inter-individual relationship between peak static FET-uptake and rCBV could be confirmed, our intra-lesional, voxel-wise analysis revealed significant positive correlations (median r = 0.374, p < 0.0001). Similarly, significant inter- and intra-individual correlations were observed between FET-slope and rCBV. However, rCBV explained only 12% of the static and 5% of the dynamic FET-PET variance and maximal overlap of respective tumour volumes was 37% on average. CONCLUSIONS: Our results show that the relation between peak values of MR-based rCBV and static FET-uptake can also be observed intra-individually on a voxel basis and also applies to a dynamic FET parameter, possibly determining hotspots of higher biological malignancy. However, just a small part of the FET-PET signal variance is explained by rCBV and tumour volumes determined by the two modalities showed only moderate overlap. These findings indicate that FET-PET and MR-based rCBV provide both congruent and complimentary information on glioma biology.

Comparison between MRI-based attenuation correction methods for brain PET in dementia patients.

INTRODUCTION: The combination of Positron Emission Tomography (PET) with magnetic resonance imaging (MRI) in hybrid PET/MRI scanners offers a number of advantages in investigating brain structure and function. A critical step of PET data reconstruction is attenuation correction (AC). Accounting for bone in attenuation maps (µ-map) was shown to be important in brain PET studies. While there are a number of MRI-based AC methods, no systematic comparison between them has been performed so far. The aim of this work was to study the different performance obtained by some of the recent methods presented in the literature. To perform such a comparison, we focused on [18F]-Fluorodeoxyglucose-PET/MRI neurodegenerative dementing disorders, which are known to exhibit reduced levels of glucose metabolism in certain brain regions. METHODS: Four novel methods were used to calculate µ-maps from MRI data of 15 patients with Alzheimer's dementia (AD). The methods cover two atlas-based methods, a segmentation method, and a hybrid template/segmentation method. Additionally, the Dixon-based and a UTE-based method, offered by a vendor, were included in the comparison. Performance was assessed at three levels: tissue identification accuracy in the µ-map, quantitative accuracy of reconstructed PET data in specific brain regions, and precision in diagnostic images at identifying hypometabolic areas. RESULTS: Quantitative regional errors of -20--10 % were obtained using the vendor's AC methods, whereas the novel methods produced errors in a margin of ±5 %. The obtained precision at identifying areas with abnormally low levels of glucose uptake, potentially regions affected by AD, were 62.9 and 79.5 % for the two vendor AC methods, the former ignoring bone and the latter including bone information. The precision increased to 87.5-93.3 % in average for the four new methods, exhibiting similar performances. CONCLUSION: We confirm that the AC methods based on the Dixon and UTE sequences provided by the vendor are inferior to alternative techniques. As a novel finding, there was no substantial difference between the recently proposed atlas-based, template-based and segmentation-based methods.

Dianthin-EGF is an effective tumor targeted toxin in combination with saponins in a xenograft model for colon carcinoma.

AIMS: The intention of this work was to lift saponin supported tumor targeted therapies onto the next level by using targeted toxins in nude mice xenotransplant models. MATERIALS & METHODS: Combined application of dianthin coupled to EGF and saponin SO-1861 was tested in a xenograft model of colon carcinoma. In vitro cytotoxicity was tested in real-time in NIH3T3 cells (no human EGF receptor expression), HER14 and human colon carcinoma HCT116 (both EGF receptor overexpressing) cells. A xenograft model was established using HCT116 cells and tumor-bearing animals were treated with SO-1861 (30 µg/treatment) and dianthin coupled to EGF (0.35 µg/treatment). Tumor progression was monitored, using (18)F-2-fluor-2-desoxy-d-glucose, by small animal PET and by x-ray computed tomography. RESULTS: In vitro results demonstrated a high-receptor specificity and the in vivo experiment showed a progressive reduction of the tumor volume and glycolytic activity in the treated group (>95% reduction; p < 0.05). CONCLUSION: This therapy has great advantage because of high specificity, low side effects and great effectiveness for future development in the treatment of colon cancer.

Rationale and design of the Myocardial Microinjury and Cardiac Remodeling Extension Study in the Sodium Lowering in Dialysate trial (Mac-SoLID study).

BACKGROUND: The Sodium Lowering in Dialysate (SoLID) trial is an ongoing a multi-center, prospective, randomised, single-blind (assessor), controlled, parallel assignment clinical trial, enrolling 96 home and self-care hemodialysis (HD) patients from 7 centers in New Zealand. The trial will evaluate the hypothesis that lower dialysate [Na+] during HD results in lower left ventricular (LV) mass. Since it's inception, observational evidence has suggested increased mortality risk with lower dialysate [Na+], possibly due to exacerbation of intra-dialytic hypotension and subsequent myocardial micro-injury. The Myocardial Micro-injury and Cardiac Remodeling Extension Study in the Sodium Lowering In Dialysate Trial (Mac-SoLID study) aims to determine whether lower dialysate [Na+] results in (i) increased levels of high-sensitivity Troponin T (hsTnT), a well-established marker of intra-dialytic myocardial micro-injury in HD populations, and (ii) increased fixed LV segmental wall motion abnormalities, a marker of recurrent myocardial stunning and micro-injury, and (iii) detrimental changes in LV geometry due to maladaptive homeostatic mechanisms. METHODS/DESIGN: The SoLID trial and the Mac-SoLID study are funded by the Health Research Council of New Zealand. Key exclusion criteria: patients who dialyse > 3.5 times per week, pre-dialysis serum sodium <135 mM, and maintenance haemodiafiltration. In addition, some medical conditions, treatments or participation in other dialysis trials that contraindicate the study intervention or confound its effects, will be exclusion criteria. The intervention and control groups will receive dialysate sodium 135 mM and 140 mM respectively, for 12 months. The primary outcome measure for the Mac-SOLID study is repeated measures of [hsTnT] at 0, 3, 6, 9, and 12 months. The secondary outcomes will be assessed using cardiac magnetic resonance imaging (MRI), and comprise LV segmental wall motion abnormality scores, LV mass to volume ratio and patterns of LV remodeling at 0 and 12 months. DISCUSSION: The Mac-SoLID study enhances and complements the SoLID trial. It tests whether potential gains in cardiovascular health (reduced LV mass) which low dialysate [Na+] is expected to deliver, are counteracted by deterioration in cardiovascular health through alternative mechanisms, namely repeated LV stunning and micro-injury. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry number: ACTRN12611000975998.

Effects of isoflurane anaesthesia depth and duration on renal function measured with [99mTc]Tc-mercaptoacetyltriglycine SPECT in mice.

BACKGROUND: The influence of anaesthetic depth and the potential influence of different anaesthetic beds and thus different handling procedures were investigated in 86 severe combined immunodeficient (SCID) mice using semi-stationary dynamic single photon emission computed tomography (SPECT) for kidney scintigraphy. Therefore, isoflurane concentrations were adjusted using respiratory rate for low (80-90 breath/min) and deep anaesthesia (40-45 breath/min). At low anaesthesia, we additionally tested the influence of single bed versus 3-mouse bed hotel; the hotel mice were anaesthetized consecutively at ~ 30, 20, and 10 min before tracer injections for positions 1, 2, and 3, respectively. Intravenous [99mTc]Tc-MAG3 injection of ~ 28 MBq was performed after SPECT start. Time-activity curves were used to calculate time-to-peak (Tmax), T50 (50% clearance) and T25 (75% clearance). RESULTS: Low and deep anaesthesia corresponded to median isoflurane concentrations of 1.3% and 1.5%, respectively, with no significant differences in heart rate (p = 0.74). Low anaesthesia resulted in shorter aortic blood clearance half-life (p = 0.091) and increased relative renal tracer influx rate (p = 0.018). A tendency toward earlier Tmax occurred under low anaesthesia (p = 0.063) with no differences in T50 (p = 0.40) and T25 (p = 0.24). Variance increased with deep anaesthesia. Compared to single mouse scans, hotel mice in position 1 showed a delayed Tmax, T50, and T25 (p < 0.05 each). Furthermore, hotel mice in position 1 showed delayed Tmax versus position 3, and delayed T50 and T25 versus position 2 and 3 (p < 0.05 each). No difference occurred between single bed and positions 2 (p = 1.0) and 3 (p = 1.0). CONCLUSIONS: Deep anaesthesia and prolonged low anaesthesia should be avoided during renal scintigraphy because they result in prolonged blood clearance half-life, delayed renal influx and/or later Tmax. Vice versa, low anaesthesia with high respiratory rates of 80-90 rpm and short duration (≤ 20 min) should be preferred to obtain representative data with low variance.

Challenges in Implementing the Local Node Infrastructure for a National Federated Machine Learning Network in Radiology.

Data-driven machine learning in medical research and diagnostics needs large-scale datasets curated by clinical experts. The generation of large datasets can be challenging in terms of resource consumption and time effort, while generalizability and validation of the developed models significantly benefit from variety in data sources. Training algorithms on smaller decentralized datasets through federated learning can reduce effort, but require the implementation of a specific and ambitious infrastructure to share data, algorithms and computing time. Additionally, it offers the opportunity of maintaining and keeping the data locally. Thus, data safety issues can be avoided because patient data must not be shared. Machine learning models are trained on local data by sharing the model and through an established network. In addition to commercial applications, there are also numerous academic and customized implementations of network infrastructures available. The configuration of these networks primarily differs, yet adheres to a standard framework composed of fundamental components. In this technical note, we propose basic infrastructure requirements for data governance, data science workflows, and local node set-up, and report on the advantages and experienced pitfalls in implementing the local infrastructure with the German Radiological Cooperative Network initiative as the use case example. We show how the infrastructure can be built upon some base components to reflect the needs of a federated learning network and how they can be implemented considering both local and global network requirements. After analyzing the deployment process in different settings and scenarios, we recommend integrating the local node into an existing clinical IT infrastructure. This approach offers benefits in terms of maintenance and deployment effort compared to external integration in a separate environment (e.g., the radiology department). This proposed groundwork can be taken as an exemplary development guideline for future applications of federated learning networks in clinical and scientific environments.

[Macrophthalmos mimics microphthalmos in an 8-month-old Great Swiss Mountain Dog]. / Makrophthalmus imitiert Mikrophthalmus bei einem 8 Monate alten Großen Schweizer Sennenhund.

An 8-month-old Great Swiss Mountain dog was presented with a suspected right-sided microphthalmos, malformed and blind globe which was present since birth. On magnetic resonance imaging an ellipsoid macrophthalmos with absence of the normal retrobulbar tissue was detected. Histology revealed a dysplastic uvea with unilateral cyst formation associated with mild lymphohistiocytic inflammation. The ciliary body covered the posterior side of the lens unilaterally and showed focal metaplastic bone formation. Slight cataract formation as well as diffuse panretinal atrophy and intravitreal retinal detachment was evident. Preoperative diagnostic imaging procedure is recommended in eyes that clinically demonstrate as microphthalmos and are planned to be enucleated. As described in this case report the bulbus may be macrophthalmic which potentially complicates the enucleation. The performance of such a procedure at a site with ophthalmologic and soft tissue expertise is advisable. To the authors' knowledge this is the first report of a macrophthalmos with multiple ocular defects in a dog.

Brain perfusion SPECT in the mouse: normal pattern according to gender and age.

Regional cerebral blood flow (rCBF) is a useful surrogate marker of neuronal activity and a parameter of primary interest in the diagnosis of many diseases. The increasing use of mouse models spawns the demand for in vivo measurement of rCBF in the mouse. Small animal SPECT provides excellent spatial resolution at adequate sensitivity and is therefore a promising tool for imaging the mouse brain. This study evaluates the feasibility of mouse brain perfusion SPECT and assesses the regional pattern of normal Tc-99m-HMPAO uptake and the impact of age and gender. Whole-brain kinetics was compared between Tc-99m-HMPAO and Tc-99m-ECD using rapid dynamic planar scans in 10 mice. Assessment of the regional uptake pattern was restricted to the more suitable tracer, HMPAO. Two HMPAO SPECTs were performed in 18 juvenile mice aged 7.5 ± 1.5weeks, and in the same animals at young adulthood, 19.1 ± 4.0 weeks (nanoSPECT/CTplus, general purpose mouse apertures: 1.2kcps/MBq, 0.7mm FWHM). The 3-D MRI Digital Atlas Database of an adult C57BL/6J mouse brain was used for region-of-interest (ROI) analysis. SPECT images were stereotactically normalized using SPM8 and a custom made, left-right symmetric HMPAO template in atlas space. For testing lateral asymmetry, each SPECT was left-right flipped prior to stereotactical normalization. Flipped and unflipped SPECTs were compared by paired testing. Peak brain uptake was similar for ECD and HMPAO: 1.8 ± 0.2 and 2.1 ± 0.6 %ID (p=0.357). Washout after the peak was much faster for ECD than for HMPAO: 24 ± 7min vs. 4.6 ± 1.7h (p=0.001). The general linear model for repeated measures with gender as an intersubject factor revealed an increase in relative HMPAO uptake with age in the neocortex (p=0.018) and the hippocampus (p=0.012). A decrease was detected in the midbrain (p=0.025). Lateral asymmetry, with HMPAO uptake larger in the left hemisphere, was detected primarily in the neocortex, both at juvenile age (asymmetry index AI=2.7 ± 1.7%, p=0.000) and at young adult age (AI=2.4 ± 1.7%, p=0.000). Gender had no effect on asymmetry. Voxel-wise testing confirmed the ROI-based findings. In conclusion, high-resolution HMPAO SPECT is a promising technique for measuring rCBF in preclinical research. It indicates lateral asymmetry of rCBF in the mouse brain as well as age-related changes during late maturation. ECD is not suitable as tracer for brain SPECT in the mouse because of its fast clearance from tissue indicating an interspecies difference in esterase activity between mice and humans.

Monitoring orthodontic tooth movement in rats after piezocision by bone scintigraphy.

AIM: Piezocision, corticocision of mineralized tissue by ultrasound showed promising results in accelerating tooth movement induced by orthodontic appliances although the biologic effects of this procedure are not well-understood so far. The aim of this study was to investigate the impact of piezocision on bone remodeling in rats by bone SPECT imaging. MATERIAL AND METHODS: Ten male Wistar rats underwent surgical placement of orthodontic appliances on each side of the maxilla followed by piezocision on one side only. Each rat underwent 99mTc-MDP bone SPECT/CT imaging before surgery (T0), and 2 (T1) and 4 weeks (T2) after surgery. Bone uptake is expressed as median [IQR] min-max in percentage of the injected activity per ml computed from the 10 voxels with the highest uptake (%IAmax10/ml). RESULTS: Pooled data regardless of the piezocision showed a significant increase in bone uptake from T0 (3.2 [2.8-3.9] 2.6-4.9) to T1 (4.4 [3.8-4.6] 3.4-4.8; p = 0.001). Thereafter, the uptake decreased to T2 (3.8 [3.1-4.4] 2.8-4.8; p = 0.116). No significant differences in bone uptake were found between the maxilla sides without and with piezocision: T1: without (4.3 [3.8-4.5] 3.4-4.8) vs. with (4.5 [3.7-4.6] 3.5-4.7; p=0.285), T2: without (4.0 [3.1-4.5] 2.8-4.8) vs. with (3.7 [3.0-4.4] 2.8-4.8; p=0.062). CONCLUSION: 99mTc-MDP bone SPECT imaging in rats was able to reproduce changes in bone uptake in the maxilla after placement of orthodontic appliances inducing measurable tooth movement. An additional effect of piezocision on bone remodeling in terms of bone uptake was not detectable which is probably due to the pronounced and significant effects induced by the orthodontic appliances per se, which may mask the potential effects of additional piezocision.

NSG-Mice Reveal the Importance of a Functional Innate and Adaptive Immune Response to Overcome RVFV Infection.

Rift Valley fever (RVF) is a zoonotic disease caused by RVF Phlebovirus (RVFV). The RVFV MP-12 vaccine strain is known to exhibit residual virulence in the case of a deficient interferon type 1 response. The hypothesis of this study is that virus replication and severity of lesions induced by the MP-12 strain in immunocompromised mice depend on the specific function of the disturbed pathway. Therefore, 10 strains of mice with deficient innate immunity (B6-IFNARtmAgt, C.129S7(B6)-Ifngtm1Ts/J, B6-TLR3tm1Flv, B6-TLR7tm1Aki, NOD/ShiLtJ), helper T-cell- (CD4tm1Mak), cytotoxic T-cell- (CD8atm1Mak), B-cell- (Igh-Jtm1DhuN?+N2), combined T- and B-cell- (NU/J) and combined T-, B-, natural killer (NK) cell- and macrophage-mediated immunity (NOD.Cg-PrkdcscidIl2rgtm1WjI/SzJ (NSG) mice) were subcutaneously infected with RVFV MP-12. B6-IFNARtmAgt mice were the only strain to develop fatal disease due to RVFV-induced severe hepatocellular necrosis and apoptosis. Notably, no clinical disease and only mild multifocal hepatocellular necrosis and apoptosis were observed in NSG mice, while immunohistochemistry detected the RVFV antigen in the liver and the brain. No or low virus expression and no lesions were observed in the other mouse strains. Conclusively, the interferon type 1 response is essential for early control of RVFV replication and disease, whereas functional NK cells, macrophages and lymphocytes are essential for virus clearance.

Rift Valley Fever Virus Non-Structural Protein S Is Associated with Nuclear Translocation of Active Caspase-3 and Inclusion Body Formation.

Rift Valley fever phlebovirus (RVFV) causes Rift Valley fever (RVF), an emerging zoonotic disease that causes abortion storms and high mortality rates in young ruminants as well as severe or even lethal complications in a subset of human patients. This study investigates the pathomechanism of intranuclear inclusion body formation in severe RVF in a mouse model. Liver samples from immunocompetent mice infected with virulent RVFV 35/74, and immunodeficient knockout mice that lack interferon type I receptor expression and were infected with attenuated RVFV MP12 were compared to livers from uninfected controls using histopathology and immunohistochemistry for RVFV nucleoprotein, non-structural protein S (NSs) and pro-apoptotic active caspase-3. Histopathology of the livers showed virus-induced, severe hepatic necrosis in both mouse strains. However, immunohistochemistry and immunofluorescence revealed eosinophilic, comma-shaped, intranuclear inclusions and an intranuclear (co-)localization of RVFV NSs and active caspase-3 only in 35/74-infected immunocompetent mice, but not in MP12-infected immunodeficient mice. These results suggest that intranuclear accumulation of RVFV 35/74 NSs is involved in nuclear translocation of active caspase-3, and that nuclear NSs and active caspase-3 are involved in the formation of the light microscopically visible inclusion bodies.

Accurate Monte Carlo Modeling of Small-Animal Multi-Pinhole SPECT for Non-Standard Multi-Isotope Applications.

Recent advances in preclinical SPECT instrumentation enable non-standard multi-isotope acquisitions at the edge of physical feasibility to improve efficiency of pharmaceutical research. Due to the variety of applications, optimization of imaging hardware, acquisition protocols and reconstruction algorithms is a central and recurring task. For this purpose, we developed a Monte Carlo simulation model of a preclinical state-of-the-art multi-pinhole SPECT system, the NanoSPECT/CTPLUS, with emphasis on high accuracy for multi-isotope experiments operating near the system range limits. The GATE/ GEANT4 model included an accurate description of multi-pinhole collimators and all substructures of the detector back compartment. The readout electronics was modeled with a variety of signal processors partially extended to incorporate non-simplified measured response functions. The final model was able to predict energy spectra, planar images and tomographic reconstructions with high accuracy for both standard and non-standard multi-isotope experiments. Complex activity distributions could be reproduced for a wide range of noise levels and different modes of angular undersampling. Using the example of a dual-isotope triple-tracer experiment, the model has proven to be a powerful tool for protocol optimization and quantitative image correction at the performance range limits of multi-isotope multi-pinhole SPECT.

Severity of Subjective Cognitive Complaints and Worries in Older Adults Are Associated With Cerebral Amyloid-ß Load.

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-ß) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-ß load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-ß, as well as regional amyloid-ß load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-ß load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-ß load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-ß load in the parietal cortex. Higher levels of worry were associated with higher amyloid-ß load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-ß burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.

Respiratory motion correction for enhanced quantification of hepatic lesions in simultaneous PET and DCE-MR imaging.

Simultaneous positron-emission tomography (PET)-magnetic resonance (MR) imaging is a hybrid technique in oncological hepatic imaging combining soft-tissue and functional contrast of dynamic contrast enhanced MR (DCE-MR) with metabolic information from PET. In this context, respiratory motion represents a major challenge by introducing blurring, artifacts and misregistration in the liver. In this work, we propose a free-breathing 3D non-rigid respiratory motion correction framework for simultaneously acquired DCE-MR and PET data, which makes use of higher spatial resolution MR data to derive motion information used directly during image reconstruction to minimize image blurring and motion artifacts. The main aim was to increase contrast of hepatic metastases to improve their detection and characterization. DCE-MR data were acquired at 3T through a golden radial phase encoding scheme, enabling derivation of motion fields. These were used in the motion compensated image reconstruction of DCE-MR time-series (48 time-points, 6 s temporal resolution, 1.5 mm isotropic spatial resolution) and 3D PET activity map, which was subsequently interpolated to the DCE-MR resolution. The extended Tofts model was fitted to DCE-MR data, obtaining functional parametric maps related to perfusion such as the endothelial permeability (Kt). Fifty-seven hepatic metastases were identified and analyzed. Quantitative evaluations of motion correction in PET images demonstrated average percentage increases of 16% ± 5% (mean ± SD) in Contrast (C), 18% ± 6% in SUVmeanand 14% ± 2% in SUVmax, while DCE-MR andKtscored contrast-to-noise-ratio increases of 64% ± 3% and 90% ± 6%, respectively. Motion-corrected data visually showed improved image contrast of hepatic metastases and effectively reduced blurring and motion artefacts. Scatter plots of SUVmeanversusKtsuggested that the proposed framework improved differentiation ofKtmeasurements. The presented motion correction framework for simultaneously acquired PET-DCE-MR data provides accurately aligned images with increased contrast of hepatic lesions allowing for improved detection and characterization.