Outcomes of endoscopic ultrasound-guided pancreatic FNAC diagnosis for solid and cystic lesions at Manchester Royal Infirmary based upon the Papanicolaou Society of Cytopathology pancreaticobiliary terminology classification scheme.

OBJECTIVE: To compare endoscopic ultrasound (EUS)-FNAC diagnosis of pancreatic lesions with patient outcome based upon the Papanicolaou Society of Cytopathology pancreaticobiliary terminology classification scheme diagnostic categories: Panc 1 (non-diagnostic); Panc 2 (negative for malignancy/neoplasia); Panc 3 (atypical); Panc 4B (neoplastic, benign); Panc 4O (neoplastic, other); Panc 5 (suspicious of malignancy); and Panc 6 (positive/malignant). METHODS: All EUS-FNA pancreas specimens taken at Manchester Royal Infirmary in 2015 were prospectively classified according to the above scheme at the time of cytology reporting and data recorded prospectively. Subsequently, outcomes based on clinical follow-up or histopathology diagnosis were compared with the cytology diagnosis. RESULTS: 120 EUS-FNA pancreas specimens from 111 patients were received, of which 112 (93.3%) specimens had follow-up data. There were 79 and 41 EUS-FNA pancreas specimens from solid and cystic lesions, respectively. Based on the cytology diagnosis the specimens were classified as Panc 1 (7.5%), Panc 2 (33.3%), Panc 3 (2.5%), Panc 4B (2.5%), Panc 4O (15.0%), Panc 5 (3.3%) and Panc 6 (35.9%). The performance indicators for diagnosis of malignancy or neoplasia with malignant potential, included sensitivity (95.4%), specificity (100%), positive predictive value (100%), negative predictive value (92.3%), false positive rate (0%) and false negative rate (4.6%). CONCLUSIONS: The Papanicolaou Society of Cytopathology pancreaticobiliary terminology classification scheme is a logical system that can easily be introduced in a diagnostic cytopathology service. This classification scheme acts as an aid to diagnostic reporting, clear communication of significant results including risk of neoplasia/malignancy to clinicians, clinical audit and comparison of results with other centres.

A retrospective 3-year study of salivary gland FNAC with categorisation using the Milan reporting system.

INTRODUCTION: To assess our practice using the recently developed standardised classification system designated The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and to ascertain the rates of malignancy for each category by means of a retrospective study. METHODS: All salivary gland FNAC samples received between 1 January 2013 and 31 December 2015 were retrospectively assigned a diagnostic category code from the MSRSGC. Cytology results were correlated with subsequent histology (where available), and clinical and radiological follow up. RESULTS: A total of 287 salivary gland FNA samples were received from 272 patients. The specimens were classified as non-diagnostic (21.3%), non-neoplastic (22%), atypia of undetermined significance (2.4%), neoplasm benign (36.9%), neoplasm of uncertain malignant potential (5.2%), suspicious for malignancy (1.7%) and malignant (10.5%; low grade 1.4% and high grade 9.1%). Histological and clinical/radiological follow up was available for 138 (48.1%) specimens, clinical/radiological follow up only for 145 (50.5%) and no follow up for the remaining four (1.4%) samples. The risk of malignancy for each category was non-diagnostic (8.5%), non-neoplastic (1.6%), atypia of undetermined significance (0%), neoplasm benign (1.9%), neoplasm of uncertain malignant potential (26.7%), suspicious for malignancy (100%) and malignant (100%). CONCLUSIONS: The MSRSGC appears to be a useful tool to guide clinical management and provide an indication of possible risk of malignancy. We favour implementing use of these categories in our reporting practice with a future re-evaluation to assess maintenance of service quality as well as the clinical utility of this reporting system.

Multiplex KRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction.

Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy. Patients and methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care. Results: Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of ≥ 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001). Conclusion(s): Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival.

Differential release of manure-borne bioactive phosphorus forms to runoff and leachate under simulated rain.

Limited information exists on the unhindered release of bioactive phosphorus (P) from a manure layer to model the partitioning and transport of component P forms before they reach an underlying soil. Rain simulations were conducted to quantify effects of intensity (30, 60, and 90 mm h-1) on P release from an application of 60 Mg ha-1 of dairy manure. Runoff contained water-extractable- (WEP), exchangeable and enzyme-labile bioactive P (TBIOP), in contrast to the operationally defined "dissolved-reactive P" form. The released P concentrations and flow-weighed mass loads were described by the log-normal probability density function. At a reference condition of 30 mm h-1 and maintaining the surface at a 5% incline, runoff was minimal, and WEP accounted for 20.9% of leached total P (TP) concentrations, with an additional 25-30% as exchangeable and enzyme-labile bioactive P over the 1-h simulation. On a 20% incline, increased intensity accelerated occurrence of concentrationmax and shifted the skewed P concentration distribution more to the left. Differences in trends of WEP, TBIOP, or net enzyme-labile P (PHPo) cumulative mass released per unit mass of manure between intensities were attributable to the higher frequency of raindrops striking the manure layer, thus increasing detachment and load of colloidal PHPo of the water phases. Thus, detailed knowledge of manure physical characteristics, bioactive P distribution in relation to rain intensity, and attainment of steady-state of water fluxes were critical factors in improved prediction of partitioning and movement of manure-borne P under rainfall.

Angiogenesis and airway reactivity in asthmatic Brown Norway rats.

Expanded and aberrant bronchial vascularity, a prominent feature of the chronic asthmatic airway, might explain persistent airway wall edema and sustained leukocyte recruitment. Since it is well established that there are causal relationships between exposure to house dust mite (HDM) and the development of asthma, determining the effects of HDM in rats, mammals with a bronchial vasculature similar to humans, provides an opportunity to study the effects of bronchial angiogenesis on airway function directly. We studied rats exposed bi-weekly to HDM (Der p 1; 50 µg/challenge by intranasal aspiration, 1, 2, 3 weeks) and measured the time course of appearance of increased blood vessels within the airway wall. Results demonstrated that within 3 weeks of HDM exposure, the number of vessels counted within airway walls of bronchial airways (0.5-3 mm perimeter) increased significantly. These vascular changes were accompanied by increased airway responsiveness to methacholine. A shorter exposure regimen (2 weeks of bi-weekly exposure) was insufficient to cause a significant increase in functional vessels or reactivity. Yet, 19F/1H MR imaging at 3T following αvß3-targeted perfluorocarbon nanoparticle infusion revealed a significant increase in 19F signal in rat airways after 2 weeks of bi-weekly HDM, suggesting earlier activation of the process of neovascularization. Although many antigen-induced mouse models exist, mice lack a bronchial vasculature and consequently lack the requisite human parallels to study bronchial edema. Overall, our results provide an important new model to study the impact of bronchial angiogenesis on chronic inflammation and airways hyperreactivity.

Balanced UTE-SSFP for 19F MR imaging of complex spectra.

PURPOSE: A novel technique for highly sensitive detection of multiresonant fluorine imaging agents was designed and tested with the use of dual-frequency 19F/1H ultrashort echo times (UTE) sampled with a balanced steady-state free precession (SSFP) pulse sequence and three-dimensional (3D) radial readout. METHODS: Feasibility of 3D radial balanced UTE-SSFP imaging was demonstrated for a phantom comprising liquid perfluorooctyl bromide (PFOB). Sensitivity of the pulse sequence was measured and compared with other sequences imaging the PFOB (CF2 )6 line group including UTE radial gradient-echo (GRE) at α = 30°, as well as Cartesian GRE, balanced SSFP, and fast spin-echo (FSE). The PFOB CF3 peak was also sampled with FSE. RESULTS: The proposed balanced UTE-SSFP technique exhibited a relative detection sensitivity of 51 µmolPFOB(-1) min(-1/2) (α = 30°), at least twice that of other sequence types with either 3D radial (UTE GRE: 20 µmolPFOB(-1) min(-1/2) ) or Cartesian k-space filling (GRE: 12 µmolPFOB(-1) min(-1/2) ; FSE: 16 µmolPFOB(-1) min(-1/2) ; balanced SSFP: 23 µmolPFOB(-1) min(-1/2) ). In vivo imaging of angiogenesis-targeted PFOB nanoparticles was demonstrated in a rabbit model of cancer on a clinical 3 Tesla scanner. CONCLUSION: A new dual 19F/1H balanced UTE-SSFP sequence manifests high SNR, with detection sensitivity more than two-fold better than traditional techniques, and alleviates imaging problems caused by dephasing in complex spectra.

Depth-Dependent Survival of Escherichia coli and Enterococci in Soil after Manure Application and Simulated Rainfall.

Once released, manure-borne bacteria can enter runoff via interaction with the thin mixing layer near the soil surface. The objectives of this work were to document temporal changes in profile distributions of manure-borne Escherichia coli and enterococci in the near-surface soil layers after simulated rainfalls and to examine differences in survival of the two fecal indicator bacteria. Rainfall simulations were performed in triplicate on soil-filled boxes with grass cover and solid manure application for 1 h with rainfall depths of 30, 60, and 90 mm. Soil samples were collected weekly from depth ranges of 0 to 1, 1 to 2, 2 to 5, and 5 to 10 cm for 1 month. Rainfall intensity was found to have a significant impact on the initial concentrations of fecal indicator bacteria in the soil. While total numbers of enterococci rapidly declined over time, E. coli populations experienced initial growth with concentration increases of 4, 10, and 25 times the initial levels at rainfall treatment depths of 30, 60, and 90 mm, respectively. E. coli populations grew to the approximately the same level in all treatments. The 0- to 1-cm layer contained more indicator bacteria than the layers beneath it, and survival of indicator bacteria was better in this layer, with decimation times between 12 and 18 days after the first week of growth. The proportion of bacteria in the 0- to 1-cm layer grew with time as the total number of bacteria in the 0- to 10-cm layer declined. The results of this work indicate the need to revisit the bacterial survival patterns that are assumed in water quality models.

Improved quantitative (19) F MR molecular imaging with flip angle calibration and B1 -mapping compensation.

PURPOSE: To improve (19) F flip angle calibration and compensate for B1 inhomogeneities in quantitative (19) F MRI of sparse molecular epitopes with perfluorocarbon (PFC) nanoparticle (NP) emulsion contrast agents. MATERIALS AND METHODS: Flip angle sweep experiments on PFC-NP point source phantoms with three custom-designed (19) F/(1) H dual-tuned coils revealed a difference in required power settings for (19) F and (1) H nuclei, which was used to calculate a calibration ratio specific for each coil. An image-based correction technique was developed using B1 -field mapping on (1) H to correct for (19) F and (1) H images in two phantom experiments. RESULTS: Optimized (19) F peak power differed significantly from that of (1) H power for each coil (P < 0.05). A ratio of (19) F/(1) H power settings yielded a coil-specific and spatially independent calibration value (surface: 1.48 ± 0.06; semicylindrical: 1.71 ± 0.02, single-turn-solenoid: 1.92 ± 0.03). (1) H-image-based B1 correction equalized the signal intensity of (19) F images for two identical (19) F PFC-NP samples placed in different parts of the field, which were offset significantly by ~66% (P < 0.001), before correction. CONCLUSION: (19) F flip angle calibration and B1 -mapping compensations to the (19) F images employing the more abundant (1) H signal as a basis for correction resulted in a significant change in the quantification of sparse (19) F MR signals from targeted PFC NP emulsions.

Atherosclerotic neovasculature MR imaging with mixed manganese-gadolinium nanocolloids in hyperlipidemic rabbits.

A high r1 relaxivity manganese-gadolinium nanocolloid (αvß3-MnOL-Gd NC) was developed and effectively detected atherosclerotic angiogenesis in rabbits fed cholesterol-rich diets for 12 months using a clinical MRI scanner (3T). 3D mapping of neovasculature signal intensity revealed the spatial coherence and intensity of plaque angiogenic expansion, which may, with other high risk MR bioindicators, help identify high-risk patients with moderate (40% to 60%) vascular stenosis. Microscopy confirmed the predominant media and plaque distribution of fluorescent αvß3-MnOL-Gd NC, mirroring the MR data. An expected close spatial association of αvß3-integrin neovasculature and macrophages was noted, particularly within plaque shoulder regions. Manganese oleate bioelimination occurred via the biliary system into feces. Gd-DOTA was eliminated through the bile-fecal and renal excretion routes. αvß3-MnOL-Gd NC offers an effective vehicle for T1w neovascular imaging in atherosclerosis. From the clinical editor: Cerebrovascular accidents are a leading cause of mortality and morbidity worldwide. The acute formation of thrombus following atherosclerotic plaque rupture has been well recognized as the etiology of stroke. The authors studied microanatomical features of vulnerable atherosclerotic plaque in this article, in an attempt to identify those with high risk of rupture. Gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC) was developed as a novel contrast agent for MRI. They show that this agent is effective in providing neovascular imaging.

Synergy between surface and core entrapped metals in a mixed manganese-gadolinium nanocolloid affords safer MR imaging of sparse biomarkers.

High-relaxivity T1-weighted (T1w) MR molecular imaging nanoparticles typically present high surface gadolinium payloads that can elicit significant acute complement activation (CA). The objective of this research was to develop a high T1w contrast nanoparticle with improved safety. We report the development, optimization, and characterization of a gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC; 138±10 (Dav)/nm; PDI: 0.06; zeta: -27±2 mV). High r1 particulate relaxivity with minute additions of Gd-DOTA-lipid conjugate to the MnOL nanocolloid surface achieved an unexpected paramagnetic synergism. This hybrid MnOL-Gd NC provided optimal MR TSE signal intensity at 5 nM/voxel and lower levels consistent with the level expression anticipated for sparse biomarkers, such as neovascular integrins. MnOL NC produced optimal MR TSE signal intensity at 10 nM/voxel concentrations and above. Importantly, MnOL-Gd NC avoided acute CA in vitro and in vivo while retaining minimal transmetallation risk. From the clinical editor: The authors developed a gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC) in this study. These were used as a high-relaxivity paramagnetic MR molecular imaging agent in experimental models. It was shown that MnOL-Gd NC could provide high T1w MR contrast for targeted imaging. As the level of gadolinium used was reduced, there was also reduced risk of systemic side effects from complement activation.

Characterization of early neovascular response to acute lung ischemia using simultaneous (19)F/ (1)H MR molecular imaging.

Angiogenesis is an important constituent of many inflammatory pulmonary diseases, which has been unappreciated until recently. Early neovascular expansion in the lungs in preclinical models and patients is very difficult to assess noninvasively, particularly quantitatively. The present study demonstrated that (19)F/(1)H MR molecular imaging with αvß3-targeted perfluorocarbon nanoparticles can be used to directly measure neovascularity in a rat left pulmonary artery ligation (LPAL) model, which was employed to create pulmonary ischemia and induce angiogenesis. In rats 3 days after LPAL, simultaneous (19)F/(1)H MR imaging at 3T revealed a marked (19)F signal in animals 2 h following αvß3-targeted perfluorocarbon nanoparticles [(19)F signal (normalized to background) = 0.80 ± 0.2] that was greater (p = 0.007) than the non-targeted (0.30 ± 0.04) and the sham-operated (0.07 ± 0.09) control groups. Almost no (19)F signal was found in control right lung with any treatment. Competitive blockade of the integrin-targeted particles greatly decreased the (19)F signal (p = 0.002) and was equivalent to the non-targeted control group. Fluorescent and light microscopy illustrated heavy decorating of vessel walls in and around large bronchi and large pulmonary vessels. Focal segmental regions of neovessel expansion were also noted in the lung periphery. Our results demonstrate that (19)F/(1)H MR molecular imaging with αvß3-targeted perfluorocarbon nanoparticles provides a means to assess the extent of systemic neovascularization in the lung.

Assessing intrarenal nonperfusion and vascular leakage in acute kidney injury with multinuclear (1) H/(19) F MRI and perfluorocarbon nanoparticles.

PURPOSE: We sought to develop a unique sensor-reporter approach for functional kidney imaging that employs circulating perfluorocarbon nanoparticles and multinuclear (1) H/(19) F MRI. METHODS: (19) F spin density weighted and T1 weighted images were used to generate quantitative functional mappings of both healthy and ischemia-reperfusion (acute kidney injury) injured mouse kidneys. (1) H blood-oxygenation-level-dependent (BOLD) MRI was also employed as a supplementary approach to facilitate the comprehensive analysis of renal circulation and its pathological changes in acute kidney injury. RESULTS: Heterogeneous blood volume distributions and intrarenal oxygenation gradients were confirmed in healthy kidneys by (19) F MRI. In a mouse model of acute kidney injury, (19) F MRI, in conjunction with blood-oxygenation-level-dependent MRI, sensitively delineated renal vascular damage and recovery. In the cortico-medullary junction region, we observed 25% lower (19) F signal (P < 0.05) and 70% longer (1) H T2* (P < 0.01) in injured kidneys compared with contralateral kidneys at 24 h after initial ischemia-reperfusion injury. We also detected 71% higher (19) F signal (P < 0.01) and 40% lower (1) H T2* (P < 0.05) in the renal medulla region of injured kidneys compared with contralateral uninjured kidneys. CONCLUSION: Integrated (1) H/(19) F MRI using perfluorocarbon nanoparticles provides a multiparametric readout of regional perfusion defects in acutely injured kidneys.

Comparing temperature effects on Escherichia coli, Salmonella, and Enterococcus survival in surface waters.

UNLABELLED: The objective of this study was to compare dependency of survival rates on temperature for indicator organisms Escherichia coli and Enterococcus and the pathogen Salmonella in surface waters. A database of 86 survival datasets from peer-reviewed papers on inactivation of E. coli, Salmonella and Enterococcus in marine waters and of E. coli and Salmonella in lake waters was assembled. The Q10 model was used to express temperature effect on survival rates obtained from linear sections of semi-logarithmic survival graphs. Available data were insufficient to establish differences in survival rates and temperature dependencies for marine waters where values of Q10  = 3 and a survival rate of 0·7 day(-1) could be applied. The Q10 values in lake waters were substantially lower in marine waters, and Salmonella inactivation in lake water was, on average, twice as fast as E. coli; data on E. coli substantially outnumber data on Enterococcus and Salmonella. The relative increase in inactivation with increase in temperature is higher in marine waters than lake water, and differences in inactivation between Salmonella and E. coli at a given temperature were significant in lake water but not in marine waters. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbiological quality of surface waters is of paramount importance for public health. The novelty of this work is using a large compendium of published data to develop the first comparison of temperature effects on survival of the pathogen Salmonella and water quality indicator micro-organisms Escherichia coli and Enterococcus in natural waters. The existing relatively large body of knowledge on E. coli survival appears to be useful to assess the effect of temperature on survival of Salmonella. Moreover, results of this work constitute an essential input in models to support environmental management decisions on the use of surface water sources in agriculture, aquaculture and recreation.

MR cholangiography demonstrates unsuspected rapid biliary clearance of nanoparticles in rodents: implications for clinical translation.

Due to their small size, lower cost, short reproduction cycle, and genetic manipulation, rodents have been widely used to test the safety and efficacy for pharmaceutical development in human disease. In this report, MR cholangiography demonstrated an unexpected rapid (<5 min) biliary elimination of gadolinium-perfluorocarbon nanoparticles (approximately 250 nm diameter) into the common bile duct and small intestine of rats, which is notably different from nanoparticle clearance patterns in larger animals and humans. Unawareness of this dissimilarity in nanoparticle clearance mechanisms between small animals and humans may lead to fundamental errors in predicting nanoparticle efficacy, pharmacokinetics, biodistribution, bioelimination, and toxicity. From the clinical editor: Comprehensive understanding of nanoparticle clearance is a clear prerequisite for human applications of nanomedicine-based therapeutic approaches. Through a novel use of MR cholangiography, this study demonstrates unusually rapid hepatic clearance of gadolinium-perfluorocarbon nanoparticles in rodents, in a pattern that is different than what is observed in larger animals and humans, raising awareness of important differences between common rodent-based models and larger mammals.

Performance of Weibull and Linear Semi-logarithmic Models in Simulating Inactivation in Waters.

Modeling inactivation of indicator microorganisms is a necessary component of microbial water quality forecast and management recommendations. The linear semi-logarithmic (LSL) model is commonly used to simulate the dependencies of bacterial concentrations in waters on time. There were indications that assumption of the semi-logarithmic linearity may not be accurate enough in waters. The objective of this work was to compare performance of the LSL and the two-parametric Weibull inactivation models with data on survival of indicator organism in various types of water from a representative database of 167 laboratory experiments. The Weibull model was preferred in >99% of all cases when the root mean squared errors and Nash-Sutcliffe statistics were compared. Comparison of corrected Akaike statistic values gave the preference to the Weibull model in only 35% of cases. This was caused by (i) a small number of experimental points on some inactivation curves, (ii) closeness of the shape parameter of the Weibull equation to one, and (iii) piecewise log-linear inactivation dynamic that could be well described by neither of the two models compared. Based on the Akaike test, the Weibull model was favored in agricultural, lake, and pristine waters, whereas the LSL model was preferred for groundwater, wastewater, rivers, and marine waters. The decimal reduction time parameter of both the LSL and Weibull models exhibited an Arrhenius-type dependence on temperature. Overall, the existing inactivation data indicate that the application of the Weibull model can improve the predictive capabilities of microbial water quality modeling.

Cardiomyocyte architectural plasticity in fetal, neonatal, and adult pig hearts delineated with diffusion tensor MRI.

Cardiomyocyte organization is a critical determinant of coordinated cardiac contractile function. Because of the acute opening of the pulmonary circulation, the relative workload of the left ventricle (LV) and right ventricle (RV) changes substantially immediately after birth. We hypothesized that three-dimensional cardiomyocyte architecture might be required to adapt rapidly to accommodate programmed perinatal changes of cardiac function. Isolated fixed hearts from pig fetuses or pigs at midgestation, preborn, postnatal day 1 (P1), postnatal day 5, postnatal day 14 (P14), and adulthood (n = 5 for each group) were acquired for diffusion-weighted magnetic resonance imaging. Cardiomyocyte architecture was visualized by three-dimensional fiber tracking and was quantitatively evaluated by the measured helix angle (α(h)). Upon the completion of MRI, hearts were sectioned and stained with hematoxylin/eosin (H&E) to evaluate cardiomyocyte alignment, with picrosirius red to evaluate collagen content, and with anti-Ki67 to evaluate postnatal cell proliferation. The helical architecture of cardiomyocyte was observed as early as the midgestational period. Postnatal changes of cardiomyocyte architecture were observed from P1 to P14, which primary occurred in the septum and RV free wall (RVFW). In the septum, the volume ratio of LV- vs. RV-associated cardiomyocytes rapidly changed from RV-LV balanced pattern at birth to LV dominant pattern by P14. In the RVFW, subendocardial α(h) decreased by ~30° from P1 to P14. These findings indicate that the helical architecture of cardiomyocyte is developed as early as the midgestation period. Substantial and rapid adaptive changes in cardiac microarchitecture suggested considerable developmental plasticity of cardiomyocyte form and function in the postnatal period in response to altered cardiac mechanical function.

Molecular MR imaging of neovascular progression in the Vx2 tumor with αvß3-targeted paramagnetic nanoparticles.

PURPOSE: To assess the dependence of neovascular molecular magnetic resonance (MR) imaging on relaxivity (r1) of αvß3-targeted paramagnetic perfluorocarbon (PFC) nanoparticles and to delineate the temporal-spatial consistency of angiogenesis assessments for individual animals. MATERIALS AND METHODS: Animal protocols were approved by the Washington University Animal Studies Committee. Proton longitudinal and transverse relaxation rates of αvß3-targeted and nontargeted PFC nanoparticles incorporating gadolinium diethylenetrianime pentaacedic acid (Gd-DTPA) bisoleate (BOA) or gadolinium tetraazacyclododecane tetraacetic acid (Gd-DOTA) phosphatidylethanolamine (PE) into the surfactant were measured at 3.0 T. These paramagnetic nanoparticles were compared in 30 New Zealand White rabbits (four to six rabbits per group) 14 days after implantation of a Vx2 tumor. Subsequently, serial MR (3.0 T) neovascular maps were developed 8, 14, and 16 days after tumor implantation by using αvß3-targeted Gd-DOTA-PE nanoparticles (n = 4) or nontargeted Gd-DOTA-PE nanoparticles (n = 4). Data were analyzed with analysis of variance and nonparametric statistics. RESULTS: At 3.0 T, Gd-DTPA-BOA nanoparticles had an ionic r1 of 10.3 L · mmol(-1) · sec(-1) and a particulate r1 of 927000 L · mmol(-1) · sec(-1). Gd-DOTA-PE nanoparticles had an ionic r1 of 13.3 L · mmol(-1) · sec(-1) and a particulate r1 of 1 197000 L · mmol(-1) · sec(-1). Neovascular contrast enhancement in Vx2 tumors (at 14 days) was 5.4% ± 1.06 of the surface volume with αvß3-targeted Gd-DOTA-PE nanoparticles and 3.0% ± 0.3 with αvß3-targeted Gd-DTPA-BOA nanoparticles (P = .03). MR neovascular contrast maps of tumors 8, 14, and 16 days after implantation revealed temporally consistent and progressive surface enhancement (1.0% ± 0.3, 4.5% ± 0.9, and 9.3% ± 1.4, respectively; P = .0008), with similar time-dependent changes observed among individual animals. CONCLUSION: Temporal-spatial patterns of angiogenesis for individual animals were followed to monitor longitudinal tumor progression. Neovasculature enhancement was dependent on the relaxivity of the targeted agent.

Rapid quantification of oxygen tension in blood flow with a fluorine nanoparticle reporter and a novel blood flow-enhanced-saturation-recovery sequence.

We present a novel blood flow-enhanced-saturation-recovery (BESR) sequence, which allows rapid in vivo T1 measurement of blood for both (1)H and (19)F nuclei. BESR sequence is achieved by combining homogeneous spin preparation and time-of-flight image acquisition and therefore preserves high time efficiency and signal-to-noise ratio for (19)F imaging of circulating perfluorocarbon nanoparticles comprising a perfluoro-15-crown-5-ether core and a lipid monolayer (nominal size = 250 nm). The consistency and accuracy of the BESR sequence for measuring T1 of blood was validated experimentally. With a confirmed linear response feature of (19)F R1 with oxygen tension in both salt solution and blood sample, we demonstrated the feasibility of the BESR sequence to quantitatively determine the oxygen tension within mouse left and right ventricles under both normoxia and hyperoxia conditions. Thus, (19)F BESR MRI of circulating perfluorocarbon nanoparticles represents a new approach to noninvasively evaluate intravascular oxygen tension.