Repeatability and reproducibility of cardiac manganese-enhanced magnetic resonance imaging.

Manganese-enhanced magnetic resonance imaging can provide a surrogate measure of myocardial calcium handling. Its repeatability and reproducibility are currently unknown. Sixty-eight participants: 20 healthy volunteers, 20 with acute myocardial infarction, 18 with hypertrophic and 10 with non-ischemic dilated cardiomyopathy underwent manganese-enhanced magnetic resonance imaging. Ten healthy volunteers were re-scanned at 3 months. Native T1 values and myocardial manganese uptake were assessed for intra and inter-observer repeatability. Scan-rescan reproducibility was assessed in ten healthy volunteers. Intra-observer and inter-observer correlation was excellent in healthy volunteers for mean native T1 mapping [Lin's correlation coefficient (LCC) 0.97 and 0.97 respectively] and myocardial manganese uptake (LCC: 0.99 and 0.96 respectively). Scan-rescan correlation for native T1 and myocardial manganese uptake was also excellent. Similarly, intra-observer correlations for native T1 and myocardial manganese uptake in patients with acute myocardial infarction (LCC: 0.97 and 0.97 respectively), hypertrophic (LCC: 0.98 and 0.97 respectively) and dilated cardiomyopathy (LCC: 0.99 and 0.95 respectively) were excellent. Limits of agreement were broader in patients with dilated cardiomyopathy. Manganese-enhanced magnetic resonance imaging has high repeatability and reproducibility in healthy myocardium and high repeatability in diseased myocardium. However, further study is needed to establish robustness in pathologies with diffuse myocardial fibrosis.

Manganese-enhanced magnetic resonance imaging in dilated cardiomyopathy and hypertrophic cardiomyopathy.

AIMS: The aim of this study is to quantify altered myocardial calcium handling in non-ischaemic cardiomyopathy using magnetic resonance imaging. METHODS AND RESULTS: Patients with dilated cardiomyopathy (n = 10) or hypertrophic cardiomyopathy (n = 17) underwent both gadolinium and manganese contrast-enhanced magnetic resonance imaging and were compared with healthy volunteers (n = 20). Differential manganese uptake (Ki) was assessed using a two-compartment Patlak model. Compared with healthy volunteers, reduction in T1 with manganese-enhanced magnetic resonance imaging was lower in patients with dilated cardiomyopathy [mean reduction 257 ± 45 (21%) vs. 288 ± 34 (26%) ms, P < 0.001], with higher T1 at 40 min (948 ± 57 vs. 834 ± 28 ms, P < 0.0001). In patients with hypertrophic cardiomyopathy, reductions in T1 were less than healthy volunteers [mean reduction 251 ± 86 (18%) and 277 ± 34 (23%) vs. 288 ± 34 (26%) ms, with and without fibrosis respectively, P < 0.001]. Myocardial manganese uptake was modelled, rate of uptake was reduced in both dilated and hypertrophic cardiomyopathy in comparison with healthy volunteers (mean Ki 19 ± 4, 19 ± 3, and 23 ± 4 mL/100 g/min, respectively; P = 0.0068). In patients with dilated cardiomyopathy, manganese uptake rate correlated with left ventricular ejection fraction (r2 = 0.61, P = 0.009). Rate of myocardial manganese uptake demonstrated stepwise reductions across healthy myocardium, hypertrophic cardiomyopathy without fibrosis and hypertrophic cardiomyopathy with fibrosis providing absolute discrimination between the healthy myocardium and fibrosed myocardium (mean Ki 23 ± 4, 19 ± 3, and 13 ± 4 mL/100 g/min, respectively; P < 0.0001). CONCLUSION: The rate of manganese uptake in both dilated and hypertrophic cardiomyopathy provides a measure of altered myocardial calcium handling. This holds major promise for the detection and monitoring of dysfunctional myocardium, with the potential for early intervention and prognostication.

Manganese-Enhanced T1 Mapping in the Myocardium of Normal and Infarcted Hearts.

Background: Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods: T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 µmol/kg)) or chelated (mangafodipir (22-44 µmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100-200 µmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson's trichrome (MTC). Results: Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30-43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI -14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI -9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI -10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=-0.61, P=0.022). Conclusions: MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.

Multimodality quantitative assessments of myocardial perfusion using dynamic contrast enhanced magnetic resonance and 15O-labelled water positron emission tomography imaging.

Kinetic modelling of myocardial perfusion imaging data allows the absolute quantification of myocardial blood flow (MBF) and can improve the diagnosis and clinical assessment of coronary artery disease (CAD). Positron emission tomography (PET) imaging is considered the reference standard technique for absolute quantification, whilst oxygen-15 (15O)-water has been extensively implemented for MBF quantification. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has also been used for MBF quantification and showed comparable diagnostic performance against (15O)-water PET studies. We investigated for the first time the diagnostic performance of two different PET MBF analysis softwares PMOD and Carimas, for obstructive CAD detection against invasive clinical standard methods in 20 patients with known or suspected CAD. Fermi and distributed parameter modelling-derived MBF quantification from DCE-MRI was also compared against (15O)-water PET, in a subgroup of 6 patients. The sensitivity and specificity for PMOD was significantly superior for obstructive CAD detection in both per vessel (0.83, 0.90) and per patient (0.86, 0.75) analysis, against Carimas (0.75, 0.65), (0.81, 0.70), respectively. We showed strong, significant correlations between MR and PET MBF quantifications (r=0.83-0.92). However, DP and PMOD analysis demonstrated comparable and higher haemodynamic differences between obstructive versus (no, minor or non)-obstructive CAD, against Fermi and Carimas analysis. Our MR method assessments against the optimum PET reference standard technique for perfusion analysis showed promising results in per segment level and can support further multi-modality assessments in larger patient cohorts. Further MR against PET assessments may help to determine their comparative diagnostic performance for obstructive CAD detection.

Distant bone metastases from carcinoma of the lip: a report of four cases.

The lip is estimated to be the most frequent location for carcinoma of the oral cavity. It occurs more frequently in men, especially those with a history of exposure to sunlight. Despite the usually effective management, regional and occasionally distant metastases do occur, especially in advanced stages. In this retrospective analysis of patients with labial carcinoma presenting with distant bone metastases in 1995-2003, the extremely limited number of patients did not allow for multivariate data analysis. From a cohort of 415 patients presenting with lip lesions, 186 cases were diagnosed as carcinoma and managed accordingly. Four patients (2.14%) showed distant bone metastases, one with concurrent axillary node metastasis. Patient demographics, tumour characteristics, case management and survival were evaluated. The distant metastasis patients were of clinical stages II-IV; initial management was wide local excision with reconstruction for all cases, with one undergoing concurrent neck dissection and one adjuvant radiotherapy. Time for distant bone metastasis was 9-21 months, subsequent survival 3-14 months and overall survival 13-35 months. Distant metastases from labial carcinoma are rare, not exceeding 2%. Metastasis to bone and axillary lymph nodes is exceptionally rare and can be attributed to either inadequate initial management or aggressive tumour behaviour.

Study of water sorption, solubility and modulus of elasticity of light-cured dimethacrylate-based dental resins.

Polydimethacrylate resins were prepared by photopolymerization of Bis-GMA, TEGDMA, UDMA or Bis-EMA (4) monomer, initiated by camphoroquinone/N,N-dimethylaminoethyl methacrylate system. The study of physical properties of these resins showed that TEGDMA seems to create the most dense polymer network, which however is the most flexible (0.74GPa), absorbs the highest amount of water (6.33 wt%) and releases the lowest amount of unreacted monomer (2.41 microg/mm(3)). UDMA and Bis-EMA (4) create more rigid networks, which absorb lower water and release higher unreacted monomer than TEGDMA. Bis-EMA (4) absorbs the lowest water amount (1.79 wt%) and releases the highest amount of unreacted monomer (14.21 microg/mm(3)). Bis-GMA leads to the formation of the most rigid network (1.43 GPa), which absorbs lower water than the resin made by TEGDMA but higher than the resin made by UDMA and Bis-EMA (4). Copolymers of Bis-GMA with the other monomers were also prepared, using various monomer combinations and molar ratios. Copolymers Bis-GMA/TEGDMA (50/50 and 70/30 wt%) showed significantly higher values for Young's modulus (1.83 and 1.78 GPa) than those predicted by the linear dependence of the values on the copolymer composition. Gradual replacement of TEGDMA with UDMA or/and Bis-EMA (4) in copolymerization with Bis-GMA resulted in more flexible resins with lower water sorption and higher solubility values, depending on the TEGDMA content.

Effect of chemical structure on degree of conversion in light-cured dimethacrylate-based dental resins.

In this work the room-temperature photopolymerization of Bis-GMA, Bis-EMA, urethane dimethacrylate (UDMA) and triethylene glycol dimethacrylate (TEGDMA) induced by camphoroquinone/N,N-dimethylaminoethyl methacrylate, as photo-initiator system, was followed by FT-IR. The results obtained were then fitted by a non-linear least square method to a rational function, which permitted the accurate calculation of the limiting degree of conversion. The latter was found to increase in the order Bis-GMA < Bis-EMA < UDMA < TEGDMA. This trend is discussed in connection with the chemical structure of dimethacrylates. The photopolymerization of mixtures of Bis-GMA/TEGDMA, Bis-GMA/UDMA and Bis-GMA/Bis-EMA showed a good linear relationship of degree of conversion with the mole fraction of Bis-GMA and in the case of the first pair also with the Tg of the initial monomer mixture.

Simultaneous determination of equivalence volumes and acid dissociation constants from potentiometric titration data.

New iterative methods for analysis of potentiometric titration data of (a) mixtures of weak monoprotic acids with their conjugate bases, (b) solutions of polyprotic (di- and triprotic) acids, and (c) mixtures of two diprotic acids are presented. These methods, using data exclusively resulting from the acidic region of the titration curve permits the accurate determination of the analytical concentration of one or more acids even if the titration is stopped well before the end point of the titration. For the titration of a solution containing a conjugate acid/base pair, the proposed procedure enables the extraction of the initial composition of the mixture, as well as the dissociation constant of the concerned acid. Thus, it is possible by this type of analysis to distinguish whether a weak acid has been contaminated by a strong base and define the extent of the contamination. On the other hand, for the titration of polyprotic acids, the proposed approach enables the extraction of the accurate values of the equivalence volume and the dissociation constants K(i) even when the ionization stages overlap. Finally, for the titration of a mixture of two diprotic acids the proposed procedure enables the determination of the composition of the mixture even if the sum of the concentrations of the acids is not known. This method can be used in the analysis of solutions containing two diastereoisomeric forms of a weak diprotic acid. The test of the proposed procedures by means of ideal and Monte Carlo simulated data revealed that these methods are fairly applicable even when the titration data are considerably obscured by 'noise' or contain an important systematic error. The proposed procedures were also successfully applied to experimental titration data.

Acid-base equilibria in binary water/organic solvent systems Dissociation of citric acid in water/dioxan and water/methanol solvent systems at 25 degrees.

The thermodynamic constants of citric acid were determined at 25 degrees in water/dioxan and water/methanol mixtures with 10, 20, 30, 40 and 50% v/v organic co-solvent content. Simple relations allowing the calculation of palpha*(H) of citrate buffer solutions are proposed (alpha*(H) being the hydrogen-ion activity referred to the standard state in the corresponding medium). The palpha*(H) values of some citrate buffer solutions, suitable for standardization, are reported. The pK values obtained are discussed in relation to the nature and composition of the solvent, as well as the structure of the acid molecule.