AKA-TPG: A Program for Kinetic and Epidemiological Analysis of Data from Labeled Glucose Investigations Using the Two-Pool Model and Database Technology

Background: The Two-Pool Glucose (TPG) model has an important role to play in diabetes research since it enables analysis of data obtained from the frequently sampled labeled (hot) glucose tolerance test (FSHGT). TPG modeling allows determination of the separate effects of insulin on the disposal of glucose and on the hepatic production of glucose. It therefore provides a basis for the accurate estimation of glucose effectiveness, insulin sensitivity, and the profile of the rate of endogenous glucose production. Until now, there has been no program available dedicated to the TPG model, and a number of technical reasons have deterred researchers from performing TPG analysis. Methods and Results: In this paper, we describe AKA-TPG, a new program that combines automatic kinetic analysis of the TPG model data with database technologies. AKA-TPG enables researchers who have no expertise in modeling to quickly fit the TPG model to individual FSHGT data sets consisting of plasma concentrations of unlabeled glucose, labeled glucose, and insulin. Most importantly, because the entire process is automated, parameters are almost always identified, and parameter estimates are accurate and reproducible. AKA-TPG enables the demographic data of hundreds of individual subjects, their individual unlabeled and labeled glucose and insulin data, and each subject\u27s parameters and indices derived from AKA-TPG to be securely stored in, and retrieved from, a database. We describe how the stratification and population analysis tools in AKA-TPG are used and present population estimates of TPG model parameters for young, healthy (without diabetes) Nordic men. Conclusion: Researchers now have a practical tool to enable kinetic and epidemiological analysis of TPG data sets

Simultaneous PET/MRI with 13C magnetic resonance spectroscopic imaging (hyperPET): phantom-based evaluation of PET quantification

BACKGROUND: Integrated PET/MRI with hyperpolarized (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) offers simultaneous, dual-modality metabolic imaging. A prerequisite for the use of simultaneous imaging is the absence of interference between the two modalities. This has been documented for a clinical whole-body system using simultaneous (1)H-MRI and PET but never for (13)C-MRSI and PET. Here, the feasibility of simultaneous PET and (13)C-MRSI as well as hyperpolarized (13)C-MRSI in an integrated whole-body PET/MRI hybrid scanner is evaluated using phantom experiments. METHODS: Combined PET and (13)C-MRSI phantoms including a NEMA [(18)F]-FDG phantom, (13)C-acetate and (13)C-urea sources, and hyperpolarized (13)C-pyruvate were imaged repeatedly with PET and/or (13)C-MRSI. Measurements evaluated for interference effects included PET activity values in the largest sphere and a background region; total number of PET trues; and (13)C-MRSI signal-to-noise ratio (SNR) for urea and acetate phantoms. Differences between measurement conditions were evaluated using t tests. RESULTS: PET and (13)C-MRSI data acquisition could be performed simultaneously without any discernible artifacts. The average difference in PET activity between acquisitions with and without simultaneous (13)C-MRSI was 0.83 (largest sphere) and −0.76 % (background). The average difference in net trues was −0.01 %. The average difference in (13)C-MRSI SNR between acquisitions with and without simultaneous PET ranged from −2.28 to 1.21 % for all phantoms and measurement conditions. No differences were significant. The system was capable of (13)C-MRSI of hyperpolarized (13)C-pyruvate. CONCLUSIONS: Simultaneous PET and (13)C-MRSI in an integrated whole-body PET/MRI hybrid scanner is feasible. Phantom experiments showed that possible interference effects introduced by acquiring data from the two modalities simultaneously are small and non-significant. Further experiments can now investigate the benefits of simultaneous PET and hyperpolarized (13)C-MRI in vivo studies

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes.</p> <p>Methods</p> <p>Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured.</p> <p>Results</p> <p>The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia.</p> <p>Conclusions</p> <p>Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.</p> <p>Trial registration number</p> <p>at <url>http://www.clinicaltrial.gov</url>: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00298844">NCT00298844</a></p

Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes

The electron-donor and unique redox properties of the tetrathiafulvalene (TTF, 1) moiety have led to diverse applications in many areas of chemistry. Monopyrrolotetrathiafulvalenes (MPTTFs, 4) and bispyrrolotetrathiafulvalenes (BPTTFs, 5) are useful structural motifs and have found widespread use in fields such as supramolecular chemistry and molecular electronics. Protocols enabling the synthesis of functionalised MPTTFs and BPTTFs are therefore of broad interest. Herein, we present the synthesis of a range of functionalised MPTTF and BPTTF species. Firstly, the large-scale preparation of the precursor species N-tosyl-(1,3)-dithiolo[4,5-c]pyrrole-2-one (6) is described, as well as the synthesis of the analogue N-tosyl-4,6-dimethyl-(1,3)-dithiolo[4,5-c]pyrrole-2-one (7). Thereafter, we show how 6 and 7 can be used to prepare BPTTFs using homocoupling reactions and functionalised MPTTFs using cross-coupling reactions with a variety of 1,3-dithiole-2-thiones (19). Subsequently, the incorporation of more complex functionality is discussed. We show how the 2-cyanoethyl protecting group can be used to afford MPTTFs functionalised with thioethers, exemplified by a series of ethylene glycol derivatives. Additionally, the merits of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an alternative to the most common deprotecting agent, CsOH·H2O are discussed. Finally, we show how a copper-mediated Ullman-type reaction can be applied to the N-arylation of MPTTFs and BPTTFs using a variety of aryl halides

Simultaneous hyperpolarized 13C-pyruvate MRI and 18F-FDG-PET in cancer (hyperPET):feasibility of a new imaging concept using a clinical PET/MRI scanner

In this paper we demonstrate, for the first time, the feasibility of a new imaging concept - combined hyperpolarized (13)C-pyruvate magnetic resonance spectroscopic imaging (MRSI) and (18)F-FDG-PET imaging. This procedure was performed in a clinical PET/MRI scanner with a canine cancer patient. We have named this concept hyper PET. Intravenous injection of the hyperpolarized (13)C-pyruvate results in an increase of (13)C-lactate, (13)C-alanine and (13)C-CO(2) ((13)C-HCO(3)) resonance peaks relative to the tissue, disease and the metabolic state probed. Accordingly, with dynamic nuclear polarization (DNP) and use of (13)C-pyruvate it is now possible to directly study the Warburg Effect through the rate of conversion of (13)C-pyruvate to (13)C-lactate. In this study, we combined it with (18)F-FDG-PET that studies uptake of glucose in the cells. A canine cancer patient with a histology verified local recurrence of a liposarcoma on the right forepaw was imaged using a combined PET/MR clinical scanner. PET was performed as a single-bed, 10 min acquisition, 107 min post injection of 310 MBq (18)F-FDG. (13)C-chemical shift imaging (CSI) was performed just after FDG-PET and 30 s post injection of 23 mL hyperpolarized (13)C-pyruvate. Peak heights of (13)C-pyruvate and (13)C-lactate were quantified using a general linear model. Anatomic (1)H-MRI included axial and coronal T1 vibe, coronal T2-tse and axial T1-tse with fat saturation following gadolinium injection. In the tumor we found clearly increased (13)C-lactate production, which also corresponded to high (18)F-FDG uptake on PET. This is in agreement with the fact that glycolysis and production of lactate are increased in tumor cells compared to normal cells. Yet, most interestingly, also in the muscle of the forepaw of the dog high (18)F-FDG uptake was observed. This was due to activity in these muscles prior to anesthesia, which was not accompanied by a similarly high (13)C-lactate production. Accordingly, this clearly demonstrates how the Warburg Effect directly can be demonstrated by hyperpolarized (13)C-pyruvate MRSI. This was not possible with (18)F-FDG-PET imaging due to inability to discriminate between causes of increased glucose uptake. We propose that this new concept of simultaneous hyperpolarized (13)C-pyruvate MRSI and PET may be highly valuable for image-based non-invasive phenotyping of tumors. This methods may be useful for treatment planning and therapy monitoring

The Coulomb four-body problem in a classical framework: Triple photoionization of lithium

Formulating a quasiclassical approach we determine the cross section for the complete four-body break-up of the lithium ground state following single photon absorption from threshold up to 220 eV excess energy. In addition, we develop a new classification scheme for three-electron ionizing trajectories in terms of electron-electron collisions, thereby identifying two main ionization paths which the three electrons in the ground state of lithium follow to escape to the continuum. The dominant escape paths manifest themselves in a characteristic ``T-shape'' break-up pattern of the three electrons which implies observable structures in the electronic angular correlation probability. This break-up pattern prevails for excess energies so low that the Wannier threshold law $\sigma\propto E^{\alpha}$ describes already the triple ionization cross section, whose predicted value $\alpha=2.16$ we can confirm quantitatively