Glycine N-methyltransferase (GNMT) is the main enzyme responsible for catabolism of excess hepatic S-adenosylmethionine (SAMe). GNMT is absent in hepatocellular carcinoma (HCC), messenger RNA (mRNA) levels are significantly lower in livers of patients at risk of developing HCC, and GNMT has been proposed to be a tumor-susceptibility gene for liver cancer. The identification of several children with liver disease as having mutations of the GNMT gene further suggests that this enzyme plays an important role in liver function. In the current study we studied development of liver pathologies including HCC in GNMTknockout (GNMT-KO) mice. GNMT-KO mice have elevated serum aminotransferase, methionine, and SAMe levels and develop liver steatosis, fibrosis, and HCC. We found that activation of the Ras and Janus kinase ( T he first steps in mammalian methionine metabolism are conversion to S-adenosylmethionine (SAMe) and transfer of the methyl group of SAMe to a large variety of substrates (including DNA, RNA, histones, and small molecules such as glycine, guanidinoacetate, and phosphatidylethanolamine) with the formation of S-adenosylhomocysteine (SAH), an inhibitor of many SAMe-dependent methyltransferases. 1 Although there are a large number of SAMe-dependent methyltransferases, 2 methylation of glycine by glycine Nmethyltransferase (GNMT) to form sarcosine (N-methylglycine) is one of the reactions that contribute most to total transmethylation flux. 3 The importance of GNMT is to remove excess SAMe and maintain a constant hepatic SAMe/SAH ratio to avoid aberrant methylation. 2 Consistent with this function, the activation of GNMT in rats by the administration of retinoic acid causes a reduction in plasma methionine and homocysteine levels, as well as in liver DNA methylation. 4,5 In GNMT-knockout (GNMT-KO) mice, liver SAMe content is elevated 35-fold, and the SAMe/SAH ratio increases about 100-fold, 6 and individuals with GNMT mutations, which leads to inactive forms of the enzyme, have elevated plasma levels of methionine and SAMe but a normal concentration of homocysteine. 7,8 GNMT is expressed in the liver, pancreas, and prostate 9 and is absent in hepatocellular carcinoma (HCC) 10 and down-regulated in the livers of patients at risk of Abbreviations: GNMT, HCC, hepatocellular carcinoma; H3K27me3, trimethylated Received September 10, 2007; accepted November 26, 2007. Supported by NIH grants AA12677, AA13847, and AT-1576 (to S.C.L. and J.M.M.); DK15289 (to C.W.), PN IϩD SAF 2005-00855, HEPADIP-EULSHM-CT-205, and ETORTEK 2005 (to J.M.M. and M.L.M.-C.); Program Ramón y Cajal (to M.L.M.-C.); and Fundación "La Caixa" (to M.L.M.-C., R.M., and A.M.A.).

In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the Blood Oxygen Level Dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41 + 1 weeks), and 10 preterm infants (median PMA 34 + 4 weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brain's response to stimuli across the last trimester of gestation and beyond.

We present a technique to measure the longitudinal relaxation time constant of venous blood (T(1b) ) in vivo in a few seconds. The MRI sequence consists of a thick-slab adiabatic inversion, followed by a series of slice-selective excitations and single-shot echo planar imaging readouts. The time intervals between excitations were chosen so that blood in macroscopic vessels is fully refreshed between excitations, making the blood signal follow an unperturbed inversion recovery curve. Static tissue, which experiences the inversion and all excitation pulses, quickly reaches a steady state at a low signal as a result of partial saturation. This allows blood-filled voxels to be discriminated from those containing static tissue, and to be fitted voxel-by-voxel to a simple inversion recovery model. The sequence was tested on a flow phantom with the proposed method, yielding T(1) values consistent to within 3% of those obtained using a conventional inversion recovery sequence with a spin-echo readout. The method was applied to seven adult volunteers and 18 neonates. The blood T(1) of the neonates (1799 ± 206 ms; range, 1393-2035 ms) was found to be more variable than that of adults (1717 ± 39 ms; range, 1662-1779 ms). A linear correlation between the inverse of T(1b) and the haematocrit was established in 12 neonates (R(2)  = 0.90).

Changes in the structure and electrical behaviour of the left atrium are known to occur with conditions that predispose to atrial fibrillation (AF) and in response to prolonged periods of AF. We review the evidence that changes in myocardial thickness in the left atrium are an important part of this pathological remodelling process. Autopsy studies have demonstrated changes in the thickness of the atrial wall between patients with different clinical histories. Comparison of the reported tissue dimensions from pathological studies provides an indication of normal ranges for atrial wall thickness. Imaging studies, most commonly done using cardiac computed tomography, have demonstrated that these changes may be identified non-invasively. Experimental evidence using isolated tissue preparations, animal models of AF, and computer simulations proves that the three-dimensional tissue structure will be an important determinant of the electrical behaviour of atrial tissue. Accurately identifying the thickness of the atrial may have an important role in the non-invasive assessment of atrial structure. In combination with atrial tissue characterization, a comprehensive assessment of the atrial dimensions may allow prediction of atrial electrophysiological behaviour and in the future, guide radiofrequency delivery in regions based on their tissue thickness.

Abstract-It has been suggested that left ventricular fibrosis in spontaneously hypertensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic treatment with the angiotensin II type 1 receptor antagonist losartan results in diminished synthesis of collagen type I molecules and reversal of myocardial fibrosis in SHR. This study was designed to investigate whether losartan also affects the extracellular degradation of collagen type I fibers in the left ventricle of SHR. 4 -9 Chronic blockade of the angiotensin II type 1 (AT 1 ) receptor with losartan resulted in the normalization of collagen synthesis and reversal of left ventricular fibrosis in SHR, which suggests a role for angiotensin II in increased collagen synthesis in that model. 6 The excess of ventricular collagen in patients with hypertensive LVH may be a result of both exaggerated collagen synthesis and inadequate collagen degradation. 10,11 The ratelimiting step in the extracellular degradation of collagen is the catalytic cleavage by interstitial matrix metalloproteinases (MMPs). 12 Nine MMPs have been identified, cloned, and sequenced, and these are divided into 3 groups (collagenase, stromelysin, and gelatinase) that are based broadly on substrate preferences. Interstitial collagenase (MMP-1) accounts for the degradation of up to 40% of newly synthesized collagen type I and type III in different tissues. 13 The MMP activity is regulated by a family of naturally occurring tissue inhibitors of metalloproteinases (TIMPs). 12,14 Four members of this family have been identified: TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Unlike the other TIMPs, TIMP-1 is synthesized by most types of connective tissue cells, acts against all members of the MMPs family of enzymes, and is

HighlightsAn open-source atrial wall thickness CT and MRI dataset (n=20) with consensus ground truth obtained with statistical estimation from expert delineation (n=2).Exploring a range of metrics for evaluating and ranking wall segmentation and thickness algorithms (n=6), and benchmarks were set on each metric.New three-dimensional mean thickness atlases for atrial wall thickness derived from the consensus ground truth. The atlas was also transformed into a two-dimensional flat map of thickness.

Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF.

AimsAtrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue.Methods and resultsA previously developed biophysically detailed three-dimensional canine atrial model is applied. Effects of AF-induced electrical remodelling are introduced based on published experimental data, as changes of ion channel currents (ICaL, IK1, Ito, and IKur), the action potential (AP) and cell-to-cell coupling levels. Pharmacological effects are introduced by blocking specific ion channel currents. A combination of electrical heterogeneity (AP tissue gradients of 5–12 ms) and anisotropy (conduction velocities of 0.75–1.25 and 0.21–0.31 m/s along and transverse to atrial fibres) can results in the generation of wave breaks in the PV region. However, a long wavelength (171 mm) prevents the wave breaks from developing into re-entry. Electrical remodelling leads to decreases in the AP duration, conduction velocity and wavelength (to 49 mm), such that re-entry becomes sustained. Pharmacological effects on the tissue heterogeneity and vulnerability (to wave breaks and re-entry) are quantified to show that drugs that increase the wavelength and stop re-entry (IK1 and IKur blockers) can also increase the heterogeneity (AP gradients of 26–27 ms) and the likelihood of wave breaks.ConclusionBiophysical modelling reveals large conduction block areas near the PVs, which are due to discontinuous fibre arrangement enhanced by electrical heterogeneity. Vulnerability to re-entry in such areas can be modulated by pharmacological interventions.