Background-It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high-energy phosphate metabolism. Methods and Results-We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age-, sex-, and body mass index-matched control subjects. Cardiac high-energy phosphate metabolites were measured at rest using 31 P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high-energy phosphate metabolites, intracellular pH, and oxygenation were measured using 31 P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50Ϯ0.11, than the healthy volunteers, at 2.30Ϯ0.12. The cardiac PCr/ATP ratios correlated negatively with the fasting plasma free fatty acid concentrations. Although skeletal muscle energetics and pH were normal at rest, PCr loss and pH decrease were significantly faster during exercise in the patients with diabetes, who had lower exercise tolerance. After exercise, PCr recovery was slower in the patients with diabetes and correlated with tissue reoxygenation times. The exercise times correlated negatively with the deoxygenation rates and the hemoglobin (Hb)A 1c levels and the reoxygenation times correlated positively with the HbA 1c levels. Conclusions-Type

Our data provide evidence of a bioenergetic deficit in genotype-confirmed HCM, which is present to a similar degree in three disease-gene groups. The presence of energetic abnormalities, even in those without hypertrophy, supports a proposed link between altered cardiac energetics and development of the disease phenotype.

Exercise therapy improves short-term metabolic, brain, physical, and cognitive function, without changes in glucose control following stroke. The long-term impact of exercise on stroke recurrence, cardiovascular health, and disability should now be explored.

Neurodevelopmental disorders could be caused by maternal antibodies or other serum factors. We detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5-1.0 ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring, comparing with offspring of mice injected with sera from mothers of healthy children. This evidence supports a role for maternal antibodies in some forms of neurodevelopmental disorder.

Proton MR spectroscopy (1 H-MRS) provides indices of neuronal damage in the central nervous system (CNS); however, it has not been extensively applied in the spinal cord. This work describes an optimized proton spectroscopy protocol for examination of the human cervical spinal cord. B 0 field mapping of the cord revealed periodic inhomogeneities due to susceptibility differences with surrounding tissue. By combining field maps and experimental data, we found that the optimum voxel size was 9 ؋ 7 ؋ 35 mm 3 placed with the inferior end of the voxel above vertebral body C2. Metabolite concentrations were determined in the cervical cord in six healthy controls by shortecho point-resolved spectroscopy (PRESS) volume localization. The results were compared with metabolite concentrations in the brainstem, cerebellum, and cortex in the same individuals. The concentrations in the cervical cord were as follows: Nacetyl-aspartate (NAA) 17.3 ؎ 0.5, creatine (Cr) 9.5 ؎ 0.9, and choline 2.7 ؎ 0.5 mmol/l. The NAA concentration was significantly lower in the cord than in the brainstem (Mann-Whitney, P < 0.025), and higher than in the cortex (P < 0.005) and cerebellum (P < 0.005). Cr was significantly lower in the cord than in the cerebellum (P < 0.05). There were no significant differences between Cr concentrations in the spinal cord compared to the cortex and brainstem.Magn Proton magnetic resonance spectroscopy ( 1 H-MRS) is a valuable noninvasive technique for assessing the biochemistry of the human brain. This is reflected by the increasing clinical applications of spectroscopy to investigate neurological disorders (1,2). Proton MRS of the brain has applications in multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), space-occupying lesions, and various metabolic disorders (3). However, in 10 -15% of MS patients (4) and in other diseases, such as ALS, the clinical picture is dominated by spinal cord pathology. Furthermore, diseases such as Friedreich's ataxia, compressive syndromes, subacute combined degeneration, and anterior spinal artery syndrome all principally affect the spinal cord.Spinal cord atrophy (an indirect marker of irreversible axonal loss within the spinal cord) has been shown to correlate with disability in MS (5). We have shown in both stroke (6) and MS (7) that with the use of small spectroscopy voxels to target the main pathways of the motor system (i.e., the posterior limb of the internal capsule), it is possible to demonstrate a correlation between N-acetylaspartate (NAA) levels and clinical measures of function within that pathway. This suggests that 1 H-MRS of the cord itself would reveal abnormalities in those diseases in which pathology is specific to the cord. This may provide information regarding neuronal viability, and thus provide physiological, diagnostic, and prognostic insights.It is technically challenging to perform spectroscopy on the spinal cord. The spinal cord is small compared to the size of the voxel in a typical spectroscopy examination, which limits the available signal-t...

The synthesis and spectroscopic properties of a series of CF(3)-labelled lanthanide(III) complexes (Ln=Gd, Tb, Dy, Ho, Er, Tm) with amide-substituted ligands based on 1,4,7,10-tetraazacyclododecane are described. The theoretical contributions of the (19)F magnetic relaxation processes in these systems are critically assessed and selected volumetric plots are presented. These plots allow an accurate estimation of the increase in the rates of longitudinal and transverse relaxation as a function of the distance between the Ln(III) ion and the fluorine nucleus, the applied magnetic field, and the re-rotational correlation time of the complex, for a given Ln(III) ion. Selected complexes exhibit pH-dependent chemical shift behaviour, and a pK(a) of 7.0 was determined in one example based on the holmium complex of an ortho-cyano DO3A-monoamide ligand, which allowed the pH to be assessed by measuring the difference in chemical shift (varying by over 14 ppm) between two (19)F resonances. Relaxation analyses of variable-temperature and variable-field (19)F, (17)O and (1)H NMR spectroscopy experiments are reported, aided by identification of salient low-energy conformers by using density functional theory. The study of fluorine relaxation rates, over a field range of 4.7 to 16.5 T allowed precise computation of the distance between the Ln(III) ion and the CF(3) reporter group by using global fitting methods. The sensitivity benefits of using such paramagnetic fluorinated probes in (19)F NMR spectroscopic studies are quantified in preliminary spectroscopic and imaging experiments with respect to a diamagnetic yttrium(III) analogue.

We report the use of high-speed magetic resonance imaging to follow the changes in image intens in the human visual cortex during stimulation by a flashing checkerboard stimulus. Measurements were made in a 2.1-T, 1-m-diameter magnet, part of a Bruker Biospec spectrometer that we had programmed to do echo-planar imaging. A 15-cm-diameter surface coil was used to transmit and receive signals. Images were acquired during periods of stimulation from 2 s to 180 s. Images were acquired in 65.5 ms in a 10-mm slice with in-plane voxel size of 6 x 3 mm. Repetition time (TR) was generally 2 s, although for the long flashing periods, TR = 8 s was used. Voxels were located onto an inversion recovery image taken with 2 x 2 mm in-plane resolution. Image intensity increased after onset ofthe stimulus. The mean change in signal relative to the prestimulation level (AS/S) was 9.7% (SD = 2.8%, n = 20) with an echo time of 70 ms. Irrespective of the period of stimulation, the increase in magnetic resonance signal intensity was delayed relative to the stimulus. The mean delay measured from the start of stimulation for each protocol was as follows: 2-s stimulation, delay = 3.5 s (SD = 0.5 s, n = 10) (the delay exceeds stimulus duration); 20-to 24-s stimulation, delay = 5 s (SD = 2 s, n = 20).Functional mapping of the brain by nuclear magnetic resonance (NMR) methods has recently been demonstrated by two techniques. The first method uses a bolus of paramagnetic contrast agent (gadolinium/diethylenetriaminepentaacetic acid) as a tracer for blood volume (1). The agent is injected into the arm and produces variations in local blood volume magnetic susceptibility as the bolus passes through the capillary bed of the brain. The changes in susceptibility are monitored by using a transverse relaxation time (T2)-weighted, fast magnetic resonance-imaging sequence, such as echo-planar imaging (EPI) (2) or fast low-angle shot (FLASH) (3). This method is subject to the same assumptions as all kinetic tracer methods (4), but within these restrictions it gives a quantitative result. With this method Belliveau et al. (5) have made measurements in the human visual cortex and demonstrated an increase in blood volume during stimulation. The main drawback of the technique is the need for at least two injections of contrast agent to measure the resting and activated brain states.The second method relies solely on the paramagnetic effects of hemoglobin. In the oxygenated state (HbO2), the molecule is diamagnetic, but once dissociated from oxygen (deoxyhemoglobin; Hb), it becomes paramagnetic. Thus, changes in Hb concentration will also result in magnetic susceptibility changes in the capillaries. Complications may arise because the paramagnetic agent is not evenly distributed throughout the blood but is compartmentalized inside the erythrocytes. Ogawa et al. (6) have studied the effect of inhaled 02 content on the intensity of gradient-echo images ofrat brain at 7 T. They have shown that a decrease in oxygen content produces dark streaks in the i...

Qualitative studies suggest that patients with primary biliary cirrhosis (PBC) experience significant problems with memory and concentration. Studies of nonhepatic disease have linked hypotension and cognitive impairment. In this study, we determined the prevalence of cognitive symptoms in PBC, examined the relationship between symptoms and overt cognitive impairment and structural brain lesions, and explored the role of autonomic dysfunction. The prevalence of cognitive symptoms was determined in 198 patients with PBC. Twenty-eight representative early-stage female patients with PBC and 11 matched controls underwent formal cognitive testing at baseline and after 2 years of follow-up. Autonomic nervous system function was assessed according to heart rate variability and baroreflex sensitivity. Eleven subjects with PBC had structural brain lesions quantified via magnetic resonance imaging. Cognitive symptoms were frequent in our PBC population, with 53% of patients experiencing moderate or severe problems with concentration and/or memory, which were unrelated in their severity to biochemical and histological makers of liver disease severity, suggesting that this symptom burden is largely or entirely unrelated to hepatic encephalopathy. Perceived cognitive symptoms correlated with objectively assessed cognitive impairment (r 2 ‫؍‬ 0.2, P < 0.05). Cognitive deficits were seen in the PBC cohort compared with controls, with significant decline detected over 2 years of follow-up. Correlations were seen between cognitive performance (full-scale intelligence quotient) and systolic blood pressure (P ‫؍‬ 0.01, r 2 ‫؍‬ 0.2) with decline in cognitive function associated with autonomic abnormalities. Structural brain lesions were found in PBC, the density of which correlated with degree of cognitive impairment (P ‫؍‬ 0.01, r 2 ‫؍‬ 0.5) and autonomic function (P ‫؍‬ 0.03, r 2 ‫؍‬ 0.2). Conclusion: Cognitive symptoms are prevalent in PBC independent of liver disease severity and are associated with poorer performance on objective cognitive testing. Cognitive impairment is, in turn, associated with structural brain lesions and autonomic dysfunction, which may predict risk of cognitive decline. (HEPATOLOGY 2008;48:541-549.) P rimary biliary cirrhosis (PBC) is a chronic cholestatic liver disease with an autoimmune etiology. 1 In addition to the risk of progressive liver disease, culminating in biliary cirrhosis with its associated complications, patients frequently experience non-stage-associated symptoms that can often lead to significant impairment of their quality of life. [2][3][4][5][6] Research into the non-end-stage disease-associated factors that lead to impairment of quality of life in PBC has, to date, largely focused on fatigue; a symptom which affects a significant proportion of patients and which is associated with impairment in normal physical functioning. 7-10 However, patient reports, and qualitative studies performed in the derivation of a PBC-specific quality of life measure, the PBC-40, suggest the existence of...