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Purpose: To determine whether the magnetization transfer ratio (MTR) of the globus pallidus (GP) in patients with primary biliary cirrhosis (PBC) correlates with age, disease stage, and fatigue, using T(1) and T(2) mapping to determine whether the mechanism of change is consistent with manganese deposition in the GP as suggested by previous reports.Materials and Methods: In all, 30 early-stage PBC patients, four end-stage PBC patients, and 14 female controls were recruited to age-matched groups. MTR, T(1) and T(2) measurements were performed. A bilateral region of interest (ROI)-based analysis was used to calculate GP MTR, T(1), and T(2) values. These were correlated with age, disease status, and fatigue.Results: MTR measurements showed a significant, negative correlation with age for controls and early-stage PBC patients, a positive correlation with T(2), and no correlation with T(1). Only GP T(2) is significantly lower in early-stage PBC patients than controls, while end-stage patients demonstrated a simultaneous reduction in T(1) and MTR, consistent with GP manganese deposition.Conclusion: MTR measurements correlate with age in both early-stage patient and control groups, but are not associated with manganese deposition or fatigue severity: only the end-stage disease group shows changes in MTR, T(1), T(2) that are consistent with manganese deposition. [ABSTRACT FROM AUTHOR]

Background: Dysferlin plays a key role in cell membrane repair; its absence or malfunction in patients with dysferlin-deficient limb girdle muscular dystrophy leads to muscle fibre death. Muscle magnetic resonance (MR) imaging allows non-invasive and repeatable measurements that can report on pathological changes observed in dysferlinopathy patients (DP). We aimed to demonstrate the feasibility of utilising volume-localised 23 Na spectroscopy as a novel approach to characterise muscle Na + content and biexponential T 2 * at rest, and dynamically post-exercise, in patients with dysferlinopathy and in matched healthy controls., Methods: Adult DP and age and sex matched healthy volunteers (HV) were recruited and scanned on a 3 T clinical MR scanner. Following baseline scans, participants performed physiotherapist-guided isometric dorsiflexion contractions until tibialis anterior (TA) muscle exhaustion. Dynamic volume-localised sodium-23 ( 23 Na)- and proton ( 1 H)-MR scans were acquired serially for 35 min post-exercise. MR data were analysed to determine TA lipid content, change in TA sodium content, biexponential sodium T 2 * properties and TA water 1 H T 2 ., Results: Ten DP (mean age ± standard deviation [SD]: 38.0 ± 10.8 years; 80% female) and 10 HV (mean age ± SD: 38.9 ± 11.5 years) were scanned. Baseline muscle water 1 H T 2 and sodium concentration were significantly higher in DP compared to matched controls ( 1 H T 2 DP [SD] = 33.8 [2.7] ms, 1 H T 2 HV  = 29.3 [1.1] ms, p < 0.001; [ 23 Na] DP  = 36.2 [11.4] mM, [ 23 Na] HV  = 19.6 [3.1] mM, p < 0.001). 1 H T 2 and sodium content in healthy controls showed significant post-exercise elevation with a slower time-to-peak for sodium content compared to 1 H T 2 . 1 H T 2 and sodium content change post-exercise was highly variable in the DP group. Notably, 23 Na dynamics in one DP with normal muscle fat fraction were similar to HV. Biexponential 23 Na T 2 * was measured at baseline in HV (T 2 * slow  = 13.4 [2.3] ms, T 2 * fast  = 2.2 [1.3] ms), and DP (T 2 * slow  = 14.0 [1.5] ms and T 2 * fast  = 1.0 [0.5] m). Equivalent measurements post-exercise revealed an increase in the fraction of the slow-relaxing component in HV (p < 0.05), consistent with oedematous changes., Conclusions: Assessment of TA muscle fat fraction, 1 H T 2 , sodium content and sodium T 2 * relaxation properties revealed differences at baseline and in post-exercise dynamics between patients with dysferlinopathy and matched controls. Post-exercise 23 Na recovery dynamics followed a well-defined time course in HV. Heterogeneous alterations in sodium content and MR relaxation properties in DP may reflect altered ion homeostasis associated with chronic muscle damage., (© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background Pulmonary function tests are central to diagnosis and monitoring of respiratory diseases but do not provide information on regional lung function heterogeneity. Fluorine 19 ( 19 F) MRI of inhaled perfluoropropane permits quantitative and spatially localized assessment of pulmonary ventilation properties without tracer gas hyperpolarization. Purpose To assess regional lung ventilation properties using 19 F MRI of inhaled perfluoropropane in participants with asthma, participants with chronic obstructive pulmonary disease (COPD), and healthy participants, including quantitative evaluation of bronchodilator response in participants with respiratory disease. Materials and Methods This prospective, dual-center study included participants with asthma or COPD from July 2019 to September 2022 and healthy participants from May 2018 to June 2019. Participants underwent conventional spirometry, proton MRI, and 19 F MRI following inhalation of a 79% perfluoropropane and 21% oxygen gas mixture. Three-dimensional 19 F MRI scans were acquired during a single breath hold. For participants with asthma or COPD, spirometric and MRI measurements were repeated following administration of nebulized salbutamol. Ventilation defect percentage (VDP) was calculated from perfluoropropane distribution. Linear mixed-effects models were used to assess differences in VDP between participant groups and before and after bronchodilator administration. Results Thirty-five participants with asthma (mean age, 50 years ± 18 [SD]; 21 male participants), 21 participants with COPD (mean age, 69 years ± 6; 14 male participants), and 38 healthy participants (mean age, 41 years ± 11; 20 male participants) were evaluated. 19 F MRI-derived VDP was elevated in participants with COPD (geometric mean, 27.2%) and participants with asthma (geometric mean, 8.3%) compared with healthy participants (geometric mean, 1.8%; geometric mean ratio, 15.2 [95% CI: 11.1, 20.6] for COPD and 4.6 [95% CI: 3.2, 6.6] for asthma; P < .001 for both). After bronchodilator administration, VDP was reduced by 33% in participants with asthma (from 8.3% to 5.6%) and 14% in participants with COPD (from 27.2% to 23.3%; P < .001 for both). Conclusion 19 F MRI of inhaled perfluoropropane was sensitive to changes in regional ventilation properties associated with lung disease and enabled quantification of changes following bronchodilator therapy. Published under a CC BY-NC-ND 4.0 license. Supplemental material is available for this article. See also the editorial by Unger in this issue.

Background: Lithium is an effective mood stabiliser, but its mechanism of action is incompletely defined. Even at very low doses, lithium may have neuroprotective effects, but it is not clear if these relate to brain lithium concentration in vivo. We have developed magnetic resonance imaging ( 7 Li-MRI) methods to detect lithium in the brain following supplementation at a very low dose., Methods: Lithium orotate supplements were taken by nine healthy adult male subjects (5 mg daily) for up to 28 days, providing 2-7 % of the lithium content of a typical therapeutic lithium carbonate dose. One-dimensional 7 Li-images were acquired on a 3.0 T MRI scanner. All subjects were scanned on day 14 or 28; seven were scanned on both, one at baseline and one after 7-days washout., Results: 7 Li-MR signal amplitude was broadly stable between days 14 and 28. Two subjects had notably higher 7 Li-signal intensities (approximately 2-4×) compared to other study participants., Limitations: Lithium adherence was self-reported by all participants without formal validation. The coarse spatial resolution necessary for detection of low concentrations of 7 Li exhibits imperfect spatial separation of signal from adjacent pixels., Conclusions: 7 Li-MRI performed using a clinical 3T scanner demonstrated detection of lithium in the brain at very low concentration, in the range of approximately 10-60 mM. The methods are suited to studies assessing low dose lithium administration in psychiatric and neurodegenerative disorders, and permit the comparison of different lithium salt preparations at a time of emerging interest in the field., Competing Interests: Declaration of competing interest RS declares honoraria from Janssen (unrelated to this work). All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the reproducibility of percentage ventilated lung volume (%VV) measurements in healthy volunteers acquired by fluorine ( 19 F)-MRI of inhaled perfluoropropane, implemented at two research sites., Methods: In this prospective, ethically approved study, 40 healthy participants were recruited (May 2018-June 2019) to one of two research sites. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% perfluoropropane/21% oxygen gas mixture. Each gas inhalation session lasted about 30 seconds, consisting of three deep breaths of gas followed by a breath-hold. Four 19 F-MR ventilation images were acquired per participant, each separated by approximately 6 minutes. The value of %VV was determined by registering separately acquired 1 H images to ventilation images before semi-automated image segmentation, performed independently by two observers. Reproducibility of %VV measurements was assessed by components of variance, intraclass correlation coefficients, coefficients of variation (CoV), and the Dice similarity coefficient., Results: The MRI scans were well tolerated throughout, with no adverse events. There was a high degree of consistency in %VV measurements for each participant (CoV observer1 = 0.43%; CoV observer2 = 0.63%), with overall precision of %VV measurements determined to be within ± 1.7% (95% confidence interval). Interobserver agreement in %VV measurements revealed a high mean Dice similarity coefficient (SD) of 0.97 (0.02), with only minor discrepancies between observers., Conclusion: We demonstrate good reproducibility of %VV measurements in a group of healthy participants using 19 F-MRI of inhaled perfluoropropane. Our methods have been successfully implemented across two different study sites, supporting the feasibility of performing larger multicenter clinical studies., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Proton longitudinal relaxation (T 1 ) is a quantitative MRI-derived tissue parameter sensitive to myelin, macromolecular, iron and water content. There is some evidence to suggest that cortical T 1 is elevated in bipolar disorder and that lithium administration reduces cortical T 1 . However, T 1 has not yet been quantified in separate groups containing lithium-treated patients, lithium-naïve patients, and matched healthy controls., Methods: Euthymic patients with bipolar disorder receiving lithium (n = 18, BDL) and those on other medications but naïve to lithium (n = 20, BDC) underwent quantitative T 1 mapping alongside healthy controls (n = 18, HC). T 1 was compared between groups within the cortex, white matter and subcortical structures using regions of interest (ROI) derived from the Desikan-Killiany atlas. Effect sizes for each ROI were computed for BDC vs BDL groups and Bipolar Disorder vs HC groups., Results: No significant differences in T 1 were identified between BDL and BDC groups when corrected for multiple comparisons. Patients with bipolar disorder had significantly higher mean T 1 in a range of ROIs compared to healthy controls, including bilateral motor, somatosensory and superior temporal regions, subcortical structures and white matter., Conclusions: The higher T 1 values observed in the patients with bipolar disorder may reflect abnormal tissue microstructure. Whilst the precise mechanism remains unknown, these findings may have a basis in differences in myelination, macromolecular content, iron and water content between patients and controls., (© 2019 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Purpose: To assess alveolar perfusion by applying dynamic susceptibility contrast MRI to 19 F-MRI of inhaled perfluoropropane (PFP). We hypothesized that passage of gadolinium-based contrast agent (GBCA) through the pulmonary microvasculature would reduce magnetic susceptibility differences between water and gas components of the lung, elevating the T 2 ∗ of PFP., Methods: Lung-representative phantoms were constructed of aqueous PFP-filled foams to characterize the impact of aqueous/gas phase magnetic susceptibility differences on PFP T 2 ∗ . Aqueous phase magnetic susceptibility was modulated by addition of different concentrations of GBCA. In vivo studies were performed to measure the impact of intravenously administered GBCA on the T 2 ∗ of inhaled PFP in mice (7.0 Tesla) and in healthy volunteers (3.0 Tesla)., Results: Perfluoropropane T 2 ∗ was sensitive to modulation of magnetic susceptibility difference between gas and water components of the lung, both in phantom models and in vivo. Negation of aqueous/gas phase magnetic susceptibility difference was achieved in lung-representative phantoms and in mice, resulting in a ~2 to 3× elevation in PFP T 2 ∗ (3.7 to 8.5 ms and 0.7 to 2.6 ms, respectively). Human studies demonstrated a transient elevation of inhaled PFP T 2 ∗ (1.50 to 1.64 ms) during passage of GBCA bolus through the lung circulation, demonstrating sensitivity to lung perfusion., Conclusion: We demonstrate indirect detection of a GBCA in the pulmonary microvasculature via changes to the T 2 ∗ of gas phase PFP within directly adjacent alveoli. This approach holds potential for assessing alveolar perfusion by dynamic susceptibility contrast 19 F-MRI of inhaled PFP, with concurrent assessment of lung ventilation properties, relevant to lung physiology and disease., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin ) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290 -deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Purpose: To accelerate 19 F-MR imaging of inhaled perfluoropropane using compressed sensing methods, and to optimize critical scan acquisition parameters for assessment of lung ventilation properties., Methods: Simulations were performed to determine optimal acquisition parameters for maximal perfluoropropane signal-to-noise ratio (SNR) in human lungs for a spoiled gradient echo sequence. Optimized parameters were subsequently employed for 19 F-MRI of inhaled perfluoropropane in a cohort of 11 healthy participants using a 3.0 T scanner. The impact of 1.8×, 2.4×, and 3.0× undersampling ratios on 19 F-MRI acquisitions was evaluated, using both retrospective and prospective compressed sensing methods., Results: 3D spoiled gradient echo 19 F-MR ventilation images were acquired at 1-cm isotropic resolution within a single breath hold. Mean SNR was 11.7 ± 4.1 for scans acquired within a single breath hold (duration = 18 s). Acquisition of 19 F-MRI scans at shorter scan durations (4.5 s) was also demonstrated as feasible. Application of both retrospective (n = 8) and prospective (n = 3) compressed sensing methods demonstrated that 1.8× acceleration had negligible impact on qualitative image appearance, with no statistically significant change in measured lung ventilated volume. Acceleration factors of 2.4× and 3.0× resulted in increasing differences between fully sampled and undersampled datasets., Conclusion: This study demonstrates methods for determining optimal acquisition parameters for 19 F-MRI of inhaled perfluoropropane and shows significant reduction in scan acquisition times (and thus participant breath hold duration) by use of compressed sensing., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need., Structure: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence., Conclusions: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Background: Lithium treatment is associated with an increase in magnetic resonance imaging derived measures of white matter integrity, but the relationship between the spatial distribution of brain lithium and white matter integrity is unknown., Methods: Euthymic patients with bipolar disorder receiving lithium (n = 12) and those on other medications but naïve to lithium (n = 17) underwent diffusion imaging alongside matched healthy controls (n = 16). Generalised fractional anisotropy (gFA) within white matter was compared between groups using a standard space white matter atlas. Lithium-treated patients underwent novel multinuclear lithium magnetic resonance imaging ( 7 Li-MRI) to determine the relative lithium concentration across the brain. The relationship between 7 Li-MRI signal intensity and gFA was investigated at the resolution of the 7 Li-MRI sequence in native space., Results: Lithium-treated bipolar disorder and healthy control groups had higher mean white matter gFA than the bipolar disorder group treated with other medications (t = 2.5, p < 0.05; t = 2.7, p < 0.03, respectively). No differences in gFA were found between patients taking lithium and healthy controls (t = 0.02, p = 1). These effects were seen consistently across most regions in the white matter atlas. In the lithium-treated group, a significant effect of the 7 Li-MRI signal in predicting the gFA (p < 0.01) was identified in voxels containing over 50% white matter., Limitations: Cross-sectional evaluation of a relatively small cohort., Conclusions: The higher gFA values observed in the lithium-treated bipolar disorder group suggests that long-term lithium is associated with greater white matter integrity. Our novel analysis supports this further, showing a positive association between white matter gFA and the spatial distribution of lithium., (Copyright © 2019. Published by Elsevier B.V.)

Lithium is a major treatment for bipolar disorder and the likelihood of a favourable response may be determined by its distribution in the brain. Lithium can be directly detected by magnetic resonance (MR), but previous 7 Li MR spectroscopy studies have demonstrated that this is challenging compared to conventional 1 H MR imaging due to the MR properties of the lithium nucleus and its low concentration in brain tissue, as dictated by therapeutic dose. We have tested and implemented a highly efficient balanced steady-state free precession 7 Li-MRI method to address these challenges and enable MRI of brain lithium in a short duration scan. We report a 3D 7 Li-MRI acquisition with 25 mm isotropic resolution in an 8-min scan that demonstrates heterogeneity in lithium concentration within the brain in subjects with bipolar disorder. This represents the direct imaging of a pharmaceutical agent in its target organ and notably expands the repertoire of techniques available to investigate the effects of lithium in man.

The purpose of this study was to assess the effects of sucrose vs. glucose ingestion on postexercise liver and muscle glycogen repletion. Fifteen well-trained male cyclists completed two test days. Each test day started with glycogen-depleting exercise, followed by 5 h of recovery, during which subjects ingested 1.5 g·kg(-1)·h(-1) sucrose or glucose. Blood was sampled frequently and (13)C magnetic resonance spectroscopy and imaging were employed 0, 120, and 300 min postexercise to determine liver and muscle glycogen concentrations and liver volume. Results were as follows: Postexercise muscle glycogen concentrations increased significantly from 85 ± 27 (SD) vs. 86 ± 35 mmol/l to 140 ± 23 vs. 136 ± 26 mmol/l following sucrose and glucose ingestion, respectively (no differences between treatments: P = 0.673). Postexercise liver glycogen concentrations increased significantly from 183 ± 47 vs. 167 ± 65 mmol/l to 280 ± 72 vs. 234 ± 81 mmol/l following sucrose and glucose ingestion, respectively (time × treatment, P = 0.051). Liver volume increased significantly over the 300-min period after sucrose ingestion only (time × treatment, P = 0.001). As a result, total liver glycogen content increased during postexercise recovery to a greater extent in the sucrose treatment (from 53.6 ± 16.2 to 86.8 ± 29.0 g) compared with the glucose treatment (49.3 ± 25.5 to 65.7 ± 27.1 g; time × treatment, P < 0.001), equating to a 3.4 g/h (95% confidence interval: 1.6-5.1 g/h) greater repletion rate with sucrose vs. glucose ingestion. In conclusion, sucrose ingestion (1.5 g·kg(-1)·h(-1)) further accelerates postexercise liver, but not muscle glycogen repletion compared with glucose ingestion in trained athletes., (Copyright © 2016 the American Physiological Society.)

The purpose of this study was to define the effect of glucose ingestion compared with sucrose ingestion on liver and muscle glycogen depletion during prolonged endurance-type exercise. Fourteen cyclists completed two 3-h bouts of cycling at 50% of peak power output while ingesting either glucose or sucrose at a rate of 1.7 g/min (102 g/h). Four cyclists performed an additional third test for reference in which only water was consumed. We employed (13)C magnetic resonance spectroscopy to determine liver and muscle glycogen concentrations before and after exercise. Expired breath was sampled during exercise to estimate whole body substrate use. After glucose and sucrose ingestion, liver glycogen levels did not show a significant decline after exercise (from 325 ± 168 to 345 ± 205 and 321 ± 177 to 348 ± 170 mmol/l, respectively; P > 0.05), with no differences between treatments. Muscle glycogen concentrations declined (from 101 ± 49 to 60 ± 34 and 114 ± 48 to 67 ± 34 mmol/l, respectively; P < 0.05), with no differences between treatments. Whole body carbohydrate utilization was greater with sucrose (2.03 ± 0.43 g/min) vs. glucose (1.66 ± 0.36 g/min; P < 0.05) ingestion. Both liver (from 454 ± 33 to 283 ± 82 mmol/l; P < 0.05) and muscle (from 111 ± 46 to 67 ± 31 mmol/l; P < 0.01) glycogen concentrations declined during exercise when only water was ingested. Both glucose and sucrose ingestion prevent liver glycogen depletion during prolonged endurance-type exercise. Sucrose ingestion does not preserve liver glycogen concentrations more than glucose ingestion. However, sucrose ingestion does increase whole body carbohydrate utilization compared with glucose ingestion. This trial was registered at https://www.clinicaltrials.gov as NCT02110836., (Copyright © 2015 the American Physiological Society.)

Objective: Although impairment in pancreatic insulin secretion is known to precede the clinical diagnosis of type 2 diabetes by up to a decade, fasting blood glucose concentration only rises abnormally once the impairment reaches a critical threshold. Despite its centrality to the pathogenesis of type 2 diabetes, the pancreas is the least studied organ due to its inaccessible anatomical position. Previous ultrasound and CT studies have suggested a possible decrease in pancreatic volume in type 2 diabetes. However, ultrasound techniques are relatively insensitive while CT uses ionizing radiation, making these modalities unsuitable for precise, longitudinal studies designed to explore the underlying mechanisms of type 2 diabetes. Hence there is a need to develop a non-invasive, safe and precise method to quantitate pancreas volume., Methods: We developed and applied magnetic resonance imaging at 3.0T to obtain balanced turbo field echo (BTFE) structural images of the pancreas, together with 3-point Dixon images to quantify pancreatic triglyceride content. Pancreas volume, morphology and triglyceride content was quantified in a group of 41 subjects with well-controlled type 2 diabetes (HbA1c ≤ 7.6%) taking only metformin (duration of T2DM 5.7 ± 0.7 years), and a control group of 14 normal glucose tolerance subjects matched for age, weight and sex., Results: The mean pancreatic volume was found to be 33% less in type 2 diabetes than in normal glucose tolerant subjects (55.5 ± 2.8 vs. 82.6 ± 4.8 cm3; p < 0.0001). Pancreas volume was positively correlated with HOMA-β in the type 2 diabetes subjects (r = 0.31; p = 0.03) and controls (r = 0.46; p = 0.05) considered separately; and in the whole population studied (r = 0.37; p = 0.003). In type 2 diabetes, the pancreas was typically involuted with a serrated border. Pancreatic triglyceride content was 23% greater (5.4 ± 0.3 vs. 4.4 ± 0.4%; p = 0.02) in the type 2 diabetes group., Conclusion: This study describes for the first time gross abnormalities of the pancreas in early type 2 diabetes and quantifies the decrease in pancreas size, the irregular morphology and increase in fat content.

In health, food carbohydrate is stored as glycogen in muscle and liver, preventing a deleterious rise in osmotically active plasma glucose after eating. Glycogen concentrations increase sequentially after each meal to peak in the evening, and fall to fasting levels thereafter. Skeletal muscle accounts for the larger part of this diurnal buffering capacity with liver also contributing. The effectiveness of this diurnal mechanism has not been previously studied in Type 2 diabetes. We have quantified the changes in muscle and liver glycogen concentration with 13C magnetic resonance spectroscopy at 3.0 T before and after three meals consumed at 4 h intervals. We studied 40 (25 males; 15 females) well-controlled Type 2 diabetes subjects on metformin only (HbA1c (glycated haemoglobin) 6.4±0.07% or 47±0.8 mmol/mol) and 14 (8 males; 6 females) glucose-tolerant controls matched for age, weight and body mass index (BMI). Muscle glycogen concentration increased by 17% after day-long eating in the control group (68.1±4.8 to 79.7±4.2 mmol/l; P=0.006), and this change inversely correlated with homoeostatic model assessment of insulin resistance [HOMA-IR] (r=-0.56; P=0.02). There was no change in muscle glycogen in the Type 2 diabetes group after day-long eating (68.3±2.6 to 67.1±2.0 mmol/mol; P=0.62). Liver glycogen rose similarly in normal control (325.9±25.0 to 388.1±30.3 mmol/l; P=0.005) and Type 2 diabetes groups (296.1±16.0 to 350.5±6.7 mmol/l; P<0.0001). In early Type 2 diabetes, the major physiological mechanism for skeletal muscle postprandial glycogen storage is completely inactive. This is directly related to insulin resistance, although liver glycogen storage is normal.

Context: Although dipeptidyl-peptidase-4 inhibitors exert their major action via an incretin mechanism, a favorable effect of vildagliptin on lipid metabolism remains unexplained., Objective: The objective was to examine hepatic triglyceride levels and insulin sensitivity on vildagliptin., Design: This was a 6-month, randomized, double-blind, placebo-controlled trial., Setting: This was an outpatient study at a university clinical research center., Patients: Individuals with type 2 diabetes (n = 44) and glycated hemoglobin ≤ 7.6% on stable metformin therapy were included., Intervention: Intervention was vildagliptin 50 mg twice a day or placebo over 6 months., Main Outcome Measures: Main outcome measures were hepatic triglyceride levels and insulin sensitivity., Results: Mean fasting liver triglyceride content decreased by 27% with vildagliptin, from 7.3 ± 1.0% (baseline) to 5.3 ± 0.9% (endpoint). There was no change in the placebo group. The between-group difference in change from baseline was significant (P = .013). Mean fasting plasma glucose concentration decreased over the study period with vildagliptin vs placebo by -1.0 mmol/L (P = .018), and there was a positive correlation between these decrements and liver triglyceride in the vildagliptin group at 3 months (r = 0.47; P = .02) and 6 months (r = 0.44; P = .03). Plasma alanine aminotransferase fell from 27.2 ± 2.8 to 20.3 ± 1.4 IU/L in the vildagliptin group (P = .0007), and there was a correlation between the decrements in alanine aminotransferase and liver triglyceride (r = 0.83; P < .0001). Insulin sensitivity during the euglycemic clamp was similar in each group at baseline (3.24 ± 0.30 vs 3.19 ± 0.38 mg/kg/min) and did not change (adjusted mean change of 0.26 ± 0.22 vs 0.32 ± 0.22 mg/kg/min; P = .86). Mean body weight decreased by 1.6 ± 0.5 vs 0.4 ± 0.5 kg in the vildagliptin and placebo groups, respectively (P = .08)., Conclusions: This study demonstrates that the dipeptidyl-peptidase-4 inhibitor vildagliptin brings about a clinically significant decrease in hepatic triglyceride levels during 6 months of therapy unrelated to change in body weight. There was no change in peripheral insulin sensitivity.

Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically.

Unlabelled: Oxidative stress (OS) plays a central role in the progression of liver disease and in damage to liver by toxic xenobiotics. We have developed methods for noninvasive assessment of hepatic OS defenses by measuring flux through the glutathione (GSH) synthesis pathway. (13) C-labeled GSH is endogenously produced and detected by in vivo magnetic resonance after administration of [2-(13) C]-glycine. We report on a successful first-ever human demonstration of this approach as well as preclinical studies demonstrating perturbed GSH metabolism in models of acute and chronic OS. Human studies employed oral administration of [2-(13) C]-glycine and (13) C spectroscopy on a 3T clinical magnetic resonance (MR) imaging scanner and demonstrated detection and quantification of endogenously produced (13) C-GSH after labeled glycine ingestion. Plasma analysis demonstrated that glycine (13) C fractional enrichment achieved steady state during the 6-hour ingestion period. Mean rate of synthesis of hepatic (13) C-labeled GSH was 0.32 ± 0.18 mmole/kg/hour. Preclinical models of acute OS and nonalcoholic steatohepatitis (NASH) comprised CCl4 -treated and high-fat, high-carbohydrate diet-fed Sprague-Dawley rats, respectively, using intravenous administration of [2-(13) C]-glycine and observation of (13) C-label metabolism on a 7T preclinical MR system. Preclinical studies demonstrated a 54% elevation of GSH content and a 31% increase in flux through the GSH synthesis pathway at 12 hours after acute insult caused by CCl4 administration, as well as a 23% decrease in GSH content and evidence of early steatohepatitis in the model of NASH., Conclusion: Our data demonstrate in vivo (13) C-labeling and detection of GSH as a biomarker of tissue OS defenses, detecting chronic and acute OS insults. The methods are applicable to clinical research studies of hepatic OS in disease states over time as well as monitoring effects of therapeutic interventions., (Copyright © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.)

The present study evaluated whether the inclusion of protein (PRO) and amino acids (AA) within a maltodextrin (MD) and galactose (GAL) recovery drink enhanced post-exercise liver and muscle glycogen repletion. A total of seven trained male cyclists completed two trials, separated by 7 d. Each trial involved 2 h of standardised intermittent cycling, followed by 4 h recovery. During recovery, one of two isoenergetic formulations, MD-GAL (0.9 g MD/kg body mass (BM) per h and 0.3 g GAL/kg BM per h) or MD-GAL-PRO+AA (0.5 g MD/kg BM per h, 0.3 g GAL/kg BM per h, 0.4 g whey PRO hydrolysate plus l-leucine and l-phenylalanine/kg BM per h) was ingested at every 30 min. Liver and muscle glycogen were measured after depletion exercise and at the end of recovery using 1H-13C-magnetic resonance spectroscopy. Despite higher postprandial insulin concentations for MD-GAL-PRO+AA compared with MD-GAL (61.3 (se 6.2) v. 29.6 (se 3.0) mU/l, (425.8 (se 43.1) v. 205.6 (se 20.8) pmol/l) P= 0.03), there were no significant differences in post-recovery liver (195.3 (se 2.6) v. 213.8 (se 18.0) mmol/l) or muscle glycogen concentrations (49.7 (se 4.0) v. 51.1 (se 7.9) mmol/l). The rate of muscle glycogen repletion was significantly higher for MD-GAL compared with MD-GAL-PRO+AA (5.8 (se 0.7) v. 3.7 (se 0.6) mmol/l per h, P= 0.04), while there were no significant differences in the rate of liver glycogen repletion (15.0 (se 2.5) v. 13.0 (se 2.7) mmol/l per h). PRO and AA within a MD-GAL recovery drink, compared with an isoenergetic mix of MD-GAL, did not enhance but matched liver and muscle glycogen recovery. This suggests that the increased postprandial insulinaemia only compensated for the lower MD content in the MD-GAL-PRO+AA treatment.

Background & Aims: Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used (1)H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model., Methods: Human studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4weeks of sebelipase alfa treatment. Hepatic (1)H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content., Results: CE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa., Conclusions: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Normal pregnancy is associated with insulin resistance although the mechanism is not understood. Increased intramyocellular lipid is closely associated with the insulin resistance of type 2 diabetes and obesity, and the aim of this study was to determine whether this was so for the physiological insulin resistance of pregnancy. Eleven primiparous healthy pregnant women (age: 27-39 years, body mass index 24.0±3.1 kg/m2) and no personal or family history of diabetes underwent magnetic resonance studies to quantify intramyocellular lipid, plasma lipid fractions, and insulin sensitivity. The meal-related insulin sensitivity index was considerably lower in pregnancy (45.6±9.9 vs. 193.0±26.1; 10(-4) dl/kg/min per pmol/l, p=0.0002). Fasting plasma triglyceride levels were elevated 3-fold during pregnancy (2.3±0.2 vs. 0.8±0.1 mmol/l, p<0.01) and the low-density density lipoprotein fraction, responsible for fatty acid delivery to muscle and other tissues, was 6-fold elevated (0.75±0.43 vs. 0.12±0.09 mmol/l; p=0.001). However, mean intramyocellular lipid concentrations of the soleus muscle were not different during pregnancy (20.0±2.3 vs. 19.1±3.2 mmol/l, p=0.64). The pregnancy effect on muscle insulin resistance is distinct from that underlying type 2 diabetes., (© Georg Thieme Verlag KG Stuttgart · New York.)

The metabolism of glycine into glutathione was monitored noninvasively in vivo in intact rat mammary adenocarcinomas (R3230Ac) by MRI and MRS. Metabolism was tracked by following the isotope label from intravenously infused [2-(13)C]-glycine into the glycinyl residue of glutathione. Signals from [2-(13)C]-glycine and γ-glutamylcysteinyl-[2-(13)C]-glycine ((13)C-glutathione) were detected by nonlocalized (13)C spectroscopy, as these resonances are distinct from background signals. In addition, using spectroscopic imaging methods, heterogeneity in the in vivo tumor distribution of glutathione was observed. In vivo spectroscopy also detected isotope incorporation from [2-(13)C]-glycine into both the 2- and 3-carbons of serine. Analyses of tumor tissue extracts showed single- and multiple-label incorporation from [2-(13)C]-glycine into serine from metabolism through the serine hydroxymethyltransferase and glycine cleavage system pathways. Mass spectrometric analysis of extracts also showed that isotope-labeled serine is further metabolized via the trans-sulfuration pathway, as (13)C isotope labels appear in both the glycinyl and cysteinyl residues of glutathione. Our studies demonstrate the use of MRI and MRS for the monitoring of tumor metabolic processes central to oxidative stress defense., (Copyright © 2011 John Wiley & Sons, Ltd.)

Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We hypothesized that any impairment in insulin-stimulated muscle ATP production could merely reflect the lower rates of muscle glucose uptake and glycogen synthesis, rather than cause it. If this is correct, muscle ATP turnover rates in type 2 diabetes could be increased if glycogen synthesis rates were normalized by the mass-action effect of hyperglycemia. Isoglycemic- and hyperglycemic-hyperinsulinemic clamps were performed on type 2 diabetic subjects and matched controls, with muscle ATP turnover and glycogen synthesis rates measured using (31)P- and (13)C-magnetic resonance spectroscopy, respectively. In diabetic subjects, hyperglycemia increased muscle glycogen synthesis rates to the level observed in controls at isoglycemia [from 19 ± 9 to 41 ± 12 μmol·l(-1)·min(-1) (P = 0.012) vs. 40 ± 7 μmol·l(-1)·min(-1) in controls]. This was accompanied by a modest increase in muscle ATP turnover rates (7.1 ± 0.5 vs. 8.6 ± 0.7 μmol·l(-1)·min(-1), P = 0.04). In controls, hyperglycemia brought about a 2.5-fold increase in glycogen synthesis rates (100 ± 24 vs. 40 ± 7 μmol·l(-1)·min(-1), P = 0.028) and a 23% increase in ATP turnover rates (8.1 ± 0.9 vs. 10.0 ± 0.9 μmol·l(-1)·min(-1), P = 0.025) from basal state. Muscle ATP turnover rates correlated positively with glycogen synthesis rates (r(s) = 0.46, P = 0.005). Changing the rate of muscle glucose metabolism in type 2 diabetic subjects alters demand for ATP synthesis at rest. In type 2 diabetes, skeletal muscle ATP turnover rates reflect the rate of glucose uptake and glycogen synthesis, rather than any primary mitochondrial defect.

Lithium (Li) is a core for many neuropsychiatric conditions. The safe serum range of Li treatment is narrow, and regular monitoring by blood test is required, although serum levels are thought to be a poor indicator of Li concentration in the brain itself. Brain Li concentration can be measured by magnetic resonance spectroscopy. However, little data exist in the healthy human brain, and there are no studies of the relaxation properties of brain (7)Li at 3 T. Here, 11 healthy male subjects were prescribed Li over a period of 11 days. In seven subjects, the in vivo T(1) of (7)Li was measured to be 2.1 ± 0.7 s. In the remaining subjects, spectroscopic imaging (1D) yielded a mean brain (7)Li concentration of 0.71 ± 0.1 mM, with no significant difference between gray and white matter. Mean serum concentration was 0.9 ± 0.16 mM, giving a mean brain/serum ratio of 0.78 ± 0.26., (Copyright © 2011 Wiley-Liss, Inc.)

Aims/hypothesis: Pathophysiological abnormalities in early diabetic nephropathy are poorly understood. We employed MRI to characterise renal perfusion, tissue oxygenation and kidney size in non-diabetic volunteers and type 1 diabetic patients without and with early renal disease., Methods: We studied ten control participants (C; age 40.0 [range 31-54] years), nine longstanding normotensive type 1 diabetic patients (T1Normo; age 40.1 [31-50] years, estimated glomerular filtration rate [eGFR] 83.4 ± 10.6 ml min(-1) 1.73 m(-2)) and eight microalbuminuric type 1 diabetic patients (T1Micro; age 42.4 [33-52] years, eGFR 71.6 ± 13.7 ml min(-1) 1.73 m(-2)). Six microalbuminuric patients were restudied after 4 weeks without renin-angiotensin-aldosterone system inhibitors. Phase contrast angiography and kidney blood oxygen level dependent (BOLD) (R(2)(*)) MRI were performed, before and during water diuresis. Contrast-enhanced MRI was performed at baseline urine flow rate. Renal artery flow, renal vascular resistance (RVR), cortical and medullary volumes, and R(2)(*) were determined., Results: Renal cortical and medullary volumes were similar in all groups (cortex: C 108 ± 16, T1Normo 112 ± 21, T1Micro 111 ± 10 cm(3)/1.73 m(2); medulla: C 35 ± 14, T1Normo 29 ± 10, 33 ± 6 cm(3)/1.73 m(2)). RVR increased from control to normoalbuminuric to microalbuminuric type 1 diabetic patients (C 0.061 ± 0.018, T1Normo 0.077 ± 0.014, T1Micro 0.093 ± 0.024 mmHg ml(-1) min(-1) 1.73 m(-2), ANOVA p = 0.012). RVR correlated inversely with eGFR in normoalbuminuric, but not in microalbuminuric diabetic patients. Renal artery flow was lower in the whole diabetes cohort (control 740 ± 205 vs diabetes 591 ± 128 ml min(-1) 1.73 m(-2), p = 0.035)., Conclusions/interpretation: Cortical and medullary volumes remain normal in early diabetic nephropathy. Decreased renal flow in longstanding normoalbuminuric type 1 diabetic patients may reflect intrarenal vascular stiffening, whereas in the microalbuminuric patients it may also reflect increased intraglomerular pressure.

Suppression of lipolysis by acipimox is known to improve insulin-stimulated glucose disposal, and this is an important phenomenon. The mechanism has been assumed to be an enhancement of glucose storage as glycogen, but no direct measurement has tested this concept or its possible relationship to the reported impairment in insulin-stimulated muscle ATP production. Isoglycaemic-hyperinsulinaemic clamps with [13C]glucose infusion were performed on Type 2 diabetic subjects and matched controls with measurement of glycogen synthesis by 13C MRS (magnetic resonance spectroscopy) of muscle. 31P saturation transfer MRS was used to quantify muscle ATP turnover rates. Glucose disposal rates were restored to near normal in diabetic subjects after acipimox (6.2 ± 0.8 compared with 4.8 ± 0.6 mg·kgffm⁻¹·min⁻¹; P<0.01; control 6.6 ± 0.5 mg·kgffm⁻¹·min⁻¹; where ffm, is fat-free mass). The increment in muscle glycogen concentration was 2-fold higher in controls compared with the diabetic group, and acipimox administration to the diabetic group did not increase this (2.0 ± 0.8 compared with 1.9 ± 1.1 mmol/l; P<0.05; control, 4.0 ± 0.8 mmol/l). ATP turnover rates did not increase during insulin stimulation in any group, but a modest decrease in the diabetes group was prevented by lowering plasma NEFAs (non-esterified fatty acids; 8.4 ± 0.7 compared with 7.1 ± 0.5 μmol·g⁻¹·min⁻¹; P<0.05; controls 8.6 ± 0.8 μmol·g⁻¹·min⁻¹). Suppression of lipolysis increases whole-body glucose uptake with no increase in the rate of glucose storage as glycogen but with increase in whole-body glucose oxidation rate. ATP turnover rate in muscle exhibits no relationship to the acute metabolic effect of insulin.

The cysteine precursor L-2-oxothiazolidine-4-carboxylate (OTZ, procysteine) can raise cysteine concentration, and thus glutathione levels, in some tissues. OTZ has therefore been proposed as a prodrug for combating oxidative stress. We have synthesized stable isotope labeled OTZ (i.e. L-2-oxo-[5-(13)C]-thiazolidine-4-carboxylate, (13)C-OTZ) and tracked its uptake and metabolism in vivo in rat brain by (13)C magnetic resonance spectroscopy. Although uptake and clearance of (13)C-OTZ was detectable in rat brain following a bolus dose by in vivo spectroscopy, no incorporation of isotope label into brain glutathione was detectable. Continuous infusion of (13)C-OTZ over 20 h, however, resulted in (13)C-label incorporation into glutathione, taurine, hypotaurine and lactate at levels sufficient for detection by in vivo magnetic resonance spectroscopy. Examination of brain tissue extracts by mass spectrometry confirmed only low levels of isotope incorporation into glutathione in rats treated with a bolus dose and much higher levels after 20 h of continuous infusion. In contrast to some previous studies, bolus administration of OTZ did not alter brain glutathione levels. Even a continuous infusion of OTZ over 20 h failed to raise brain glutathione levels. These studies demonstrate the utility of in vivo magnetic resonance for non-invasive monitoring of antioxidant uptake and metabolism in intact brain. These types of experiments can be used to evaluate the efficacy of various interventions for maintenance of brain glutathione.

Mitochondrial dysfunction has been proposed to underlie the insulin resistance of type 2 diabetes. However, the relative time course of insulin action in stimulating ATP turnover rate and glucose uptake in skeletal muscle has not been examined. These two parameters were measured in young healthy subjects using the (31)P MRS saturation transfer method in conjunction with the euglycaemic hyperinsulinaemic clamp technique respectively. Glucose infusion rate rose rapidly from 0 to 2.90 ± 0.11 mg/kg(ffm)/min during the first 10 min of insulin infusion and further to 6.17 ± 0.57 mg/kg(ffm)/min between 15 and 45 min. In contrast, baseline ATP turnover rate was 9.0 ± 0.4 µmol/g/min of muscle and did not change during the first 45 min of insulin infusion. Between 50 and 80 minutes ATP turnover rate increased by 8% and remained steady to 150 minutes (9.7 ± 0.5 µmol/g/min of muscle, p = 0.03 vs baseline). The in vivo time course of insulin stimulation of skeletal muscle ATP turnover rate is not consistent with a rate limiting effect upon the initiation of insulin-stimulated glycogen synthesis., (Copyright © 2010 John Wiley & Sons, Ltd.)

Chemically-fixed nervous tissues are well-suited for high-resolution, time-intensive MRI acquisitions without motion artifacts, such as those required for brain atlas projects, but the aldehyde fixatives used may significantly alter tissue MRI properties. To test this hypothesis, this study characterized the impact of common aldehyde fixatives on the MRI properties of a rat brain slice model. Rat cortical slices immersion-fixed in 4% formaldehyde demonstrated 21% and 81% reductions in tissue T(1) and T(2), respectively (P < 0.001). The T(2) reduction was reversed by washing slices with phosphate-buffered saline (PBS) for 12 h to remove free formaldehyde solution. Diffusion MRI of cortical slices analyzed with a two-compartment analytical model of water diffusion demonstrated 88% and 30% increases in extracellular apparent diffusion coefficient (ADC(EX)) and apparent restriction size, respectively, when slices were chemically-fixed with 4% formaldehyde (P

The glycemic index (GI) of dietary carbohydrates influences glycogen storage in skeletal muscle and circulating nonesterified fatty acid (NEFA) concentrations. We hypothesized that diets differing only in GI would alter intramuscular lipid oxidation and glycogen usage in skeletal muscle and liver during subsequent exercise. Endurance-trained individuals (n = 9) cycled for 90 min at 70% Vo(2peak) and then consumed either high- or low-GI meals over the following 12 h. The following day after an overnight fast, the 90-min cycle was repeated. (1)H and (13)C magnetic resonance spectroscopy was used before and after exercise to assess intramuscular lipid and glycogen content of the vastus muscle group and liver. Blood and expired air samples were collected at 15-min intervals throughout exercise. NEFA availability was reduced during exercise in the high- compared with the low-GI trial (area under curve 44.5 +/- 6.0 vs. 38.4 +/- 7.30 mM/h, P < 0.05). Exercise elicited an approximately 55% greater reduction in intramyocellular triglyceride (IMCL) in the high- vs. low-GI trial (1.6 +/- 0.2 vs. 1.0 +/- 0.3 mmol/kg wet wt, P < 0.05). There was no difference in the exercise-induced reduction of the glycogen pool in skeletal muscle (76 +/- 8 vs. 68 +/- 5 mM) or in liver (65 +/- 8 vs. 71 +/- 4 mM) between the low- and high-GI trials, respectively. High-GI recovery diets reduce NEFA availability and increase reliance on IMCL during moderate-intensity exercise. Skeletal muscle and liver glycogen storage or usage are not affected by the GI of an acute recovery diet.

High-resolution imaging of human autopsy tissues may improve our understanding of in vivo MRI findings, but interpretation is complicated because samples are obtained by immersion fixation following a postmortem interval (PMI). This study tested the hypotheses that immersion fixation and PMI's from 0-24 h would alter the water relaxation and diffusion properties in rat cortical slice and spinal cord models of human nervous tissue. Diffusion data collected from rat cortical slices at multiple diffusion times (10-60 ms) and b-values (7-15,000 s/mm(2)) were analyzed using a two-compartment model with exchange. Rat spinal cords were characterized with standard diffusion tensor imaging (21 directions, b=1250 s/mm(2)). Switching from perfusion- to immersion-fixation at 0 h PMI altered most MRI properties of rat cortical slices and spinal cords, including a 22% decrease in fractional anisotropy (P<0.001). After 4 h PMI, cortical slice T(1) and T(2) increased 22% and 65% respectively (P<0.001), transmembrane water exchange decreased 23% (P<0.001) and intracellular proton fraction increased 25% (P=0.002). After 6 h PMI, spinal cord white matter fractional anisotropy had decreased 38% (P<0.001). MRI property changes were observed for PMIs up to 24 h. The MRI changes correlated with protease activity and histopathological signs of autolysis. Thus, immersion fixation and/or even short PMIs (4-6 h) altered the MRI properties of rat nervous tissue. This suggests comparisons between in vivo clinical MRI and MRI data from human autopsy tissues should be interpreted with caution.

We present a method for MR detection of (17)O-labeled phosphate groups. The method employs the T(2) relaxivity effect of (17)O on (31)P nuclei to distinguish between (17)O-labeled and unlabeled phosphate groups, and uses spin-echo (SE) acquisitions with RF decoupling at the (17)O frequency to generate (31)P spectra that show only (17)O-labeled phosphate groups. The method provides an alternative to spin-labeling experiments, which are limited to the study of rapidly exchanging phosphate groups by the T(1) relaxation rates of phosphorus nuclei. We demonstrate separation of MR signals from labeled and unlabeled phosphate-containing compounds, and characterization of the T(2) effect of (17)O on phosphate nuclei in (17)O-labeled phosphate groups. Previous (17)O and (18)O phosphate-labeled studies used mass spectrometry or high-resolution MR spectroscopy (MRS) to detect the presence of an isotopic label, which requires ex vivo sample preparation. In our method the detection of (17)O-labeled phosphate is manifested as a large change in (31)P T(2), and thus allows in vivo detection using simple MR methods. Thus this method may have potential for in vivo studies of bioenergetics and the metabolism of phosphate-containing compounds.

This report introduces a novel method to characterize the diffusion-time dependence of the diffusion-weighted magnetic resonance (MR) signal in biological tissues. The approach utilizes the theory of diffusion in disordered media where two parameters, the random walk dimension and the spectral dimension, describe the evolution of the average propagators obtained from q-space MR experiments. These parameters were estimated, using several schemes, on diffusion MR spectroscopy data obtained from human red blood cell ghosts and nervous tissue autopsy samples. The experiments demonstrated that water diffusion in human tissue is anomalous, where the mean-square displacements vary slower than linearly with diffusion time. These observations are consistent with a fractal microstructure for human tissues. Differences observed between healthy human nervous tissue and glioblastoma samples suggest that the proposed methodology may provide a novel, clinically useful form of diffusion MR contrast.

Ex vivo biological sample imaging can complement in vivo MRI studies. Since ex vivo studies are typically performed at room temperature, and samples are frequently preserved by fixation, it is important to understand how environmental and chemical changes dictated by ex vivo studies alter the physical and MR properties of a sample. Diffusion and relaxation time measurements were used to assess the effects of temperature change and aldehyde fixation on the biophysical and MR properties of a model biological tissue comprised of erythrocyte ghosts suspended in buffer or agarose gel. Sample temperature was varied between 10 degrees C and 37 degrees C. Diffusion MRI data were analyzed with a biophysically appropriate two-compartment exchange model. Temperature change resulted in a complex alteration of water diffusion properties due to the compartmental nature of tissues and alteration in membrane permeability. Formaldehyde, Karnovsky's solution, and glutaraldehyde all caused statistically significant changes to the biophysical and MR properties of the samples. Fixation caused large decreases in water proton T2, which was restored to near prefixation values by washing free fixative from the samples. Water membrane permeability was also significantly altered by fixation. This study demonstrates that relating in vivo MR data to chemically fixed ex vivo data requires an understanding of the effects of sample preparation., (Copyright 2006 Wiley-Liss, Inc.)

Observation of translational self-diffusion of water molecules using magnetic resonance (MR) techniques has proven to be a powerful means to probe tissue microstructure. The collected MR signal depends on experimentally controllable parameters as well as the descriptors of tissue geometry. In order to obtain the latter, one needs to employ accurate models to characterize the dependence of the signal on the varied experimental parameters. In this work, a simple model describing diffusion in disordered media and fractal spaces is shown to describe the diffusion-time dependence of the diffusion attenuated MR signal obtained from biological specimens successfully. The model enables one to quantify the evolution of the average water displacement probabilities in terms of two exponents--dw and ds. The experiments performed on excised human neural tissue samples and human red blood cell ghosts indicate that these two parameters are sensitive to tissue microstructure. Therefore, it may be possible to use the proposed scheme to generate novel contrast mechanism for classifying and segmenting tissue.

Magnetic resonance spectroscopic imaging has been used to follow glutathione metabolism and evaluate glutathione heterogeneity in intact tumor tissue. Stable isotope-labeled glutathione was detected in s.c. implanted fibrosarcoma tumors in anesthetized rats following infusion of [2-13C]glycine. Using 1H-decoupled 13C magnetic resonance spectroscopy, the appearance of [2-13C]glycine at 42.4 ppm and the subsequent incorporation of this isotope label into the glycyl residue of glutathione at 44.2 ppm can be detected. The identity and relative concentrations of labeled metabolites observed in the in vivo spectrum were confirmed in studies of tissue extracts. The high level of isotopic enrichment and the concentration of glutathione in tumor tissue allow for collection of spatially localized spectra using 13C chemical shift imaging methods. These data provide the first direct images of glutathione in intact tumor tissue and show metabolic heterogeneity. This method may lead to the ability to monitor changes in tumor tissue redox state that may ultimately affect diagnosis, monitoring, and treatment.

Diffusion magnetic resonance imaging (MRI) provides a surrogate marker of acute brain pathology, yet few studies have resolved the evolution of water diffusion changes during the first 8 hours after acute injury, a critical period for therapeutic intervention. To characterize this early period, this study used a 17.6-T wide-bore magnet to measure multicomponent water diffusion at high b-values (7 to 8,080 s/mm(2)) for rat hippocampal slices at baseline and serially for 8 hours after treatment with the calcium ionophore A23187. The mean fast diffusing water fraction (Ffast) progressively decreased for slices treated with 10-microM/L A23187 (-20.9 +/- 6.3% at 8 hours). Slices treated with 50-micromol/L A23187 had significantly reduced Ffast 80 minutes earlier than slices treated with 10-microM/L A23187 (P < 0.05), but otherwise, the two doses had equivalent effects on the diffusion properties of tissue water. Correlative histologic analysis showed dose-related selective vulnerability of hippocampal pyramidal neurons (CA1 > CA3) to pathologic swelling induced by A23187, confirming that particular intravoxel cell populations may contribute disproportionately to water diffusion changes observed by MRI after acute brain injury. These data suggest diffusion-weighted images at high b-values and the diffusion parameter Ffast may be highly sensitive correlates of cell swelling in nervous issue after acute injury.

Diffusion MRI has the potential to probe the compartmental origins of MR signals acquired from human nervous tissue. However, current experiments in human subjects require long diffusion times, which may confound data interpretation due to the effects of compartmental exchange. To investigate human nervous tissue at shorter diffusion times, and to determine the relevance of previous diffusion studies in rat hippocampal slices, water diffusion in 20 perfused human hippocampal slices was measured using a wide-bore 17.6-T magnet equipped with 1000-mT/m gradients. These slices were procured from five patients undergoing temporal lobectomy for epilepsy. Tissue viability was confirmed with electrophysiological measurements. Diffusion-weighted water signal attenuation in the slices was well-described by a biexponential function (R(2) > 0.99). The mean diffusion parameters for slices before osmotic perturbation were 0.686 +/- 0.082 for the fraction of fast diffusing water (F(fast)), 1.22 +/- 0.22 x 10(-3) mm(2)/s for the fast apparent diffusion coefficient (ADC), and 0.06 +/- 0.02 x 10(-3) mm(2)/s for the slow ADC. Slice perturbations with 20% hypotonic and 20% hypertonic artificial cerebrospinal fluid led to changes in F(fast) of -8.2% and +10.1%, respectively (ANOVA, P < 0.001). These data agree with previous diffusion studies of rat brain slices and human brain in vivo, and should aid the development of working models of water diffusion in nervous tissue, and thus increase the clinical utility of diffusion MRI., (Copyright 2003 Wiley-Liss, Inc.)

A tissue model composed of erythrocyte ghosts was developed to study the effects of compartmentation on the MR signal acquired from biological tissues. This simple and flexible model offers control over the biophysical parameters that contribute to multicomponent signals arising from cellular systems. Cell density, size, intra- and extracellular composition, and membrane permeability can be independently altered. The effects of cell density and cell size on water diffusion properties were assessed. The data demonstrate non-monoexponential water diffusion in ghost cell suspensions of 17-67% cell density. Data were analysed with the widely employed two-compartment (biexponential) model, and with a two-compartment model that accounted for exchange between compartments. Water exchange between the intra- and extracellular compartments appeared to be significant over the range of diffusion times studied (7-35 ms). The biexponential fit to the ghost data appeared to be underparameterised as the ADCs and relative fractions of the fast and slow components were dependent on the experimental acquisition parameters, specifically the diffusion time. However, both analysis methods proved effective at tracking changes in the ghost model when it was perturbed. This was demonstrated with cell density variation, cell swelling and shrinkage experiments, and reduction of membrane water permeability using a water channel blocker (pCMBS). We anticipate that this model system could be used to investigate compartmental diffusion effects to simulate a range of pathologies, especially ischemic stroke., (Copyright 2002 Wiley-Liss, Inc.)

In this article we report on progress in high magnetic field MRI at the University of Florida in support of our new 750MHz wide bore and 11.7T/40cm MR instruments. The primary emphasis is on the associated rf technology required, particularly high frequency volume and phased array coils. Preliminary imaging results at 750MHz are presented. Our results imply that the pursuit of even higher fields seems warranted.

Dynamic magnetic resonance imaging was used to monitor solute diffusion through aggregates of Chinese hamster ovary cells growing on macroporous carriers in a fixed-bed bioreactor. Diffusion-weighted (1)H magnetic resonance imaging (MRI) and scanning electron microscopy demonstrated that cell growth in the bioreactor was heterogeneous, with the highest cell densities being found at the periphery of the carriers. T(1)-weighted magnetic resonance imaging measurements of the inflow of a commonly used magnetic resonance contrast agent, gadolinium-diethylenetriaminopentaacetic acid (Gd-DTPA), showed that migration of the agent through the peripheral cell masses could be explained by diffusion. However, appearance of the contrast agent in the center of the carriers was too fast to be explained by simple diffusion and indicated that these regions were perfused by convective flow. The average diffusivity of Gd-DTPA through the cell mass was found to be (2.4 +/- 0.2) x 10(-10) m(2) sec(-) (mean +/- SEM). This technique will be useful in the characterization and development of high-cell-density bioreactor systems, in which solute transport plays a critical role in cell growth and physiology., (Copyright 2001 John Wiley & Sons, Inc.)

Non-invasive magnetic resonance imaging and spectroscopy techniques have been used to monitor the growth and distribution of Chinese hamster ovary K1 cells growing in a fixed bed bioreactor composed of macroporous carriers. Diffusion-weighted 1H magnetic resonance spectroscopy was used to monitor the volume fraction of the bioreactor occupied by the cells and diffusion-weighted 1H magnetic resonance imaging was used to map cell distribution. The imaging measurements demonstrated that cell growth in the bioreactor was heterogeneous, with the highest cell densities being found at the surface of the carriers. The increase in the volume fraction occupied by the cells during cell growth showed a close correlation with bioreactor ATP content measured using 31P magnetic resonance spectroscopy. These magnetic resonance measurements, in conjunction with measurements of bioreactor glucose consumption, allowed estimation of the specific glucose consumption rate. This declined during the culture, in parallel with medium glucose concentration.