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1.  The Clinical Outcome Study for dysferlinopathy 
Neurology: Genetics  2016;2(4):e89.
To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.
The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.
There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.
These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.
PMCID: PMC4994875  PMID: 27602406
2.  Nuclear factor one B (NFIB) encodes a subtype-specific tumour suppressor in glioblastoma 
Oncotarget  2016;7(20):29306-29320.
Glioblastoma (GBM) is an essentially incurable and rapidly fatal cancer, with few markers predicting a favourable prognosis. Here we report that the transcription factor NFIB is associated with significantly improved survival in GBM. NFIB expression correlates inversely with astrocytoma grade and is lowest in mesenchymal GBM. Ectopic expression of NFIB in low-passage, patient-derived classical and mesenchymal subtype GBM cells inhibits tumourigenesis. Ectopic NFIB expression activated phospho-STAT3 signalling only in classical and mesenchymal GBM cells, suggesting a mechanism through which NFIB may exert its context-dependent tumour suppressor activity. Finally, NFIB expression can be induced in GBM cells by drug treatment with beneficial effects.
PMCID: PMC5045397  PMID: 27083054
glioblastoma (GBM); glioma; nuclear factor I B (NFIB); tumour suppressor gene; GBM subtype
3.  EphA2 Is a Therapy Target in EphA2-Positive Leukemias but Is Not Essential for Normal Hematopoiesis or Leukemia 
PLoS ONE  2015;10(6):e0130692.
Members of the Eph family of receptor tyrosine kinases and their membrane bound ephrin ligands have been shown to play critical roles in many developmental processes and more recently have been implicated in both normal and pathological processes in post-embryonic tissues. In particular, expression studies of Eph receptors and limited functional studies have demonstrated a role for the Eph/ephrin system in hematopoiesis and leukemogenesis. In particular, EphA2 was reported on hematopoietic stem cells and stromal cells. There are also reports of EphA2 expression in many different types of malignancies including leukemia, however there is a lack of knowledge in understanding the role of EphA2 in hematopoiesis and leukemogenesis. We explored the role of EphA2 in hematopoiesis by analyzing wild type and EphA2 knockout mice. Mature, differentiated cells, progenitors and hematopoietic stem cells derived from knockout and control mice were analyzed and no significant abnormality was detected. These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis. Comparative studies using EphA2-negative MLL-AF9 leukemias derived from EphA2-knockout animals showed that there was no detectable functional role for EphA2 in the initiation or progression of the leukemic process. However, expression of EphA2 in leukemias initiated by MLL-AF9 suggested that this protein might be a possible therapy target in this type of leukemia. We showed that treatment with EphA2 monoclonal antibody IF7 alone had no effect on tumorigenicity and latency of the MLL-AF9 leukemias, while targeting of EphA2 using EphA2 monoclonal antibody with a radioactive payload significantly impaired the leukemic process. Altogether, these results identify EphA2 as a potential radio-therapeutic target in leukemias with MLL translocation.
PMCID: PMC4470658  PMID: 26083390
4.  Non-invasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker 
Hepatology (Baltimore, Md.)  2014;59(6):2321-2330.
Oxidative stress plays a central role in the progression of liver disease and in damage to liver via toxic xenobiotics. We have developed methods for non-invasive assessment of hepatic oxidative stress defences by measuring flux through the glutathione synthesis pathway. 13C-labelled glutathione is endogenously produced and detected by in vivo magnetic resonance following administration of [2-13C]-glycine. We report successful first-in-man demonstration of this approach, and preclinical studies demonstrating perturbed glutathione metabolism in models of acute and chronic oxidative stress. Human studies employed oral administration of [2-13C]-glycine and 13C spectroscopy on a 3T clinical MRI scanner, and demonstrated detection and quantification of endogenously produced 13C-glutathione following labelled glycine ingestion. Plasma analysis demonstrated that glycine 13C fractional enrichment achieved steady state during the 6h ingestion period. Mean rate of synthesis of hepatic 13C-labelled glutathione was 0.32 ± 0.18 mmole/kg/h. Preclinical models of acute oxidative stress and non-alcoholic steatohepatitis (NASH) comprised CCl4-treated and high fat, high carbohydrate diet-fed Sprague Dawley rats respectively, using intravenous administration of [2-13C]-glycine and observation of 13C-label metabolism on a 7T preclinical MR system. Preclinical studies demonstrated a 54% elevation of glutathione content and a 31% increase in flux through the glutathione synthesis pathway at 12h after acute insult caused by CCl4 administration, and 23% decrease in glutathione content and evidence of early steatohepatitis in the model of NASH.
Our data demonstrate in vivo 13C-labelling and detection of glutathione as a biomarker of tissue oxidative stress defences, detecting chronic and acute oxidative stress insults. The methods are applicable to clinical research studies of hepatic oxidative stress in disease states over time as well as to monitoring the effects of therapeutic interventions.
PMCID: PMC4160151  PMID: 24242936
13C spectroscopy; dynamic magnetic resonance; metabolism; glutathione synthetase; serine hydroxymethyltransferase
5.  White matter correlates of cognitive dysfunction after mild traumatic brain injury 
Neurology  2014;83(6):494-501.
To relate neurophysiologic changes after mild/moderate traumatic brain injury to cognitive deficit in a longitudinal diffusion tensor imaging investigation.
Fifty-three patients were scanned an average of 6 days postinjury (range = 1–14 days). Twenty-three patients were rescanned 1 year later. Thirty-three matched control subjects were recruited. At the time of scanning, participants completed cognitive testing. Tract-Based Spatial Statistics was used to conduct voxel-wise analysis on diffusion changes and to explore regressions between diffusion metrics and cognitive performance.
Acutely, increased axial diffusivity drove a fractional anisotropy (FA) increase, while decreased radial diffusivity drove a negative regression between FA and Verbal Letter Fluency across widespread white matter regions, but particularly in the ascending fibers of the corpus callosum. Raised FA is hypothesized to be caused by astrogliosis and compaction of axonal neurofilament, which would also affect cognitive functioning. Chronically, FA was decreased, suggesting myelin sheath disintegration, but still regressed negatively with Verbal Letter Fluency in the anterior forceps.
Acute mild/moderate traumatic brain injury is characterized by increased tissue FA, which represents a clear neurobiological link between cognitive dysfunction and white matter injury after mild/moderate injury.
PMCID: PMC4142001  PMID: 25031282
6.  Effect of Vildagliptin on Hepatic Steatosis 
Although dipeptidyl-peptidase-4 inhibitors exert their major action via an incretin mechanism, a favorable effect of vildagliptin on lipid metabolism remains unexplained.
The objective was to examine hepatic triglyceride levels and insulin sensitivity on vildagliptin.
This was a 6-month, randomized, double-blind, placebo-controlled trial.
This was an outpatient study at a university clinical research center.
Individuals with type 2 diabetes (n = 44) and glycated hemoglobin ≤7.6% on stable metformin therapy were included.
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.
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).
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.
PMCID: PMC4399299  PMID: 25664602
8.  Challenges in quantifying the patient-reported burden of herpes zoster and post-herpetic neuralgia in the UK: learnings from the Zoster Quality of Life (ZQOL) study 
BMC Research Notes  2013;6:486.
Acute presentation of herpes zoster (HZ) and the subsequent development of post-herpetic neuralgia (PHN) can have a significant impact on patients’ lives. To date, evidence regarding the human and economic burden of HZ and PHN in the UK is limited. To address this knowledge gap a national, multicentre, large-scale real-world study was conducted to inform the scientific community and healthcare decision-makers. This paper outlines difficulties encountered and challenges to conducting real-world studies in the UK, methods used to overcome these hurdles and strategies that can be employed to promote and facilitate the conduct of future studies.
The Zoster Quality of Life (ZQOL) study is the first UK-wide and largest observational study investigating patient burden associated with HZ and PHN. A total of 383 patients (229 HZ; 154 PHN) over the age of 50 years were recruited from 42 primary and secondary/tertiary care centres. Patient-reported outcome (PRO) assessments of pain, quality of life and treatment satisfaction were completed by all participants and supplemented by clinical information from participating physicians.
Key challenges encountered during the conduct of this study can be broadly categorised as follows: 1) identification of centres willing/able to participate in the study: lack of resources and limited research experience were major barriers to recruitment of centres for participation in the study; 2) obtaining local research & development (R&D) approval: lack of clearly defined processes and requirements specific to real-world studies and limited degree of standardisation between R&D departments in approval procedures led to significant variability in submission requirements and lead times for obtaining approval; 3) recruitment of study participants: rates of recruitment were slower than anticipated, meaning it was necessary to extend the study recruitment period and increase the number of participating centres.
Initiatives designed to promote and facilitate the conduct of research in the UK are important for real-world studies. The ZQOL study shows that opportunities exist for real-word research. However, streamlining the R&D approval process where possible and further incentivising the participation of primary care centres in such studies would help to further facilitate the generation of real-world evidence to inform healthcare decisions.
PMCID: PMC4222087  PMID: 24274819
Herpes zoster; Post-herpetic neuralgia; Real-world; Burden
9.  Extraocular Muscle Atrophy and Central Nervous System Involvement in Chronic Progressive External Ophthalmoplegia 
PLoS ONE  2013;8(9):e75048.
Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterised by bilateral progressive ptosis and ophthalmoplegia. These ocular features can develop either in isolation or in association with other prominent neurological deficits (CPEO+). Molecularly, CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction.
Ten age-matched normal controls and twenty patients with CPEO were recruited nine patients with single, large-scale mtDNA deletions and eleven patients with multiple mtDNA deletions secondary to mutations in POLG, PEO1, OPA1, and RRM2B. All subjects underwent a standardised brain and orbital MRI protocol, together with proton magnetic resonance spectroscopy in two voxels located within the parietal white matter and the brainstem.
There was evidence of significant extraocular muscle atrophy in patients with single or multiple mtDNA deletions compared with controls. There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels. Volumetric brain measurements revealed marked cortical and cerebellar atrophy among patients with CPEO+ phenotypes.
The results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO.
PMCID: PMC3785524  PMID: 24086434
10.  Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: Non-invasive identification and treatment monitoring by magnetic resonance 
Journal of Hepatology  2013;59(3):543-549.
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 1H 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.
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 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content.
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.
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.
PMCID: PMC3749380  PMID: 23624251
CESD, cholesteryl ester storage disease; LAL, lysosomal acid lipase; CE, cholesteryl ester; TG, triglyceride; ERT, enzyme replacement therapy; NAFLD, non-alcoholic fatty liver disease; Wolman disease; Cholesteryl ester storage disease; 1H MR spectroscopy; 13C MR spectroscopy; Liver fat; Lysosomal acid lipase; LIPA; LAL deficiency; Enzyme replacement therapy; Sebelipase alfa
11.  Impact of Friedreich’s Ataxia on health-care resource utilization in the United Kingdom and Germany 
Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder that causes progressive damage to the central and peripheral nervous systems having a significant impact upon quality of life. With little information in the literature, cross-sectional observational studies were conducted in the UK and Germany to collect data on resource use and the burden of the disease on individuals and their caregivers.
Cross-sectional observational studies were conducted in the UK and Germany to estimate the burden of FRDA on individuals and on the respective healthcare systems. A total of 75 individuals in the UK and 28 in Germany were recruited to the study. Participants in both countries were asked to complete a Patient and Caregiver Information Form (PCIF), regarding access to, and use of, healthcare resources, and the impact FRDA has on their lifestyle. In Germany, doctors were asked to complete a Patient Record Form (PRF). Analyses of annual direct and indirect resource utilization were conducted for both countries while costs were calculated for the UK only. These figures were compared to the costs associated with Parkinson’s disease; one of the most common neurodegenerative conditions and the one most similar in terms of disease progression.
The results showed that the annual burden of FRDA is significant and falls on the health and social care sectors, on society, on caregivers and on the individuals themselves. In the UK FRDA had a total annual cost per person of between £11,818 and £18,774 depending on whether the cost of long-term unemployment was included.
Typically the largest component of direct costs is associated with professional care. Given the high proportion of children and young adults recruited and the long disease duration, (typically 40-50 years for FRDA, compared with 20 years for Parkinson’s disease), these figures may underestimate the true burden of the disease.
It is hoped that these estimates of resource utilization, can help in understanding the previously unquantified burden of FRDA. Given the long disease duration, management strategies should seek to minimise the impact of the condition on individuals and their caregivers, while maximising quality of life.
PMCID: PMC3599305  PMID: 23448170
Ataxia; Friedreich’s Ataxia; Quality of life; Cost of illness; Resource utilization
12.  Qualitative systematic reviews of treatment burden in stroke, heart failure and diabetes - Methodological challenges and solutions 
Treatment burden can be defined as the self-care practices that patients with chronic illness must perform to respond to the requirements of their healthcare providers, as well as the impact that these practices have on patient functioning and well being. Increasing levels of treatment burden may lead to suboptimal adherence and negative outcomes. Systematic review of the qualitative literature is a useful method for exploring the patient experience of care, in this case the experience of treatment burden. There is no consensus on methods for qualitative systematic review. This paper describes the methodology used for qualitative systematic reviews of the treatment burdens identified in three different common chronic conditions, using stroke as our exemplar.
Qualitative studies in peer reviewed journals seeking to understand the patient experience of stroke management were sought. Limitations of English language and year of publication 2000 onwards were set. An exhaustive search strategy was employed, consisting of a scoping search, database searches (Scopus, CINAHL, Embase, Medline & PsycINFO) and reference, footnote and citation searching. Papers were screened, data extracted, quality appraised and analysed by two individuals, with a third party for disagreements. Data analysis was carried out using a coding framework underpinned by Normalization Process Theory (NPT).
A total of 4364 papers were identified, 54 were included in the review. Of these, 51 (94%) were retrieved from our database search. Methodological issues included: creating an appropriate search strategy; investigating a topic not previously conceptualised; sorting through irrelevant data within papers; the quality appraisal of qualitative research; and the use of NPT as a novel method of data analysis, shown to be a useful method for the purposes of this review.
The creation of our search strategy may be of particular interest to other researchers carrying out synthesis of qualitative studies. Importantly, the successful use of NPT to inform a coding frame for data analysis involving qualitative data that describes processes relating to self management highlights the potential of a new method for analyses of qualitative data within systematic reviews.
PMCID: PMC3568050  PMID: 23356353
Qualitative systematic review; Normalization process theory; Stroke; Treatment burden
13.  Boundaries and e-health implementation in health and social care 
The major problem facing health and social care systems globally today is the growing challenge of an elderly population with complex health and social care needs. A longstanding challenge to the provision of high quality, effectively coordinated care for those with complex needs has been the historical separation of health and social care. Access to timely and accurate data about patients and their treatments has the potential to deliver better care at less cost.
To explore the way in which structural, professional and geographical boundaries have affected e-health implementation in health and social care, through an empirical study of the implementation of an electronic version of Single Shared Assessment (SSA) in Scotland, using three retrospective, qualitative case studies in three different health board locations.
Progress in effectively sharing electronic data had been slow and uneven. One cause was the presence of established structural boundaries, which lead to competing priorities, incompatible IT systems and infrastructure, and poor cooperation. A second cause was the presence of established professional boundaries, which affect staffs’ understanding and acceptance of data sharing and their information requirements. Geographical boundaries featured but less prominently and contrasting perspectives were found with regard to issues such as co-location of health and social care professionals.
To provide holistic care to those with complex health and social care needs, it is essential that we develop integrated approaches to care delivery. Successful integration needs practices such as good project management and governance, ensuring system interoperability, leadership, good training and support, together with clear efforts to improve working relations across professional boundaries and communication of a clear project vision. This study shows that while technological developments make integration possible, long-standing boundaries constitute substantial risks to IT implementations across the health and social care interface which those initiating major changes would do well to consider before committing to the investment.
PMCID: PMC3465217  PMID: 22958223
14.  Effects of raising muscle glycogen synthesis rate on skeletal muscle ATP turnover rate in type 2 diabetes 
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 31P- and 13C-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 (rs = 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.
PMCID: PMC3233777  PMID: 21917633
mitochondrial function; insulin resistance; hyperglycemia
15.  Inhibition of lipolysis in Type 2 diabetes normalizes glucose disposal without change in muscle glycogen synthesis rates 
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.
PMCID: PMC3174053  PMID: 21388348
glucose disposal; lipolysis; magnetic resonance spectroscopy; muscle glycogen; non-esterified fatty acid; Type 2 diabetes; APE, atom percentage excess; BMI, body mass index; CV, coefficient of variation; ffm, fat-free mass; MR, magnetic resonance; MRS, magnetic resonance spectroscopy; NEFA, non-esterified fatty acid
16.  What Does Voluntary Disenrollment from Medicare+Choice Plans Mean to Beneficiaries? 
Health Care Financing Review  2002;24(1):117-132.
The Balanced Budget Act (BBA) of 1997 required CMS to report publicly Medicare managed care (MMC) plan voluntary disenrollment rates. To ensure disenrollment rates would be meaningful to beneficiaries in health plan choice, CMS funded the development of surveys and reporting formats to identify and present the reasons that beneficiaries voluntarily leave plans. Public reporting of reasons on the Medicare Web site began in 2002. We discuss results from extensive audience testing of disenrollment rates and reasons materials. Medicare beneficiaries do not easily understand disenrollment. We also discuss challenges in presenting useful disenrollment information and policy implications for public reporting.
PMCID: PMC4194787  PMID: 12553297
17.  Noninvasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker 
Hepatology (Baltimore, Md.)  2014;59(6):2321-2330.
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. 13C-labeled GSH is endogenously produced and detected by in vivo magnetic resonance after administration of [2-13C]-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 [2-13C]-glycine and 13C spectroscopy on a 3T clinical magnetic resonance (MR) imaging scanner and demonstrated detection and quantification of endogenously produced 13C-GSH after labeled glycine ingestion. Plasma analysis demonstrated that glycine 13C fractional enrichment achieved steady state during the 6-hour ingestion period. Mean rate of synthesis of hepatic 13C-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 [2-13C]-glycine and observation of 13C-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 13C-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.
PMCID: PMC4160151  PMID: 24242936

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