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A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease.
Payne, T, Appleby, M, Buckley, E, van Gelder, LMA, Mullish, BH, Sassani, M, Dunning, MJ, Hernandez, D, Scholz, SW, McNeill, A, et al
Movement disorders : official journal of the Movement Disorder Society. 2023;(8):1493-1502
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Abstract
BACKGROUND Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. OBJECTIVES To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement. METHODS The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31 P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment. RESULTS UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31 P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups. CONCLUSIONS High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT).
Leslie, WS, Ali, E, Harris, L, Messow, CM, Brosnahan, NT, Thom, G, McCombie, EL, Barnes, AC, Sattar, N, Taylor, R, et al
Diabetologia. 2021;(9):1927-1938
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AIMS/HYPOTHESIS Our aim was to evaluate the safety and efficacy of a planned therapeutic withdrawal of all antihypertensive and diuretic medications, on commencing a formula low-energy diet replacement, targeting remission of type 2 diabetes. METHODS Post hoc analysis of changes in BP, antihypertensive medication prescriptions and symptoms during the initial total diet replacement phase was performed in the intervention arm of the Diabetes Remission Clinical Trial (n = 143) and in the subset (n = 69) who discontinued antihypertensive medications at the start of total diet replacement. The Counterweight-Plus total diet replacement provided about 3470 kJ/day (830 kcal) with automatic reductions in all nutrients, including sodium, to achieve marked negative energy balance and rapid weight loss over 12-20 weeks, with regular BP monitoring and an antihypertensive reintroduction protocol based on current clinical guidelines. RESULTS Of 143 intervention group participants who commenced total diet replacement, 78 (55%) were on treatment for hypertension at baseline. The overall mean BP fell significantly from the start of total diet replacement (week 1) and was significantly lower at week 20, after total diet replacement finished, and also at 12 and 24 months. Of the 78 participants previously on treatment for hypertension, 65 (83%) stopped all antihypertensive and diuretic medications as per protocol, and four (5%) stopped some drugs. These 69 participants experienced no immediate (within the first week) change in BP, but their mean BP fell significantly from 9 weeks. No excessive rises in BP were recorded in individuals, but antihypertensive medications were reintroduced during total diet replacement to manage raised BP for 19/69 (27.5%) participants, mostly within the first 3-7 weeks, despite some weight loss. Reintroduction of antihypertensive medications was necessary for 5/19 participants previously on one drug, and for 14/19 previously on two or more drugs. Of the 69 who stopped antihypertensives, 19 (28%) remained off medications at 24 months. Among the 53 participants who achieved sustained remissions of diabetes at 24 months (with a mean weight loss of 11.4 kg), 31 had been previously treated for hypertension. Twenty-seven stopped medication at baseline, and 15/27 required reintroduction of antihypertensive medications. Mild to moderate dizziness, suggesting some postural hypotension, was reported during total diet replacement by 51 participants, 15 of whom had recorded dizziness at baseline prior to starting total diet replacement, with nine of these on antihypertensive or diuretic medications. CONCLUSIONS/INTERPRETATION Replacing antihypertensive medications with a 3470 kJ/day (830 kcal) diet to induce weight loss reduces BP substantially and may increase mild dizziness. It is safe to stop antihypertensives, but BP should be monitored regularly, particularly for those taking two or more antihypertensives, as over two-thirds will require reintroduction of some medications. Long-term support to maintain weight loss is vital. TRIAL REGISTRATION ISRCTN registry, number 03267836.
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Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery.
Taylor, R, Al-Mrabeh, A, Zhyzhneuskaya, S, Peters, C, Barnes, AC, Aribisala, BS, Hollingsworth, KG, Mathers, JC, Sattar, N, Lean, MEJ
Cell metabolism. 2018;(4):547-556.e3
Abstract
The Diabetes Remission Clinical Trial reported return and persistence of non-diabetic blood glucose control in 46% of people with type 2 diabetes of up to 6 years duration. Detailed metabolic studies were performed on a subgroup (intervention, n = 64; control, n = 26). In the intervention group, liver fat content decreased (16.0% ± 1.3% to 3.1% ± 0.5%, p < 0.0001) immediately after weight loss. Similarly, plasma triglyceride and pancreas fat content decreased whether or not glucose control normalized. Recovery of first-phase insulin response (0.04[-0.05-0.32] to 0.11[0.0005-0.51] nmol/min/m2, p < 0.0001) defined those who returned to non-diabetic glucose control and this was durable at 12 months (0.11[0.005-0.81] nmol/min/m2, p = 0.0001). Responders were similar to non-responders at baseline but had shorter diabetes duration (2.7 ± 0.3 versus 3.8 ± 0.4 years; p = 0.02). This study demonstrates that β cell ability to recover long-term function persists after diagnosis, changing the previous paradigm of irreversible loss of β cell function in type 2 diabetes.
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Acceptability of a very-low-energy diet in Type 2 diabetes: patient experiences and behaviour regulation.
Rehackova, L, Araújo-Soares, V, Adamson, AJ, Steven, S, Taylor, R, Sniehotta, FF
Diabetic medicine : a journal of the British Diabetic Association. 2017;34(11):1554-1567
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Patients with type 2 diabetes can return to normal blood glucose levels through substantial weight loss. While many studies have addressed this, very few have assessed the effects of adherence to a very-low-energy diet (VLED) on patients’ quality of life. The aim of this study was to evaluate the experiences of adhering to VLED for patients in remission for type 2 diabetes. Fifteen participants were interviewed before and after the 8-week VLED intervention and narratives were analysed. This study identified common barriers, facilitators and strategies used by the participants. Overall, participants found adherence easier than anticipated, and found barriers to be offset by suggested behaviour-regulation strategies. Based on this study, the authors conclude dietary treatment for reversal of type 2 diabetes is acceptable and feasible in motivated patients, and suggest further controlled research be done to confirm the validity and applicability of these findings.
Abstract
AIMS: To evaluate the acceptability of an 8-week very-low-energy diet for remission of Type 2 diabetes, and to identify barriers and facilitators of adherence and behaviour-regulation strategies used by participants in the Counterbalance study. METHODS Eighteen of 30 participants in the Counterbalance study (ISRCTN88634530) took part in semi-structured interviews. Of these, 15 participants were interviewed before and after the 8-week very-low-energy diet intervention. Thematic analysis was used to analyse the narratives. RESULTS The prospect of diabetes remission, considerable weight loss, and long-term health improvement provided participants with substantial initial motivation. This motivation was sustained through the experience of rapid weight loss, improvements in blood glucose levels, social support and increased physical and psychological well-being. Overall, adherence to the very-low-energy diet for 8 weeks was perceived as much easier than anticipated, but required personal effort. Participants addressed challenges by removing food from the environment, planning, avoidance of tempting situations or places, and self-distraction. Weight loss and improvements in blood glucose levels lead to a sense of achievement and improvements in physical and psychological wellbeing. CONCLUSIONS Dietary treatment for reversal of Type 2 diabetes is acceptable and feasible in motivated participants, and the process is perceived as highly gratifying. Research outside of controlled trial settings is needed to gauge the generalisability of these findings.
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Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study).
Marwood, L, Taylor, R, Goldsmith, K, Romeo, R, Holland, R, Pickles, A, Hutchinson, J, Dietch, D, Cipriani, A, Nair, R, et al
BMC psychiatry. 2017;(1):231
Abstract
BACKGROUND Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.
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Very Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiological Changes in Responders and Nonresponders.
Steven, S, Hollingsworth, KG, Al-Mrabeh, A, Avery, L, Aribisala, B, Caslake, M, Taylor, R
Diabetes care. 2016;(5):808-15
Abstract
OBJECTIVE Type 2 diabetes mellitus (T2DM) is generally regarded as an irreversible chronic condition. Because a very low-calorie diet (VLCD) can bring about acute return to normal glucose control in some people with T2DM, this study tested the potential durability of this normalization. The underlying mechanisms were defined. RESEARCH DESIGN AND METHODS People with a T2DM duration of 0.5-23 years (n = 30) followed a VLCD for 8 weeks. All oral agents or insulins were stopped at baseline. Following a stepped return to isocaloric diet, a structured, individualized program of weight maintenance was provided. Glucose control, insulin sensitivity, insulin secretion, and hepatic and pancreas fat content were quantified at baseline, after return to isocaloric diet, and after 6 months to permit the primary comparison of change between post-weight loss and 6 months in responders. Responders were defined as achieving fasting blood glucose <7 mmol/L after return to isocaloric diet. RESULTS Weight fell (98.0 ± 2.6 to 83.8 ± 2.4 kg) and remained stable over 6 months (84.7 ± 2.5 kg). Twelve of 30 participants achieved fasting plasma glucose <7 mmol/L after return to isocaloric diet (responders), and 13 of 30 after 6 months. Responders had a shorter duration of diabetes and a higher initial fasting plasma insulin level. HbA1c fell from 7.1 ± 0.3 to 5.8 ± 0.2% (55 ± 4 to 40 ± 2 mmol/mol) in responders (P < 0.001) and from 8.4 ± 0.3 to 8.0 ± 0.5% (68 ± 3 to 64 ± 5 mmol/mol) in nonresponders, remaining constant at 6 months (5.9 ± 0.2 and 7.8 ± 0.3% [41 ± 2 and 62 ± 3 mmol/mol], respectively). The responders were characterized by return of first-phase insulin response. CONCLUSIONS A robust and sustainable weight loss program achieved continuing remission of diabetes for at least 6 months in the 40% who responded to a VLCD by achieving fasting plasma glucose of <7 mmol/L. T2DM is a potentially reversible condition.
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Tracking post-infectious fatigue in clinic using routine Lab tests.
Harvey, JM, Broderick, G, Bowie, A, Barnes, ZM, Katz, BZ, O'Gorman, MRG, Vernon, SD, Fletcher, MA, Klimas, NG, Taylor, R
BMC pediatrics. 2016;16:54
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Chronic fatigue syndrome (CFS) is a complex disease with many different symptoms and there are no definitive tests for diagnosis. This cohort study of 301 adolescents, who had suffered a viral infection, aimed to analyse several commonly used biological markers to determine who may experience CFS symptoms. The results showed variations in several biomarkers, however, decreases in hormones related to the stress response were highly predictive of CFS. Sex hormones and the proportion of immune cells were also markedly disrupted. It was concluded that assessing stress hormones, sex hormones and the proportion of immune cells could be used to diagnose CFS following a viral infection. This study could be used by healthcare professionals to understand that several commonly tested biomarkers could be potentially used to diagnose post-viral CFS.
Abstract
BACKGROUND While biomarkers for chronic fatigue syndrome (CFS) are beginning to emerge they typically require a highly specialized clinical laboratory. We hypothesized that subsets of commonly measured laboratory markers used in combination could support the diagnosis of post-infectious CFS (PI-CFS) in adolescents following infectious mononucleosis (IM) and help determine who might develop persistence of symptoms. METHODS Routine clinical laboratory markers were collected prospectively in 301 mono-spot positive adolescents, 4 % of whom developed CFS (n = 13). At 6, 12, and 24 months post-diagnosis with IM, 59 standard tests were performed including metabolic profiling, liver enzyme panel, hormone profiles, complete blood count (CBC), differential white blood count (WBC), salivary cortisol, and urinalysis. Classification models separating PI-CFS from controls were constructed at each time point using stepwise subset selection. RESULTS Lower ACTH levels at 6 months post-IM diagnosis were highly predictive of CFS (AUC p = 0.02). ACTH levels in CFS overlapped with healthy controls at 12 months, but again showed a trend towards a deficiency at 24 months. Conversely, estradiol levels depart significantly from normal at 12 months only to recover at 24 months (AUC p = 0.02). Finally, relative neutrophil count showed a significant departure from normal at 24 months in CFS (AUC p = 0.01). Expression of these markers evolved differently over time between groups. CONCLUSIONS Preliminary results suggest that serial assessment of stress and sex hormones as well as the relative proportion of innate immune cells measured using standard clinical laboratory tests may support the diagnosis of PI-CFS in adolescents with IM.
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Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.
Lim, EL, Hollingsworth, KG, Aribisala, BS, Chen, MJ, Mathers, JC, Taylor, R
Diabetologia. 2011;(10):2506-14
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AIMS/HYPOTHESIS Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. METHODS Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m(2), nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. RESULTS After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003). Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%). Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003). The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min(-1) m(-2); p < 0.001) and approached control values (0.62 ± 0.15 nmol min(-1) m(-2); p = 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min(-1) m(-2)). Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03). CONCLUSIONS/INTERPRETATION Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake.
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Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer.
Tsavachidou, D, McDonnell, TJ, Wen, S, Wang, X, Vakar-Lopez, F, Pisters, LL, Pettaway, CA, Wood, CG, Do, KA, Thall, PF, et al
Journal of the National Cancer Institute. 2009;(5):306-20
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BACKGROUND Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation. METHODS Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 microg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided. RESULTS The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051). CONCLUSIONS We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type- and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications.
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Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion to decrease in hepatic triglyceride content.
Ravikumar, B, Gerrard, J, Dalla Man, C, Firbank, MJ, Lane, A, English, PT, Cobelli, C, Taylor, R
Diabetes. 2008;(9):2288-95
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OBJECTIVE Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes. RESEARCH DESIGN AND METHODS Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging. RESULTS Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 +/- 1.0 vs. 12.2 +/- 0.7 micromol . kg(-1) . min(-1), P = 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 +/- 0.25 vs. 1.26 +/- 0.30 micromol . kg(-1) . min(-1), P < 0.001). Hepatic triglyceride content decreased by approximately 50% (P = 0.03), and muscle (anterior tibialis) triglyceride content decreased by approximately 55% (P = 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r = 0.64, P = 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r = -0.63, P = 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP. CONCLUSIONS Reduction in hepatic triglyceride by pioglitazone is very closely related to improvement in fasting and postprandial EGP in type 2 diabetes.