Protection From Clinical Peripheral Sensory Neuropathy in Alström Syndrome in Contrast to Early-Onset Type 2 Diabetes

OBJECTIVE—Alström syndrome, with type 2 diabetes, and blindness could confer a high risk of foot ulceration. Clinical testing for neuropathy in Alström syndrome and matched young-onset type 2 diabetic subjects was therefore undertaken

Cardiac magnetic resonance imaging in Alström syndrome

<p>Abstract</p> <p>Background</p> <p>A case series of the cardiac magnetic resonance imaging findings in seven adult Alström patients.</p> <p>Methods</p> <p>Seven patients from the National Specialist Commissioning Group Centre for Alström Disease, Torbay, England, UK, completed the cardiac magnetic resonance imaging protocol to assess cardiac structure and function in Alström cardiomyopathy.</p> <p>Results</p> <p>All patients had some degree of left and right ventricular dysfunction. Patchy mid wall gadolinium delayed enhancement was demonstrated, suggesting an underlying fibrotic process. Some degree of cardiomyopathy was universal. No evidence of myocardial infarction or fatty infiltration was demonstrated, but coronary artery disease cannot be completely excluded. Repeat scanning after 18 months in one subject showed progression of fibrosis and decreased left ventricular function.</p> <p>Conclusion</p> <p>Adult Alström cardiomyopathy appears to be a fibrotic process causing impairment of both ventricles. Serial cardiac magnetic resonance scanning has helped clarify the underlying disease progression and responses to treatment. Confirmation of significant mutations in the <it>ALMS1 </it>gene should lead to advice to screen the subject for cardiomyopathy, and metabolic disorders.</p

Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome : an observational study

BACKGROUND: Alström syndrome is a rare inherited ciliopathy with progressive multisystem involvement. Dilated cardiomyopathy is common in infancy and recurs or presents de novo in adults with high rates of premature cardiovascular death. Although Alström syndrome is characterised by fibrosis in solid organs such as the liver, the pathogenesis of related cardiomyopathy are not clear. To date it is not known whether diffuse interstitial myocardial fibrosis is present before the onset of heart failure symptoms or changes in conventional parameters of left ventricular function. METHODS: In this observational study, 26 patients with Alström syndrome (mean age 27 ± 9 years, 65 % male, 24 h ABPM 130 ± 14 / 77 ± 9 mmHg) without symptomatic cardiovascular disease were recruited from a single centre and compared to matched healthy controls. All subjects underwent cardiac MRI (1.5 T) to assess ventricular function, diffuse interstitial myocardial fibrosis by measurement of extracellular volume on T1-mapping (MOLLI) and coarse replacement fibrosis using standard late gadolinium enhancement imaging. RESULTS: Global extracellular volume was increased in Alström syndrome with wider variation compared to controls (0.30 ± 0.05 vs. 0.25 ± 0.01, p < 0.05). Left ventricular long axis function and global longitudinal strain were impaired in Alström syndrome without change in ejection fraction, ventricular size or atrial stress (NT-proBNP) (p < 0.05). Global extracellular volume was associated with reduced peak systolic longitudinal strain (r = −0.73, p < 0.01) and strain rate (r = −0.57, p < 0.01), increased QTc interval (r = 0.49, p < 0.05) and serum triglycerides (r = 0.66, p < 0.01). Nine (35 %) patients had diffuse mid-wall late gadolinium enhancement in a non-coronary artery distribution. CONCLUSION: Diffuse interstitial myocardial fibrosis is common in Alström syndrome and is associated with impaired left ventricular systolic function. Serial studies are required to determine whether global extracellular volume may be an independent imaging biomarker of vulnerability to dilated cardiomyopathy and heart failure

Threshold for detection of diabetic peripheral sensory neuropathy using a range of research grade monofilaments in persons with Type 2 diabetes mellitus

<p>Abstract</p> <p>Aims</p> <p>To identify the threshold of reduced sensory perception in Type 2 diabetes mellitus (Type 2 DM) using a range of research grade monofilaments.</p> <p>Methods</p> <p>Three groups of participants were recruited into a between subject, cross-sectional study. Group 1(NEW), persons with Type 2 DM diagnosed for less than 2 years (<it>n </it>= 80); Group 2 (EST) persons with Type 2 DM diagnosed for more than 2 years (<it>n </it>= 91), and Group 3, a Comparison group without Type 2 DM (<it>n </it>= 73), resulted in a total study population, <it>n </it>= 244. Research grade monofilaments (2, 4, 6, 8 and 10-gram) were employed using standardised protocol, at 6 sites on the plantar aspect of both feet. The demographic and anthropometric measures of gender, age, height, weight, body mass index (BMI), blood pressure and duration of Type 2 DM since diagnosis (if applicable) of the participants were analysed.</p> <p>Results</p> <p>Perception of the research grade monofilaments differed significantly between the 3 groups (p < 0.05). The 6-gram monofilament was found to be the threshold of normal perception, based on 90% of the Comparison group perceiving the 6-gram monofilament at all sites in contrast to 64% of NEW and 48% of EST groups.</p> <p>Conclusion</p> <p>The 6-gram monofilament was identified as the threshold of normal sensory perception. Inability to perceive the 6-gram monofilament indicates, when using the method described in this study, that diminution of sensory perception is evident. Employing a range of monofilaments, 6, 8 and 10-grams in Type 2 DM foot screening would allow the clinical detection of deteriorating sensory perception and enable implementation of foot protection strategies at an earlier stage than is currently practised.</p

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p&lt;0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p&lt;0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (&lt;1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Duration of diabetes predicts aortic pulse wave velocity and vascular events in Alström Syndrome

CONTEXT: Alström syndrome is characterized by increased risk of cardiovascular disease from childhood. OBJECTIVE: To explore the association between risk factors for cardiovascular disease, aortic pulse wave velocity, and vascular events in Alström syndrome. DESIGN: Cross-sectional analyses with 5-year follow-up. SETTING: The UK NHS nationally commissioned specialist clinics for Alström syndrome. PATIENTS: Thirty-one Alström patients undertook vascular risk assessment, cardiac studies, and aortic pulse wave velocity measurement. Subsequent clinical outcomes were recorded. INTERVENTIONS: Insulin resistance was treated with lifestyle intervention and metformin, and diabetes with the addition of glitazones, glucagon-like peptide 1 agonists, and/or insulin. Thyroid and T deficiencies were corrected. Dyslipidemia was treated with statins and nicotinic acid derivatives. Cardiomyopathy was treated with standard therapy as required. MAIN OUTCOME MEASURES: The associations of age, gender, and risk factors for cardiovascular disease with aortic pulse wave velocity were assessed and correlated with the effects of reduction in left ventricular function. Vascular events were monitored for 5 years. RESULTS: Aortic pulse wave velocity was positively associated with the duration of diabetes (P = .001) and inversely with left ventricular ejection fraction (P = .036). Five of the cohort with cardiovascular events had higher aortic pulse wave velocity (P = .0247), and all had long duration of diabetes. CONCLUSIONS: Duration of diabetes predicted aortic pulse wave velocity in Alström syndrome, which in turn predicted cardiovascular events. This offers hope of secondary prevention because type 2 diabetes can be delayed or reversed by lifestyle interventions. J Clin Endocrinol Metab 2015 Aug; 100(8):E1116-24