Fiber Type Conversion by PGC-1α Activates Lysosomal and Autophagosomal Biogenesis in Both Unaffected and Pompe Skeletal Muscle

PGC-1α is a transcriptional co-activator that plays a central role in the regulation of energy metabolism. Our interest in this protein was driven by its ability to promote muscle remodeling. Conversion from fast glycolytic to slow oxidative fibers seemed a promising therapeutic approach in Pompe disease, a severe myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) which is responsible for the degradation of glycogen. The recently approved enzyme replacement therapy (ERT) has only a partial effect in skeletal muscle. In our Pompe mouse model (KO), the poor muscle response is seen in fast but not in slow muscle and is associated with massive accumulation of autophagic debris and ineffective autophagy. In an attempt to turn the therapy-resistant fibers into fibers amenable to therapy, we made transgenic KO mice expressing PGC-1α in muscle (tgKO). The successful switch from fast to slow fibers prevented the formation of autophagic buildup in the converted fibers, but PGC-1α failed to improve the clearance of glycogen by ERT. This outcome is likely explained by an unexpected dramatic increase in muscle glycogen load to levels much closer to those observed in patients, in particular infants, with the disease. We have also found a remarkable rise in the number of lysosomes and autophagosomes in the tgKO compared to the KO. These data point to the role of PGC-1α in muscle glucose metabolism and its possible role as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. These findings may have implications for therapy of lysosomal diseases and other disorders with altered autophagy

Lipid Metabolism Crosstalk in the Brain: Glia and Neurons

Until recently, glial cells have been considered mainly support cells for neurons in the mammalian brain. However, many studies have unveiled a variety of glial functions including electrolyte homeostasis, inflammation, synapse formation, metabolism, and the regulation of neurotransmission. The importance of these functions illuminates significant crosstalk between glial and neuronal cells. Importantly, it is known that astrocytes secrete signals that can modulate both presynaptic and postsynaptic function. It is also known that the lipid compositions of the pre- and post-synaptic membranes of neurons greatly impact functions such as vesicle fusion and receptor mobility. These data suggest an essential lipid-mediated communication between glial cells and neurons. Little is known, however, about how the lipid metabolism of both cell types may interact. In this review, we discuss neuronal and glial lipid metabolism and suggest how they might interact to impact neurotransmission

Increasing integrated testing in community settings through interventions for change, including the Spring European Testing Week

Background: Maximising access to testing by targeting more than one infection is effective in identifying new infections in settings or populations. Within the EU funded Joint Action INTEGRATE, this paper examined the feasibility and impact of expanding integrated testing for HIV, hepatitis C (HCV), chlamydia, gonorrhoea and/or syphilis in four community-based pilots through targeted interventions in Croatia, Italy and Poland and the Spring European Testing Week since community settings are key in detecting new infections and reaching key populations. Methods: Pilots led by local INTEGRATE partners prioritised testing for other infections or key populations. The Croatian pilot expanded testing for men who have sex with men to syphilis, chlamydia and gonorrhoea. Italian partners implemented a HIV and HCV testing/information event at a migrant centre. A second Italian pilot tested migrants for HIV and HCV through outreach and a low-threshold service for people who use drugs. Polish partners tested for HIV, HCV and syphilis among people who inject drugs in unstable housing via a mobile van. Pilots monitored the number of individuals tested for each infection and reactive results. The pilot Spring European Testing Week from 18 to 25 May 2018 was an INTEGRATE-driven initiative to create more testing awareness and opportunities throughout Europe. Results: The Croatian pilot found a high prevalence for each syphilis, chlamydia and gonorrhoea respectively, 2.1%, 12.4% and 6.7%. The Italian migrant centre pilot found low proportions who were previously tested for HIV (24%) or HCV (11%) and the second Italian pilot found an HCV prevalence of 6.2%, with low proportions previously tested for HIV (33%) or HCV (31%). The Polish pilot found rates of being previously tested for HIV, HCV and syphilis at 39%, 37%, and 38%, respectively. Results from the Spring European Testing Week pilot showed it was acceptable with increased integrated testing, from 50% in 2018 to 71% in 2019 in participants. Conclusions: Results show that integrated testing is feasible and effective in community settings, in reaching key populations and minimising missed testing opportunities, and the pilots made feasible because of the European collaboration and funding. For sustainability and expansion of integrated community testing across Europe, local government investment in legislation, financial and structural support are crucial.The INTEGRATE Joint Action was co-funded by the 3rd Health Programme of the European Union under grant agreement no 761319. The EuroTEST/European Testing Week initiative has received funding and grants from Gilead Sciences, ViiV Healthcare, Janssen, Merck/MSD and the European Commission under the 3rd and 2nd Health Programmes. HUHIV: CheckPoint Zagreb is funded by cooperation programs by the City of Zagreb and Ministry of Health incl. HIV, HCV and syphilis rapid tests, CT/NG tests are donated by Cepheid with the contribution of the Department of Immunological and Molecular Diagnostics of the Clinic for Infectious Diseases Dr Fran Mihaljević during the pilot project. CRI/FVM: For the pilot activity in the migrant centre, HIV and HCV rapid tests were donated by FVM/CRI. Moreover, FVM contributed with the staff and equipment (mobile unit). FVM: The medical centre and outreach street unit are funded by the Health Department of Lazio Regional Administration of Italy. NAC/FES: Funding for FES pilot in 2019 was provided by NAC. FES secured their staff, mobile unit and tests. Daniel Simões is the recipient of PhD Grant PD/BD/128008/2016 from Fundação para a Ciência e Tecnologia (FCT). All funders had no role in the study design, analysis, decision to publish, or preparation of the manuscript

Data-as-a-Service Platform for Delivering Healthy Lifestyle and Preventive Medicine: Concept and Structure of the DAPHNE Project

Background: Overweight and obesity is related to many health problems and diseases. The current obesity epidemic, which is a major health problem, is closely related to a lack of physical activity, high levels of sedentary behavior, and increased energy intake; with evidence to show increasing incidence of these issues in the younger population. Tackling obesity and its comorbid conditions requires a holistic approach encompassing attention on physical activity, healthy diet, and behavioral activation in order to enable and maintain meaningful and long-term weight loss and weight maintenance. Objective: The objective of the Data-as-a-Service Platform for Healthy Lifestyle and Preventive Medicine (DAPHNE) project is to develop a breakthrough information communications technology (ICT) platform for tracking health, weight, physical activity, diet, lifestyle, and psychological components within health care systems, whereby the platform and clinical support is linked. Methods: The DAPHNE platform aims to deliver personalized guidance services for lifestyle management to the citizen/patient by means of (1) advanced sensors and mobile phone apps to acquire and store continuous/real-time data on lifestyle aspects, behavior, and surrounding environment; (2) individual models to monitor their health and fitness status; (3) intelligent data processing for the recognition of behavioral trends; and (4) specific services for personalized guidance on healthy lifestyle and disease prevention. It is well known that weight loss and maintenance of weight loss are particularly difficult. This tool will address some of the issues found with conventional treatment/advice in that it will collect data in real time, thereby reducing reliability issues known with recalling events once they have passed and will also allow adjustment of behavior through timely support and recommendations sent through the platform without the necessity of formal one-to-one visits between patient and clinician. Patient motivation/compliance is a particular issue with conventional weight loss regimes; DAPHNE aims to increase the individuals’ awareness of their own behavior and fosters their accountability. Results: The project has been funded and the research work has started. Results for the validation of the different components is due imminently. Conclusions: In contrast with previous existing solutions, the DAPHNE project tackles the obesity problem from a clinical point of view, designing the different interfaces for its use by patients (adults and children), physicians, and caregivers. A specific design for children and adolescent patients treated for obesity has been followed, guided by pediatric physicians at hospitals in Europe. The final clinical validation of the DAPHNE platform will be carried out in different European hospitals, testing the platform in both adolescents and adults

The effect of training in reduced energy density eating and food self-monitoring accuracy on weight loss maintenance

Background: Failure to maintain weight losses in lifestyle change programs continues to be a major problem and warrants investigation of innovative approaches to weight control.Objective: The goal of this study was to compare two novel group interventions, both aimed at improving weight loss maintenance, with a control group.Methods and Procedures: A total of 103 women lost weight on a meal replacement&ndash;supplemented diet and were then randomized to one of three conditions for the 14-week maintenance phase: cognitive-behavioral treatment (CBT); CBT with an enhanced food monitoring accuracy (EFMA) program; or these two interventions plus a reduced energy density eating (REDE) program. Assessments were conducted periodically through an 18-month postintervention. Outcome measures included weight and self-reported dietary intake. Data were analyzed using completers only as well as baseline-carried-forward imputation.Results: Participants lost an average of 7.6 plusminus 2.6 kg during the weight loss phase and 1.8 plusminus 2.3 kg during the maintenance phase. Results do not suggest that the EFMA intervention was successful in improving food monitoring accuracy. The REDE group decreased the energy density (ED) of their diets more so than the other two groups. However, neither the REDE nor the EFMA condition showed any advantage in weight loss maintenance. All groups regained weight between 6- and 18-month follow-ups.Discussion: Although no incremental weight maintenance benefit was observed in the EFMA or EFMA + REDE groups, the improvement in the ED of the REDE group\u27s diet, if shown to be sustainable in future studies, could have weight maintenance benefits.<br /

Prevalence and risk factors of diabetes and impaired fasting glucose in Nauru

<p>Abstract</p> <p>Background</p> <p>No comprehensive assessment of diabetes prevalence in Nauru has been conducted since an extreme prevalence was documented more than two decades ago. This study aims to determine the prevalence and risk factors of diabetes and impaired fasting glucose.</p> <p>Methods</p> <p>A nationwide survey in 2004 of people aged 15- 64 years (n = 1592). Fasting plasma glucose levels were used to defined diabetes (≥7.0 mmol/l or 126 mg/dl) and prediabetes (6.1-6.9 mmol/l or 110-125 mg/dl).</p> <p>Results</p> <p>The sex-standardized prevalence of diabetes was 13.0% (95% CI: 10.6, 15.4) in men, 14.4% (11.9, 16.9) in women, and 13.7% (12.0, 15.4) combined. The sex-standardized prevalence of prediabetes was 6.4% (4.6, 8.2) for men, 5.5% (3.9, 7.2) for women, and 6.0% (4.8, 7.3) combined. The prevalence of diabetes for individuals 15-24, 25-34, 35-44, 45-54 and 55-64 years was 4.5%, 7.6%, 24.1%, 32.9%, and 42.7%, respectively. The prevalence of prediabetes for the same age categories was 4.2%, 8.8%, 5.9%, 6.6%, 7.1%, respectively. Multivariable, multinomial logit modeling found risk factors for prediabetes were high cholesterol levels (OR: 2.02, 95% CI: 1.66, 2.47) and elevated waist circumference (OR: 1.04, 95% CI: 1.00, 1.08), and for diabetes were age in years (OR: 1.06; 95% CI: 1.04, 1.07), cholesterol levels (OR: 1.84, 95% CI: 1.58, 2.14) and waist circumference (OR: 1.04, 95% CI: 1.02, 1.07).</p> <p>Conclusions</p> <p>Diabetes remains a major public health problem in Nauru, affecting one out of every ten people. While the prevalence of diabetes has declined, its burden has persisted among the old but also extended towards the younger age groups.</p

Compositional analysis of the associations between 24-h movement behaviours and cardio-metabolic risk factors in overweight and obese adults with pre-diabetes from the PREVIEW study: cross-sectional baseline analysis

Background: Physical activity, sedentary time and sleep have been shown to be associated with cardio-metabolic health. However, these associations are typically studied in isolation or without accounting for the effect of all movement behaviours and the constrained nature of data that comprise a finite whole such as a 24 h day. The aim of this study was to examine the associations between the composition of daily movement behaviours (including sleep, sedentary time (ST), light intensity physical activity (LIPA) and moderate-to-vigorous activity (MVPA)) and cardio-metabolic health, in a cross-sectional analysis of adults with pre-diabetes. Further, we quantified the predicted differences following reallocation of time between behaviours. Methods: Accelerometers were used to quantify daily movement behaviours in 1462 adults from eight countries with a body mass index (BMI) ≥25 kg·m− 2 , impaired fasting glucose (IFG; 5.6–6.9 mmol·l − 1 ) and/or impaired glucose tolerance (IGT; 7.8–11.0 mmol•l − 1 2 h following oral glucose tolerance test, OGTT). Compositional isotemporal substitution was used to estimate the association of reallocating time between behaviours. Results: Replacing MVPA with any other behaviour around the mean composition was associated with a poorer cardio-metabolic risk profile. Conversely, when MVPA was increased, the relationships with cardiometabolic risk markers was favourable but with smaller predicted changes than when MVPA was replaced. Further, substituting ST with LIPA predicted improvements in cardio-metabolic risk markers, most notably insulin and HOMA-IR. Conclusions: This is the first study to use compositional analysis of the 24 h movement composition in adults with overweight/obesity and pre-diabetes. These findings build on previous literature that suggest replacing ST with LIPA may produce metabolic benefits that contribute to the prevention and management of type 2 diabetes. Furthermore, the asymmetry in the predicted change in risk markers following the reallocation of time to/from MVPA highlights the importance of maintaining existing levels of MVPA. Trial registration: ClinicalTrials.gov (NCT01777893)