In vivo screening reveals interactions between Drosophila Manf and genes involved in the mitochondria and the ubiquinone synthesis pathway

Background: Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF) form an evolutionarily conserved family of neurotrophic factors. Orthologues for MANF/CDNF are the only neurotrophic factors as yet identified in invertebrates with conserved amino acid sequence. Previous studies indicate that mammalian MANF and CDNF support and protect brain dopaminergic system in non-cell-autonomous manner. However, MANF has also been shown to function intracellularly in the endoplasmic reticulum. To date, the knowledge on the interacting partners of MANF/CDNF and signaling pathways they activate is rudimentary. Here, we have employed the Drosophila genetics to screen for potential interaction partners of Drosophila Manf (DmManf) in vivo. Results: We first show that DmManf plays a role in the development of Drosophila wing. We exploited this function by using Drosophila UAS-RNAi lines and discovered novel genetic interactions of DmManf with genes known to function in the mitochondria. We also found evidence of an interaction between DmManf and the Drosophila homologue encoding Ku70, the closest structural homologue of SAP domain of mammalian MANF. Conclusions: In addition to the previously known functions of MANF/CDNF protein family, DmManf also interacts with mitochondria-related genes. Our data supports the functional importance of these evolutionarily significant proteins and provides new insights for the future studies.Peer reviewe

Extracorporeal photopheresis in the treatment of acute graft-versus-host disease : a single-center experience

BACKGROUND: Steroid-refractory acute graft-versushost disease (aGVHD) is a serious complication after hematopoietic stem cell transplantation. The long-term outcome of the patients is poor. Various immunosuppressive agents have been proposed as the second-line therapy but none of them has turned out more effective than the others. Extracorporeal photopheresis (ECP) is a treatment option that does not predispose the patients to severe side effects of the immunosuppressive drugs. STUDY DESIGN AND METHODS: We analyzed the treatment results of ECP in 52 patients with steroidrefractory or steroid-dependent aGVHD. Eighty-one percent of the patients suffered from a severe, Grade III or IV, aGVHD. ECP was started alone as the second-line treatment in 23 patients and in combination with an immunosuppressive drug in 18 patients. Eleven patients received ECP as the third-line or later treatment. RESULTS: A total of 62% of the patients responded, with 48% achieving complete response. In the patients with complete or partial response, the probabilities of survival at 4 years were 54 and 17%, respectively. The outcome of nonresponders was poor. The 1-year overall survivals of the patients with ECP as the second-line treatment either alone or in combination with an immunosuppressive drug or as the third-line treatment were 51, 28, and 18%, respectively. In multivariate analysis, starting ECP no later than 10 days after the start of the first-line treatment correlated with a good response and a consequent survival benefit. CONCLUSION: Extracorporeal photopheresis is an effective and well-tolerated treatment that should be considered as a second-line treatment for aGVHD.Peer reviewe

Psychosocial determinants for adherence to a healthy lifestyle and intervention participation in the FINGER trial : an exploratory analysis of a randomised clinical trial

Background and aims Psychosocial factors may affect adherence to lifestyle interventions and lifestyle changes. The role of psychosocial factors in dementia prevention needs more research. We aimed at clarify the issue in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Methods The population included 1260 participants aged 60-77 years at risk for cognitive decline, randomised to a multidomain lifestyle intervention or regular health advice for 2 years. Adherence was evaluated as participation in the provided activities and actual lifestyle changes, separately for each domain (diet, exercise, social/cognitive activity, vascular risk management) and combined into multidomain. Psychosocial factors were measured at trial baseline (depressive symptoms; study perception; health-related quality of life, HRQoL) and earlier life (hopelessness; satisfaction with family life, achievements, and financial situation). Results Depressive symptoms, hopelessness, and nonpositive study perception were negatively and HRQoL positively associated with participation in the multidomain intervention. Depressive symptoms, lower HRQoL, hopelessness and dissatisfaction with financial situation were associated with unhealthier lifestyles at baseline. Baseline depressive symptoms and lower HRQoL predicted less improvement in lifestyle, but did not modify the intervention effect on lifestyle change. Discussion and conclusions Several psychosocial factors were associated with participation in lifestyle intervention, while fewer of them contributed to lifestyle changes. Although the intervention was beneficial for lifestyle changes independent of psychosocial factors, those most in need of lifestyle improvement were less likely to be active. Tailoring lifestyle-modifying strategies based on the need for psychosocial support may add efficacy in future trials. Trial Registry ClinicalTrials.gov NCT01041989 2010-01-05Peer reviewe

Occupational complexity and cognition in the FINGER multidomain intervention trial

Introduction Lifetime exposure to occupational complexity is linked to late-life cognition, and may affect benefits of preventive interventions. Methods In the 2-year multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we investigated, through post hoc analyses (N = 1026), the association of occupational complexity with cognition. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Results Higher levels of occupational complexity were associated with better baseline cognition. Measures of occupational complexity had no association with intervention effects on cognition, except for occupational complexity with data, which was associated with the degree of intervention-related gains for executive function. Discussion In older adults at increased risk for dementia, higher occupational complexity is associated with better cognition. The cognitive benefit of the FINGER intervention did not vary significantly among participants with different levels of occupational complexity. These exploratory findings require further testing in larger studies.Peer reviewe

Recruitment and Baseline Characteristics of Participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)-A Randomized Controlled Lifestyle Trial

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Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics : The FINGER trial

Introduction: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) multidomain lifestyle intervention trial (NCT01041989) demonstrated beneficial effects on cognition. We investigated whether sociodemographics, socioeconomic status, baseline cognition, or cardiovascular factors influenced intervention effects on cognition. Methods: The FINGER recruited 1260 people from the general Finnish population (60-77 years, at risk for dementia). Participants were randomized 1: 1 to multidomain intervention (diet, exercise, cognition, and vascular risk management) and regular health advice. Primary outcome was change in cognition (Neuropsychological Test Battery z-score). Prespecified analyses to investigate whether participants' characteristics modified response to intervention were carried out using mixed-model repeated-measures analyses. Results: Sociodemographics (sex, age, and education), socioeconomic status (income), cognition (Mini-Mental State Examination), cardiovascular factors (body mass index, blood pressure, cholesterol, fasting glucose, and overall cardiovascular risk), and cardiovascular comorbidity did not modify response to intervention (P-values for interaction > .05). Conclusions: The FINGER intervention was beneficial regardless of participants' characteristics and can thus be implemented in a large elderly population at increased risk for dementia. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.Peer reviewe

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Children’s and adolescents’ rising animal-source food intakes in 1990–2018 were impacted by age, region, parental education and urbanicity

Animal-source foods (ASF) provide nutrition for children and adolescents’ physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the world’s child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 15–19 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes.publishedVersio

Incident type 2 diabetes attributable to suboptimal diet in 184 countries

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.8–14.4 million) incident T2D cases, representing 70.3% (68.8–71.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.0–27.1%)), excess refined rice and wheat intake (24.6% (22.3–27.2%)) and excess processed meat intake (20.3% (18.3–23.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.4–87.7%)) and Latin America and the Caribbean (81.8% (80.1–83.4%)); and lowest proportional burdens were in South Asia (55.4% (52.1–60.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally.publishedVersio